CN117412959A - Substituted 1-aryl-1 '-heteroaryl compounds, substituted 1,1' -biaryl compounds, and methods of use thereof - Google Patents

Abstract

The present disclosure provides substituted 1-aryl-1 '-heteroaryl compounds, substituted 1,1' -biaryl compounds, analogs thereof, and compositions comprising the same. In one aspect, the provided compounds are useful for treating, ameliorating and/or preventing hepatitis b virus (hepatitis B virus, HBV) and/or hepatitis delta virus (hepatitis D virus, HDV) infections in a patient. In another aspect, the provided compounds are useful for treating, ameliorating, and/or preventing cancer in a patient. The provided compounds have the formula (I): (I) wherein: a is (AA) or (BB).

Description

Substituted 1-aryl-1 '-heteroaryl compounds, substituted 1,1' -biaryl compounds, and methods of use thereof

Cross Reference to Related Applications

Priority is claimed in accordance with 35U.S. c. ≡119 (e) for U.S. provisional application No. 63/167,440 filed on 29 th 3.2021 and U.S. provisional application No. 63/291,666 filed on 20 th 12.2021, all of which are hereby incorporated by reference in their entireties.

Background

Hepatitis b virus (hepatitis B virus, HBV) is a non-cytopathic hepadnavirus belonging to the hepadnaviridae family. Hepatitis b is one of the most prevalent diseases in the world and is listed by the U.S. institute of allergy and infectious disease (NIAID) as a highly prioritised area of interest. Although most people will resolve the infection after acute symptoms, about 30% of cases become chronic. It is estimated that 3.5-4 million people worldwide suffer from chronic hepatitis b, leading to 50-100 tens of thousands of deaths each year, mainly due to the development of hepatocellular carcinoma, cirrhosis and/or other complications.

There are a limited number of drugs currently approved for the management of chronic hepatitis b, including two formulations (standard and pegylated) that inhibit interferon-alpha and five nucleoside/nucleotide analogs (lamivudine, adefovir, entecavir, telbivudine, and tenofovir) that inhibit HBV DNA polymerase. Currently, the first line treatment of choice is entecavir, tenofovir and/or peginterferon alpha-2 a. However, polyethylene glycol interferon alpha-2 a achieves ideal serologic milestones in only one third of the treated patients and is often accompanied by serious side effects. Entecavir and tenofovir are potent HBV inhibitors, but require long-term or possibly lifetime administration to continue to inhibit HBV replication, and may eventually fail due to the presence of drug resistant virus. Thus, there is an urgent need to introduce new, safe, and effective therapies for chronic hepatitis b.

Hepatitis delta virus (hepatitis D virus, HDV) is a small circular enveloped RNA virus that can propagate only in the presence of HBV. In particular, HDV requires HBV surface antigen protein to self-reproduce. Infection with both HBV and HDV can lead to more serious complications than infection with HBV alone. These complications include a greater likelihood of experiencing liver failure in acute infections and rapidly developing cirrhosis, and an increased chance of developing liver cancer in chronic infections. When combined with hepatitis b, hepatitis d has the highest mortality rate among all hepatitis infections. The transmission pathway of HDV is similar to HBV. Infections are mainly limited to people at high risk of HBV infection, especially those who inject drug addicts and who receive clotting factor concentrates.

Currently, there is no effective antiviral therapy available for the treatment of acute or chronic hepatitis d. Interferon-alpha is given weekly for 12 to 18 months as the only approved therapy for hepatitis delta. The response to the therapy is limited because only about one-fourth of patients cannot detect serum HDV RNA 6 months after therapy.

Thus, there is a need in the art to identify novel compounds useful for treating, ameliorating, and/or preventing HBV infection in a subject. In certain embodiments, the novel compounds are useful in HBV infected patients, patients at risk of HBV infection, and/or patients infected with drug resistant HBV. In other embodiments, the HBV infected subject is further infected with HDV. The present invention addresses this need.

Disclosure of Invention

The present disclosure provides certain compounds of formula (I), or salts, solvates, geometric isomers, stereoisomers, or tautomers thereof, or any mixtures thereof, wherein the substituents in (I) are defined elsewhere herein:

the present disclosure further provides pharmaceutical compositions comprising at least one compound of the present disclosure and at least one pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition further comprises at least one additional agent that treats, ameliorates, and/or prevents a hepatitis virus infection.

The present disclosure further provides methods of treating, ameliorating, and/or preventing a hepatitis virus infection in a subject. In certain embodiments, the methods comprise administering to a subject in need thereof a therapeutically effective amount of at least one compound of the present disclosure and/or at least one pharmaceutical composition of the present disclosure. In certain embodiments, the subject is infected with Hepatitis B Virus (HBV). In certain embodiments, the subject is infected with Hepatitis Delta Virus (HDV). In certain embodiments, the subject is infected with HBV and HDV.

The present disclosure further provides methods of treating, ameliorating, and/or preventing cancer in a subject. In certain embodiments, the methods comprise administering to a subject in need thereof a therapeutically effective amount of at least one compound of the present disclosure and/or at least one pharmaceutically acceptable composition of the present disclosure. In certain embodiments, the cancer may be amenable to treatment by inhibiting PD-1, PD-L1, or PD-1/PD-L1 interactions. In certain embodiments, the cancer is at least one of: pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain cancer, bone cancer, soft tissue sarcoma, non-small cell lung cancer, or colon cancer. In certain embodiments, the cancer is at least one of: acute Lymphoblastic Leukemia (ALL), acute Myelogenous Leukemia (AML), chronic Lymphocytic Leukemia (CLL), small Lymphocytic Lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic Myelogenous Leukemia (CML), multiple Myeloma (MM), non-hodgkin's lymphoma (NHL), mantle Cell Lymphoma (MCL), follicular lymphoma, macroglobulinemia (WM), T cell lymphoma, B cell lymphoma, and Diffuse Large B Cell Lymphoma (DLBCL).

Detailed Description

The present disclosure relates in certain aspects to the discovery of certain substituted 1-aryl-1 '-heteroaryl or substituted 1,1' -biaryl compounds. In one aspect, the compounds of the present disclosure are useful for treating, ameliorating, and/or preventing Hepatitis B Virus (HBV) infection and/or hepatitis b virus-hepatitis d virus (HBV-HDV) infection and related conditions in a subject. In certain embodiments, these compounds are administered in conjunction with at least one other agent for treating, ameliorating and/or preventing a viral infection. In other embodiments, the subject is infected with HBV. In still other embodiments, the HBV infected subject is further infected with HDV. In another aspect, the compounds of the present disclosure are useful for treating, ameliorating and/or preventing cancer and related conditions in a subject.

Definition of the definition

As used herein, each of the following terms has the meanings associated therewith in this section. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, nomenclature used herein and laboratory procedures in animal pharmacology, pharmaceutical science, separation science, and organic chemistry are those well known and commonly employed in the art. It should be understood that the order of steps or order for performing certain actions is not important so long as the present teachings remain operable. Furthermore, two or more steps or actions may be performed simultaneously or non-simultaneously.

As used herein, the articles "a" and "an" refer to one of the grammatical objects of the article or to more than one (i.e., to at least one). For example, "an element" means one element or more than one element.

As used herein, the term "alkenyl" alone or in combination with other terms, unless otherwise indicated, refers to a stable mono-or di-unsaturated straight or branched hydrocarbon radical having the stated number of carbon atoms. Examples include ethenyl, propenyl (or allyl), crotyl (crotyl), isopentenyl, butadienyl, 1, 3-pentadienyl, 1, 4-pentadienyl and higher homologs and isomers. Examples of functional groups representing olefins are-CH ₂ -CH＝CH ₂ 。

As used herein, unless otherwise indicated, the term "alkoxy" used alone or in combination with other terms refers to an alkyl group as defined elsewhere herein having the indicated number of carbon atoms attached to the remainder of the molecule via an oxygen atom, e.g., such as methoxy, ethoxy, 1-propoxy, 2-propoxy (or isopropoxy), and higher homologs and isomers. Specific examples are (C ₁ -C ₃ ) Alkoxy groups such as, but not limited to, ethoxy and methoxy.

As used herein, unless otherwise indicated, the term "alkyl" by itself or as part of another substituent means a compound having the indicated number of carbon atoms (i.e., C ₁ -C ₁₀ Represents a straight or branched hydrocarbon of 1 to 10 carbon atoms) and includes straight, branched, or cyclic substituents. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl. Specific examples are (C) ₁ -C ₆ ) Alkyl groups such as, but not limited to, ethyl, methyl, isopropyl, isobutyl, n-pentyl, n-hexyl, and cyclopropylmethyl.

As used herein, the term "alkynyl", alone or in combination with other terms, refers to a stable straight or branched hydrocarbon radical having a carbon-carbon triple bond of the stated number of carbon atoms, unless otherwise indicated. Non-limiting examples include ethynyl and propynyl, and higher homologs and isomers. The term "propargyl" means in the form of-CH ₂ -c≡ch is an example group. The term "homopropargyl" means in the form of-CH ₂ CH ₂ -c≡ch is an example group.

As used herein, the term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings and having aromatic character, i.e., having (4n+2) delocalized pi (pi) electrons (where 'n' is an integer).

As used herein, unless otherwise indicated, the term "aryl" used alone or in combination with other terms refers to a carbocyclic aromatic system containing one or more rings (typically one, two or three rings) wherein the rings may be linked together in a pendant manner, such as biphenyl, or may be fused, such as naphthalene. Examples include phenyl, anthracyl and naphthyl. Aryl groups also include, for example, benzene or naphthalene rings fused to one or more saturated or partially saturated carbocycles (e.g., bicyclo [4.2.0] octa-1, 3, 5-trienyl or indanyl), which may be substituted at one or more carbon atoms of the aromatic ring and/or saturated or partially saturated ring.

As used herein, the term "aryl- (C) ₁ -C ₆ ) Alkyl "refers to a functional group in which 1 to 6 carbon alkylene chains are attached to an aryl group, e.g., -CH ₂ CH ₂ -phenyl or-CH ₂ -phenyl (or benzyl). Specific examples are aryl-CH ₂ -and aryl-CH (CH) ₃ ) -. The term "substituted aryl- (C) ₁ -C ₆ ) Alkyl "refers to aryl- (C) wherein aryl is substituted ₁ -C ₆ ) Alkyl functional groups. Specific examples are substituted aryl (CH) ₂ ) -. Similarly, the term "heteroaryl- (C) ₁ -C ₆ ) Alkyl "refers to a functional group in which 1 to 3 carbon alkylene chains are attached to a heteroaryl group, e.g., -CH ₂ CH ₂ -a pyridinyl group. Specific examples are heteroaryl- (CH) ₂ ) -. The term "substituted heteroaryl- (C) ₁ -C ₆ ) Alkyl "refers to heteroaryl- (C) wherein the heteroaryl is substituted ₁ -C ₆ ) Alkyl functional groups. Specific examples are substituted heteroaryl- (CH) ₂ )-。

In one aspect, the terms "co-administration" and "co-administration" in reference to a subject refer to administration of a compound and/or composition of the present disclosure to a subject and also compounds and/or compositions that can treat or prevent a disease or disorder contemplated herein. In certain embodiments, the co-administered compounds and/or compositions are administered alone or in any kind of combination as part of a monotherapy method. The co-administered compounds and/or compositions can be formulated in any variety of combinations as mixtures and solutions of solids and liquids in various solid, gel, and liquid formulations.

As used herein, unless otherwise indicated, the term "cycloalkyl" by itself or as part of another substituent refers to a cyclic hydrocarbon having the indicated number of carbon atoms (i.e., C ₃ -C ₆ Refers to a cyclic group comprising a cyclic group consisting of 3 to 6 carbon atoms) and includes linear, branched or cyclic substituents. (C) ₃ -C ₆ ) Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl ring may be optionally substituted. Non-limiting examples of cycloalkyl groups include: cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, 2, 3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, decalinyl, 2, 5-dimethylcyclopentyl, 3, 5-dichlorocyclohexyl, 4-hydroxycyclohexyl, 3, 5-trimethylcyclohex-1-yl, octahydropentenyl, octahydro-1H-indenyl, 3a,4,5,6,7 a-hexahydro-3H-inden-4-yl, decahydro azulenyl; bicyclo [6.2.0 ]]Decyl, decahydronaphthyl, and dodecahydro-1H-fluorenyl. The term "cycloalkyl" also includes bicyclic hydrocarbon rings, non-limiting examples of which include bicyclo [2.1.1 ]]Hexalkyl and bicyclo [2.2.1]Heptyl and bicyclo [3.1.1]Heptyl, 1, 3-dimethyl [2.2.1]Heptane (heptane)-2-yl, bicyclo [2.2.2]Octyl, and bicyclo [3.3.3]Undecyl (undecyl).

As used herein, the term "DCM" refers to dichloromethane.

As used herein, a "disease" is a state of health of a subject, wherein the subject is unable to maintain homeostasis, and wherein the subject's health continues to deteriorate if the disease is not improved.

As used herein, a "disorder" in a subject is a state of health in which the subject is able to maintain steady state, but in which the subject's state of health is less favorable than the state of health without the disorder. If untreated, the condition does not necessarily result in a further decrease in the health state of the subject.

As used herein, the term "halide" refers to a halogen atom bearing a negative charge. The halide anion is fluoride (F) ^- ) Chloride ion (Cl) ^- ) Bromide ion (Br) ^- ) And iodide ion (I) ^- )。

As used herein, unless otherwise indicated, the term "halo" or "halogen" alone or as part of another substituent refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

As used herein, the term "hepatitis b virus" (or HBV) refers to a virus species of the genus Orthohepadnavirus (i.e., a part of the hepadnaviridae family of viruses) and is capable of causing liver inflammation in humans.

As used herein, the term "hepatitis delta virus" (or HDV) refers to a virus species of the genus Deltaviridae (Deltaviridae) that is capable of causing liver inflammation in humans. The HDV particles comprise an envelope provided by HBV and surrounding the RNA genome and an HDV antigen. The HDV genome is a single negative strand circular RNA molecule of approximately 1.7kb in length. The genome contains multiple sense and antisense Open Reading Frames (ORFs), only one of which is functional and conserved. The RNA genome replicates through RNA intermediates, i.e., antigenomes. Genomic RNA and its complement, the antigenome, can act as a ribozyme to perform self-cleavage and self-ligation reactions. The third RNA present in the infected cells, which is also complementary to the genome, is 800bp long and polyadenylation, an mRNA that synthesizes delta antigen (HDAg).

As used herein, unless otherwise indicated, the term "heteroalkenyl" by itself or in combination with another term means a stable straight or branched chain mono-or di-unsaturated hydrocarbon group consisting of the stated number of carbon atoms and one or two heteroatoms selected from O, N and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Up to two heteroatoms may be placed in succession. Examples include-ch=ch-O-CH ₃ 、-CH＝CH-CH ₂ -OH、-CH ₂ -CH＝N-OCH ₃ 、-CH＝CH-N(CH ₃ )-CH ₃ and-CH ₂ -CH＝CH-CH ₂ -SH。

As used herein, unless otherwise indicated, the term "heteroalkyl" by itself or in combination with another term refers to a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from O, N and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) may be located at any position of the heteroalkyl group, including between the remainder of the heteroalkyl group and the fragment to which it is attached, as well as to the most distal carbon atom in the heteroalkyl group. Examples include: -OCH ₂ CH ₂ CH ₃ 、-CH ₂ CH ₂ CH ₂ OH、-CH ₂ CH ₂ NHCH ₃ 、-CH ₂ SCH ₂ CH ₃ and-CH ₂ CH ₂ S(＝O)CH ₃ . At most two heteroatoms may be contiguous, e.g., -CH ₂ NH-OCH ₃ or-CH ₂ CH ₂ SSCH ₃ 。

As used herein, the term "heteroaryl" or "heteroaromatic" refers to a heterocycle having aromatic character. Polycyclic heteroaryl groups may include one or more partially saturated rings. Examples include tetrahydroquinoline and 2, 3-dihydrobenzofuranyl.

As used herein, unless otherwise indicated, the term "heterocycle" or "heterocyclyl" or "heterocyclic" by itself or as part of another substituent refers to an unsubstituted or substituted, stable, mono-or polycyclic, heterocyclic ring system comprising carbon atoms and at least one heteroatom selected from N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen atom may optionally be quaternized. Unless otherwise indicated, the heterocyclic ring system may be attached to any heteroatom or carbon atom that provides a stable structure. The heterocyclic ring may be aromatic or non-aromatic in nature. In certain embodiments, the heterocycle is heteroaryl.

Examples of the non-aromatic heterocycle include monocyclic groups such as aziridine, ethylene oxide, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane, 2, 3-dihydrofuran, 2, 5-dihydrofuran, tetrahydrofuran, tetrahydrothiophene (thiophane), piperidine, 1,2,3, 6-tetrahydropyridine, 1, 4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran, 2, 3-dihydropyran, tetrahydropyran, 1, 4-dioxane, 1, 3-dioxane, homopiperazine, homopiperidine, 1, 3-dioxacycloheptane, 4,7-dihydro-1, 3-dioxacycloheptane (4, 7-dihydro-1, 3-dioxa-epin), and cyclohexane (oxamethyl oxide).

Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl (e.g., without limitation, 2-and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,3, 4-triazolyl, tetrazolyl, 1,2, 3-thiazolyl, 1,2, 3-oxadiazolyl, 1,3, 4-thiazolyl, and 1,3, 4-oxadiazolyl.

Examples of polycyclic heterocycles include indolyl (such as, but not limited to, 3-, 4-, 5-, 6-, and 7-indolyl), indolinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl (such as, but not limited to, 1-and 5-isoquinolinyl), 1,2,3, 4-tetrahydroisoquinolinyl, cinnolinyl (cinnolinyl), quinoxalinyl (such as, but not limited to, 2-and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1, 8-naphthyridinyl, 1, 4-benzodioxanyl, coumarin, dihydrocoumarin, 1, 5-naphthyridinyl, benzofuranyl (such as, but not limited to, 3-, 4-, 5-, 6-, and 7-benzofuranyl), 2, 3-dihydrobenzofuranyl, 1, 2-benzoxazolyl, benzothienyl (such as, but not limited to, 3-, 4-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl (such as, but not limited to, 2-benzothiazolyl and 5-benzothiazolyl), benzotriazolyl, benzofuranyl (such as, thiozolyl), benzofuranyl, pyrrolyl, and thiozolyl (such as, pyrrolidyl).

The above list of heterocyclyl and heteroaryl moieties is intended to be representative, not limiting.

As used herein, the term "PD-L1 inhibitor" includes any compound capable of directly or indirectly inhibiting the expression and/or function of a programmed death ligand 1 (PD-L1) protein. PD-L1, also known as cluster 274 (CD 274) or B7 homolog 1 (B7-H1), is a type 1 transmembrane protein that plays an important role in inhibiting the adaptive arm of the immune system, tissue allograft, autoimmune disease, and hepatitis during pregnancy. PD-L1 binds to its receptor, the inhibitory checkpoint molecule PD-1 (found on activated T cells, B cells, and bone marrow cells) in order to modulate activation or inhibition of the adaptive arm of the immune system. In certain embodiments, the PD-L1 inhibitor inhibits expression and/or function of PD-L1 by at least 5%, at least 10%, at least 20%, at least 50%, at least 75%, or at least 90%.

As used herein, the term "pharmaceutical composition" or "composition" refers to a mixture of at least one compound useful in the present disclosure and a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a subject.

As used herein, the term "pharmaceutically acceptable" refers to materials, such as carriers or diluents, that do not abrogate the biological activity or properties of the compounds useful in the present disclosure and that are relatively non-toxic, i.e., that can be administered to a subject without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which they are comprised.

As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent or encapsulating material, that participates in carrying or transporting a compound useful in the present disclosure within or to a subject such that it may perform a desired function. Typically, such constructs are carried or transported from one organ or body part to another organ or body part. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compounds useful in this disclosure, and not deleterious to the subject. Some examples of materials that may be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdery tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; diols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; a surfactant; alginic acid; non-thermal raw water; isotonic saline; ringer's solution; ethanol; phosphate buffer solution; and other non-toxic compatible substances used in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, absorption delaying agents, and the like that are compatible with the activity of the compounds useful in the present disclosure and are physiologically acceptable to the subject. Supplementary active compounds may also be incorporated into the compositions. The "pharmaceutically acceptable carrier" may further include pharmaceutically acceptable salts of the compounds useful in the present disclosure. Other additional ingredients that may be included in pharmaceutical compositions used in the practice of the present disclosure are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, ed., mack Publishing co.,1985, easton, pa), which is incorporated herein by reference.

As used herein, the term "pharmaceutically acceptable salt" refers to salts of the administered compounds prepared from pharmaceutically acceptable non-toxic acids and/or bases including inorganic acids, inorganic bases, organic acids, inorganic bases, solvates (including hydrates) and clathrates (clathrates) thereof.

As used herein, a "pharmaceutically effective amount", "therapeutically effective amount", or "effective amount" of a compound is an amount of the compound that is sufficient to provide a beneficial effect to a subject to whom the compound is administered.

The term "preventing", "pre-stop" or "avoiding" as used herein refers to avoiding or delaying the onset of symptoms associated with a disease or condition in a subject who does not develop such symptoms at the beginning of administration of an agent or compound. Diseases, conditions, and disorders are used interchangeably herein.

The term "specifically binds" or "specifically binds" as used herein refers to a first molecule that preferentially binds to a second molecule (e.g., a particular receptor or enzyme), but not necessarily only binds to the second molecule.

As used herein, the terms "subject" and "individual" and "patient" are used interchangeably and may refer to a human or non-human mammal or bird. Non-human mammals include, for example, livestock and pets, such as sheep, cattle, swine, canine, feline, and murine mammals. In certain embodiments, the subject is a human.

As used herein, the term "substituted" refers to an atom or group of atoms that has been substituted for hydrogen as a substituent attached to another group.

As used herein, the term "substituted alkyl", "substituted cycloalkyl", "substituted alkenyl", or "substituted alkynyl" refers to an alkyl, cycloalkyl, alkenyl, or alkynyl group as defined elsewhere herein, independently selected from halogen, -OH, alkoxy, tetrahydro-2-H-pyranyl, -NH ₂ 、NH(C ₁ -C ₆ Alkyl), -N (C) ₁ -C ₆ Alkyl group ₂ 1-methyl-imidazol-2-yl, pyridin-3-yl, pyridin-4-yl, -C (=o) OH, -C (=o) O (C) ₁ -C ₆ ) Alkyl, trifluoromethyl, -c≡n, -C (=o) NH ₂ 、-C(＝O)NH(C ₁ -C ₆ ) Alkyl, -C (=o) N ((C) ₁ -C ₆ ) Alkyl group ₂ 、-SO ₂ NH ₂ 、-SO ₂ NH(C ₁ -C ₆ Alkyl), -SO ₂ N(C ₁ -C ₆ Alkyl group ₂ 、-C(＝NH)NH ₂ and-NO ₂ Substituted with one, two or three substituents, in certain embodiments independently selected from halogen, -OH, alkoxy, -NH ₂ Trifluoromethyl, -N (CH) ₃ ) ₂ and-C (=o) OH, in certain embodiments independently selected from halogen, alkoxy, and-OH. Examples of substituted alkyl groups include, but are not limited to, 2-difluoropropyl, 2-carboxycyclopentyl, and 3-chloropropyl.

For aryl, aryl- (C) ₁ -C ₃ ) Alkyl and heterocyclyl, the term "substituted" as applied to the rings of these groups refers to any level of substitution where such substitution is allowed, i.e., mono-, di-, tri-, tetra-or penta-substitution. The substituents are independently selected and the substitution may be at any chemically feasible position. In certain embodiments, the number of substituents varies between 1 and 4. In other embodiments, the number of substituents varies between 1 and 3. In yet further embodiments, the number of substituents varies between 1 and 2. In yet other embodiments, the substituents are independently selected from C ₁ -C ₆ Alkyl, -OH, C ₁ -C ₆ Alkoxy, halogen, amino, acetamido, and nitro. As used herein, where the substituent is an alkyl or alkoxy group, the carbon chain may be branched, straight or cyclic.

In certain embodiments, each occurrence of alkyl or cycloalkyl is independently optionally substituted with at least one substituent selected from the group consisting of: c (C) ₁ -C ₆ Alkyl, halo, -OR, phenyl (thereby producing (in a non-limiting example) optionally substituted phenyl- (C) ₁ -C ₃ Alkyl), such as, but not limited to, benzyl or substituted benzyl) and-N (R), wherein each occurrence of R is independently H, C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl groups. In other embodiments, each occurrence of aryl or heteroaryl is independently optionally substituted with at least one substituent selected from the group consisting of: c (C) ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Haloalkoxy, halo, -CN, -OR, -N (R) (R), -NO ₂ 、-S(＝O) ₂ N (R) (R), acyl, and C ₁ -C ₆ Alkoxycarbonyl, wherein each occurrence of R is independently H, C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl groups. In yet other embodiments, each occurrence of aryl or heteroaryl is independently optionally substituted with at least one substituent selected from the group consisting of: c (C) ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Haloalkoxy, halo, -CN, -OR, -N (R) (R), and C ₁ -C ₆ Alkoxycarbonyl, wherein each occurrence of R is independently H, C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl groups.

When two substituents together form a ring having the indicated number of ring atoms (e.g., R ² And R is ³ Together with the nitrogen to which they are attached, form a ring having 3 to 7 ring members, which may have carbon atoms and optionally one or more (e.g., 1 to 3) additional heteroatoms independently selected from nitrogen, oxygen, or sulfur. The ring may be saturated or partially saturated and may be optionally substituted with one or more substituents, non-limiting examples including carbonyl (c=o).

Whenever any one of the terms or their prefix roots appears in the name of a substituent, the name should be interpreted to include those limitations provided herein. For example, whenever any of the terms "alkyl" or "aryl" or their prefix roots appear in the name of a substituent (e.g., arylalkyl, alkylamino), the name should be interpreted to include those limitations given herein elsewhere for "alkyl" and "aryl", respectively.

In certain embodiments, substituents of a compound are disclosed in groups or ranges. Concrete embodimentsThe description is intended to include each and every single subcombination of the members of these groups and ranges. For example, the term "C _1-6 Alkyl "is specifically intended to disclose C alone ₁ 、C ₂ 、C ₃ 、C ₄ 、C ₅ 、C ₆ 、C ₁ -C ₆ 、C ₁ -C ₅ 、C ₁ -C ₄ 、C ₁ -C ₃ 、C ₁ -C ₂ 、C ₂ -C ₆ 、C ₂ -C ₅ 、C ₂ -C ₄ 、C ₂ -C ₃ 、C ₃ -C ₆ 、C ₃ -C ₅ 、C ₃ -C ₄ 、C ₄ -C ₆ 、C ₄ -C ₅ And C ₅ -C ₆ An alkyl group.

The terms "treat," "treatment" and "medical" as used herein refer to reducing the frequency or severity of symptoms of a disease or condition experienced by a subject by administering an agent or compound to the subject.

The range is as follows: throughout this disclosure, various aspects of the invention may be presented in a range format. It should be understood that the description of the range format is merely for convenience and brevity and should not be construed as a inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all possible subranges and individual values within the range. For example, a description of a range such as 1 to 6 should be considered to have specifically disclosed sub-ranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual values within this range such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the width of the range.

Compounds of formula (I)

Programmed death ligand 1 (PD-L1), also known as cluster 274 (CD 274) or B7 homolog 1 (B7-H1), is a human transmembrane protein that plays a major role in suppressing the immune system as desired. In general, the presence of foreign antigens in the body triggers the proliferation of antigen-specific cd8+ T cells in the lymph nodes. However, the binding of PD-L1 to the receptor programmed cell death protein (PD-1) or B7.1 membrane protein, both of which are found on activated T cells, B cells, and bone marrow cells, transmits an inhibitory signal, which reduces proliferation of cd8+ T cells in the lymph nodes. Such interactions effectively suppress the immune system and avoid detection and destruction of antigens.

In certain embodiments, small molecule immunomodulators that target the PD-1/PD-L1 signaling pathway are used to treat, ameliorate, and/or prevent Hepatitis B Virus (HBV) infection and related conditions in a subject. In other embodiments, inhibition of PDL-1 enhances an immune response to at least one HBV antigen.

The present disclosure includes compounds of formula (I), or salts, solvates, prodrugs, stereoisomers (e.g., enantiomers or diastereomers in non-limiting examples, and any mixtures thereof, e.g., mixtures of enantiomers and/or diastereomers thereof in any ratio in non-limiting examples), tautomers, and/or geometric isomers, and any mixtures thereof. It should be noted that the absolute stereochemistry of the chiral center(s) expressed in any structure depicted herein and/or in the compounds named herein is merely illustrative and non-limiting.

In certain embodiments, the compound of formula (I) is:

wherein:

a is

Y is NR ^3b Or O;

l is selected from the group consisting of-C (R ^3g )(R ^3h )-、-(C(R ^3g )(R ^3h ))-(C(R ³ⁱ )(R ^3j ) -and a bond;

X ¹ selected from CR' ¹ And N;

X ² selected from CR' ² And N;

X ³ selected from CR' ³ And N;

X ⁴ selected from CR' ¹ And N;

X ⁵ selected from CR' ² And N;

X ⁶ selected from CR' ³ And N;

wherein X is ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ And X ⁶ One to four of which are N;

R' ¹ 、R' ² 、R' ³ 、R" ¹ 、R" ² and R'. ³ Each independently selected from H, halogen, C ₁ -C ₃ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₃ Alkoxy, cyano, C ₁ -C ₃ Haloalkyl, and C ₁ -C ₃ Haloalkoxy groups;

R ^1a and R is ^1b Each independently selected from H, halogen, C ₁ -C ₃ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₃ Alkoxy, cyano, C ₁ -C ₃ Haloalkyl, and C ₁ -C ₃ Haloalkoxy groups;

R ^1c and R is ^1d Each independently selected from the group consisting of:

wherein Z is ¹ Each occurrence of (2) is CR ^V10 Or N;

R ^2a selected from C (O) OR ^I 、-C(＝O)NR ⁶ R ⁶ Optionally substituted heterocyclyl, - (CH) ₂ ) _1-3 (optionally substituted heterocyclyl), optionally substituted C ₁ -C ₆ Alkoxy, optionally substituted C ₁ -C ₆ Aminoalkyl, C (=o) (optionally substituted C ₁ -C ₆ Alkyl), and optionally substituted C ₁ -C ₆ A group consisting of a hydroxyalkyl group, and a hydroxyl group,

wherein R is ^2a Independently selected from the group consisting of optionally substituted heterocyclyl, optionally substituted C ₁ -C ₆ Alkyl, optionally substituted C ₁ -C ₆ Hydroxyalkyl, optionally substituted cycloalkyl, and optionally substituted- (CH) ₂ ) _1-2 (heterocyclyl) a group consisting of,

wherein R is ^2a Two optional substituents of (a) may be combined with the atom to which they are bound to form an optionally substituted C ₂ -C ₈ Heterocyclyl or optionally substituted C ₃ -C ₈ A cycloalkyl group,

wherein R is ^I Each occurrence of (a) is independently H, C ₁ -C ₆ Alkyl, or C ₃ -C ₈ Cycloalkyl, wherein alkyl or cycloalkyl is independently optionally substituted with halogen, -OH, C ₁ -C ₆ Alkoxy, -NH ₂ 、-NH(C ₁ -C ₆ Alkyl), and-N (C) ₁ -C ₆ Alkyl) (C) ₁ -C ₆ Alkyl) at least one of which is substituted,

wherein R is ⁶ Each occurrence of (a) is independently H, C ₁ -C ₆ Alkyl, or C ₃ -C ₈ Cycloalkyl, wherein alkyl or cycloalkyl is independently optionally substituted with halogen, -OH, C ₁ -C ₆ Alkoxy, -NH ₂ 、-NH(C ₁ -C ₆ Alkyl), and-N (C) ₁ -C ₆ Alkyl) (C) ₁ -C ₆ Alkyl) at least one of which is substituted,

R ^2b selected from H, - (CH) ₂ ) _1-3 C(＝O)OR ^I 、-(CH ₂ ) _1-3 C(＝O)NR ^I R ^I Optionally substituted heterocyclyl, - (CH) ₂ ) _1-2 (optionally substituted heterocyclyl), optionally substitutedC ₁ -C ₆ Alkyl, optionally substituted C ₁ -C ₆ Haloalkyl, optionally substituted C ₁ -C ₆ Alkoxy, optionally substituted C ₁ -C ₆ Aminoalkyl, and optionally substituted C ₁ -C ₆ A group consisting of a hydroxyalkyl group, and a hydroxyl group,

wherein R is ^2b Independently selected from the group consisting of optionally substituted C ₁ -C ₆ Alkyl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, and optionally substituted- (CH) ₂ ) _1-3 (heterocyclyl) groups;

R ^3a 、R ^3b 、R ^3c 、R ^3d 、R ^3e 、R ^3f 、R ^3g 、R ^3h 、R ³ⁱ and R ^3j Each independently selected from H, halogen, C ₁ -C ₃ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Haloalkyl, and C ₁ -C ₃ Haloalkoxy groups;

R ⁵ selected from the group consisting of H, C ₁ -C ₃ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Haloalkyl, and C ₁ -C ₃ A group consisting of haloalkoxy groups,

wherein R is ⁵ And R is ^2b Can be combined with the nitrogen atom to which they are bound to form C ₃ -C ₁₂ A heterocyclic group;

R ^4a and R is ^4b Each occurrence of (a) is independently selected from the group consisting of H, C ₁ -C ₃ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Haloalkyl, and C ₁ -C ₃ A group consisting of haloalkoxy groups,

wherein R is ^4a And R is ^4b Can combine with the carbon atoms to which they are bound to form a carbonyl group (c=o);

R ^V1 、R ^V2 、R ^V3 、R ^V4 、R ^V5 、R ^V6 、R ^V7 、R ^V8 、R ^V9 and R ^V10 Each occurrence of (a) is independently selected from the group consisting of H, C ₁ -C ₃ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₃ Alkoxy, cyano, halogen, C ₁ -C ₃ Haloalkyl, and C ₁ -C ₃ Haloalkoxy groups; and is also provided with

R ^V11 Selected from the group consisting of H, C ₁ -C ₃ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Haloalkyl, and C ₁ -C ₃ Haloalkoxy groups.

In certain embodiments, if R ^1c And R is ^1d The same applies, then at least one of the following:

(a) If X ¹ Is N, then R ^1c Z in (a) ¹ If present, CR ^V10 And;

(b) If X ⁶ Is N, then R ^1d Z in (a) ¹ If present, CR ^V10 。

In certain embodiments, at least one of the following applies:

(a) If X ¹ Is N, then R ^1c Z in (a) ¹ If present, CR ^V10 And;

(b) If X ⁶ Is N, then R ^1d Z in (a) ¹ If present, CR ^V10 。

In certain embodiments, if X ³ Is N, then X ⁴ Is CR' ¹ . In certain embodiments, if X ⁴ Is N, then X ³ Is CR' ³ 。

In certain embodiments, if X ¹ Is N, then R ^1c Heteroaryl groups that are not ring nitrogen atoms adjacent to a bond.

In certain embodiments, if X ⁶ Is N, then R ^1d Heteroaryl groups that are not ring nitrogen atom adjacent to a bond.

In certain embodiments, the compound of formula (I) is:

in certain embodiments, the compound of formula (I) is:

in certain embodiments, the compound of formula (I) is:

in certain embodiments, the compound of formula (I) is:

in certain embodiments, the compound of formula (I) is:

in certain embodiments, the compound of formula (I) is:

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in certain embodiments, the compound of formula (I) is:

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in certain embodiments, the compound of formula (I) is:

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in certain embodiments, the compound of formula (I) is:

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in certain embodiments, the compound of formula (I) is:

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in certain embodiments, the compound of formula (I) is:

in certain embodiments, the compound of formula (I) is:

at a certain positionIn some embodiments, the compound of formula (I) is:

in certain embodiments, the compound of formula (I) is:

in certain embodiments, R' ² 、R' ³ 、R" ¹ 、R" ² And R'. ³ Each of is H, and X ¹ Is N. In certain embodiments, R' ¹ 、R' ³ 、R" ¹ 、R" ² And R'. ³ Each of is H, and X ² Is N. In certain embodiments, R' ¹ 、R' ² 、R" ¹ 、R" ² And R'. ³ Each of is H, and X ³ Is N. In certain embodiments, R' ¹ 、R' ² 、R' ³ 、R" ² And R'. ³ Each of is H, and X ⁴ Is N. In certain embodiments, R' ¹ 、R' ² 、R' ³ 、R ^"1 And R'. ³ Each of is H, and X ⁵ Is N. In certain embodiments, R' ¹ 、R' ² 、R' ³ 、R" ¹ And R'. ² Each of is H, and X ⁶ Is N. In certain embodiments, R' ² 、R' ³ 、R" ² And R'. ³ Each of is H, and X ¹ And X ⁴ Is N. In certain embodiments, R' ² 、R' ³ 、R" ¹ And R'. ³ Each of is H, and X ¹ And X ⁵ Is N. In certain embodiments, R' ² 、R' ³ 、R" ¹ And R'. ² Each of is H, and X ¹ And X ⁶ Is N. In certain embodiments, R' ¹ 、R' ³ 、R" ² And R'. ³ Each of is H, and X ² And X ⁴ Is N. In certain embodiments, R' ¹ 、R' ³ 、R" ¹ And R'. ³ Each of is H, and X ² And X ⁵ Is N. In certain embodiments, R' ¹ 、R' ³ 、R" ¹ And R'. ² Each of is H, and X ² And X ⁶ Is N. In certain embodiments, R' ¹ 、R' ² 、R" ¹ And R'. ³ Each of is H, and X ³ And X ⁵ Is N. In certain embodiments, R' ¹ 、R' ² 、R" ¹ And R'. ² Each of is H, and X ³ And X ⁶ Is N. In certain embodiments, R' ² 、R" ¹ 、R" ² And R'. ³ Each of is H, and X ¹ And X ³ Is N. In certain embodiments, R' ¹ 、R' ² 、R' ³ And R'. ² Each of is H, and X ⁴ And X ⁶ Is N.

In certain embodiments, L is a bond and R ^3a 、R ^3c 、R ^3d 、R ^3e And R ^3f Is H. In certain embodiments, L is a bond and Y is NR ^3b And R is ^3a 、R ^3b 、R ^3c 、R ^3d 、R ^3e And R ^3f Is H. In certain embodiments, L is-C (R ^3g )(R ^3h ) -and R ^3a 、R ^3c 、R ^3d 、R ^3e 、R ^3f 、R ^3g And R ^3h Is H. In certain embodiments, L is-C (R ^3g )(R ^3h ) Y is NR ^3b And R is ^3a 、R ^3b 、R ^3c 、R ^3d 、R ^3e 、R ^3f 、R ^3g And R ^3h Is H. In certain embodiments, L is- (C (R ^3g )(R ^3h ))(C(R ³ⁱ )(R ^3j ) -and R ^3a 、R ^3c 、R ^3d 、R ^3e 、R ^3f 、R ^3g 、R ^3h 、R ³ⁱ And R ^3j Is H. In certain embodiments, L is-C (R ^3g )(R ^3h )-Y is NR ^3b And R is ^3a 、R ^3b 、R ^3c 、R ^3d 、R ^3e 、R ^3f 、R ^3g 、R ^3h 、R ³ⁱ And R ^3j Is H.

In certain embodiments, R ^3a Is H. In certain embodiments, R ^3a Is halogen. In certain embodiments, R ^3a Is C ₁ -C ₃ An alkyl group. In certain embodiments, R ^3a Is C ₃ -C ₈ Cycloalkyl groups. In certain embodiments, R ^3a Is C ₁ -C ₃ An alkoxy group. In certain embodiments, R ^3a Is C ₁ -C ₃ A haloalkyl group. In certain embodiments, R ^3a Is C ₁ -C ₃ Haloalkoxy groups.

In certain embodiments, R ^3b Is H. In certain embodiments, R ^3b Is halogen. In certain embodiments, R ^3b Is C ₁ -C ₃ An alkyl group. In certain embodiments, R ^3b Is C ₃ -C ₈ Cycloalkyl groups. In certain embodiments, R ^3b Is C ₁ -C ₃ An alkoxy group. In certain embodiments, R ^3b Is C ₁ -C ₃ A haloalkyl group. In certain embodiments, R ^3b Is C ₁ -C ₃ Haloalkoxy groups.

In certain embodiments, R ^3c Is H. In certain embodiments, R ^3c Is halogen. In certain embodiments, R ^3c Is C ₁ -C ₃ An alkyl group. In certain embodiments, R ^3c Is C ₃ -C ₈ Cycloalkyl groups. In certain embodiments, R ^3c Is C ₁ -C ₃ An alkoxy group. In certain embodiments, R ^3c Is C ₁ -C ₃ A haloalkyl group. In certain embodiments, R ^3c Is C ₁ -C ₃ Haloalkoxy groups.

In certain embodiments, R ^3d Is H. In certain embodiments, R ^3d Is halogen. In certain embodiments, R ^3d Is C ₁ -C ₃ An alkyl group. At a certain positionIn some embodiments, R ^3d Is C ₃ -C ₈ Cycloalkyl groups. In certain embodiments, R ^3d Is C ₁ -C ₃ An alkoxy group. In certain embodiments, R ^3d Is C ₁ -C ₃ A haloalkyl group. In certain embodiments, R ^3d Is C ₁ -C ₃ Haloalkoxy groups.

In certain embodiments, R ^3e Is H. In certain embodiments, R ^3e Is halogen. In certain embodiments, R ^3e Is C ₁ -C ₃ An alkyl group. In certain embodiments, R ^3e Is C ₃ -C ₈ Cycloalkyl groups. In certain embodiments, R ^3e Is C ₁ -C ₃ An alkoxy group. In certain embodiments, R ^3e Is C ₁ -C ₃ A haloalkyl group. In certain embodiments, R ^3e Is C ₁ -C ₃ Haloalkoxy groups.

In certain embodiments, R ^3f Is H. In certain embodiments, R ^3f Is halogen. In certain embodiments, R ^3f Is C ₁ -C ₃ An alkyl group. In certain embodiments, R ^3f Is C ₃ -C ₈ Cycloalkyl groups. In certain embodiments, R ^3f Is C ₁ -C ₃ An alkoxy group. In certain embodiments, R ^3f Is C ₁ -C ₃ A haloalkyl group. In certain embodiments, R ^3f Is C ₁ -C ₃ Haloalkoxy groups.

In certain embodiments, R ^3g Is H. In certain embodiments, R ^3g Is halogen. In certain embodiments, R ^3g Is C ₁ -C ₃ An alkyl group. In certain embodiments, R ^3g Is C ₃ -C ₈ Cycloalkyl groups. In certain embodiments, R ^3g Is C ₁ -C ₃ An alkoxy group. In certain embodiments, R ^3g Is C ₁ -C ₃ A haloalkyl group. In certain embodiments, R ^3g Is C ₁ -C ₃ Haloalkoxy groups.

In certain embodiments, R ^3h Is H. In certain embodiments, R ^3h Is halogen. In certain embodiments, R ^3h Is C ₁ -C ₃ An alkyl group. In certain embodiments, R ^3h Is C ₃ -C ₈ Cycloalkyl groups. In certain embodiments, R ^3h Is C ₁ -C ₃ An alkoxy group. In certain embodiments, R ^3h Is C ₁ -C ₃ A haloalkyl group. In certain embodiments, R ^3h Is C ₁ -C ₃ Haloalkoxy groups.

In certain embodiments, R ³ⁱ Is H. In certain embodiments, R ³ⁱ Is halogen. In certain embodiments, R ³ⁱ Is C ₁ -C ₃ An alkyl group. In certain embodiments, R ³ⁱ Is C ₃ -C ₈ Cycloalkyl groups. In certain embodiments, R ³ⁱ Is C ₁ -C ₃ An alkoxy group. In certain embodiments, R ³ⁱ Is C ₁ -C ₃ A haloalkyl group. In certain embodiments, R ³ⁱ Is C ₁ -C ₃ Haloalkoxy groups.

In certain embodiments, R ^3j Is H. In certain embodiments, R ^3j Is halogen. In certain embodiments, R ^3j Is C ₁ -C ₃ An alkyl group. In certain embodiments, R ^3j Is C ₃ -C ₈ Cycloalkyl groups. In certain embodiments, R ^3j Is C ₁ -C ₃ An alkoxy group. In certain embodiments, R ^3j Is C ₁ -C ₃ A haloalkyl group. In certain embodiments, R ^3j Is C ₁ -C ₃ Haloalkoxy groups.

In certain embodiments, R ^1a Is H. In certain embodiments, R ^1a Is methyl. In certain embodiments, R ^1a Is F. In certain embodiments, R ^1a Is Cl. In certain embodiments, R ^1a Is CF (CF) ₃ . In certain embodiments, R ^1a Is CN.

In certain embodiments, R ^1b Is H. In certain embodiments, R ^1b Is methyl. In certain embodiments, R ^1b Is F. In certain embodiments, R ^1b Is Cl. At a certain positionIn some embodiments, R ^1b Is CF (CF) ₃ . In certain embodiments, R ^1b Is CN.

In certain embodiments, R ^1a And R is ^1b The same applies.

In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted 5-oxopyrrolidin-2-yl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted 5-oxopyrrolidin-2-yl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (C ₁ -C ₆ Alkyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl group ₂ . In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (C ₁ -C ₆ Haloalkyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (C) ₁ -C ₆ Haloalkyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (C ₁ -C ₆ Hydroxyalkyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (C ₁ -C ₆ Hydroxyalkyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 C(＝O)O(C ₁ -C ₆ Alkyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _{0- 2} N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 C(＝O)O(C ₁ -C ₆ Alkyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl group ₎ C(＝O)(C ₁ -C ₆ Alkyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 NHC(＝O)(C ₁ -C ₆ Alkyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl group ₎ C(＝O)(C ₁ -C ₆ Alkyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 NHC(＝O)(C ₁ -C ₆ Alkyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted oxetanyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted oxetanyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted oxapentanyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted oxacyclopentylalkyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted oxanyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted oxaalkyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted cyclobutyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted cyclobutyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted cyclohexyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl group(CH ₂ ) _0-2 (optionally substituted cyclohexyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted C) ₅ -C ₆ Cycloalkyl sulfonyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted C) ₅ -C ₆ Cycloalkyl sulfonyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted azetidinyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted azetidinyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted pyrrolidinyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted pyrrolidinyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted piperidinyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted piperidinyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 (optionally substituted guanidinyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 (optionally substituted azetidinyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(C(CH ₂ ) _2-5 )C(＝O)O(C ₁ -C ₆ Alkyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (C (CH) ₂ ) _2-5 )C(＝O)O(C ₁ -C ₆ Alkyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH(C ₁ -C ₃ Alkyl)) C (=o) O (C) ₁ -C ₆ Alkyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH (C) ₁ -C ₃ Alkyl)) C (=o) O (C) ₁ -C ₆ Alkyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-1 (C ₅ -C ₉ Bridged cycloalkyl) (CH ₂ ) _0-1 C(＝O)O(C ₁ -C ₆ Alkyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-1 (C ₅ -C ₉ Bridged cycloalkyl) (CH ₂ ) _0-1 C(＝O)O(C ₁ -C ₆ Alkyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-1 (CHOH)(CH ₂ ) _0-1 C(＝O)O(C ₁ -C ₆ Alkyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-1 (CHO(C ₁ -C ₆ Alkyl)) (CH ₂ ) _0-1 C(＝O)O(C ₁ -C ₆ Alkyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-1 (CHOH)(CH ₂ ) _0-1 C(＝O)O(C ₁ -C ₆ Alkyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-1 (CHO(C ₁ -C ₆ Alkyl)) (CH ₂ ) _0-1 C(＝O)O(C ₁ -C ₆ Alkyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 (optionally substituted azetidinyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 (C ₄ -C ₁₀ Bridged heterocycloalkyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 (optionally substituted pyrrolidinyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 (optionally substituted piperidinyl)). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 (optionally substituted morpholinyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 (optionally substituted piperazinyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 (optionally substituted piperazin-2-yl). In certain embodiments, R ^2a is-C (CH) ₃ )N(C ₁ -C ₆ Alkyl group ₂ . In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (CHF ₂ ). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (CHF ₂ ). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-4 (CH ₂ F) A. The invention relates to a method for producing a fibre-reinforced plastic composite In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-4 (CH ₂ F) A. The invention relates to a method for producing a fibre-reinforced plastic composite In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) C (=o) CH ₃ . In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 NHC(＝O)CH ₃ . In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) C (=o) CH ₃ . In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 NHC(＝O)CH ₃ . In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) C ((C (=O) OC) ₁ -C ₆ Alkyl) ((CH) ₂ ) _0-2 O(C ₁ -C ₆ Alkyl)). In certain embodiments, R ^2a Is- (CH) ₂ ) _{0- 2} NHC((C(＝O)OC ₁ -C ₆ Alkyl) ((CH) ₂ ) _0-2 O(C ₁ -C ₆ Alkyl)). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) C ((C (=o) OH ((CH) ₂ ) _0-2 O(C ₁ -C ₆ Alkyl)). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) C ((C (=O) OC) ₁ -C ₆ Alkyl) ((CH) ₂ ) _0-2 OH)). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NHC((C(＝O)OH)((CH ₂ ) _0-2 O(C ₁ -C ₆ Alkyl)). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) C ((C (=o) OH ((CH) ₂ ) _0-2 OH)). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NHC((C(＝O)OC ₁ -C ₆ Alkyl) ((CH) ₂ ) _0-2 OH)). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NHC((C(＝O)OH((CH ₂ ) _0-2 OH)). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _1-4 N(C ₁ -C ₆ Alkyl) C (=o) Me. In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _1-4 NHC (=o) Me. In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _1-4 N(C ₁ -C ₆ Alkyl) C (=o) Me. In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _1-4 NHC (=o) Me. In certain embodiments, R ^2a Is- (CH) ₂ ) _{0- 2} N(C ₁ -C ₆ Alkyl) (CH ₂ ) _1-5 C(＝O)N(C ₁ -C ₆ Alkyl) (C) ₁ -C ₆ Alkyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _1-5 C(＝O)N(C ₁ -C ₆ Alkyl) (C) ₁ -C ₆ Alkyl group). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _1-5 C(＝O)NH(C ₁ -C ₆ Alkyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _1-5 C(＝O)NH ₂ . In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _1-5 C(＝O)NH(C ₁ -C ₆ Alkyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _1-5 C(＝O)NH ₂ . In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted cyclopropyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted cyclopropyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted butyrolactone-2-yl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted butyrolactone-2-yl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted tetrahydro-4-thiopyranyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted oxazolyl) in certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted tetrahydro-4-thiopyranyl). In certain embodiments, R ^2a is-CH (CH) ₃ )NH(CH ₂ ) _0-2 (optionally substituted piperidinyl). In certain embodiments, R ^2a is-CH (CH) ₃ )N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted piperidinyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted piperazinyl). In certain embodiments, R ^2a Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted piperazinyl). In certain embodiments, R ^2a Is C (=o) OH.

In certain embodiments, R ^2b Is- (CH) ₂ ) _0-2 (optionally substituted 5-oxopyrrolidin-2-yl). In certain embodiments, R ^2b Is- (CH) ₂ ) _0-2 (optionally substituted piperidinyl). In certain embodiments, R ^2b Is- (CH) ₂ ) _0-2 (C ₁ -C ₆ Alkyl). In certain embodiments, R ^2b Is- (CH) ₂ ) _0-2 (C ₁ -C ₆ Haloalkyl). In certain embodiments, R ^2b Is- (CH) ₂ ) _0-2 (C ₁ -C ₆ Hydroxyalkyl). In certain embodiments, R ^2b Is- (CH) ₂ ) _0-2 (optionally substituted cyclopropyl). In certain embodiments, R ^2b Is- (CH) ₂ ) _0-2 (optionally substituted cyclobutyl). In certain embodiments, R ^2b Is- (CH) ₂ ) _0-2 C(＝O)O(C ₁ -C ₆ Alkyl). In certain embodiments, R ^2b Is- (CH) ₂ ) _0-2 (optionally substituted azetidinyl). In certain embodiments, R ^2b Is- (CH) ₂ ) _{0- 2} C (=o) OH. In certain embodiments, R ^2b Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) CH ₃ . In certain embodiments, R ^2b Is- (CH) ₂ ) _0-2 NHCH ₃ . In certain embodiments, R ^2b Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 C(＝O)O(C ₁ -C ₆ Alkyl). In certain embodiments, R ^2b Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 C(＝O)O(C ₁ -C ₆ Alkyl). In certain embodiments, R ^2b Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 C (=o) OH. In certain embodiments, R ^2b Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 C (=o) OH. In certain embodiments, R ^2b Is- (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted 5-oxopyrrolidin-2-yl). In certain embodiments, R ^2b Is- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted 5-oxopyrrolidin-2-yl). In certain embodiments, R ^2b Is- (CH) ₂ ) _0-2 C(＝O)N(C ₁ -C ₆ Alkyl) (C) ₁ -C ₆ Alkyl). In certain embodiments, R ^2b Is- (CH) ₂ ) _0-2 C(＝O)NH(C ₁ -C ₆ Alkyl). In certain embodiments, R ^2b Is- (CH) ₂ ) _0-2 C(＝O)NH ₂ . In certain embodiments, R ^2b Is- (CH) ₂ ) _0-2 CH(OC ₁ -C ₆ Alkyl) CH ₂ F. In certain embodiments, R ^2b Is- (CH) ₂ ) _0-2 CH(OH)CH ₂ F。

In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is- >In certain embodiments, R ^2a Is OR (OR) ^c . In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatAt a certain positionIn some embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn some casesIn embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In some casesIn embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In some embodimentsWherein R is ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is thatIn certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->In certain embodiments, R ^2a Is->

In certain embodiments, R ^a Is H. In certain embodiments, R ^a Is C ₁ -C ₃ An alkyl group. In certain embodiments, R ^a Is C ₃ -C ₈ Cycloalkyl groups. In certain embodiments, R ^a Is C ₁ -C ₃ An alkoxy group. In certain embodiments, R ^a Is C ₁ -C ₃ A haloalkyl group. In certain embodiments, R ^a Is C ₁ -C ₃ Haloalkoxy groups. In certain embodiments, R ^a is-C (=O) C ₁ -C ₃ An alkyl group. In certain embodiments, R ^a Is H. In certain embodiments, R ^a Is methyl. In certain embodiments, R ^a Is ethyl. In certain embodiments, R ^a Is isopropyl. In certain embodiments, R ^a is-C (=O) CH ₃ 。

In certain embodiments, R ^b Is H. In certain embodiments, R ^b Is C ₁ -C ₃ An alkyl group. In certain embodiments, R ^b Is C ₃ -C ₈ Cycloalkyl groups. In certain embodiments, R ^b Is C ₁ -C ₃ An alkoxy group. In certain embodiments, R ^b Is C ₁ -C ₃ A haloalkyl group. In certain embodiments, R ^b Is C ₁ -C ₃ Haloalkoxy groups. In certain embodiments, R ^b is-C (=O) C ₁ -C ₃ An alkyl group. In certain embodiments, R ^b Is H. In certain embodiments, R ^b Is methyl. In certain embodiments, R ^b Is ethyl. In certain embodiments, R ^b Is isopropyl. In certain embodiments, R ^b is-C (=O) CH ₃ 。

In certain embodiments, R ^c Is H. In certain embodiments, R ^c Is C ₁ -C ₃ An alkyl group. In certain embodiments, R ^c Is C ₃ -C ₈ Cycloalkyl groups. In certain embodiments, R ^c Is C ₁ -C ₃ An alkoxy group. In certain embodiments, R ^c Is C ₁ -C ₃ A haloalkyl group. In certain embodiments, R ^c Is C ₁ -C ₃ Haloalkoxy groups. In certain embodiments, R ^c is-C (=O) C ₁ -C ₃ An alkyl group. In certain embodiments, R ^c Is H. In certain embodiments, R ^c Is methyl. In certain embodiments, R ^c Is ethyl. In certain embodiments, R ^c Is isopropyl. In certain embodiments, R ^c is-C (=O) CH ₃ 。

In certain embodiments, R ^d Is H. In certain embodiments, R ^d Is C ₁ -C ₃ An alkyl group. In certain embodiments, R ^d Is C ₃ -C ₈ Cycloalkyl groups. In certain embodiments, R ^d Is C ₁ -C ₃ An alkoxy group. In certain embodiments, R ^d Is C ₁ -C ₃ A haloalkyl group. In certain embodiments, R ^d Is C ₁ -C ₃ Haloalkoxy groups. In certain embodiments, R ^d is-C (=O) C ₁ -C ₃ An alkyl group. In certain embodiments, R ^d Is H. In certain embodiments, R ^d Is methyl. In certain embodiments, R ^d Is ethyl. In certain embodiments, R ^d Is isopropyl. In certain embodiments, R ^d is-C (=O) CH ₃ 。

In certain embodiments, R ^e Is H. In certain embodiments, R ^e Is C ₁ -C ₃ An alkyl group. In certain embodiments, R ^e Is C ₃ -C ₈ Cycloalkyl groups. In certain embodiments, R ^e Is C ₁ -C ₃ An alkoxy group. In certain embodiments, R ^e Is C ₁ -C ₃ A haloalkyl group. In certain embodiments, R ^e Is C ₁ -C ₃ Haloalkoxy groups. In certain embodiments, R ^e is-C (=O) C ₁ -C ₃ An alkyl group. In certain embodiments, R ^e Is H. In certain embodiments, R ^e Is methyl. In certain embodiments, R ^e Is ethyl. In certain embodiments, R ^e Is isopropyl. In certain embodiments, R ^e is-C (=O) CH ₃ 。

In certain embodiments, R ^f Is H. In certain embodiments, R ^f Is C ₁ -C ₃ An alkyl group. In certain embodiments, R ^f Is C ₃ -C ₈ Cycloalkyl groups. In some embodiments of the present invention, in some embodiments,R ^f is C ₁ -C ₃ An alkoxy group. In certain embodiments, R ^f Is C ₁ -C ₃ A haloalkyl group. In certain embodiments, R ^f Is C ₁ -C ₃ Haloalkoxy groups. In certain embodiments, R ^f is-C (=O) C ₁ -C ₃ An alkyl group. In certain embodiments, R ^f Is H. In certain embodiments, R ^f Is methyl. In certain embodiments, R ^f Is ethyl. In certain embodiments, R ^f Is isopropyl. In certain embodiments, R ^f is-C (=O) CH ₃ 。

In certain embodiments, R ^g Is optionally substituted C ₂ -C ₆ Heteroaryl groups. In certain embodiments, R ^g Is an optionally substituted phenyl group. In certain embodiments, R ^g Is phenyl. In certain embodiments, R ^g Is a 2-furyl group. In certain embodiments, R ^g Is a 2-pyridyl group. In certain embodiments, R ^g Is 3-pyridyl. In certain embodiments, R ^g Is 4-pyridyl. In certain embodiments, R ^g Is 3-chloro-2-pyridinyl.

In certain embodiments, R ^2b Is thatIn certain embodiments, R ^2b Is->In certain embodiments, R ^2b Is methyl. In certain embodiments, R ^2b Is->In certain embodiments, R ^2b Is thatIn certain embodiments, R ^2b Is->In certain embodiments, R ^2b Is->In certain embodiments, R ^2b Is->In certain embodiments, R ^2b Is->In certain embodiments, R ^2b Is thatIn certain embodiments, R ^2b Is- >In certain embodiments, R ^2b Is thatIn certain embodiments, R ^2b Is->In certain embodiments, R ^2b Is->In certain embodiments, R ^2b Is->In certain embodiments, R ^2b Is thatIn certain embodiments, R ^2b Is->In certain embodiments, R ^2b Is thatIn certain embodiments, R ^2b Is->In certain embodiments, R ^2b Is thatIn certain embodiments, R ^2b Is->In certain embodiments, R ^2b Is thatIn certain embodiments, R ^2b Is->In certain embodiments, R ^2b Is thatIn certain embodiments, R ^2b Is->In certain embodiments, R ^2b Is->In certain embodiments, R ^2b Is->In certain embodiments, R ^2b Is->

In certain embodiments, R ⁱ Is H. In certain embodiments, R ⁱ Is C ₁ -C ₃ An alkyl group. In some implementationsIn the example, R ⁱ Is C ₃ -C ₈ Cycloalkyl groups. In certain embodiments, R ⁱ Is C ₁ -C ₃ An alkoxy group. In certain embodiments, R ⁱ Is C ₁ -C ₆ A haloalkyl group. In certain embodiments, R ⁱ Is C ₁ -C ₃ Haloalkoxy groups. In certain embodiments, R ⁱ is-C (=O) C ₁ -C ₃ An alkyl group. In certain embodiments, R ⁱ Is methyl. In certain embodiments, R ⁱ is-C (=O) CH ₃ 。

In certain embodiments, R ⁱⁱ Is H. In certain embodiments, R ⁱⁱ Is C ₁ -C ₃ An alkyl group. In certain embodiments, R ⁱⁱ Is C ₃ -C ₈ Cycloalkyl groups. In certain embodiments, R ⁱⁱ Is C ₁ -C ₃ An alkoxy group. In certain embodiments, R ⁱⁱ Is C ₁ -C ₆ A haloalkyl group. In certain embodiments, R ⁱⁱ Is C ₁ -C ₃ Haloalkoxy groups. In certain embodiments, R ⁱⁱ is-C (=O) C ₁ -C ₃ An alkyl group. In certain embodiments, R ⁱⁱ Is methyl. In certain embodiments, R ⁱⁱ is-C (=O) CH ₃ 。

In certain embodiments, R ⁱⁱⁱ Is H. In certain embodiments, R ⁱⁱⁱ Is C ₁ -C ₃ An alkyl group. In certain embodiments, R ⁱⁱⁱ Is C ₃ -C ₈ Cycloalkyl groups. In certain embodiments, R ⁱⁱⁱ Is C ₁ -C ₃ An alkoxy group. In certain embodiments, R ⁱⁱⁱ Is C ₁ -C ₆ A haloalkyl group. In certain embodiments, R ⁱⁱⁱ Is C ₁ -C ₃ Haloalkoxy groups. In certain embodiments, R ⁱⁱⁱ is-C (=O) C ₁ -C ₃ An alkyl group. In certain embodiments, R ⁱⁱⁱ Is methyl. In certain embodiments, R ⁱⁱⁱ is-C (=O) CH ₃ 。

In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->At a certain positionIn some embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn some embodimentsWherein R is ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->At a certain positionIn some embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->/>

In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In some casesIn embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is- >In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn some embodiments of the present invention, in some embodiments,R ^1d is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn some casesIn embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->

In certain embodiments, R ^a1 Is H. In certain embodiments, R ^a1 Is C ₁ -C ₆ An alkyl group. In certain embodiments, R ^a1 Is C ₃ -C ₈ Cycloalkyl groups. In certain embodiments, R ^a1 Is C ₁ -C ₆ An alkoxy group. In certain embodiments, R ^a1 Is C ₁ -C ₆ A haloalkyl group. In certain embodiments, R ^a1 Is C ₁ -C ₆ Haloalkoxy groups. In certain embodiments, R ^a1 Is methyl. In certain embodiments, R ^a1 Is ethyl. In certain embodiments, R ^a1 Is isopropyl. In certain embodiments, R ^a1 Is 2-methylpropyl.

In certain embodiments, R ^a2 Is H. In certain embodiments, R ^a2 Is C ₁ -C ₆ An alkyl group. In certain embodiments, R ^a2 Is C ₃ -C ₈ Cycloalkyl groups. In certain embodiments, R ^a2 Is C ₁ -C ₆ An alkoxy group. In certain embodiments, R ^a2 Is C ₁ -C ₆ A haloalkyl group. In certain embodiments, R ^a2 Is C ₁ -C ₆ Haloalkoxy groups. In certain embodiments, R ^a2 Is methyl. In certain embodiments, R ^a2 Is ethyl. In certain embodiments, R ^a2 Is isopropyl. In certain embodiments, R ^a2 Is 2-methylpropyl.

In some implementationsIn the example, R ^a3 Is H. In certain embodiments, R ^a3 Is C ₁ -C ₆ An alkyl group. In certain embodiments, R ^a3 Is C ₃ -C ₈ Cycloalkyl groups. In certain embodiments, R ^a3 Is C ₁ -C ₆ An alkoxy group. In certain embodiments, R ^a3 Is C ₁ -C ₆ A haloalkyl group. In certain embodiments, R ^a3 Is C ₁ -C ₆ Haloalkoxy groups. In certain embodiments, R ^a3 Is methyl. In certain embodiments, R ^a3 Is ethyl. In certain embodiments, R ^a3 Is isopropyl. In certain embodiments, R ^a3 Is 2-methylpropyl.

In certain embodiments, R ^a4 Is H. In certain embodiments, R ^a4 Is C ₁ -C ₆ An alkyl group. In certain embodiments, R ^a4 Is C ₃ -C ₈ Cycloalkyl groups. In certain embodiments, R ^a4 Is C ₁ -C ₆ An alkoxy group. In certain embodiments, R ^a4 Is C ₁ -C ₆ A haloalkyl group. In certain embodiments, R ^a4 Is C ₁ -C ₆ Haloalkoxy groups. In certain embodiments, R ^a4 Is methyl. In certain embodiments, R ^a4 Is ethyl. In certain embodiments, R ^a4 Is isopropyl. In certain embodiments, R ^a4 Is 2-methylpropyl.

In certain embodiments, R ^a5 Is H. In certain embodiments, R ^a5 Is C ₁ -C ₆ An alkyl group. In certain embodiments, R ^a5 Is C ₃ -C ₈ Cycloalkyl groups. In certain embodiments, R ^a5 Is C ₁ -C ₆ An alkoxy group. In certain embodiments, R ^a5 Is C ₁ -C ₆ A haloalkyl group. In certain embodiments, R ^a5 Is C ₁ -C ₆ Haloalkoxy groups. In certain embodiments, R ^a5 Is methyl. In certain embodiments, R ^a5 Is ethyl. In certain embodiments, R ^a5 Is isopropyl. In certain embodiments, R ^a5 Is 2-methylpropyl.

In certain embodiments, R ^a6 Is H. In certain embodiments, R ^a6 Is C ₁ -C ₆ An alkyl group. In certain embodiments, R ^a6 Is C ₃ -C ₈ Cycloalkyl groups. In certain embodiments, R ^a6 Is C ₁ -C ₆ An alkoxy group. In certain embodiments, R ^a6 Is C ₁ -C ₆ A haloalkyl group. In certain embodiments, R ^a6 Is C ₁ -C ₆ Haloalkoxy groups. In certain embodiments, R ^a6 Is methyl. In certain embodiments, R ^a6 Is ethyl. In certain embodiments, R ^a6 Is isopropyl. In certain embodiments, R ^a6 Is 2-methylpropyl.

In certain embodiments, R ^a7 Is H. In certain embodiments, R ^a7 Is C ₁ -C ₆ An alkyl group. In certain embodiments, R ^a7 Is C ₃ -C ₈ Cycloalkyl groups. In certain embodiments, R ^a7 Is C ₁ -C ₆ An alkoxy group. In certain embodiments, R ^a7 Is C ₁ -C ₆ A haloalkyl group. In certain embodiments, R ^a7 Is C ₁ -C ₆ Haloalkoxy groups. In certain embodiments, R ^a7 Is methyl. In certain embodiments, R ^a7 Is ethyl. In certain embodiments, R ^a7 Is isopropyl. In certain embodiments, R ^a7 Is 2-methylpropyl.

In certain embodiments, R ^b1 Is H. In certain embodiments, R ^b1 Is C ₁ -C ₆ An alkyl group. In certain embodiments, R ^b1 Is C ₃ -C ₈ Cycloalkyl groups. In certain embodiments, R ^b1 Is C ₁ -C ₆ An alkoxy group. In certain embodiments, R ^b1 Is cyano. In certain embodiments, R ^b1 Is halogen. In certain embodiments, R ^b1 Is C ₁ -C ₆ A haloalkyl group. In certain embodiments, R ^b1 Is C ₁ -C ₆ Haloalkoxy groups. In certain embodiments, R ^b1 Is methyl. In some embodiments，R ^b1 Is methoxy. In certain embodiments, R ^b1 Is chlorine. In certain embodiments, R ^b1 Is fluorine. In certain embodiments, R ^b1 Is ethoxy. In certain embodiments, R ^b1 Is trifluoromethyl. In certain embodiments, R ^b1 Is difluoromethoxy.

In certain embodiments, R ^b2 Is H. In certain embodiments, R ^b2 Is C ₁ -C ₆ An alkyl group. In certain embodiments, R ^b2 Is C ₃ -C ₈ Cycloalkyl groups. In certain embodiments, R ^b2 Is C ₁ -C ₆ An alkoxy group. In certain embodiments, R ^b2 Is cyano. In certain embodiments, R ^b2 Is halogen. In certain embodiments, R ^b2 Is C ₁ -C ₆ A haloalkyl group. In certain embodiments, R ^b2 Is C ₁ -C ₆ Haloalkoxy groups. In certain embodiments, R ^b2 Is methyl. In certain embodiments, R ^b2 Is methoxy. In certain embodiments, R ^b2 Is chlorine. In certain embodiments, R ^b2 Is fluorine. In certain embodiments, R ^b2 Is ethoxy. In certain embodiments, R ^b2 Is trifluoromethyl. In certain embodiments, R ^b2 Is difluoromethoxy.

In certain embodiments, R ^c1 Is H. In certain embodiments, R ^c1 Is C ₁ -C ₆ An alkyl group. In certain embodiments, R ^c1 Is C ₃ -C ₈ Cycloalkyl groups. In certain embodiments, R ^c1 Is C ₁ -C ₆ An alkoxy group. In certain embodiments, R ^c1 Is C ₁ -C ₆ A haloalkyl group. In certain embodiments, R ^c1 Is C ₁ -C ₆ Haloalkoxy groups. In certain embodiments, R ^c1 Is methyl.

In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In some embodiments of the present invention, in some embodiments,R ^1c is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In some embodimentsWherein R is ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In some embodiments of the present invention, in some embodiments,R ^1c is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In some embodimentsWherein R is ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In some casesIn embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->At a certain positionIn some embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is thatIn certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is->In certain embodiments, R ^1c Is that

In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In some casesIn embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->At a certain positionIn some embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In some implementationsIn the example, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is- >In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In some implementationsIn the example, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is thatIn certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->In certain embodiments, R ^1d Is->

In certain embodiments, the compound is selected from:

8- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -3- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4H-pyrido [1,2-a ] pyrimidin-4-one;

8- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -3- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4H-pyrido [1,2-a ] pyrimidin-4-one;

8- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -3- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4H-pyrido [1,2-a ] pyrimidin-4-one;

8- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -3- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4H-pyrido [1,2-a ] pyrimidin-4-one;

8- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4H-pyrido [1,2-a ] pyrimidin-4-one;

8- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4H-pyrido [1,2-a ] pyrimidin-4-one;

8- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4H-pyrido [1,2-a ] pyrimidin-4-one;

8- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4H-pyrido [1,2-a ] pyrimidin-4-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5 s, 5's) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (2-methoxy-4, 1-phenylene)) bis (methylene)) bis (azanediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 s,5' r) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (2-methoxy-4, 1-phenylene)) bis (methylene)) bis (azanediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 r, 5's) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (2-methoxy-4, 1-phenylene)) bis (methylene)) bis (azanediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 r,5' r) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (2-methoxy-4, 1-phenylene)) bis (methylene)) bis (azanediyl)) bis (methylene)) bis (pyrrolidin-2-one);

n- (1- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-yl) acetamide;

(S) -N- (1- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-yl) acetamide;

(R) -N- (1- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-yl) acetamide;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (((R) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (((R) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5 s, 5's) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (2-fluoro-6-methoxy-4, 1-phenylene)) bis (methylene)) bis (azanediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 s,5' r) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (2-fluoro-6-methoxy-4, 1-phenylene)) bis (methylene)) bis (azanediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 r, 5's) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (2-fluoro-6-methoxy-4, 1-phenylene)) bis (methylene)) bis (azanediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 r,5' r) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (2-fluoro-6-methoxy-4, 1-phenylene)) bis (methylene)) bis (azanediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((4- (3, 3' -dichloro-2 ' - (1-methyl-3- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indol-6-yl) - [4,4' -bipyridin ] -2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3, 3' -dichloro-2 ' - (1-methyl-3- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indol-6-yl) - [4,4' -bipyridin ] -2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3, 3' -dichloro-2 ' - (1-methyl-3- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indol-6-yl) - [4,4' -bipyridin ] -2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3, 3' -dichloro-2 ' - (1-methyl-3- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indol-6-yl) - [4,4' -bipyridin ] -2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(5 s, 5's) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (1-methyl-1H-indol-6, 3-diyl)) bis (methylene)) bis (azetidinediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 s,5' r) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (1-methyl-1H-indol-6, 3-diyl)) bis (methylene)) bis (azetidinediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 r, 5's) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (1-methyl-1H-indol-6, 3-diyl)) bis (methylene)) bis (azetidinediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 r,5' r) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (1-methyl-1H-indol-6, 3-diyl)) bis (methylene)) bis (azetidinediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(S) -5- (((4- (3, 3' -dichloro-2 ' - (1-methyl-3- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) - [4,4' -bipyridin ] -2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3, 3' -dichloro-2 ' - (1-methyl-3- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) - [4,4' -bipyridin ] -2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3, 3' -dichloro-2 ' - (1-methyl-3- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) - [4,4' -bipyridin ] -2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3, 3' -dichloro-2 ' - (1-methyl-3- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) - [4,4' -bipyridin ] -2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one;

(S) -5- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one;

(R) -5- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one;

(R) -5- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-4- (((S) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-4- (((R) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-4- (((S) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-4- (((R) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((5- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -3-methoxypyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((5- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -3-methoxypyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((5- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -3-methoxypyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((5- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -3-methoxypyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -oxetan-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((R) -oxetan-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -oxetan-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((R) -oxetan-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,3' -bipyridyl ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((S) -2-hydroxypropyl) -1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((R) -2-hydroxypropyl) -1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((S) -2-hydroxypropyl) -1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((R) -2-hydroxypropyl) -1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- ((S) -2-hydroxypropyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- ((R) -2-hydroxypropyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((S) -2-hydroxypropyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((R) -2-hydroxypropyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-indol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-indol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-hydroxyethyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-hydroxyethyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-methoxyethyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-methoxyethyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((methylamino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((methylamino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- ((ethylamino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- ((ethylamino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- ((dimethylamino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- ((dimethylamino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -oxetan-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((R) -oxetan-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -oxetan-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((R) -oxetan-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (((S) -2-hydroxypropyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3- ((((R) -2-hydroxypropyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (((S) -2-hydroxypropyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (((R) -2-hydroxypropyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-hydroxy-2-methylpropyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-hydroxy-2-methylpropyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one;

(S) -5- ((6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one;

(R) -5- ((6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one;

(R) -5- ((6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- ((isobutylamino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- ((isobutylamino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-hydroxyethyl) (methyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-hydroxyethyl) (methyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (((S) -2-methoxypropyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3- ((((R) -2-methoxypropyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (((S) -2-methoxypropyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3- ((((R) -2-methoxypropyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((((R) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((R) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -5-methoxy-1, 2,3, 4-tetrahydroisoquinolin-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -5-methoxy-1, 2,3, 4-tetrahydroisoquinolin-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -5-methoxy-1, 2,3, 4-tetrahydroisoquinolin-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -5-methoxy-1, 2,3, 4-tetrahydroisoquinolin-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxy-2-methylpropyl) -5-methoxy-1, 2,3, 4-tetrahydroisoquinolin-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxy-2-methylpropyl) -5-methoxy-1, 2,3, 4-tetrahydroisoquinolin-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (2-hydroxy-2-methylpropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (2-hydroxy-2-methylpropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (5-fluoro-2- (2-hydroxy-2-methylpropyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (5-fluoro-2- (2-hydroxy-2-methylpropyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(R) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (3-hydroxy-3-methylbutyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (3-hydroxy-3-methylbutyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (2- (1-hydroxycyclobutyl) ethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (2- (1-hydroxycyclobutyl) ethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (7- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) quinolin-3-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (7- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) quinolin-3-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (7- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) quinolin-3-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (7- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) quinolin-3-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxy-3-methylbutyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxy-3-methylbutyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (3- (((1-acetylazetidin-3-yl) amino) methyl) -1-methyl-1H-indol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (3- (((1-acetylazetidin-3-yl) amino) methyl) -1-methyl-1H-indol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-indol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-indol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (4- (3- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (4- (3- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((((S) -oxetan-2-yl) methyl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((((R) -oxetan-2-yl) methyl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((((S) -oxetan-2-yl) methyl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((((R) -oxetan-2-yl) methyl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (((R) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (((R) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (3- (2- (2- ((1-acetylpiperidin-4-yl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (2- ((1-acetylpiperidin-4-yl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (2- (piperidin-4-yl) ethyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (2- (piperidin-4-yl) ethyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (3-fluoropropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (3-fluoropropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

5- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (((R) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (((R) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -L-proline isopropyl ester;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -D-proline isopropyl ester;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -L-proline isopropyl ester;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -D-proline isopropyl ester;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- ((S) -2-hydroxypropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- ((R) -2-hydroxypropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- ((S) -2-hydroxypropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- ((R) -2-hydroxypropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4-chloro-6- (2-chloro-3- (3-chloro-2- (4- ((((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4-chloro-6- (2-chloro-3- (3-chloro-2- (4- ((((R) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4-chloro-6- (2-chloro-3- (3-chloro-2- (4- ((((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4-chloro-6- (2-chloro-3- (3-chloro-2- (4- ((((R) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (3-fluoropropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (3-fluoropropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (((4, 4-difluorocyclohexyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((4, 4-difluorocyclohexyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (2- (1-hydroxycyclopropyl) ethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (2- (1-hydroxycyclopropyl) ethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((R) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((R) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid isopropyl ester;

(S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid isopropyl ester;

(R) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid isopropyl ester;

(R) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid isopropyl ester;

(S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid;

(S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid;

(R) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid;

(R) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -L-proline;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -D-proline;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -L-proline;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -D-proline;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((1R, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((1R, 3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((1 s, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((1S, 3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((1 r, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((1S, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((S) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((S) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((R) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((R) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((isopropylamino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((isopropylamino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((isobutylamino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((isobutylamino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

2- (((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethan-1-ol;

2- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (2- (piperidin-4-yl) ethyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethan-1-ol;

(S) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((1R, 3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((1 s, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((1S, 3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((1 r, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((1R, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((1S, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(S) -2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] oct-7-one;

1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((S) -2-hydroxypropyl) amino) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (((((R) -2-hydroxypropyl) amino) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((S) -2-hydroxypropyl) amino) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (((((R) -2-hydroxypropyl) amino) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(S) -5- (((4- (4- (3- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (4- (3- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((((S) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((((R) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((((S) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((((R) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- ((methylamino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- ((methylamino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (4- (3- (3- (((1-acetylazetidin-3-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (4- (3- (3- (((1-acetylazetidin-3-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((4, 4-difluorocyclohexyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((4, 4-difluorocyclohexyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((2-hydroxyethyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((2-hydroxyethyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (3- ((((S) -2-hydroxypropyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (3- ((((R) -2-hydroxypropyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (3- ((((S) -2-hydroxypropyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (3- ((((R) -2-hydroxypropyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((2-hydroxy-2-methylpropyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((2-hydroxy-2-methylpropyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((2-methoxyethyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((2-methoxyethyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((2-hydroxyethyl) (methyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((2-hydroxyethyl) (methyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (((3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(R) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (((3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3-methyl-2- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3-methyl-2- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3-methyl-2- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3-methyl-2- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(S) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) - (4- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) glycine;

(R) - (4- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) glycine;

3-chloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) -2- (4, 5-dihydro-1H-imidazol-2-yl) -3-methoxyphenyl) pyridine;

(S) - (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) glycine;

(R) - (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) glycine;

(S) - (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) glycine isopropyl ester;

(R) - (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) glycine isopropyl ester;

(S) -5- ((((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(R) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((isopropylamino) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(R) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((isopropylamino) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(5S) -5- (((6- (2-chloro-3- (3-chloro-2- (5- (((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5S) -5- (((6- (2-chloro-3- (3-chloro-2- (5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5R) -5- (((6- (2-chloro-3- (3-chloro-2- (5- (((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5R) -5- (((6- (2-chloro-3- (3-chloro-2- (5- (((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5S) -5- ((((6- (2-chloro-3- (3-chloro-2- (5- (((S) -2-hydroxypropyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5S) -5- (((6- (2-chloro-3- (3-chloro-2- (5- (((R) -2-hydroxypropyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5R) -5- (((6- (2-chloro-3- (3-chloro-2- (5- (((S) -2-hydroxypropyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5R) -5- (((6- (2-chloro-3- (3-chloro-2- (5- (((R) -2-hydroxypropyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxy-5-methylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((R) -2-hydroxypropyl) amino) methyl) -3-methoxy-5-methylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxy-5-methylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((R) -2-hydroxypropyl) amino) methyl) -3-methoxy-5-methylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5-methyl-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5-methyl-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5-methyl-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5-methyl-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5-methyl-4- ((methyl (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5-methyl-4- ((methyl (((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5-methyl-4- ((methyl (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5-methyl-4- ((methyl (((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxy-5-methylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((R) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxy-5-methylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxy-5-methylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((R) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxy-5-methylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (1- (azetidin-3-yl) -1H-pyrazol-4-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (1- (azetidin-3-yl) -1H-pyrazol-4-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (1- (azetidin-3-ylmethyl) -1H-pyrazol-4-yl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (1- (azetidin-3-ylmethyl) -1H-pyrazol-4-yl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -1- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid;

(R) -1- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((S) -oxetan-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -oxetan-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -oxetan-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -oxetan-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) - (4- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) glycine isopropyl ester;

(R) - (4- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) glycine isopropyl ester;

(S) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -L-alanine isopropyl ester;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -D-alanine isopropyl ester;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -L-alanine isopropyl ester;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -D-alanine isopropyl ester;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -L-alanine;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -D-alanine;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -L-alanine;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -D-alanine;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (((1 r,3 r) -3-hydroxycyclobutyl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (((1S, 3S) -3-hydroxycyclobutyl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (((1S, 3 r) -3-hydroxycyclobutyl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (((1 s,3 s) -3-hydroxycyclobutyl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (((1 r,3 r) -3-hydroxycyclobutyl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (((1 s, 3R) -3-hydroxycyclobutyl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (((1R, 3 s) -3-hydroxycyclobutyl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (((1R, 3R) -3-hydroxycyclobutyl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -1- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid isopropyl ester;

(R) -1- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid isopropyl ester;

1- (6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine;

1- (6- (2-chloro-3- (3-chloro-2- (4- ((dimethylamino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N, N-dimethylamine;

2- (((6- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxyethyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) ethan-1-ol;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indol-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indol-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

5- (3-chloro-4- (2-chloro-3- (5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3- (5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3- (5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3- (5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

(S) -5- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (2- (((5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

(R) -5- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (2- (((5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

(S) -5- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (2- (((5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

(R) -5- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (2- (((5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

(S) -2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-fluoro-6-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-fluoro-6-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- (((3-fluoropropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- (((3-fluoropropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

methyl (S) -2- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) acetate;

methyl (R) -2- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) acetate;

(S) -2- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) acetic acid;

(R) -2- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) acetic acid;

(S) -5- (((6- (3- (2- (2- ((1R, 3S, 4S) -2-azabicyclo [2.2.1] heptan-3-yl) -1H-benzo [ d ] imidazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (3- (2- (2- ((1R, 3S, 4S) -2-azabicyclo [2.2.1] heptan-3-yl) -1H-benzo [ d ] imidazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (3- (2- (2- ((1R, 3R, 4S) -2-azabicyclo [2.2.1] heptan-3-yl) -1H-benzo [ d ] imidazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (3- (2- (2- ((1R, 3R, 4S) -2-azabicyclo [2.2.1] heptan-3-yl) -1H-benzo [ d ] imidazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (3- (2- (2- ((1S, 3S,4 r) -2-azabicyclo [2.2.1] heptan-3-yl) -1H-benzo [ d ] imidazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (3- (2- (2- ((1 s,3s, 4R) -2-azabicyclo [2.2.1] heptan-3-yl) -1H-benzo [ d ] imidazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (3- (2- (2- ((1S, 3r,4 r) -2-azabicyclo [2.2.1] heptan-3-yl) -1H-benzo [ d ] imidazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (3- (2- (2- ((1 s,3R, 4R) -2-azabicyclo [2.2.1] heptan-3-yl) -1H-benzo [ d ] imidazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- (((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -5-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (6- (2-chloro-3- (3-chloro-2- (3-methoxy-5- ((methylamino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine;

chloro-3- (3-chloro-2- (3- (((2-hydroxyethyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethan-1-ol;

(S) -1- (((6- (2-chloro-3- (3-chloro-2- (3- (((S) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(S) -1- (((6- (2-chloro-3- (3-chloro-2- (3- ((((R) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (2-chloro-3- (3-chloro-2- (3- ((((S) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (2-chloro-3- (3-chloro-2- (3- ((((R) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(S) -5- ((((3 ' -chloro-2 ' - ((S) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((S) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((R) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((S) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((R) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((S) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((R) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((R) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (((6- (((S) -4- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((S) -4- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -4- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -4- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

methyl 1- (((6- (((S) -4- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylate;

methyl 1- (((6- (((S) -4- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylate;

methyl 1- (((6- (((R) -4- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylate;

methyl 1- (((6- (((R) -4- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylate;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indol-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indol-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine;

2- (((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethan-1-ol;

(S) -1- (((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) piperidin-1-yl) ethan-1-one;

1- (((6- (((S) -4- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((S) -4- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -4- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -4- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

(S) -5- ((((3 ' -chloro-2 ' - ((S) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((S) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((R) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((R) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((R) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((S) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((S) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((R) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -4- ((3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) amino) -3-hydroxybutyric acid;

(R) -4- ((3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) amino) -3-hydroxybutyric acid;

3- ((3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) amino) propanoic acid;

(S) -1- (3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) pyrrolidine-3-carboxylic acid;

(R) -1- (3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) pyrrolidine-3-carboxylic acid;

2- (1- (3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) azetidin-3-yl) acetic acid;

2- (3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) -2-azaspiro [3.3] heptane-6-carboxylic acid;

3- ((3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) amino) bicyclo [1.1.1] pentane-1-carboxylic acid;

3- (((3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) amino) methyl) bicyclo [1.1.1] pentane-1-carboxylic acid;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] sulfazepin) -8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] sulfan-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

5- (3-chloro-4- (2-chloro-3- (4-fluoro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3- (4-fluoro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3- (4-fluoro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3- (4-fluoro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4, 5-dihydro-1H-imidazol-2-yl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (4, 5-dihydro-1H-imidazol-2-yl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -4- ((4- (3-chloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) amino) -3-hydroxybutyric acid;

(R) -4- ((4- (3-chloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) amino) -3-hydroxybutyric acid;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((S) -oxetan-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((R) -oxetan-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((S) -oxetan-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((S) -oxetan-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2,1-f ] [1,2,4] triazin-2-yl) methyl) azetidine-3-carboxylic acid methyl ester;

(R) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2,1-f ] [1,2,4] triazin-2-yl) methyl) azetidine-3-carboxylic acid methyl ester;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- ((S) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- ((S) -5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- ((S) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (((6- (((S) -5- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((S) -5- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

(S) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

2- ((6- (((S) -5- (3 ' -chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((S) -5- (3 ' -chloro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3 ' -chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3 ' -chloro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -N- (5- (3 ' -chloro-6-methoxy-5- ((methylamino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine;

(R) -N- (5- (3 ' -chloro-6-methoxy-5- ((methylamino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine;

1- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

(S) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -5- (3-chloro-2- (3-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -5- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

2- ((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -N- (5- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine;

(R) -N- (5- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine;

1- (((6- (((S) -5- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((S) -5- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

(S) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

2- ((6- (((S) -5- (3 ' -chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((S) -5- (3 ' -chloro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((S) -5- (3 ' -chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3 ' -chloro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -1- (3 ' -chloro-6-methoxy-2 ' - (5- ((6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) -N-methyl methylamine;

(R) -1- (3 ' -chloro-6-methoxy-2 ' - (5- ((6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) -N-methyl methylamine;

1- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

(S) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -5- (3-chloro-2- (3-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -5- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

2- ((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -1- (6- ((5- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) -N-methyl methylamine;

(R) -1- (6- ((5- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) -N-methyl methylamine;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (8-chloro-6- ((((S) -2-hydroxypropyl) amino) methyl) -5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (8-chloro-6- ((((R) -2-hydroxypropyl) amino) methyl) -5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (8-chloro-6- ((((S) -2-hydroxypropyl) amino) methyl) -5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (8-chloro-6- ((((R) -2-hydroxypropyl) amino) methyl) -5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((8-chloro-2- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5-methoxyquinolin-6-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((8-chloro-2- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5-methoxyquinolin-6-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((8-chloro-2- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5-methoxyquinolin-6-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((8-chloro-2- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5-methoxyquinolin-6-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (3-hydroxy-3-methylbutyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (3-hydroxy-3-methylbutyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -4- ((4- (3-chloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) amino) -3-hydroxybutyric acid isopropyl ester;

(R) -4- ((4- (3-chloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) amino) -3-hydroxybutyric acid isopropyl ester;

(S) -5- (((6- (3- (2- (4- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (4- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

n- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) propan-2-amine;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -1- (((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(S) -1- (((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(1 r,3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3R) -3- (((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r, 3S) -3- (((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1S, 3S) -3- (((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 s) -3- (((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s, 3R) -3- (((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1S, 3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3 s) -3- (((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(S) -1- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol;

(S) -1- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol;

(R) -1- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol;

(R) -1- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol;

(S) -1- ((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -3-methylazetidin-3-ol;

(R) -1- ((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -3-methylazetidin-3-ol;

(S) - ((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) glycine methyl ester;

(R) - ((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) glycine methyl ester;

(S) -2- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) -3-hydroxybutyric acid;

(R) -4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) -3-hydroxybutyric acid;

3- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) propanoic acid;

6- (3-chloro-4- (2-chloro-3- (5- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -N- (4- (3 ' -chloro-6-methoxy-5- ((methylamino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine;

(R) -N- (4- (3 ' -chloro-6-methoxy-5- ((methylamino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine;

(1S, 3 r) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1 r, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3R) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1R, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3R) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1R, 3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3R) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1 s, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3R) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 r) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 r) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1 r, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 r) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1S, 3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 r) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1S, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3 s) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1R, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3 s) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1R, 3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3 s) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1 s, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3 s) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3R) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1R, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r, 3S) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1 r, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r, 3S) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1S, 3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r, 3S) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1S, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s, 3R) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1R, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s, 3R) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1R, 3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s, 3R) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1 s, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s, 3R) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1S, 3 r) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1S, 3 r) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1S, 3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1S, 3 r) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1S, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 s) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1R, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 s) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1R, 3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 s) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1 s, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 s) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s, 3R) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1R, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1S, 3S) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1 r, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1S, 3S) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1S, 3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1S, 3S) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1S, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid;

(R) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -2-azaspiro [3.3] heptane-6-carboxylic acid;

3- (((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) bicyclo [1.1.1] pentane-1-carboxylic acid;

(S) - ((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) glycine;

(R) - ((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) glycine;

2- ((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

6- (3-chloro-4- (2-chloro-3- (5- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (5- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (5- ((((1 r,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (5- ((((1 s,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (5- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (5- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (5- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (5- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (5- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -oxetan-2-yl) methyl) amino) methyl) -1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((((R) -oxetan-2-yl) methyl) amino) methyl) -1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -oxetan-2-yl) methyl) amino) methyl) -1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((R) -oxetan-2-yl) methyl) amino) methyl) -1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((8-chloro-2- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5-methoxyquinolin-6-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((8-chloro-2- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5-methoxyquinolin-6-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((8-chloro-2- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5-methoxyquinolin-6-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((8-chloro-2- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5-methoxyquinolin-6-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (3- (2- (4- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (4- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (8-chloro-6- (((2-hydroxyethyl) amino) methyl) -5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (8-chloro-6- (((2-hydroxyethyl) amino) methyl) -5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -1- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) pyrrolidine-3-carboxylic acid;

(R) -1- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) pyrrolidine-3-carboxylic acid;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -5- (((4- (4- (3- (6- (((1-acetylpiperidin-4-yl) amino) methyl) -8-chloro-5-methoxyquinolin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (4- (3- (6- (((1-acetylpiperidin-4-yl) amino) methyl) -8-chloro-5-methoxyquinolin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

5- (3-chloro-4- (2-chloro-3 '-fluoro-5' -methoxy-4 '- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,1' -biphenyl ] -3-yl) pyridin-2-yl) -2- (2- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3 '-fluoro-5' -methoxy-4 '- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,1' -biphenyl ] -3-yl) pyridin-2-yl) -2- (2- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3 '-fluoro-5' -methoxy-4 '- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,1' -biphenyl ] -3-yl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3 '-fluoro-5' -methoxy-4 '- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,1' -biphenyl ] -3-yl) pyridin-2-yl) -2- (2- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

2- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2-azaspiro [3.3] heptane-6-carboxylic acid;

2- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -1- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) pyrrolidine-3-carboxylic acid isopropyl ester;

(R) -1- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) pyrrolidine-3-carboxylic acid isopropyl ester;

1- (4- ((4- (4- (3- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-hydroxyethyl) (methyl) amino) methyl) -1-methyl-1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-hydroxyethyl) (methyl) amino) methyl) -1-methyl-1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -1- (6- ((6- ((4- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

(R) -1- (6- ((6- ((4- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

1- (6- ((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

2- ((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

n- ((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2-oxaspiro [3.3] heptane-6-amine;

(1- ((((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) cyclopropyl) methanol;

(S) -1- (((3 ' -chloro-2 ' - ((S) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) propan-2-ol;

(S) -1- (((3 ' -chloro-2 ' - ((R) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) propan-2-ol;

(S) -1- (((3 ' -chloro-2 ' - ((R) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) propan-2-ol;

(S) -1- (((3 ' -chloro-2 ' - ((S) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) propan-2-ol;

(R) -1- (((3 ' -chloro-2 ' - ((R) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) propan-2-ol;

(R) -1- (((3 ' -chloro-2 ' - ((R) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) propan-2-ol;

(R) -1- (((3 ' -chloro-2 ' - ((S) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) propan-2-ol;

(R) -1- (((3 ' -chloro-2 ' - ((S) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) propan-2-ol;

(S) -1- (4- (((6- ((4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(R) -1- (4- (((6- ((4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- ((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- ((S) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- ((S) -5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -5- ((((R) -6- (3-chloro-4- (2-chloro-3- (5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((R) -6- (3-chloro-4- (2-chloro-3- (5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((S) -6- (3-chloro-4- (2-chloro-3- (5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((S) -6- (3-chloro-4- (2-chloro-3- (5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((R) -6- (3-chloro-4- (2-chloro-3- (5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((R) -6- (3-chloro-4- (2-chloro-3- (5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((S) -6- (3-chloro-4- (2-chloro-3- (5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((S) -6- (3-chloro-4- (2-chloro-3- (5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((R) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((R) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((R) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((R) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((R) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((R) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((((1S, 4S) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((((1S, 4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r, 4S) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((((1R, 4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s, 4R) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((((1R, 4R) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) azetidine-3-carboxylic acid;

(R) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) azetidine-3-carboxylic acid;

(S) -1- (2- (((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) ethyl) cyclopropane-1-carboxylic acid;

(R) -1- (2- (((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) ethyl) cyclopropane-1-carboxylic acid;

1- (4- (((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- ((4- (4- (3- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -L-homoserine;

((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -L-homoserine;

((6- (2-chloro-3- (3-chloro-2- ((S) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -L-homoserine;

((6- (2-chloro-3- (3-chloro-2- ((S) -5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -L-homoserine;

((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -D-homoserine;

((6- (2-chloro-3- (3-chloro-2- ((S) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -D-homoserine;

((6- (2-chloro-3- (3-chloro-2- ((S) -5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -D-homoserine;

((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -D-homoserine;

(5 s, 5's) -5,5' - ((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (8-methoxy-3, 4-dihydroisoquinoline-6, 2 (1H) -diyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 s,5' r) -5,5' - ((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (8-methoxy-3, 4-dihydroisoquinoline-6, 2 (1H) -diyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 r, 5's) -5,5' - ((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (8-methoxy-3, 4-dihydroisoquinoline-6, 2 (1H) -diyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 r,5' r) -5,5' - ((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (8-methoxy-3, 4-dihydroisoquinoline-6, 2 (1H) -diyl)) bis (methylene)) bis (pyrrolidin-2-one);

((3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) -5' -methoxy- [2,3' -bipyridin ] -6' -yl) methyl) -L-homoserine methyl ester;

((3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) -5' -methoxy- [2,3' -bipyridin ] -6' -yl) methyl) -L-homoserine methyl ester;

((3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) -5' -methoxy- [2,3' -bipyridin ] -6' -yl) methyl) -D-homoserine methyl ester;

((3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) -5' -methoxy- [2,3' -bipyridin ] -6' -yl) methyl) -D-homoserine methyl ester;

(S) -5- (((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((((S) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((((R) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((((S) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((((R) -2-oxotetrahydrofuran-3-yl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (((S) -4- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (((S) -4- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (((R) -4- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (((S) -4- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -4- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -4- (3-chloro-2- (3-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((R) -4- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -4- (3-chloro-2- (3-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -1- (((6- (((S) -4- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) propan-2-ol;

(S) -1- (((6- (((S) -4- (3-chloro-2- (4- (((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) propan-2-ol;

(S) -1- (((6- (((R) -4- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) propan-2-ol;

(S) -1- (((6- (((R) -4- (3-chloro-2- (4- (((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (((S) -4- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (((S) -4- (3-chloro-2- (4- (((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (((R) -4- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (((R) -4- (3-chloro-2- (4- (((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) propan-2-ol;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -3- (6- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propionic acid methyl ester;

(R) -methyl 3- (6- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propanoate;

methyl 3- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propanoate;

(S) -1- (((6- (2-chloro-3- (2- (4- ((((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(S) -1- (((6- (2-chloro-3- (2- (4- ((((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (2-chloro-3- (2- (4- ((((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (2-chloro-3- (2- (4- ((((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(S) -2- (6- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) acetamide;

(R) -2- (6- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) acetamide;

1- (6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((methylamino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine;

1- (4- (((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-indol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid isopropyl ester;

(R) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid isopropyl ester;

Isopropyl 3- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) propionate;

(S) -4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) -3-hydroxybutyric acid isopropyl ester;

(R) -4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) -3-hydroxybutyric acid isopropyl ester;

isopropyl 2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -2-azaspiro [3.3] heptane-6-carboxylate;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-fluorophenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((methylamino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine;

2- ((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methylamine;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-fluoro-6-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one;

(S) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-indazol-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-indazol-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -5- (((6- (3- (2- (2- ((1-acetylpiperidin-4-yl) methyl) -8-chloro-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (2- ((1-acetylpiperidin-4-yl) methyl) -8-chloro-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) -1, 2-dihydro-3H-pyrrolo [3,4-c ] pyridin-3-one;

6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2- (2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) -1, 2-dihydro-3H-pyrrolo [3,4-c ] pyridin-3-one;

6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) -1, 2-dihydro-3H-pyrrolo [3,4-c ] pyridin-3-one;

6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2- (2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) -1, 2-dihydro-3H-pyrrolo [3,4-c ] pyridin-3-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) imidazo [1,2-a ] pyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) imidazo [1,2-a ] pyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) imidazo [1,2-a ] pyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) imidazo [1,2-a ] pyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -2- (4- (3-chloro-4- (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one;

(R) -2- (4- (3-chloro-4- (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one;

(S) -3- (6- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propionic acid;

(R) -3- (6- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propionic acid;

3- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propionic acid;

1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) cyclopropane-1-carboxylic acid methyl ester;

2- ((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoro-2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -2- ((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoro-2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- ((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoro-2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) cyclopropane-1-carboxylic acid;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

1, 1-dioxo 4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) tetrahydro-2H-thiopyran;

1- (3- (((6- (3- (2- (4- (((1-acetylazetidin-3-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) azetidin-1-one;

(S) -1- (((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(S) -1- (((6- (2-chloro-3- (3-chloro-2- (4- (((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (2-chloro-3- (3-chloro-2- (4- (((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

2- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((5-oxo-6-azaspiro [3.4] oct-2-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) -6-azaspiro [3.4] octan-5-one;

1- (2- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((2- (2-oxopyrrolidin-1-yl) ethyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethyl) pyrrolidin-2-one;

(S) -2- ((3 ' -chloro-6-methoxy-2 ' - (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one;

(R) -2- ((3 ' -chloro-6-methoxy-2 ' - (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one;

(S) -1- (6- ((5- ((4- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxy-6- (trifluoromethyl) pyrazin-2-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

(R) -1- (6- ((5- ((4- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxy-6- (trifluoromethyl) pyrazin-2-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

(S) -2- (4- (3-chloro-4- (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-2-yl) -2-fluoro-6-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one;

(R) -2- (4- (3-chloro-4- (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-2-yl) -2-fluoro-6-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (oxetan-3-ylmethyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (oxetan-3-ylmethyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (3- (2- (3- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (3- (2- (3- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-indazol-3-yl) methyl) pyrrolidine-3-carboxylic acid;

(S) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-indazol-3-yl) methyl) pyrrolidine-3-carboxylic acid;

(R) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-indazol-3-yl) methyl) pyrrolidine-3-carboxylic acid;

(R) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-indazol-3-yl) methyl) pyrrolidine-3-carboxylic acid;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) imidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) imidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) imidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) imidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

1- (4- (((5- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -3-methoxypyrazin-2-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1S, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1S, 3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1R, 3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1R, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1,1'- ((((3, 3' -dichloro- [4,4 '-bipyridine ] -2,2' -diyl) bis (2-fluoro-6-methoxy-4, 1-phenylene)) bis (methylene)) bis (azanediyl)) bis (piperidin-4, 1-diyl)) bis (ethane-1-one);

(S) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (cyclopropanecarbonyl) piperidin-4-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (cyclopropyl) methanone;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (2- (((1-acetylpiperidin-4-yl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (2- (((1-acetylpiperidin-4-yl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (3- (2- (2- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (2- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) -2, 5-diazaspiro [3.4] octan-6-one;

(R) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) -2, 5-diazaspiro [3.4] octan-6-one;

(S) -5- ((((6- (3- (2- (2- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (2- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

n- (1- ((6- (3- (2- (4- ((4-acetamidopiperidin-1-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

2,2'- ((3, 3' -dichloro- [4,4 '-bipyridine ] -2,2' -diyl) bis (2-fluoro-6-methoxy-4, 1-phenylene)) bis (methylene)) bis (2, 6-diazaspiro [3.4] octan-7-one);

2- (4- (4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) -3-fluoropyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

n- (1- (4- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) piperidin-4-yl) acetamide;

n- ((6- (2-chloro-3- (3-chloro-2- (4- (((1-isopropylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1-isopropylpiperidin-4-amine;

n- ((6- (2-chloro-3- (3-chloro-2- (4- (((4, 4-difluorocyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4, 4-difluorocyclohexane-1-amine;

2- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (2-hydroxyethyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-ol;

n- (2- (((6- (3- (2- (4- (((2-acetamidoethyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) ethyl) acetamide;

1- (6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((tetrahydro-2H-pyran-4-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N- ((tetrahydro-2H-pyran-4-yl) methyl) methylamine;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((1-propionylpiperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

2- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (4- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) piperidin-1-yl) ethan-1-one;

1- (6- (2-chloro-3- (2- (3-methoxy-4- ((methylamino) methyl) phenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methylamine;

(S) -5- ((((6- (3- (2- (4- ((S) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (4- ((S) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (4- ((R) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (4- ((R) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -2- ((3 ' -chloro-6-methoxy-2 ' - (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one;

(R) -2- ((3 ' -chloro-6-methoxy-2 ' - (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-fluoropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -4- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) dihydrofuran-2 (3H) -one;

(R) -4- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) dihydrofuran-2 (3H) -one;

(S) -3- ((methyl 4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) -4-hydroxybutyrate;

(R) -3- ((methyl 4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) -4-hydroxybutyrate;

(S) -3- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) dihydrofuran-2 (3H) -one;

(R) -3- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) dihydrofuran-2 (3H) -one;

n- (1- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

(S) -3- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) -4-hydroxybutyric acid;

(R) -3- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) -4-hydroxybutyric acid;

(4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -L-homoserine;

(4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -D-homoserine;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1-propionylpiperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) propan-1-one;

(4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (cyclopropanecarbonyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (cyclopropyl) methanone;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1-isobutyrylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methylpropan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- (((1-isobutyrylpiperidin-4-yl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methylpropan-1-one;

n- ((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

1, 1-dioxo 4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) tetrahydro-2H-thiopyran;

(S) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) azetidine-3-carboxylic acid;

(R) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) azetidine-3-carboxylic acid;

(S) -1- (2- (((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) amino) ethyl) cyclopropane-1-carboxylic acid;

(R) -1- (2- (((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) amino) ethyl) cyclopropane-1-carboxylic acid;

(4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (cyclobutanecarbonyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (cyclobutyl) methanone;

7- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((2-oxo-1, 7-diazaspiro [3.5] nonan-7-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -1, 7-diazaspiro [3.5] nonan-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

n- (1- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

(R) -N- (1- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

(S) -N- (1- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

(S) -N- (1- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

(R) -N- (1- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

n- (3- (((6- (3- (2- (4- (((3-acetamidopropyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) propyl) acetamide;

4- (((6- (2-chloro-3- (3-chloro-2- (4- (((2, 6-dioxopiperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidine-2, 6-dione;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (2-methoxy-4- (4- (3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) -2-methylphenyl) -3-methylpyridin-2-yl) phenyl) -N-methylamine;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

n- (4- (4- (3- (5- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2-oxaspiro [3.3] heptan-6-amine;

(S) -2- (4- (3-chloro-4- (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one;

(R) -2- (4- (3-chloro-4- (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one;

(S) -1- (6- ((5- ((4- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxy-6- (trifluoromethyl) pyrazin-2-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

(R) -1- (6- ((5- ((4- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxy-6- (trifluoromethyl) pyrazin-2-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

2- (4- (4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) -3-methylpyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1R, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1R, 3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1S, 3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1S, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

1- (4- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) piperidin-1-yl) -2-methylpropan-1-one;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (methylsulfonyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (methylsulfonyl) piperidin-4-amine;

5- (((6- (3- (2- (4- (((5-amino-5-oxopentyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) pentanoylalkane;

1- ((R) -3- (((6- (3- (2- (4- ((((R) -1-acetylpyrrolidin-3-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-1-yl) ethan-1-one;

1- ((S) -3- (((6- (3- (2- (4- ((((R) -1-acetylpyrrolidin-3-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-1-yl) ethan-1-one;

1- ((R) -3- (((6- (3- (2- (4- ((((S) -1-acetylpyrrolidin-3-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-1-yl) ethan-1-one;

1- ((S) -3- (((6- (3- (2- (4- ((((S) -1-acetylpyrrolidin-3-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-1-yl) ethan-1-one;

1- (4- (((6- (3- (6 ' - ((1-acetylpiperidin-4-yl) amino) methyl) -3-chloro-5 ' -methoxy- [2,3' -bipyridin ] -4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- ((3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) -5' -methoxy- [2,3' -bipyridin ] -6' -yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -N- (1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-3-yl) methyl) piperidin-4-yl) acetamide;

(R) -N- (1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-3-yl) methyl) piperidin-4-yl) acetamide;

(S) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (4- (((6- (3- (2- (4- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (3- (2- (4- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((3, 3-dimethylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methylpropan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (methylsulfonyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1R, 4R) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1R, 4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s, 4R) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r, 4S) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1S, 4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1S, 4S) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(1 r,3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 s) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 s) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 s) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 s) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 s) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 s) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 s) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 s) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2-azaspiro [3.3] heptan-6-ol;

6- (4- (4- (3- (5- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2-oxa-6-azaspiro [3.3] heptane;

(S) -1- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) pyrrolidine-3-carboxylic acid;

(R) -1- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) pyrrolidine-3-carboxylic acid;

3- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) propanoic acid;

3- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) propanoic acid;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -1- (6- (3- (2- (4- ((S) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethan-1-amine;

(R) -1- (6- (3- (2- (4- ((S) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethan-1-amine;

(S) -1- (6- (3- (2- (4- ((R) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethan-1-amine;

(R) -1- (6- (3- (2- (4- ((R) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethan-1-amine;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3- (difluoromethoxy) phenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (6- (3- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine;

1- ((6- (2-chloro-3- (3-chloro-2- (4- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -3-methylazetidin-3-ol;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (2-methoxyacetyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methoxyethan-1-one;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6-oxo-2, 5-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2, 5-diazaspiro [3.4] oct-6-one;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

N- (1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) piperidin-4-yl) acetamide;

n- (1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6-oxo-2, 5-diazaspiro [3.4] octane-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) piperidin-4-yl) acetamide;

n- (1- (4- (4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) piperidin-4-yl) acetamide;

(S) -N- (1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) piperidin-4-yl) acetamide;

(R) -N- (1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) piperidin-4-yl) acetamide;

2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) nicotinonitrile;

(S) -4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-3-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-3-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-3-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-3-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- (((6- (3- (2- (4- ((4-amino-4-methylpiperidin-1-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -4- (((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) methyl) pyrrolidin-2-one;

(R) -4- (((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) methyl) pyrrolidin-2-one;

2- (4- (3-chloro-4- (3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) -2-methylphenyl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

4- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (morpholinomethyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) morpholine;

1- ((6- (2-chloro-3- (3-chloro-2- (4- ((4-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-ol;

1- (4- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) piperidin-1-yl) -2-methoxyethan-1-one;

(S) -5- (((6- (2-chloro-3- (2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (2- (3-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

2- (2-methoxy-4- (4- (3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) -2-methylphenyl) -3-methylpyridin-2-yl) benzyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((piperidin-4-ylamino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1-methyl-2-oxopiperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylpiperidin-2-one;

4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (dimethylcarbamoyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -N, N-dimethylpiperidine-1-carboxamide;

N- ((6- (2-chloro-3- (3-chloro-2- (4- (((1- (2, 2-difluoroethyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (2, 2-difluoroethyl) piperidin-4-amine;

(4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (furan-2-carbonyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (furan-2-yl) methanone;

(4- (((6- (3- (2- (4- (((1-benzoylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (phenyl) methanone;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1-phenylpiperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1-phenylpiperidin-4-amine;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (piperidin-4-yl) piperidin-4-amine;

n- (2-methoxy-4- (4- (3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) -2-methylphenyl) -3-methylpyridin-2-yl) benzyl) tetrahydro-2H-pyran-4-amine;

N- ((6- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (6- ((6- (3- (6 ' - ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-chloro-5 ' -methoxy- [2,3' -bipyridin ] -4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

n- ((4- (3- (5- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloro-5 ' -methoxy- [2,3' -bipyridin ] -6' -yl) methyl) -2-oxaspiro [3.3] heptan-6-amine;

2- ((3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6-oxo-2, 5-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) -5' -methoxy- [2,3' -bipyridin ] -6' -yl) methyl) -2, 5-diazaspiro [3.4] octan-6-one;

n- ((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

N- (1- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) -2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) nicotinonitrile;

4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) -2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) nicotinonitrile;

(S) -1- ((6- (2-chloro-3- (3-chloro-2- (4- (((S) -3-hydroxypyrrolidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) pyrrolidin-3-ol;

(S) -1- ((6- (2-chloro-3- (3-chloro-2- (4- (((R) -3-hydroxypyrrolidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) pyrrolidin-3-ol;

(R) -1- ((6- (2-chloro-3- (3-chloro-2- (4- (((S) -3-hydroxypyrrolidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) pyrrolidin-3-ol;

(R) -1- ((6- (2-chloro-3- (3-chloro-2- (4- (((R) -3-hydroxypyrrolidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) pyrrolidin-3-ol;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methyl (tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (2, 2-trifluoroethyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (2, 2-trifluoroethyl) piperidin-4-amine;

2- (4- (3-chloro-4- (2-fluoro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] oct-7-one;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-fluorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

n- ((6- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-fluorophenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

n- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -N-methyltetrahydro-2H-pyran-4-amine;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) (methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (2-hydroxyacetyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-hydroxyethan-1-one;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (piperidin-2-yl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (piperidin-2-yl) piperidin-4-amine;

n- ((6- (2-chloro-3- (3-chloro-2- (4- (((1- (3-chloropyridin-2-yl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (3-chloropyridin-2-yl) piperidin-4-amine;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((2-methoxyethyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2-methoxyethane-1-amine;

3-chloro-4- (2-chloro-3- (6-methoxy-5- ((4-methoxypiperidin-1-yl) methyl) pyridin-2-yl) phenyl) -2- (3-methoxy-4- ((4-methoxypiperidin-1-yl) methyl) phenyl) pyridine;

(1 s,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-fluoropyridin-4-yl) -2-fluorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(1 r,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

2- (4- (3-fluoro-4- (2-fluoro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] oct-7-one;

n- ((6- (2-fluoro-3- (3-fluoro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6-oxo-2, 5-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) -2, 5-diazaspiro [3.4] octan-6-one;

1- ((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -3-methylazetidin-3-ol;

(4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (cyclohexanecarbonyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (cyclohexyl) methanone;

4- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((3-oxopiperazin-1-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperazin-2-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (morpholinomethyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((4-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) - (2- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxy-4-oxopyrrolo [2,1-f ] [1,2,4] triazin-3 (4H) -yl) ethyl) glycine;

(R) - (2- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxy-4-oxopyrrolo [2,1-f ] [1,2,4] triazin-3 (4H) -yl) ethyl) glycine;

n- (1- ((6- (3- (2- (4- ((4-acetamidopiperidin-1-yl) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

N- ((6- (2-chloro-3- (2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

(1 r,4 r) -4- (((6- (2-chloro-3- (2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

6- (4- (4- (3- (5- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-methylpyridin-2-yl) -2-methoxyphenylmethyl) -2-oxa-6-azaspiro [3.3] heptane;

4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (methoxycarbonyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidine-1-carboxylic acid methyl ester;

n- (1- ((6- (3- (2- (4- ((4-acetamidopiperidin-1-yl) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

n- (1- ((6- (3- (2- (4- ((4-acetamidopiperidin-1-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -N-methyltetrahydro-2H-pyran-4-amine;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) piperidin-1-yl) ethan-1-one;

2- (4- (4- (3- (5- ((7-oxa-2-azaspiro [3.5] nonan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -7-oxa-2-azaspiro [3.5] nonane;

2- (1- ((6- (2-chloro-3- (3-chloro-2- (4- ((3- (2-hydroxypropane-2-yl) azetidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) azetidin-2-ol;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) pyrrolidin-2-one;

(R) -4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (((R) -5-oxopyrrolidin-3-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) pyrrolidin-2-one;

(S) -4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (((R) -5-oxopyrrolidin-3-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) pyrrolidin-2-one;

(R) -4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (((S) -5-oxopyrrolidin-3-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) pyrrolidin-2-one;

(S) -4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (((S) -5-oxopyrrolidin-3-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) pyrrolidin-2-one;

2- ((6- (3-chloro-4- (2-chloro-3- (5- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) -2-azaspiro [3.3] heptan-6-ol;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (morpholinomethyl) imidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((3, 3-difluoropyrrolidin-1-yl) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- ((6- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) -3-methylazetidine-3-carbonitrile;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2, 2-difluoroethyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

4- (2- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) ethyl) piperazin-2-one;

2- (3- (6- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) -2-oxopyrrolidin-1-yl) acetic acid;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methoxyethan-1-one;

1- (4- (((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- ((4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) piperidin-1-yl) ethan-1-one;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-thiopyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-thiopyran-4-amine;

1- (2- ((6- (3- (2- (4- ((7-acetyl-2, 7-diazaspiro [3.5] nonan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 7-diazaspiro [3.5] nonan-7-yl) ethan-1-one;

(S) -5- ((((6- (((S) -4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- ((((6- (((R) -4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((R) -4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (5- ((4-hydroxypiperidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((1 s,4 r) -4-methoxycyclohexyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((1 r,4 s) -4-methoxycyclohexyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((1 s,4 s) -4-methoxycyclohexyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

(R) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((3-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((3-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((1- (2-methoxyacetyl) piperidin-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (4- (((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methoxyethan-1-one;

1- (6- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

2- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (3- (2- (4- ((2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (4- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (4- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (3- ((((6- (3- (2- (4- (((1-acetylazetidin-3-yl) methyl) (methyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) azetidin-1-one;

1- (4- (((4- (4 '- ((1-acetylpiperidin-4-yl) amino) methyl) -2-chloro-3' -methoxy- [1,1 '-biphenyl ] -3-yl) -3-chloro-5' -methoxy- [2,3 '-bipyridin ] -6' -yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- ((2 '-chloro-3' - (3-chloro-5 '-methoxy-6' - ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) - [2,3 '-bipyridin ] -4-yl) -3-methoxy- [1,1' -biphenyl ] -4-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1-hydroxycyclopropyl) methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) cyclopropan-1-ol;

n- ((6- (2-chloro-3- (3-chloro-2- (4- (((2, 2-difluoroethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 2-difluoroethane-1-amine;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((3-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(R) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((3-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((4- (hydroxymethyl) piperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((4- (methoxymethyl) piperidin-1-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((4-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methoxyethan-1-one;

1- (6- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1-hydroxycyclopropyl) methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((2, 2-difluoroethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

n- ((6- (2-chloro-3- (3-chloro-2- (4- ((isopropylamino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) propan-2-amine;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 s,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 r,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (4- (3- (5- ((2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (4- (((6- (3- (6- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -5-methylpyrimidin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -5- (((6- (2-chloro-3- (6- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -5-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (6- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -5-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (6- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -5-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (6- (3-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -5-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

n- ((6- (2-chloro-3- (3-chloro-2- (4- ((cyclohexylamino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) cyclohexylamine;

2- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-5-one;

2- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) -2,5, 7-triazaspiro [3.4] octan-6-one;

(S) -5- ((((2 ' - ((S) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((2 ' - ((R) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((2 ' - ((S) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((2 ' - ((R) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

n- ((6- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

n- ((6- (3- (2- (4- ((7-oxa-2-azaspiro [3.5] nonan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine; n- (4- (4- (3- (5- ((7-oxa-2-azaspiro [3.5] nonan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) tetrahydro-2H-pyran-4-amine;

(S) -5- ((((6- (3-chloro-2- ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3-chloro-2- ((R) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3-chloro-2- ((R) -1- ((6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3-chloro-2- ((S) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3-chloro-2- ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3-chloro-2- ((R) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3-chloro-2- ((R) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3-chloro-2- ((S) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-hydroxyethan-1-one;

n- ((6- (2-chloro-3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -3-fluoropropane-1-amine;

2- (4- (6- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) -5-methylpyrimidin-4-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (1- ((6- (3- (2- (4- ((4-acetylpiperidin-1-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (6- ((6- (3- (6- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -5-methylpyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-hydroxyethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-hydroxyethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-hydroxyethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-hydroxyethan-1-one;

1- (4- (((6- (3- (6- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -5-chloropyrimidin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(R) -5- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-2-one;

(S) -5- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-2-one;

(S) -5- (((6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (((S) -4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- ((((6- (((R) -4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((R) -4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- ((((6- (3-chloro-2- ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3-chloro-2- ((R) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3-chloro-2- ((R) -1- ((6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3-chloro-2- ((S) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3-chloro-2- ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3-chloro-2- ((R) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3-chloro-2- ((R) -1- ((6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3-chloro-2- ((S) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (3-methoxypropionyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -3-methoxypropane-1-one;

2- ((6- (3- (6 ' - (((1-acetylpiperidin-4-yl) amino) methyl) -3-chloro-5 ' -methoxy- [2,3' -bipyridin ] -4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-6 ' - ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -5' -methoxy- [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-6 ' - ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -5' -methoxy- [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-6 ' - ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -5' -methoxy- [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-6 ' - ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -5' -methoxy- [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -2- ((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- ((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -2- ((2 ' - (1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- ((2 ' - (1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -2- ((3 ' -chloro-6-methoxy-2 ' - (1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- ((3 ' -chloro-6-methoxy-2 ' - (1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((3 ' -chloro-2 ' - ((S) -1- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((3 ' -chloro-2 ' - ((S) -1- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((3 ' -chloro-2 ' - ((R) -1- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((3 ' -chloro-2 ' - ((R) -1- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (5-chloro-6- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyrimidin-4-yl) -2, 6-diazaspiro [3.4] oct-7-one;

(S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxy-3- (2- (methylamino) ethyl) pyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(R) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxy-3- (2- (methylamino) ethyl) pyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- ((((tetrahydro-2H-pyran-4-yl) methyl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (3- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (3- (((2-hydroxyethyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4-methyl-1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (4-methyl-1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- ((6- (3- (6- (4- ((4-acetylpiperazin-1-yl) methyl) -3-methoxyphenyl) -5-chloropyrimidin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) piperazin-1-one;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

1- (4- (((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((5- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -3-methoxypyridin-2-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- (4- (3-chloro-4- (2-chloro-3- (5-methoxy-6- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-3-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] oct-7-one;

1- (4- (((5- (3- (6 ' - ((1-acetylpiperidin-4-yl) amino) methyl) -3-chloro-5 ' -methoxy- [2,3' -bipyridin ] -4-yl) -2-chlorophenyl) -3-methoxypyridin-2-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- (4- (5-chloro-6- (2-chloro-3- (5- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxyphenylmethyl) -2-azaspiro [3.3] heptan-6-ol;

2- ((5- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -3-methoxypyridin-2-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one;

n- ((5- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -3-methoxypyridin-2-yl) methyl) tetrahydro-2H-pyran-4-amine;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6-methyl-7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -6-methyl-2, 6-diazaspiro [3.4] octan-7-one;

1- (4- (((6- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- ((6- (2-chloro-3- (3 ' -chloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) - [2,4' -bipyridin ] -2' -yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

n- ((3 ' -chloro-2 ' - (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) tetrahydro-2H-pyran-4-amine;

(S) -5- ((((3 ' -chloro-2 ' - (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

2- (4- (3-chloro-4- (3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) -2- (trifluoromethyl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

6- (4- (4- (3- (5- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -6-methoxypyridin-2-yl) -2- (trifluoromethyl) phenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2-oxa-6-azaspiro [3.3] heptane;

2- (4- (4- (3- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -1- (((6- (3- (3-chloro-2- (4- ((((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(S) -1- (((6- (3- (3-chloro-2- (4- ((((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (3- (3-chloro-2- (4- ((((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (3- (3-chloro-2- (4- ((((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

2- (((6- (2-chloro-3- (5-chloro-6- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethan-1-ol;

5- (((6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-4- (((S) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

5- (((6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-4- (((R) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-4- (((S) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] sulfan-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-4- (((R) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] sulfan-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-4- (((S) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] sulfan-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-4- (((R) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] sulfan-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((((1 s,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((((1 r,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-ethoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- ((6- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-ethoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

n- ((6- (3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) -3-fluoropropane-1-amine;

(1 r,4 r) -4- (((6- (3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

1- (6- ((6- (3- (6- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -5-chloropyrimidin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

n- (3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) picolinamide;

(3- (((6- (2-chloro-3- (3-chloro-2- (4- (((3- (hydroxymethyl) bicyclo [1.1.1] pentan-1-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) bicyclo [1.1.1] pentan-1-yl) methanol;

(1 s,3 s) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 s,3 s) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 r,3 r) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 r,3 r) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 r,3 r) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 r,3 s) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 r,3 r) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 s,3 r) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 r,3 r) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 s,3 s) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 r,3 s) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 r,3 r) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 r,3 s) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 r,3 s) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 r,3 s) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 s,3 r) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 r,3 s) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 s,3 s) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 s,3 r) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 r,3 r) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 s,3 r) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 r,3 s) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 s,3 r) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 s,3 r) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 s,3 r) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 s,3 s) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 s,3 s) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 r,3 r) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 s,3 s) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 r,3 s) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 s,3 s) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 s,3 r) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

1- (6- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((6- (2-methoxyacetyl) -2, 6-diazaspiro [3.3] heptan-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -2-methoxyethane-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

2- ((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3- (difluoromethoxy) phenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

1- (4- (((S) -1- (6- (3- (2- (4- ((S) -1- ((1-acetylpiperidin-4-yl) amino) ethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((S) -1- (6- (3- (2- (4- ((R) -1- ((1-acetylpiperidin-4-yl) amino) ethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((R) -1- (6- (3- (2- (4- ((S) -1- ((1-acetylpiperidin-4-yl) amino) ethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((R) -1- (6- (3- (2- (4- ((R) -1- ((1-acetylpiperidin-4-yl) amino) ethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) (methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) (methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (3- (3-chloro-2- (3-methoxy-4- (((1- (2-methoxyacetyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methoxyethan-1-one;

2- (4- (4- (3- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

n- (4- (4- (3- (5- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -6-methoxypyridin-2-yl) -2- (trifluoromethyl) phenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2-oxaspiro [3.3] heptan-6-amine;

2- (4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) ethan-1-ol;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -3-methoxypropane-1-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (6- (4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

(S) -5- (((6- (3- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((S) -2-hydroxypropyl) -1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((R) -2-hydroxypropyl) -1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((S) -2-hydroxypropyl) -1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((R) -2-hydroxypropyl) -1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

2- (((6- (3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethan-1-ol;

1- (6- (3- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine;

n- ((6- (3- (3-chloro-2- (3-methoxy-4- (((2-methoxyethyl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) -2-methoxyethane-1-amine;

2- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -6- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) benzonitrile;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((4-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -3-methoxypropane-1-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

n- ((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

4- (((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((1-methyl-2-oxopiperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylpiperidin-2-one;

2- (4- (((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((1- (2-hydroxyethyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-ol;

1- (4- (((6- (3- (4- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-2-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- (4- (3-chloro-2- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-4-yl) -2, 6-diazaspiro [3.4] oct-7-one;

n- (4- (3-chloro-2- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-4-yl) -2-methoxybenzyl) tetrahydro-2H-pyran-4-amine;

(S) -5- (((4- (3-chloro-2- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-4-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-2- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-4-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-2- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-4-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-2- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-4-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((1- (3-methoxypropionyl) piperidin-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

n- ((6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

1- (4- (((6- (3- (5 ' - ((1-acetylpiperidin-4-yl) amino) methyl) -3-chloro-6 ' -methoxy- [2,2' -bipyridin ] -4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- ((6- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) - [2,2' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one;

n- ((6- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,2' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

(S) -5- (((6- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,2' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,2' -bipyridyl ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,2' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,2' -bipyridyl ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- (((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -3-methoxypropane-1-one;

(S) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -3-methoxypropane-1-one;

(R) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -3-methoxypropane-1-one;

(S) -5- ((((2 ' - ((S) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((2 ' - ((R) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((2 ' - ((S) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((2 ' - ((R) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) -N-methyltetrahydro-2H-pyran-4-amine;

2- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -6- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) benzonitrile;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

(R) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxypropyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxypropyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -4' -chloro-6-methoxy- [2,3' -bipyridin ] -5' -yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- ((6- (2-chloro-3- (4 ' -chloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) - [2,3' -bipyridin ] -5' -yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (4- (((6- (3- (5- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -4-chloropyridin-3-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- (4- (4-chloro-5- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-3-yl) -2, 6-diazaspiro [3.4] oct-7-one;

1- (6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- (((oxazol-5-ylmethyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N- (oxazol-5-ylmethyl) methylamine;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((isopropylamino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

5- (((1-acetylpiperidin-4-yl) amino) methyl) -N- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) picolinamide;

n- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

N- (3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -N- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) pyridine amide;

n- (3- (3-chloro-2- (4- ((((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((S) -2-hydroxypropyl) amino) methyl) picolinamide;

N- (3- (3-chloro-2- (4- ((((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((R) -2-hydroxypropyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (4- ((((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((S) -2-hydroxypropyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (4- ((((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((R) -2-hydroxypropyl) amino) methyl) picolinamide;

1- (6- (((6- (3- (2- (4- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -2-azaspiro [3.3] heptan-2-yl) ethan-1-one;

2- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -6- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) benzonitrile;

2- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) -6- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) benzonitrile;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxyethyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- ((6- (3- (2- (4- ((4-acetylpiperazin-1-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) piperazin-1-one;

n- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(S) -N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(R) -N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

2- ((6- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxyethyl) amino) methyl) -4-methoxypyrrolo [2,1-f ] [1,2,4] triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3- (difluoromethoxy) phenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (6- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (difluoromethoxy) benzyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

1- (4- (((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3- (difluoromethoxy) phenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3- (difluoromethoxy) phenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -5- ((((6- (((S) -4- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- ((((6- (((R) -4- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -4- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((R) -4- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

1- (6- ((6- (2-chloro-3- (3-chloro-2- (4- ((6- (2-hydroxyacetyl) -2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -2-hydroxyethan-1-one;

1- (4- ((4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3',3 "-dichloro-6-methoxy- [2,4':2',4" -terpyridin ] -2 "-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

2- (4- (3 ',3 "-dichloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) - [2,4':2',4" -terpyridin ] -2 "-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one;

2- (2- ((6- (2-chloro-3- (3-chloro-2- (4- ((6- (2-hydroxyethyl) -2, 6-diazaspiro [3.4] oct-2-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] oct-6-yl) ethan-1-ol;

1- (2- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.4] oct-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] oct-6-yl) ethan-1-one;

n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) picolinamide;

5- (((1-acetylpiperidin-4-yl) amino) methyl) -N- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) picolinamide;

n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) picolinamide;

n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

N- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -N- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) pyridine amide;

n- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -5- ((((S) -2-hydroxypropyl) amino) methyl) picolinamide;

n- (2-chloro-3- (3-chloro-2- (4- ((((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -5- ((((R) -2-hydroxypropyl) amino) methyl) picolinamide;

n- (2-chloro-3- (3-chloro-2- (4- ((((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -5- ((((S) -2-hydroxypropyl) amino) methyl) picolinamide;

n- (2-chloro-3- (3-chloro-2- (4- (((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -5- ((((R) -2-hydroxypropyl) amino) methyl) picolinamide;

1- (6- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((6- (3-methoxypropionyl) -2, 6-diazaspiro [3.3] heptan-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -3-methoxypropane-1-one;

2- ((2 ' - (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((3 ' -chloro-2 ' - (2-chloro-3- (5- ((4-hydroxypiperidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridyl ] -2' -yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (difluoromethoxy) benzyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (difluoromethoxy) benzyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -5- ((((6- (((S) -4- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -4- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (((R) -4- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (((R) -4- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6- (2-methoxyacetyl) -2, 6-diazaspiro [3.3] heptan-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (difluoromethoxy) benzyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (6- ((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

1- (4- ((4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (difluoromethoxy) benzyl) amino) piperidin-1-yl) ethan-1-one;

1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -2-methoxyethane-1-one;

1- (2- ((6- (2-chloro-3- (3-chloro-2- (4- ((4-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-6-yl) ethan-1-one;

1- (2- (4- (3-chloro-4- (2-chloro-3- (5- ((4-hydroxypiperidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-6-yl) ethan-1-one;

N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((methylamino) methyl) pyridine amide;

5- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -N- (3- (2- (4- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) picolinamide;

n- (3- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((methylamino) methyl) picolinamide;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -4-methoxypyrrolo [2,1-f ] [1,2,4] triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -4-methoxypyrrolo [2,1-f ] [1,2,4] triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- (((6- (3- (2- (2- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1-hydroxycyclopropyl) methyl) amino) methyl) 8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

n- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

5- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -N- (3- (2- (4- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) picolinamide;

n- (2-chloro-3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -5- (((3-fluoropropyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

1- (((6- (((S) -5- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((S) -5- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

5- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -N- (3- (2- (4- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) picolinamide;

(S) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -N- (2-chloro-3- (5-chloro-6- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(R) -N- (2-chloro-3- (5-chloro-6- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -5- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -5- (3-chloro-2- (3-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

2- (4- (5-chloro-6- (2-chloro-3- (5- (((2-hydroxyethyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -N- (2-chloro-3- (4 ' -chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,3' -bipyridyl ] -5' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(R) -N- (2-chloro-3- (4 ' -chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,3' -bipyridyl ] -5' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((3-fluoropropyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxy-2-methylpropyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxyethyl) (methyl) amino) methyl) 8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -5- (((6- (2-chloro-3- (5-methoxy-6- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (5-methoxy-6- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (5-methoxy-6- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (5-methoxy-6- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- (((6- (3- (6- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -5-methoxypyrimidin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -N- (2-chloro-3- (3 ' -chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(R) -N- (2-chloro-3- (3 ' -chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

N- (2-chloro-3- (3 ' -chloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) - [2,4' -bipyridyl ] -2' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

2- ((6- (((S) -5- (3 ' -chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3 ' -chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((S) -5- (3 ' -chloro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3 ' -chloro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

N- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridyl ] -2' -yl) -2-chlorophenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

n- (2-chloro-3- (4 ' -chloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) - [2,3' -bipyridyl ] -5' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

n- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -4' -chloro-6-methoxy- [2,3' -bipyridyl ] -5' -yl) -2-chlorophenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

2- ((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

n- (3- (3-chloro-2- (3- (difluoromethoxy) -4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (3- (difluoromethoxy) -4- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (3- (difluoromethoxy) -4- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (3- (difluoromethoxy) -4- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

N- (3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

2- (4- (6- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) -5-methoxypyrimidin-4-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((4- (6- (2-chloro-3- (5- (((2-hydroxyethyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) -5-methoxypyrimidin-4-yl) -2-methoxyphenylmethyl) amino) ethan-1-ol;

(S) -N- (2-chloro-3- (4 ' -chloro-5- (((2-hydroxypropyl) amino) methyl) -6-methoxy- [2,3' -bipyridyl ] -5' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(R) -N- (2-chloro-3- (4 ' -chloro-5- (((2-hydroxypropyl) amino) methyl) -6-methoxy- [2,3' -bipyridyl ] -5' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

n- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -4' -chloro-6-methoxy- [2,3' -bipyridyl ] -5' -yl) -2-chlorophenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

n- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridyl ] -2' -yl) -2-chlorophenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(S) -N- (5- (3 ' -chloro-6-methoxy-5- ((methylamino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine;

(R) -N- (5- (3 ' -chloro-6-methoxy-5- ((methylamino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine;

n- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

n- ((6- (2-chloro-3- (5-methoxy-6- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

(S) -N- (3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(R) -N- (3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(S) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

2- (4- (5-chloro-6- (2-chloro-3- (5- ((((1 s,3 s) -3-hydroxycyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (5-chloro-6- (2-chloro-3- (5- ((((1 s,3 r) -3-hydroxycyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (5-chloro-6- (2-chloro-3- (5- ((((1 r,3 s) -3-hydroxycyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (5-chloro-6- (2-chloro-3- (5- ((((1 r,3 r) -3-hydroxycyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -N- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - (((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,2' -bipyridyl ] -4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(R) -N- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - (((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,2' -bipyridyl ] -4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(S) -N- (2-chloro-3- (3-chloro-5 ' - (((2-hydroxypropyl) amino) methyl) -6' -methoxy- [2,2' -bipyridyl ] -4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(R) -N- (2-chloro-3- (3-chloro-5 ' - (((2-hydroxypropyl) amino) methyl) -6' -methoxy- [2,2' -bipyridyl ] -4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(S) -N- (5- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine;

(R) -N- (5- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine;

(S) -2- (4- (5-chloro-6- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- (4- (5-chloro-6- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (6- (2-chloro-3- (6-methoxy-5- ((6-oxo-2, 5-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) -5-methoxypyrimidin-4-yl) -2-methoxyphenylmethyl) -2, 5-diazaspiro [3.4] octan-6-one;

n- (3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(S) -N- (2-chloro-3- (3 ' -chloro-5- (((2-hydroxypropyl) amino) methyl) -6-methoxy- [2,4' -bipyridyl ] -2' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(R) -N- (2-chloro-3- (3 ' -chloro-5- (((2-hydroxypropyl) amino) methyl) -6-methoxy- [2,4' -bipyridyl ] -2' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(S) -N- (2-chloro-3- (5-chloro-6- (4- (((2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(R) -N- (2-chloro-3- (5-chloro-6- (4- (((2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(S) -N- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) -5- (((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

(R) -N- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) -5- (((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

(S) -N- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

(R) -N- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

(S) -N- (3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

(R) -N- (3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

(S) -N- (3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

(R) -N- (3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

(S) -N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((methylamino) methyl) picolinamide;

(R) -N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((methylamino) methyl) picolinamide;

(S) -6- ((2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) carbamoyl) nicotinic acid;

(R) -6- ((2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) carbamoyl) nicotinic acid;

2- ((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) -2-azaspiro [3.3] heptan-6-ol;

n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(S) -N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(R) -N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(S) -N- (3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((methylamino) methyl) picolinamide;

(R) -N- (3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((methylamino) methyl) picolinamide;

n- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(1 r,4 r) -4- (((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) cyclohexan-1-ol;

1- ((3 ' -chloro-2 ' - (2-chloro-3- (5- ((4-hydroxypiperidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) piperidin-4-ol;

1- (2- ((6- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octane-6-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3 ' -chloro-5- ((4-hydroxypiperidin-1-yl) methyl) -6-methoxy- [2,4' -bipyridin ] -2' -yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

n- (3- (3-chloro-2- (3-fluoro-4- (((2-hydroxyethyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

n- ((6- (2-chloro-3- (3-chloro-2- (2- ((isopropylamino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) propan-2-amine;

(S) -5- ((((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- (((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

n- (3- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

1- (6- ((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

n- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridyl ] -2' -yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(S) -N- (3- (3-chloro-2- (3- (difluoromethoxy) -4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(R) -N- (3- (3-chloro-2- (3- (difluoromethoxy) -4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(S) -N- (3- (3 ' -chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(R) -N- (3- (3 ' -chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(R) -1- ((3 ' -chloro-2 ' - (2-chloro-3- (5- (((R) -3-hydroxypyrrolidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) pyrrolidin-3-ol;

(R) -1- ((3 ' -chloro-2 ' - (2-chloro-3- (5- (((S) -3-hydroxypyrrolidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) pyrrolidin-3-ol;

(S) -1- ((3 ' -chloro-2 ' - (2-chloro-3- (5- (((R) -3-hydroxypyrrolidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) pyrrolidin-3-ol;

(S) -1- ((3 ' -chloro-2 ' - (2-chloro-3- (5- (((S) -3-hydroxypyrrolidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) pyrrolidin-3-ol; and

1- (4- (((3 ' -chloro-2 ' - (2-chloro-3- (5- ((4-hydroxypiperidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) piperidin-1-yl) ethan-1-one.

The compounds of the present disclosure may have one or more stereogenic centers, and each stereogenic center may exist independently in either the (R) or (S) configuration. In certain embodiments, the compounds described herein exist in optically active or racemic forms. The compounds described herein include racemic, optical, regioisomeric and stereoisomeric forms, or combinations thereof, having the therapeutically useful properties described herein. The preparation of the optically active form is effected in any suitable manner, including, as non-limiting examples, by resolution of the racemic form by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. The compounds exemplified herein by the racemic formulas further represent two enantiomers or any mixture thereof, or in the case where two or more chiral centers are present, all diastereomers or any mixture thereof.

In certain embodiments, the compounds of the present disclosure exist as tautomers. All tautomers are included within the scope of the compounds described herein.

The compounds described herein also include isotopically-labeled compounds, wherein one or more atoms are replaced by an atom having the same atomic number but an atomic mass or atomic mass number different from the atomic mass or atomic mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include, but are not limited to ² H、 ³ H、 ¹¹ C、 ¹³ C、 ¹⁴ C、 ³⁶ Cl、 ¹⁸ F、 ¹²³ I、 ¹²⁵ I、 ¹³ N、 ¹⁵ N、 ¹⁵ O、 ¹⁷ O、 ¹⁸ O、 ³² P, and ³⁵ s, S. In certain embodiments, substitution with heavier isotopes such as deuterium provides greater chemical stability. Isotopically-labeled compounds are prepared by any suitable method or by using a suitable isotopically-labeled reagent in lieu of a process otherwise employing an unlabeled reagent。

In certain embodiments, the compounds described herein are labeled by other means, including but not limited to using chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

In all of the examples provided herein, examples of suitable optional substituents are not intended to limit the scope of the claimed invention. The compounds of the present invention may comprise any substituent or combination of substituents provided herein.

Salt

The compounds described herein may form salts with acids or bases, and such salts are included in the present disclosure. The term "salt" includes addition salts of free acids or bases useful in the methods of the present disclosure. The term "pharmaceutically acceptable salt" refers to salts having toxicity characteristics within the range useful in pharmaceutical applications. In certain embodiments, the salt is a pharmaceutically acceptable salt. However, pharmaceutically unacceptable salts may have properties such as high crystallinity which have utility in the practice of the present disclosure, for example, in the synthesis, purification or formulation of compounds useful in the methods of the present disclosure.

Suitable pharmaceutically acceptable acid addition salts may be prepared from inorganic acids or from organic acids. Examples of the inorganic acid include sulfate, hydrogen sulfate (hydrogen sulfate), hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid (including hydrogen phosphate and dihydrogen phosphate). Suitable organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic acids, examples of which include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, pamoic acid (or pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, sulfamic acid, 2-hydroxyethanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, stearic acid, alginic acid, β -hydroxybutyric acid, salicylic acid, galacturonic acid, glycerophosphonic acid and saccharin (e.g., saccharinate), saccharinate (saccharate)). Salts may be composed of 1 molar equivalent, 1 or more than 1 molar equivalent of the acid or base moiety relative to any of the compounds of the present disclosure.

Suitable pharmaceutically acceptable base addition salts of the compounds of the present disclosure include, for example, ammonium salts and metal salts, including alkali, alkaline earth and transition metal salts, e.g., calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts prepared from basic amines such as, for example, N' -diphenylmethyl ethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (or N-methylglucamine) and procaine. All of these salts can be prepared from the corresponding compounds by, for example, reacting the appropriate acid or base with the compound.

Combination therapy

In one aspect, the compounds of the present disclosure are used in the methods of the present disclosure in combination with one or more additional agents for treating HBV and/or HDV infection. Such additional agents may include a compound or composition identified herein, or a compound (e.g., a commercially available compound) known to treat, prevent, or ameliorate symptoms of HBV and/or HDV infection.

Non-limiting examples of one or more additional agents for treating HBV and/or HDV infection include: (a) a reverse transcriptase inhibitor; (b) a capsid inhibitor; (c) cccDNA formation inhibitors; (d) an RNA destabilizing agent; (e) an oligonucleotide targeting the HBV genome; (f) Immunostimulants, such as checkpoint inhibitors (e.g., PD-L1 inhibitors); and (g) GalNAc-siRNA conjugates targeting HBV gene transcripts; and (h) a therapeutic vaccine.

(a) Reverse transcriptase inhibitors

In certain embodiments, the reverse transcriptase inhibitor is a reverse transcriptase inhibitor (NARTI or NRTI). In other embodiments, the reverse transcriptase inhibitor is a nucleotide analog reverse transcriptase inhibitor (ntart or NtRTI).

Reported reverse transcriptase inhibitors include, but are not limited to, entecavir, cladodidine, telbivudine, lamivudine, adefovir, and tenofovir, tenofovir disoproxil (tenofovir disoproxil), tenofovir alafenamide, adefovir dipivoxil (adefovir dipovoxil), (1 r,2r,3r,5 r) -3- (6-amino-9H-9-purinyl) -2-fluoro-5- (hydroxymethyl) -4-methylenecyclopentane-1-ol (described in U.S. patent No. 8,816,074, incorporated herein by reference in its entirety), emtricitabine, abacavir, elvucitabine (elvucitidine), ganciclovir, lopvacavir, famciclovir, penciclovir, and amdoxovir.

Reported reverse transcriptase inhibitors further include, but are not limited to, entecavir, lamivudine, and (1 r,2r,3r,5 r) -3- (6-amino-9H-9-purinyl) -2-fluoro-5- (hydroxymethyl) -4-methylenecyclopentane-1-ol.

The reported reverse transcriptase inhibitors further include, but are not limited to, covalently bound phosphoramidate or phosphonamide moieties of the above-mentioned reverse transcriptase inhibitors, or are described, for example, in U.S. patent No. 8,816,074, U.S. patent application publication nos. US 2011/0245284 A1 and US2008/0286230A1, all of which are incorporated herein by reference in their entirety.

Reported reverse transcriptase inhibitors further include, but are not limited to, nucleotide analogs including phosphoramidate moieties, e.g., methyl (((1 r,3r,4r,5 r) -3- (6-amino-9H-purin-9-yl) -4-fluoro-5-hydroxy-2-methylenecyclopentyl) methoxy) (phenoxy) phosphoryl) - (D or L) -alaninate and methyl ((((1 r,3r,4r,5 r) -3-fluoro-2-hydroxy-5-methylene-4- (6-oxo-1, 6-dihydro-9H-purin-9-yl) cyclopentyl) methoxy) (phenoxy) phosphoryl) - (D or L) -alaninate. Also included are individual diastereomers thereof, which include, for example ((R) - (((1R, 3R,4R, 5R) -3- (6-amino-9H-purin-9-yl) -4-fluoro-5-hydroxy-2-methylenecyclopentyl) methoxy) methyl (phenoxy) phosphoryl) - (D or L) -alanine esters and methyl ((S) - (((1R, 3R,4R, 5R) -3- (6-amino-9H-purin-9-yl) -4-fluoro-5-hydroxy-2-methylenecyclopentyl) methoxy) (phenoxy) phosphoryl) - (D or L) -alanine esters.

The reported reverse transcriptase inhibitors further include, but are not limited to, compounds comprising a phosphamide moiety, such as, for example, tenofovir alafenamide, and those described in U.S. patent application publication No. US2008/0286230 A1, which is incorporated herein by reference in its entirety. Methods for preparing stereoselective phosphoramidate-or phosphoramidate-containing actives are described, for example, in U.S. patent No. 8,816,074 and U.S. patent application publication nos. US 2011/024584 A1 and US2008/0286230 A1, which are incorporated herein by reference in their entirety.

(b) Capsid inhibitor

As described herein, the term "capsid inhibitor" includes compounds capable of directly or indirectly inhibiting expression and/or function of a capsid protein. For example, capsid inhibitors may include, but are not limited to, any compound that inhibits capsid assembly, induces non-capsid polymer formation, promotes excessive capsid assembly or capsid assembly misorientation, affects capsid stability, and/or inhibits RNA (pgRNA) encapsidation. Capsid inhibitors also include any compound that inhibits capsid function during downstream event(s) of the replication process (e.g., viral DNA synthesis, translocation of pine ring DNA (rcDNA) to the nucleus, formation of covalently closed circular DNA (cccDNA), viral maturation, budding and/or release, etc.). For example, in certain embodiments, the inhibitor detectably inhibits the expression level or biological activity of the capsid protein, e.g., as measured using an assay described herein. In certain embodiments, the inhibitor inhibits the level of rcDNA and a product downstream of the viral lifecycle by at least 5%, at least 10%, at least 20%, at least 50%, at least 75%, or at least 90%.

Reported capsid inhibitors include, but are not limited to, the compounds described in international patent application publication nos. WO 2013006394, WO2014106019, and WO2014089296, which are incorporated herein by reference in their entirety.

Reported capsid inhibitors also include, but are not limited to, the following compounds and pharmaceutically acceptable salts and/or solvates thereof: bay-41-4109 (see International patent application publication No. WO 2013144129), AT-61 (see International patent application publication No. WO 1998033501; and King et al, 1998,Antimicrob.Agents Chemother.42 (12): 3179-3186), DVR-01, and DVR-23 (see International patent application publication No. WO 2013006394; and Campagna et al, 2013, J.Virol.87 (12): 6931), all of which are incorporated herein by reference in their entirety.

In addition, the reported capsid inhibitors include, but are not limited to, those generally and specifically described in U.S. patent application publication nos. US2015/0225355, US2015/0132258, US 2016/008383, US2016/0052921, US2019/0225593 and international patent application publications nos. WO 2013096744, WO 2014165128, WO 2014033170, WO 2014033167, WO2014033176, WO 2014131847, WO 2014161888, WO 2014184350, WO 2014184365, WO 2015059212, WO 2015011281, WO 2015118057, WO 2015109130, WO 2015073774, WO 2015180631, WO2015138895, WO 2016089990, WO 2017015451, WO 2016183266, WO 2017011552, WO2017048950, WO2017048954, WO 2017048962, WO 2017064156, WO 2018052967, WO 2018172852, WO 2020023710, and are incorporated herein by reference in their entirety.

(c) cccDNA formation inhibitors

Covalently blocked circular DNA (cccDNA) is produced in the nucleus of viral rcDNA and serves as a transcription template for viral mRNA. As described herein, the term "cccDNA formation inhibitor" includes compounds capable of directly or indirectly inhibiting the formation and/or stability of cccDNA. For example, cccDNA formation inhibitors may include, but are not limited to, any compound that inhibits capsid disintegration, entry of rcDNA into the nucleus, and/or conversion of rcDNA into cccDNA. For example, in certain embodiments, the inhibitor detectably inhibits cccDNA formation and/or stability, e.g., as measured using the assays described herein. In certain embodiments, the inhibitor inhibits cccDNA formation and/or stability by at least 5%, at least 10%, at least 20%, at least 50%, at least 75%, or at least 90%.

Reported cccDNA formation inhibitors include, but are not limited to, the compounds described in international patent application publication No. WO 2013130703, and are incorporated herein by reference in their entirety.

In addition, reported cccDNA formation inhibitors include, but are not limited to, those generally and specifically described in U.S. patent application publication No. US 2015/0038515A1, and are incorporated herein by reference in their entirety.

(d) RNA destabilizing agent

As used herein, the term "RNA destabilizer" refers to a molecule or salt or solvate thereof that reduces the total amount of HBV RNA in mammalian cell culture or in a living human subject. In a non-limiting example, the RNA destabilizing agent reduces the amount of RNA transcript(s) encoding one or more of the following HBV proteins: surface antigen, core protein, RNA polymerase and e antigen. In certain embodiments, the RNA destabilizing agent reduces the total amount of HBV RNA in mammalian cell culture or in a living human-like subject by at least 5%, at least 10%, at least 20%, at least 50%, at least 75%, or at least 90%.

Reported RNA destabilizing agents include the compounds described in U.S. patent No. 8,921,381, as well as the compounds described in U.S. patent application publication nos. US2015/0087659 and US2013/0303552, which are incorporated herein by reference in their entirety.

In addition, reported RNA destabilizing agents include, but are not limited to, those generally and specifically described in international patent application publication nos. WO 2015113990, WO 2015173164, US 2016/012344, WO 2016107832, WO 2016023877, WO 2016128335, WO 2016177655, WO 2016071215, WO 2017013046, WO 2017016921, WO 2017016960, WO 2017017042, WO 2017017043, WO 2017102648, WO 2017108630, WO 2017114812, WO 2017140821, WO 2018085619, and are incorporated herein by reference in their entirety.

(e) Oligonucleotides targeting the HBV genome

Reported oligonucleotides targeting HBV genomes include, but are not limited to, arrowhead-ARC-520 (see U.S. Pat. No. 8,809,293; and Wooddell et al 2013,Molecular Therapy 21 (5): 973-985, incorporated herein by reference in its entirety).

In certain embodiments, the oligonucleotides may be designed to target one or more genes and/or transcripts of the HBV genome. Oligonucleotides targeting the HBV genome also include, but are not limited to, isolated double stranded siRNA molecules, each comprising a sense strand and an antisense strand hybridized to the sense strand. In certain embodiments, the siRNA targets one or more genes and/or transcripts of the HBV genome.

(f) Immunostimulant

Checkpoint inhibitors

As described herein, the term "checkpoint inhibitor" includes any compound capable of inhibiting an immune checkpoint molecule that is an immune system modulator (e.g., stimulating or inhibiting immune system activity). For example, some checkpoint inhibitors block inhibitory checkpoint molecules, thereby stimulating immune system functions, such as stimulating T cell activity against cancer cells. A non-limiting example of a checkpoint inhibitor is a PD-L1 inhibitor.

As described herein, the term "PD-L1 inhibitor" includes any compound capable of directly or indirectly inhibiting the expression and/or function of a programmed death ligand 1 (PD-L1) protein. PD-L1, also known as cluster 274 (CD 274) or B7 homolog 1 (B7-H1), is a type 1 transmembrane protein that plays an important role in inhibiting the adaptive arm of the immune system, tissue allograft, autoimmune disease, and hepatitis during pregnancy. PD-L1 binds to its receptor, the inhibitory checkpoint molecule PD-1 (found on activated T cells, B cells, and bone marrow cells) in order to modulate activation or inhibition of the adaptive arm of the immune system. In certain embodiments, the PD-L1 inhibitor inhibits expression and/or function of PD-L1 by at least 5%, at least 10%, at least 20%, at least 50%, at least 75%, or at least 90%.

Reported PD-L1 inhibitors include, but are not limited to, compounds described in one of the following patent application publications: US 2018/0057455; US2018/0057486; WO 2017/106634; WO 2018/026971; WO 2018/045142; WO 2018/118848; WO 2018/119221; WO 2018/119236; WO 2018/119266; WO 2018/119286; WO 2018/121560; WO 2019/076343; WO 2019/087214; and are incorporated by reference herein in their entirety.

(g) GalNAc-siRNA conjugates targeting HBV gene transcripts

"GalNAc" is an abbreviation for N-acetylgalactosamine, and "siRNA" is an abbreviation for small interfering RNA. In GalNAc-siRNA conjugates useful in the practice of the present disclosure, siRNA targeting HBV gene transcripts are covalently bound to GalNAc. While not wishing to be bound by theory, galNAc is believed to bind to asialoglycoprotein receptors on hepatocytes, thereby facilitating siRNA targeting to HBV infected hepatocytes. siRNA enters infected hepatocytes and stimulates the destruction of HBV gene transcripts by RNA interference phenomena.

Examples of GalNAc-siRNA conjugates useful in the practice of this aspect of the present disclosure are set forth in published international application PCT/CA2017/050447 (PCT application publication No. WO/2017/177326 published at 10-19 of 2017), which is incorporated herein by reference in its entirety.

(h) Therapeutic vaccine

In certain embodiments, administration of therapeutic vaccines is useful in practicing the present disclosure for treating viral diseases in a subject. In certain embodiments, the viral disease is hepatitis virus. In certain embodiments, the hepatitis virus is at least one selected from the group consisting of Hepatitis B Virus (HBV) and Hepatitis Delta Virus (HDV). In certain embodiments, the subject is a human.

For example, synergy such as, for example, sigmoid-E may be calculated using suitable methods _max Equations (Holford and Scheiner,1981, clin. Pharmacokinet.6:429-453), loewe Additivity equations (Loewe and Muischnek,1926,Arch.Exp.Pathol Pharmacol.114:313-326) and intermediate equations (Chou and Talay, 1984,Adv.Enzyme Regul.22:27-55). Each of the equations mentioned elsewhere herein may be applied to experimental data to generate corresponding graphs to aid in assessing the effect of drug combinations. The corresponding graphs associated with the equations mentioned elsewhere herein are the concentration-effect curve, the isobologram curve, and the combination index curve, respectively.

Synthesis

The present disclosure further provides methods of preparing the compounds of the present disclosure. The compounds of the present teachings can be prepared from commercially available starting materials, compounds known in the literature, or readily prepared intermediates according to the procedures outlined herein using standard synthetic methods and procedures known to those skilled in the art. Standard synthetic methods and procedures for preparing organic molecules and functional group transformations and manipulations are readily available from the relevant scientific literature or from standard textbooks in the field.

It should be understood that other process conditions may be used where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvents, pressures, etc.) are given unless otherwise indicated. The optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions may be determined by one skilled in the art by routine optimization procedures. Those skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps presented may be varied for the purpose of optimizing the formation of the compounds described herein.

The processes described herein may be monitored according to any suitable method known in the art. For example, product formation may be achieved by spectroscopic methods (spectroscopic means), such as nuclear magnetic resonance spectroscopy (e.g., ¹ h or ¹³ C) Infrared spectroscopy, spectrophotometry (e.g., ultraviolet visible), mass spectrometry, or by chromatography such as High Performance Liquid Chromatography (HPLC), gas Chromatography (GC), gel Permeation Chromatography (GPC), or Thin Layer Chromatography (TLC).

The preparation of the compounds may involve protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of suitable protecting groups can be readily determined by one skilled in the art. Protecting group chemistry can be found, for example, in Greene et al, protective Groups in Organic Synthesis, 2 nd edition (Wiley & Sons, 1991), the entire disclosure of which is incorporated herein by reference for all purposes.

The reactions or methods described herein may be carried out in a suitable solvent that may be readily selected by one skilled in the art of organic synthesis. Suitable solvents typically do not substantially react with the reactants, intermediates, and/or products at the temperature at which the reaction is carried out, i.e., at a temperature in the range of the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, an appropriate solvent for the particular reaction step may be selected.

The compounds of formula (I) may, for examplePrepared according to the synthetic methods outlined in schemes 1-55, wherein Ar ₁ And Ar is a group ₂ Each independently selected from optionally substituted C ₆ -C ₁₀ Aryl and optionally substituted C ₄ -C ₁₀ Heteroaryl groups; r is R ¹ 、R ² 、R ³ 、R ⁴ And R ⁷ Each independently selected from H, optionally substituted C ₁ -C ₆ Alkyl, optionally substituted C ₃ -C ₈ Cycloalkyl, optionally substituted C ₁ -C ₃ Alkoxy, optionally substituted C ₁ -C ₃ Haloalkyl, and optionally substituted C ₁ -C ₃ Haloalkoxy groups, or may comprise any of the substituents otherwise disclosed in any of the embodiments of the present disclosure; z is N or C (R) ^V10 ) The method comprises the steps of carrying out a first treatment on the surface of the And R is ^1a 、R ^1b And Y is defined within the scope of the present disclosure.

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Method

The present disclosure provides methods of treating, ameliorating, and/or preventing a hepatitis virus infection in a subject. In certain embodiments, the infection comprises a Hepatitis B Virus (HBV) and/or Hepatitis Delta Virus (HDV) infection. In other embodiments, the infection comprises a Hepatitis B Virus (HBV) infection. In yet other embodiments, the infection comprises a Hepatitis Delta Virus (HDV) infection. In yet other embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of at least one compound of the present disclosure. In yet other embodiments, the compounds of the present disclosure are the only antiviral agents administered to a subject. In still other embodiments, the at least one compound in a pharmaceutically acceptable composition is administered to the subject. In yet other embodiments, at least one additional agent for treating a hepatitis virus infection is further administered to the subject. In yet other embodiments, the at least one other agent comprises at least one selected from the group consisting of: reverse transcriptase inhibitors; a capsid inhibitor; cccDNA formation inhibitors; an RNA destabilizer; an oligonucleotide targeting the HBV genome; an immunostimulant; galNAc-siRNA conjugates targeting HBV gene transcripts; and therapeutic vaccines. In yet other embodiments, the at least one compound and the at least one other agent are co-administered to the subject. In yet other embodiments, the at least one compound is co-formulated with the at least one other agent.

The present disclosure further provides methods of treating, ameliorating, and/or preventing cancer in a subject. In certain embodiments, the methods comprise administering to a subject in need thereof a therapeutically effective amount of at least one compound of the present disclosure. In other embodiments, the compounds of the present disclosure are the only anticancer agents administered to a subject. In still other embodiments, the at least one compound in a pharmaceutically acceptable composition is administered to the subject. In yet other embodiments, at least one other agent or therapy for treating, ameliorating, and/or preventing cancer is further administered to the subject. In still other embodiments, the other anti-cancer agent or therapy includes nivolumab (nivolumab), pembrolizumab (pembrolizumab), atuzumab (atezolizumab), ipilimumab (ipilimumab), chemotherapy, radiation therapy, and/or ablation therapy. In still other embodiments, the other anti-cancer agent or therapy comprises rituximab (rituxan), doxorubicin (doxorubicin), gemcitabine (gemcitabine), nivolumab, pembrolizumab, and/or ipilimumab.

In certain embodiments, the cancer may be amenable to treatment by inhibiting PD-1, PD-L1, or PD-1/PD-L1 interactions. In other embodiments, the cancer is at least one of: pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain cancer, bone cancer, soft tissue sarcoma, non-small cell lung cancer, or colon cancer. In yet other embodiments, the cancer is at least one of: lymphoma, multiple myeloma, or leukemia. In yet other embodiments, the cancer is at least one of: acute Lymphoblastic Leukemia (ALL), acute Myelogenous Leukemia (AML), chronic Lymphocytic Leukemia (CLL), small Lymphocytic Lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic Myelogenous Leukemia (CML), multiple Myeloma (MM), non-hodgkin's lymphoma (NHL), mantle Cell Lymphoma (MCL), follicular lymphoma, macroglobulinemia (WM), T cell lymphoma, B cell lymphoma, and Diffuse Large B Cell Lymphoma (DLBCL).

In certain embodiments, the subject is a mammal. In other embodiments, the mammal is a human.

Pharmaceutical composition and formulation

The present disclosure provides pharmaceutical compositions comprising at least one compound of the present disclosure, or a salt or solvate thereof, for use in practicing the methods of the present disclosure. Such a pharmaceutical composition may consist of at least one compound of the present disclosure, or a salt or solvate thereof, in a form suitable for administration to a subject, or the pharmaceutical composition may comprise at least one compound of the present disclosure, or a salt or solvate thereof, and one or more pharmaceutically acceptable carriers, one or more additional ingredients, or some combination of these. As is well known in the art, at least one compound of the present disclosure may be present in the pharmaceutical composition in the form of a physiologically acceptable salt, such as in combination with a physiologically acceptable cation or anion.

In certain embodiments, the pharmaceutical compositions used to practice the methods of the present disclosure may be administered to deliver a dose of between 1 ng/kg/day and 100 mg/kg/day. In other embodiments, the pharmaceutical compositions used to practice the present disclosure may be administered to deliver doses between 1 ng/kg/day and 1,000 mg/kg/day.

The relative amounts of the active ingredient, pharmaceutically acceptable carrier, and any additional ingredients in the pharmaceutical compositions of the present disclosure will vary depending on the identity, size (dimension) and condition of the subject being treated, and further depending on the route by which the composition is to be administered. For example, the composition may comprise between 0.1% and 100% (w/w) active ingredient.

Pharmaceutical compositions for use in the methods of the present disclosure may be suitably developed for nasal, inhalation, oral, rectal, vaginal, pleural, peritoneal, parenteral, topical, transdermal, pulmonary, intranasal, buccal, intraocular, epidural, intrathecal, intravenous, or other routes of administration. The compositions used in the methods of the present disclosure may be administered directly to the brain, brain stem, or any other portion of the central nervous system of a mammal or bird. Other contemplated formulations include engineered (projected) nanoparticles, microspheres, lipid particle formulations, coated particles, polymer conjugates, resealed erythrocytes containing the active ingredient, and immunological-based formulations.

In certain embodiments, the compositions of the present disclosure are part of a pharmaceutical matrix that allows for handling of insoluble materials and improving their bioavailability, development of controlled release or sustained release products, and production of homogeneous compositions. For example, hot melt extrusion, solid solutions, solid dispersions, size reduction techniques, molecular complexes (e.g., cyclodextrins, etc.), microparticles, and particle and formulation coating processes can be used to prepare the drug matrix. An amorphous or crystalline phase may be used in such a process.

The route(s) of administration will be apparent to the skilled artisan and will depend on a number of factors including the type and severity of the disease being treated, the type and age of the veterinary or human patient being treated, and the like.

The formulations of the pharmaceutical compositions described herein may be prepared by any method known or later developed in the pharmacological and pharmaceutical arts. Typically, this preparation method comprises the steps of: the active ingredient is combined with a carrier or one or more other auxiliary ingredients and the product is then shaped or packaged as needed or desired into single or multiple dose units.

As used herein, a "unit dose" is a discrete amount of a pharmaceutical composition comprising a predetermined amount of an active ingredient. The amount of active ingredient is typically equal to the dose of active ingredient to be administered to the subject or a convenient portion of such dose, such as, for example, half or one third of such dose. The unit dosage form may be a single daily dose or one of a plurality of daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form for each administration may be the same or different.

Although the description of the pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for ethical administration to humans, the skilled artisan will appreciate that such compositions are generally suitable for administration to a variety of animals. Improvements in pharmaceutical compositions suitable for administration to humans in order to adapt the composition to administration to a variety of animals are well known and can be designed and made by the ordinarily skilled veterinary pharmacist simply through ordinary experimentation. Subjects to which the pharmaceutical compositions of the present disclosure are contemplated to be administered include, but are not limited to, humans and other primates, mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, and dogs.

In certain embodiments, the compositions of the present disclosure are formulated using one or more pharmaceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical compositions of the present disclosure comprise a therapeutically effective amount of at least one compound of the present disclosure and a pharmaceutically acceptable carrier. Useful pharmaceutically acceptable carriers include, but are not limited to, glycerol, water, saline, ethanol, recombinant human albumin (e.g.,) Soluble gels (e.g.)>) And other pharmaceutically acceptable salt solutions, such as salts of phosphates and organic acids. At Rexamples of these and other pharmaceutically acceptable carriers are described in emington's Pharmaceutical Sciences (1991,Mack Publication Co., new Jersey).

The carrier may be a solvent or dispersion medium comprising, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycols, and the like), recombinant human albumin, soluble gelatin, suitable mixtures thereof, and vegetable oils. For example, proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the presence of the dispersion and by the use of surfactants. The action of microorganisms can be prevented by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, isotonic agents, for example, sugars, sodium chloride, or polyols, such as mannitol and sorbitol, are included in the compositions. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.

The formulations may be used in admixture with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier materials suitable for oral, parenteral, nasal, inhalation, intravenous, subcutaneous, enteral, or any other suitable means of administration known in the art. The pharmaceutical formulation may be sterilized and, if desired, mixed with adjuvants, such as lubricants, preservatives, stabilizers, wetting agents, emulsifying agents, salts for influencing osmotic buffering agents, coloring agents, flavoring agents, and/or substances which impart fragrance, and the like. They may also be combined with other active agents, for example, other analgesics, anxiolytics or hypnotics, if desired. As used herein, "additional ingredients" include, but are not limited to, one or more ingredients that can be used as a pharmaceutical carrier.

The compositions of the present disclosure may include from about 0.005% to 2.0% preservative, by total weight of the composition. In the case of exposure to environmental pollutants, preservatives are used to prevent deterioration. Examples of preservatives useful according to the present disclosure include, but are not limited to, preservatives selected from the group consisting of benzyl alcohol, sorbic acid, parahydroxybenzoic acid, prochloraz, and any combination thereof. One such preservative is a combination of about 0.5% to 2.0% benzyl alcohol and 0.05 to 0.5% sorbic acid. The composition may include antioxidants and chelating agents that inhibit degradation of the compound. For certain compounds, antioxidants are BHT, BHA, alpha-tocopherol, and ascorbic acid, exemplary ranges of which are about 0.01% to 0.3% by weight, or BHT ranges from 0.03% to 0.1% by weight, based on the total weight of the composition. The chelating agent may be present in an amount of 0.01% to 0.5% by weight, based on the total weight of the composition. Exemplary chelating agents include ethylenediamine tetraacetate (e.g., disodium edetate) and citric acid in a range of about 0.01% to 0.20% by weight or in a range of 0.02% to 0.10% by weight, based on the total weight of the composition. Chelating agents can be used to chelate metal ions in the composition, which can be detrimental to the shelf life of the formulation. For certain compounds, although BHT and disodium edetate are exemplary antioxidants and chelating agents, respectively, other suitable and equivalent antioxidants and chelating agents may be substituted as known to those skilled in the art.

Liquid suspensions may be prepared using conventional methods to suspend the active ingredient in an aqueous or oily vehicle. Aqueous vehicles include, for example, water and isotonic saline. Oily vehicles include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils (such as arachis oil, olive oil, sesame oil, or coconut oil), fractionated vegetable oils and mineral oils such as liquid paraffin. The liquid suspension may further include one or more additional ingredients including, but not limited to, suspending agents, dispersing or wetting agents, emulsifying agents, demulcents, preserving agents, buffering agents, salts, flavoring agents, coloring agents, and sweetening agents. The oily suspensions may further include a thickening agent. Known suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, and cellulose derivatives such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose. Known dispersants or wetting agents include, but are not limited to, naturally occurring phospholipids such as lecithins, condensation products of alkylene oxides with fatty acids, with long chain aliphatic alcohols, with partial esters derived from fatty acids and hexitols, or with partial esters derived from fatty acids and hexitols anhydrides (e.g., polyoxyethylene stearate, heptadecaethyleneoxycetyl, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate, respectively). Known emulsifiers include, but are not limited to, lecithin, acacia, and ionic or nonionic surfactants. Known preservatives include, but are not limited to, methyl, ethyl or n-propyl parahydroxybenzoates, ascorbic acid, and sorbic acid. Known sweeteners include, for example, glycerin, propylene glycol, sorbitol, sucrose, and saccharin.

A liquid solution of the active ingredient in an aqueous or oily solvent may be prepared in substantially the same manner as a liquid suspension, the main difference being that the active ingredient is dissolved rather than suspended in the solvent. As used herein, an "oily" liquid is a liquid that includes carbon-containing liquid molecules and that exhibits less polarity than water. The liquid solutions of the pharmaceutical compositions of the present disclosure may contain each of the components described with respect to the liquid suspension, it being understood that the suspending agent does not necessarily assist in dissolving the active ingredient in the solvent. Aqueous solvents include, for example, water and isotonic saline. Oily solvents include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils (such as arachis oil, olive oil, sesame oil, or coconut oil), fractionated vegetable oils, and mineral oils such as liquid paraffin.

The powdered and granular formulations of the pharmaceutical formulations of the present disclosure may be prepared using known methods. Such formulations may be administered directly to a subject, for example, for forming tablets, filling capsules, or preparing an aqueous or oily suspension or solution by adding an aqueous or oily vehicle thereto. Each of these formulations may further include one or more of a dispersant or wetting agent, a suspending agent, ionic and nonionic surfactants, and a preservative. Additional excipients, such as fillers and sweeteners, flavoring agents, or coloring agents, may also be included in the formulations.

The pharmaceutical compositions of the present disclosure may also be prepared, packaged, or sold in the form of an oil-in-water emulsion or a water-in-oil emulsion. The oily phase may be a vegetable oil (such as olive oil or arachis oil), a mineral oil (such as liquid paraffin), or a combination of these. Such compositions may further comprise one or more emulsifying agents, such as naturally-occurring gums (e.g., gum acacia or gum tragacanth); naturally occurring phospholipids, such as soybean or lecithin; esters or partial esters derived from a combination of fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. These emulsions may also contain additional ingredients including, for example, sweeteners or flavoring agents.

Methods of impregnating or coating a material with a chemical composition are known in the art and include, but are not limited to, methods of depositing or bonding a chemical composition onto a surface, methods of bonding a chemical composition into a material structure during synthesis of a material (i.e., such as with a physiologically degradable material), and methods of absorbing an aqueous or oily solution or suspension into an absorbent material, with or without subsequent drying. Methods of mixing the components include physical milling, the use of pellets in solid and suspension formulations, and mixing in transdermal patches as known to those skilled in the art.

Administration/administration

The administration regimen may affect the effective amount of the formulation. The therapeutic formulation may be administered to the patient either before or after the onset of the disease or disorder. Furthermore, several separate doses may be administered daily or sequentially, as well as staggered doses, or the doses may be infused continuously, or may be bolus injections. Furthermore, the dosage of the therapeutic agent may be increased or decreased proportionally to the degree of urgency of the therapeutic or prophylactic condition.

The compositions of the present disclosure may be administered to a patient, such as a mammal, such as a human, using known procedures at dosages and for periods of time effective to treat the diseases or conditions contemplated herein. The effective amount of therapeutic compound necessary to achieve a therapeutic effect can vary depending on such factors as the activity of the particular compound employed; the time of application; the rate of excretion of the compound; duration of treatment; other drugs, compounds or materials used in combination with the compounds; the state of the disease or disorder, the age, sex, weight, condition, general health and past history of the patient being treated, and similar factors well known in the medical arts. The dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several separate doses may be administered daily or the dose may be proportionally reduced as indicated by the emergency of the treatment condition. Non-limiting examples of effective dosage ranges for therapeutic compounds of the present disclosure are about 0.01mg/kg to 100mg/kg body weight per day. One of ordinary skill in the art will be able to study the relevant factors and determine the effective amount of the therapeutic compound without undue experimentation.

The compound may be administered to the animal several times a day, or may be administered less frequently, such as once a day, once a week, once every two weeks, once a month, or even less frequently, such as once every few months, or even once a year or less. It should be understood that in non-limiting examples, the amount of compound administered per day may be administered once per day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, once every other day, a daily dose of 5mg may be started on monday, a first subsequent daily dose of 5mg on wednesday, a second subsequent daily dose of 5mg on friday, etc. The frequency of dosage will be apparent to the skilled artisan and will depend on a number of factors such as, but not limited to, the type and severity of the disease being treated and the type and age of the animal.

The actual dosage level of the active ingredient in the pharmaceutical compositions of the present disclosure may be varied in order to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, while being non-toxic to the patient.

A physician, e.g., a physician or veterinarian, having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, a physician or veterinarian may begin using a dosage of the compound of the disclosure in the pharmaceutical composition at a level less than that required in order to obtain the desired therapeutic effect and gradually increasing the dosage until the desired effect is obtained.

In particular embodiments, the compound is formulated in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suitable as unitary dosages for the patient to be treated; each unit contains a predetermined amount of a therapeutic compound calculated to bind to the desired pharmaceutical vehicle to produce the desired therapeutic effect. The dosage unit forms of the present disclosure are determined by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) limitations inherent in the art of formulating/formulating such therapeutic compounds for the treatment of a disease or disorder in a patient.

In certain embodiments, the compositions of the present disclosure are administered to a patient in a dose ranging from one to five or more times per day. In other embodiments, the compositions of the present disclosure are administered to a patient in a dosage range that includes, but is not limited to, once daily, once every two days, once every three days to once a week, and once every two weeks. It will be apparent to those skilled in the art that the frequency of administration of the various compositions of the present disclosure will vary from subject to subject, depending on a number of factors including, but not limited to, age, disease or condition to be treated, sex, general health, and other factors. Accordingly, the present disclosure should not be construed as limited to any particular dosage regimen, and the precise dosage and composition to be administered to any patient will be determined by the attending physician taking into account all other factors of the patient.

The compounds of the present disclosure for administration may be within the following ranges: about 1 μg to about 7,500mg, about 20 μg to about 7,000mg, about 40 μg to about 6,500mg, about 80 μg to about 6,000mg, about 100 μg to about 5,500mg, about 200 μg to about 5,000mg, about 400 μg to about 4,000mg, about 800 μg to about 3,000mg, about 1mg to about 2,500mg, about 2mg to about 2,000mg, about 5mg to about 1,000mg, about 10mg to about 750mg, about 20mg to about 600mg, about 30mg to about 500mg, about 40mg to about 400mg, about 50mg to about 300mg, about 60mg to about 250mg, about 70mg to about 200mg, about 80mg to about 150mg, and any whole and partial increments therebetween.

In some embodiments, the dosage of a compound of the present disclosure is about 0.5 μg and about 5,000mg. In some embodiments, the dosage of a compound of the present disclosure used in the compositions described herein is less than about 5,000mg, or less than about 4,000mg, or less than about 3,000mg, or less than about 2,000mg, or less than about 1,000mg, or less than about 800mg, or less than about 600mg, or less than about 500mg, or less than about 200mg, or less than about 50mg. Similarly, in some embodiments, the dosage of the second compound as described herein is less than about 1,000mg, or less than about 800mg, or less than about 600mg, or less than about 500mg, or less than about 400mg, or less than about 300mg, or less than about 200mg, or less than about 100mg, or less than about 50mg, or less than about 40mg, or less than about 30mg, or less than about 25mg, or less than about 20mg, or less than about 15mg, or less than about 10mg, or less than about 5mg, or less than about 2mg, or less than about 1mg, or less than about 0.5mg, and any full and partial increments thereof.

In certain embodiments, the present disclosure relates to packaged pharmaceutical compositions comprising a container containing a therapeutically effective amount of a compound described herein, alone or in combination with a second pharmaceutical agent; and instructions for using the compounds to treat, prevent, or ameliorate one or more symptoms of a disease or disorder in a patient.

The term "container" includes any receptacle (receptacle) for holding a pharmaceutical composition or for managing stability or water absorption. For example, in certain embodiments, the container is a package containing a pharmaceutical composition, such as a liquid (solution and suspension), semi-solid, lyophilized solid, solution and powder, or lyophilized formulation, present in a dual chamber. In other embodiments, the container is not a package containing the pharmaceutical composition, i.e., the container is a receptacle, such as a box or vial containing the packaged pharmaceutical composition or the unpackaged pharmaceutical composition and instructions for use of the pharmaceutical composition. Furthermore, packaging techniques are well known in the art. It will be appreciated that the instructions for use of the pharmaceutical composition may be contained on a package containing the pharmaceutical composition, whereby the instructions form an increased functional relationship with the packaged product. However, it should be understood that the specification may contain information regarding the ability of the compound to perform its intended function, e.g., to treat, prevent, and/or ameliorate a disease or disorder in a patient.

Application of

Routes of administration of any of the compositions of the present disclosure include inhalation, oral, nasal, rectal, parenteral, sublingual, transdermal, transmucosal (e.g., sublingual, lingual, (per) buccal, per-urethral, vaginal (e.g., per-vaginal and perivaginal), nasal (intra), and (per) rectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, epidural, intrapleural, intraperitoneal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration.

Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, soft capsules, buccal tablets, emulsions, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, emulsions (magma), lozenge, creams, pastes, plasters, lotions, tablets (dis), suppositories, liquid sprays for nasal or oral administration, dry or atomized formulations for inhalation, compositions and formulations for intravesical administration, and the like. It should be understood that the formulations and compositions useful in the present disclosure are not limited to the particular formulations and compositions described herein.

Oral administration

For oral administration, particularly suitable are tablets, dragees, liquids, drops, capsules, caplets and soft capsules. Other formulations suitable for oral administration include, but are not limited to, powder or granule formulations, aqueous or oily suspensions, aqueous or oily solutions, pastes, gels, toothpastes, mouthwashes, coatings, mouth rinses, or emulsions. Compositions intended for oral use may be prepared according to any method known in the art and such compositions may comprise one or more agents selected from inert, non-toxic, generally Recognized As Safe (GRAS) pharmaceutical excipients suitable for use in the manufacture of tablets. Such excipients include, for example, inert diluents such as lactose; granulating and disintegrating agents, such as corn starch; binders, such as starch; and lubricants such as magnesium stearate.

The tablets may be uncoated or they may be coated by known methods to achieve delayed disintegration in the gastrointestinal tract of a subject and thereby provide a sustained release and absorption of the active ingredient. For example, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate. Further examples, as described in U.S. Pat. nos. 4,256,108;4,160,452; and 4,265,874 to form an osmotic controlled release tablet. The tablets may further comprise sweeteners, flavoring agents, coloring agents, preservatives, or some combination of these to provide a pharmaceutically palatable and palatable preparation. Hard capsules containing the active ingredient may be prepared using physiologically degradable compositions such as gelatin. The capsules contain the active ingredient and may further contain additional ingredients including, for example, inert solid diluents such as calcium carbonate, calcium phosphate, or kaolin.

Hard capsules containing the active ingredient may be prepared using physiologically degradable compositions such as gelatin. Such hard capsules contain the active ingredient and may further contain additional ingredients including, for example, inert solid diluents such as calcium carbonate, calcium phosphate or kaolin.

Soft capsules containing the active ingredient may be prepared using physiologically degradable compositions such as gelatin from animal collagen or hypromellose (a modified form of cellulose) and using an optional mixture of gelatin, water and a plasticizer such as sorbitol or glycerol. Such soft capsules comprise the active ingredient in admixture with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

For oral administration, the compounds of the present disclosure may be administered by conventional means with pharmaceutically acceptable excipients, such as binders; a filler; a lubricant; a disintegrant; or in the form of tablets or capsules prepared with a humectant. If desired, suitable methods and coating materials may be used, such as those available from Colorcon, west Point, pa. (e.g.,OY type, OYC type, organic enteric solubilityType OY-P type, aqueous enteric type OY-A type, OY-PM type and +.>White,32K 18400)The film coating system coats the tablets. It should be understood that similar types of film coatings or polymeric products from other companies may be used.

Tablets containing the active ingredient may be prepared, for example, by compression or molding the active ingredient, optionally together with one or more additional ingredients. Compressed tablets may be prepared by compressing in a suitable apparatus the active ingredient in a free-flowing form, such as a powder or granule formulation, optionally in admixture with one or more of a binder, lubricant, excipient, surfactant and dispersing agent. Molded tablets may be prepared by molding in a suitable apparatus a mixture of the active ingredient, a pharmaceutically acceptable carrier, and at least enough liquid to wet the mixture. Pharmaceutically acceptable excipients for the manufacture of tablets include, but are not limited to, inert diluents, granulating and disintegrating agents, binders and lubricants. Known dispersants include, but are not limited to, potato starch and sodium hydroxymethyl starch. Known surfactants include, but are not limited to, sodium lauryl sulfate. Known diluents include, but are not limited to, calcium carbonate, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, dibasic calcium phosphate, and sodium phosphate. Known granulating and disintegrating agents include, but are not limited to, corn starch and alginic acid. Known binders include, but are not limited to, gelatin, acacia, pregelatinized corn starch, polyvinylpyrrolidone, and hydroxypropyl methylcellulose. Known lubricants include, but are not limited to, magnesium stearate, stearic acid, silica, and talc.

Granulation techniques are well known in the pharmaceutical arts for modifying starting powders or other particulate materials of active ingredients. The powder is typically mixed with a binder material into larger permanent free-flowing agglomerates or granules, known as "granulation". For example, a general feature of a "wet" granulation process using a solvent is that the powder is mixed with a binder material and wet with water or an organic solvent under certain conditions to form a wet granular mass from which the solvent must then be evaporated.

Melt granulation generally involves the use of materials that are solid or semi-solid at room temperature (i.e., have a relatively low softening or melting point range) to facilitate granulation of powders or other materials substantially without the addition of water or other liquid solvents. When heated to a temperature in the melting point range, the low melting point solid liquefies to act as a binder or granulation medium. The liquefied solid spreads itself over the surface of the powdered material in contact therewith and upon cooling forms a solid particulate matter in which the starting materials are bound together. The resulting melt granulation may then be provided to a tablet press or packaged to produce an oral dosage form. Melt granulation improves the dissolution rate and bioavailability of an active substance (i.e., drug) by forming a solid dispersion or solid solution.

Us patent No. 5,169,645 discloses directly compressible waxy particles having improved flow characteristics. Pellets are obtained when wax is mixed in the melt with certain flow improving additives and the mixture is then cooled and pelletized. In certain embodiments, only the wax itself melts in the molten composition of the wax(s) and additive(s), and in other cases, both the wax(s) and additive(s) will melt.

The present disclosure also includes a multi-layered tablet comprising a layer providing for delayed release of one or more compounds useful in the methods of the present disclosure, and other layers providing for immediate release of one or more compounds useful in the methods of the present disclosure. Using a wax/pH sensitive polymer mixture, a gastric insoluble composition can be obtained wherein the active ingredient is entrapped (enrap) thereby ensuring its delayed release.

Liquid formulations for oral administration may be in the form of solutions, syrups or suspensions. Liquid formulations may be formulated by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methylcellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); nonaqueous vehicles (e.g., almond oil, oily esters, or ethyl alcohol); and a preservative (e.g., methylparaben or propylparaben or sorbic acid). Liquid formulations of the pharmaceutical compositions of the present disclosure suitable for oral administration may be prepared, packaged, and sold in liquid form or as a dry product intended for reconstitution with water or another suitable vehicle prior to use.

Parenteral administration

As used herein, "parenteral administration" of a pharmaceutical composition includes any route of administration characterized by physical disruption of the subject's tissue and administration of the pharmaceutical composition through a gap in the tissue. Parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, administration of the composition by surgical incision, administration of the composition by non-surgical wound penetration of tissue, and the like. In particular, parenteral administration is contemplated to include, but is not limited to, subcutaneous, intravenous, intraperitoneal, intramuscular, intrasternal injection, and renal dialysis infusion techniques.

Formulations of pharmaceutical compositions suitable for parenteral administration include the active ingredient in combination with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or continuous administration. The injectable formulations may be prepared, packaged, or sold in unit dosage forms, such as in ampoules or multi-dose containers containing a preservative. Injectable formulations may also be prepared, packaged, or sold in devices such as patient-controlled analgesia (PCA) devices. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, ointments, and implantable sustained release or biodegradable formulations. Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending agents, stabilizing agents, or dispersing agents. In one embodiment of a formulation for parenteral administration, the active ingredient is provided in dry (i.e., powder or granule) form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) and then the reconstituted composition is administered parenterally.

The pharmaceutical compositions may be prepared, packaged, or sold in the form of sterile injectable aqueous or oleaginous suspensions or solutions. The suspension or solution may be formulated according to known techniques and may contain, in addition to the active ingredient, further ingredients, such as dispersants, wetting agents, or suspending agents as described herein. Such sterile injectable preparations may be prepared using non-toxic parenterally acceptable diluents or solvents, such as, for example, water or 1, 3-butanediol. Other acceptable diluents and solvents include, but are not limited to, ringer's solution, isotonic sodium chloride solution, and fixed oils, such as synthetic mono-or diglycerides. Other parenterally administrable formulations that are useful include those that contain an active ingredient in microcrystalline form in the components of recombinant human albumin, fluidized gelatin, lipid plasmid formulations, or biodegradable polymer systems. Compositions for sustained release or implantation may comprise pharmaceutically acceptable polymers or hydrophobic materials such as emulsions, ion exchange resins, sparingly soluble polymers, or sparingly soluble salts.

Topical application

The condition for topical application of the pharmaceutical formulation is the stratum corneum of the epidermis. The stratum corneum is a highly resistant layer composed of proteins, cholesterol, sphingolipids, free fatty acids, and various other lipids, and includes keratinocytes and living cells. One of the factors limiting the permeability (flux) of the compound through the stratum corneum is the amount of active substance that can be loaded or applied onto the skin surface. The greater the amount of active substance applied per unit area of skin, the greater the concentration gradient between the skin surface and the underlying layer of skin, and thus the greater the diffusion force of the active substance through the skin. Thus, a formulation containing a higher concentration of active substance is more likely to cause more active substance to permeate through the skin at a more consistent rate than a formulation having a lower concentration, and not just the skin, all other things being equal.

Formulations suitable for topical application include, but are not limited to, liquid or semi-liquid formulations such as wipes, lotions, oil-in-water or water-in-oil emulsions, such as creams, ointments or pastes, and solutions or suspensions. Although the concentration of the active ingredient may be the same as the solubility limit of the active ingredient in the solvent, the topically applicable formulation may, for example, comprise about 1% to about 10% (w/w) of the active ingredient. Formulations for topical administration may further comprise one or more additional ingredients described herein.

Penetration enhancers may be used. These materials increase the penetration of the drug through the skin. Typical accelerators in the art include ethanol, glycerol monolaurate, PGML (polyethylene glycol monolaurate), dimethyl sulfoxide, and the like. Other accelerators include oleic acid, oleyl alcohol, ethoxy glycol, laurocapram, alkanoic acids, dimethyl sulfoxide, polar lipids, or N-methyl-2-pyrrolidone.

One acceptable vehicle for topical delivery of some compositions of the present disclosure may comprise a lipid plasmid. The composition of the lipid plasmids and their use are known in the art (i.e., U.S. patent No. 6,323,219).

In alternative embodiments, the topically active pharmaceutical composition may optionally be combined with other ingredients, such as adjuvants, antioxidants, chelating agents, surfactants, foaming agents, humectants, emulsifiers, viscosity enhancing agents, buffers, preservatives and the like. In other embodiments, the penetration or permeation enhancer is included in the composition and is effective to improve penetration of the active ingredient into the skin and through the stratum corneum relative to a composition lacking the penetration enhancer. Various permeation enhancers, including oleic acid, oleyl alcohol, ethoxy glycol, laurocapram, alkanoic acids, dimethyl sulfoxide, polar lipids, or N-methyl-2-pyrrolidone are known to those of skill in the art. In another aspect, the composition may further comprise a hydrotrope that acts to increase the disorder of the stratum corneum structure and thus allows for increased transport across the stratum corneum. Various hydrotropes such as isopropanol, propylene glycol, or sodium xylene sulfonate are known to those skilled in the art.

The topically active pharmaceutical composition should be administered in an amount effective to affect the desired change. An "effective amount" as used herein refers to an amount sufficient to cover an area of the skin surface that needs to be altered. The active compound should be present in an amount of about 0.0001% to about 15% by weight volume of the composition. For example, it should be present in an amount of about 0.0005% to about 5% of the composition; for example, it should be present in an amount of about 0.001% to about 1% of the composition. Such compounds may be of synthetic or natural origin.

Administration by buccal administration

The pharmaceutical compositions of the present disclosure may be prepared, packaged, or sold in formulations suitable for buccal administration. Such formulations may, for example, be in the form of tablets or lozenges prepared using conventional methods, and may contain, for example, from 0.1 to 20% (w/w) of the active ingredient, the balance comprising the orally dissolvable or degradable composition, and optionally one or more additional ingredients described herein. Alternatively, formulations suitable for buccal administration may include powdered or aerosolised (aerosolised) or nebulised (atomised) solutions or suspensions comprising the active ingredient. Such powdered, aerosolized, or nebulized formulations, when dispersed, may have an average particle or droplet size in the range of about 0.1 to about 200 nanometers, and may further include one or more additional ingredients described herein. The examples of formulations described herein are not exhaustive and it should be understood that the present disclosure includes additional variations of these and other formulations not described herein but known to those of skill in the art.

Rectal administration

The pharmaceutical compositions of the present disclosure may be prepared, packaged, or sold in a formulation suitable for rectal administration. Such compositions may be in the form of suppositories, retention enema formulations, and solutions for rectal or colonic lavage, for example.

Suppository formulations may be prepared by mixing the active ingredient with a non-irritating, pharmaceutically acceptable excipient which is solid at ordinary room temperature (i.e. about 20 ℃) and liquid at the rectal temperature of the subject (i.e. about 37 ℃) in a healthy human body. Suitable pharmaceutically acceptable excipients include, but are not limited to, cocoa butter, polyethylene glycols, and various glycerides. The suppository formulation may further comprise various additional ingredients including, but not limited to, antioxidants and preservatives.

Retention enema formulations or solutions for rectal or colonic lavage can be prepared by mixing the active ingredient with a pharmaceutically acceptable liquid carrier. As is well known in the art, an enema preparation may be administered using a delivery device suitable for the rectal anatomy of a subject, and the enema preparation may be packaged within the delivery device. The enema preparation may further contain various additional ingredients including, but not limited to, antioxidants and preservatives.

Additional forms of administration

Other dosage forms of the present disclosure include dosage forms as described in U.S. Pat. nos. 6,340,475, 6,488,962, 6,451,808, 5,972,389, 5,582,837, and 5,007,790. Other dosage forms of the present disclosure also include dosage forms as described in U.S. patent application nos. 20030147952, 20030104062, 20030104053, 20030044466, 20030039688, and 20020051820. Other dosage forms of the present disclosure also include dosage forms as described in PCT application Nos. WO 03/35041, WO 03/35040, WO 03/35029, WO 03/35177, WO 03/35039, WO 02/96404, WO 02/32416, WO 01/97783, WO 01/56544, WO 01/32217, WO 98/55107, WO 98/11879, WO 97/47285, WO 93/18755, and WO 90/11757.

Controlled release formulation and drug delivery system:

in certain embodiments, the compositions and/or formulations of the present disclosure may be, but are not limited to, short-term, fast-acting (rapid-offset) and/or fast-failure (rapid-offset), as well as controlled, e.g., sustained release, delayed release, and pulsatile release formulations.

The term sustained release in its conventional sense refers to a pharmaceutical formulation that gradually releases a drug over an extended period of time, although not necessarily, resulting in a substantially constant blood level of the drug over an extended period of time. The period of time may be as long as one month or more and should be longer than the same amount of release administered in the form of a bolus.

For sustained release, the compounds may be formulated with suitable polymers or hydrophobic materials that provide sustained release characteristics to the compound. Thus, the compounds used in the methods of the present disclosure may be administered in particulate form, by injection for example, or by implantation in wafer or disc form. In certain embodiments of the present disclosure, a compound useful in the present disclosure is administered to a subject using a sustained release formulation, alone or in combination with another pharmaceutical formulation.

The term delayed release is used herein in its conventional sense to refer to a pharmaceutical formulation that provides an initial release of a drug after a certain delay following administration of the drug, and may include, although is not required, from about 10 minutes up to about 12 hours. The term pulsatile release is used herein in its conventional sense to refer to a pharmaceutical formulation that provides drug release in a manner that produces a pulsatile plasma profile following drug administration. The term immediate release in its conventional sense refers to a pharmaceutical formulation that provides for release of a drug immediately after administration of the drug.

As used herein, short term refers to any period of time following drug administration up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes following drug administration and any or all full or partial increments thereof.

As used herein, fast failure refers to any period of time after administration of a drug, up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes after administration of a drug, and any full and partial increments thereof.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific procedures, embodiments, claims, and embodiments described herein. Such equivalents are considered to be within the scope of this disclosure and are covered by the appended claims. For example, it is understood that modifications utilizing art-recognized alternatives and using only routine experimentation, including but not limited to reaction times, reaction specifications (size)/volumes, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmospheres, and reaction conditions of reducing/oxidizing agents, are within the scope of the present application.

It is to be understood that wherever numerical values and ranges are provided herein, the description of the range format is merely for convenience and brevity and should not be construed as a limitation on the scope of the disclosure. Accordingly, all values and ranges encompassed by these values and ranges are intended to be covered by the scope of the present disclosure. Furthermore, the present application also contemplates all values falling within these ranges as well as the upper or lower limits of the stated ranges of values. The description of a range should be considered to have explicitly disclosed all possible sub-ranges as well as individual values within the range as well as partial integers of values within the range where appropriate. For example, a description of a range from 1 to 6 should be considered to have explicitly disclosed sub-ranges of 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual values within the ranges, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

The following examples further illustrate aspects of the present disclosure. However, they are in no way limiting of the teachings or disclosure of the present disclosure described herein.

Examples

The present disclosure will now be described with reference to the following examples. These examples are provided for illustrative purposes only and the present disclosure is not limited to these examples, but encompasses all variations apparent from the teachings provided herein.

LCMS method

LCMS method a: waters Acquity UPLC System using Waters Acquity UPLC BEH C, 1.7 μm,50×2.1mm column with an aqueous acetonitrile-based (aqueous acetonitrile based) solvent gradient of 2-98% CH over 9.5min ₃ CN/H ₂ O (0.05% TFA). Flow = 0.8mL/min.

LCMS method B: waters Acquity UPLC System using Waters Acquity UPLC BEH C, 1.7 μm,50×2.1mm column with an aqueous acetonitrile-based solvent gradient of 2-98% CH over 1.0min ₃ CN/H ₂ O (0.05% TFA). Flow = 0.8mL/min.

LCMS method C: shimadzu UFLC system using ACE UltraCore Super PhenylHexyl,2.5 μm,50×2.1mm column with an aqueous acetonitrile-based solvent gradient of 5-100% CH within 5.0min ₃ CN/H ₂ O (0.05% formic acid)). Flow rate = 1.0mL/min.

LCMS method D: waters Acquity UPLC System using Waters Acquity UPLC BEH C, 1.7 μm,50×2.1mm column with an aqueous acetonitrile-based solvent gradient of 2-98% CH over 5.0min ₃ CN/H ₂ O (0.05% TFA). Flow = 0.8mL/min.

General procedure

Suzuki coupling procedure A

With aryl halides, aryl borates/aryl borates (aryl boronic ester/acid) (1.0 eq), potassium carbonate (3.0 eq), pd (PPh) ₃ ) ₄ (0.1 eq) and dioxane/water (6:1, 0.3 m) were fed into a reaction vial equipped with a stirring bar (1.0 eq). The mixture was degassed for 20 min, capped with a TFE lined silicone spacer cap (TFE lined silicone septa cap) and stirred in a heating block (heating block) at 95 ℃ for 1 hour. Upon cooling to room temperature, water was added and the reaction mixture was extracted three times into EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was purified on a silica gel column with EtOAc in hexanes (0 to 60% gradient) as eluent.

Suzuki coupling procedure B

With aryl halides (1.0 eq), aryl borates/aryl borates (1.0 eq), potassium carbonate (3.0 eq), pd (PPh) ₃ ) ₄ (0.1 eq) and dioxane/water (6:1, 0.3 m) were fed into a reaction vial equipped with a stirring bar. The reaction mixture was degassed for 20 min, capped with a silicone spacer cap lined with TFE and stirred in a heated block (heating block) at 95 ℃ for 2 hours. After cooling to room temperature, the mixture was purified by column chromatography on silica gel using CH ₂ Cl ₂ The mixture was purified directly as eluent with MeOH (0 to 5% gradient).

Reductive amination procedure A

A mixture of bis-aldehyde (1.0 eq), amine (4.0 eq) and acetic acid (2.0 eq) in MeOH/THF (1:1) was stirred at room temperature for 2 hours. Adding NaBH slowly in portions ₃ CN (4.0 eq), the mixture was stirred for 1 hour or more (monitored by LCMS), quenched with water and extracted three times into DCM. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. By inverting the colorThe crude material was purified by chromatography (gradient of acetonitrile in water, 0.05% formic acid, 5 to 100%) and the pure combined fractions were freeze-dried to provide the product as formate salt.

Reductive amination procedure B

A mixture of aldehyde (1.0 eq), amine (2.0 eq) and acetic acid (1.0 eq) in MeOH/THF (1:1) was stirred at room temperature for 2 hours. Adding NaBH slowly in portions ₃ CN (2.0 eq), the mixture was stirred for 1 hour or more (monitored by LCMS), quenched with water and extracted three times into DCM. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo and used in the next step without purification.

General Boc deprotection procedure

On CH ₂ Cl ₂ A solution of the reductive amination or Suzuki coupling product was stirred in TFA (1:1) for 30 minutes and concentrated to dryness in vacuo. The crude material was purified by reverse phase chromatography (gradient of acetonitrile in water, 0.05% formic acid, 5 to 100%) and the pure combined fractions were freeze-dried to provide the product as formate salt.

Example 1: 3-chloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) -2- (4, 5-dihydro-1H-imidazol-2-yl) -3-methoxyphenyl) pyridine (106)

(a) 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde

To 6- (2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -2-methoxynicotinaldehyde (5.00 g,13.4 mmol) and 2, 3-dichloro-4-iodo-pyridine (4.40 g,16.1 mmol) in dioxane/H ₂ A mixture of O (6:1 (v/v), 70 mL) was added potassium carbonate (5.55 g,40.1 mmol) and [1,1' -bis (di-t-butylphosphino) ferrocene]Palladium (II) dichloride (546 mg,0.67 mmol). At N ₂ The mixture was stirred at 95℃for 1 hour. To the reaction mixture was added water (30 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by normal phase SiO ₂ Chromatography (0-10% ethyl acetate/petroleum ether) was purified to give 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (3.2 g,61% yield) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.30(s,1H),8.53(d,1H),8.23(d,1H),7.82(m,1H),7.66(t,1H),7.61(d,1H),7.57(m,1H),7.49(d,1H)4.07(s,1H).

(b) 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde

To 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (1.50 g,3.81 mmol) and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (1.30 g,4.95 mmol) in THF/H ₂ Potassium phosphate (2.43 g,11.4 mmol) and [1,1' -bis (di-tert-butylphosphino) ferrocene were added to a mixture of O (5:1 v/v,24 mL)]Palladium (II) dichloride (248 mg,0.38 mmol). At N ₂ The mixture was stirred at 80℃for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure. By flash chromatography (SiO ₂ The residue was purified with 0-50% ethyl acetate/petroleum ether to afford 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (1.17 g,40% yield) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.43(s,1H),10.31(s,1H),8.78(d,1H),8.23(d,1H),7.84-7.80(m,2H),7.68-7.59(m,3H),7.51-7.49(m,2H),7.41(d,1H),4.07(s,3H),3.99(s,3H).

(c) 3-chloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) -2- (4, 5-dihydro-1H-imidazol-2-yl) -3-methoxyphenyl) pyridine

To a mixture of 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (200 mg,0.41 mmol) and ethane-1, 2-diamine (0.47 mL,7.04 mmol) in DMA (3 mL) was added potassium carbonate (560 mg,4.05 mmol) and iodine (617 mg,2.43 mmol). The mixture was stirred at room temperature under nitrogen for 12 hours. To the mixture was added an additional portion of ethane-1, 2-diamine (2.66 ml,39.78 mmol) followed by N ₂ The mixture was stirred at room temperature for 12 hours. To the reaction mixture was added water (10 mL) followed by extraction with ethyl acetate (2×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC to afford 3-chloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) -2- (4, 5-dihydro-1H-imidazol-2-yl) -3-methoxyphenyl) pyridine (2 mg,0.73% yield) as formate salt (as a white solid). MS m/z found 573[ M+H ] ] ⁺ ； ¹ H NMR(400MHz,Methanol-d ₄ ):δ8.62(d,1H),8.45(s,1H),8.20(d,1H),7.79(d,1H),7.71(m,1H),7.53-7.51(m,2H),7.47-7.41(m,4H),4.08(s,3H),4.00-3.95(m,11H).

Example 2:2- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one (89)

To 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (200 mg,0.41 mmol) and 2, 6-diazaspiro [3.4]]Sodium triacetoxyborohydride (344 mg,1.62 mmol) and sodium acetate (133 mg,1.62 mmol) were added to a mixture of octan-7-one (204 mg,1.62 mmol) in methylene chloride (10 mL). At N ₂ The mixture was stirred at 20℃for 3 hours. The mixture was concentrated. The residue was purified by reverse phase HPLC to afford 2- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy)) as formate salt (as white solid)-4- ((7-oxo-2, 6-diazaspiro [ 3.4)]Octane-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) -2, 6-diazaspiro [3.4]Octan-7-one (37.6 mg,12% yield). LCMS: m/z found 713.1[ M+H ]]+, rt=2.54 min, (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.67(d,1H),8.34(s,1H),7.78(d,1H),7.72(m,1H),7.59-7.55(m,1H),7.51(d,1H),7.49(d,1H),7.44(m,1H),7.42-7.36(m,2H),7.30(d,1H),4.32(s,2H),4.07(s,4H),4.04(s,3H),4.02(s,3H),3.99(s,2H),3.72(s,4H),3.72(s,2H),3.64(d,2H),2.71(s,2H),2.65(s,2H).

Example 3:1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethanone (90)

To 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (90 mg,0.18 mmol) and 1- (2, 6-diazaspiro [3.3 ]]A mixture of heptan-2-yl) ethanone trifluoroacetate (120 mg,0.47 mmol) in methylene chloride (10 mL) was added sodium triacetoxyborohydride (154 mg,0.73 mmol) and sodium acetate (60 mg,0.73 mmol). At N ₂ The mixture was stirred at 20℃for 5 hours. The mixture was concentrated. The resulting residue was purified by reverse phase HPLC to afford 1- (6- ((6- (3- (4- ((6-acetyl-2, 6-diazaspiro [ 3.3)) as formate salt (as a white solid)]Heptane-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl-2-chlorophenyl) -2-methoxypyridin-3-yl methyl) -2, 6-diazaspiro [3.3]Heptane-2-yl) ethanone (16.2 mg, 12%). LCMS: m/z found 741.0[ M+H ]] ⁺ Rt=2.76 min, (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.65-8.64(m,1H),8.39(s,1H),7.75(d,1H),7.77(m,1H),7.56(m,1H),7.48-7.44(m,2H),7.42(m,1H),7.37(s,1H),7.34(m,1H),7.28(m,1H),4.35(m,4H),4.29(s,2H),4.17(s,4H),4.12(s,2H),4.08(s,2H),4.03(s,3H),3.97(s,5H),3.81(s,4H),1.84(s,6H).

Example 4: (5S) -5- [ [ [3- [ 3-chloro-4- [ 2-chloro-3- [ 6-methoxy-5- [ [ (2S) -5-oxopyrrolidin-2-yl ] methylamino ] methyl ] -2-pyridinyl ] phenyl ] -2-pyridinyl ] -7-quinolinyl ] methylamino ] methyl ] pyrrolidin-2-one (52)

Following Suzuki coupling procedure A, a mixture of 3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) quinoline-7-carbaldehyde (30 mg,0.11 mmol) and 6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl ]-2-methoxy-pyridine-3-carbaldehyde (42 mg,0.11 mmol) provided 3- [ 3-chloro-4- [ 2-chloro-3- (5-formyl-6-methoxy-2-pyridinyl) phenyl ]]-2-pyridyl group]Quinoline-7-carbaldehyde (40 mg, 73%). MS: m/z found 514.1[ M+H ]] ⁺ . Following reductive amination procedure A, starting from 3- [ 3-chloro-4- [ 2-chloro-3- (5-formyl-6-methoxy-2-pyridinyl) phenyl]-2-pyridyl group]Quinoline-7-carbaldehyde (30 mg,0.06 mmol) and (5S) -5- (aminomethyl) pyrrolidin-2-one (27 mg,0.23 mmol) provided (5S) -5- [ [ [3- [ 3-chloro-4- [ 2-chloro-3- [ 6-methoxy-5- [ [ (2S) -5-oxopyrrolidin-2-yl ] as formate salt]Methylamino group]Methyl group]-2-pyridyl group]Phenyl group]-2-pyridyl group]-7-quinolinyl]Methylamino group]Methyl group]Pyrrolidin-2-one (42 mg, 91%). MS: m/z found 710.2[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ9.19(d,1H),8.79–8.70(m,2H),8.49(s,2H),8.13–8.02(m,2H),7.80–7.69(m,3H),7.57(t,1H),7.52(d,1H),7.46(dd,1H),7.28(d,1H),4.17–4.06(m,2H),4.03(s,3H),3.96–3.83(m,4H),2.86–2.70(m,4H),2.42–2.22(m,6H),1.91–1.78(m,2H).

(a) 6- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl ] phenyl ] -2-methoxy-pyridine-3-carbaldehyde

Following Suzuki coupling procedure A, a reaction was carried out from 6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl]Preparation of 2-methoxy-pyridine-3-carbaldehyde (300 mg,0.76 mmol) and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (200 mg,0.76 mmol) this intermediateAnd (3) an object. 81% yield. MS: m/z found 493.1[ M+H ]] ⁺ .

Example 5:1- [4- [ 3-chloro-4- [ 2-chloro-3- [ 6-methoxy-5- (methylaminomethyl) -2-pyridinyl ] phenyl ] -2-pyridinyl ] -2-methoxy-phenyl ] -N-methyl-methylamine (136)

1- [4- [ 3-chloro-4- [ 2-chloro-3- [ 6-methoxy-5- (methylaminomethyl) -2-pyridinyl]Phenyl group]-2-pyridyl group]-2-methoxy-phenyl]-N-methyl-methylamine according to the reductive amination procedure A starting from 6- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl]Phenyl group]-2-methoxy-pyridine-3-carbaldehyde (40 mg,0.08 mmol) and a solution of methylamine (33% wt in ethanol, 0.32 mmol) were prepared as formate. Yield 59%. MS: m/z found 523.2[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),8.53(s,2H),7.87(d,1H),7.73(dd,1H),7.58(t,1H),7.51(d,1H),7.48(d,1H),7.45(dd,1H),7.39(d,1H),7.35(d,2H),4.26(s,2H),4.21(s,2H),4.08(s,3H),3.99(s,3H),2.74(s,6H).

Example 6:1- [4- [ 3-chloro-4- [ 2-chloro-3- [5- [ (dimethylamino) methyl ] -6-methoxy-2-pyridinyl ] phenyl ] -2-pyridinyl ] -2-methoxy-phenyl ] -N, N-dimethyl-methylamine (137)

1- [4- [ 3-chloro-4- [ 2-chloro-3- [5- [ (dimethylamino) methyl ] methyl]-6-methoxy-2-pyridinyl]Phenyl group]-2-pyridyl group]-2-methoxy-phenyl]-N, N-dimethyl-methylamine according to the reductive amination procedure A starting from 6- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl]Phenyl group]-2-methoxy-pyridine-3-carbaldehyde (40 mg,0.08 mmol) and N-methyl methylamine (2.0M solution in ethanol, 0.32 mmol) were prepared as formate. 67% yield. MS: m/z found 551.2[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.67(dd,1H),8.53(s,2H),7.82(d1H),7.74(dd,1H),7.57(t,1H),7.52(d,1H),7.48(d,1H),7.44(dd,1H),7.41(d,1H),7.37(dd,1H),7.33(d,1H),4.27(s,2H),4.05(d,3H),3.99(s,3H),3.97(s,2H),2.80(s,6H),2.61(s,6H).

Example 7:2- [ [4- [ 3-chloro-4- [ 2-chloro-3- [5- [ [ 2-hydroxyethyl (methyl) amino ] methyl ] -6-methoxy-2-pyridinyl ] phenyl ] -2-pyridinyl ] -2-methoxy-phenyl ] methyl-amino ] ethanol (138)

2- [ [4- [ 3-chloro-4- [ 2-chloro-3- [5- [ [ 2-hydroxyethyl (methyl) amino ]]Methyl group]-6-methoxy-2-pyridinyl]Phenyl group]-2-pyridyl group]-2-methoxy-phenyl]Methyl-amino group]Ethanol was prepared according to reductive amination procedure A from 6- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl]Phenyl group]-2-methoxy-pyridine-3-carbaldehyde (40 mg,0.08 mmol) and 2- (methylamino) ethanol (24 mg,0.32 mmol) were prepared as formate. Yield 70%. MS: m/z found 611.2[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),8.53(s,2H),7.86(d1H),7.73(dd,1H),7.61–7.51(m,2H),7.48(d,1H),7.43(dd,1H),7.40(d,1H),7.36(dd,1H),7.31(d,1H),4.32(s,2H),4.03(s,3H),4.00–3.93(m,5H),3.89(t,2H),3.81(t2H),3.19(t,2H),2.92(t,2H),2.77(s,3H),2.55(s,3H).

Example 8:1- [4- [ [4- [4- [3- [5- [ [ (1-acetyl-4-piperidinyl) amino ] methyl ] -6-methoxy-2-pyridinyl ] -2-chloro-phenyl ] -3-chloro-2-pyridinyl ] -2-methoxy-phenyl ] methylamino ] -1-piperidinyl ] ethanone (139)

1- [4- [ [4- [4- [3- [5- [ [ (1-acetyl-4-piperidinyl) amino ] amino]Methyl group]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]-2-methoxy-phenyl]Methylamino group]-1-piperidinyl group]The ethanone was prepared according to reductive amination procedure A from 6- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl]Phenyl group]-2-methoxy-pyridine-3-carbaldehyde (30 mg,0.06 mmol) and 1- (4-amino-1-piperidinyl) ethanone (34 mg,0.24 mmol) were prepared as formate. 77% yield. MS: m/z realMeasurement value 745.3[ M+H ] ] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.67(dd,1H),8.50–8.43(m,2H),7.91–7.84(m,1H),7.76–7.68(m,1H),7.61–7.51(m,2H),7.50–7.42(m,2H),7.39(s,1H),7.34(td,2H),4.65(t,2H),4.31(s,2H),4.19(s,2H),4.12–4.01(m,5H),3.99(s,3H),3.20(t,2H),2.70(t,2H),2.30–2.17(m,3H),2.17–2.06(m,9H),1.71–1.37(m,4H).

Example 9:1- [4- [ [4- [4- [3- [5- [ [ (1-acetyl-4-piperidinyl) -methyl-amino ] methyl ] -6-methoxy-2-pyridinyl ] -2-chloro-phenyl ] -3-chloro-2-pyridinyl ] -2-methoxy-phenyl ] methyl-amino ] -1-piperidinyl ] ethanone (140)

1- [4- [ [4- [4- [3- [5- [ [ (1-acetyl-4-piperidinyl) -methyl-amino [ (1-acetyl-4-piperidinyl)]Methyl group]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]-2-methoxy-phenyl]Methyl-amino group]-1-piperidinyl group]The ethanone was prepared according to reductive amination procedure A from 6- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl]Phenyl group]-2-methoxy-pyridine-3-carbaldehyde (30 mg,0.06 mmol) and 1- [4- (methylamino) -1-piperidinyl]Ethaneketone (38 mg,0.24 mmol) was prepared as formate. Yield 30%. MS: m/z found 773.3[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),8.49–8.42(m,2H),7.83(d,1H),7.73(d,1H),7.60–7.51(m,2H),7.50–7.45(m,1H),7.45–7.33(m,3H),7.32–7.25(m,1H),4.74(d,1H),4.65(d,1H),4.31–4.04(m,4H),4.02(s,3H),3.98(s,3H),3.91–3.84(m,2H),3.24–3.10(m,2H),2.76–2.59(m,5H),2.46(s,3H),2.24–2.11(m,10H),2.09–1.98(m,2H),1.92–1.52(m,4H).

Example 10:8- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) -amino) methyl) -pyridin-2-yl) phenyl) pyridin-2-yl) -3- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4H-pyrido [1,2-a ] pyrimidin-4-one (2)

(a) 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde

Pd (PPh) ₃ ) ₄ (309 mg,0.27 mmol), potassium carbonate (554 mg,4.01 mmol), 2, 3-dichloro-4-iodo-pyridine (470 mg,1.74 mmol), and 6- [ 2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl ]-2-methoxy-pyridine-3-carbaldehyde (500 mg,1.34 mmol) was suspended in 1, 4-dioxane/water (4:1, 15 ml) and the solution was then heated at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 15mL of water, and extracted with EtOAc (3×10 mL). Concentrating the combined organics under reduced pressure and passing through normal phase SiO ₂ The crude sample was purified by chromatography (0-30% EtOAc/hexanes) to afford 6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl ] as a tan solid]-2-methoxy-pyridine-3-carbaldehyde (373 mg,71% yield). MS: m/z found 393,395[ M+H ]] ⁺ .

(b) 4-oxo-8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -4H-pyrido [1,2-a ] pyrimidine-3-carbaldehyde

8-bromo-4-oxo-pyrido [1,2-a ] in a sealed tube]Pyrimidine-3-carbaldehyde (500 mg,1.78 mmol), 4, 5-tetramethyl-2- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,3, 2-dioxaborane (587 mg,2.31 mmol), 1' -bis (biphenylphosphino) -ferrocene-palladium (II) dichloride dichloromethane complex (145 mg,0.18 mmol), and potassium acetate (188 mg,4.98 mmol) were suspended in 10mL 1, 4-dioxane. Nitrogen was bubbled through the reaction solution for 2 minutes, then the vessel was sealed and heated at 95 ℃ for 2 hours. The reaction was cooled to room temperature and the crude mixture was filtered through CELITE. The CELITE plug was further washed with 10mL 1, 4-dioxane and 30mL EtOAc. Insoluble solids (desired product) were then removed from the CELITE plug by washing with methanol (30 mL) . The methanol solution was then concentrated under reduced pressure and the crude oil was triturated with EtOAc/hexanes. The precipitate was filtered to provide 4-oxo-8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyrido [1,2-a ] as a tan solid]Pyrimidine-3-carbaldehyde (551 mg, crude). MS: m/z found 301[ M+H ]] ⁺ . The material was used in the next step without further purification.

(c) 8- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-3-carbaldehyde

Pd (PPh) ₃ ) ₄ (41 mg,0.04 mmol), potassium carbonate (74 mg,0.53 mmol), 6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl]-2-methoxy-pyridine-3-carbaldehyde (70 mg,0.18 mmol), and 4-oxo-8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyrido [1,2-a]Pyrimidine-3-carbaldehyde (69 mg,0.23 mmol) was suspended in 1, 4-dioxane/water (4:1, 3 mL) and the solution was heated at 105℃for 20 min. The reaction was cooled to room temperature, diluted with 4mL of water, and extracted with EtOAc (3×3 mL). The combined organics were concentrated under reduced pressure and the crude sample was passed through a short SiO ₂ Column (5-100% EtOAc/hexanes) to remove some impurities. The clean fractions were concentrated under reduced pressure to provide 8- [ 3-chloro-4- [ 2-chloro-3- (5-formyl-6-methoxy-2-pyridinyl) phenyl ] as a yellow foam ]-2-pyridyl group]-4-oxo-pyrido [1,2-a ]]Pyrimidine-3-carbaldehyde (38 mg, crude). MS: m/z found 531,533[ M+H ]] ⁺ . The material was used in the next step without further purification.

(d) 8- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) -amino) methyl) -pyridin-2-yl) phenyl) pyridin-2-yl) -3- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4H-pyrido [1,2-a ] pyrimidin-4-one (2)

8- [ 3-chloro-4- [ 2-chloro-3- (5-formyl-6-methoxy-2-pyridinyl) phenyl]-2-pyridyl group]-4-oxo-pyrido [1,2-a ]]Pyrimidine-3-carbaldehyde (38 mg,0.01mmol, crude), (5S) -5- (aminomethyl) pyrrolidin-2-one (5 mg,0.04 mmol), and acetic acid (2 mg,0.03 mmol) were dissolved in MeOH/THF (1:1, 1 mL) and the solution was stirred at 25℃for 2 hours. Adding NaBH ₃ CN (2 mg,0.03 mmol) and the resulting mixture was stirred at 25℃for 1 hour. The reaction was then diluted with water (2 mL) and extracted with EtOAc (3×2 mL). The combined organics were further washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the crude sample by reverse phase HPLC to afford 8- [ 3-chloro-4- [ 2-chloro-3- [ 6-methoxy-5- [ [ [ (2S) -5-oxopyrrolidin-2-yl ] as a tan foam ]Methylamino group]Methyl group]-2-pyridyl group]Phenyl group]-2-pyridyl group]-3- [ [ [ (2S) -5-oxopyrrolidin-2-yl]Methylamino group]Methyl group]Pyrido [1,2-a ]]Pyrimidin-4-one (6 mg,11% yield). MS: m/z found 727.4,729.4[ M+H ]] ⁺ Retention time = 1.97min (method C). ¹ H NMR (400 MHz, chloroform-d) delta 9.16-9.09 (m, 1H), 8.73 (d, 1H), 8.35 (s, 1H), 8.18-8.13 (m, 1H), 7.74 (dd, 1H), 7.67-7.57 (m, 2H), 7.50 (t, 1H), 7.39 (d, 1H), 7.31 (dd, 1H), 7.27 (s, 1H), 6.20 (s, 1H), 6.03 (s, 1H), 4.03 (d, 3H), 3.87 (d, 2H), 3.82 (s, 2H), 3.78 (s, 1H), 2.81 (dt, 2H), 2.62-2.51 (m, 2H), 2.41-2.33 (m, 4H), 2.24 (m, 2H), 1.82-1.74 (m, 2H), 0.85 (d, 1H).

Example 11: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -methyl) phenyl) -pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (8)

(a) 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde

Pd (PPh) ₃ ) ₄ (23 mg,0.02 mmol), potassium carbonate (42 mg,0.30 mmol), 6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl]-2-methoxy-pyridine-3-carbaldehyde (40 mg,0.10 mmol) and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (35 mg,0.13 mmol) were suspended in 1, 4-dioxane/water (4:1, 2 ml) and the solution was then heated at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 3mL of water, and extracted with EtOAc (3×2 mL). Concentrating the combined organics under reduced pressure and passing through normal phase SiO ₂ The crude sample was purified by chromatography (5-90% etoac/hexanes) to afford 6- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl as a yellow foam]Phenyl group]-2-methoxy-pyridine-3-carbaldehyde (37 mg,73% yield). MS: m/z found 493,495[ M+H ]] ⁺ .

(b) (S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -methyl) phenyl) -pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

6- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl]Phenyl group]-2-methoxy-pyridine-3-carbaldehyde (37 mg,0.04 mmol), (5S) -5- (aminomethyl) pyrrolidin-2-one (15 mg,0.13 mmol), and acetic acid (5 mg,0.09 mmol) were dissolved in MeOH/THF (1:1, 2 mL) and then the solution was stirred at 25℃for 2 hours. Adding NaBH ₃ CN (8 mg,0.13 mmol) and the resulting mixture was stirred at 25℃for 1 hour. The reaction was then diluted with water (2 mL) and extracted with EtOAc (3×2 mL). The combined organics were further washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the crude sample by reverse phase HPLC to afford (5S) -5- [ [ [4- [ 3-chloro-4- [ 2-chloro-3- [ 6-methoxy-5- [ [ (2S) -5-oxopyrrolidin-2-yl ] as a white solid (formate) ]Methylamino group]Methyl group]-2-pyridyl group]Phenyl group]-2-pyridyl group]-2-methoxy-phenyl]-methylamino group]-methyl group]Pyrrolidin-2-one (27 mg,86% yield). LCMS: m/z found 689.4,691[ M+H ]] ⁺ Retention time = 2.04min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.65(dd,1H),7.84(d,1H),7.71(dt,1H),7.60–7.49(m,2H),7.49–7.40(m,2H),7.38(d,1H),7.37–7.29(m,2H),4.27(d,2H),4.10(d,2H),4.05(d,3H),3.99(d,5H),3.18–3.06(m,2H),3.06–2.92(m,2H),2.45–2.28(m,6H),1.94–1.81(m,2H).

Example 12: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) -methyl) -amino) -methyl) -phenyl) -pyridin-4-yl) -phenyl) -2-methoxypyridin-3-yl) methyl) -amino) methyl) -pyrrolidin-2-one (10)

(a) 6- (2-chloro-3- (3-chloro-2- (3-fluoro-4-formyl-5-methoxyphenyl) -pyridin-4-yl) -phenyl) -2-methoxynicotinaldehyde

Pd (PPh) ₃ ) ₄ (23 mg,0.02 mmol), potassium carbonate (42 mg,0.30 mmol), 6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl]-2-methoxy-pyridine-3-carbaldehyde (40 mg,0.10 mmol), and 2-fluoro-6-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (37 mg,0.13 mmol) were suspended in 1, 4-dioxane/water (4:1, 2 ml) and the solution was then heated at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 3mL of water, and extracted with EtOAc (3×2 mL). Concentrating the combined organics under reduced pressure and passing through normal phase SiO ₂ The crude sample was purified by chromatography (5-90% etoac/hexanes) to afford 6- [ 2-chloro-3- [ 3-chloro-2- (3-fluoro-4-formyl-5-methoxy-phenyl) -4-pyridinyl as a yellow foam ]Phenyl group]-2-methoxy-pyridine-3-carbaldehyde (51 mg,73% yield). MS: m/z found 511,513[ M+H ]] ⁺ .

(b) (S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) -methyl) -amino) -methyl) -phenyl) -pyridin-4-yl) -phenyl) -2-methoxypyridin-3-yl) methyl) -amino) methyl) -pyrrolidin-2-one

6- [ 2-chloro-3- [ 3-chloro-2- (3-fluoro-4-formyl-5-methoxy-phenyl) -4-pyridinyl]Phenyl group]-2-methoxy-pyridine-3-carbaldehyde (51 mg,0.06 mmol), (5S) -5- (aminomethyl) pyrrolidin-2-one (20 mg,0.18 mmol), and acetic acid (7 mg,0.12 mmol) were dissolved in MeOH/THF (1:1, 2 mL) and the solution was then stirred at 25℃for 2 hours. Sodium cyanoborohydride (11 mg,0.18 mmol) was added and the resulting mixture was stirred at 25℃for 1 hour. The reaction was then diluted with water (2 mL) and extracted with EtOAc (3×2 mL). The combined organics were further washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the crude sample by reverse phase HPLC to afford (5S) -5- [ [ [6- [ 2-chloro-3- [ 3-chloro-2- [ 3-fluoro-5-methoxy-4- [ [ [ (2S) -5-oxopyrrolidin-2-yl ] as a white solid (formate)]Methylamino group]Methyl group]Phenyl group]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl ]Methylamino group]Methyl group]Pyrrolidin-2-one (21 mg,49% yield). MS: m/z found 707.3,709[ M+H ]] ⁺ LC retention time = 2.03min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.66(d,1H),8.38(s,2H),7.82(d,1H),7.72(dd,1H),7.56(t,1H),7.48(d,1H),7.42(dd,1H),7.30(d,1H),7.22(s,1H),7.16(d,1H),4.18(s,2H),4.07(d,2H),4.05(s,3H),3.99(s,3H),3.94(s,2H),2.96(m,4H),2.40–2.30(m,6H),1.91–1.80(m,2H).

Example 13: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -5-oxopyrrolidin-2-yl) methyl) -amino) -methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (11)

The compound was prepared in the same manner as described for compound 8, using intermediate 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde. 2-methoxy-4- (4, 5-tetramethyl-1, 3-dioxaborane-2-yl) -1H-indole-3-carbaldehyde was replaced with 1-methyl-6- (4, 5-tetramethyl-1, 32-dioxaborane-2-yl) benzaldehyde. The product was obtained as a white solid (formate). LCMS: m/z found 712.4,714[ M+H ]] ⁺ Retention time = 2.14min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.64(d,1H),8.47(s,2H),7.83(d,1H),7.77(t,2H),7.71(dd,1H),7.55(t,1H),7.52–7.46(m,2H),7.45–7.40(m,2H),7.27(d,1H),4.40(s,2H),4.03(s,3H),3.93–3.82(m,6H),3.11(d,2H),2.84–2.70(m,2H),2.42–2.23(m,6H),1.92–1.76(m,2H).

Example 14: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -5-oxopyrrolidin-2-yl) methyl) -amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one (13)

The compound was prepared in the same manner as described for compound 8, using intermediate 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde. With 1-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrrolo [3,2-b ]Pyridine-3-carbaldehyde replaces 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde. The product was obtained as a white solid. LCMS: m/z found 713.3,715[ M+H ]] ⁺ Retention time = 1.97min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.79(d,1H),8.71(d,1H),8.43(s,1H),8.32(d,1H),7.84(s,1H),7.81(d,1H),7.72(dd,1H),7.57(t,1H),7.49(d,1H),7.45(dd,1H),7.30(d,1H),4.56–4.42(m,2H),4.03(d,6H),3.96(s,4H),3.26–3.11(m,2H),2.96–2.83(m,2H),2.42–2.29(m,6H),1.94–1.78(m,2H).

Example 15:8- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) -amino) methyl) phenyl) pyridin-4-yl) phenyl) -3- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4H-pyrido [1,2-a ] pyrimidin-4-one (1)

(a) 8- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-3-carbaldehyde

Pd (PPh) ₃ ) ₄ (120 mg,0.10 mmol), potassium carbonate (216 mg,1.56 mmol), (2, 3-dichloro-4-pyridinyl) boronic acid (100 mg,0.52 mmol), and 8- (3-bromo-2-chloro-phenyl) -4-oxo-pyrido [1, 2-a)]Pyrimidine-3-carbaldehyde (265 mg,0.73 mmol) was suspended in 1, 4-dioxane/water (4:1, 5 mL) and the solution was heated at 105℃for 20 min. The reaction was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×5 mL). The combined organics were concentrated under reduced pressure and purified by flash chromatography (SiO ₂ The crude sample was purified with 5-90% EtOAc/hexanes to provide 8- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl ] as a yellow foam ]-4-oxo-pyrido [1,2-a ]]Pyrimidine-3-carbaldehyde (74 mg,33% yield). MS: m/z found 430,432[ M+H ]] ⁺ .

(b) 8- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-3-carbaldehyde

Pd (PPh) ₃ ) ₄ (19 mg,0.02 mmol), potassium carbonate (34 mg,0.24 mmol), 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (25 mg,0.10 mmol), and 8- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl]-4-oxo-pyrido [1,2-a ]]Pyrimidine-3-carbaldehyde (35 mg,0.08 mmol) was suspended in 1, 4-dioxane/water (4:1, 1 mL) and the solution was heated at 105℃for 20 min. The reaction was cooled to room temperature, diluted with 3mL of water, and extracted with EtOAc (3×2 mL). Concentrating the combined organics under reduced pressure and passing through normal phase SiO ₂ The crude sample was purified by chromatography (5-100% EtOAc/hexanes) to afford 8- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyri-dine as a yellow foamBoydo group]Phenyl group]-4-oxo-pyrido [1,2-a ]]Pyrimidine-3-carbaldehyde (43 mg, crude). MS: m/z found 530,532[ M+H ]] ⁺ . The material was used in the next step without further purification.

(c) 8- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) -amino) methyl) phenyl) pyridin-4-yl) phenyl) -3- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4H-pyrido [1,2-a ] pyrimidin-4-one

8- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl]Phenyl group]-4-oxo-pyrido [1,2-a ]]Pyrimidine-3-carbaldehyde (43 mg,0.08 mmol), (5S) -5- (aminomethyl) pyrrolidin-2-one (28 mg,0.24 mmol), and acetic acid (10 mg,0.16 mmol) were dissolved in MeOH/THF (1:1, 1 mL) and the solution was stirred at 25℃for 2 hours. Adding NaBH ₃ CN (10 mg,0.16 mmol) and the resulting mixture was stirred at 25℃for 1 hour. The reaction was then diluted with water (2 mL) and extracted with EtOAc (3×2 mL). The combined organics were further washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the crude sample by reverse phase HPLC to afford 8- [ 2-chloro-3- [ 3-chloro-2- [ 3-methoxy-4- [ [ [ (2S) -5-oxopyrrolidin-2-yl ] as a white foam (formate)]Methylamino group]Methyl group]Phenyl group]-4-pyridinyl]Phenyl group]-3- [ [ [ (2S) -5-oxopyrrolidin-2-yl]Methylamino group]Methyl group]Pyrido [1,2-a ]]Pyrimidin-4-one (7 mg,12% yield). MS: m/z found 726.4,728.4[ M+H ]] ⁺ LC retention time = 1.97min (method C). ¹ H NMR (400 MHz, chloroform-d) δ9.09 (d, 1H), 8.67 (d, 1H), 8.33 (s, 1H), 7.76 (d, 1H), 7.59-7.50 (m, 2H), 7.43 (dd, 1H), 7.36 (dd, 1H), 7.34-7.29 (m, 2H), 7.25 (s, 2H), 6.19 (s, 1H), 6.01 (s, 1H), 3.91 (d, 3H), 3.88-3.70 (m, 6H), 2.79 (ddd, 2H), 2.54 (ddd, 2H), 2.39-2.32 (m, 4H), 2.30-2.15 (m, 2H), 1.75 (dt, 2H).

Example 16: (S) -5- ((6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one (37)

(a) 2-chloro-6-methoxypyridin-4-amine

A solution of 2, 6-dichloropyridin-4-amine (150 g,0.92 mol) and sodium methoxide (60 g,1.1 mol) in NMP (600 mL) was stirred at 140℃for 12 hours. To the mixture was added water (2L) and extracted with EtOAc (2 x 3L). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. By rapid SiO ₂ The residue was purified by chromatography (0-20% EtOAc/petroleum ether) to afford 2-chloro-6-methoxypyridin-4-amine (77.4 g) as a yellow solid. ¹ H NMR(400MHz,CDCl ₃ ):δ6.16(s,1H),5.76(s,1H),4.20-4.02(m,2H),3.82(s,3H).

(b) 6-chloro-3-iodo-2-methoxypyridin-4-amine

A mixture of 2-chloro-6-methoxypyridin-4-amine (50 g,315 mmol) and N-iodosuccinimide (74.5 g,331 mmol) in DMF (300 mL) was stirred at room temperature for 1 hour. The mixture was diluted with water (200 mL) and extracted with EtOAc (300 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. By rapid SiO ₂ The residue was purified by chromatography (0-20% EtOAc/petroleum ether) to afford 6-chloro-3-iodo-2-methoxy-pyridin-4-amine (90 g) as a yellow solid. ¹ H NMR(400MHz,CDCl ₃ ):δ6.51-6.41(m,2H),6.36(s,1H),3.79(s,3H).

(c) 4, 6-dichloro-3-iodo-2-methoxypyridine

To copper chloride (5.67 g,42.2 mmol) and tert-butyl nitrite (5.44 g,52.7 mmol) at 0deg.C in CH ₃ The solution in CN (80 mL) was added dropwise to CH ₃ 6-chloro-3-iodo-2-methoxypyridin-4-amine (10 g,35.2 mmol) in CN (40 mL). The mixture was stirred at room temperature for 12 hours. The reaction mixture was then diluted with water (50 mL) and extracted with EtOAc (2×100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. By rapid SiO ₂ The residue was purified by chromatography (0-3% EtOAc/petroleum ether) to afford 4, 6-dichloro-3-iodo-2-methoxypyridine (9 g,84% yield) as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ7.45(s,1H),3.92(s,3H).

(d) 4, 6-dichloro-2-methoxynicotinaldehyde

To a solution of 4, 6-dichloro-3-iodo-2-methoxypyridine (4.5 g,14.8 mmol) in THF (60 mL) at-70℃was added n-BuLi (11.85 mL,2.5 mol/L). The mixture was stirred at-70℃for 0.5 h, after which time ethyl formate (2.19 g,29.6 mmol) was added. The reaction was stirred at-70℃for 0.5 h. The mixture was combined with another batch on the same scale. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. By rapid SiO ₂ Chromatography (0-5% EtOAc/petroleum ether) purified the residue to afford 4, 6-dichloro-2-methoxynicotinaldehyde (5 g,82% yield) as a white solid. NMR (400 MHz, DMSO-d) ₆ ):δ10.32(s,1H),6.98(s,1H),4.01(s,3H).

(f) 6- (3-bromo-2-chlorophenyl) -4-chloro-2-methoxy nicotinaldehyde

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To 4, 6-dichloro-2-methoxynicotinaldehyde (4.9 g,23.8 mmol), 2- (3-bromo-2-chlorophenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (7.17 g,22.6 mmol) in dioxane/H ₂ O (5:1, 60 mL)Cesium carbonate (23.3 g,71.4 mmol) and tetrakis (triphenylphosphine) palladium (1.37 g,1.19 mmol) were added. The mixture was stirred under nitrogen at 100 ℃ for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×200 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was triturated with EtOAc/petroleum ether (1/5, 60 ml) at room temperature for 0.5h to afford 6- (3-bromo-2-chlorophenyl) -4-chloro-2-methoxynicotinaldehyde as a white solid (5.3 g,62% yield). ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.36(s,1H),7.94(d,1H),7.67(d,1H),7.56(s,1H),7.45(t,1H),4.02(s,3H).

(g) (S) -5- ((((6- (3-bromo-2-chlorophenyl) -4-chloro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

To a mixture of 6- (3-bromo-2-chlorophenyl) -4-chloro-2-methoxynicotinaldehyde (13.8 g,38.2 mmol), (S) -5- (aminomethyl) pyrrolidin-2-one, HCl (11.5 g,76.4 mmol) in methylene chloride/trimethyl orthoformate (15:1 (v/v), 160 mL) was added sodium acetate (12.5 g,153 mmol). The mixture was stirred at room temperature under nitrogen for 1 hour. Sodium triacetoxyborohydride (24.3 g,115 mmol) was added and the mixture was taken up in N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated to provide (S) -5- ((((6- (3-bromo-2-chlorophenyl) -4-chloro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (17.5 g, crude, m/z:458[ M+H)] ⁺ ). The crude product was used directly without further purification.

(h) (S) - ((6- (3-bromo-2-chlorophenyl) -4-chloro-2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To (S) -5- ((((6- (3-bromo-2-chlorophenyl) -4-chloro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (17.5 g,38.1 mmol) and tert-butoxycarbonyl carbonateA mixture of tert-butyl ester (tert-butoxycarbonyl tert-butyl carbonate) (26.6 g,122 mmol) in methylene chloride (150 mL) was added TEA (13.3 mL,95.3 mmol). At N ₂ The mixture was stirred at room temperature for 1 hour. The mixture was filtered and the filtrate was concentrated. By flash chromatography (SiO ₂ The residue was purified with 0-80% EtOAc/petroleum ether to afford tert-butyl (S) - ((6- (3-bromo-2-chlorophenyl) -4-chloro-2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (15 g, 70%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ7.95(dd,1H),7.86(s,1H),7.66(s,1H),7.49-7.45(m,2H),4.74-4.58(m,2H),3.82(s,3H),3.82-3.77(s,1H),3.33(s,1H),3.12-3.00(m,1H),2.19-2.08(m,3H),1.81-1.74(m,1H),1.47-1.33(m,9H).

(j) (S) - ((4-chloro-6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To tert-butyl (S) - ((6- (3-bromo-2-chlorophenyl) -4-chloro-2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (8 g,14.3 mmol), potassium carbonate (5.93 g,42.9 mmol) and [1, 1-bis (biphenylphosphino) ferrocene]Palladium (II) dichloride in dichloromethane complex (284 mg,0.72 mmol) in dioxane/H ₂ A mixture of O (6:1, 140 mL) was added (2, 3-dichloropyridin-4-yl) boronic acid (3.02 g,15.7 mmol). At N ₂ The mixture was stirred at 95℃for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2×200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. By flash chromatography (SiO ₂ The residue was purified with 0-3% EtOAc/petroleum ether to afford tert-butyl (S) - ((4-chloro-6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (8.5 g) as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.57(d,1H),7.82(s,2H),7.69-7.63(m,2H),7.58(dd,1H),7.46(s,1H),4.73-4.62(m,2H),3.98(s,3H),3.81-3.80(m,1H),3.32(s,1H),3.13(s,1H),2.19-2.07(m,3H),1.73(s,1H),1.46-1.32(m,9H).

(k) (S) -5- ((6-bromo-8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one

To a mixture of 6-bromo-8-methoxy-1, 2,3, 4-tetrahydroisoquinoline, HCl (500 mg,1.79 mmol) in MeCN (100 mL) was added (5S) -5- (bromomethyl) pyrrolidin-2-one (418 mg,2.33 mmol) and potassium carbonate (744 mg,5.38 mmol). At N ₂ The mixture was stirred at 100℃for 12 hours. To this mixture was added (5S) -5- (bromomethyl) pyrrolidin-2-one (63.9 mg,0.36 mmol) and the mixture was stirred at 100℃for an additional 12 hours. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. By flash chromatography (SiO ₂ The residue was purified with 0-10% THF/EtOAc to provide (S) -5- ((6-bromo-8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one (0.6 g,98% yield, m/z:339,341[ M+H)] ⁺ )。

(l) (S) -5- ((8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one

To (S) -5- ((6-bromo-8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one (460 mg,1.36 mmol), 4', 5', A mixture of 5' -octamethyl-2, 2' -bis (1, 3, 2-dioxaborane) (1.03 g,4.07 mmol) in dioxane (8 mL) was added potassium acetate (266 mg,2.71 mmol) and [1,1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) dichloride (111 mg,0.14 mmol). At N ₂ The mixture was stirred at 130℃for 3 hours. The mixture was filtered and washed with EtOAc (20 mL) and concentrated. By flash chromatography (SiO ₂ The residue was purified by gradient of EtOAc/petroleum ether in THF (20%) 0-100% to afford @S) -5- ((8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one (0.49 g,65.48% yield, m/z:387[ M+H)] ⁺ Observed).

(m) (4-chloro-6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

To (S) -5- ((8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxabor-an-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one (250 mg,0.65 mmol), (S) - ((4-chloro-6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tert-butyl (5-oxopyrrolidin-2-yl) methyl) carbamate (324 mg,0.52 mmol) in dioxane/H ₂ Potassium carbonate (268 mg,1.94 mmol) and [1, 1-bis (biphenylphosphino) ferrocene were added to a mixture in O (6:1, 7 mL)]Palladium (II) chloride dichloromethane complex (52.8 mg,0.06 mmol). At N ₂ The mixture was stirred at 110℃for 0.5 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. By flash chromatography (SiO ₂ The residue was purified with 0-100% EtOAc/petroleum ether to provide ((4-chloro-6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester (250 mg,45% yield, m/z:849[ M+H ] methyl)] ⁺ Observed).

(n) (S) -5- ((6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one

To a solution of ((4-chloro-6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (240 mg,0.28 mmol) in methylene chloride (10 mL) was added TFA (5 mL,67.53 mmol). The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide (S) -5- ((6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one (74.8 mg,32% yield, observed m/z:749[ m+h ] ] ⁺ )。 ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.74(d,1H),7.77-7.75(m,3H),7.66-7.54(m,4H),7.19(s,2H),4.63(m,1H),4.43-4.14(m,4H),4.02(s,3H),3.92(s,3H),3.89-3.70(m,3H),3.27-3.10(m,2H),2.27-2.17(m,6H),1.82-1.79(m,2H).

Example 17: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (61)

(a) (S) -5- ((6-bromo-8-fluoro-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one

To a mixture of 6-bromo-8-fluoro-1, 2,3, 4-tetrahydroisoquinoline (0.35 g,1.52 mmol) and (S) -5- (bromomethyl) pyrrolidin-2-one (0.35 g,1.98 mmol) in MeCN (10 mL) was added potassium carbonate (0.63 g,4.56 mmol). The mixture was stirred at 100℃for 12 hours. The mixture was filtered and the filtrate was concentrated. By rapid colourSpectroscopy (SiO) ₂ The residue was purified from 50-100% ethyl acetate/petroleum ether to 10% MeOH/ethyl acetate to provide (5S) -5- [ (6-bromo-8-fluoro-3, 4-dihydro-1H-isoquinolin-2-yl) methyl as a yellow solid]Pyrrolidin-2-one (0.32 g,61% yield). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ7.17(s,1H),7.12(d,1H),4.03-3.97(m,1H),3.76-3.58(m,2H),2.95-2.92(m,2H),2.89-2.84(m,1H),2.78-2.72(m,1H),2.70-2.58(m,2H),2.42-2.26(m,3H),1.91-1.83(m,1H).

(b) (S) -5- ((8-fluoro-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one

To a mixture of (S) -5- ((6-bromo-8-fluoro-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one (0.27 g,0.84 mmol) and bis (pinacolato) diboron (bis (pinacolato) diboron) (0.64 g,2.52 mmol) in dioxane (4 mL) was added potassium acetate (0.25 g,2.52 mmol) and 1,1' -bis (biphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (0.07 g,0.08 mmol). The mixture was stirred at 130℃for 12 hours. The solvent was evaporated and purified by flash chromatography (SiO ₂ The residue was purified from 50-100% ethyl acetate/petroleum ether to 10% MeOH/ethyl acetate to provide (S) -5- ((8-fluoro-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one (0.3 g,95% yield). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ7.35(s,1H),7.18(d,1H),4.04-4.01(m,1H),3.83-3.71(m,2H),2.98-2.88(m,3H),2.82-2.78(m,1H),2.76-2.61(m,2H),2.40-2.29(m,3H),1.92-1.82(m,1H),1.36(m,12H).

(c) (S) - ((6- (3-bromo-2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

6- (3-bromo-2-chlorophenyl) -2-methoxy at room temperatureA mixture of methylnicotinaldehyde (20 g,61 mmol), (5S) -5- (aminomethyl) pyrrolidin-2-one, HCl (14 g,92 mmol) and sodium acetate (13 g,153 mmol) in methylene chloride/trimethoxy methane (5:1, 300 mL) was stirred for 4 hours. Sodium triacetoxyborohydride (26 g,122 mmol) was added to the mixture and the mixture was stirred at N ₂ Stirred at room temperature for 2 hours. To this solution were added di-tert-butyl dicarbonate (di-tert-butyl decarbonate) (42 mL,183 mmol) and triethylamine (30 mL,214 mmol) in methylene chloride (80 mL). At N ₂ The mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. By flash chromatography (SiO ₂ The residue was purified with 0-20% ethyl acetate/petroleum ether to provide tert-butyl (S) - ((6- (3-bromo-2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (20 g,62% yield, 526[ m+h ] observed as a yellow solid ] ⁺ )。

(d) (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To tert-butyl (S) - ((6- (3-bromo-2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (12 g,23 mmol), 1' -bis (biphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (0.93 g,1.14 mmol) and potassium carbonate (9.5 g,68 mmol) in dioxane/H ₂ A mixture of O mixture (6:1, 140 mL) was added to (2, 3-dichloro-4-pyridinyl) boronic acid (3.5 g,18 mmol) in dioxane (150 mL). The mixture was stirred under nitrogen at 95 ℃ for 1 hour. The mixture was diluted with water (50 mL) and extracted with EtOAc (2×200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. By flash chromatography (SiO ₂ The residue was purified with 0-15% EtOAc/petroleum ether to provide tert-butyl (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (7 g, observed m/z:591[ M+H ]) as a yellow solid] ⁺ )。 ¹ H NMR(400MHz,DMSO-d ₆ ):δ.8.51(d,1H),7.77-7.73(m,2H),7.65-7.56(m,2H),7.50-7.44(m,2H),7.31-7.29(m,1H),4.47-4.35(m,2H),3.94(s,3H),3.78-3.76(m,1H),3.33-3.27(m,2H),2.22-2.04(m,3H),1.73-1.72(m,1H),1.44-1.30(m,9H).

(e) (6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

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To (S) -5- ((8-fluoro-6- (4, 5-tetramethyl-1, 3, 2-dioxabor-an-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one (0.24 g,0.63 mmol) and (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tert-butyl (5-oxopyrrolidin-2-yl) methyl) carbamate (0.25 g,0.42 mmol) in dioxane/H ₂ A mixture of 1,1' -bis (biphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (0.02 g,0.02 mmol) and potassium carbonate (0.18 g,1.27 mmol) was added to a mixture of O mixtures (25:1, 5.2 mL). The mixture was stirred at 110℃for 2.5 hours. To the mixture was added water (15 mL). The mixture was extracted with ethyl acetate (2×15 mL). The combined organic phases were washed with brine (2×15 mL), dried over anhydrous sodium sulfate, filtered and concentrated. By flash chromatography (SiO ₂ The residue was purified to give tert-butyl ((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (50 mg,6% yield, observed m/z 803[ M+H) ] ⁺ )。

(f) (S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

To ((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester (0.04 g,0.05 mmol) in CH ₂ Cl ₂ Trifluoroacetic acid (0.8 mL) was added to the mixture in (0.5 mL). The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated. The residue was purified by reverse phase HPLC to provide (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (8.1 mg,18% yield, observed m/z:703[ m+h)]+)。 ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.71(d,1H),7.85(d,1H),7.75-7.65(m,3H),7.60(t,1H),7.54-7.48(m,2H),7.32-7.28(m,3H),3.93(s,3H),3.84-3.63(m,6H),2.93(m,2H),2.77(m,2H),2.61-2.56(m,4H),2.23-2.08(m,6H),1.79-1.67(m,2H).

Example 18: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (3-fluoropropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (65)

(a) 6-bromo-8-fluoro-2- (3-fluoropropyl) -1,2,3, 4-tetrahydroisoquinoline

To a mixture of 6-bromo-8-fluoro-1, 2,3, 4-tetrahydroisoquinoline (0.29 g,1.26 mmol) and 1-bromo-3-fluoro-propane (0.27 g,1.89 mmol) in MeCN (10 mL) was added potassium carbonate (0.52 g,3.78 mmol). The mixture was stirred at 100℃for 12 hours. The mixture was filtered and the filtrate was concentrated.By flash chromatography (SiO ₂ The residue was purified 0-10% ethyl acetate/petroleum ether to provide 6-bromo-8-fluoro-2- (3-fluoropropyl) -1,2,3, 4-tetrahydroisoquinoline as a yellow oil (0.23 g,48% yield). ¹ H NMR(400MHz,CDCl ₃ ):δ7.00(s,1H),6.95(d,1H),4.54(t,1H),4.42(t,J＝6Hz,1H),3.50(s,2H),2.82-2.80(m,2H),2.66-2.60(m,4H),1.97-1.86(m,2H).

(b) 8-fluoro-2- (3-fluoropropyl) -6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,2,3, 4-tetrahydroisoquinoline

To a mixture of 6-bromo-8-fluoro-2- (3-fluoropropyl) -1,2,3, 4-tetrahydroisoquinoline (0.21 g,0.72 mmol) and bis (pinacolato) diboron (0.55 g,2.17 mmol) in dioxane (4 mL) was added 1,1' -bis (biphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (0.03 g,0.036 mmol) and potassium acetate (0.21 g,2.17 mmol). The mixture was stirred at 120℃for 12 hours. The solvent was evaporated and purified by flash chromatography (SiO ₂ The residue was purified 0-10% ethyl acetate/petroleum ether to provide 8-fluoro-2- (3-fluoropropyl) -6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,2,3, 4-tetrahydroisoquinoline as a yellow oil (0.2 g,81% yield). ¹ H NMR(400MHz,CDCl ₃ ):δ7.28(s,1H),7.19-7.16(m,1H),4.55(t,1H),4.43(t,1H),3.60(s,2H),2.85(m,2H),2.67-2.63(m,4H),1.98-1.91(m,2H),1.27(s,12H).

(c) (S) - ((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (3-fluoropropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

To 8-fluoro-2- (3-fluoropropyl) -6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,2,3, 4-tetrahydroisoquinoline (0.18 g,0.55 mmol) and (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxy)Tert-butyl (5-oxopyrrolidin-2-yl) methyl) carbamate (0.18 g,0.3 mmol) in dioxane/H ₂ A mixture of 1,1' -bis (biphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (0.025 g,0.03 mmol) and potassium carbonate (0.13 g,0.91 mmol) was added to a mixture of O mixtures (40:3, 4.3 mL). The mixture was stirred at 110℃for 4 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. By flash chromatography (SiO ₂ The residue was purified with 0-100% ethyl acetate/petroleum ether to provide tert-butyl (S) - ((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (3-fluoropropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (0.14 g,40% yield, observed m/z:766[ M+H ] ] ⁺ )。

(d) (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (3-fluoropropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

To tert-butyl (S) - ((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (3-fluoropropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (0.13 g,0.17 mmol) in CH ₂ Cl ₂ To the mixture in (0.5 mL) was added trifluoroacetic acid (2 mL,27 mmol). The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide (S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (3-fluoropropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (25.1 mg,19% yield, observed m/z:666[ m+h)] ⁺ )。 ¹ H NMR(400MHz,DMSO):δ8.71(d,1H),7.85(d,1H),7.74-7.69(m,2H),7.60(t,1H),7.53-7.48(m,2H),7.32-7.28(m,3H),4.60(t,1H),4.48(t,1H),3.93(s,3H),3.78-3.70(m,2H),3.67-3.64(m,3H),2.92-2.90(m,2H),2.74-2.71(m,2H),2.64(t,2H),2.58(d,2H),2.16-2.09(m,3H),1.99-1.89(m,2H),1.72-1.67(m,1H).

Example 19: (S) - ((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (3-fluoropropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester (72)

(a) N- (4-bromo-2-chlorophenyl) -2, 2-dimethoxyethylamine

To a mixture of 4-bromo-2-chloro-benzaldehyde (34 g,155 mmol) and 2, 2-dimethoxyethylamine (16.28 g,155 mmol) in ethanol (500 mL) was added sodium cyanoborohydride (7.04 g,186 mmol). The mixture was stirred at room temperature for 12 hours. To the mixture was added aqueous ammonium chloride solution (200 mL). The mixture was extracted with ethyl acetate (2×100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. By rapid SiO ₂ The residue was purified by chromatography (0-100% ethyl acetate/petroleum ether) to afford N- [ (4-bromo-2-chloro-phenyl) methyl as a white solid]-2, 2-dimethoxy-ethylamine. (42 g, observed 307[ M+H)] ⁺ )。

(b) N- (4-bromo-2-chlorophenyl) -N- (2, 2-dimethoxyethyl) benzenesulfonamide

To N- [ (4-bromo-2-chloro-phenyl) methyl]-2, 2-dimethoxy-ethylamine (46 g,149 mmol) and triethylamine (37 ml,268 mmol) in CH ₂ Cl ₂ 4-dimethylaminopyridine (0.92 g,7.45 mmol) and benzenesulfonyl chloride (31.6 g, 178 mmol) were added to the mixture (350 mL). The mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (2 x250 mL). Wash with brine (2 x250 mL)The combined organic phases were washed, dried over anhydrous sodium sulfate, filtered and concentrated. By flash chromatography (SiO ₂ 0-100% ethyl acetate/petroleum ether) to provide N- [ (4-bromo-2-chloro-phenyl) methyl as a white solid]-N- (2, 2-dimethoxyethyl) benzenesulfonamide (57 g,85% yield). ¹ H NMR(400MHz,CDCl ₃ ):δ:7.81-7.80(m,2H),7.61-7.57(m,1H),7.53-7.49(m,2H),7.45(m,1H),7.35(s,2H),4.50(s,2H),4.34(t,J＝5.2Hz,1H),3.29-3.21(m,7H).

(c) 6-bromo-8-chloroisoquinoline

To aluminum chloride (28 g,212 mmol) at-5℃in CH ₂ Cl ₂ The mixture in (150 mL) was added CH at once ₂ Cl ₂ N- [ (4-bromo-2-chloro-phenyl) methyl in (150 mL)]N- (2, 2-Dimethoxyethyl) benzenesulfonamide (19 g,42.3 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was quenched with 1N aqueous HCl solution (200 mL) at-10deg.C and quenched with CH ₂ Cl ₂ (400 mL) extraction. The organic phase was washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. By rapid SiO ₂ Chromatography (0-15% ethyl acetate/petroleum ether) purify the residue to provide 6-bromo-8-chloro-isoquinoline (5.5 g,18% yield, 243[ m+h ] as observed as a yellow solid] ⁺ )。

(d) 6-bromo-8-chloro-1, 2,3, 4-tetrahydroisoquinoline

At N ₂ To a mixture of 6-bromo-8-chloro-isoquinoline (2 g,8.25 mmol) in glacial acetic acid (50 mL) was added sodium cyanoborohydride (1.09 g,28.9 mmol) in portions. The mixture was stirred at room temperature for 3 hours. To the mixture was added dropwise saturated aqueous sodium bicarbonate solution (50 mL) and sodium carbonate solution (50 mL). The mixture was extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with brine (2×25 mL), dried over anhydrous sodium sulfate, and concentratedFiltered and concentrated to provide 6-bromo-8-chloro-1, 2,3, 4-tetrahydroisoquinoline (1.5 g, crude, 60% yield). The material was used without any purification. ¹ H NMR(400MHz,DMSO-d ₆ ):δ7.47(d,1H),7.32(s,1H),3.75(s,2H),2.90-2.83(m,2H),2.71-2.69(m,2H).

(e) 6-bromo-8-chloro-2- (3-fluoropropyl) -1,2,3, 4-tetrahydroisoquinoline

To a mixture of 6-bromo-8-chloro-1, 2,3, 4-tetrahydroisoquinoline (0.4 g,1.62 mmol) and 1-bromo-3-fluoro-propane (0.46 g,3.25 mmol) in acetonitrile (25 mL) was added potassium carbonate (0.67 g,4.87 mmol). The mixture was stirred at 100℃for 12 hours. The mixture was filtered and the filtrate was concentrated. By rapid SiO ₂ Chromatography (0-50% EtOAc/petroleum ether) purified the residue to afford 6-bromo-8-chloro-2- (3-fluoropropyl) -3, 4-dihydro-1H-isoquinoline (0.26 g,44% yield, 308[ m+h ] observed] ⁺ )。

(f) 8-chloro-2- (3-fluoropropyl) -6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,2,3, 4-tetrahydroisoquinoline

To a mixture of 6-bromo-8-chloro-2- (3-fluoropropyl) -3, 4-dihydro-1H-isoquinoline (0.22 g,0.72 mmol) and bis (pinacolato) diboron (0.55 g,2.15 mmol) in dioxane (10 mL) was added potassium acetate (0.21 g,2.15 mmol) and 1,1' -bis (biphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (0.06 g,0.07 mmol). The mixture was stirred at 120 ° for 12 hours. The mixture was concentrated and purified by flash chromatography (SiO ₂ The residue was purified 0-15% ethyl acetate/petroleum ether to provide 8-chloro-2- (3-fluoropropyl) -6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydro-1H-isoquinoline as a yellow oil (0.1 g,39% yield). ¹ H NMR(400MHz,CDCl ₃ ):δ7.53(s,1H),7.39(s,1H),4.55(t,J＝1.6Hz,1H),4.45-4.42(m,1H),3.64-3.52(m,2H),2.92-2.85(m,2H),2.65(m,4H),1.97-1.85(m,2H),1.27(s,12H).

(g) N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [ 8-chloro-2- (3-fluoropropyl) -3, 4-dihydro-1H-isoquinolin-6-yl ] -4-pyridinyl ] phenyl ] -2-methoxy-3-pyridinyl ] methyl ] -N- [ [ (2S) -5-oxopyrrolidin-2-yl ] methyl ] carbamic acid tert-butyl ester

To 8-chloro-2- (3-fluoropropyl) -6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydro-1H-isoquinoline (0.07 g,0.2 mmol) and N- [ [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl ] ]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (0.09 g,0.15 mmol) in dioxane/H ₂ A mixture of potassium carbonate (0.06 g,0.45 mmol) and 1,1' -bis (biphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (0.02 g,0.02 mmol) was added to a mixture of O mixtures (10:1, 1.1 mL). The mixture was stirred at 110℃for 5 hours. The solvent was evaporated and the residue was purified by preparative TLC (silica gel, etOAc: meoh=3:1) to afford N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [ 8-chloro-2- (3-fluoropropyl) -3, 4-dihydro-1H-isoquinolin-6-yl as a yellow oil]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (0.04 g,23% yield, 781[ M+H ] observed] ⁺ )。

(h) (S) - ((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (3-fluoropropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

To N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [ 8-chloro-2- (3-fluoropropyl) -3, 4-dihydro-1H-isoquinolin-6-yl ]]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (0.06 g,0.77 mmol) in CH ₂ Cl ₂ (0.2 mL) of the mixtureTrifluoroacetic acid (0.75 ml,10 mmol) was added. The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide (5S) -5- [ [ [6- [ 2-chloro-3- [ 3-chloro-2- [ 8-chloro-2- (3-fluoropropyl) -3, 4-dihydro-1H-isoquinolin-6-yl ]]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methylamino group]Methyl group]Pyrrolidin-2-one (2.5 mg,5% yield, 682[ M+H ] observed] ⁺ )。 ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.63(d,1H),7.83(d,1H),7.71(dd,1H),7.58-7.54(m,2H),7.46-7.42(m,3H),7.32(d,1H),4.62(t,1H),4.50(t,1H),4.12-4.11(m,2H),4.06(s,3H),3.95(m,1H),3.88(s,2H),3.07-2.87(m,8H),2.40-2.33(m,3H),2.15-2.05(m,2H),1.89-1.83(m,1H).

Example 20: (S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (67)

(a) (S) -5- ((6-bromo-8-chloro-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one

To a mixture of 6-bromo-8-chloro-1, 2,3, 4-tetrahydroisoquinoline (0.5 g,2 mmol) and (5S) -5- (bromomethyl) pyrrolidin-2-one (0.47 g,2.64 mmol) in MeCN (25 mL) was added potassium carbonate (0.84 g,6.08 mmol). The mixture was stirred at 100℃for 12 hours. The mixture was filtered and the filtrate was concentrated. By flash chromatography (SiO ₂ The residue was purified from 50-100% ethyl acetate/petroleum ether to 10% MeOH/ethyl acetate to provide (S) -5- ((6-bromo-8-chloro-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one (420 mg,60% yield) as a yellow solid. ¹ H NMR(400MHz,DMSO):δ7.61(s,1H),7.52(d,1H),7.38(s,1H),3.80-3.78(m,1H),3.60-3.53(m,2H),2.85-2.82(m,2H),2.72-2.68(m,2H),2.60-2.53(m,2H),2.19-2.08(m,3H),1.74-1.69(m,1H).

(b) (S) -5- ((8-chloro-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one

To a mixture of (S) -5- ((6-bromo-8-chloro-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one (0.37 mg,1.08 mmol) and bis (pinacolato) diboron (0.82 g,3.23 mmol) in dioxane (10 mL) was added potassium acetate (0.32 g,3.23 mmol) and 1,1' -bis (biphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (0.09 g,0.11 mmol). The mixture was stirred at 120 ° for 12 hours. The solvent was evaporated and purified by flash chromatography (SiO ₂ The residue was purified with 50-100% ethyl acetate/petroleum ether to afford (S) -5- ((8-chloro-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one (0.28 g,66% yield) as a yellow oil. ¹ H NMR (400 MHz, methanol-d) ₄ ):δ7.38(s,1H),7.33(s,1H),3.90(m,1H),3.69-3.58(m,2H),2.83-2.79(m,4H),2.61-2.52(m,2H),2.26-2.20(m,3H),1.79-1.74(m,1H),1.23(s,12H).

(c) (6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To (S) -5- ((8-chloro-6- (4, 5-tetramethyl-1, 3, 2-dioxabor-an-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one (0.24 g,0.61 mmol) and (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tert-butyl (5-oxopyrrolidin-2-yl) methyl) carbamate (0.18 g,0.3 mmol) in dioxane/H ₂ 1,1' -bis (biphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane was added to a mixture in O mixture (25:2, 5.4 mL)The complex (0.025 g,0.03 mmol) and potassium carbonate (0.13 g,0.91 mmol). The mixture was stirred at 110℃for 3 hours. The mixture was diluted with water (10 mL) and brine (10 mL). The mixture was extracted with ethyl acetate/THF mixture (1:1, 20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. By flash chromatography (SiO ₂ 50-100% ethyl acetate/Petroleum ether to 10% MeOH/ethyl acetate) to purify the residue to afford ((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (0.16 g,39% yield, m/z:819[ M=H)] ⁺ )。

(d) (S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

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To ((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (0.15 g,0.18 mmol) in CH ₂ Cl ₂ Trifluoroacetic acid (2 mL) was added to the mixture in (0.5 mL). The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated. The residue was purified by reverse phase HPLC to provide (S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (9.3 mg,6% yield, observed m/z 719[ m+h] ⁺ )。 ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.72(d,1H),7.84(d,1H),7.74-7.46(m,7H),7.28(d,1H),3.92(s,3H),3.84-3.81(m,1H),3.72-3.62(m,5H),2.93(m,2H),2.78-2.73(m,2H),2.61-2.56(m,4H),2.23-2.08(m,6H),1.76-1.66(m,2H).

Example 21: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- ((S) -2-hydroxypropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (69)

(a) (S) -1- (6-bromo-8-chloro-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol:

to a solution of 6-bromo-8-chloro-1, 2,3, 4-tetrahydroisoquinoline (400 mg,1.62 mmol) and (2S) -2-methyl oxirane (1.14 mL,16.2 mmol) in EtOH (40 mL) was added triethylamine (0.67 mL,4.87 mmol). The mixture was stirred at 50℃for 3 hours. The reaction mixture was concentrated under reduced pressure. By rapid SiO ₂ The residue was purified by chromatography (10-20% EtOAc/petroleum ether) to afford (S) -1- (6-bromo-8-chloro-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol as a yellow oil (349 mg,71% yield). ¹ H NMR (400 MHz, methanol-d) ₄ )δ7.36(s,1H),7.20(s,1H),3.99-3.96(m,1H),3.76(d1 H),3.55(d,1H),2.93-2.88(m,3H),2.67-2.65(m,1H),2.57-2.47(m,2H),1.19(d,3H).

(b) (S) -1- (8-chloro-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol:

to (S) -1- (6-bromo-8-chloro-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (279 mg,0.92 mmol), 4', 5', A mixture of 5' -octamethyl-2, 2' -bis (1, 3, 2-dioxaborane) (698 mg,2.75 mmol) and potassium acetate (270 mg,2.75 mmol) in dioxane (8 mL) was added 1,1' -bis (biphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (74.8 mg,0.09 mmol). The mixture was stirred under nitrogen at 110 ℃ for 12 hours. The mixture was concentrated. By flash chromatography (SiO ₂ ,10-15％The residue was purified with EtOAc/petroleum ether to provide (S) -1- (8-chloro-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (180 mg,56% yield, m/z:352[ M+H)] ⁺ )。

(c) (6- (2-chloro-3- (3-chloro-2- (8-chloro-2- ((S) -2-hydroxypropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

For (S) -1- (8-chloro-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (115 mg,328 mol), (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (97 mg,164 mol), potassium carbonate (68.0 mg,492 mol) in H ₂ The mixture in O (0.3 mL) and dioxane (3 mL) was degassed. To this mixture was added 1,1' -bis (biphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (13.4 mg,16.4 umol). The mixture was stirred under nitrogen at 110 ℃ for 12 hours. The mixture was concentrated and purified by preparative TLC (SiO ₂ The residue was purified with 10% MeOH/methylene chloride to provide tert-butyl ((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- ((S) -2-hydroxypropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (60 mg,44% yield, observed m/z:780[ m+h)] ⁺ )。

(d) (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- ((S) -2-hydroxypropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

To ((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- ((S) -2-hydroxypropyl) -1,2,3, 4-tetrahydroisoquinoline)A solution of tert-butyl (6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (90 mg,0.12 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (6.5 mL,87.8 mmol). The mixture was stirred at 25℃for 30 minutes. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- ((S) -2-hydroxypropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (11.6 mg,14% yield, m/z:680[ m+h ] ⁺ )。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.71(d,1H),7.89(d,1H),7.74-7.69(m,2H),7.63-7.50(m,4H),7.46(s,1H),7.32(d,1H),3.95-3.87(m,6H),3.72(s,3H),2.94-2.92(m,2H),2.80-2.67(m,4H),2.59-2.56(m,2H),2.18-2.09(m,3H),1.76-1.72(m,1H),1.10(d,3H).

Example 22: (S) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (86)

(a) (S) -1- (6-bromo-8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol

To a mixture of 6-bromo-8-methoxy-1, 2,3, 4-tetrahydroisoquinoline, HCl (0.25 g,0.9 mmol) in EtOH (4 mL) was added N-ethyl-N-isopropyl-propan-2-amine (0.94 mL,5.38 mmol) and (2S) -2-methyl-oxirane (0.38 mL,5.38 mmol). The mixture was stirred at room temperature for 12 hours. The mixture was concentrated to give (S) -1- (6-bromo-8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (0.35 g, crude, m/z:300[ M+H)] ⁺ )。

(b) (S) -1- (8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol

To a mixture of (S) -1- (6-bromo-8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (0.3 g,1 mmol) and bis (pinacolato) diboron (0.63 g,2.5 mmol) in dioxane (6 mL) was added potassium acetate (0.2 g,2 mmol) and 1,1' -bis (biphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (0.04 g,0.05 mmol). The mixture was stirred at 115℃for 3 hours. The mixture was concentrated and purified by flash chromatography (SiO ₂ The residue was purified from 0-15% ethyl acetate/petroleum ether to 20% MeOH/ethyl acetate to provide (S) -1- (8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (0.17 g,45% yield, observed m/z:348[ m+h)] ⁺ )。 ¹ H NMR (400 MHz, methanol-d) ₄ ):δ7.23(s,1H),7.17(s,1H),4.26-4.20(m,1H),4.18-4.10(m,2H),3.89(s,3H),3.30-3.23(m,2H),3.10-3.07(m,2H),3.03-2.95(m,2H),1.37(s,12H),1.27-1.25(m,3H).

(c) (4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

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To tert-butyl (S) - ((4-chloro-6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (0.17 g,0.27 mmol) and (S) -1- (8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (0.095 g,0.27 mmol) in dioxane/H ₂ A mixture of potassium carbonate (0.11 g,0.82 mmol) and 1,1' -bis (biphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (0.022 g,0.03 mmol) were added to a mixture of O mixtures (8:1, 4.5 mL). The mixture was stirred at 110℃for 5 hours. With water (5 mL) andthe mixture was diluted with brine (5 mL). The mixture was extracted with ethyl acetate/THF mixture (1:1, 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (silica gel, ethyl acetate: meoh=2:1) to give ((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) as a yellow solid (0.13 g,29% yield, m/z:810[ m+h ] methyl) carbamic acid tert-butyl ester ] ⁺ )。

(d) (S) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

To ((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (0.13 g,0.15 mmol) in CH ₂ Cl ₂ Trifluoroacetic acid (1.5 mL) was added to the mixture in (0.3 mL). The mixture was stirred at room temperature for 10 minutes. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide (S) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (26.4 mg,22% yield, observed m/z:710[ m+h)] ⁺ )。 ¹ H NMR(400MHz,DMSO):δ8.70(d,1H),7.75(dd,1H),7.65-7.59(m,2H),7.54-7.53(m,1H),7.49(d,1H),7.40(s,1H),7.06(s,2H),3.96(s,3H),3.92-3.87(m,3H),3.82(s,3H),3.66-3.57(m,3H),2.87-2.86(m,2H),2.78-2.77(m,2H),2.59-2.55(m,2H),2.45-2.43(m,2H),2.16-2.08(m,3H),1.72-1.64(m,1H),1.10(d,3H).

Example 23: (S) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (104)

(a) (R) -1- (6-bromo-8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol

To a mixture of 6-bromo-8-methoxy-1, 2,3, 4-tetrahydroisoquinoline, HCl (0.5 g,1.8 mmol) in EtOH (6 mL) was added N-ethyl-N-isopropyl-propan-2-amine (1.9 mL,10.8 mmol) and (2R) -2-methyl-oxirane (1 mL,14.4 mmol). The mixture was stirred at room temperature for 12 hours. The mixture was concentrated to give (R) -1- (6-bromo-8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (0.6 g, crude, m/z:300[ M+H)] ⁺ )。

(b) (R) -1- (8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol

To a mixture of (R) -1- (6-bromo-8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (0.6 g,2 mmol) and bis (pinacolato) diboron (1.02 g,4 mmol) in dioxane (15 mL) was added 1,1' -bis (biphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (0.065 g,0.08 mmol) and potassium acetate (0.39 g,4 mmol). The mixture was stirred at 115℃for 12 hours. The mixture was concentrated and purified by flash chromatography (SiO ₂ The residue was purified from 0-100% THF 30% to 5% MeOH in ethyl acetate/petroleum ether to provide (R) -1- (8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (0.45 g,55% yield). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ7.20(s,1H),7.14(s,1H),4.17-4.12(m,1H),3.87(s,3H),3.24-2.90(m,6H),2.82-2.80(m,2H),1.36(s,12H),1.24-1.22(m,3H).

(c) (4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

To (R) -1- (8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (0.16 g,0.46 mmol) and (S) - ((4-chloro-6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester (5-oxopyrrolidin-2-yl) methyl) (0.13 g,0.21 mmol) in dioxane/H ₂ A mixture of 1,1' -bis (biphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (0.017 g,0.021 mmol) and potassium carbonate (0.086 g,0.62 mmol) was added to a mixture of O mixtures (10:1, 3.3 mL). The mixture was stirred at 110℃for 9 hours. The mixture was diluted with water (5 mL) and brine (5 mL). The mixture was extracted with ethyl acetate/THF mixture (1:1, 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (silica gel, ethyl acetate: meoh=2:1) to give ((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) as a brown solid (tert-butyl (0.06 g,29% yield, m/z:810[ m+h ] methyl) carbamate ] ⁺ ).

(d) (S) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

To ((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl)) Phenyl) -2-methoxypyridin-3-yl) methyl (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (0.055 g,0.068 mmol) in CH ₂ Cl ₂ Trifluoroacetic acid (1 mL) was added to the mixture in (0.3 mL). The mixture was stirred at room temperature for 10 minutes. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide (S) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (14.3 mg,26% yield, m/z:710[ m+h] ⁺ )。 ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.70(d,1H),7.76-7.74(m,1H),7.67(m,1H),7.63-7.59(m,1H),7.54-7.53(m,1H),7.49(d,1H),7.40(s,1H),7.05(s,2H),3.96(s,3H),3.86-3.82(m,6H),3.58-3.52(m,3H),2.86(m,2H),2.72-2.67(m,4H),2.45-2.33(m,2H),2.09(m,3H),1.67(m,1H),1.09(d,3H).

Example 24: (S) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (124)

(a) 6-bromo-2- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinoline

To a mixture of 6-bromo-8-methoxy-1, 2,3, 4-tetrahydroisoquinoline (0.4 g,1.65 mmol) and 2-bromoethoxy-tert-butyl-dimethyl-silane (0.59 g,2.48 mmol) in MeCN (8 mL) was added triethylamine (1.4 mL,9.91 mmol). The mixture was stirred at 100℃for 12 hours. The mixture was concentrated, and water (5 mL) and brine (5 mL) were added to the residue. The mixture was extracted with ethyl acetate/THF mixture (1:1, 20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. By flash chromatography (SiO ₂ 0-30% ethyl acetate/petroleum ether) purificationThe residue was taken up to give 6-bromo-2- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinoline (0.45 g,62% yield). ¹ H NMR(400MHz,CDCl ₃ ):δ6.80(s,1H),6.70(s,1H),3.79-3.76(m,2H),3.71(s,3H),3.50(m,2H),2.76-2.65(m,6H),0.84(s,9H),0.00(s,6H).

(b) 2- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,2,3, 4-tetrahydroisoquinoline

To a mixture of 6-bromo-2- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinoline (0.42 g,1.05 mmol) and bis (pinacolato) diboron (0.45 g,1.78 mmol) in dioxane (5 mL) was added potassium acetate (0.21 g,2.1 mmol) and 1,1' -bis (biphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (0.04 g,0.05 mmol). The mixture was stirred at 110℃for 12 hours. By rapid SiO ₂ Chromatography (0-30% THF in ethyl acetate/petroleum ether) purify the residue to provide 2- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,2,3, 4-tetrahydroisoquinoline (0.4 g,78% yield). ¹ H NMR(400MHz,CDCl ₃ ):δ7.13(s,1H),6.98(s,1H),3.85-3.71(m,5H),3.67-3.58(m,2H),2.83(m,2H),2.75-2.70(m,4H),1.27(s,12H),0.83(s,9H),0.00(s,6H).

(c) (S) - ((6- (3- (2- (2- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -4-chloro-2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To 2- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -8-methoxy-6- (4, 5-tetramethylene)Methyl-1, 3, 2-dioxaborane-2-yl) -1,2,3, 4-tetrahydroisoquinoline (0.21 g,0.46 mmol) and tert-butyl (5-oxopyrrolidin-2-yl) methyl) carbamate (0.16 g,0.26 mmol) in dioxane/H ₂ A mixture of 1,1' -bis (biphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (0.01 g,0.015 mmol) and potassium carbonate (0.11 g,0.77 mmol) was added to a mixture of O mixtures (10:1, 4.4 mL). The mixture was stirred at 110℃for 8 hours. The mixture was diluted with water (5 mL) and brine (5 mL). The mixture was extracted with ethyl acetate/THF mixture (1:1, 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (silica gel, ethyl acetate: meoh=5:1) to afford tert-butyl (S) - ((6- (3- (2- (2- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -4-chloro-2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (0.1 g,23% yield, observed m/z:912[ m+h ] ] ⁺ )。

(d) (S) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

To tert-butyl (6- (3- (2- (2- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -4-chloro-2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (0.095 g,0.1 mmol) in CH ₂ Cl ₂ Trifluoroacetic acid (2.5 mL) was added to the mixture in (0.5 mL). The mixture was stirred at room temperature for 8 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide (S) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one(28.1 mg,35% yield, observed m/z:696[ M+H)] ⁺ )。 ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.72(d,1H),7.76(dd,1H),7.65-7.61(m,2H),7.56-7.52(m,2H),7.44(s,1H),7.13(d,2H),4.15-3.92(m,7H),3.86(s,3H),3.76-3.68(m,3H),3.30-3.20(m,2H),3.09-3.04(m,2H),2.68-2.67(m,2H),2.53-2.52(m,2H),2.18-2.09(m,3H),1.75-1.67(m,1H).

Example 25: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (50)

(a) (S) -1- (6-bromo-8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol

To a solution of 6-bromo-8-methoxy-1, 2,3, 4-tetrahydroisoquinoline hydrochloride (0.15 g,0.54 mmol) and (S) -2-methyl oxirane (0.63 g,10.77 mmol) in ethanol (7 mL) was added N, N-diisopropylethylamine (0.19 mL,1.08 mmol). The mixture was stirred at 85 ℃ for 1 hour and then concentrated under reduced pressure. By flash chromatography (SiO ₂ The residue was purified with a linear gradient elution of 0-5% MeOH/methylene chloride to provide (S) -1- (6-bromo-8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (0.094 g, 58%). LCMS: m/z found 300[ M+H ]] ⁺ Rt=0.59 min (method B).

(b) (S) -1- (8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol

With (S) -1- (6-bromo-8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (0.10 g,0.32 mmol), bis (frequency)Pinacolato) diboron (0.09 g,0.35 mmol), potassium acetate (0.09 g,0.89 mmol), and Pd (dppf) ₂ Cl ₂ -CH ₂ Cl ₂ (0.03 g,0.03 mmol) was fed to the pressure vessel. The vessel was purged with nitrogen for 5 minutes, then 7mL of dry dioxane was added and the mixture was bubbled with nitrogen for 5 minutes. The mixture was stirred at 90 ℃ for 1h and allowed to cool to room temperature. By passing throughThe mixture was filtered and the filter cake was washed with ethyl acetate (3×20 mL). The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (SiO ₂ Linear gradient elution with 0-10% methanol/methylene chloride) provided (S) -1- (8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (0.08 g,73% yield). LCMS: m/z found 348[ M+H ]] ⁺ Rt=0.70 min (method B).

(c) (6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

With (S) -1- (8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (0.08 g,0.23 mmol), (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (0.14 g,0.23 mmol), cesium carbonate (0.23 g 0.69 mmol), and Pd (PPh) ₃ ) ₄ (0.03 g,0.02 mmol) the pressure vessel was fed and the vessel flushed with nitrogen. Dioxane (6 mL) was added and the mixture was bubbled with nitrogen, then 0.75mL of water was added. The mixture was stirred at 90℃for 1 hour. The mixture was cooled to room temperature byFiltration and use of ethyl acetate(3X 15 mL) the filter cake was washed. The filtrate was concentrated under reduced pressure and purified by flash chromatography (SiO ₂ The residue was purified with a linear gradient of 0-5% methanol/methylene chloride to give tert-butyl ((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (0.09 g,50% yield). LCMS: m/z found 776[ M+H ]] ⁺ Rt=0.83 min (method B).

(d) (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

The scintillation vial was charged with ((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (0.10 g,0.12 mmol) and 5mL of 1:1 (v/v) TFA/methylene chloride was added and the mixture stirred at room temperature for 10 minutes. The mixture was then concentrated and the residue was purified by semi-preparative HPLC to provide 59mg (66%) of (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one diformate. LCMS: m/z found 676[ M+H ] ] ⁺ Rt=1.68 min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.61(d,1H),7.77(d,1H),7.68(d,1H),7.53(t,1H),7.46–7.35(m,2H),7.26(d,1H),7.14(s,2H),4.32(s,2H),4.25(m,2H),4.04–3.95(m,5H),3.89(d,2H),3.49(s,3H),3.21–3.04(m,4H),2.93–2.79(m,2H),2.40–2.24(m,3H),1.87–1.75(m,1H),1.24(d,3H).

Example 26: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (3-hydroxy-3-methylbutyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (49)

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (3-hydroxy-3-methylbutyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one) is prepared from 4-bromo-2-methylbutan-2-ol and 6-bromo-8-methoxy-1, 2,3, 4-tetrahydroisoquinoline hydrochloride in a manner analogous to compound 50. LCMS: m/z found 704[ M+H ]] ⁺ Rt=1.77 min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.60(d,1H),7.77(d,1H),7.68(d,1H),7.53(t,1H),7.45–7.35(m,2H),7.26(d,1H),7.13(s,2H),4.24(s,2H),4.04–3.95(m,5H),3.90(s,3H),3.42(s,2H),3.35–3.24(m,3H),3.15(t,2H),2.93–2.78(m,2H),2.40–2.22(m,3H),1.97–1.88(m,2H),1.89–1.75(m,1H),1.27(s,6H).

Example 27: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (2- (1-hydroxycyclobutyl) ethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (51)

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (1-hydroxycyclobutyl) ethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one) is prepared from 1- (2-bromoethyl) cyclobutan-1-ol and 6-bromo-8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-3-yl) ethyl in a similar manner to compound 50. LCMS: m/z found 716[ M+H ] ] ⁺ Rt=1.84 min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.60(d,1H),7.78(dd,1H),7.68(s,1H),7.53(d,1H),7.45–7.35(m,2H),7.27(d,1H),7.14(s,2H),4.28(s,2H),4.07–3.93(m,5H),3.90(s,4H),3.45(t,2H),3.35–3.25(m,2H),3.16(t,2H),2.96–2.82(m,2H),2.41–2.23(m,3H),2.15–2.04(m,7H),1.90–1.69(m,1H),1.67–1.52(m,1H).

Example 28: (5S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxy-3-methylbutyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (53)

(5S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxy-3-methylbutyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one) is prepared from 1-bromo-3-methylbutan-2-ol and 6-bromo-8-methoxy-1, 2,3, 4-tetrahydroisoquinoline hydrochloride in a similar manner to compound 50. LCMS: m/z found 704[ M+H ]] ⁺ Rt=1.84 min, (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.60(d,1H),8.44(s,1H),7.75(d,1H),7.68(dd,1H),7.52(t,1H),7.46–7.34(m,2H),7.24(d,1H),7.13(s,2H),4.27(q,2H),4.00(s,3H),3.91–3.86(m,5H),3.83–3.73(m,1H),3.48–3.36(m,2H),3.24–3.06(m,5H),2.85–2.70(m,2H),2.39–2.20(m,3H),1.85–1.74(m,1H),1.77–1.64(m,1H),0.97(d,6H).

Example 29: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (54)

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one) is prepared from 2-bromoethanol and 6-bromo-8-methoxy-1, 2,3, 4-tetrahydroisoquinoline hydrochloride in a similar manner to compound 50. LCMS: m/z found 662[ M+H ] ] ⁺ Rt=1.60 min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.61(d,1H),7.79(d,1H),7.68(dd,1H),7.53(t,1H),7.45–7.35(m,2H),7.27(d,1H),7.14(s,2H),4.87(s,1H),4.32(s,2H),4.11–3.98(m,5H),3.98–3.87(m,6H),3.49(t,2H),3.31(d,1H),3.18(t,2H),3.00–2.86(m,2H),2.41–2.23(m,3H),1.91–1.77(m,1H).

Example 30: (S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (2- (piperidin-4-yl) ethyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (64)

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (2- (piperidin-4-yl) ethyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one) was prepared in analogy to compound 50 from tert-butyl 4- (2-bromoethyl) piperidine-1-carboxylate and 6-bromo-8-methoxy-1, 2,3, 4-tetrahydroisoquinoline hydrochloride. LCMS: m/z found 729[ M+H ]] ⁺ Rt=1.58 min, (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.59(d,1H),8.41(s,1H),7.79(d,1H),7.69(d,1H),7.53(t,1H),7.45–7.35(m,2H),7.27(d,1H),7.10(s,2H),4.09–3.95(m,7H),3.88(d,4H),3.36(s,2H),3.19–3.10(m,4H),3.01–2.92(m,6H),2.39–2.24(m,3H),1.99(d,2H),1.81–1.64(m,4H),1.45(t,2H).

Example 31:2- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (2- (piperidin-4-yl) ethyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethan-1-ol (85)

In a similar manner to compound 50, tert-butyl 4- (2-bromoethyl) piperidine-1-carboxylate and 6-bromo-8-methoxy-1, 2,3, 4-tetramethoxy-1, 2-tetralin-4-yl) methyl) amino are prepared in the initial conversion with 2- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (2- (piperidin-4-yl) ethyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethan-1-ol and in the final conversion with 2-aminoethanol Hydrogen isoquinoline hydrochloride. LCMS: m/z found 676[ M+H ]] ⁺ at 1.58min, (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.57(d,1H),8.50(s,2H),7.78(d,1H),7.68(d,1H),7.52(t,1H),7.42–7.35(m,2H),7.28(d,1H),7.02(d,2H),4.04(d,4H),3.85(s,3H),3.74(t,2H),3.64(s,2H),3.35(d,2H),2.98–2.90(m,5H),2.79(t,2H),2.65(t,2H),1.97(d,3H),1.71–1.52(m,3H),1.41(t,2H).

Example 32: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (2- (1-hydroxycyclopropyl) ethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (74)

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (1-hydroxycyclopropyl) ethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one) was prepared from 1- (2-bromoethyl) cyclopropan-1-ol and 6-bromo-8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-3-yl) ethyl) in an analogous manner to compound 50. LCMS: m/z found 702[ M+H ]] ⁺ Rt=1.82 min, (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.57(d,1H),8.49(s,1H),7.75–7.63(m,2H),7.51(t,1H),7.43–7.33(m,2H),7.22(d,1H),7.06–6.99(m,2H),3.99(s,2H),3.92–3.76(m,6H),3.68(s,2H),3.00–2.87(m,4H),2.86–2.75(m,4H),2.76–2.61(m,2H),2.52(q,2H),2.37–2.18(m,3H),1.85–1.72(m,1H),1.02(t,3H).

Example 33: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (5-fluoro-2- (2-hydroxy-2-methylpropyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (47)

In a similar manner to compound 50, 2-dimethyloxirane is used in a first step in EtOH at 70 ℃And 7-bromo-5-fluoro-1, 2,3, 4-tetrahydroisoquinoline-HCl to prepare (S) -5- (((6- (2-chloro-3- (3-chloro-2- (5-fluoro-2- (2-hydroxy-2-methylpropyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one. LCMS: m/z found 678[ M+H ] ] ⁺ Rt=1.73 min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ) Delta 8.60 (d, 1H), 7.74-7.19 (m, 8H), 4.01 (s, 3H), 3.85-3.82 (m, 4H), 2.95-2.85 (m, 4H), 2.71-2.65 (m, 2H), 2.53 (s, 2H), 2.35-2.24 (m, 3H), 1.84-1.76 (m, 1H), 1.23 (s, 6H) and 0.09 (d, 1H).

Example 34: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (2-hydroxy-2-methylpropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (46)

In a similar manner to compound 50, (S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (2-hydroxy-2-methylpropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one was prepared in EtOH at 70 ℃ in a first step with 2, 2-dimethyloxirane and 6-bromo-8-fluoro-1, 2,3, 4-tetrahydroisoquinolin-1- (2-hydroxy-2-methylpropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl. LCMS: m/z found 678[ M+H ]] ⁺ Rt=1.70 min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ) Delta 8.60 (dd, 1H), 7.74-7.16 (m, 8H), 4.01 (s, 3H), 3.85-3.80 (m, 5H), 3.00-2.94 (m, 4H), 2.75-2.65 (m, 2H), 2.56 (s, 2H), 2.35-2.25 (m, 3H), 1.85-1.76 (m, 1H) and 1.24 (s, 6H).

Example 35: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxy-2-methylpropyl) -5-methoxy-1, 2,3, 4-tetrahydroisoquinolin-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (45)

In a similar manner to compound 50, in a first step at 70℃(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxy-2-methylpropyl) -5-methoxy-1, 2,3, 4-tetrahydroisoquinolin-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one) was prepared from 2, 2-dimethyloxirane and 7-bromo-5-methoxy-1, 2,3, 4-tetrahydroisoquinolin-HCl. LCMS: m/z found 690[ M+H ]] ⁺ Rt=1.76 min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ) Delta 8.59 (dd, 1H), 8.53 (s, 1H), 7.76-7.23 (m, 6H), 7.03 (s, 1H), 6.95 (s, 1H), 4.12 (m, 1H), 4.01 (s, 3H), 3.87-3.81 (m, 7H), 3.00-2.95 (m, 2H), 2.82-2.80 (m, 2H), 2.75-2.68 (m, 2H), 2.56 (s, 2H), 2.35-2.25 (m, 3H), 1.84-1.75 (m, 1H) and 1.24 (s, 6H).

Example 36: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -5-methoxy-1, 2,3, 4-tetrahydroisoquinolin-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (44)

In a similar manner to compound 50, (S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -5-methoxy-1, 2,3, 4-tetrahydroisoquinolin-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one was prepared in EtOH at 70 ℃ in the first step using (S) -2-methyl oxirane and 7-bromo-5-methoxy-1, 2,3, 4-tetrahydroisoquinoline-HCl. LCMS: m/z found 676[ M+H ] ] ⁺ Rt=1.71 min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ) Delta 8.60 (dd, 1H), 8.59 (s, 1H), 7.76-7.35 (m, 5H), 7.24 (dd, 1H), 7.08 (s, 1H), 7.02 (s, 1H), 4.12 (m, 1H), 4.01-3.81 (m, 11H), 3.10-3.03 (m, 2H), 2.92-2.87 (m, 3H), 2.76-2.65 (m, 5H), 2.35-2.23 (m, 3H), 1.84-1.77 (m, 1H) and 1.20 (dd, 1H).

Example 37:6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one (102)

(a) 1- (4-bromo-1H-pyrrol-2-yl) -2, 2-trichloroethane ketone

To a cooled solution (0 ℃) of 2, 2-trichloro-1- (1H-pyrrol-2-yl) ethanone (20 g,94 mmol) in ACN (100 mL) was added NBS (16.8 g,94 mmol) in portions. The reaction was stirred at 25℃for 1.5 hours. The reaction mixture was quenched by slow addition of water (15 ml,15.0 mL/g) and cooled to 0deg.C. The solids were allowed to reduce saturation for a further 1 hour. The solid was filtered, washed with water (15 ml,5.0 ml/g) and dried in vacuo to afford 1- (4-bromo-1H-pyrrol-2-yl) -2, 2-trichloroethane ketone (25 g,91% yield) as a black solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ＝12.84(s,1H),7.54(dd,1H),7.33(dd,1H).

(b) 4-bromo-1H-pyrrole-2-carboxamide

To a mixture of 1- (4-bromo-1H-pyrrol-2-yl) -2, 2-trichloroethane ketone (25 g,85.8 mmol) in ACN (125 mL) was added 30% NH ₃ .H ₂ O (75.00 mL). The reaction was stirred at 25℃for 12 hours. The reaction mixture was concentrated under reduced pressure to afford 4-bromo-1H-pyrrole-2-carboxamide as a black solid (15 g,92% yield). The material was used without any purification.

(c) 1-amino-4-bromo-1H-pyrrole-2-carboxamide

To a mixture of NaH (1.59 g,39.7 mmol) suspended in DMF (15 mL) at 0deg.C was slowly added 4-bromo-1H-pyrrole-2-carboxamide (5 g,26.4 mmol). After stirring at 0℃for 1 hour, O- (2, 4-dinitrophenyl) hydroxylamine (8.43 g, 42.3)A solution of mmol) in DMF (3 mL) was added dropwise for 30 min. The resulting reaction mixture was stirred at 0℃for 1.5 hours. The reaction was quenched by slow addition of saturated aqueous sodium thiosulfate (120 mL). The resulting mixture was extracted with ethyl acetate (3×80 mL). The organic layer was washed with 10% aqueous lithium chloride (3×60 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated and purified by flash chromatography (SiO ₂ The residue was purified with 0-100% EtOAc/petroleum ether to afford the product 1-amino-4-bromo-1H-pyrrole-2-carboxamide (3 g,55% yield). ¹ H NMR(400MHz,DMSO-d ₆ )δ＝7.93(br,1H),7.27-7.25(m,1H),7.00(d,1H),6.74(d,1H).

(d) 2- ((4-bromo-2-carbamoyl-1H-pyrrol-1-yl) amino) -2-glyoxylate ethyl ester

To a mixture of 1-amino-4-bromo-1H-pyrrole-2-carboxamide (3 g,12.5 mmol) and pyridine (0.99 g,12.5 mmol) in THF (10 mL) was added ethyl 2-chloro-2-glyoxylate (1.71 g,12.5 mmol). The resulting reaction mixture was stirred at 25 ℃ for 3 hours. The mixture was concentrated under reduced pressure. The residue was suspended in methylene chloride (10 mL) and the solid was collected by filtration to give ethyl 2- ((4-bromo-2-carbamoyl-1H-pyrrol-1-yl) amino) -2-glyoxylate (2.5 g,65% yield) as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ＝12.16(s,1H),7.59(br,1H),7.20(d,1H),7.08(br,1H),6.94(d,1H),4.31(q,2H),1.31(t,3H).

(e) 6-bromo-4-oxo-3, 4-dihydropyrrolo [2,1-f ] [1,2,4] triazine-2-carboxylic acid ethyl ester

A mixture of ethyl 2- ((4-bromo-2-carbamoyl-1H-pyrrol-1-yl) amino) -2-glyoxylate (2.1 g,6.9 mmol), trimethylchlorosilane (16.6 g,152 mmol) and TEA (21.2 mL,152 mmol) in DCE (210 mL) was heated at 110℃for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated. By waterThe reaction mixture was diluted (80 mL) and extracted with EtOAc (3X 60 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. By rapid SiO ₂ Chromatography (0-100% EtOAc/petroleum ether) of the residue afforded 6-bromo-4-oxo-3, 4-dihydropyrrolo [2,1-f as a yellow solid][1,2,4]Triazine-2-carboxylic acid ethyl ester (1.1 g). ¹ H NMR(400MHz,DMSO-d ₆ )δ＝12.31(br,1H),8.05(s,1H),7.13(s,1H),4.39(q,2H),1.35(t,3H).

(f) 6-bromo-3-methyl-4-oxo-3, 4-dihydropyrrolo [2,1-f ] [1,2,4] triazine-2-carboxylic acid ethyl ester

To 6-bromo-4-oxo-3, 4-dihydropyrrolo [2,1-f][1,2,4]Methyl iodide (0.74 g,5.24 mmol) was added dropwise to a mixture of triazine-2-carboxylic acid ethyl ester (1.5 g,5.24 mmol) and potassium carbonate (0.72 g,5.24 mmol) in DMF (20 mL). The mixture was stirred at 25℃for 1 hour. The reaction mixture was diluted with water (30 mL) and saturated aqueous ammonium chloride (50 mL). The aqueous layer was extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. By flash chromatography (SiO ₂ 0-100% EtOAc/petroleum ether) to afford 6-bromo-3-methyl-4-oxo-3, 4-dihydropyrrolo [2,1-f ] as a yellow solid][1,2,4]Triazine-2-carboxylic acid ethyl ester (1.02 g,64% yield). ¹ H NMR(400MHz,DMSO-d ₆ )δ＝7.95(d,1H),7.09(d,1H),4.40(q,2H),3.42(s,3H),1.32(t,3H).

(g) 6-bromo-2- (hydroxymethyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one

To 6-bromo-3-methyl-4-oxo-3, 4-dihydropyrrolo [2,1-f ] at 0deg.C][1,2,4]A mixture of triazine-2-carboxylic acid ethyl ester (0.5 g,1.67 mmol) in THF/MeOH (10:11, 21 mL) was added sodium borohydride (0.19 g,5 mmol). The mixture was stirred at 20 ℃Stirring is carried out for 2 hours. The reaction mixture was quenched by the addition of water (20 mL) and then extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. By rapid SiO ₂ Chromatography (0-100% EtOAc/petroleum ether) purified the residue to afford 6-bromo-2- (hydroxymethyl) -3-methylpyrrolo [2,1-f ] as a yellow solid][1,2,4]Triazin-4 (3H) -one (0.35 g,81% yield). ¹ H NMR(400MHz,DMSO-d ₆ )δ7.83(d,1H),7.00(d,1H),5.88(t,1H),4.48(d,2H),3.50(s,3H).

(h) 6-bromo-2- (((tert-butyldimethylsilyl) oxy) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one

To 6-bromo-2- (hydroxymethyl) -3-methylpyrrolo [2,1-f][1,2,4]A solution of triazin-4 (3H) -one (3 g,11.6 mmol) in DMF (45 mL) was added tert-butyldimethylchlorosilane (2.14 mL,17.4 mmol) and imidazole (1.58 g,23.3 mmol). The mixture was stirred at room temperature for 3 hours. Partitioning the reaction mixture at H ₂ O (80 mL) and EtOAC (60 mL). The organic phase was separated, washed with brine (30 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. By flash chromatography (SiO ₂ The residue was purified with 0-50% EtOAc/petroleum ether to afford 6-bromo-2- (((tert-butyldimethylsilyl) oxy) methyl) -3-methylpyrrolo [2, 1-f) as a yellow solid][1,2,4]Triazin-4 (3H) -one (3.98 g,92% yield). ¹ H NMR(400MHz,CDCl3):δ7.29(d,1H),7.01(d,1H),4.63(s,2H),3.62(s,3H),0.91(s,9H),0.13(s,6H).

(i) 2- (((tert-butyldimethylsilyl) oxy) methyl) -3-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxabor-an-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one

To 6-bromo-2- (((tert-butyldimethylsilyl) oxy)Methyl) -3-methylpyrrolo [2,1-f][1,2,4]Triazin-4 (3H) -one (3.88 g,10.4 mmol), 4', 5', A mixture of 5' -octamethyl-2, 2' -bis (1, 3, 2-dioxaborane) (5.29 g,20.8 mmol), potassium acetate (2.05 g,20.84 mmol) in dioxane (80 mL) was added 1,1' -bis (biphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (851 mg,1.04 mmol). The mixture was stirred at 110℃for 12 hours. Partitioning the reaction mixture at H ₂ O (50 mL) and EtOAC (70 mL). The organic phase was separated, washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. By flash chromatography (SiO ₂ The residue was purified with 0-10% EtOAc/petroleum ether to afford 2- (((tert-butyldimethylsilyl) oxy) methyl) -3-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaboran-2-yl) pyrrolo [2, 1-f) as a yellow solid][1,2,4]Triazin-4 (3H) -one (2.4 g,54.9% yield). ¹ H NMR(400MHz,CDCl ₃ ):δ7.63(d,1H),7.33(d,1H),4.64(s,2H),3.60(s,3H),1.34(s,12H),0.90(s,9H),0.12(s,6H).

(j) (S) - ((6- (3- (2- (2- (((tert-butyldimethylsilyl) oxy) methyl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2,1-f ] [1,2,4] triazin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To 2- (((tert-butyldimethylsilyl) oxy) methyl) -3-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxabor-2-yl) pyrrolo [2,1-f][1,2,4]Triazin-4 (3H) -one (200 mg,0.48 mmol) and tert-butyl (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (282 mg,0.48 umol) in THF/H ₂ A mixture of potassium carbonate (198 mg,1.43 mmol) and tetrakis (triphenylphosphine) palladium (0) (55.1 mg,0.48 mmol) was added to the mixture in O (7 ml, 6/1). The reaction was stirred at 80℃for 12 hours. By H ₂ The mixture was diluted with O (30 mL) and extracted with EtOAc (120 mL). The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. By rapid colour Spectroscopy (SiO) ₂ The residue was purified from 0-100% EtOAc/petroleum ether to 0-100% MeOH/EtOAc to provide (S) - ((6- (3- (2- (2- (((tert-butyldimethylsilyl) oxy) methyl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2, 1-f)][1,2,4]Triazin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester. (1.2 g, m/z:848[ M+H)] ⁺ ).

(k) (S) - ((6- (2-chloro-3- (3-chloro-2- (2- (hydroxymethyl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2,1-f ] [1,2,4] triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

To (S) - ((6- (3- (2- (2- (((tert-butyldimethylsilyl) oxy) methyl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2, 1-f)][1,2,4]A mixture of tert-butyl triazin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (1.1 g,1.30 mmol) in THF (5 mL) was added to TBAF (1.94 mL,1.94mmol, 1M in THF). The mixture was stirred at room temperature for 12 hours. The mixture was concentrated and purified by flash chromatography (SiO ₂ The residue was purified with 0-100% EtOAc/petroleum ether and then 0-100% MeOH/EtOAc to provide (S) - ((6- (2-chloro-3- (3-chloro-2- (2- (hydroxymethyl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2, 1-f) ][1,2,4]Triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (660 mg,52% yield. M/z:734[ M+H ]] ⁺ )。 ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.62(d,1H),8.21(d,1H),8.11(s,1H),7.89-7.87(m,1H),7.71(dd,1H),7.64(s,1H),7.71(t,1H),7.58-7.54(m,2H),7.40(dd,1H),7.31(d,1H),7.29(d,1H),6.94(s,1H),4.66(s,2H),4.52(s,2H),4.03(s,3H),4.02-3.98(m,1H),3.65(s,3H),3.46-3.40(m,2H),2.40-2.28(m,3H),1.85-1.83(m,1H),1.42(s,19H).

(l) (S) - ((6- (2-chloro-3- (3-chloro-2- (2-formyl-3-methyl-4-oxo-3, 4-dihydropyrrolo [2,1-f ] [1,2,4] triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

To (S) - ((6- (2-chloro-3- (3-chloro-2- (2- (hydroxymethyl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2, 1-f)][1,2,4]A mixture of tert-butyl triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl ((5-oxopyrrolidin-2-yl) methyl) carbamate (540 mg,0.74 mmol) in methylene chloride (10 mL) was added to Dess-Martin periodate (Dess-Martin periodinane) (624 mg,1.47 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was evaporated and purified by flash chromatography (SiO ₂ The residue was purified with 0-100% EtOAc/petroleum ether to afford (S) - ((6- (2-chloro-3- (3-chloro-2- (2-formyl-3-methyl-4-oxo-3, 4-dihydropyrrolo [2, 1-f)) as a yellow solid][1,2,4]Triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (420 mg,78% yield).

(m) ((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2,1-f ] [1,2,4] triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To (S) - ((6- (2-chloro-3- (3-chloro-2- (2-formyl-3-methyl-4-oxo-3, 4-dihydropyrrolo [2, 1-f)][1,2,4]A mixture of tert-butyl triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (150 mg,0.2 mmol) in methylene chloride (5 mL) was added sodium acetate (50.4 mg,0.61 mmol) and 3-amino-1-methyl-cyclobutanol, HCl (31.1 mg,0.23 mmol). The mixture was stirred at room temperature for 12 hours. Sodium cyanoborohydride (38.6)mg,0.61 mmol) and the mixture was stirred for a further 1 hour. The residue was purified by preparative TLC (20% MeOH/EtOAc) to afford ((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2, 1-f) as a white solid][1,2,4]Triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (100 mg,49% yield). M/z 717[ M+H ] ] ⁺ )。

(n) 6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one

To ((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2, 1-f)][1,2,4]Triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (100 mg,0.12 mmol) in methylene chloride (1 mL) was added 2, 2-trifluoro acetic acid (2 mL,27.0 mmol) and stirred at room temperature for 0.5 hours. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC to provide 6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrrolo [2,1-f][1,2,4]Triazin-4 (3H) -one (22.9 mg,24% yield). m/z 717[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.67(d,1H),8.22(d,1H),8.11(s,1H),7.89-7.87(m,1H),7.71(dd,1H),7.64(s,1H),7.60(t,1H),7.53(d,1H),7.47(dd,1H),7.38(d,1H),7.33-7.32(m,1H),4.72(s,1H),3.95(s,4H),3.76-3.73(m,2H),3.51(s,3H),3.26-3.25(m,5H),2.16-2.08(m,5H),1.76-1.71(m,2H),1.23(s,3H).

Example 38:6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (((((S) -2-hydroxypropyl) amino) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one (91)

(a) (6- (2-chloro-3- (3-chloro-2- (2- ((((S) -2-hydroxypropyl) amino) methyl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2,1-f ] [1,2,4] triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To a mixture of tert-butyl (6- (2-chloro-3- (3-chloro-2- (2-formyl-3-methyl-4-oxo-3, 4-dihydropyrrolo [2,1-f ] [1,2,4] triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) - ((5-oxopyrrolidin-2-yl) methyl) carbamate (30 mg,0.04 mmol) in methylene chloride (2 mL) was added sodium acetate (10.1 mg,0.12 mmol) and (S) -1-aminopropane-2-ol (4.61 mg,0.06 mmol). The mixture was stirred at room temperature for 11 hours. Sodium cyanoborohydride (7.72 mg,0.12 mmol) was added to the mixture and stirred for an additional 1 hour. The mixture was purified by preparative TLC (20% meoh/EtOAc) to afford ((6- (2-chloro-3- (3-chloro-2- (2- (((S) -2-hydroxypropyl) amino) methyl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2,1-f ] [1,2,4] triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) as a white solid (17 mg,52% yield).

(b) 6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((S) -2-hydroxypropyl) amino) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one

To ((6- (2-chloro-3- (3-chloro-2- (2- ((((S) -2-hydroxypropyl) amino) methyl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2, 1-f)][1,2,4]Triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (17 mg,21.5 umol) in methylene chloride (0.3 mL) was added 2, 2-trifluoroacetic acid (0.3 mL,4.05 mmol). The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated directly under reduced pressure. Purification of the residue by reverse phase HPLC to afford 6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((S) -2-hydroxypropyl) amino) methyl) -3-methylpyrrolo [2,1-f][1,2,4]Triazin-4 (3H) -one (7 mg,9.42umol,43.8% yield). m/z 691[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO):δ8.69(d,1H),8.24(d,1H),8.15(s,2H),7.85(d,1H),7.73(d,1H),7.69(s,1H),7.60(t,1H),7.55(d,1H),7.48(d,1H),7.40(d,1H),7.30(d,1H),3.93(s,3H),3.87-3.82(m,3H),3.75-3.64(m,6H),3.55(s,4H),2.16-2.08(m,3H),1.72-1.70(m,1H),1.05(d,3H).

Example 39:6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3-methyl-2- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one (103)

(a) (6- (2-chloro-3- (3-chloro-2- (3-methyl-4-oxo-2- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3, 4-dihydropyrrolo [2,1-f ] [1,2,4] triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To (S) - ((6- (2-chloro-3- (3-chloro-2- (2-formyl-3-methyl-4-oxo-3, 4-di)Hydrogen pyrrolo [2,1-f][1,2,4]A mixture of tert-butyl triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (150 mg,0.2 mmol) in methylene chloride (2 mL) was added sodium acetate (50.4 mg,0.61 mmol) and (S) -5- (aminomethyl) pyrrolidin-2-one, HCl (34.0 mg,0.23 mmol). The mixture was stirred at room temperature for 12 hours. Sodium cyanoborohydride (38.6 mg,0.61 mmol) was added to the mixture and stirring was continued for 1 hour. The residue was purified by preparative TLC (20% MeOH/EtOAc) to afford ((6- (2-chloro-3- (3-chloro-2- (3-methyl-4-oxo-2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3, 4-dihydropyrrolo [2, 1-f) as a white solid][1,2,4]Triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (70 mg,30% yield, m/z:830[ M+H) ] ⁺ )

(b) 6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3-methyl-2- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one

To ((6- (2-chloro-3- (3-chloro-2- (3-methyl-4-oxo-2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3, 4-dihydropyrrolo [2, 1-f)][1,2,4]A mixture of tert-butyl triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (70 mg,0.08 mmol) in methylene chloride (1 mL) was added 2, 2-trifluoro acetic acid (2 mL g,27.0 mmol). The mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated under vacuum. Purification of the residue by reverse phase HPLC to afford 6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3-methyl-2- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyrrolo [2, 1-f)][1,2,4]Triazin-4 (3H) -one (20.1 mg,30% yield). m/z 730[ M+H ]] ⁺ ). ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.66(d,1H),8.21(d,1H),8.12(s,1H),7.82(d,1H),7.71(dd,1H),7.67(s,1H),7.64(s,1H),7.57(t,1H),7.52(d,1H),7.45(dd,1H),7.37(d,1H),7.27(d,1H),3.91(s,3H),3.79(s,2H),3.72(s,2H),3.65-3.57(m,2H),3.52(s,3H),2.60(d,2H),2.56(d,2H),2.13-2.04(m,6H),1.69-1.66(m,2H).

Example 40:6- [ 3-chloro-4- [ 2-chloro-3- [ 6-methoxy-5- [ [ [ (2S) -5-oxopyrrolidin-2-yl ] methylamino ] methyl ] -2-pyridinyl ] phenyl ] -2-pyridinyl ] -2- [ (isopropylamino) methyl ] -3-methyl-pyrrolo [2,1-f ] [1,2,4] triazin-4-one (111)

(a) N- [ [6- [ 2-chloro-3- [2- [ (isopropylamino) methyl ] -3-methyl-4-oxo-pyrrolo [2,1-f ] [1,2,4] triazin-6-yl ] phenyl ] -2-methoxy-3-pyridinyl ] methyl ] -N- [ [ (2S) -5-oxopyrrolidin-2-yl ] methyl ] carbamic acid tert-butyl ester

To N- [ [6- [ 2-chloro-3- [2- (hydroxymethyl) -3-methyl-4-oxo-pyrrolo [2,1-f][1,2,4]Triazin-6-yl]Phenyl group]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]A solution of tert-butyl carbamate (20 mg,0.03 mmol) in methylene chloride (0.4 mL) was added methanesulfonyl chloride (2.53 uL,0.03 mmol) and triethylamine (11 uL,0.08 mmol). The reaction was stirred at room temperature for 1 hour. The solvent was evaporated and the residue taken in DMF (0.4 mL) before propane-2-amine (22 uL,0.27 mmol) was added. The reaction was stirred at room temperature for 12 hours. The solvent was evaporated and the residue was suspended in water. Collecting the precipitate formed to provide N- [ [6- [ 2-chloro-3- [2- [ (isopropylamino) methyl ]]-3-methyl-4-oxo-pyrrolo [2,1-f][1,2,4]Triazin-6-yl]Phenyl group]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (14 mg, 75.8%). The material was used as such without any purification. M/z: [ M+H ] ] ⁺ 776.1

(b) 6- [ 3-chloro-4- [ 2-chloro-3- [ 6-methoxy-5- [ [ [ (2S) -5-oxopyrrolidin-2-yl ] methylamino ] methyl ] -2-pyridinyl ] phenyl ] -2-pyridinyl ] -2- [ (isopropylamino) methyl ] -3-methyl-pyrrolo [2,1-f ] [1,2,4] triazin-4-one

To N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [2- [ (isopropylamino) methyl ]]-3-methyl-4-oxo-pyrrolo [2,1-f][1,2,4]Triazin-6-yl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]A solution of tert-butyl carbamate (14 mg,0.02 mmol) in methylene chloride (0.4 mL) was added TFA (69 uL,0.90 mmol). The reaction was stirred at room temperature for 30 minutes. The solvent was evaporated and the residue was purified by reverse phase HPLC (acetonitrile: water) to afford 6- [ 3-chloro-4- [ 2-chloro-3- [ 6-methoxy-5- [ [ [ (2S) -5-oxopyrrolidin-2-yl)]Methylamino group]Methyl group]-2-pyridyl group]Phenyl group]-2-pyridyl group]-2- [ (isopropylamino) methyl group]-3-methyl-pyrrolo [2,1-f][1,2,4]Triazin-4-one (8 mg, 65.6%). M/z: [ M+H ]] ⁺ ＝677.1. ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.59(d,1H),8.51(s,1H),8.20(d,1H),7.75(d,1H),7.72–7.66(m,2H),7.53(t,1H),7.37(dd,1H),7.27(dd,2H),4.09(s,2H),4.02(s,3H),3.92–3.81(m,3H),3.54(s,3H),3.16(p,1H),2.81–2.68(m,2H),2.41–2.22(m,3H),1.89–1.74(m,1H),1.25(d,6H).

Example 41:6- [ 3-chloro-4- [ 2-chloro-3- [ 6-methoxy-5- [ [ [ (2S) -5-oxopyrrolidin-2-yl ] methylamino ] methyl ] -2-pyridinyl ] phenyl ] -2-pyridinyl ] -2- [ (6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl ] -3-methyl-pyrrolo [2,1-f ] [1,2,4] triazin-4-one (48)

(a) N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [2- [ (6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl ] -3-methyl-4-oxo-pyrrolo [2,1-f ] [1,2,4] triazin-6-yl ] -4-pyridinyl ] phenyl ] -2-methoxy-3-pyridinyl ] methyl ] -N- [ [ (2S) -5-oxopyrrolidin-2-yl ] methyl ] carbamic acid tert-butyl ester

To N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [2- (hydroxymethyl) -3-methyl-4-oxo-pyrrolo [2,1-f][1,2,4]Triazin-6-yl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]A solution of tert-butyl carbamate (16 mg,0.02 mmol) in methylene chloride (0.3 mL) was added methanesulfonyl chloride (3 uL,0.04 mmol) and TEA (15 uL,0.11 mmol). The reaction was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was suspended in DMF (0.5 mL). To this suspension was added potassium carbonate (8 mg,0.07 mmol) and 2-azaspiro [3.3]]Heptan-6-ol, HCL (9 mg,0.07 mmol) and stirred at room temperature for 72 hours. The solvent was evaporated and the residue was suspended in water. The precipitate formed is collected to provide N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [2- [ (6-hydroxy-2-azaspiro [3.3]]Heptane-2-yl) methyl]-3-methyl-4-oxo-pyrrolo [2,1-f][1,2,4]Triazin-6-yl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl ]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (13 mg, 88%). The material was used in the next step. M/z: [ M+H ]] ⁺ ＝829.2

(b) 6- [ 3-chloro-4- [ 2-chloro-3- [ 6-methoxy-5- [ [ [ (2S) -5-oxopyrrolidin-2-yl ] methylamino ] methyl ] -2-pyridinyl ] phenyl ] -2-pyridinyl ] -2- [ (6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl ] -3-methyl-pyrrolo [2,1-f ] [1,2,4] triazin-4-one

To N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [2- [ (6-hydroxy-2-azaspiro [3.3]]Heptane-2-yl) methyl]-3-methyl-4-oxo-pyrrolo [2,1-f][1,2,4]Triazin-6-yl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]A solution of tert-butyl carbamate (15 mg,0.02 mmol) in methylene chloride (0.3 mL) was added TFA (69 uL,0.90 m)mol). The reaction was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was purified by reverse phase HPLC (acetonitrile: water) to afford 6- [ 3-chloro-4- [ 2-chloro-3- [ 6-methoxy-5- [ [ [ (2S) -5-oxopyrrolidin-2-yl)]Methylamino group]Methyl group]-2-pyridyl group]Phenyl group]-2-pyridyl group]-2- [ (6-hydroxy-2-azaspiro [3.3]]Heptane-2-yl) methyl]-3-methyl-pyrrolo [2,1-f][1,2,4]Triazin-4-one (5 mg, 37.9%). M/z: [ M+H ]] ⁺ ＝729.3. ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.60(d,1H),8.22(s,1H),7.84(d,1H),7.71(d,2H),7.56(t,1H),7.40(d,1H),7.31(dd,2H),4.22(s,2H),4.14(s,3H),4.07(s,3H),3.98(s,2H),3.90(d,4H),3.49(s,3H),3.03(s,2H),2.60(s,3H),2.36(s,2H),2.14(d,2H),1.87(s,1H).

Example 42:6- [ 3-chloro-4- [ 2-chloro-3- [ 6-methoxy-5- [ [ [ (2S) -5-oxopyrrolidin-2-yl ] methylamino ] methyl ] -2-pyridinyl ] phenyl ] -2-pyridinyl ] -2- [ (3-hydroxy-3-methyl-azetidin-1-yl) methyl ] -3-methyl-pyrrolo [2,1-f ] [1,2,4] triazin-4-one (110)

(a) N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [2- [ (3-hydroxy-3-methyl-azetidin-1-yl) methyl ] -3-methyl-4-oxo-pyrrolo [2,1-f ] [1,2,4] triazin-6-yl ] -4-pyridinyl ] phenyl ] -2-methoxy-3-pyridinyl ] methyl ] -N- [ [ (2S) -5-oxopyrrolidin-2-yl ] methyl ] carbamic acid tert-butyl ester

To N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [2- (hydroxymethyl) -3-methyl-4-oxo-pyrrolo [2,1-f][1,2,4]Triazin-6-yl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]A solution of tert-butyl carbamate (23 mg,0.03 mmol) in methylene chloride (0.4 mL) was added methanesulfonyl chloride (3 uL,0.04 mmol) and triethylamine (13 uL,0.09 mmol). The reaction was stirred at room temperature for 1h. The solvent was evaporated and the residue taken in DMF (0.4 mL). To this mixture were added potassium carbonate (12 mg,0.09 mmol) and 3-methyl etherThe reaction was stirred at room temperature for 12 hours with monoazetidin-3-ol, HCl (11 mg,0.09 mmol). The solvent was evaporated and the residue was suspended in water. The precipitate formed is collected to provide N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [2- [ (3-hydroxy-3-methyl-azetidin-1-yl) methyl ] ]-3-methyl-4-oxo-pyrrolo [2,1-f][1,2,4]Triazin-6-yl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (13 mg, 51.7%). The material was used as such without any purification. [ M+H ]] ⁺ ＝804.2

(b) 6- [ 3-chloro-4- [ 2-chloro-3- [ 6-methoxy-5- [ [ [ (2S) -5-oxopyrrolidin-2-yl ] methylamino ] methyl ] -2-pyridinyl ] phenyl ] -2-pyridinyl ] -2- [ (3-hydroxy-3-methyl-azetidin-1-yl) methyl ] -3-methyl-pyrrolo [2,1-f ] [1,2,4] triazin-4-one

To N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [2- [ (3-hydroxy-3-methyl-azetidin-1-yl) methyl]-3-methyl-4-oxo-pyrrolo [2,1-f][1,2,4]Triazin-6-yl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]A solution of tert-butyl carbamate (13 mg,0.02 mmol) in methylene chloride (0.4 mL) was added TFA (61 uL,0.81 mmol). The reaction was stirred at room temperature for 30 minutes. The solvent was evaporated and the residue was purified by reverse phase HPLC (acetonitrile: water) to afford 6- [ 3-chloro-4- [ 2-chloro-3- [ 6-methoxy-5- [ [ [ (2S) -5-oxopyrrolidin-2-yl)]Methylamino group]Methyl group]-2-pyridyl group]Phenyl group]-2-pyridyl group]-2- [ (3-hydroxy-3-methyl-azetidin-1-yl) methyl ]-3-methyl-pyrrolo [2,1-f][1,2,4]Triazin-4-one (10 mg, 53.6%). M/z: [ M+H ]] ⁺ ＝704.4. ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.59(d,1H),8.45(s,1H),8.18(d,1H),7.79(d,1H),7.70(dd,1H),7.66(d,1H),7.54(t,1H),7.38(dd,1H),7.33–7.24(m,2H),4.04(s,3H),4.02(d,2H),3.93(q,1H),3.87(s,2H),3.57(s,3H),3.56–3.52(m,2H),2.89(h,2H),2.42–2.26(m,3H),1.84(m,1H),1.49(s,3H).

EXAMPLE 43 6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one (87)

(a) (S) - ((6- (3- (2- (2- (((tert-butyldimethylsilyl) oxy) methyl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2,1-f ] [1,2,4] triazin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -4-chloro-2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To tert-butyl (S) - ((4-chloro-6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (200 mg,319 umol) and 2- (((tert-butyldimethylsilyl) oxy) methyl) -3-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,1-f][1,2,4]Triazin-4 (3H) -one (201 mg,479 umol) in THF/H ₂ A mixture of potassium carbonate (132 mg,958 umol) and tetrakis (triphenylphosphine) platinum (36.9 mg,31.9 umol) was added to the mixture in O (6:1, 7 mL). At N ₂ The mixture was stirred at 80℃for 2 hours. The mixture was filtered and the filtrate was concentrated. By flash chromatography (SiO ₂ The residue was purified with 0-100% EtOAc/petroleum ether to afford (S) - ((6- (3- (2- (2- (((tert-butyldimethylsilyl) oxy) methyl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2, 1-f)][1,2,4]Triazin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -4-chloro-2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (200 mg,70% yield 882[ M+H)] ⁺ ).

(b) (S) - ((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- (hydroxymethyl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2,1-f ] [1,2,4] triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To (S) - ((6- (3- (2- (2- (((tert-butyldimethylsilyl) oxy) methyl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2, 1-f)][1,2,4]A mixture of tert-butyl triazin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -4-chloro-2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (180 mg,204 mol) in THF (10 mL) was added tetrabutylammonium fluoride (1 mol/L in THF, 0.31 mL). At N ₂ The mixture was stirred at room temperature for 4 hours. The mixture was combined with another batch on a 100mg scale. The mixture was concentrated and purified by preparative TLC (SiO ₂ The residue was purified with EtOAc in meoh=9:1 to afford (S) - ((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- (hydroxymethyl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2, 1-f)][1,2,4]Triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (155 mg,768[ M+H ]] ⁺ Observed).

(c) (S) - ((4-chloro-6- (2-chloro-3- (3-chloro-2- (2-formyl-3-methyl-4-oxo-3, 4-dihydropyrrolo [2,1-f ] [1,2,4] triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To (S) - ((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- (hydroxymethyl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2, 1-f)][1,2,4]A solution of t-butyl triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl (-5-oxopyrrolidin-2-yl) methyl) carbamate (150 mg, 195. Mu. Mol) in methylene chloride (5 mL) was added to dess-martin periodate (165 mg, 390. Mu. Mol). The mixture was stirred at room temperature under nitrogen for 30 minutes. The mixture was filtered and the filtrate was concentrated. By flash chromatography (SiO ₂ 0-100% EtOAc/petroleum ether) purification residueTo provide (S) - ((4-chloro-6- (2-chloro-3- (3-chloro-2- (2-formyl-3-methyl-4-oxo-3, 4-dihydropyrrolo [2, 1-f) ][1,2,4]Triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (85 mg,57% yield, 766[ M+H)] ⁺ Observed).

(d) ((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2,1-f ] [1,2,4] triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To (S) - ((4-chloro-6- (2-chloro-3- (3-chloro-2- (2-formyl-3-methyl-4-oxo-3, 4-dihydropyrrolo [2, 1-f)][1,2,4]A mixture of t-butyl triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (80 mg,104 umol) and (1 r,3 r) -3-amino-1-methylcyclobutanol, HCl (28.7 mg,209 umol) in MeOH (5 mL) was added sodium acetate (42.8 mg,521 umol). After the mixture was stirred for 5 hours, sodium cyanoborohydride (13.1 mg,209 umol) was added. At N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and purified by preparative TLC (SiO ₂ The residue was purified with EtOAc: meoh=4:1) to afford ((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2, 1-f) ][1,2,4]Triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (75 mg,57% yield, 851[ M+H ]] ⁺ )。

(e) 6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one

To ((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2, 1-f)][1,2,4]A solution of t-butyl triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (70 mg,0.08 mmol) in methylene chloride (3 mL) was added TFA (3 mL,40.5 mmol). The mixture was stirred at room temperature under nitrogen for 30 minutes. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide 6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrrolo [2, 1-f) as a white solid ][1,2,4]Triazin-4 (3H) -one (15 mg,23% yield, observed m/z:690[ M+H)] ⁺ )。 ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.66(d,1H),8.21(d,1H),7.73(dd,1H),7.63(s,1H),7.59(t,1H),7.53(d,1H),7.49(dd,1H),7.39(s,1H),7.36(d,1H),4.67(s,1H),3.94(s,3H),3.87(s,2H),3.71(s,2H),3.61-3.58(m,1H),3.52(s,3H),3.40-3.36(m,1H),2.65(d,2H),2.13-2.04(m,5H),1.71-1.64(m,3H),1.23(s,3H).

Example 44:5- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one (66)

(a) 5-bromo-2- (2, 2-dimethoxyethyl) isoindolin-1-one

To a mixture of methyl 4-bromo-2- (bromomethyl) benzoate (3 g,9.74 mmol) in MeOH (60 mL) under nitrogen2, 2-Dimethoxyethylamine (5.31 ml,48.7 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated. To the residue were added water (30 mL) and a saturated aqueous brine solution (30 mL). The mixture was extracted with ethyl acetate/THF mixture (1:1, 100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. By flash chromatography (SiO ₂ The residue was purified with 0-50% EtOAc/petroleum ether to afford 5-bromo-2- (2, 2-dimethoxyethyl) isoindolin-1-one (2.7 g, 92%) as a white solid.

(b) 2- (5-bromo-1-oxoisoindolin-2-yl) acetaldehyde

To a mixture of 5-bromo-2- (2, 2-dimethoxyethyl) isoindolin-1-one (1.3 g,4.33 mmol) in methylene chloride (30 mL) was added TFA (6.50 mL,87.8 mmol) and H in one portion ₂ O (1 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo to provide 2- (5-bromo-1-oxoisoindolin-2-yl) acetaldehyde (1.8 g) as trifluoroacetate salt (as a yellow oil) which was used in the next step without further purification.

(c) (S) - (2- (5-bromo-1-oxoisoindolin-2-yl) ethyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To a mixture of 2- (5-bromo-1-oxoisoindolin-2-yl) acetaldehyde (1.8 g,7.08 mmol) in methylene chloride/MeOH (1/1, 40 mL) was added TEA (9.86 mL,70.8 mmol) followed by (S) -5- (aminomethyl) pyrrolidin-2-one, HCl (1.07 g,7.08 mmol) and sodium cyanoborohydride (1.34 g,21.2 mmol). The mixture was stirred at room temperature for 12 hours. To this mixture was added di-tert-butyl dicarbonate (3.10 g,14.2 mmol) and stirred at room temperature for 2 hours. The mixture was concentrated under vacuum and used with H ₂ O (30 mL) was diluted, extracted with THF/EtOAc (1/3, 100 mL) and dried over anhydrous sodium sulfate and filtered. Concentrating the filtrate, and introducingFlash chromatography (SiO ₂ The residue was purified from 0-100% EtOAc/petroleum ether to 0-20% MeOH/EtOAc to provide tert-butyl (S) - (2- (5-bromo-1-oxoisoindolin-2-yl) ethyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (1.5 g, 44%) as a pale yellow oil.

(d) (S) - (2- (1-oxo-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) isoindolin-2-yl) ethyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To a mixture of tert-butyl (S) - (2- (5-bromo-1-oxoisoindolin-2-yl) ethyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (1 g,2.21 mmol) and 4,4', 5' -octamethyl-2, 2 '-bis (1, 3, 2-dioxaborane) (1.68 g,6.63 mmol) in dioxane (20 mL) was added potassium acetate (434 mg,4.42 mmol) followed by 1,1' -bis (biphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (181 mg,0.22 mmol). The reaction was stirred at 130℃for 3 hours. After cooling, the mixture was filtered and washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure. By flash chromatography (SiO ₂ The residue was purified with 0-100% EtOAc/petroleum ether, then 0-20% MeOH/EtOAc) to afford tert-butyl (S) - (2- (1-oxo-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) isoindolin-2-yl) ethyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (410 mg,37% yield) as an orange solid. ¹ H NMR (400 MHz, methanol-d) ₄ ):δ7.93(s,1H),7.90-7.84(m,1H),7.81-7.73(m,1H),4.61(d,2H),3.98(s,1H),3.82(s,2H),3.68-3.57(m,2H),3.37(s,2H),2.40-2.24(m,3H),1.84(br,1H),1.39(s,12H),1.22(s,9H).

(e) 5- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one

To tert-butyl (S) - (2- (1-oxo-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) isoindolin-2-yl) ethyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (10 mg,20 umol) and tert-butyl (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (12 mg,20 umol) in dioxane/H ₂ A mixture of O (100/1, 2.02 mL) was added potassium phosphate (4 mg,20 umol) and di-tert-butyl (cyclopentyl) phosphine; palladium dichloride; iron (1.3 mg,2.0 umol). The reaction was stirred at 110℃for 3 hours. After cooling, H was added to the mixture combined with another batch at 50mg scale ₂ O (10 mL) and extracted with EtOAc (20 mL). The organic layer was concentrated under vacuum. The residue was purified by preparative TLC (20% MeOH/EtOAc) to provide N- [ [6- [3- [2- [2- [2- [ tert-butoxycarbonyl- [ [ (2S) -5-oxopyrrolidin-2-yl ] as a white solid]Methyl group]Amino group]Ethyl group]-1-oxo-isoindolin-5-yl]-3-chloro-4-pyridinyl]-2-chloro-phenyl]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (32 mg, 28%).

(f) 5- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one

To N- [ [6- [3- [2- [2- [2- [ tert-butoxycarbonyl- [ [ (2S) -5-oxopyrrolidin-2-yl ]]Methyl group]Amino group]Ethyl group]-1-oxo-isoindolin-5-yl]-3-chloro-4-pyridinyl]-2-chloro-phenyl]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]A mixture of tert-butyl carbamate (50 mg, 54. Mu. Mol) in methylene chloride (0.3 mL) was added TFA (3.00 mL,40.5 mmol) and stirred at room temperature for 0.5 h. The reaction was concentrated under reduced pressure and the residue was purified by reverse phase HPLC to afford 5- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) as a white solid) Phenyl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one. m/z 728[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.75(d,1H),8.16(s,2H),7.90(s,1H),7.85(d,1H),7.80(s,2H),7.75-7.73(m,1H),7.68(d,2H),7.61(t,1H),7.57(d,1H),7.52(dd,1H),7.29(d,1H),4.62(s,2H),3.93(s,3H),3.73(d,2H),3.69-3.57(m,6H),2.86-2.83(m,3H),2.15-2.05(m,7H),1.72-1.66(m,2H).

Example 45: (S) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) -methyl) -1-methyl-1H-pyrrolo [3,2-b ] -pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (21)

(a) (S) -5- ((((6- (3-bromo-2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

A mixture of 6- (3-bromo-2-chlorophenyl) -2-methoxynicotinaldehyde (20 g,61 mmol), (5S) -5- (aminomethyl) -pyrrolidin-2-one hydrochloride (14 g,92 mmol), and sodium acetate (13 g,153 mmol) in a methylene chloride/trimethoxymethane mixture (5:1 (v/v), 300 mL) was stirred at room temperature for 4 hours. Sodium triacetoxyborohydride (26 g,122 mmol) was added in portions and added in N ₂ The reaction was stirred at room temperature for 2 hours. The reaction was then diluted with water (500 mL) and extracted with methylene chloride (3 x300 mL). The combined organics were further washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford (S) -5- ((((6- (3-bromo-2-chlorophenyl) -2-methoxypyridin-3-yl) methyl-) -amino) -methyl) -pyrrolidin-2-one (26 g, crude, observed m/z:426[ m+h) as a clear oil] ⁺ ). The crude product was used directly without further purification.

(b) (S) - ((6- (3-bromo-2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To a solution of (S) -5- ((((6- (3-bromo-2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one in DCM/trimethoxymethane mixture (5:1, 300 mL) was added di-tert-butyl dicarbonate (42 mL, 183mmol) and triethylamine (30 mL,214 mmol) in DCM (80 mL). At N ₂ The mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered to provide a filtrate. The filtrate was concentrated under reduced pressure and passed through normal phase SiO ₂ The crude residue was purified by chromatography (0-20% ethyl acetate/petroleum ether) to afford tert-butyl (S) - ((6- (3-bromo-2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (20 g,62% yield, observed m/z:526[ M+H ]) as a yellow solid ] ⁺ )。

(c) (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

Tert-butyl (S) - ((6- (3-bromo-2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (12 g,23 mmol), 1' -bis (biphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (0.93 g,1.14 mmol) and potassium carbonate (9.5 g,68 mmol) in 1, 4-dioxane/H ₂ The mixture in the O mixture (6:1, 140 mL) was degassed and N ₂ Purging 3 times, then (2, 3-dichloro-4-pyridinyl) boronic acid (3.5 g,18 mmol) in 1, 4-dioxane (150 mL) was added dropwise to the mixture at 95 ℃ over 2 hours. At N ₂ The mixture was stirred at 95℃for a further 1 hour. The reaction was diluted with water (250 mL) and extracted with EtOAc (2X 200 mL). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. By normal phase SiO ₂ Chromatography (0-15% Et)The crude residue was purified by OAc/Petroleum ether to afford tert-butyl (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (7 g, observed m/z:591[ M+H) ] ⁺ )。 ¹ H NMR(400MHz,DMSO-d ₆ ):δ.8.51(d,1H),7.77-7.73(m,2H),7.65-7.56(m,2H),7.50-7.44(m,2H),7.31-7.29(m,1H),4.47-4.35(m,2H),3.94(s,3H),3.78-3.76(m,1H),3.33-3.27(m,2H),2.22-2.04(m,3H),1.73-1.72(m,1H),1.44-1.30(m,9H).

(d) (S) - ((6- (2-chloro-3- (3-chloro-2- (3-formyl-1-methyl-1H-pyrrolo [3,2-b ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

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Pd (PPh) ₃ ) ₄ (31 mg,0.03 mmol), potassium carbonate (56 mg,0.41 mmol), N- [ [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl ]]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Carbamic acid tert-butyl ester (80 mg,0.14 mmol), and 1-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaboran-2-yl) pyrrolo [3,2-b]Pyridine-3-carbaldehyde (58 mg,0.20 mmol) was suspended in 1, 4-dioxane/water (4:1 (v/v), 2 mL) and the solution was then heated at 105℃for 20 min. The reaction was cooled to room temperature, diluted with 4mL of water, and extracted with EtOAc (3×3 mL). Concentrating the combined organics under reduced pressure and passing through normal phase SiO ₂ The crude sample was purified by chromatography (0-6% MeOH/DCM) to afford N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (3-formyl-1-methyl-pyrrolo [3,2-b ] as a yellow foam]Pyridin-6-yl) -4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (37 mg,39% yield). MS: m/z found 715.3,717[ M+H ] ] ⁺ .

(e) N- [ [6- [3- [2- [3- [ [ (1-acetyl-4-piperidinyl) amino ] methyl ] -1-methyl-pyrrolo [3,2-b ] pyridin-6-yl ] -3-chloro-4-pyridinyl ] -2-chloro-phenyl ] -2-methoxy-3-pyridinyl ] methyl ] -N- [ [ (2S) -5-oxopyrrolidin-2-yl ] methyl ] carbamic acid tert-butyl ester

N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (3-formyl-1-methyl-pyrrolo [3,2-b ]]Pyridin-6-yl) -4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (18 mg,0.03 mmol), 1- (4-amino-1-piperidinyl) ethanone (5 mg,0.04 mmol), and acetic acid (2 mg,0.03 mmol) were dissolved in MeOH/THF (1:1, 1 mL) and the solution was stirred at 25℃for 2 hours. Adding NaBH ₃ CN (3 mg,0.05 mmol) and the resulting mixture was stirred at 25℃for 1 hour. The reaction was then diluted with water (2 mL) and extracted with EtOAc (3×2 mL). The combined organics were further washed with brine (3 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to provide N- [ [6- [3- [2- [3- [ [ (1-acetyl-4-piperidinyl) amino ] as a yellow oil]Methyl group]-1-methyl-pyrrolo [3,2-b]Pyridin-6-yl]-3-chloro-4-pyridinyl]-2-chloro-phenyl]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl ]Methyl group]Tert-butyl carbamate (21 mg, crude). MS: m/z found 841.4, 843[ M+H ]] ⁺ . The material was used in the next step without further purification.

(f) (S) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

N- [ [6- [3- [2- [3- [ [ (1-acetyl-4-piperidinyl) amino ] amino group]Methyl group]-1-methyl-pyrrolo [3,2-b]Pyridin-6-yl]-3-chloro-4-pyridinyl]-2-chloro-phenyl]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (21 mg,0.02mmol, crude) was dissolved in 1mL DCM and 4M HCl solution (25. Mu.L, 0.10 mmol) in 1, 4-dioxane was added. The reaction was stirred at room temperature for 20 minAnd the solvent was removed under reduced pressure. The crude sample was purified by reverse phase HPLC to provide (5S) -5- [ [ [6- [3- [2- [3- [ [ (1-acetyl-4-piperidinyl) amino ] as a white solid (formate salt)]Methyl group]-1-methyl-pyrrolo [3,2-b]Pyridin-6-yl]-3-chloro-4-pyridinyl]-2-chloro-phenyl]-2-methoxy-3-pyridinyl]Methylamino group]Methyl group]Pyrrolidin-2-one (12 mg,65% yield). MS: m/z found 741.4,743.3[ M+H ] ] ⁺ LC retention time = 2.02min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.77(d,1H),8.71(d,1H),8.53(s,1H),8.30(d,1H),7.80(s,1H),7.75(d,1H),7.72(dd,1H),7.56(t,1H),7.49(d,1H),7.43(dd,1H),7.26(d,1H),4.61(d,1H),4.44(s,2H),4.02(s,4H),3.95(s,3H),3.85(d,3H),3.33(s,1H),3.17(t,1H),2.77–2.63(m,3H),2.37–2.19(m,5H),2.12(s,3H),1.87–1.76(m,1H),1.63–1.50(m,1H),1.52–1.39(m,1H).

Example 46: (S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -oxetan-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -methyl) -amino) -methyl) -pyrrolidin-2-one (22)

In the same manner as described for compound 21, intermediate (S) - ((6- (2-chloro-3- (3-chloro-2- (3-formyl-1-methyl-1H-pyrrolo [3, 2-b))]Preparation of tert-butyl (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -oxetan-2-yl) methyl) amino) methyl) -1H-pyrrolo [3, 2-b)) methyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamate]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -methyl) -amino) -methyl) -pyrrolidin-2-one. (S) -oxetan-2-ylmethylamine is used instead of 1- (4-aminopiperidin-1-yl) ethan-1-one. The product was obtained as a yellow solid. MS: m/z found 686.3,688[ M+H ]] ⁺ LC retention time = 2.01min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.80(d,1H),8.71(d,1H),8.50(s,1H),8.33(d,1H),7.90(s,1H),7.76(d,1H),7.72(dd,1H),7.56(t,1H),7.49(d,1H),7.44(dd,1H),7.27(d,1H),4.64(s,2H),4.53(s,1H),4.02(s,3H),3.97(s,3H),3.87(dd,3H),3.62(q,1H),3.57–3.42(m,2H),3.38(d,1H),2.84–2.68(m,2H),2.39–2.15(m,4H),2.04(s,1H),1.82(m,1H).

Example 47: (S) -5- (((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((((S) -5-oxopyrrolidin-2-yl) -methyl) -amino) -methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (23)

In the same manner as described for compound 21, the intermediate tert-butyl (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate was used to prepare (S) -5- (((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((((S) -5-oxopyrrolidin-2-yl) -methyl) -amino) -methyl) - [2,3' -bipyridine)]-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one. 1-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyrrolo [3,2-b ] with 3-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) Pi Kaolin aldehyde]Pyridine-3-carbaldehyde. The (formate) product was obtained as a pale yellow solid. MS: m/z found 690.3,693[ M+H ]] ⁺ LC retention time = 1.98min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.70(dd,1H),8.52(d,1H),8.42(s,2H),7.80(d,2H),7.75–7.67(m,1H),7.60–7.51(m,1H),7.50(dd,1H),7.43(d,1H),7.32–7.19(m,1H),4.32(d,2H),4.04(d,3H),4.03–3.95(m,6H),3.91(s,1H),3.17–2.99(m,2H),2.99–2.74(m,2H),2.34(t,6H),2.01–1.75(m,2H).

Example 48: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((S) -2-hydroxypropyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] -oxazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (25)

(a) (S) -1- (8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) propan-2-ol

(2S) -2-methyl ethylene oxide (127 mg,2.19 mmol), 8-bromo-2,3,4,5-tetrahydro-1,4-benzoxazepine (8-bromoo-2, 3,4, 5-tetrahydroxy-1, 4-benzoxazepine) (50 mg,0.22 mmol), and DIEA (38. Mu.L, 0.22 mmol) were suspended in 2mL EtOH and the mixture stirred at 85℃for 1 hour. The reaction was concentrated and the residue was dissolved in 2mL EtOAc. The organic solution was washed with water (2×2 mL), brine (2×2 mL), dried over sodium sulfate, filtered, and concentrated to provide a clear oil (46 mg, crude). MS: m/z found 286,288[ M+H ]] ⁺ . The material was used in the next step without further purification.

(2S) -1- (8-bromo-3, 5-dihydro-2H-1, 4-benzoxazepin-4-yl) propan-2-ol (46 mg,0.16mmol, crude), 4, 5-tetramethyl-2- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,3, 2-dioxaborane (53 mg,0.21 mmol), 1' -bis (biphenylphosphino) -ferrocene-palladium (II) dichloride dichloromethane complex (13 mg,0.02 mmol), and potassium acetate (47 mg,0.48 mmol) were suspended in 2mL of 1, 4-dioxane in a sealed tube. Nitrogen was bubbled through the reaction solution for 2 minutes, then the vessel was sealed and heated at 95 ℃ for 6 hours. The reaction was cooled to room temperature and the mixture was filtered through CELITE. The filtrate was concentrated under reduced pressure and passed through normal phase SiO ₂ Chromatography (0-5% MeOH/DCM) of the crude oil afforded (2S) -1- [8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 5-dihydro-2H-1, 4-benzoxazepin-4-yl as a brown oil]Propan-2-ol (25 mg,47% yield). MS: m/z found 334[ M+H ]] ⁺ .

(b) (6- (2-chloro-3- (3-chloro-2- (4- ((S) -2-hydroxypropyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

Pd (PPh) ₃ ) ₄ (17 mg,0.02 mmol), potassium carbonate (31 mg,0.23 mmol), N- [ [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl ]]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Carbamic acid tert-butyl ester (53 mg,0.09 mmol), and (2S) -1- [8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 5-dihydro-2H-1, 4-benzoxazepin-4-yl]Propane-2-ol (25 mg,0.08 mmol) was suspended in 1, 4-dioxane/water (4:1, 1 mL) and the solution was then heated at 105℃for 20 min. The reaction was cooled to room temperature, diluted with 3mL of water, and extracted with EtOAc (3×2 mL). The combined organics were concentrated under reduced pressure and purified by flash chromatography (SiO ₂ 0-6% MeOH/DCM) to provide N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [4- [ (2S) -2-hydroxypropyl ] as a white foam ]-3, 5-dihydro-2H-1, 4-benzoxazepin-8-yl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (15 mg,27% yield). MS: m/z found 762.3, 764[ M+H ]] ⁺ .

(c) (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((S) -2-hydroxypropyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] -oxazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [4- [ (2S) -2-hydroxypropyl ] amino acid]-3, 5-dihydro-2H-1, 4-benzoxazepin-8-yl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (13 mg,0.02 mmol) was dissolved in 0.5mL DCM and a 4M HCl solution (17. Mu.L, 0.07 mmol) in 1, 4-dioxane was added. The reaction was stirred at room temperature for 20 minutes and the solvent was removed under reduced pressure. Purification of the crude sample by reverse phase HPLC to afford (5S) -5- [ [ [6- [ 2-chloro-3- [ 3-chloro-2- [4- [ (2S) -2-hydroxypropyl ] as a white solid (formate)]3, 5-dihydro-2H-1, 4-Benzooxazepin-8-yl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methylamino group]Methyl group]Pyrrolidin-2-one (10 mg,94% yield). MS: m/z found 662.2,664[ M+H ] ] ⁺ LC retention time = 2.01min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.61(d,1H),8.40(s,1H),7.80(d,1H),7.71(dd,1H),7.55(t,1H),7.44–7.40(m,2H),7.38(d,2H),7.33(d,1H),7.30(d,1H),4.18(dd,2H),4.14(s,2H),4.03(d,6H),3.92(s,1H),3.33(d,2H),2.97–2.84(m,2H),2.71(dd,1H),2.60(dd,1H),2.41–2.26(m,3H),1.92–1.77(m,1H),1.16(d,3H).

Example 49: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (26)

In the same manner as described for compound 25, the intermediate N- [ [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl ] was utilized]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Preparation of S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2, 3,4, 5-tetrahydrobenzo [ f))][1,4]Oxazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one. With 8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2, 3-dihydrobenzo [ f][1,4]Oxazepine-4 (5H) -carboxylic acid tert-butyl ester instead of (S) -1- (8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2, 3-dihydrobenzo [ f ]][1,4]Oxazepin-4 (5H) -yl) propan-2-ol. The product was obtained as a white solid. MS: m/z found 604.3,606.1[ M+H ]] ⁺ LC retention time = 1.98min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.64(d,1H),8.43(s,2H),7.80(d,1H),7.71(dd,1H),7.55(t,1H),7.52–7.38(m,5H),7.29(d,1H),4.38(s,2H),4.31–4.23(m,2H),4.04(s,3H),4.00(d,2H),3.92(d,1H),3.55(dd,2H),2.94–2.80(m,2H),2.41–2.22(m,3H),1.92–1.78(m,1H).

Example 50: (5S) -5- ((((6- (2-chloro-3- (3-chloro-2- (5- (((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (diastereomeric mixture) (112)

(a) (S) - ((6- (2-chloro-3- (3-chloro-2- (5-oxo-5, 6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

N- [ [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl ]]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (200 mg,0.34 mmol), pd (PPh) ₃ ) ₄ (78 mg,0.07 mmol), potassium carbonate (140 mg,1.01 mmol), and 6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) tetralin-1-one (138 mg,0.51 mmol) were suspended in 1, 4-dioxane/water (4:1, 4 mL), and the solution was then heated at 105℃for 20 minutes. The reaction was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×5 mL). Concentrating the combined organics under reduced pressure and passing through normal phase SiO ₂ The crude sample was purified by chromatography (0-4% MeOH/DCM) to provide N- [2- [3- [3- [5- [ [ tert-butoxycarbonyl- [ (2S) -5-oxopyrrolidin-2-yl ] as a yellow foam]Methyl group]Amino group]Methyl group]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-2-chloro-phenyl]-5,6,7, 8-tetrahydroquinolin-5-yl]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (226 mg, 56%). MS: m/z found 701,703[ M+H ]] ⁺ 。

(b) (6- (2-chloro-3- (3-chloro-2- (5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (1-oxo-tetralin-6-yl) -4-pyridinyl ]]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (65 mg,0.09 mmol), (5S) -5- (aminomethyl) pyrrolidin-2-one (21 mg,0.19 mmol), and titanium tetraethoxide (63 mg,0.28 mmol) were suspended in 1mL anhydrous THF. The reaction mixture was heated in a sealed tube at 105 ℃ for 3 hours. The reaction was cooled to-50 ℃ and sodium borohydride (7 mg,0.19 mmol) was added under a nitrogen flow, then the mixture was warmed to room temperature over 1 hour. The reaction was then added dropwise to an ice water solution (5 mL) and also 5mL EtOAc. The resulting slurry was filtered through CELITE. The filtrate was extracted with EtOAc (3×5 mL) and the combined organics were further washed with brine (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide N- [ [6- [ 2-chloro-3- [5- [ [ (2S) -2-hydroxypropyl ] as a yellow foam]Amino group]-5,6,7, 8-tetrahydroquinolin-2-yl]Phenyl group]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (21 mg, crude, racemic mixture). MS: m/z found 799,801[ M+H ]] ⁺ . The material was used in the next step without further purification.

(c) (5S) -5- (((6- (2-chloro-3- (3-chloro-2- (5- (((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [1- [ [ (2S) -5-oxopyrrolidin-2-yl ]]Methylamino group]Tetralin-6-yl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (34 mg,0.04 mmol) was dissolved in 1mL DCM and a solution of 1, 4-dioxane (39. Mu.L, 0.16 mmol) in 4M HCl was added. The reaction was stirred at room temperature for 20 minutes and the solvent was removed under reduced pressure. The crude sample was purified by reverse phase HPLC to provide (5S) -5- [ [ [6- [ 2-chloro-3- ] as formate salt[ 3-chloro-2- [1- [ [ (2S) -5-oxopyrrolidin-2-yl]Methylamino group]Tetralin-6-yl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methylamino group]Methyl group]Pyrrolidin-2-one (21 mg,75% yield, diastereomeric mixture). LCMS: m/z found 699,701[ M+H ]] ⁺ Retention time = 2.03min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.60(d,1H),7.76(d,1H),7.70(dd,1H),7.54(t,2H),7.48(d,1H),7.44–7.36(m,3H),7.26(d,1H),4.02(s,4H),3.96–3.78(m,4H),2.82(m,6H),2.39–2.25(m,6H),2.01(s,3H),1.92–1.75(m,3H).

Example 51: (5S) -5- ((((6- (2-chloro-3- (3-chloro-2- (5- (((S) -2-hydroxypropyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (diastereomeric mixture) (113)

The compound was prepared in the same manner as described for compound 112 using intermediate tert-butyl (S) - ((6- (2-chloro-3- (3-chloro-2- (5-oxo-5, 6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate. (S) -5- (aminomethyl) pyrrolidin-2-one was replaced with (S) -1-aminopropane-2-ol. LCMS: m/z found 660,662[ M+H ]] ⁺ Retention time = 2.12min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.63(d,1H),8.49(s,1H),7.76(d,1H),7.70(dd,1H),7.58(d,2H),7.54(t,2H),7.45(d,1H),7.40(dd,1H),7.26(d,1H),4.59(s,1H),4.02(s,4H),3.88(dd,3H),3.18–3.05(m,1H),3.02–2.84(m,3H),2.82–2.69(m,2H),2.38–2.25(m,3H),2.20(s,2H),2.02(d,1H),1.97–1.77(m,2H),1.25(dd,3H).

Example 52: (S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxy-5-methylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (114)

In the same manner as described for compound 21, tert-butyl (S) -5- ((((6- (2-chloro-3- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxy-5-methylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one was prepared using the intermediate (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester. 1-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -pyrrolo [3,2-b ] is replaced with 2-methoxy-6-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -benzaldehyde ]Pyridine-3-carbaldehyde. The product was obtained as a white solid (formate). LCMS: m/z found 664,666[ M+H ]] ⁺ Retention time = 2.07min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.64(d,1H),8.49(s,1H),7.76(d,1H),7.73–7.68(m,1H),7.55(t,1H),7.46(d,1H),7.43–7.37(m,1H),7.26(d,1H),7.22(s,2H),4.44–4.30(m,2H),4.10(d,1H),4.02(s,3H),3.97(s,3H),3.88(dd,3H),3.16(dd,1H),2.90(dd,1H),2.84–2.71(m,2H),2.51(s,3H),2.39–2.24(m,3H),1.82(dd,1H),1.25(d,3H).

Example 53: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5-methyl-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (115)

In the same manner as described for compound 21, tert-butyl (S) -5- ((((6- (2-chloro-3- (3-methoxy-5-methyl-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) amino) methyl) pyrrolidin-2-one was prepared using the intermediate (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester. 2-methoxy-6-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -benzaldehyde is used to replace 1-methyl-6- (4, 5,5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyrrolo [3,2-b]Pyridine-3-carbaldehyde. The product was obtained as a white solid (formate). MS: m/z found 703,705[ M+H ]] ⁺ LC retention time = 2.04min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.63(d,1H),8.46(s,1H),7.78(d,1H),7.71(dd,1H),7.55(t,1H),7.45(d,1H),7.41(dd,1H),7.27(d,1H),7.20(s,2H),4.23(s,2H),4.03(s,3H),4.02–3.94(m,6H),3.90(d,1H),3.08(dd,2H),2.82(h,2H),2.49(s,3H),2.43–2.28(m,6H),1.95–1.78(m,2H).

Example 54: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5-methyl-4- ((methyl (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (117)

In the same manner as described for compound 21, tert-butyl (S) -5- ((((6- (2-chloro-2- (3-methoxy-5-methyl-4- ((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) amino) methyl) pyrrolidin-2-one was prepared using the intermediate (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester. 1-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -pyrrolo [3,2-b ] is replaced with 2-methoxy-6-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -benzaldehyde]Pyridine-3-carbaldehyde. The product was obtained as a white solid (formate). MS: m/z found 717,719[ M+H ]] ⁺ LC retention time = 2.07min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.61(d,1H),8.42(s,1H),7.79(d,1H),7.71(d,1H),7.55(t,1H),7.42(t,2H),7.29(d,1H),7.14(s,2H),4.04(s,3H),4.00(d,2H),3.97–3.85(m,6H),3.75(d,1H),2.88(t,2H),2.65(d,2H),2.48(s,3H),2.43–2.23(m,9H),1.92–1.77(m,1H),1.73(s,1H).

Example 55: (S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxy-5-methylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (118)

In the same manner as described for compound 21, tert-butyl (S) -5- ((((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate was prepared using the intermediate (S) - ((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxy-5-methylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl pyrrolidin-2-one. 1-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -pyrrolo [3,2-b ] is replaced with 2-methoxy-6-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -benzaldehyde]Pyridine-3-carbaldehyde. The product was obtained as a white solid (formate). MS: m/z found 678,680[ M+H ]] ⁺ LC retention time = 2.10min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.63(d,1H),8.53(s,1H),7.74(d,1H),7.70(d,1H),7.54(t,1H),7.47–7.43(m,1H),7.40(d,1H),7.24(d,1H),7.20(s,2H),4.16(s,2H),4.01(t,3H),3.94(s,3H),3.89–3.77(m,3H),2.69(dd,5H),2.50(d,3H),2.30(m,3H),1.80(d,1H),1.21(d,3H).

Example 56: (5S) -5- [ [ [6- [3- [2- [3- [ [ (1-acetyl-4-piperidinyl) amino ] methyl ] -1-methyl-indol-6-yl ] -3-chloro-4-pyridinyl ] -2-chloro-phenyl ] -2-methoxy-3-pyridinyl ] methylamino ] methyl ] pyrrolidin-2-one (28)

(a) N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (3-formyl-1-methyl-indol-6-yl) -4-pyridinyl ] phenyl ] -2-methoxy-3-pyridinyl ] methyl ] -N- [ [ (2S) -5-oxopyrrolidin-2-yl ] methyl ] carbamic acid tert-butyl ester

Following Suzuki coupling procedure B, a compound selected from the group consisting of N- [ [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl ]]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Preparation of N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (3-formyl-1-methyl-indol-6-yl) -4-pyridinyl ] by tert-butyl carbamate (300 mg,0.51 mmol) and 1-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) indole-3-carbaldehyde (144 mg,0.51 mmol)]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate. 80% yield. MS: m/z found 714.2[ M+H ]] ⁺ .

(b) (5S) -5- [ [ [6- [3- [2- [3- [ [ (1-acetyl-4-piperidinyl) amino ] methyl ] -1-methyl-indol-6-yl ] -3-chloro-4-pyridinyl ] -2-chloro-phenyl ] -2-methoxy-3-pyridinyl ] methylamino ] methyl ] pyrrolidin-2-one

Starting material N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (3-formyl-1-methyl-indol-6-yl) -4-pyridinyl ] using reductive amination procedure B]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (25 mg,0.03 mmol) and 1- (4-amino-1-piperidinyl) ethanone (10 mg,0.07 mmol) provide N- [ [6- [3- [2- [3- [ [ (1-acetyl-4-piperidinyl) amino ] as crude material ]Methyl group]-1-methyl-indol-6-yl]-3-chloro-4-pyridinyl]-2-chloro-phenyl]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate, 75% LCMS yield. MS: m/z found 840.3[ M+H ]] ⁺ . The crude material is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Deprotection step 96% LCMS yield. MS: m/z found 740.3[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.54(s,2H),7.82(d,1H),7.78–7.73(m,2H),7.71(dd,1H),7.55(t,1H),7.52–7.47(m,2H),7.45–7.40(m,2H),7.26(d,1H),4.63(d,1H),4.39(s,2H),4.09–4.00(m,4H),3.90(s,3H),3.88–3.78(m,3H),3.40–3.32(m,1H),3.24–3.11(m,1H),2.79–2.62(m,3H),2.39–2.17(m,5H),2.13(s,3H),1.82(m,1H),1.66–1.40(m,2H).

Example 57: (5S) -5- [ [ [6- [ 2-chloro-3- [ 3-chloro-2- [3- [ (2-hydroxyethylamino) methyl ] -1-methyl-indol-6-yl ] -4-pyridyl ] phenyl ] -2-methoxy-3-pyridyl ] methylamino ] methyl ] pyrrolidin-2-one (29)

By reductive amination procedure B, starting from N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (3-formyl-1-methyl-indol-6-yl) -4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (20 mg,0.03 mmol) and 2-aminoethanol (4 mg,0.06 mmol) provided N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [3- [ (2-hydroxyethylamino) methyl ] as crude material]-1-methyl-indol-6-yl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate, 73% LCMS yield. MS: m/z found 759.3[ M+H ] ] ⁺ . The crude material is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Deprotection step 97% LCMS yield. MS: m/z found 659.2[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.55(s,2H),7.82(d,1H),7.78–7.73(m,2H),7.71(dd,1H),7.55(t,1H),7.51–7.46(m,2H),7.47–7.39(m,2H),7.26(d,1H),4.38(s,2H),4.02(s,3H),3.90(s,3H),3.88–3.81(m,3H),3.81–3.77(m,2H),3.09(t,2H),2.77–2.62(m,2H),2.39–2.21(m,3H),1.88–1.75(m,1H).

Example 58: (5S) -5- [ [ [6- [ 2-chloro-3- [ 3-chloro-2- [3- [ (2-methoxyethylamino) methyl ] -1-methyl-indol-6-yl ] -4-pyridyl ] phenyl ] -2-methoxy-3-pyridyl ] methylamino ] methyl ] pyrrolidin-2-one (30)

By reductive amination procedure B, starting from N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (3-formyl-1-methyl)Phenyl-indol-6-yl) -4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (20 mg,0.03 mmol) and 2-methoxyethylamine (4 mg,0.06 mmol) provided N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [3- [ (2-methoxyethylamino) methyl ] as crude material]-1-methyl-indol-6-yl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate, 74% LCMS yield. MS: m/z found 773.3[ M+H ]] ⁺ . The crude material was deprotected and purified using a general Boc deprotection procedure to provide the final product as formate. Deprotection step 98% LCMS yield. MS: m/z found 673.2[ M+H ] ] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.55(s,2H),7.81(d,1H),7.79–7.73(m,2H),7.71(dd,1H),7.55(t,1H),7.51–7.46(m,2H),7.45–7.39(m,2H),7.26(d,1H),4.36(s,2H),4.02(s,3H),3.90(s,3H),3.88–3.77(m,3H),3.67–3.56(m,2H),3.40(s,3H),3.16(t,2H),2.76–2.63(m,2H),2.39–2.22(m,3H),1.83(td,1H).

Example 59: (5S) -5- [ [ [6- [ 2-chloro-3- [ 3-chloro-2- [ 1-methyl-3- (methylaminomethyl) indol-6-yl ] -4-pyridinyl ] phenyl ] -2-methoxy-3-pyridinyl ] methylamino ] methyl ] pyrrolidin-2-one (31)

By reductive amination procedure B, starting from N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (3-formyl-1-methyl-indol-6-yl) -4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (20 mg,0.03 mmol) and a solution of methylamine (33% wt in ethanol, 0.06 mmol) provided N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [ 1-methyl-3- (methylaminomethyl) indol-6-yl ] as crude material]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate, 73% LCMS yield. MS: m/z found 729.3[ M+H ]] ⁺ . The crude material is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Deprotection step 96% LCMS yield. MS: m/z found 629.2[M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.54(s,2H),7.83(d,1H),7.79(d,J＝1.3Hz,1H),7.75(d,1H),7.71(dd,1H),7.59–7.48(m,3H),7.47–7.40(m,2H),7.26(d,1H),4.41(s,2H),4.02(s,3H),3.91(s,3H),3.89–3.75(m,3H),2.77–2.62(m,5H),2.39–2.23(m,3H),1.89–1.74(m,1H).

Example 60: (5S) -5- [ [ [6- [ 2-chloro-3- [ 3-chloro-2- [3- (ethylaminomethyl) -1-methyl-indol-6-yl ] -4-pyridinyl ] phenyl ] -2-methoxy-3-pyridinyl ] methylamino ] methyl ] pyrrolidin-2-one (32)

By reductive amination procedure B, starting from N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (3-formyl-1-methyl-indol-6-yl) -4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (20 mg,0.03 mmol) and ethylamine solution (2.0M in THF, 0.06 mmol) provided N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [3- (ethylaminomethyl) -1-methyl-indol-6-yl ] as crude material]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate, 72% LCMS yield. MS: m/z found 743.3[ M+H ]] ⁺ . The crude material is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Deprotection step 95% LCMS yield. MS: m/z found 643.2[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.55(s,2H),7.83(d,1H),7.79–7.77(m,1H),7.75(d,1H),7.71(dd,1H),7.56(t,1H),7.53–7.48(m,2H),7.46–7.40(m,2H),7.26(d,1H),4.40(s,2H),4.02(s,3H),3.91(s,3H),3.89–3.77(m,3H),3.12(q,2H),2.77–2.62(m,2H),2.39–2.22(m,3H),1.89–1.75(m,1H),1.33(t,3H).

Example 61: (5S) -5- [ [ [6- [ 2-chloro-3- [ 3-chloro-2- [3- [ (dimethylamino) methyl ] -1-methyl-indol-6-yl ] -4-pyridinyl ] phenyl ] -2-methoxy-3-pyridinyl ] methylamino ] methyl ] pyrrolidin-2-one (33)

By reductive amination procedure B, starting from N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (3-formyl-1-methyl-indol-6-yl) -4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl ]Methyl group]Tert-butyl carbamate (20 mg,0.03 mmol) and N-methyl methylamine solution (2.0M in ethanol, 0.06mmol afforded N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [3- [ (dimethylamino) methyl ] as crude material]-1-methyl-indol-6-yl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate, 77% LCMS yield. MS: m/z found 743.3[ M+H ]] ⁺ . The crude material is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Deprotection step 96% LCMS yield. MS: m/z found 643.2[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.54(s,2H),7.81(d,1H),7.77(d,1H),7.75(d,1H),7.71(dd,1H),7.55(t,1H),7.51–7.47(m,2H),7.45–7.38(m,2H),7.26(d,1H),4.24(s,2H),4.02(s,3H),3.91(s,3H),3.89–3.78(m,3H),2.77–2.61(m,2H),2.68(s,6H),2.37–2.24(m,3H),1.87–1.76(m,1H).

Example 62: (5S) -5- [ [ [6- [ 2-chloro-3- [ 3-chloro-2- [ 1-methyl-3- [ [ [ (2S) -oxetan-2-yl ] methylamino ] methyl ] indol-6-yl ] -4-pyridinyl ] phenyl ] -2-methoxy-3-pyridinyl ] methylamino ] methyl ] pyrrolidin-2-one (34)

By reductive amination procedure B, starting from N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (3-formyl-1-methyl-indol-6-yl) -4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (20 mg,0.03 mmol) and [ (2S) -oxetan-2-yl]Methylamine (5 mg,0.06 mmol) provided N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [ 1-methyl-3- [ [ (2S) -oxetan-2-yl ] as crude material ]Methylamino group]Methyl group]Indol-6-yl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrroleAlk-2-yl]Methyl group]Tert-butyl carbamate, 73% LCMS yield. MS: m/z found 785.3[ M+H ]] ⁺ . The crude material was provided as the final product of formate according to the general Boc deprotection procedure. Deprotection step 96% LCMS yield. MS: m/z found 685.2[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.63(d,1H),8.55(s,2H),7.79(d,1H),7.75(d,1H),7.73(s,1H),7.71(dd,1H),7.55(t,1H),7.48–7.38(m,4H),7.26(d,1H),5.03(dd,1H),4.75–4.66(m,1H),4.57(dt,1H),4.21(s,2H),4.02(s,3H),3.88(s,3H),3.86–3.76(m,3H),3.21(dd,1H),3.01(dd,1H),2.82–2.62(m,3H),2.54–2.42(m,1H),2.37–2.23(m,3H),1.89–1.75(m,1H).

Example 63: (5S) -5- [ [ [6- [ 2-chloro-3- [ 3-chloro-2- [3- [ [ [ (2S) -2-hydroxypropyl ] amino ] methyl ] -1-methyl-indol-6-yl ] -4-pyridinyl ] phenyl ] -2-methoxy-3-pyridinyl ] methylamino ] methyl ] pyrrolidin-2-one (35)

By reductive amination procedure B, starting from N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (3-formyl-1-methyl-indol-6-yl) -4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (20 mg,0.03 mmol) and (2S) -1-aminopropane-2-ol (4 mg,0.06 mmol) provide N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [3- [ [ [ (2S) -2-hydroxypropyl ] as crude material]Amino group]Methyl group]-1-methyl-indol-6-yl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (83.1% LCMS yield), found MS: m/z 773.3[ M+H ] ] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 96% LCMS yield. MS: m/z found 673.2[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.55(s,2H),7.82(d,1H),7.77(t,1H),7.75(d,1H),7.71(dd,1H),7.55(t,1H),7.52–7.47(m,2H),7.45–7.40(m,2H),7.26(d,1H),4.39(s,2H),4.07–3.99(m,4H),3.90(s,3H),3.87–3.78(m,3H),3.03(dd,1H),2.84(dd,1H),2.76–2.63(m,2H),2.38–2.20(m,3H),1.83(td,1H),1.20(d,3H).

Example 64: (5S) -5- [ [ [6- [ 2-chloro-3- [ 3-chloro-2- [3- [ [ (2-hydroxy-2-methyl-propyl) amino ] methyl ] -1-methyl-indol-6-yl ] -4-pyridinyl ] phenyl ] -2-methoxy-3-pyridinyl ] methylamino ] methyl ] pyrrolidin-2-one (36)

By reductive amination procedure B, starting from N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (3-formyl-1-methyl-indol-6-yl) -4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (25 mg,0.03 mmol) and 1-amino-2-methyl-propan-2-ol (6 mg,0.07 mmol) provided N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [3- [ [ (2-hydroxy-2-methyl-propyl) amino ] as crude material]Methyl group]-1-methyl-indol-6-yl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (90% LCMS yield), MS: m/z found 787.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 97% LCMS yield. MS: m/z found 687.3[ M+H ] ] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.54(s,2H),7.84(d,1H),7.79–7.78(m,1H),7.75(d,1H),7.71(dd,1H),7.59–7.53(m,2H),7.51(dd,1H),7.46–7.40(m,2H),7.26(d,1H),4.45(s,2H),4.02(s,3H),3.91(s,3H),3.89–3.79(m,3H),2.96(s,2H),2.78–2.62(m,2H),2.37–2.22(m,3H),1.88–1.74(m,1H),1.25(s,6H).

Example 65: (5S) -5- [ [ [6- [ 2-chloro-3- [ 3-chloro-2- [3- [ (isobutylamino) methyl ] -1-methyl-indol-6-yl ] -4-pyridinyl ] phenyl ] -2-methoxy-3-pyridinyl ] methylamino ] methyl ] pyrrolidin-2-one (38)

By reductive amination procedure B, starting from N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (3-formyl-1-methyl-indol-6-yl) -4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N-[[(2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (25 mg,0.03 mmol) and 2-methylpropan-1-amine (5 mg,0.07 mmol) provided N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [3- [ (isobutylamino) methyl ] as crude material]-1-methyl-indol-6-yl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (74% LCMS yield), MS: m/z found 771.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 96% LCMS yield. MS: m/z found 671.3[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d1H),8.54(s,2H),7.87–7.81(m,1H),7.78(d,1H),7.75(d,1H),7.71(dd,1H),7.59–7.53(m,2H),7.51(dd,1H),7.46–7.40(m,2H),7.26(d,1H),4.42(s,2H),4.02(s,3H),3.91(s,3H),3.89–3.77(m,3H),2.89(d,2H),2.76–2.63(m,2H),2.38–2.23(m,3H),2.06–1.95(m,1H),1.87–1.75(m,1H),1.02(d,6H).

Example 66: (5S) -5- [ [ [6- [ 2-chloro-3- [ 3-chloro-2- [3- [ [ 2-hydroxyethyl (methyl) amino ] methyl ] -1-methyl-indol-6-yl ] -4-pyridinyl ] phenyl ] -2-methoxy-3-pyridinyl ] methylamino ] methyl ] pyrrolidin-2-one (39)

By reductive amination procedure B, starting from N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (3-formyl-1-methyl-indol-6-yl) -4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (25 mg,0.03 mmol) and 2- (methylamino) ethanol (5 mg,0.07 mmol) provided N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [3- [ [ 2-hydroxyethyl (methyl) amino ] as crude material]Methyl group]-1-methyl-indol-6-yl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (81% LCMS yield), MS: m/z found 773.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 97% LCMS yield. MS: m/z found 673.2[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.54(s,2H),7.83(d,1H),7.78(d,1H),7.75(d,1H),7.71(dd,1H),7.55(t,1H),7.53–7.47(m,2H),7.45–7.39(m,2H),7.26(d,1H),4.37(s,2H),4.02(s,3H),3.91(s,3H),3.85(dd,5H),3.10(t,2H),2.76–2.63(m,5H),2.37–2.22(m,3H),1.87–1.75(m,1H).

Example 67: (5S) -5- [ [ [6- [ 2-chloro-3- [ 3-chloro-2- [3- [ [ [ (2S) -2-methoxypropyl ] amino ] methyl ] -1-methyl-indol-6-yl ] -4-pyridinyl ] phenyl ] -2-methoxy-3-pyridinyl ] methylamino ] methyl ] pyrrolidin-2-one (40)

By reductive amination procedure B, starting from N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (3-formyl-1-methyl-indol-6-yl) -4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl ]Methyl group]Tert-butyl carbamate (25 mg,0.03 mmol) and (2S) -2-methoxypropane-1-amine (6 mg,0.07 mmol) provide N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [3- [ [ [ (2S) -2-methoxypropyl ] as crude material]Amino group]Methyl group]-1-methyl-indol-6-yl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (62% LCMS yield), MS: m/z found 787.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 96% LCMS yield. MS: m/z found 687.3[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.63(d,1H),8.55(s,2H),7.80(d,1H),7.76–7.68(m,3H),7.55(t,1H),7.50–7.38(m,4H),7.26(d,1H),4.29(s,2H),4.02(s,3H),3.89(s,3H),3.87–3.78(m,3H),3.62(ddd,1H),3.36(s,3H),2.98(dd,1H),2.86(dd,1H),2.76–2.63(m,2H),2.37–2.22(m,3H),1.89–1.75(m,1H),1.16(d,3H).

Example 68: (5S) -5- [ [ [6- [ 2-chloro-3- [ 3-chloro-2- [ 1-methyl-3- [ [ [ (2S) -tetrahydrofuranyl-2-yl ] methylamino ] methyl ] indol-6-yl ] -4-pyridinyl ] phenyl ] -2-methoxy-3-pyridinyl ] methylamino ] methyl ] pyrrolidin-2-one (41)

Reductive amination procedure B starting from N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (3-formyl-1-methyl-indol-6-yl) -4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (25 mg,0.03 mmol) and [ (2S) -tetrahydrofuran-2-yl]Methylamine (7 mg,0.07 mmol) provided N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [ 1-methyl-3- [ [ (2S) -tetrahydrofuran-2-yl ] as crude material ]Methylamino group]Methyl group]Indol-6-yl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (78% LCMS yield), MS: m/z found 799.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 96% LCMS yield. MS: m/z found 699.3[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.63(d,1H),8.55(s,2H),7.85–7.79(m,1H),7.78–7.68(m,3H),7.55(t,1H),7.51–7.46(m,2H),7.45–7.39(m,2H),7.26(d,1H),4.43–4.29(m,2H),4.14(dtd,1H),4.02(s,3H),3.93–3.76(m,8H),3.09(dd,1H),2.93(dd,1H),2.77–2.63(m,2H),2.38–2.21(m,3H),2.15–2.02(m,1H),1.99–1.89(m,2H),1.82(m,1H),1.58(m,1H).

Example 69: (5S) -5- [ [ [6- [ 2-chloro-3- [ 3-chloro-2- [ 1-methyl-3- [ (tetrahydropyran-4-ylamino) methyl ] indol-6-yl ] -4-pyridinyl ] phenyl ] -2-methoxy-3-pyridinyl ] methylamino ] methyl ] pyrrolidin-2-one (42)

Reductive amination procedure B starting from N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (3-formyl-1-methyl-indol-6-yl) -4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (25 mg,0.03 mmol) and tetrahydropyran-4-amine (7 mg,0.07 mmol) provided N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [ 1-methyl-3- [ (tetrahydropyran-4-ylamino) methyl ] as crude material]Indol-6-yl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (75%LCMS yield), MS: m/z found 799.3[ m+h ] ] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 97% LCMS yield. MS: m/z found 699.3[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.63(d,1H),8.54(s,2H),7.80(d,1H),7.75(dd,2H),7.71(dd,1H),7.55(t,1H),7.49–7.38(m,4H),7.26(d,1H),4.30(s,2H),4.05–3.97(m,5H),3.89(s,3H),3.88–3.78(m,3H),3.44(td,2H),3.26–3.15(m,1H),2.76–2.63(m,2H),2.37–2.23(m,3H),2.12–2.00(m,2H),1.88–1.76(m,1H),1.63(m,2H).

Example 70: (5S) -5- [ [ [6- [ 2-chloro-3- [ 3-chloro-2- [3- [ [ (1, 1-dioxothialan-4-yl) amino ] methyl ] -1-methyl-indol-6-yl ] -4-pyridinyl ] phenyl ] -2-methoxy-3-pyridinyl ] methylamino ] methyl ] pyrrolidin-2-one (43)

Reductive amination procedure B starting from N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (3-formyl-1-methyl-indol-6-yl) -4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (25 mg,0.03 mmol) and 1, 1-dioxo-thian-4-amine (10 mg,0.07 mmol) provide N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [3- [ [ (1, 1-dioxothian-4-yl) amino ] as crude material]Methyl group]-1-methyl-indol-6-yl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (84% LCMS yield), MS: m/z found 847.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 98% LCMS yield. MS: m/z found 747.2[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.63(d,1H),8.55(s,2H),7.79(d,1H),7.76(d,1H),7.73(d,1H),7.71(dd 1H),7.55(t,1H),7.48–7.37(m,4H),7.27(d,1H),4.21(s,2H),4.03(s,3H),3.94–3.78(m,6H),3.25–3.07(m,5H),2.82–2.67(m,2H),2.46–2.37(m,2H),2.37–2.23(m,3H),2.19–2.08(m,2H),1.88–1.76(m,1H).

Example 71: (5S) -5- [ [ [6- [3- [2- [3- [ [ (1-acetylazetidin-3-yl) amino ] methyl ] -1-methyl-indol-6-yl ] -3-chloro-4-pyridinyl ] -2-chloro-phenyl ] -2-methoxy-3-pyridinyl ] methylamino ] methyl ] pyrrolidin-2-one (55)

Reductive amination procedure B starting from N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (3-formyl-1-methyl-indol-6-yl) -4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (30 mg,0.04 mmol) and 1- (3-aminoazetidin-1-yl) ethanone (10 mg,0.08 mmol) provide N- [ [6- [3- [2- [3- [ [ (1-acetylazetidin-3-yl) amino ] as crude material]Methyl group]-1-methyl-indol-6-yl]-3-chloro-4-pyridinyl]-2-chloro-phenyl]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (88% LCMS yield), MS: m/z found 812.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 84% LCMS yield. MS: m/z found 712.3[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.62(d,1H),8.54(s,2H),7.79–7.77(m,1H),7.77–7.74(m,1H),7.71(td,2H),7.55(t,1H),7.45–7.38(m,3H),7.31(s,1H),7.27(d,1H),4.31(dd,1H),4.09(dd,1H),4.03(s,3H),4.02(s,2H),3.92(dd,1H),3.90–3.87(m,2H),3.87–3.83(m,4H),3.79(m,1H),3.70(dd,J＝10.2,5.1Hz,1H),2.82–2.68(m,2H),2.38–2.24(m,3H),1.90–1.77(m,4H).

Example 72: (5S) -5- [ [ [6- [3- [2- [3- [ [ (1-acetyl-4-piperidinyl) -methyl-amino ] methyl ] -1-methyl-indol-6-yl ] -3-chloro-4-pyridinyl ] -2-chloro-phenyl ] -2-methoxy-3-pyridinyl ] methylamino ] methyl ] pyrrolidin-2-one (56)

Reductive amination procedure B starting from N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (3-formyl-1-methyl-indol-6-yl) -4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinesBase group]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Carbamic acid tert-butyl ester (40 mg,0.06 mmol) and 1- [4- (methylamino) -1-piperidinyl]Ethaneketone (17 mg,0.11 mmol) provides N- [ [6- [3- [2- [3- [ [ (1-acetyl-4-piperidinyl) -methyl-amino ] as crude material]Methyl group]-1-methyl-indol-6-yl]-3-chloro-4-pyridinyl]-2-chloro-phenyl]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (83% LCMS yield), found MS: m/z 854.4[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 97% LCMS yield. MS: m/z found 754.3[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.55(s,2H),7.81(d,1H),7.79–7.73(m,2H),7.71(dd,1H),7.55(t,1H),7.52–7.46(m,2H),7.45–7.40(m,2H),7.26(d,1H),4.70(d,1H),4.34(s,2H),4.15–3.95(m,5H),3.91(s,3H),3.89–3.79(m,3H),3.15(t,1H),2.79–2.69(m,2H),2.63(s,4H),2.38–2.22(m,3H),2.21–2.09(m,5H),1.88–1.75(m,2H),1.72–1.59(m,1H).

Example 73: (5S) -5- [ [ [6- [ 2-chloro-3- [ 3-chloro-2- [3- [ [ (4, 4-difluorocyclohexyl) amino ] methyl ] -1-methyl-indol-6-yl ] -4-pyridinyl ] phenyl ] -2-methoxy-3-pyridinyl ] methylamino ] methyl ] pyrrolidin-2-one (73)

Reductive amination procedure B starting from N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (3-formyl-1-methyl-indol-6-yl) -4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl ]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (20 mg,0.03 mmol) and 4, 4-difluorocyclohexylamine (8 mg,0.06 mmol) provided N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [3- [ [ (4, 4-difluorocyclohexyl) amino ] as crude material]Methyl group]-1-methyl-indol-6-yl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (60% LCMS yield), MS: m/z found 833.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 97% LCMS yield. MS: m/z actual measurement733.3[M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d 4): delta 8.64 (d, 1H), 8.54 (s, 2H), 7.83 (d, 1H), 7.79-7.74 (m, 2H), 7.71 (dd, 1H), 7.59-7.47 (m, 3H), 7.46-7.37 (m, 2H), 7.26 (d, 1H), 4.46 (s, 2H), 4.03 (s, 3H), 3.91 (s, 3H), 3.89-3.78 (m, 3H), 3.38-3.19 (m, 1H), 2.79-2.64 (m, 2H), 2.38-2.25 (m, 5H), 2.25-2.13 (m, 2H), 2.02-1.67 (m, 5H).

Example 74: (5S) -5- [ [ [6- [ 2-chloro-3- (3-chloro-2-isoindolin-5-yl-4-pyridinyl) phenyl ] -2-methoxy-3-pyridinyl ] methylamino ] methyl ] pyrrolidin-2-one (116)

Following Suzuki coupling procedure B, a reaction mixture was prepared from tert-butyl 5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) isoindoline-2-carboxylate (30 mg,0.09 mmol) and N- [ [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl ] ]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (51 mg,0.09 mmol) provides 5- [4- [3- [5- [ [ tert-butoxycarbonyl- [ [ (2S) -5-oxopyrrolidin-2-yl [ (tert-butoxycarbonyl)]Methyl group]Amino group]Methyl group]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]Isoindoline-2-carboxylic acid tert-butyl ester (55 mg, 81.7%). MS: m/z found 774.3[ M+H ]] ⁺ . Deprotection and purification of the suzuki product Boc provided the final product as formate. The deprotection step was 98% yield, but the yield of formate form after isolation was 21%. MS: m/z found 574.2[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.51(br s,2H),7.80–7.75(m,1H),7.75–7.69(m,3H),7.55(t,2H),7.47(d,1H),7.41(d,1H),7.27(d,1H),5.50(s,1H),4.68(s,4H),4.03(s,3H),3.96–3.82(m,3H),2.85–2.70(m,2H),2.39–2.23(m,3H),1.89–1.76(m,1H).

Example 75: (5S) -5- [ [ [6- [3- [2- [1- (azetidin-3-yl) pyrazol-4-yl ] -3-chloro-4-pyridinyl ] -2-chloro-phenyl ] -2-methoxy-3-pyridinyl ] methylamino ] methyl ] pyrrolidin-2-one (119)

Following Suzuki coupling procedure B, 3- [4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyrazol-1-yl]Azetidine-1-carboxylic acid tert-butyl ester (30 mg,0.09 mmol) and N- [ [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (51 mg,0.09 mmol) provides 3- [4- [4- [3- [5- [ [ tert-butoxycarbonyl- [ [ (2S) -5-oxopyrrolidin-2-yl ] ]Methyl group]Amino group]Methyl group]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]Pyrazol-1-yl]Azetidine-1-carboxylic acid tert-butyl ester (55 mg, 82%). MS: m/z found 778.3[ M+H ]] ⁺ . Deprotection and purification of the suzuki product Boc provided the final product as formate. The deprotection step was 97% yield, but the yield of formate form after isolation was 56%. MS: m/z found 578.2[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.58(d,1H),8.50(d,2H),8.40(s,1H),7.78(d,1H),7.71(dd,1H),7.54(t,1H),7.37(dd,1H),7.30–7.24(m,2H),5.52(p,1H),4.63–4.45(m,4H),4.04(s,3H),4.02–3.83(m,3H),2.93–2.72(m,2H),2.42–2.23(m,3H),1.93–1.77(m,1H).

Example 76: (5S) -5- [ [ [6- [3- [2- [1- (azetidin-3-ylmethyl) pyrazol-4-yl ] -3-chloro-4-pyridinyl ] -2-chloro-phenyl ] -2-methoxy-3-pyridinyl ] methylamino ] methyl ] pyrrolidin-2-one (120)

Following Suzuki coupling procedure B, 3- [ [4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyrazol-1-yl]Methyl group]Azetidine-1-carboxylic acid tert-butyl ester (30 mg,0.08 mmol) and N- [ [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (49 mg,0.08 mmol) provides 3- [ [4- [4- [3- [5- [ [ tert-butoxycarbonyl- [ [ (2S) -5-oxopyrrolidin-2-yl ]]Methyl group]Amino group]Methyl group]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]Pyrazol-1-yl]Methyl group]Azetidine-1-carboxylic acid tert-butyl ester (56 mg, 84.0%). MS: m/z found 792.3[ M+ H] ⁺ . Deprotection and purification of the suzuki product Boc provided the final product as formate. The protection step was carried out in 98% yield, but the yield of formate form after isolation was 67%. MS: m/z found 592.2[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.57(d,1H),8.46(d,3H),8.26(s,1H),7.80(d,1H),7.71(dd,1H),7.55(t,1H),7.38(dd,1H),7.32–7.22(m,2H),4.55–4.43(m,2H),4.19–4.05(m,4H),4.05(s,3H),4.01(d,2H),3.94–3.87(m,1H),3.49(p,1H),2.96–2.79(m,2H),2.43–2.27(m,3H),1.94–1.77(m,1H).

Example 77: (S) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (4- ((((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (71)

(a) 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde

To a mixture of 4-bromo-2-methoxy-benzaldehyde (5.0 g,23.2 mmol) and bis (pinacolato) diboron (11.8 g,46.50 mmol) in dioxane (50 mL) was added potassium acetate (6.85 g,69.7 mmol) and [1,1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) dichloride (1.9 g,2.33 mmol). The mixture was stirred under nitrogen at 95 ℃ for 5 hours. The mixture was filtered. By normal phase SiO ₂ The concentrated filtrate was purified by chromatography (8-50% ethyl acetate/petroleum ether) to afford 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (4.4 g, 72%) as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.40(s,1H),7.70(d,J＝7.6Hz,1H),7.38-7.36(m,2H),3.95(s,3H),1.33(s,12H).

(b) (S) - ((4-chloro-6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

To tert-butyl (S) - ((4-chloro-6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (as described for compound 37 (500 mg,0.80 mmol) and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (314 mg,1.20 mmol) in THF/H ₂ Potassium phosphate (508 mg,2.39 mmol) and [1,1' -bis (di-tert-butylphosphino) ferrocene were added to a mixture of O (6:1 v/v,28 mL)]Palladium (II) dichloride (52 mg,0.08 mmol). The mixture was stirred under nitrogen at 80 ℃ for 1 hour. The reaction mixture was diluted with water (20 mL) and the mixture extracted with ethyl acetate (2×50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. By flash chromatography (SiO ₂ The crude material was purified 0-3% ethyl acetate/petroleum ether to provide tert-butyl (S) - ((4-chloro-6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (360 mg) as a yellow solid. MS: m/z found 725[ M+H ]] ⁺ .

(c) (4-chloro-6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To a mixture of tert-butyl (S) - ((4-chloro-6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (200 mg,0.28 mmol) and (S) -1- (methylamino) propan-2-ol (49.1 mg,0.55 mmol) in methylene chloride (10 mL) was added sodium acetate (67.8 mg,0.83 mmol). At N ₂ The mixture was stirred at room temperature for 12 hours. Adding inSodium cyanoborohydride (51.9 mg,0.83 mmol) and N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and purified by preparative TLC (SiO ₂ 4:1 Ethyl acetate: meOH) the resulting crude material was purified to afford tert-butyl ((4-chloro-6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (110 mg, 50%) as a white solid. MS: m/z found 798[ M+H ]] ⁺ .

(d) (S) -5- (((4-chloro-6- (2-chloro-3- (3-chloro-2- (4- ((((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

To a solution of tert-butyl ((4-chloro-6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (100 mg,0.12 mmol) in methylene chloride (5 mL) was added TFA (5 mL,67.5 mmol). At N ₂ The mixture was stirred at room temperature for 20 minutes. The mixture was concentrated. The crude product was purified by reverse phase HPLC to afford (S) -5- (((4-chloro-6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (14.5 mg,15% yield) as formate salt (as a white solid). LCMS: m/z found 700.1[ M+H ]] ⁺ Rt=2.98 min, (method a); ¹ H NMR(400MHz,MeOH-d ₄ ):δ8.60(d,J＝4.8Hz,1H),7.75(dd,J ₁ ＝1.6Hz,J ₂ ＝7.6Hz,1H),7.60-7.55(m,2H),7.51-7.44(m,3H),7.42-7.38(m,2H),4.60-4.53(m,1H),4.42-4.41(m,1H),4.23-4.20(m,1H),4.10-4.07(m,5H),4.02(s,3H),3.88-3.87(m,1H),3.24-3.21(m,1H),3.10-3.04(m,1H),2.88(s,3H),2.79-2.76(m,2H),2.38-2.27(m,3H),1.86-1.81(m,1H),1.26(d,J＝6Hz,3H).

example 78: (S) - (4- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) glycine (105)

(a) (S) -2- ((4- (4- (3- (5- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4-chloro-6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) acetic acid

At N ₂ Sodium acetate (25 mg,0.31 mmol) was added at one time to a mixture of (S) - ((4-chloro-6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (75 mg,0.1 mmol) and glycine (15 mg,0.21 mmol) in methylene chloride (2 mL) under an atmosphere. The mixture was stirred at room temperature for 3 hours. Sodium cyanoborohydride (20 mg,0.31 mmol) was added. The mixture was stirred at room temperature for 12 hours. Methanol (2 mL) was added and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated. The residue was purified by preparative TLC (silica gel, 3:1 ethyl acetate: meOH) to give (S) -2- ((4- (4- (3- (5- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4-chloro-6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) acetic acid (15 mg,16% yield) as a yellow solid. MS: m/z found 784[ M+H ] ]+.

(b) (S) -2- ((4- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) acetic acid

To a mixture of (S) -2- ((4- (4- (3- (5- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4-chloro-6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) acetic acid (14 mg,0.018 mmol) in methylene chloride (0.1 mL) was added trifluoroacetic acid (0.7 mL) at one time. The mixture was stirred at room temperature for 5 minutes. The mixture was concentrated. The residue was purified by reverse phase HPLC to provide (S) -2- ((4- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-methoxybenzyl) amino) acetic acid (3.1 mg,23% yield) as formate salt (as a white solid). MS: m/z found 684[ M+H ]]+； ¹ H NMR (400 MHz, methanol-d 4): delta 8.55 (d, 1H), 7.63 (m, 1H), 7.48 (t, 1H), 7.41 (d, 1H), 7.37-7.35 (m, 2H), 7.30-7.29 (m, 2H), 7.24 (m, 1H), 4.22 (s, 2H), 4.07 (s, 2H), 3.97 (s, 3H), 3.90 (s, 3H), 3.82-3.79 (m, 1H), 3.42 (s, 2H), 2.83-2.73 (m, 2H), 2.30-2.19 (m, 3H), 1.79-1.70 (m, 1H).

Example 79: (S) -2- ((4- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) acetic acid isopropyl ester (123)

In a similar manner to compound 105, isopropyl (S) -2- ((4- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((5-oxo-pyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) acetate was prepared from tert-butyl (S) - ((4-chloro-6- (2-chloro-3- (4-chloro-3-methoxy-3- (4-chloro-6-methoxy-5- (((5-oxo-pyrrolidin-2-yl) methyl) amino) methyl) pyridin-4-yl) phenyl) methyl) 2-methoxypyridin-3-yl) methyl) carbamate and isopropyl 2-amino acetate. LCMS: m/z found 728.0[ M+H ]]+, rt=3.32 min, (method a); ¹ h NMR (400 MHz, methanol-d 4): delta 8.64 (d, 1H), 7.74 (m, 1H), 7.58 (t, 1H), 7.47-7.44 (m, 2H), 7.41-7.37 (m, 2H), 7.29-7.27 (m, 2H), 5.08-5.02 (m, 1H), 4.06-4.03 (m, 5H), 3.94 (s, 3H), 3.88-3.83 (m, 3H), 3.37 (s, 2.73-2.68 (m, 2H), 2.37-2.26 (m),3H),1.87-1.80(m,1H),1.27(d,6H).

Example 80: (S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (75)

(a) (S) - ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

To tert-butyl (S) -tert-butyl ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (2.00 g,3.38 mmol), 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde) (1.51 g,5.74 mmol) in THF (40 mL) and H ₂ Potassium phosphate (2.20 g,10 mmol) and [1,1' -bis (di-tert-butylphosphino) ferrocene were added to a mixture in O (6 mL)]Palladium (II) dichloride (0.22 g,0.33 mmol). At N ₂ The mixture was stirred at 80℃for 2 hours. The mixture was filtered and concentrated. By flash chromatography (SiO ₂ The residue was purified with 0-8% ethyl acetate/petroleum ether to afford tert-butyl (S) - ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (1.80 g,2.60 mmol) as a yellow solid.

(b) (6- (2-chloro-3- (3-chloro-2- (4- ((((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester (((S) -5-oxopyrrolidin-2-yl) methyl)

To a mixture of tert-butyl (S) - ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (200 mg,0.29 mmol) and (2S) -1- (methylamino) propan-2-ol (75 mg,0.87 mmol) in methylene chloride (10 mL) was added sodium acetate (71 mg,0.87 mmol) and sodium triacetoxyborohydride (54.5 mg,0.87 mmol). At N ₂ The mixture was stirred at 20℃for 4 hours. The filtrate was concentrated. By preparative TLC (SiO) ₂ The residue was purified with 25% MeOH in ethyl acetate to give tert-butyl ((6- (2-chloro-3- (3-chloro-2- (4- ((((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (130 mg,59% yield) as a white solid. MS: m/z observed 764[ M+H ]] ⁺ 。

(c) (S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one

To a solution of tert-butyl ((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (115 mg,0.15 mmol) in methylene chloride (9 mL) was added trifluoroacetic acid (2 mL,27 mmol). At N ₂ The mixture was stirred at 20℃for 20 min. The mixture was concentrated and the resulting residue was purified by reverse phase HPLC to provide (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (6.4 mg,5.7% yield) as formate salt (as a white solid). LCMS: m/z found 664.0[ M+H ]]+, rt=2.79 min, (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,J＝4.8Hz,1H),7.76(d,J＝7.6Hz,1H),7.71(m,1H),7.58-7.53(m,2H),7.48(d,1H),7.43-7.42(m,2H),7.37(m,1H),7.27(d,1H),4.52-4.51(m,2H),4.23-4.21(m,1H),4.03(s,3H),4.00(s,3H),3.98(m,2H),3.90-3.89(m,1H),3.18-3.04(m,2H),2.86-2.81(m,5H),2.38-2.23(m,3H),1.86-1.81(m,1H),1.23(d,3H).

Example 81: (S) -2- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) acetic acid (107)

In a similar manner to compound 105, (S) -2- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxo-pyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-methoxybenzyl) amino) acetate was prepared from (S) - ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester and glycine. LCMS: m/z found 650.1[ M+H ]]+, rt=2.67 min, (method a); ¹ H NMR (400 MHz, methanol-d 4): delta 8.67 (d, 1H), 7.85 (d, 1H), 7.74 (m, 1H), 7.59 (t, 1H), 7.52 (d, 1H), 7.48-7.44 (m, 2H), 7.40 (s, 1H), 7.35-7.30 (m, 2H), 4.34 (s, 2H), 4.13 (m, 2H), 4.08 (s, 3H), 4.01 (s, 3H), 3.99-3.97 (m, 1H), 3.54 (s, 2H), 3.06-2.97 (m, 2H), 2.45-2.32 (m, 3H), 1.92-1.85 (m, 1H).

Example 82: (S) -2- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) acetic acid isopropyl ester (108)

In a similar manner to compound 105, tert-butyl (S) - ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamateAnd isopropyl 2-aminoacetate hydrochloride preparation of isopropyl (S) -2- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-methoxybenzyl) amino) acetate. Observed MS: m/z 692[ M+H ]] ⁺ ； ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.54(d,1H),7.68(d,1H),7.61(m,1H),7.46(t,1H),7.36-7.31(m,3H),7.24-7.17(m,3H),5.02-4.96(m,1H),4.00(s,2H),3.92(s,3H),3.86(s,3H),3.84(m,2H),3.79-3.77(m,1H),3.53(s,2H),2.76-2.68(m,2H),2.28-2.18(m,3H),1.77-1.72(m,1H),1.18(d,6H).

Example 83: (S) -1- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) cyclopropanecarboxylic acid (121)

In a similar manner to compound 105, (S) -1- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-methoxybenzyl) amino) cyclopropanecarboxylic acid was prepared as a formate salt from tert-butyl (S) - ((6- (2-chloro-3- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate and 1-aminocyclopropane carboxylic acid. LCMS: m/z found 676.0[ M+H ]]+, rt=2.67 min, (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),7.90(d,1H),7.72(m,1H),7.57(t,1H),7.53(m,1H),7.47-7.43(m,2H),7.38-7.36(m,2H),7.34-7.32(m,1H),4.53(s,2H),4.38-4.31(m,2H),4.09(s,3H),4.08-4.05(m,1H),3.98(s,3H),3.26-3.21(m,2H),2.45-2.36(m,3H),1.94-1.89(m,1H),1.61-1.58(m,2H),1.44-1.40(m,2H).

Example 84: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (126)

(S) -5- ((((6- (2-chloro-3- (4- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tert-butyl (5-oxopyrrolidin-2-yl) methyl) carbamate and 1, 1-dioxo 4-aminotetrahydro-2H-thiopyran hydrochloride) pyrrolidin-2-one was prepared in analogy to compound 105 using (S) - ((6- (2-chloro-3- (4- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl). LCMS: m/z found 723.9[ M+H ] ]+, rt=2.66 min, (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),7.90(d,1H),7.73-7.71(m,1H),7.60-7.53(m,3H),7.48-7.46(m,2H),7.40-7.35(m,3H),4.37-4.30(m,4H),4.09(s,3H),4.04-4.02(m,1H),4.00(s,3H),3.58-3.55(m,1H),3.28-3.12(m,5H),2.60(m,2H),2.43 -2.27(m,6H),1.94-1.89(m,1H).

Example 85: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (127)

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one) is prepared from tert-butyl (5-oxopyrrolidin-2-yl) methyl) carbamate and tetrahydropyran-4-amine in analogy to compound 105. LCMS: m/z found 676.1[ M+H ]]+, rt=2.77 min, (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),8.40(s,1H),7.78(m,1H),7.72-7.70(m,1H),7.57-7.52(m,2H),7.47(d,1H),7.42-7.39(m,2H),7.35(d,1H),7.28-7.25(m,1H),4.31(s,2H),4.07-3.91(m,11H),3.46(t,3H),2.84(m,2H),2.36-2.30(m,3H),2.13-2.10(m,2H),1.84-1.72(m,3H).

Example 86: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (70)

(a) (S) - ((6- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

A solution of (S) - ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tert-butyl (5-oxopyrrolidin-2-yl) methyl) carbamate (250 mg,0.36 mmol) and 2-aminoethanol (33.1 mg,0.54 mmol) in methylene chloride (4 mL) and 1, 3-hexafluoro-2-propanol (1 mL) was stirred at 15℃for 2 hours. To the mixture was added sodium cyanoborohydride (45 mg,0.72 mmol). The mixture was stirred at 15℃for 2 hours. The mixture was concentrated and the resulting residue was purified by reverse phase HPLC to provide tert-butyl (S) - ((6- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate as a yellow solid (200 mg,75% yield). MS: m/z found 736[ M+H ] +.

(c) (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

To a solution of tert-butyl (S) - ((6- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (200 mg,0.27 mmol) in DCM (5 mL) was added trifluoroacetic acid (0.9 mL,12.2 mmol). The mixture was stirred at 15℃for 0.5 h. The reaction mixture was concentrated and purified by reverse phase HPLC to provide compound (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (57 mg,33% yield) as formate salt (as white solid). LCMS: m/z found 636.1[ M+H ] ]+, rt=2.53 min, (method a); ¹ h NMR (400 MHz, methanol-d) ₄ )δ8.68(d,1H),8.45(s,1H),7.82(d,1H),7.74(m,1H),7.60-7.53(m,2H),7.49(d,1H),7.45-7.42(m,2H),7.37(d,1H),7.30(d,1H),4.35(s,2H),4.06(s,3H),4.02-3.93(m,6H),3.86(t,2H),3.18(t,2H),2.95-2.85(m,2H),2.43-2.31(m,3H),1.89-1.82(m,1H).

Example 87: (S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-2-carboxylic acid isopropyl ester (68)

(a) (S) -1- (4- (4- (3- (5- (((tert-Butoxycarbonyl) (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) pyrrolidine-2-carboxylic acid isopropyl ester

At N ₂ To (S) - ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (0.20 g,0.29 mmol) and (S) -pyrrolidine-2-carboxylic acid isobutyl ester under an atmosphereA mixture of propyl ester hydrochloride (0.08 g,0.43 mmol) in methylene chloride (3 mL) was added sodium acetate (95 mg,1.16 mmol) and sodium triacetoxyborohydride (0.18 g,0.87 mmol) in one portion. The mixture was stirred at room temperature for 2 hours. The mixture was purified by preparative TLC (silica gel, ethyl acetate: meoh=5:1) to afford (S) -1- (4- (4- (3- (5- (((tert-butoxycarbonyl) (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) pyrrolidine-2-carboxylic acid isopropyl ester as a pale yellow solid (70 mg,21% yield). MS: m/z found 832[ M+H ] ]+.

(b) (S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-2-carboxylic acid isopropyl ester

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To a mixture of (S) -1- (4- (4- (3- (5- (((tert-butoxycarbonyl) (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) pyrrolidine-2-carboxylic acid isopropyl ester (70 mg,0.08 mmol) in methylene chloride (0.3 mL) was added trifluoroacetic acid (1.2 mL) at one time. The mixture was stirred at room temperature for 10 minutes. The mixture was concentrated. The crude product was purified by reverse phase HPLC to afford isopropyl (S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-methoxybenzyl) pyrrolidine-2-carboxylate (25.5 mg,37% yield) as formate salt (as white solid). LCMS: m/z found 732.0[ M+H ]]+, rt=3.36 min, (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),8.35(s,1H),7.84(d,1H),7.74(m,1H),7.58(t,1H),7.52-7.44(m,3H),7.35-7.32(m,3H),5.07-4.88(m,1H),4.27(s,2H),4.14-4.06(m,5H),3.96-3.94(m,4H),3.84-3.81(m,1H),3.39-3.37(m,1H),3.03-2.94(m,3H),2.44-2.34(m,4H),2.03-1.87(m,4H),1.28-1.25(m,6H).

Example 88: (S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid isopropyl ester (76)

(a) (S) -pyrrolidine-3-carboxylic acid isopropyl ester

At N ₂ Thionyl chloride (0.28 mL,3.91 mmol) was added in one portion to a mixture of (3S) -pyrrolidine-3-carboxylic acid (0.3 g,2.61 mmol) in propane-2-ol (3 mL) under atmosphere. The mixture was stirred at 95℃for 24 hours. The mixture was concentrated to give isopropyl (S) -pyrrolidine-3-carboxylate (0.5 g,99% yield) as the hydrochloride salt (as yellow gum). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ4.98-4.89(m,1H),3.48-3.40(m,2H),3.28-3.22(m,3H),2.30-2.08(m,2H),1.22-1.16(m,6H).

(b) (S) -1- (4- (4- (3- (5- (((tert-Butoxycarbonyl) (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) pyrrolidine-3-carboxylic acid isopropyl ester

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At N ₂ To a mixture of tert-butyl (S) - ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (0.25 g,0.36 mmol) and isopropyl (S) -pyrrolidine-3-carboxylate hydrochloride (0.14 g,0.72 mmol) in methylene chloride (3 mL) was added sodium acetate (90 mg,1.08 mmol) and sodium triacetoxyborohydride (0.23 g,1.08 mmol) at one time under atmosphere. The mixture was stirred at room temperature for 0.5 hours. The mixture was purified by preparative TLC (silica gel, ethyl acetate: meoh=3:1) to afford (S) -1- (4- (4- (3-)) as a pale yellow solid 5- (((tert-Butoxycarbonyl) ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid isopropyl ester (140 mg,40% yield). MS: m/z found 832[ M+H ]]+.

(c) (S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid isopropyl ester

To a mixture of (S) -1- (4- (4- (3- (5- (((tert-butoxycarbonyl) (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid isopropyl ester (0.135 g,0.16 mmol) in methylene chloride (0.5 mL) was added trifluoroacetic acid (1.5 mL) at one time. The mixture was stirred at room temperature for 10 minutes. The mixture was concentrated. The residue was purified by reverse phase HPLC to provide (S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-methoxybenzyl) pyrrolidine-3-carboxylic acid isopropyl ester (59.1 mg,46% yield) as formate salt (as white solid). LCMS: m/z found 732.1[ M+H ] ]+, rt=3.24 min, (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.67(d,1H),8.46(s,1H),7.81-7.79(m,1H),7.73(m,1H),7.60-7.54(m,2H),7.49(d,1H),7.45-7.37(m,3H),7.30-7.28(m,1H),5.10-5.00(m,1H),4.35-4.33(m,2H),4.05(s,3H),4.00-3.92(m,6H),3.51-3.46(m,2H),3.30(m,3H),2.86-2.78(m,2H),2.42-2.23(m,5H),1.89-1.81(m,1H),1.29-1.25(m,6H).

Example 89: (S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid (77)

(a) (S) -1- (4- (4- (3- (5- (((tert-butoxycarbonyl) (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) pyrrolidine-3-carboxylic acid

To a mixture of tert-butyl (S) - ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (200 mg,0.36 mmol) and (S) -pyrrolidine-3-carboxylic acid (66.6 mg,0.58 mmol) in methylene chloride (10 mL) was added sodium acetate (71.2 mg,0.86 mmol), sodium triacetoxyborohydride (184 mg,0.87 mmol) and under N ₂ The mixture was stirred at room temperature for 5 hours. The mixture was concentrated and purified by preparative TLC (SiO ₂ 3:1 Ethyl acetate: meOH) purification of the crude product to afford (S) -1- (4- (4- (3- (5- (((tert-butoxycarbonyl) (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid (75 mg, 32%) as a white solid. MS: m/z found 790[ M+H ] ] ⁺ .

(b) (S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid

To a solution of (S) -1- (4- (4- (3- (5- (((tert-butoxycarbonyl) (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid (70 mg,0.09 mmol) in methylene chloride (4 mL) was added TFA (4 mL,54 mmol) and under N ₂ The mixture was stirred at room temperature for 20 minutes. The mixture was concentrated and the crude product purified by reverse phase HPLCTo afford (S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (15 mg, 23%) as formate salt (as white solid). LCMS: m/z found 690.0[ M+H ]] ⁺ Rt=2.69 min, (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.68(d,1H),8.36(s,1H),7.85(d,1H),7.74(m,1H),7.63-7.56(m,2H),7.48(d,1H),7.46-7.43(m,2H),7.39(m,1H),7.33(d,1H),4.50(d,2H),4.12(d,2H),4.08(s,3H),4.02(s,3H),3.99-3.97(m,1H),3.66-3.62(m,1H),3.49-3.46(m,3H),3.16-3.15(m,1H),3.03-3.00(m,2H),2.42-2.29(m,5H),1.92-1.85(m,1H).

Example 90: (S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-2-carboxylic acid (78)

In analogy to compound 77, the actual value of (S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-methoxybenzyl) pyrrolidine-2-carboxylic acid formate LCMS: m/z 690.3[ M+H ] was prepared from tert-butyl (S) - ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester and (S) -pyrrolidine-2-carboxylic acid hydrochloride]+, rt=2.77 min, (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),7.86(m,1H),7.71(m,1H),7.59-7.52(m,2H),7.45-7.44(m,2H),7.44(s,1H),7.35(d,2H),4.53(m,1H),4.42(m,1H),4.24(s,2H),4.08(s,3H),4.00(s,3H),3.98-3.95(m,1H),3.63-3.58(m,1H),3.23-3.13(m,3H),2.48-2.38(m,5H),2.25-2.21(m,2H),1.93-1.88(m,2H).

Example 91: (S) -2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one (88)

In a similar manner to compound 68, tert-butyl (S) - ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate and 2, 6-diazaspiro [3.4]Octan-7-one (S) -2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4 ]The preparation of formate from octane-7-ketone. LCMS: m/z found 700.1[ M+H ]]+, rt=2.55 min, (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.67(d,1H),8.41(s,1H),7.83(d,1H),7.74(m,1H),7.58(t,1H),7.52(d,1H),7.48(d,1H),7.44(m,1H),7.39(d,1H),7.36(m,1H),7.31(d,1H),4.36(s,2H),4.12(s,4H),4.07(s,3H),4.07-4.02(m,2H),3.99(s,3H),3.96-3.94(m,1H),3.68(s,2H),2.97-2.91(m,2H),2.72(s,2H),2.41-2.33(m,3H),1.90-1.86(m,1H).

Example 92: (S) -5- ((((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (109)

In a similar manner to compound 68, (S) -5- ((((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one) was prepared as a formate salt from (S) - ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester and 1-acetyl-4-aminopiperidine. LCMS: m/z found 718.3[ M+H ]]+, rt=2.60 min, (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.56(d,1H),8.27(m,1H),7.70(m,1H),7.62(m,1H),7.48-7.43(m,2H),7.38(d,1H),7.34-7.30(m,2H),7.26(m,1H),7.19(m,1H),4.59-4.56(m,1H),4.23(s,2H),3.95-3.82(m,10H),3.38-3.22(m,1H),3.14-3.11(m,1H),2.79-2.76(m,2H),2.60-2.57(m,1H),2.29-2.11(m,5H),2.04(s,3H),1.57-1.54(m,1H),1.46-1.42(m,2H).

Example 93: (S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((S) -oxetan-2-ylmethyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (122)

In a similar manner to compound 68, (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) pyridin-4-yl) methyl) amino) pyrrolidin-2-one) was prepared from (S) - ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester and (S) -oxetan-2-ylmethylamine as formate salt with (6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((S) -oxetan-2-ylmethyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl. LCMS: m/z found 662.1[ M+H ] ]+, rt=2.69 min, (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),7.90(d,1H),7.72(m,1H),7.58(t,1H),7.52(d,1H),7.47-7.42(m,2H),7.39-7.34(m,3H),5.14-5.09(m,1H),4.75-4.71(m,1H),4.67-4.63(m,1H),4.35-4.30(m,4H),4.09(s,3H),4.06-4.05(m,1H),3.99(s,3H),3.52-3.47(m,1H),3.26-3.24(m,3H),2.86-2.83(m,1H),2.54-2.36(m,4H),1.95-1.89(m,1H).

Example 94: (S) -2- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) propanoic acid isopropyl ester (125)

In a similar manner to compound 68, a compound selected from the group consisting of (S) - ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl)) was used) Pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester and isopropyl (S) -2-aminopropionate hydrochloride isopropyl (S) -2- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-methoxyphenylmethyl) amino) propionate was prepared as a formate. LCMS: m/z found 706.2[ M+H ]]+, rt=3.21 min, (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.57(d,1H),7.81(d,1H),7.63(m,1H),7.49(t,1H),7.43(d,1H),7.42-7.41(m,2H),7.30-7.25(m,3H),5.07-5.04(m,1H),4.26(m,4H),4.04-3.95(m,5H),3.90(s,3H),3.20-3.16(m,2H),2.34-2.27(m,3H),1.82(m,1H),1.51(d,3H),1.24-1.22(m,6H).

Example 95: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (79)

(a) (S) - ((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

At N ₂ N- [ [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl ] is reacted under an atmosphere at 85 DEG C]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (0.46 g,0.78 mmol), 2-fluoro-6-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (as described for compound 91 (0.44 g,1.6 mmol), [1,1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) dichloride (0.05 g,0.08 mmol) and potassium phosphate (0.50 g,2.4 mmol) in H ₂ The mixture in O/THF (1:5, 12 mL) was stirred for 4 hours. The reaction mixture was filtered and taken up in H ₂ O (2X 50 mL) was diluted and extracted with ethyl acetate (2X 100 mL). H for combined organic layers ₂ O (2X 100 mL) was washed, dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by flash chromatography (SiO ₂ 0-80% ethyl acetate/petroleum ether) to afford tert-butyl (S) - ((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (0.80 g) as a brown solid.

(b) (6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

To N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (3-fluoro-4-formyl-5-methoxy-phenyl) -4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]A mixture of tert-butyl carbamate (0.25 g,0.35 mmol) and 3-amino-1-methyl-cyclobutanol hydrochloride (0.06 g,0.40 mmol) in methylene chloride/MeOH (1:2, 6 mL) was added sodium acetate (86 mg,1.00 mmol) andmolecular sieves (50 mg,0.35 mmol). The mixture was stirred at room temperature for 12 hours. Sodium triacetoxyborohydride (0.2 g,0.9 mmol) was added to the mixture. After stirring at room temperature for 1 hour, the crude reaction mixture was used subsequently.

(c) (S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

To N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [ 3-fluoro-4- [ [ (3-hydroxy-3-methyl-cyclobutyl) amino ]]Methyl group]-5-methoxy-phenyl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Trifluoroacetic acid (10 mL) was added to the above solution of carbamate in methylene chloride (4 mL). The mixture was stirred at room temperature for 0.5 hours. The reaction mixture was filtered to provide a residue. The residue was purified by reverse phase HPLC to provide (S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (31.9 mg, 12%). LCMS: m/z found 695.4[ M+H ] ]+, rt=2.77 min, (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.69(d,1H),8.39(s,1H),7.86(d,1H),7.74(m,1H),7.59(t,1H),7.51(d,1H),7.45(m,1H),7.33-7.28(m,2H),7.22(m,1H),4.25(s,2H),4.12(br s,2H),4.08(s,3H),4.04(s,3H),4.00-3.94(m,2H),3.06-2.96(m,2H),2.45-2.38(m,5H),2.26-2.21(m,2H),1.94-1.85(m,1H),1.41(s,3H).

Example 96: (S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((S) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (80)

Formate was prepared in analogy to compound 79 using ((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((S) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (0.3 g,0.42 mmol) and (S) -1-aminopropane-2-ol) 5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((S) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one. LCMS: m/z found 668.0[ M+H ]]+, rt=2.57 min, (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ.8.66(d,1H),8.40(s,2H),7.82(d,1H),7.70(d,1H),7.55(t,1H),7.48(d,1H),7.41(m,1H),7.29(d,1H),7.25(s,1H),7.19(d,1H),4.35(s,2H),4.07-3.95(m,10H),3.10(m,1H),2.96-2.85(m,3H),2.40-2.31(m,3H),1.90-1.81(m,1H),1.22(d,J＝6.4Hz,3H).

Example 97: (S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((R) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (81)

(a) (6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((R) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester (((S) -5-oxopyrrolidin-2-yl) methyl)

At N ₂ A mixture of (S) - ((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (0.25 g,0.35 mmol), (R) -1-aminopropane-2-ol hydrochloride (51 mg,0.46 mmol) and sodium acetate (87 mg,1 mmol) in methylene chloride/trimethoxymethane mixture (5:1, 12 mL) was stirred at room temperature for 12 hours. Sodium triacetoxyborohydride (0.15 g,0.70 mmol) was added. At N ₂ The mixture was stirred at room temperature for 1 hour. The mixture was filtered and the filtrate was concentrated. By preparative TLC (SiO) ₂ The resulting residue was purified with ethyl acetate: meOH) to afford tert-butyl ((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((R) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (0.25 g,77% yield) as a yellow solid.

(b) (S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((R) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one

At N ₂ A mixture of tert-butyl ((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((R) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (0.18 g,0.23 mmol) in a methylene chloride/trifluoroacetic acid mixture (4:5, 9 mL) was stirred at room temperature for 0.5 hours. The mixture was concentrated. The resulting residue was purified by reverse phase HPLC to afford (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- (((R) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (52.5 mg,31% yield) as formate salt (as a white solid). LCMS: m/z found 668.1[ M+H ] ]+, rt=2.65 min, (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ7.69(d,1H),8.43(br s,2H),7.84(d,1H),7.74(m,1H),7.58(t,1H),7.51(d,1H),7.44(m,1H),7.32-7.29(m,2H),7.22(m,1H),4.39(s,2H),4.13-4.04(m,9H),4.01-3.95(m,1H),3.13(m,1H),2.98-2.89(m,3H),2.41-2.33(m,3H),1.93-1.84(m,1H),1.26(d,3H).

Example 98: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((isopropylamino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (82)

In a similar manner to compound 81, (S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((isopropylamino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) pyrrole is purified using tert-butyl ((6- (2-chloro-3- (3-fluoro-4- (((S) -2-hydroxypropyl) amino) methyl) -5-methoxypyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrole with tert-butyl ((S) -5-oxopyrrolidin-2-yl) methyl) carbamate and propane-2-amineThe alkyl-2-ketone is prepared into formate. LCMS: m/z found 652.1[ M+H ]]+, rt=2.78 min, (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.70(d,1H),8.46(s,1H),7.88(s,1H),7.75(d,1H),7.59(t,1H),7.51(d,1H),7.45(d,1H),7.34-7.29(m,2H),7.23(d,1H),4.35(s,2H),4.15-4.04(m,9H),3.57-3.50(m,1H),3.05(m,2H),2.38(m,3H),1.89(m,1H),1.45(d,6H).

Example 99: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((isobutylamino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (83)

In a similar manner to compound 81, (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((isobutylamino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester and 2-methylpropan-1-amine) was prepared as a formate salt with ((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((isobutylamino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one. LCMS: m/z found 666.1[ M+H ] ]+, rt=3.06 min, (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.67(d,1H),8.35(s,1H),7.86-7.74(m,1H),7.72(m,1H),7.56(t,1H),7.49(d,1H),7.42(m,1H),7.30-7.27(m,2H),7.21(d,1H),4.34(s,2H),4.03(m,8H),3.93(br s,1H),2.95-2.92(m,4H),2.37-2.31(m,3H),2.14-2.07(m,1H),1.85(br s,1H),1.06(d,6H).

Example 100: (S) -5- ((((5- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) -methyl) -amino) -methyl) phenyl) pyridin-4-yl) phenyl) -3-methoxypyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one (20)

(a) (S) -5- ((((5-bromo-3-methoxypyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one

5-bromo-3-methoxy-pyrazine-2-carbaldehyde (200 mg,0.92 mmol), (5S) -5- (aminomethyl) pyrrolidin-2-one (137 mg,1.20 mmol), and acetic acid (66 mg,1.11 mmol) were dissolved in MeOH/THF (1:1, 5 mL) and the solution was then stirred at 25℃for 2 hours. Adding NaBH ₃ CN (87 mg,1.38 mmol) and the resulting mixture was stirred at 25℃for 1 hour. The reaction was then diluted with water (10 mL) and extracted with DCM (3×5 mL). The combined organics were further washed with brine (5 mL), dried over sodium sulfate, filtered, and concentrated. By flash chromatography (SiO ₂ The crude sample was purified with 5-20% MeOH/DCM to provide (5S) -5- [ [ (5-bromo-3-methoxy-pyrazin-2-yl) methylamino]Methyl group]Pyrrolidin-2-one (205 mg,71% yield). MS: m/z found 315, 317[ M+H ]] ⁺ .

(b) (S) - ((5-bromo-3-methoxypyrazin-2-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

(5S) -5- [ [ (5-bromo-3-methoxy-pyrazin-2-yl) methylamino]-methyl group]Pyrrolidin-2-one (162 mg,0.44 mmol), N-diisopropylethylamine (0.3 mL,1.75 mmol), and di-tert-butyl dicarbonate (0.19 g,0.87 mmol) were dissolved in 6mL THF and the mixture was stirred at room temperature for 12 hours. The reaction was diluted with EtOAc (10 mL) and saturated aqueous NaHCO ₃ (5 mL. Times.2) the resulting solution was washed followed by brine (5 mL. Times.2). The organic layer was concentrated under reduced pressure and purified by flash chromatography (SiO ₂ 0-5% MeOH/DCM) to provide the N- [ (5-bromo-3-methoxy-pyrazin-2-yl) methyl]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (175 mg,96% yield). MS: m/z found 415, 417[ M+H ]] ⁺ .

(c) (S) - ((3-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyrazin-2-yl) methyl) ((5-oxopyrrolidin-2-yl) -methyl) -carbamic acid tert-butyl ester

N- [ (5-bromo-3-methoxy-pyrazin-2-yl) methyl group is introduced into a sealed tube]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (156 mg,0.38 mmol), 4, 5-tetramethyl-2- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,3, 2-dioxaborane (0.13 g,0.53 mmol), 1' -bis (biphenylphosphino) -ferrocene-palladium (II) dichloride dichloromethane complex (31 mg,0.04 mmol), and potassium acetate (0.11 g,1.13 mmol) are suspended in 4mL 1, 4-dioxane. Nitrogen was bubbled through the reaction solution for 2 minutes, then the vessel was sealed and heated at 95 ℃ for 6 hours. The mixture was cooled to room temperature and passed through And (5) filtering. The filtrate was concentrated under reduced pressure and the crude oil was dissolved in 2mL EtOAc. Hexane was added dropwise with vigorous stirring until a dark solid precipitated from solution. The solid was filtered and the filtrate concentrated under reduced pressure to provide N- [ [ 3-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyrazin-2-yl as a brown oil]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (0.21 g, crude). MS: m/z found 381[ M+H ]] ⁺ (boric acid fragments).

(d) (S) - ((5- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -3-methoxypyrazin-2-yl) methyl) carbamic acid tert-butyl ester

Pd (PPh) ₃ ) ₄ (12 mg,0.01 mmol), potassium carbonate (21 mg,0.15 mmol), 4- [4- (3-bromo-2-chloro-phenyl) -3-chloro-2-pyridinyl]-2-methoxy-benzaldehyde (22 mg,0.05 mmol), and N- [ [ 3-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane)-2-yl) pyrazin-2-yl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (30 mg,0.07 mmol) was suspended in 1, 4-dioxane/water (4:1, 1 mL) and the solution was heated at 105℃for 20 min. The reaction was cooled to room temperature, diluted with 3mL of water, and extracted with EtOAc (3×2 mL). The combined organics were concentrated under reduced pressure and purified by flash chromatography (SiO ₂ 0-4% MeOH/DCM) to provide N- [ [5- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl ] as a yellow foam]Phenyl group]-3-methoxy-pyrazin-2-yl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (18 mg,52% yield). MS: m/z found 692.3, 694.3[ M+H ]] ⁺ .

(e) (5- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -3-methoxypyrazin-2-yl) methyl) carbamic acid tert-butyl ester (S) -5-oxopyrrolidin-2-yl) methyl

N- [ [5- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl ]]Phenyl group]-3-methoxy-pyrazin-2-yl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (18 mg,0.03 mmol), (5S) -5- (aminomethyl) pyrrolidin-2-one (4 mg,0.04 mmol), and acetic acid (2 mg,0.03 mmol) were dissolved in MeOH/THF (1:1, 1 mL) and the solution was stirred at 25℃for 2 hours. Adding NaBH ₃ CN (3 mg,0.05 mmol) and the resulting mixture was stirred at 25℃for 1 hour. The reaction was then diluted with water (2 mL) and extracted with EtOAc (3×3 mL). The combined organics were further washed with brine (3 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to provide N- [ [5- [ 2-chloro-3- [ 3-chloro-2- [ 3-methoxy-4- [ [ (2S) -5-oxopyrrolidin-2-yl ] ]Methylamino group]Methyl group]Phenyl group]-4-pyridinyl]Phenyl group]-3-methoxy-pyrazin-2-yl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (20 mg, crude). MS: m/z found 790.4,792[ M+H ]] ⁺ . The material was used in the next step without further purification.

(f) (S) -5- (((5- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) -methyl) -amino) -methyl) phenyl) pyridin-4-yl) phenyl) -3-methoxypyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one

N- [ [5- [ 2-chloro-3- [ 3-chloro-2- [ 3-methoxy-4- [ [ [ (2S) -5-oxopyrrolidin-2-yl ]]Methylamino group]-methyl group]Phenyl group]-4-pyridinyl]Phenyl group]-3-methoxy-pyrazin-2-yl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (20 mg,0.03mmol, crude) was dissolved in 1mL DCM and a solution of 1, 4-dioxane (25 μl,0.10 mmol) in 4M HCl was added. The reaction was stirred at room temperature for 20 minutes and the solvent was removed under reduced pressure. Purification of the crude sample by reverse phase HPLC to afford (5S) -5- [ [ [4- [ 3-chloro-4- [ 2-chloro-3- [ 6-methoxy-5- [ [ (2S) -5-oxopyrrolidin-2-yl ] as a pale yellow solid (formate)]Methylamino group]Methyl group]Pyrazin-2-yl]Phenyl group]-2-pyridyl group]-2-methoxy-phenyl ]Methylamino group]Methyl group]Pyrrolidin-2-one (8 mg,47% yield). LCMS: found m/z 690.5,692[ M+H ]] ⁺ Retention time = 1.90min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.66(d,1H),8.45(s,1H),8.41(s,2H),7.77(dd,1H),7.61(t,1H),7.52–7.46(m,3H),7.37(d,1H),7.33(dd,1H),4.25–4.18(m,2H),4.15(d,2H),4.08(s,3H),3.98(s,5H),3.10–3.01(m,2H),2.93(m,2H),2.44–2.27(m,6H),1.95–1.78(m,2H).

Example 101: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (3)

(a) 8-chloro-1-methyl-1, 2,3, 5-tetrahydro-4H-benzo [ e ] [1,4] diazepine-4-carboxylic acid tert-butyl ester

Sodium hydride (55 mg, 60% in oil suspension, 1.38 mmol) was suspended in 6mL anhydrous DMF and the solution cooled to 0deg.C. A solution of tert-butyl 8-chloro-1, 2,3, 5-tetrahydro-1, 4-benzodiazepine-4-carboxylate (300 mg,1.06 mmol) in 3mL DMF was slowly added over 2 minutes. The resulting mixture was warmed to room temperature and stirred for 30 minutes, then cooled back to 0 ℃. Methyl iodide (92 μl,1.49 mmol) was added dropwise, and the reaction mixture was then warmed to 50 ℃ and stirred for 12 hours. The mixture was diluted with 20mL of water and extracted with EtOAc (3×20 mL). The combined organics were concentrated under reduced pressure and purified by flash chromatography (SiO ₂ The residue was purified with 0-40% EtOAc/hexanes to provide tert-butyl 8-chloro-1-methyl-3, 5-dihydro-2H-1, 4-benzodiazepine-4-carboxylate (321 mg,82% yield). MS: m/z found 297.1, 299.2[ M+H ] ] ⁺ .

(b) 1-methyl-8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,2,3, 5-tetrahydro-4H-benzo [ e ] [1,4] diazepine-4-carboxylic acid tert-butyl ester

8-chloro-1-methyl-3, 5-dihydro-2H-1, 4-benzodiazepine-4-carboxylic acid tert-butyl ester (100 mg,0.34 mmol), 4, 5-tetramethyl-2- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,3, 2-dioxaborane (128 mg,0.51 mmol), pd in a sealed tube ₂ (dba) ₃ (31 mg,0.03 mmol), xphos (30 mg), and potassium acetate (92 mg,0.94 mmol) were suspended in 3mL of 1, 4-dioxane. Nitrogen was bubbled through the reaction solution for 2 minutes, then the vessel was sealed and heated at 100 ℃ for 12 hours. The mixture was cooled to room temperature and passed throughThe mixture was filtered. The filtrate was concentrated under reduced pressure and purified by flash chromatography (SiO ₂ 0-20% EtOAc/hexanes) to provide 1-methyl-8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 5-dihydro-tert-butyl 2H-1, 4-benzodiazepine-4-carboxylate (71 mg,43% yield). MS: m/z found 389.2[ M+H ]] ⁺ .

(c) 8- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1, 2,3, 5-tetrahydro-4H-benzo [ e ] [1,4] diazepine-4-carboxylic acid tert-butyl ester

Pd (PPh) ₃ ) ₄ (41 mg,0.04 mmol), potassium carbonate (74 mg,0.53 mmol), 6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl ]-2-methoxy-pyridine-3-carbaldehyde (70 mg,0.18 mmol), and 1-methyl-8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 5-dihydro-2H-1, 4-benzodiazepine-4-carboxylic acid tert-butyl ester (90 mg,0.23 mmol) were suspended in 1, 4-dioxane/water (4:1, 3 ml), and the solution was heated at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 5mL of water, and extracted with EtOAc (3×3 mL). The combined organics were concentrated under reduced pressure and purified by flash chromatography (SiO ₂ 5-60% EtOAc/hexanes) to provide 8- [ 3-chloro-4- [ 2-chloro-3- (5-formyl-6-methoxy-2-pyridinyl) phenyl as a yellow foam]-2-pyridyl group]-1-methyl-3, 5-dihydro-2H-1, 4-benzodiazepine-4-carboxylic acid tert-butyl ester (88 mg,79% yield). MS: m/z found 619.3,621[ M+H ]] ⁺ .

(d) (S) -8- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1, 2,3, 5-tetrahydro-4H-benzo [ e ] [1,4] diazepine-4-carboxylic acid tert-butyl ester

8- [ 3-chloro-4- [ 2-chloro-3- (5-formyl-6-methoxy-2-pyridinyl) phenyl]-2-pyridyl group]-1-methyl-3, 5-dihydro-2H-1, 4-benzodiazepine-4-carboxylic acid tert-butyl ester (40 mg,0.06 mmol), (5S) -5- (aminomethyl) pyrrolidin-2-one (11 mg,0.10 mmol), and acetic acid (4 mg,0.06 mmol) were dissolved in MeOH/THF (1:1 (v/v), 2 mL) The solution was then stirred at 25 ℃ for 2 hours. Sodium cyanoborohydride (8.11 mg,0.13 mmol) was added and the resulting mixture was stirred at 25℃for 1 hour. The reaction was then diluted with water (3 mL) and extracted with methylene chloride (3 x2 mL). The combined organics were further washed with brine (3 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to provide (S) -8- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1, 2,3, 5-tetrahydro-4H-benzo [ e) as a white foam][1,4]Diazepine-4-carboxylic acid tert-butyl ester (41 mg, crude). MS: m/z found 717.5, 719[ M+H ]] ⁺ . The material was used in the next step without further purification.

(e) (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

8- [ 3-chloro-4- [ 2-chloro-3- [ 6-methoxy-5- [ [ [ (2S) -5-oxopyrrolidin-2-yl]Methylamino group]Methyl group]-2-pyridyl group]Phenyl group]-2-pyridyl group]-tert-butyl 1-methyl-3, 5-dihydro-2H-1, 4-benzodiazepine-4-carboxylate (41 mg,0.06 mmol) was dissolved in 1mL of methylene chloride and a solution of 1, 4-dioxane (57 μl,0.23 mmol) in 4M HCl was added. The reaction was stirred at room temperature for 20 minutes and the solvent was removed under reduced pressure. Purification of the crude sample by reverse phase HPLC to afford (5S) -5- [ [ [6- [ 2-chloro-3- [ 3-chloro-2- (1-methyl-2, 3,4, 5-tetrahydro-1, 4-benzodiazepine-8-yl) -4-pyridinyl ] ]Phenyl group]-2-methoxy-3-pyridinyl]Methylamino group]Methyl group]Pyrrolidin-2-one (26 mg,73% yield) (formate). LCMS: m/z found 617.3.619.4[ M+H ]] ⁺ Retention time = 2.08min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.64(d,1H),8.50(s,1H),7.77(d,1H),7.71(dd,1H),7.55(t,1H),7.48–7.39(m,3H),7.38(d,1H),7.31(dd,1H),7.27(d,1H),4.33(s,2H),4.03(s,3H),3.98–3.83(m,3H),3.37(q,2H),3.28(d,2H),3.02(s,3H),2.86–2.75(m,2H),2.41–2.24(m,3H),1.83(tt,1H).

Example 102: n- (1- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-yl) acetamide (5)

In the same manner as described for compound 3, intermediate 8- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1, 2,3, 5-tetrahydro-4H-benzo [ e][1,4]Preparation of the compound from t-butyl diazepine-4-carboxylate. N- (1-aminopropan-2-yl) acetamide is used to replace (S) -5- (aminomethyl) pyrrolidin-2-one. LCMS: m/z found 619.3,621.3[ M+H ]] ⁺ Retention time = 2.13min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.64(dd,1H),8.51(s,3H),7.83–7.78(m,1H),7.71(dt,1H),7.56(td,1H),7.48–7.40(m,3H),7.37(d,1H),7.31(ddd,2H),4.32(s,2H),4.19(s,1H),4.16–4.02(m,5H),3.37(d,1H),3.32–3.25(m,3H),3.02(d,3H),3.00–2.94(m,1H),2.90(dd,1H),1.97(d,3H),1.21(dd,3H).

Example 103: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (6)

(a) (S) -5- ((6-bromo-8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one

6-bromo-8-methoxy-1, 2,3, 4-tetrahydroisoquinoline hydrochloride (100 mg,0.36 mmol), methanesulfonic acid [ (2S) -5-oxopyrrolidin-2-yl]Methyl ester (90 mg,0.47 mmol), and potassium carbonate (149 mg,1.08 mmol) were suspended in3mL acetonitrile/0.3 mL DMF. The mixture was then heated at 85 ℃ for 12 hours. The reaction was cooled to room temperature, diluted with water (6 mL) and extracted with EtOAc (3×5 mL). The combined organic extracts were washed with water (5 mL), brine (5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford (5S) -5- [ (6-bromo-8-methoxy-3, 4-dihydro-1H-isoquinolin-2-yl) methyl as a pale brown oil]Pyrrolidin-2-one (118 mg, crude). MS: m/z found 339,341[ M+H ]] ⁺ . The material was used in the next step without further purification.

(b) (S) -5- ((8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one

(5S) -5- [ (6-bromo-8-methoxy-3, 4-dihydro-1H-isoquinolin-2-yl) methyl ] in a sealed tube]Pyrrolidin-2-one (50 mg,0.15 mmol), 4, 5-tetramethyl-2- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,3, 2-dioxaborane (52 mg,0.21 mmol), 1' -bis (biphenylphosphino) -ferrocene-palladium (II) dichloride dichloromethane complex (12 mg,0.01 mmol), and potassium acetate (40 mg,0.41 mmol) were suspended in 2mL of 1, 4-dioxane. Nitrogen was bubbled through the reaction solution for 2 minutes, then the vessel was sealed and heated at 95 ℃ for 6 hours. The reaction was cooled to room temperature and passed through The mixture was filtered. The filtrate was concentrated under reduced pressure and the crude oil was dissolved in 2mL of EtOAc. Hexane was added dropwise with vigorous stirring until a dark solid precipitated from solution. The solid was filtered and the filtrate concentrated under reduced pressure to provide (5S) -5- [ [ 8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydro-1H-isoquinolin-2-yl as a pale brown oil]Methyl group]Pyrrolidin-2-one (56 mg, crude). MS: m/z found 387[ M+H ]] ⁺ . The material was used in the next step without further purification.

(c) (S) -6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde

Pd (PPh) ₃ ) ₄ (33 mg,0.03 mmol), potassium carbonate (60 mg,0.43 mmol), 6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl]-2-methoxy-pyridine-3-carbaldehyde (74 mg,0.19 mmol) and (5S) -5- [ [ 8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydro-1H-isoquinolin-2-yl ]]Methyl group]Pyrrolidin-2-one (56 mg,0.14 mmol) was suspended in 1, 4-dioxane/water (4:1, 3 ml) and the solution was then heated at 105 ℃ for 20 minutes. The mixture was cooled to room temperature, diluted with 3mL of water, and extracted with EtOAc (3×2 mL). The combined organic extracts were concentrated under reduced pressure and purified by flash chromatography (SiO ₂ Purification of the crude sample with 0-6% MeOH/methylene chloride to afford 6- [ 2-chloro-3- [ 3-chloro-2- [ 8-methoxy-2- [ [ (2S) -5-oxopyrrolidin-2-yl)]Methyl group]-3, 4-dihydro-1H-isoquinolin-6-yl]-4-pyridinyl]Phenyl group]-2-methoxy-pyridine-3-carbaldehyde (25 mg,28% yield). MS: m/z found 617,619[ M+H ]] ⁺ .

(d) (S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

Will 6- [ 2-chloro-3- [ 3-chloro-2- [ 8-methoxy-2- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]-3, 4-dihydro-1H-isoquinolin-6-yl]-4-pyridinyl]Phenyl group]-2-methoxy-pyridine-3-carbaldehyde (25 mg,0.04 mmol), (5S) -5- (aminomethyl) pyrrolidin-2-one (14 mg,0.12 mmol), and acetic acid (5 mg,0.08 mmol) were dissolved in MeOH/THF (1:1, 1 mL) and then the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (8 mg,0.12 mmol) was added and the resulting mixture was stirred at 25 ℃ for 1 hour. Followed by dilution with water (2 mL)The mixture was extracted with EtOAc (3×2 mL). The combined organics were further washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the residue by reverse phase HPLC to afford (5S) -5- [ [ [6- [ 2-chloro-3- [ 3-chloro-2- [ 8-methoxy-2- [ [ (2S) -5-oxopyrrolidin-2-yl ] ]Methyl group]-3, 4-dihydro-1H-isoquinolin-6-yl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]-methylamino group]-methyl group]Pyrrolidin-2-one (8 mg,27% yield). LCMS: m/z found 715.3,717.3[ M+H ]] ⁺ Retention time = 2.01min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.60(d,1H),8.43(s,1H),7.79(d,1H),7.70(dd,1H),7.55(t,1H),7.44–7.38(m,2H),7.28(d,1H),7.08–7.00(m,2H),4.04(s,4H),3.97(d,2H),3.87(s,4H),3.77(d,1H),3.64(d,1H),2.98(t,2H),2.95–2.59(m,6H),2.33(tt,6H),1.91–1.79(m,2H).

Example 104: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (7)

(a) 6- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinoline-2 (1H) -carboxylic acid tert-butyl ester

Pd (PPh) ₃ ) ₄ (23 mg,0.02 mmol), potassium carbonate (42 mg,0.30 mmol), 6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl]-2-methoxy-pyridine-3-carbaldehyde (40 mg,0.10 mmol), and 8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (47 mg,0.12 mmol) were suspended in 1, 4-dioxane/water (4:1, 3 ml), and the solution was then heated at 105 ℃ for 20 minutes. The reaction was cooled to room temperature, diluted with 5mL of water, and extracted with EtOAc (3×3 mL). The combined organics were concentrated under reduced pressure and purified by flash chromatography (SiO ₂ 0-6% MeOH/DCM) to provide a crude sample to afford 6- [ 3-chloro-4- [ 2-chloro-3- (5-formyl-6-methoxy-2-pyridinyl) phenyl ]-2-pyridyl group]-8-methoxy-3, 4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (44 mg,70% yield). MS: m/z found 620.2, 622[ M+H ]] ⁺ .

(b) (S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinoline-2 (1H) -carboxylic acid tert-butyl ester

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6- [ 3-chloro-4- [ 2-chloro-3- (5-formyl-6-methoxy-2-pyridinyl) phenyl]-2-pyridyl group]-8-methoxy-3, 4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (44 mg,0.07 mmol), (5S) -5- (aminomethyl) pyrrolidin-2-one (24 mg,0.21 mmol), and acetic acid (9 mg,0.14 mmol) were dissolved in MeOH/THF (1:1, 2 mL) and the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (13 mg,0.21 mmol) was added and the resulting mixture was stirred at 25℃for 1 hour. The mixture was then diluted with water (2 mL) and extracted with methylene chloride (3 x2 mL). The combined organic extracts were further washed with brine (3 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to provide 6- [ 3-chloro-4- [ 2-chloro-3- [ 6-methoxy-5- [ [ [ (2S) -5-oxopyrrolidin-2-yl)]Methylamino group]-methyl group]-2-pyridyl group]Phenyl group]-2-pyridyl group]-8-methoxy-3, 4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (50 mg, crude). MS: m/z found 719[ M+H ] ] ⁺ .

(c) (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

Will 6- [ 3-chloro-4- [ 2-chloro-3- [ 6-methoxy-5- [ [ [ (2S) -5-oxopyrrolidin-2-yl]Methylamino group]Methyl group]-2-pyridyl group]Phenyl group]-2-pyridyl group]-8-methoxy-3, 4-dihydro-1H-isoquinolineTert-butyl-2-carboxylate (50 mg,0.07mmol, crude) was dissolved in 1mL of methylene chloride and a solution of 1, 4-dioxane (70. Mu.L, 10mg,0.28 mmol) in 4M HCl was added. The mixture was stirred at room temperature for 20min and the solvent was removed under reduced pressure. Purification of the residue by reverse phase HPLC to afford (5S) -5- [ [ [6- [ 2-chloro-3- [ 3-chloro-2- (8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -4-pyridinyl ]]Phenyl group]-2-methoxy-3-pyridinyl]Methylamino group]Methyl group]Pyrrolidin-2-one (11 mg,26% yield) (formate). LCMS: m/z found 618.25,620[ M+H ]] ⁺ Retention time = 2.12min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.63(dd,1H),8.49(s,1H),7.76(d,1H),7.71(dt,1H),7.59–7.51(m,1H),7.45(dd,1H),7.44–7.37(m,1H),7.30–7.21(m,1H),7.17(d,2H),4.30(s,2H),4.02(d,3H),3.92(d,3H),3.87(dd,3H),3.49(t,2H),3.15(t,2H),2.82–2.69(m,2H),2.39–2.23(m,3H),1.82(dt,1H).

Example 105: (S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-4- (((S) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) -pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (19)

The compound was prepared in a similar manner as described for compound 6 using intermediate 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde. With (S) -5- ((1-methyl-8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,2,3, 5-tetrahydro-4H-benzo [ e ]][1,4]Diazepin-4-yl) methyl) pyrrolidin-2-one replaces (S) -5- ((8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one. LCMS: m/z found 714.4,716[ M+H ]] ⁺ Retention time = 2.08min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.60(d,1H),8.42(s,1H),7.81(d,1H),7.70(dd,1H),7.55(t,1H),7.45–7.38(m,2H),7.30(dd,2H),7.25–7.13(m,2H),4.04(d,4H),3.96(d,4H),3.04(t,4H),2.93(d,5H),2.56(h,2H),2.35(td,5H),2.29–2.20(m,1H),1.90–1.70(m,2H).

Example 106: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (27)

(a) (R) -1- (6-bromo-8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol

To a solution of 6-bromo-8-methoxy-1, 2,3, 4-tetrahydroisoquinoline hydrochloride (0.25 g,0.90 mmol) and (R) -2-methyl oxirane (0.52 g,8.97 mmol) in ethanol (7 mL) was added N, N-diisopropylethylamine (0.01 g,0.01 mmol). The mixture was stirred at 85 ℃ for 1 hour and then concentrated under reduced pressure. By flash chromatography, gradient (SiO ₂ The residue was purified with 0-5% MeOH/methylene chloride to afford (R) -1- (6-bromo-8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (0.18 g,67% yield). LCMS: m/z found 300[ M+H ]] ⁺ Rt=0.58 min, (method B).

(b) (R) -1- (8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol:

with (R) -1- (6-bromo-8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (0.18 g,0.60 mmol), bis (pinacolato) diboron (0.17 g,0.66 mmol), potassium acetate (0.16 g,1.68 mmol), and Pd (dppf) ₂ Cl ₂ -CH ₂ Cl ₂ (0.05 g,0.06 mmol) was fed to the pressure vessel. The flask was purged with nitrogen for 5 minutes, then 7mL of dry dioxane was added and the reaction was bubbled with nitrogen for an additional 5 minutes. The vessel was sealed and the mixture was stirred at 90 ℃ for 1 hour. However, the method is thatAfter cooling the mixture to room temperature byFilter and wash the filter cake with ethyl acetate (3×20 mL). The filtrate was concentrated under reduced pressure and purified by flash chromatography using a gradient (SiO ₂ The residue was purified with 0-10% methanol/methylene chloride to afford (R) -1- (8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (0.15 g,75% yield). LCMS: m/z found 348[ M+H ] ] ⁺ Rt=0.68 min (method B).

(c) (R) -6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde:

with (R) -1- (8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (0.15 g,0.43 mmol), 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (0.17 g,0.43 mmol), cs ₂ CO ₃ (0.42 g 1.30 mmol), and Pd (PPh) ₃ ) ₄ (0.05 g,0.04 mmol) was fed to the pressure vessel. The vessel was then purged with nitrogen. Dioxane (6 mL) was added and the reaction bubbled with nitrogen, then 0.75mL of water was added. The vessel was sealed and the mixture was stirred at 90 ℃ for 1 hour. The mixture was cooled to room temperature byFilter and wash the filter cake with ethyl acetate (3×15 mL). The filtrate was concentrated under reduced pressure and purified by flash chromatography (SiO ₂ The residue was purified using a linear gradient elution of 0-10% methanol/methylene chloride to provide (R) -6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (0.22 g,90% yield). LCMS: m/z found 578[ M+H ]] ⁺ Rt=0.81 min (method B).

(d) (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

To a mixture of (R) -6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (0.22 g,0.39mmol,1 eq) and (S) -5- (aminomethyl) pyrrolidin-2-one (0.09 g,0.77 mmol) in 1:1 (v/v) THF/MeOH (6 mL) was added acetic acid (0.05 g,0.77 mmol)Molecular sieves (1 g). The mixture was then stirred at room temperature for 2 hours. Sodium cyanoborohydride (0.06 g,0.97 mmol) was added and the mixture was stirred at room temperature for 10 minutes. The reaction was quenched with water (2 mL), then diluted with 50mL of ethyl acetate, and washed with saturated brine, then concentrated under reduced pressure. The residue was purified by semi-preparative HPLC to provide 55mg (21%) of (S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one diformate. LCMS: m/z found 676[ M+H ]] ⁺ Rt=1.64 min, method D. ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.60(d,1H),8.40(s,1H),7.76(d,1H),7.68(dd,1H),7.52(t,1H),7.45–7.34(m,2H),7.25(d,1H),7.13(s,2H),4.34–4.17(m,3H),4.01(s,3H),3.98–3.86(m,6H),3.49–3.39(m,2H),3.20–3.00(m,4H),2.89–2.78(m,2H),2.40–2.21(m,3H),1.89–1.75(m,1H),1.23(d,3H).

Example 107: (S) -5- (((6- (3- (2- (2- ((1-acetylpiperidin-4-yl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (62)

In an analogous manner to compound 27, (S) -5- (((6- (3- (2- (2- ((1-acetylpiperidin-4-yl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one, compound 62, was prepared from 1- (4- (bromomethyl) piperidin-1-yl) ethan-1-one and 6-bromo-8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-1-yl) methyl) amino-methyl). LCMS: m/z found 757[ M+H ]] ⁺ Rt=1.74 min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.58(d,1H),8.43(s,1H),7.75(d,1H),7.68(dd,1H),7.52(t,1H),7.43–7.34(m,2H),7.25(d,1H),7.04(d,2H),4.51(d,1H),4.00(s,3H),3.99–3.81(m,7H),3.78(s,2H),3.14(t,1H),2.97(dd,4H),2.85–2.71(m,2H),2.70–2.59(m,3H),2.39–2.20(m,3H),2.13–1.96(m,4H),1.93–1.79(m,3H),1.28–1.10(m,2H).

Example 108: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (63)

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one) was prepared from 1-bromo-3-fluoropropane and 6-bromo-8-methoxy-1, 2,3, 4-tetrahydroisoquinoline-hydrochloride in an analogous manner to compound 27. LCMS: m/z found 678[ M+H ]] ⁺ Rt=1.74 min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.58(d,1H),8.48(s,1H),7.69(dd,2H),7.51(t,1H),7.43–7.34(m,2H),7.23(d,1H),7.08–7.01(m,2H),4.58(t,1H),4.46(t,1H),4.00(s,3H),3.94–3.79(m,6H),3.75(s,2H),3.00(t,2H),2.90(t,2H),2.86–2.77(m,2H),2.78–2.64(m,2H),2.39–2.19(m,3H),2.13–1.96(m,2H),1.86–1.73(m,1H).

Example 109:2- (((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethan-1-ol (84)

In a similar manner to compound 27, 2- (((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethan-1-ol was prepared from 1-bromo-3-fluoropropane and 6-bromo-8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-e-hydrochloride. LCMS: m/z found 625[ M+H ]] ⁺ Rt=1.72 min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.57(d,1H),8.48(s,1H),7.82(d,1H),7.68(dd,1H),7.53(t,1H),7.43–7.36(m,2H),7.30(d,1H),7.03(d,2H),4.57(t,1H),4.45(t,1H),4.17(s,2H),4.04(s,3H),3.85(s,3H),3.82–3.74(m,2H),3.71(s,2H),3.10–3.02(m,2H),2.98(t,J＝5.9Hz,2H),2.86(t,2H),2.83–2.74(m,2H),2.11–1.93(m,2H).

Example 110: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (((1 r,3 r) -3-hydroxycyclobutyl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (133)

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (((1 r,3 r) -3-hydroxycyclobutyl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one) was prepared from (1 r,3 r) -3- (bromomethyl) cyclobutan-1-ol and 6-bromo-8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-1-hydrochloride in an analogous manner to compound 27. LCMS: m/z found 702[ M+H ]] ⁺ Rt=1.74 min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.57(d,1H),8.49(s,1H),7.75–7.63(m,2H),7.51(t,1H),7.42–7.33(m,2H),7.22(d,1H),7.03(d,2H),4.31(t1H),3.99(s,3H),3.83(d,6H),3.75(d,2H),2.98(t,2H),2.90(d,2H),2.81(d,2H),2.76–2.61(m,3H),2.35–2.20(m,3H),2.18–2.09(m,4H),1.84–1.73(m,1H).

Example 111: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (((1S, 3S) -3-hydroxycyclobutyl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (134)

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (((1S, 3S) -3-hydroxycyclobutyl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one) was prepared from (1S, 3S) -3- (bromomethyl) cyclobutan-1-ol and 6-bromo-8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-1-hydrochloride in an analogous manner to compound 27. LCMS: found 702[ M+H ] at 1.74min m/z] ⁺ (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.57(d,1H),8.49(s,1H),7.75–7.63(m,2H),7.51(t,1H),7.42–7.33(m,2H),7.22(d,1H),7.04(d,2H),4.14–4.02(m,1H),3.99(s,3H),3.84(d,6H),3.77(s,2H),2.96(dd,4H),2.82(d,2H),2.77–2.62(m,2H),2.56–2.45(m,2H),2.38–2.18(m,3H),2.13(q,1H),1.85–1.72(m,1H),1.70–1.58(m,2H).

Example 112: (S) -methyl 2- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) acetate (150)

(S) -2- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) acetic acid methyl ester was prepared from methyl 2-bromoacetate and 6-bromo-8-methoxy-1, 2,3, 4-tetrahydroisoquinoline-hydrochloride in an analogous manner to compound 27. LCMS: m/z found 690[ M+H ]] ⁺ Rt=1.75 min (methodD). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.56(d,1H),7.75–7.63(m,2H),7.51(t,1H),7.42–7.32(m,2H),7.22(d,1H),7.02(d,2H),3.99(s,3H),3.86–3.74(m,6H),3.73(d,5H),3.47(s,2H),2.96(t,2H),2.86(t,2H),2.74–2.60(m,2H),2.38–2.17(m,3H),1.84–1.72(m,1H).

Example 113: (S) -2- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) acetic acid (151)

To a solution of (S) -methyl 2- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) acetate (0.03 g,0.04 mmol) in dioxane (1.5 mL) was added a solution of lithium hydroxide monohydrate (0.003g, 0.07 mmol) in water (0.5 mL). The mixture was stirred at room temperature for 5 minutes and then purified directly by semi-preparative HPLC to provide 22mg (92%) of (S) -2- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) acetic acid diformate. LCMS: m/z found 676[ M+H ]] ⁺ Rt=1.63 min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.61(d,1H),8.46(s,1H),7.78–7.65(m,2H),7.53(t,1H),7.46–7.35(m,2H),7.24(d,1H),7.15(d,2H),4.41(s,2H),4.00(s,3H),3.95–3.79(m,6H),3.79(s,2H),3.58(t,2H),3.22(t,2H),2.83–2.68(m,2H),2.41–2.20(m,3H),1.88–1.74(m,1H).

Example 114: (5S) -5- [ [ [4- [4- [3- [3- [ [ (1-acetyl-4-piperidinyl) amino ] methyl ] -1-methyl-pyrrolo [2,3-b ] pyridin-6-yl ] -2-chloro-phenyl ] -3-chloro-2-pyridinyl ] -2-methoxy-phenyl ] methylamino ] methyl ] pyrrolidin-2-one (57)

(a) N- [ [4- [ 3-chloro-4- [ 2-chloro-3- (3-formyl-1-methyl-pyrrolo [2,3-b ] pyridin-6-yl) phenyl ] -2-pyridinyl ] -2-methoxy-phenyl ] methyl ] -N- [ [ (2S) -5-oxopyrrolidin-2-yl ] methyl ] carbamic acid tert-butyl ester

Following Suzuki coupling procedure B, a compound selected from the group consisting of N- [ [4- [4- (3-bromo-2-chloro-phenyl) -3-chloro-2-pyridinyl]-2-methoxy-phenyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Carbamic acid tert-butyl ester (315 mg,0.50 mmol) and (3-formyl-1-methyl-pyrrolo [2, 3-b)]Preparation of N- [ [4- [ 3-chloro-4- [ 2-chloro-3- (3-formyl-1-methyl-pyrrolo [2,3-b ] by pyridine-6-yl) boronic acid (101 mg,0.50 mmol)]Pyridin-6-yl) phenyl]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate. 320mg,90% yield. MS: m/z found 714.2[ M+H ]] ⁺ .

(b) (5S) -5- [ [ [4- [4- [3- [3- [ [ (1-acetyl-4-piperidinyl) amino ] methyl ] -1-methyl-pyrrolo [2,3-b ] pyridin-6-yl ] -2-chloro-phenyl ] -3-chloro-2-pyridinyl ] -2-methoxy-phenyl ] methylamino ] methyl ] pyrrolidin-2-one

Reductive amination procedure B starting from N- [ [4- [ 3-chloro-4- [ 2-chloro-3- (3-formyl-1-methyl-pyrrolo [2,3-B ]]Pyridin-6-yl) phenyl]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (30 mg,0.04 mmol) and 1- (4-amino-1-piperidinyl) ethanone (12 mg,0.08 mmol) provide N- [ [4- [4- [3- [3- [ [ (1-acetyl-4-piperidinyl) amino ] as crude material ]Methyl group]-1-methyl-pyrrolo [2,3-b]Pyridin-6-yl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]-2-methoxy-phenyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (88% LCMS yield), MS: m/z found 840.3[ M+H ]] ⁺ Which is deprotected and purified by a general Boc deprotection procedureTo provide the final product as formate. Yield 98%. MS: m/z found 740.3[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.52(s,2H),8.24(d,1H),7.71(dd,1H),7.64(s,1H),7.59(t,1H),7.48–7.41(m,4H),7.33–7.27(m,2H),4.63(d,1H),4.39(s,2H),4.09–3.84(m,11H),3.19(t,1H),2.85–2.74(m,2H),2.70(t,1H),2.37–2.27(m,3H),2.22(t,2H),2.13(s,3H),1.86–1.76(m,1H),1.57(m,1H),1.46(m,1H).

Example 115: (5S) -5- [ [ [4- [ 3-chloro-4- [ 2-chloro-3- [ 1-methyl-3- [ [ (2S) -oxetan-2-yl ] methylamino ] methyl ] pyrrolo [2,3-b ] pyridin-6-yl ] phenyl ] -2-pyridinyl ] -2-methoxy-phenyl ] methylamino ] methyl ] pyrrolidin-2-one (58)

Reductive amination procedure B starting from N- [ [4- [ 3-chloro-4- [ 2-chloro-3- (3-formyl-1-methyl-pyrrolo [2,3-B ]]Pyridin-6-yl) phenyl]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (30 mg,0.04 mmol) and [ (2S) -oxetan-2-yl]Methylamine (7 mg,0.08 mmol) provided N- [ [4- [ 3-chloro-4- [ 2-chloro-3- [ 1-methyl-3- [ [ (2S) -oxetan-2-yl ] as crude material]Methylamino group]Methyl group]Pyrrolo [2,3-b]Pyridin-6-yl]Phenyl group]-2-pyridyl group]-2-methoxy-phenyl ]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (88% LCMS yield), MS: m/z found 785.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 97% yield. MS: m/z found 685.2[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.53(s,2H),8.24(d,1H),7.71(dd,1H),7.63–7.54(m,2H),7.48–7.39(m,4H),7.33–7.25(m,2H),5.06(m,1H),4.77–4.66(m,1H),4.61(dt,1H),4.40–4.28(m,2H),4.02–3.89(m,8H),3.87(t,1H),3.39–3.32(m,1H),3.14(dd,1H),2.86–2.70(m,3H),2.57–2.43(m,1H),2.38–2.24(m,3H),1.87–1.75(m,1H).

Example 116: (5S) -5- [ [ [4- [ 3-chloro-4- [ 2-chloro-3- [ 1-methyl-3- [ (tetrahydropyran-4-ylamino) methyl ] pyrrolo [2,3-b ] pyridin-6-yl ] phenyl ] -2-pyridinyl ] -2-methoxy-phenyl ] methylamino ] methyl ] pyrrolidin-2-one (59)

Reductive amination procedure B starting from N- [ [4- [ 3-chloro-4- [ 2-chloro-3- (3-formyl-1-methyl-pyrrolo [2,3-B ]]Pyridin-6-yl) phenyl]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (30 mg,0.04 mmol) and tetrahydropyran-4-amine (9 mg,0.08 mmol) provided N- [ [4- [ 3-chloro-4- [ 2-chloro-3- [ 1-methyl-3- [ (tetrahydropyran-4-ylamino) methyl ] as crude material]Pyrrolo [2,3-b]Pyridin-6-yl]Phenyl group]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (89% LCMS yield), MS: m/z found 799.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 97% yield. MS: m/z found 699.3[ M+H ] ] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.52(s,2H),8.25(d,1H),7.72(dd,1H),7.67(s,1H),7.60(t,1H),7.50–7.41(m,4H),7.33–7.26(m,2H),4.44(s,2H),4.06(dd,2H),4.02–3.96(m,2H),3.96–3.93(m,6H),3.88(t,1H),3.53–3.35(m,3H),2.85–2.73(m,2H),2.39–2.26(m,3H),2.13(d,2H),1.86–1.78(m,1H),1.70(m,2H).

Example 117: (5S) -5- [ [ [4- [ 3-chloro-4- [ 2-chloro-3- [3- [ [ (1, 1-dioxothiadin-4-yl) amino ] methyl ] -1-methyl-pyrrolo [2,3-b ] pyridin-6-yl ] phenyl ] -2-pyridinyl ] -2-methoxy-phenyl ] methylamino ] methyl ] pyrrolidin-2-one (60)

Reductive amination procedure B starting from N- [ [4- [ 3-chloro-4- [ 2-chloro-3- (3-formyl-1-methyl-pyrrolo [2,3-B ]]Pyridin-6-yl) phenyl]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (30 mg,0.04 mmol) and 1, 1-diOxothiazid-4-amine (9 mg,0.08 mmol) provides N- [ [4- [ 3-chloro-4- [ 2-chloro-3- [3- [ [ (1, 1-dioxo-thiaid-N-4-yl) amino ] as a crude material]Methyl group]-1-methyl-pyrrolo [2,3-b]Pyridin-6-yl]Phenyl group]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (87% LCMS yield), MS: m/z found 847.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Yield 98%. MS: m/z found 747.2[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.50(s,2H),8.20(d,1H),7.71(dd,1H),7.58(t,1H),7.50(s,1H),7.48–7.43(m,3H),7.39(d,1H),7.35–7.28(m,2H),4.15(s,2H),4.12–4.01(m,2H),3.96(s,3H),3.94–3.90(m,1H),3.90(s,3H),3.24–3.06(m,5H),2.97–2.83(m,2H),2.43–2.27(m,5H),2.19–2.05(m,2H),1.89–1.78(m,1H).

Example 118: (5S) -5- [ [ [4- [4- [3- [3- [ [ (1-acetyl-4-piperidinyl) -methyl-amino ] methyl ] -1-methyl-pyrrolo [2,3-b ] pyridin-6-yl ] -2-chloro-phenyl ] -3-chloro-2-pyridinyl ] -2-methoxy-phenyl ] methylamino ] methyl ] pyrrolidin-2-one (92)

Reductive amination procedure B starting from N- [ [4- [ 3-chloro-4- [ 2-chloro-3- (3-formyl-1-methyl-pyrrolo [2,3-B ]]Pyridin-6-yl) phenyl]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Carbamic acid tert-butyl ester (30 mg,0.04 mmol) and 1- [4- (methylamino) -1-piperidinyl]Ethaneketone (13 mg,0.08 mmol) provides N- [ [4- [4- [3- [3- [ [ (1-acetyl-4-piperidinyl) -methyl-amino ] as crude material]Methyl group]-1-methyl-pyrrolo [2,3-b]Pyridin-6-yl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]-2-methoxy-phenyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (61% LCMS yield), MS: m/z found 754.3[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.51(s,2H),8.20(d,1H),7.72(dd,1H),7.62–7.54(m,2H),7.49–7.39(m,4H),7.32(s,1H),7.31–7.26(m,1H),4.67(d,1H),4.17(s,2H),4.09–3.98(m,3H),3.98–3.85(m,2H),3.95(s,3H),3.92(s,3H),3.14(t,2H),2.89–2.76(m,2H),2.68–2.58(m,1H),2.51(s,3H),2.40–2.23(m,3H),2.13(s,3H),2.11–2.05(m,2H),1.86–1.55(m,2H).

Example 119: (5S) -5- [ [ [4- [ 3-chloro-4- [ 2-chloro-3- [ 1-methyl-3- [ [ (2S) -tetrahydrofuranyl-2-yl ] methylamino ] methyl ] pyrrolo [2,3-b ] pyridin-6-yl ] phenyl ] -2-pyridinyl ] -2-methoxy-phenyl ] methylamino ] methyl ] pyrrolidin-2-one (93)

Reductive amination procedure B starting from N- [ [4- [ 3-chloro-4- [ 2-chloro-3- (3-formyl-1-methyl-pyrrolo [2,3-B ]]Pyridin-6-yl) phenyl]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (30 mg,0.04 mmol) and [ (2S) -tetrahydrofuran-2-yl ]Methylamine (9 mg,0.08 mmol) provided N- [ [4- [ 3-chloro-4- [ 2-chloro-3- [ 1-methyl-3- [ [ (2S) -tetrahydrofuran-2-yl ] as crude material]Methylamino group]Methyl group]Pyrrolo [2,3-b]Pyridin-6-yl]Phenyl group]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (77% LCMS yield), MS: m/z found 799.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 97% LCMS yield. MS: m/z found 699.3[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.54(s,2H),8.23(d,1H),7.71(dd,1H),7.62(s,1H),7.59(t,1H),7.46(dt,3H),7.41(d,1H),7.32–7.24(m,2H),4.44–4.31(m,2H),4.21–4.09(m,1H),3.97–3.76(m,11H),3.11(m,1H),2.94(m,1H),2.78–2.63(m,2H),2.38–2.23(m,3H),2.10(m,1H),2.00–1.88(m,2H),1.85–1.73(m,1H),1.67–1.51(m,1H).

Example 120: (5S) -5- [ [ [4- [ 3-chloro-4- [ 2-chloro-3- [ 1-methyl-3- (methylaminomethyl) pyrrolo [2,3-b ] pyridin-6-yl ] phenyl ] -2-pyridinyl ] -2-methoxy-phenyl ] methylamino ] methyl ] pyrrolidin-2-one (94)

Reductive amination procedure B starting from N- [ [4- [ 3-chloro-4- [ 2-chloro-3- (3-formyl-1-methyl-pyrrolo [2,3-B ]]Pyridin-6-yl) phenyl]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (30 mg,0.04 mmol) and a solution of methylamine (33% wt in ethanol, 0.08 mmol) provided N- [ [4- [ 3-chloro-4- [ 2-chloro-3- [ 1-methyl-3- (methylaminomethyl) pyrrolo [2,3-b ] as crude material]Pyridin-6-yl ]Phenyl group]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (78% LCMS yield), MS: m/z found 729.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 97% LCMS yield. MS: m/z found 629.2[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.52(s,2H),8.25(d,1H),7.71(dd,1H),7.67(s,1H),7.59(t,1H),7.50–7.39(m,4H),7.32–7.24(m,2H),4.41(s,2H),4.01–3.95(m,2H),3.94(s,6H),3.87(m,1H),2.83–2.75(m,2H),2.37–2.23(m,3H),1.86–1.74(m,1H).

Example 121: (5S) -5- [ [ [4- [4- [3- [3- [ [ (1-acetylazetidin-3-yl) amino ] methyl ] -1-methyl-pyrrolo [2,3-b ] pyridin-6-yl ] -2-chloro-phenyl ] -3-chloro-2-pyridinyl ] -2-methoxy-phenyl ] methylamino ] methyl ] pyrrolidin-2-one (95)

Reductive amination procedure B starting from N- [ [4- [ 3-chloro-4- [ 2-chloro-3- (3-formyl-1-methyl-pyrrolo [2,3-B ]]Pyridin-6-yl) phenyl]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (30 mg,0.04 mmol) and 1- (3-aminoazetidin-1-yl) ethanone (10 mg,0.08 mmol) provide N- [ [4- [4- [3- [3- [ [ (1-acetylazetidin-3-yl) amino ] as crude material]Methyl group]-1-methyl-pyrrolo [2,3-b]Pyridin-6-yl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]-2-methoxy-phenyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl ]Methyl group]Carbamic acid tert-butyl esterEster (73% LCMS yield), MS: m/z found 812.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 96% LCMS yield. MS: m/z found 712.3[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.49(s,2H),8.19(d,1H),7.71(dd,1H),7.58(t,1H),7.50–7.41(m,4H),7.38(d,1H),7.36–7.29(m,2H),4.34(t,1H),4.14–4.04(m,3H),4.01–3.90(m,7H),3.89(s,3H),3.81–3.72(m,1H),3.72–3.65(m,1H),3.00–2.87(m,2H),2.41–2.28(m,3H),1.92–1.76(m,1H),1.84(s,3H).

Example 122: (5S) -5- [ [ [4- [ 3-chloro-4- [ 2-chloro-3- [3- [ [ (4, 4-difluorocyclohexyl) amino ] methyl ] -1-methyl-pyrrolo [2,3-b ] pyridin-6-yl ] phenyl ] -2-pyridinyl ] -2-methoxy-phenyl ] methylamino ] methyl ] pyrrolidin-2-one (96)

Reductive amination procedure B starting from N- [ [4- [ 3-chloro-4- [ 2-chloro-3- (3-formyl-1-methyl-pyrrolo [2,3-B ]]Pyridin-6-yl) phenyl]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (30 mg,0.04 mmol) and 4, 4-difluorocyclohexylamine (10 mg,0.08 mmol) provided N- [ [4- [ 3-chloro-4- [ 2-chloro-3- [3- [ [ (4, 4-difluorocyclohexyl) amino ] as crude material]Methyl group]-1-methyl-pyrrolo [2,3-b]Pyridin-6-yl]Phenyl group]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (74% LCMS yield), MS: m/z found 833.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 97% LCMS yield. MS: m/z found 733.3[ M+H ] ] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.53(s,2H),8.22(d,1H),7.71(dd,1H),7.62–7.55(m,2H),7.48–7.38(m,4H),7.33–7.24(m,2H),4.31(s,2H),3.98–3.89(m,8H),3.89–3.80(m,1H),3.19–3.06(m,1H),2.80–2.67(m,2H),2.37–2.25(m,3H),2.24–2.10(m,4H),2.00–1.76(m,3H),1.73–1.57(m,2H).

Example 123: (5S) -5- [ [ [4- [ 3-chloro-4- [ 2-chloro-3- [3- [ (2-hydroxyethylamino) methyl ] -1-methyl-pyrrolo [2,3-b ] pyridin-6-yl ] phenyl ] -2-pyridinyl ] -2-methoxy-phenyl ] methylamino ] methyl ] pyrrolidin-2-one (97)

Reductive amination procedure B starting from N- [ [4- [ 3-chloro-4- [ 2-chloro-3- (3-formyl-1-methyl-pyrrolo [2,3-B ]]Pyridin-6-yl) phenyl]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (30 mg,0.04 mmol) and 2-aminoethanol (5 mg,0.08 mmol) provided N- [ [4- [ 3-chloro-4- [ 2-chloro-3- [3- [ (2-hydroxyethylamino) methyl ] as crude material]-1-methyl-pyrrolo [2,3-b]Pyridin-6-yl]Phenyl group]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (88% LCMS yield), MS: m/z found 759.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 97% yield. MS: m/z found 659.2[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.53(s,2H),8.25(d,1H),7.71(dd,1H),7.67(s,1H),7.59(t,1H),7.49–7.45(m,3H),7.42(d,1H),7.31–7.24(m,2H),4.44(s,2H),3.98–3.89(m,8H),3.90–3.84(m,1H),3.83–3.79(m,2H),3.18–3.08(m,2H),2.80–2.67(m,2H),2.40–2.24(m,3H),1.85–1.75(m,1H).

Example 124: (5S) -5- [ [ [4- [ 3-chloro-4- [ 2-chloro-3- [3- [ [ [ (2S) -2-hydroxypropyl ] amino ] methyl ] -1-methyl-pyrrolo [2,3-b ] pyridin-6-yl ] phenyl ] -2-pyridinyl ] -2-methoxy-phenyl ] methylamino ] methyl ] pyrrolidin-2-one (98)

Reductive amination procedure B starting from N- [ [4- [ 3-chloro-4- [ 2-chloro-3- (3-formyl-1-methyl-pyrrolo [2,3-B ]]Pyridin-6-yl) phenyl]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (30 mg, 0)04 mmol) and (2S) -1-aminopropane-2-ol (6 mg,0.08 mmol) to afford N- [ [4- [ 3-chloro-4- [ 2-chloro-3- [3- [ [ (2S) -2-hydroxypropyl ] as crude material]Amino group]Methyl group]-1-methyl-pyrrolo [2,3-b]Pyridin-6-yl]Phenyl group]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (86% LCMS yield), MS: m/z found 773.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 98% LCMS yield. MS: m/z found 673.2[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.54(s,2H),8.24(d,1H),7.71(dd,1H),7.65(s,1H),7.59(t,1H),7.51–7.44(m,3H),7.42(d,1H),7.31–7.23(m,2H),4.40(s,2H),4.03(dd,1H),3.97–3.89(m,8H),3.89–3.82(m,1H),3.09–3.00(m,1H),2.85(dd,1H),2.76–2.67(m,2H),2.38–2.22(m,3H),1.89–1.73(m,1H),1.21(d,3H).

Example 125: (5S) -5- [ [ [4- [ 3-chloro-4- [ 2-chloro-3- [3- [ [ (2-hydroxy-2-methyl-propyl) amino ] methyl ] -1-methyl-pyrrolo [2,3-b ] pyridin-6-yl ] phenyl ] -2-pyridinyl ] -2-methoxy-phenyl ] methylamino ] methyl ] pyrrolidin-2-one (99)

Reductive amination procedure B starting from N- [ [4- [ 3-chloro-4- [ 2-chloro-3- (3-formyl-1-methyl-pyrrolo [2,3-B ]]Pyridin-6-yl) phenyl]-2-pyridyl group ]-2-methoxy-phenyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (30 mg,0.04 mmol) and 1-amino-2-methyl-propan-2-ol (7 mg,0.08 mmol) provided N- [ [4- [ 3-chloro-4- [ 2-chloro-3- [3- [ [ (2-hydroxy-2-methyl-propyl) amino ] as crude material]Methyl group]-1-methyl-pyrrolo [2,3-b]Pyridin-6-yl]Phenyl group]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (87% LCMS yield), MS: m/z found 787.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 96% LCMS yield. MS: m/z found 687.3[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.54(s,2H),8.25(d,1H),7.75–7.68(m,1H),7.64(s,1H),7.59(t,1H),7.48–7.44(m,3H),7.41(d,1H),7.31–7.22(m,2H),4.37(s,2H),3.93(s,6H),3.90(d,2H),3.87–3.81(m,1H),2.90(s,2H),2.77–2.67(m,2H),2.38–2.22(m,3H),1.79(dd,1H),1.25(s,6H).

Example 126: (5S) -5- [ [ [4- [ 3-chloro-4- [ 2-chloro-3- [3- [ (2-methoxyethylamino) methyl ] -1-methyl-pyrrolo [2,3-b ] pyridin-6-yl ] phenyl ] -2-pyridinyl ] -2-methoxy-phenyl ] methylamino ] methyl ] pyrrolidin-2-one (100)

Reductive amination procedure B starting from N- [ [4- [ 3-chloro-4- [ 2-chloro-3- (3-formyl-1-methyl-pyrrolo [2,3-B ]]Pyridin-6-yl) phenyl]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (30 mg,0.04 mmol) and 2-methoxyethylamine (6 mg,0.08 mmol) provided N- [ [4- [ 3-chloro-4- [ 2-chloro-3- [3- [ (2-methoxyethylamino) methyl ] as crude material ]-1-methyl-pyrrolo [2,3-b]Pyridin-6-yl]Phenyl group]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (83% LCMS yield), MS: m/z found 773.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 96% LCMS yield. MS: m/z found 673.2[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.54(s,2H),8.24(d,1H),7.71(dd,1H),7.65(s,1H),7.59(t,1H),7.50–7.44(m,3H),7.42(d,1H),7.31–7.20(m,2H),4.40(s,2H),3.97–3.90(m,8H),3.90–3.83(m,1H),3.68–3.60(m,2H),3.41(s,3H),3.20(t,2H),2.80–2.67(m,2H),2.38–2.22(m,3H),1.87–1.74(m,1H).

Example 127: (5S) -5- [ [ [4- [ 3-chloro-4- [ 2-chloro-3- [3- [ [ 2-hydroxyethyl (methyl) amino ] methyl ] -1-methyl-pyrrolo [2,3-b ] pyridin-6-yl ] phenyl ] -2-pyridinyl ] -2-methoxy-phenyl ] methylamino ] methyl ] pyrrolidin-2-one (101)

Reductive amination procedure B starting from N- [ [4- [ 3-chloro-4- [ 2-chloro-3- (3-formyl-1-methyl-pyrrolo [2,3-B ]]Pyridin-6-yl) phenyl]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (30 mg,0.04 mmol) and 2- (methylamino) ethanol (6 mg,0.08 mmol) provided N- [ [4- [ 3-chloro-4- [ 2-chloro-3- [3- [ [ 2-hydroxyethyl (methyl) amino) as crude material]Methyl group]-1-methyl-pyrrolo [2,3-b]Pyridin-6-yl]Phenyl group]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (80% LCMS yield), MS: m/z found 773.3[ M+H ] ] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 97% LCMS yield. MS: m/z found 673.2[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.54(s,2H),8.23(d,1H),7.71(dd,1H),7.63–7.55(m,2H),7.48–7.38(m,4H),7.32–7.20(m,2H),4.21(s,2H),3.96–3.89(m,8H),3.89–3.84(m,1H),3.82(t,2H),3.02–2.91(m,2H),2.77–2.68(m,2H),2.61(s,3H),2.37–2.22(m,3H),1.80(m,1H).

Example 128: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) -methyl) -amino) -methyl) -phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (17)

(a) 4- (4- (3-bromo-2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzaldehyde

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Pd (PPh) ₃ ) ₄ (121 mg,0.10 mmol), potassium carbonate (0.22 g,1.56 mmol), 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (0.14 g,0.52 mmol), and 4- (3-bromo-2)-chloro-phenyl) -2, 3-dichloro-pyridine (0.18 g,0.52 mmol) was suspended in 1, 4-dioxane/water (4:1, 4 ml) and the solution was then heated at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 6mL of water, and extracted with EtOAc (3×4 mL). The combined organic extracts were concentrated under reduced pressure and purified by flash chromatography (SiO ₂ The crude sample was purified with 0-60% EtOAc/hexanes to provide 4- [4- (3-bromo-2-chloro-phenyl) -3-chloro-2-pyridinyl as a yellow foam]-2-methoxy-benzaldehyde (155 mg,68% yield). MS: m/z found 437,439[ M+H ] ] ⁺ .

(b) 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridine-3-carbaldehyde

Pd (PPh) ₃ ) ₄ (28 mg,0.02 mmol), potassium carbonate (51 mg,0.37 mmol), 4- [4- (3-bromo-2-chloro-phenyl) -3-chloro-2-pyridinyl]-2-methoxy-benzaldehyde (53 mg,0.12 mmol), and 1-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaboran-2-yl) pyrrolo [2, 3-b)]Pyridine-3-carbaldehyde (35 mg,0.12 mmol) was suspended in 1, 4-dioxane/water (4:1, 2 mL) and the solution was then heated at 105℃for 20 min. The reaction was cooled to room temperature, diluted with 3mL of water, and extracted with EtOAc (3×2 mL). The combined organics were concentrated under reduced pressure and purified by flash chromatography (SiO ₂ The crude sample was purified with 0-10% MeOH/methylene chloride to provide 6- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl as a yellow foam]Phenyl group]-1-methyl-pyrrolo [2,3-b]Pyridine-3-carbaldehyde (25 mg,40% yield). MS: m/z found 516,518[ M+H ]] ⁺ .

(c) (S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) -methyl) -amino) -methyl) -phenyl) -pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

6- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl]Phenyl group]-1-methyl-pyrrolo [2,3-b]Pyridine-3-carbaldehyde (25 mg,0.03 mmol), (5S) -5- (aminomethyl) pyrrolidin-2-one (10 mg,0.09 mmol), and acetic acid (4 mg,0.06 mmol) were dissolved in MeOH/THF (1:1, 1 mL) and the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (6 mg,0.09 mmol) was added and the resulting mixture was stirred at 25 ℃ for 1 hour. The reaction was then diluted with water (2 mL) and extracted with EtOAc (3×2 mL). The combined organics were further washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the residue by reverse phase HPLC to afford (5S) -5- [ [ [4- [ 3-chloro-4- [ 2-chloro-3- [ 1-methyl-3- [ [ (2S) -5-oxopyrrolidin-2-yl ] as a white solid (formate)]Methylamino group]Methyl group]Pyrrolo [2,3-b]Pyridin-6-yl]Phenyl group]-2-pyridyl group]-2-methoxy-phenyl]Methylamino group]Methyl group]Pyrrolidin-2-one (9 mg,43% yield). LCMS: m/z found 712.35,714[ M+H ]] ⁺ Retention time = 2.05min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.65(d,1H),8.48(s,1H),8.23(d,1H),7.71(dd,1H),7.62–7.54(m,2H),7.49–7.41(m,4H),7.34(d,1H),7.31(dd,1H),4.35–4.23(m,2H),4.17–4.06(m,2H),3.96(s,3H),3.91(s,5H),3.07–2.88(m,4H),2.41–2.29(m,6H),1.91–1.78(m,2H).

Example 129: (S) -5- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one (18)

The compound was prepared in the same manner as described for compound 17 using intermediate 4- (4- (3-bromo-2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzaldehyde. Substitution of (S) -5- ((8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one for 1-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyrrolo [2,3-b]Pyridine-3-carbaldehyde. Obtained as a yellow solid (formic acid)Salts). LCMS: m/z found 714.3,716.3[ M+H ]] ⁺ Retention time = 2.10min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.65–8.59(m,1H),8.52(s,1H),7.49(d,2H),7.42(dd,2H),7.34(dd,1H),7.32–7.23(m,2H),6.80(s,2H),4.07–3.96(m,3H),3.94(s,3H),3.88(t,1H),3.83(d,3H),3.74(d,1H),3.60(d,1H),2.94(d,2H),2.91–2.65(m,5H),2.61(dd,1H),2.34(qd,6H),1.81(dd,2H).

Example 130: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (9)

(a) 4- (3-bromo-2-chlorophenyl) -2, 3-dichloropyridine

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1, 3-dibromo-2-chloro-benzene (0.55 g,2.04 mmol), 2, 3-dichloro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -pyridine (0.40 g,1.46 mmol), 1' -bis (biphenylphosphino) -ferrocene-palladium (II) dichloride dichloromethane complex (0.12 g,0.15 mmol), and potassium carbonate (0.56 g,4.09 mmol) were suspended in 10mL1, 4-dioxane in a sealed tube. Nitrogen was bubbled through the reaction solution for 2 minutes, then the vessel was sealed and heated at 75 ℃ for 12 hours. The mixture was cooled to room temperature and passed through And (5) filtering. The filtrate was concentrated under reduced pressure and purified by flash chromatography (SiO ₂ The crude oil was purified with 0-20% EtOAc/hexanes to provide 4- (3-bromo-2-chloro-phenyl) -2, 3-dichloro-pyridine (225 mg,46% yield). MS: m/z found 337.8,339.8[ M+H ]] ⁺ .

(b) 8- (4- (3-bromo-2-chlorophenyl) -3-chloropyridin-2-yl) -1-methyl-1, 2,3, 5-tetrahydro-4H-benzo [ e ] [1,4] diazepine-4-carboxylic acid tert-butyl ester

Pd (PPh) ₃ ) ₄ (26 mg,0.02 mmol), potassium carbonate (46 mg,0.33 mmol), 4- (3-bromo-2-chloro-phenyl) -2, 3-dichloro-pyridine (37 mg,0.11 mmol), and tert-butyl 1-methyl-8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 5-dihydro-2H-1, 4-benzodiazepine-4-carboxylate (43 mg,0.11 mmol) were suspended in 1, 4-dioxane/water (4:1, 3 mL), and the solution was heated at 105℃for 20 min. The mixture was cooled to room temperature, diluted with 3mL of water, and extracted with EtOAc (3×2 mL). The combined organic extracts were concentrated under reduced pressure and purified by flash chromatography (SiO ₂ 5-40% EtOAc/hexanes) to provide 8- [4- (3-bromo-2-chloro-phenyl) -3-chloro-2-pyridinyl]-tert-butyl 1-methyl-3, 5-dihydro-2H-1, 4-benzodiazepine-4-carboxylate (18 mg,29% yield). MS: m/z found 564.3[ M+H ]] ⁺ .

(c) 8- (3-chloro-4- (2-chloro-3- (3-formyl-1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -1-methyl-1, 2,3, 5-tetrahydro-4H-benzo [ e ] [1,4] diazepine-4-carboxylic acid tert-butyl ester

Pd (PPh) ₃ ) ₄ (7 mg,0.01 mmol), potassium carbonate (13 mg,0.10 mmol), 1-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyrrolo [2, 3-b)]Pyridine-3-carbaldehyde (9 mg,0.03 mmol), and 8- [4- (3-bromo-2-chloro-phenyl) -3-chloro-2-pyridinyl]-tert-butyl 1-methyl-3, 5-dihydro-2H-1, 4-benzodiazepine-4-carboxylate (18 mg,0.03 mmol) was suspended in 1, 4-dioxane/water (4:1, 1 ml) and the solution was then heated at 105 ℃ for 20 min. The mixture was cooled to room temperature, diluted with 3mL of water, and extracted with EtOAc (3×2 mL). The combined organic extracts were concentrated under reduced pressure and purified by flash chromatography (SiO ₂ The crude sample was purified with 5-80% EtOAc/hexanes to provide 8- [ 3-chloro-4- [ 2-chloro-3- (3-formyl-1-methyl-pyrrolo [2, 3-b)]Pyridin-6-yl) Phenyl group]-2-pyridyl group]-1-methyl-3, 5-dihydro-2H-1, 4-benzodiazepine-4-carboxylic acid tert-butyl ester (17 mg,61% yield). MS: m/z found 642, 644[ M+H ]] ⁺ .

(d) (S) -8- (3-chloro-4- (2-chloro-3- (1-methyl-3- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -1-methyl-1, 2,3, 5-tetrahydro-4H-benzo [ e ] [1,4] diazepine-4-carboxylic acid tert-butyl ester

8- [ 3-chloro-4- [ 2-chloro-3- (3-formyl-1-methyl-pyrrolo [2,3-b ] ]Pyridin-6-yl) phenyl]-2-pyridyl group]-1-methyl-3, 5-dihydro-2H-1, 4-benzodiazepine-4-carboxylic acid tert-butyl ester (17 mg,0.03 mmol), (5S) -5- (aminomethyl) pyrrolidin-2-one (6 mg,0.05 mmol), and acetic acid (3 mg,0.05 mmol) were dissolved in MeOH/THF (1:1, 2 mL) and the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (5 mg,0.08 mmol) was added and the resulting mixture was stirred at 25 ℃ for 1 hour. The mixture was then diluted with water (2 mL) and extracted with methylene chloride (3 x2 mL). The combined organics were further washed with brine (3 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to provide 8- [ 3-chloro-4- [ 2-chloro-3- [ 1-methyl-3- [ [ [ (2S) -5-oxopyrrolidin-2-yl ] as a yellow foam]Methylamino group]Methyl group]Pyrrolo [2,3-b]Pyridin-6-yl]Phenyl group]-2-pyridyl group]-tert-butyl 1-methyl-3, 5-dihydro-2H-1, 4-benzodiazepine-4-carboxylate (19 mg, crude). MS: m/z found 740.4,742[ M+H ]] ⁺ .

(e) (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] -diazepin-8-yl) -pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -methyl) -amino) -methyl) -pyrrolidin-2-one

8- [ 3-chloro-4- [ 2-chloro-3- [ 1-methyl-3- [ [ [ (2S) -5-oxopyrrolidin-2-yl ]Methylamino group]-methyl group]Pyrrolo [2,3-b ]]Pyridin-6-yl]Phenyl group]-2-pyridyl group]-1-methyl-3, 5-dihydro-2H-1, 4-benzodiazepine-4-carboxylic acid tert-butyl ester (19 mg,0.03 mmol) was dissolved in 0.5mL DCM and a solution of 1, 4-dioxane (26 μl,0.10 mmol) in 4M HCl was added. The mixture was stirred at room temperature for 20 minutes and the solvent was removed under reduced pressure. Purification of the residue by reverse phase HPLC to afford (5S) -5- [ [ [6- [ 2-chloro-3- [ 3-chloro-2- (1-methyl-2, 3,4, 5-tetrahydro-1, 4-benzodiazepine-8-yl) -4-pyridinyl ]]Phenyl group]-1-methyl-pyrrolo [2,3-b]Pyridin-3-yl]Methylamino group]Methyl group]Pyrrolidin-2-one (8 mg,48% yield) (formate). LCMS: m/z found 640,642[ M+H ]] ⁺ Retention time = 2.17min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.65(d,1H),8.49(s,2H),8.22(d,1H),7.71(dd,1H),7.58(t,1H),7.54(s,1H),7.49–7.43(m,3H),7.41(d,1H),7.38(d,1H),7.32(dd,1H),4.33(s,2H),4.22(d,2H),3.91(s,4H),3.40–3.35(m,2H),3.03(s,3H),2.94(t,2H),2.38–2.27(m,3H),1.89–1.78(m,1H).

Example 131: (S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- ((S) -2-hydroxypropyl) -1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] -diazepin-8-yl) -pyridin-4-yl) -phenyl) -2-methoxypyridin-3-yl) -methyl) -amino) -methyl) -pyrrolidin-2-one (24)

(a) 8- (4- (3-bromo-2-chlorophenyl) -3-chloropyridin-2-yl) -1-methyl-1, 2,3, 5-tetrahydro-4H-benzo [ e ] [1,4] diazepine-4-carboxylic acid tert-butyl ester

Pd (PPh) ₃ ) ₄ (45 mg,0.04 mmol), potassium carbonate (80 mg,0.58 mmol), 1-methyl-8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 5-dihydro-2H-1, 4-benzodiazepine-4-carboxylic acid tert-butyl ester (75 mg,0.19 mmol), and 4- (3-bromo-2-chloro-phenyl) -2, 3-dichloro-pyridine (65 mg,0.19 mmol) were suspended in 1, 4-dioxane/water (4:1, 2 ml), and the solution was heated at 105℃for 20 min. Cooling the mixture Cooled to room temperature, diluted with 3mL of water and extracted with EtOAc (3×3 mL). The combined organic extracts were concentrated under reduced pressure and purified by flash chromatography (SiO ₂ 0-40% EtOAc/hexanes) to provide 8- [4- (3-bromo-2-chloro-phenyl) -3-chloro-2-pyridinyl]-tert-butyl 1-methyl-3, 5-dihydro-2H-1, 4-benzodiazepine-4-carboxylate (75 mg,69% yield). MS: m/z found 564.1[ M+H ]] ⁺ .

(b) 8- (4- (3-bromo-2-chlorophenyl) -3-chloropyridin-2-yl) -1-methyl-2, 3,4, 5-tetrahydro-1H-benzo- [ e ] [1,4] diazepine

8- [4- (3-bromo-2-chloro-phenyl) -3-chloro-2-pyridinyl]-tert-butyl 1-methyl-3, 5-dihydro-2H-1, 4-benzodiazepine-4-carboxylate (75 mg,0.13 mmol) was dissolved in 2mL of methylene chloride and a solution of 1, 4-dioxane (133 μl,0.53 mmol) in 4M HCl was added. The mixture was stirred at room temperature for 3 hours, then the precipitate was filtered and washed with methylene chloride (5 mL). The solid was further dried under vacuum to provide 8- [4- (3-bromo-2-chloro-phenyl) -3-chloro-2-pyridinyl]-1-methyl-2, 3,4, 5-tetrahydro-1, 4-benzodiazepine (51 mg,82% yield) (HCl salt). MS: m/z found 464[ M+H ]] ⁺ .

(c) (S) -1- (8- (4- (3-bromo-2-chlorophenyl) -3-chloropyridin-2-yl) -1-methyl-1, 2,3, 5-tetrahydro-4H-benzo [ e ] [1,4] diazepin-4-yl) propan-2-ol

8- [4- (3-bromo-2-chloro-phenyl) -3-chloro-2-pyridinyl]-1-methyl-2, 3,4, 5-tetrahydro-1, 4-benzodiazepine hydrochloride (25 mg,0.05 mmol), (2S) -2-methyl oxirane (29 mg,0.50 mmol), and DIEA (26. Mu.L, 0.15 mmol) were suspended in 1mL EtOH and the mixture was stirred at 85℃for 1 hour. The reaction was concentrated and the residue was dissolved in 2mL EtOAc. The organic solution was washed with water (2×2 mL), brine (2×2 mL), dried over sodium sulfate, filtered and concentrated to provide a pale yellow oil(2S) -1- [8- [4- (3-bromo-2-chloro-phenyl) -3-chloro-2-pyridinyl]-1-methyl-3, 5-dihydro-2H-1, 4-benzodiazepine-4-yl]Propan-2-ol (20 mg, crude). MS: m/z found 522[ M+H ]] ⁺ . The material was used in the next step without further purification.

(d) (S) - ((6-chloro-2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

6-chloro-2-methoxy-pyridine-3-carbaldehyde (400 mg,2.33 mmol), (5S) -5- (aminomethyl) pyrrolidin-2-one (0.35 g,3.03 mmol), and acetic acid (0.17 g,2.80 mmol) were dissolved in MeOH/THF (1:1, 10 mL) and then the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (0.22 g,3.50 mmol) was added and the resulting mixture was stirred at 25℃for 1 hour. The reaction was then diluted with water (20 mL) and extracted with methylene chloride (3 x10 mL). The combined organics were further washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford (5S) -5- [ [ (6-chloro-2-methoxy-3-pyridinyl) methylamino as a yellow oil ]Methyl group]Pyrrolidin-2-one (0.63 g, crude). MS: m/z found 270[ M+H ]] ⁺ .

(5S) -5- [ [ (6-chloro-2-methoxy-3-pyridinyl) methylamino]Methyl group]Pyrrolidin-2-one (6278 mg,2.33mmol, crude), DIEA (1619 μl,9.31 mmol), and di-tert-butyl dicarbonate (1016 mg,4.66 mmol) were dissolved in 10mL THF, and the mixture was stirred at room temperature for 12 hours. The reaction was diluted with EtOAc (15 mL) and saturated aqueous NaHCO ₃ (10 mL. Times.2) the resulting solution was washed followed by brine (10 mL. Times.2). The organic layer was concentrated under reduced pressure and purified by flash chromatography (SiO ₂ 0-5% MeOH/DCM) to provide N- [ (6-chloro-2-methoxy-3-pyridinyl) methyl]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (788 mg,92% yield). MS: m/z found 370[ M+H ]] ⁺ .

(e) (S) - ((2-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridin-3-yl) methyl) carbamic acid tert-butyl ester

Tert-butyl N- [ (6-chloro-2-methoxy-3-pyridinyl) methyl ] -N- [ [ (2S) -5-oxopyrrolidin-2-yl ] methyl ] carbamate (0.35 g,0.94 mmol), 4, 5-tetramethyl-2- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,3, 2-dioxaborane (0.34 g,1.32 mmol), 1' -bis (biphenylphosphino) -ferrocene-palladium (II) dichloride dichloromethane complex (77 mg,0.09 mmol), and potassium acetate (0.28 g,2.82 mmol) were suspended in 10mL 1, 4-dioxane in a sealed tube. Nitrogen was bubbled through the reaction solution for 2 minutes, then the vessel was sealed and heated at 95 ℃ for 6 hours. The reaction was cooled to room temperature and the mixture was filtered through CELITE. The filtrate was concentrated under reduced pressure and the crude oil was dissolved in 3mL EtOAc. Hexane was added dropwise with vigorous stirring until a dark solid precipitated from solution. The solid was filtered and the filtrate concentrated under reduced pressure to afford tert-butyl N- [ [ 2-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3-pyridinyl ] methyl ] -N- [ [ (2S) -5-oxopyrrolidin-2-yl ] methyl ] carbamate (434 mg, crude). The material was used in the next step without further purification.

(f) (6- (2-chloro-3- (3-chloro-2- (4- ((S) -2-hydroxypropyl) -1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

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Pd (PPh) ₃ ) ₄ (9 mg,0.01 mmol), potassium carbonate (16 mg,0.11 mmol), (2S) -1- [8- [4- (3-bromo-2-chloro-phenyl) -3-chloro-2-pyridinyl)]-1-methyl-3, 5-dihydro-2H-1, 4-benzodiazepine-4-yl]Propan-2-ol (20 mg,0.04 mmol), and N- [ [ 2-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (26 mg,0.06 mmol) was suspended in 1, 4-dioxane/water (4:1 (v/v), 1 mL) and the solution was then heated at 105 ℃ for 20 min. The mixture was cooled to room temperature, diluted with 3mL of water, and extracted with EtOAc (3×2 mL). The combined organics were concentrated under reduced pressure and purified by flash chromatography (SiO ₂ 0-8% MeOH/DCM) to provide an N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [4- [ (2S) -2-hydroxypropyl ] sample]-1-methyl-3, 5-dihydro-2H-1, 4-benzodiazepine-8-yl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl ]Methyl group]Tert-butyl carbamate (13 mg,45% yield). MS: m/z found 775.4,777[ M+H ]] ⁺ .

(g) (S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- ((S) -2-hydroxypropyl) -1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] -diazepin-8-yl) -pyridin-4-yl) -phenyl) -2-methoxypyridin-3-yl) -methyl) -amino) -methyl) -pyrrolidin-2-one

N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [4- [ (2S) -2-hydroxypropyl ] amino acid]-1-methyl-3, 5-dihydro-2H-1, 4-benzodiazepine-8-yl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (13 mg,0.02 mmol) was dissolved in 0.5mL of methylene chloride and a solution of 1, 4-dioxane (17. Mu.L, 0.07 mmol) in 4M HCl was added. The mixture was stirred at room temperature for 20 minutes and the solvent was removed under reduced pressure. Purification of the residue by reverse phase HPLC to afford (5S) -5- [ [ [6- [ 2-chloro-3- [ 3-chloro-2- [4- [ (2S) -2-hydroxypropyl ]]-1-methyl-3, 5-dihydro-2H-1, 4-benzodiazepine-8-yl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methylamino group]Methyl group]Pyrrolidin-2-one (2 mg,17% yield) (formate). LCMS: m/z found 675.3,677[ M+H ]] ⁺ Retention time = 2.07min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.63(d,1H),8.49(s,3H),7.77(d,1H),7.71(dd,1H),7.55(t,1H),7.46–7.38(m,3H),7.31(s,1H),7.28(t,2H),4.33(q,2H),4.15(s,1H),4.03(s,3H),3.90(dd,3H),3.41–3.31(m,4H),2.99(s,4H),2.89–2.71(m,3H),2.40–2.19(m,3H),1.90–1.70(m,1H),1.21(d,3H).

Example 132: (5S, 5' S) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (2-methoxy-4, 1-phenylene)) -bis (methylene)) -bis (azanediyl)) bis (pyrrolidin-2-one) (4)

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(a) 2,2', 3' -tetrachloro-4, 4' -bipyridine

Pd (PPh) ₃ ) ₄ (0.24 g,0.21 mmol), potassium carbonate (0.43 g,3.13 mmol), (2, 3-dichloro-4-pyridinyl) boronic acid (0.20 g,1.04 mmol), and 2, 3-dichloro-4-iodo-pyridine (0.37 g,1.36 mmol) were suspended in 1, 4-dioxane/water (4:1, 10 mL), and then the solution was heated at 105℃for 20 min. The mixture was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×5 mL). Concentrating the combined organics under reduced pressure and passing through normal phase SiO ₂ The crude sample was purified by chromatography (5-60% EtOAc/hexanes) to afford 2, 3-dichloro-4- (2, 3-dichloro-4-pyridinyl) pyridine (96 mg,44% yield) as a tan solid. MS: m/z found 295,297[ M+H ]] ⁺ .

(b) 4,4'- (3, 3' -dichloro- [4,4 '-bipyridine ] -2,2' -diyl) bis (2-methoxybenzaldehyde)

Pd (PPh) ₃ ) ₄ (35 mg,0.03 mmol), potassium carbonate (63 mg,0.46 mmol), 2, 3-dichloro-4- (2, 3-dichloro-4-pyridinyl) pyridine (45 mg,0.15 mmol), and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (100 mg,0.38 mmol) were suspended in 1, 4-dioxane/water (4:1, 2 ml), and the solution was then heated at 105℃for 20 min. The mixture was cooled to room temperature, diluted with 3mL of water, and extracted with EtOAc (3×2 mL). Concentrating the combined organics And passing the crude sample through a short SiO ₂ Column (5-90% EtOAc/hexanes) to remove some impurities. The clean fractions were combined and concentrated under reduced pressure to provide 4- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl as a yellow foam]-2-pyridyl group]-2-methoxy-benzaldehyde (75 mg, crude). MS: m/z found 493,495[ M+H ]] ⁺ .

(c) (5S, 5' S) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (2-methoxy-4, 1-phenylene)) -bis (methylene)) -bis (azanediyl)) bis (methylene)) bis (pyrrolidin-2-one)

4- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl]-2-pyridyl group]-2-methoxy-benzaldehyde (75 mg,0.09mmol, crude), (5S) -5- (aminomethyl) pyrrolidin-2-one (31 mg,0.27 mmol), and acetic acid (11 mg,0.18 mmol) were dissolved in MeOH/THF (1:1, 2 mL) and then the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (17 mg,0.27 mmol) was added and the resulting mixture was stirred at 25 ℃ for 1 hour. The reaction was then diluted with water (3 mL) and extracted with EtOAc (3×2 mL). The combined organics were further washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the residue by reverse phase HPLC to afford (5S) -5- [ [ [4- [ 3-chloro-2- [ 3-methoxy-4- [ [ (2S) -5-oxopyrrolidin-2-yl ] as a white solid (formate) ]Methylamino group]Methyl group]Phenyl group]-4-pyridinyl]-2-pyridyl group]-2-methoxy-phenyl]Methylamino group]Methyl group]Pyrrolidin-2-one (6 mg,10% yield). LCMS: m/z found 689.4,691[ M+H ]] ⁺ Retention time = 1.94min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.70(d,2H),8.49(s,2H),7.54–7.42(m,4H),7.38–7.22(m,4H),4.12–4.02(m,4H),3.96(s,6H),3.92(q,2H),2.89(h,4H),2.41–2.27(m,6H),1.91–1.76(m,2H).

Example 133: (5S, 5' S) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (2-fluoro-6-methoxy-4, 1-phenylene)) -bis (methylene) bis (azetidinediyl)) bis (methylene)) bis (pyrrolidin-2-one) (12)

In a similar manner to that described for compound 4, (5 s, 5's) -5,5' - (((((3, 3' -dichloro- [4,4' -bipyridine)) was prepared using the intermediate 2,2', 3' -tetrachloro-4, 4' -bipyridine]-2,2' -diyl) bis (2-fluoro-6-methoxy-4, 1-phenylene)) -bis (azanediyl) bis (methylene)) bis (pyrrolidin-2-one. 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde is replaced by 2-fluoro-6-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde. The product was obtained as a white solid (formate). LCMS: found 725.3,727.2[ M+H ]] ⁺ Retention time = 1.90min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.72(d,2H),8.41(s,1H),7.51(d,2H),7.21(s,2H),7.15(dd,2H),4.11(s,4H),3.98(s,6H),3.91(s,2H),2.95–2.82(m,4H),2.41–2.26(m,6H),1.89–1.76(m,2H).

Example 134: (S) -5- (((4- (3, 3' -dichloro-2 ' - (1-methyl-3- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indol-6-yl) - [4,4' -bipyridin ] -2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one (14)

(a) 6- (3, 3' -dichloro-2 ' - (4-formyl-3-methoxyphenyl) - [4,4' -bipyridyl ] -2-yl) -1-methyl-1H-indole-3-carbaldehyde

Pd (PPh) ₃ ) ₄ (24 mg,0.02 mmol), potassium carbonate (42 mg,0.31 mmol), 2, 3-dichloro-4- (2, 3-dichloro-4-pyridinyl) pyridine (30 mg,0.10 mmol), 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (29 mg,0.11 mmol), and 1-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) indole-3-carbaldehydeAldehyde (32 mg,0.11 mmol) was suspended in 1, 4-dioxane/water (4:1, 2 mL) and the solution was heated at 105℃for 20 min. The mixture was cooled to room temperature, diluted with 3mL of water, and extracted with EtOAc (3×2 mL). The combined organics were concentrated under reduced pressure and purified by flash chromatography (SiO ₂ 0-50% EtOAc/hexanes) to afford the desired product 6- [ 3-chloro-4- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl) as a gray solid]-2-pyridyl group]-1-methyl-indole-3-carbaldehyde (27 mg,51% yield). MS: m/z found 516.1,518.1[ M+H ]] ⁺ . Separation of homodimeric product: 6- [ 3-chloro-4- [ 3-chloro-2- (3-formyl-1-methyl-indol-6-yl) -4-pyridinyl ] in the form of a tan solid]-2-pyridyl group]-1-methyl-indole-3-carbaldehyde (8.60 mg,15.6% yield, m/z found 540[ M+H ] ] ⁺ ) 4- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl ] in the form of a white solid]-2-pyridyl group]-2-methoxy-benzaldehyde (6.00 mg,11.9% yield, m/z found 494[ M+H] ⁺ )。

(b) (S) -5- (((4- (3, 3' -dichloro-2 ' - (1-methyl-3- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indol-6-yl) - [4,4' -bipyridin ] -2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one

6- [ 3-chloro-4- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl]-2-pyridyl group]-1-methyl-indole-3-carbaldehyde (27 mg,0.05 mmol), (5S) -5- (aminomethyl) pyrrolidin-2-one (18 mg,0.16 mmol), and acetic acid (6 mg,0.10 mmol) were dissolved in MeOH/THF (1:1, 1 mL) and the solution was then stirred at 25℃for 2 hours. Sodium cyanoborohydride (9.86 mg,0.16 mmol) was added and the resulting mixture was stirred at 25℃for 1 hour. The mixture was then diluted with water (2 mL) and extracted with EtOAc (3×2 mL). The combined organics were further washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the crude sample by reverse phase HPLC to afford (5S) -5- [ [ [4- [ 3-chloro-2- [ 1-methyl-3- [ [ (2S) -5-oxopyrrolidin-2-yl ] as a white solid (formate)]-methylamino group ]-methyl group]-indol-6-yl]-4-pyridinyl]-2-pyridyl group]-2-methoxy-phenyl]Methylamino group]Methyl group]Pyrrolidin-2-one (14 mg,37% yield). LCMS: m/z found 712.35,714[ M+H ]] ⁺ Retention time = 1.95min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.70(dd,2H),8.48(s,2H),7.84(d,1H),7.79–7.75(m,1H),7.51(s,2H),7.49(d,1H),7.47(d,1H),7.46(s,1H),7.35(s,1H),7.32(d,1H),4.38(d,2H),4.11–4.01(m,2H),3.96(s,5H),3.90(s,3H),3.09(t,2H),2.89(t,2H),2.42–2.25(m,6H),1.92–1.78(m,2H).

Example 135: (5S, 5' S) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (1-methyl-1H-indol-6, 3-diyl)) bis (methylene)) bis (azetidinediyl)) bis (methylene)) bis (pyrrolidin-2-one) (15)

Will 6- [ 3-chloro-4- [ 3-chloro-2- (3-formyl-1-methyl-indol-6-yl) -4-pyridyl]-2-pyridyl group]-1-methyl-indole-3-carbaldehyde (9 mg,0.02 mmol), (5S) -5- (aminomethyl) pyrrolidin-2-one ((5 mg,0.05 mmol), and acetic acid (2 mg,0.03 mmol) were dissolved in MeOH/THF (1:1, 1 mL) and then the solution was stirred at 25℃for 2 hours sodium cyanoborohydride (3 mg,0.05 mmol) was added and the resulting mixture was stirred at 25℃for 1 hour then the mixture was diluted with water (2 mL) and extracted with EtOAc (3X 2 mL), the combined organics were further washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure the crude sample was purified by reverse phase HPLC to afford (5S) -5- [ [ [ [6- [ 3-chloro-4- [ 3-chloro-2- [ 1-methyl-3- [ [ (2S) -5-oxopyrrolidin-2-yl ] as a white solid (formate) ]Methylamino group]Methyl group]Indol-6-yl]-4-pyridinyl]-2-pyridyl group]-1-methyl-indol-3-yl]Methylamino group]Methyl group]Pyrrolidin-2-one (7 mg,50% yield). LCMS: m/z found 736.6[ M+H ]] ⁺ Retention time = 2.01min (method C ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.68(dd,2H),7.79(d,2H),7.74(s,2H),7.50–7.43(m,4H),7.37(s,2H),4.22–4.04(m,4H),3.93–3.82(m,8H),2.88(q,4H),2.38–2.21(m,6H),1.88–1.74(m,2H).

Example 136: (S) -5- (((4- (3, 3' -dichloro-2 ' - (1-methyl-3- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) - [4,4' -bipyridin ] -2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one (16)

Compounds were prepared in the same manner as described for compound 14 using intermediate 2,2', 3' -tetrachloro-4, 4' -bipyridine. The product was obtained as a white solid (formate). LCMS: m/z found 713.35,715.3[ M+H ]] ⁺ Retention time = 1.89min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.77(d,2H),8.71(d,1H),8.50(s,1H),8.31(d,1H),7.79(s,1H),7.52(dd,2H),7.46(d,1H),7.36–7.28(m,2H),4.44–4.27(m,2H),4.10–4.02(m,2H),3.95(d,8H),3.06(qd,2H),2.87(h,2H),2.42–2.28(m,6H),1.92–1.77(m,2H).

Example 137: (S) -5- ((((3 ' -chloro-2 ' - ((S) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one (128)

(a) (S) -6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy nicotinic carbonitrile

Sodium hydride (60% in oil suspension) (0.15 g,3.86 mmol) was suspended in 6mL anhydrous DMF and the solution cooled to 0deg.C. A solution of (1S) -4-bromoindan-1-ol (0.63 g,2.97 mmol) in 2mL DMF was slowly added over 2 minutes. The resulting mixture was warmed to room temperature and stirred for 30 minutes, then cooled back to 0 ℃. 6-chloro-2-methoxy-pyridine-3-carbonitrile (500 mg,2.97 mmol) in 3ml DMF was added dropwise and the reaction mixture was then warmed To 25 ℃ and stirred for 3 hours. The mixture was then diluted with 20mL of water and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with water (30 mL), brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. By flash chromatography (SiO ₂ 0-10% EtOAc/hexanes) to provide 6- [ (1S) -4-bromoindan-1-yl]Oxygen-2-methoxy-pyridine-3-carbonitrile (730 mg,72% yield). MS: m/z found 345,347[ M+H ]] ⁺ .

(b) (S) -6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) oxy) -5-iodo-2-methoxynicotinic carbonitrile

6- [ (1S) -4-bromoindan-1-yl]Oxygen-2-methoxy-pyridine-3-carbonitrile (0.30 g,0.87 mmol), 1-iodopyrrolidine-2, 5-dione (0.22 g,0.96 mmol), and potassium acetate (0.85 g,8.69 mmol) were suspended in 6mL of acetic acid and the mixture was stirred at 85℃for 16 h. The mixture was then diluted with 20mL of EtOAc and 20mL of water. The solution was cooled to 0 ℃ and 2M NaOH solution was slowly added until the solution reached about pH 9. The mixture was extracted with EtOAc (3×20 mL) and the combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. By flash chromatography (SiO ₂ 0-10% EtOAc/hexanes) to provide 6- [ (1S) -4-bromoindan-1-yl ]Oxygen-5-iodo-2-methoxy-pyridine-3-carbonitrile (218 mg,53% yield). MS: m/z found 472[ M+H ]] ⁺ . ¹ H NMR (400 MHz, chloroform-d) δ8.10 (d, 1H), 7.49 (d, 1H), 7.38 (d, 1H), 7.14 (t, 1H), 6.56-6.47 (m, 1H), 4.07 (d, 3H), 3.22-3.13 (m, 1H), 2.96 (m, 1H), 2.72 (m, 1H), 2.32-2.18 (m, 1H).

(c) (S) -6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) -nicotinic carbonitrile

In a microwave vial, 6- [ (1S) -4-bromoindan-1-yl]Oxygen-5-iodo-2-methoxy-pyridine-3-carbonitrile (150 mg,0.32 mmol)And cuprous iodide (90 mg,0.47 mmol) was suspended in 4mL DMF. 2, 2-difluoro-2-fluorosulfonyl-acetic acid methyl ester (122 mg,0.63 mmol) was added and the mixture was purged with nitrogen for 5 minutes. The mixture was then subjected to microwave irradiation and the reaction temperature was maintained at 107 ℃ for 3 hours. The mixture was cooled to room temperature, diluted with 5mL of EtOAc, and the insoluble copper salt was removed by filtration. The filtrate was washed with water (3×10 mL) and the organic solution was concentrated under reduced pressure. By flash chromatography (SiO ₂ 0-10% EtOAc/hexanes) to provide 6- [ (1S) -4-bromoindan-1-yl]Oxygen-2-methoxy-5- (trifluoromethyl) pyridine-3-carbonitrile (84 mg,64% yield). ¹ H NMR (400 MHz, chloroform-d) δ8.03 (s, 1H), 7.50 (d, 1H), 7.34 (d, 1H), 7.13 (t, 1H), 6.63 (dd, 1H), 4.14 (s, 3H), 3.18 (m, 1H), 3.04-2.92 (m, 1H), 2.81-2.66 (m, 1H), 2.26 (m, 1H).

(d) (S) -6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) -nicotinaldehyde

6- [ (1S) -4-bromoindan-1-yl ] under nitrogen atmosphere]Oxygen-2-methoxy-5- (trifluoromethyl) pyridine-3-carbonitrile (84 mg,0.20 mmol) was dissolved in 2mL of toluene and the mixture was cooled to-78 ℃. A solution of DIBAL-H (0.41 ml,0.41mmol, 1M in methylene chloride) was added dropwise over 15 minutes, and the mixture was then warmed to room temperature and stirred for an additional 30 minutes. The mixture was then cooled to 0deg.C and a mixture of 1M aqueous HCl and MeOH (1:1 (v/v), 10 mL) was added to quench the reaction. The resulting solution was warmed to room temperature and stirred vigorously for 1 hour, then diluted with EtOAc (10 mL) and basified with aqueous 2M NaOH solution. The mixture was extracted with EtOAc (3×5 mL) and the combined organics were further washed with brine (5 mL), dried over sodium sulfate, then filtered and concentrated under reduced pressure. By flash chromatography (SiO ₂ 0-10% EtOAc/hexanes) to provide 6- [ (1S) -4-bromoindan-1-yl]Oxygen-2-methoxy-5- (trifluoromethyl) pyridine-3-carbaldehyde (30 mg,36% yield). ¹ H NMR (400 MHz, chloroform-d) δ10.23 (s, 1H), 8.36 (s, 1H), 7.49 (d, 1H), 7.37 (d, 1H), 7.13 (t, 1H), 6.67 (t, 1H), 4.15 (d, 3H), 3.28-3.1 0(m,1H),2.96(m,1H),2.83–2.70(m,1H),2.28(m,1H).

(e) (S) -2-methoxy-6- ((4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -5- (trifluoromethyl) nicotinaldehyde

6- [ (1S) -4-bromoindan-1-yl in a sealed tube]Oxygen-2-methoxy-5- (trifluoromethyl) pyridine-3-carbaldehyde (87 mg,0.21 mmol), 4, 5-tetramethyl-2- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,3, 2-dioxaborane (106 mg,0.42 mmol), 1' -bis (biphenylphosphino) -ferrocene-palladium (II) dichloride dichloromethane complex (17 mg,0.02 mmol), and potassium carbonate (81 mg,0.59 mmol) were suspended in 4mL 1, 4-dioxane. Nitrogen was bubbled through the reaction solution for 2 minutes, then the vessel was sealed and heated at 95 ℃ for 6 hours. The mixture was then cooled to room temperature and passed throughAnd (5) filtering. The filtrate was concentrated under reduced pressure and purified by flash chromatography (SiO ₂ The residue was purified with 0-10% EtOAc/hexanes to provide 2-methoxy-6- [ (1S) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) indan-1-yl]Oxygen-5- (trifluoromethyl) pyridine-3-carbaldehyde (80 mg,83% yield). MS: m/z found 464[ M+H ]] ⁺ . ¹ H NMR (400 MHz, chloroform-d) δ10.22 (s, 1H), 8.34 (s, 1H), 7.78 (d, 1H), 7.52 (d, 1H), 7.23 (d, 1H), 6.62 (dd, 1H), 4.15 (s, 3H), 3.40 (m, 1H), 3.21-3.08 (m, 1H), 2.68 (m, 1H), 2.31-2.10 (m, 1H), 1.34 (s, 12H).

(f) 2',3' -dichloro-6-methoxy- [2,4' -bipyridine ] -5-carbaldehyde

Pd (PPh) ₃ ) ₄ (0.24 g,0.21 mmol), 6-chloro-2-methoxy-pyridine-3-carbaldehyde (0.72 g,4.17 mmol), potassium carbonate (0.86 g,6.26 mmol), and (2, 3-dichloro-4-pyridinyl) boronic acid (0.40 g)2.09 mmol) was suspended in 1, 4-dioxane/water (4:1 (v/v), 10 mL) and the solution was heated at 105℃for 20 min. The mixture was cooled to room temperature, diluted with 20mL of water, and extracted with EtOAc (3×10 mL). The combined organics were concentrated under reduced pressure and purified by flash chromatography (SiO ₂ The crude sample was purified 0-30% EtOAc/hexanes to provide N- [2- [3- [3- [5- [ [ tert-butoxycarbonyl- [ [ (2S) -5-oxopyrrolidin-2-yl [ ] with]Methyl group]Amino group]Methyl group]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-2-chloro-phenyl]-5,6,7, 8-tetrahydroquinolin-5-yl]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (186 mg,32% yield). MS: m/z found 283,285[ M+H ]] ⁺ .

(g) (S) - ((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridin ] -5-yl) -methyl) - ((5-oxopyrrolidin-2-yl) -methyl) -carbamic acid tert-butyl ester

6- (2, 3-dichloro-4-pyridinyl) -2-methoxy-pyridine-3-carbaldehyde (186 mg,0.66 mmol), acetic acid (39 mg,0.66 mmol), and (5S) -5- (aminomethyl) pyrrolidin-2-one (113 mg,0.99mmol were dissolved in MeOH/THF (1:1 (v)/5 mL) and then the solution was stirred at 25℃for 2 hours sodium cyanoborohydride (83 mg,1.31 mmol) was added and the resulting mixture was stirred at 25℃for 1 hour then the mixture was diluted with water (10 mL) and extracted with EtOAc (3X 10 mL) the combined organics were further washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford (5S) -5- [ [ [6- (2, 3-dichloro-4-pyridinyl) -2-methoxy-3-pyridinyl) ]Methylamino group]Methyl group]Pyrrolidin-2-one (250 mg, crude). MS: m/z found 381,383[ M+H ]] ⁺ . The material was used in the next step without further purification.

(5S) -5- [ [ [6- (2, 3-dichloro-4-pyridinyl) -2-methoxy-3-pyridinyl]-methylamino group]-methyl group]Pyrrolidin-2-one (0.25 g,0.66mmol, crude) and N, N-diisopropylethylamine (0.23 mL,1.31 mmol) were dissolved in 5mL of THF and then di-tert-butyl dicarbonate (0.22 g,0.98 mmol) was added in portions. The resulting mixture was stirred at room temperature for 4 hours. EtOAc (15 ml) was added to the reaction mixtureIn the mixture, saturated aqueous NaHCO ₃ The resulting solution was washed with solution (10 mL. Times.2) and brine (10 mL. Times.2). The organic phase was concentrated under reduced pressure and purified by flash chromatography (SiO ₂ 0-5% MeOH/DCM) to provide N- [ [6- (2, 3-dichloro-4-pyridinyl) -2-methoxy-3-pyridinyl)]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (0.30 g,96% yield). MS: m/z found 481,483[ M+H ]] ⁺ .

(h) ((3 ' -chloro-2 ' - ((S) -1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) carbamic acid tert-butyl ester

Pd (PPh) ₃ ) ₄ (24 mg,0.02 mmol), potassium carbonate (43 mg,0.31 mmol), 2-methoxy-6- [ (1S) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) indan-1-yl]Oxygen-5- (trifluoromethyl) pyridine-3-carbaldehyde (48 mg,0.10 mmol), and N- [ [6- (2, 3-dichloro-4-pyridinyl) -2-methoxy-3-pyridinyl)]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (75 mg,0.16 mmol) was suspended in 1, 4-dioxane/water (4:1 (v/v), 2 mL) and the solution was heated at 105 ℃ for 20 min. The mixture was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×5 mL). The combined organics were concentrated under reduced pressure and purified by flash chromatography (SiO ₂ The residue was purified with 0-4% MeOH/DCM to afford N- [ [6- [ 3-chloro-2- [ (1S) -1- [ [ 5-formyl-6-methoxy-3- (trifluoromethyl) -2-pyridinyl)]Oxygen gas]Indan-4-yl]-4-pyridinyl]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (45 mg,56% yield). MS: m/z observed 782,784[ M+H ]] ⁺ .

(i) ((3 ' -chloro-2 ' - ((S) -1- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) carbamic acid tert-butyl ester((S) -5-oxopyrrolidin-2-yl) methyl)

N- [ [6- [ 3-chloro-2- [ (1S) -1- [ [ 5-formyl-6-methoxy-3- (trifluoromethyl) -2-pyridinyl ]]Oxygen gas]Indan-4-yl]-4-pyridinyl]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (15 mg,0.02 mmol), acetic acid (2 mg,0.04 mmol), and (2S) -1-aminopropane-2-ol (4 mg,0.06 mmol) were dissolved in MeOH/THF (1:1 (v/v), 1 mL) and the resulting solution was stirred at 25℃for 6 hours. Sodium cyanoborohydride (2 mg,0.04 mmol) was added and the resulting mixture was stirred at 25℃for 1 hour. The mixture was then diluted with water (2 mL) and extracted with EtOAc (3×2 mL). The combined organics were further washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford N- [ [6- [ 3-chloro-2- [ (1S) -1- [ [5- [ [ [ (2S) -2-hydroxypropyl ] as a yellow oil]Amino group]Methyl group]-6-methoxy-3- (trifluoromethyl) -2-pyridinyl]Oxygen gas]Indan-4-yl]-4-pyridinyl]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (16 mg, crude). MS: m/z found 841,843[ M+H ]] ⁺ . The material was used in the next step without further purification.

(j) (S) -5- ((((3 ' -chloro-2 ' - ((S) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one

N- [ [6- [ 3-chloro-2- [ (1S) -1- [ [5- [ [ [ (2S) -2-hydroxypropyl ] p]Amino group]Methyl group]-6-methoxy-3- (trifluoromethyl) -2-pyridinyl]Oxygen gas]Indan-4-yl]-4-pyridinyl]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (16 mg,0.02mmol, crude) was dissolved in 1mL MeOH and a solution of 1, 4-dioxane (19 μl,0.08 mmol) in 4M HCl was added. The mixture was stirred at room temperatureMix for 1 hour and remove the solvent under reduced pressure. Purification of the residue by reverse phase HPLC to afford (5S) -5- [ [ [6- [ 3-chloro-2- [ (1S) -1- [ [5- [ [ (2S) -2-hydroxypropyl ] as a white solid (formate)]Amino group]Methyl group]-6-methoxy-3- (trifluoromethyl) -2-pyridinyl]Oxygen gas]Indan-4-yl]-4-pyridinyl]-2-methoxy-3-pyridinyl]Methylamino group]Methyl group]Pyrrolidin-2-one (8 mg,56% yield) LCMS: m/z found 741,744[ M+H ]] ⁺ Retention time = 2.28min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.61(d,1H),8.05(s,1H),7.85(d,1H),7.71(d,1H),7.56(s,1H),7.48–7.37(m,3H),6.71(s,1H),4.21(d,2H),4.17(t,3H),4.05(t,4H),3.97(s,2H),3.90(s,1H),3.14–2.97(m,2H),2.92–2.70(m,5H),2.35(d,4H),1.84(s,1H),1.24(d,3H).

Example 138:1- (((6- (((S) -4- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) -amino) -methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid (129)

In a similar manner to that described for compound 128, intermediate ((3 ' -chloro-2 ' - ((S) -1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine) was utilized ]-5-yl) methyl (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester preparation 1- (((6- (((S) -4- (3 '-chloro-6-methoxy-5- (((S) -5-oxopyrrolidin-2-yl) methyl) -amino) -methyl) - [2,4' -bipyridine)]-2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino-cyclopropane-1-carboxylic acid. 1-aminocyclopropane-1-carboxylic acid was used instead of (S) -1-aminopropane-2-ol. LCMS: m/z found 767,769[ M+H ]] ⁺ Retention time = 2.30min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.61(d,1H),8.42(s,1H),8.04(s,1H),7.84(d,1H),7.74–7.66(m,1H),7.56(s,1H),7.46–7.35(m,3H),6.70(d,1H),4.32(s,2H),4.15(d,3H),4.05(s,3H),3.91(d,3H),3.00(s,1H),2.89–2.66(m,4H),2.38–2.14(m,4H),1.84(s,1H),1.39(s,2H),1.18(s,2H).

Example 139: (S) -5- ((((3 ' -chloro-2 ' - ((S) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one (165)

In a similar manner to that described for compound 128, intermediate ((3 ' -chloro-2 ' - ((S) -1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine) was utilized]-5-yl) methyl (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester preparation (S) -5- (((3 ' -chloro-2 ' - ((S) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine) ]-5-yl) methyl) amino) methyl) pyrrolidin-2-one. (R) -1-aminopropane-2-ol was used instead of (S) -1-aminopropane-2-ol. LCMS: m/z found 741,743[ M+H ]] ⁺ Retention time = 2.27min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.61(d,1H),8.04(s,1H),7.84(d,1H),7.71(d,1H),7.56(s,1H),7.42(d,3H),6.71(s,1H),4.18(d,5H),4.04(s,4H),3.90(s,3H),3.03(d,2H),2.80(d,5H),2.28(d,4H),1.84(s,1H),1.24(s,3H).

Example 140: (S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one (166)

In a similar manner to that described for compound 128, intermediate ((3 '-chloro-2' - ((S) -1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy was utilized- [2,4' -bipyridine]-5-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester preparation of (S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridine]-5-yl) methyl) amino) methyl) pyrrolidin-2-one. (S) -1-aminopropane-2-ol was replaced with (S) -5- (aminomethyl) pyrrolidin-2-one. MS: m/z found 780,782[ M+H ] ] ⁺ LC retention time = 2.25min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.61(dd,1H),8.37(s,1H),7.97(s,1H),7.86(d,1H),7.71(d,1H),7.55(s,1H),7.44(d,1H),7.40(d,2H),6.69(s,1H),4.13(d,3H),4.06(d,3H),3.98(d,4H),3.91(s,2H),3.00(s,1H),2.94–2.68(m,6H),2.35(q,6H),2.22(s,1H),1.85(t,2H).

Example 141: methyl 1- (((6- (((S) -4- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylate (149)

(a) (S) -6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxynicotinonitrile

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(1S) -4-bromoindan-1-amine; hydrochloride (0.60 g,2.41 mmol), 6-chloro-2-methoxy-pyridine-3-carbonitrile (0.41 g,2.41 mmol), and N, N-diisopropylethylamine (624 mg,4.83 mmol) were suspended in 10mL of NMP and the mixture was stirred at 100℃for 16 h. The mixture was cooled to room temperature, diluted with 30mL EtOAc and washed with water (2×30 mL), brine (2×20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. By flash chromatography (SiO ₂ The residue was purified with 0-30% EtOAc/hexanes to provide 6- [ [ (1S) -4-bromoindan-1-yl]Amino group]-2-methoxy-pyridine-3-carbonitrile (224 mg)27% yield). MS: m/z found 344,346[ M+H ]] ⁺ .

(b) (S) -6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -5-iodo-2-methoxynicotinic carbonitrile

6- [ [ (1S) -4-bromoindan-1-yl ]Amino group]2-methoxy-pyridine-3-carbonitrile (0.22 g,0.65 mmol), 1-iodopyrrolidine-2, 5-dione (0.16 g,0.72 mmol), and potassium acetate (0.64 g,6.51 mmol) were suspended in 4ml of acetic acid and the mixture was stirred at room temperature for 30 min. The mixture was then diluted with 50mL of water and the precipitate was collected by filtration. The filter cake was further washed with water (2×50 mL) and then dried to afford 6- [ [ (1S) -4-bromoindan-1-yl]Amino group]-5-iodo-2-methoxy-pyridine-3-carbonitrile (0.29 g,95% yield). MS: m/z found 470,472[ M+H ]] ⁺ .

(c) (S) -6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) -nicotinic carbonitrile

6- [ [ (1S) -4-bromoindan-1-yl ] in a microwave vial]Amino group]5-iodo-2-methoxy-pyridine-3-carbonitrile (0.29 g,0.61 mmol) and cuprous iodide (0.18 g,0.92 mmol) were suspended in 8mL of DMF. 2, 2-difluoro-2-fluorosulfonyl-acetic acid methyl ester (0.24 g,1.23 mmol) was added and the mixture was purged with nitrogen for 5 minutes. The mixture was then subjected to microwave irradiation to maintain a reaction temperature of 107 ℃ for 3 hours. The mixture was cooled to room temperature, diluted with 10mL of EtOAc, and the insoluble copper salt was removed by filtration. The filtrate was washed with water (3×20 mL) and the organic solution was concentrated under reduced pressure. By flash chromatography (SiO ₂ The residue was purified with 0-10% EtOAc/hexanes to provide 6- [ [ (1S) -4-bromoindan-1-yl]Amino group]-2-methoxy-5- (trifluoromethyl) pyridine-3-carbonitrile (235 mg,93% yield). MS: m/z found 412,414[ M+H ]] ⁺ .

(d) (S) -6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) -nicotinaldehyde

6- [ [ (1S) -4-bromoindan-1-yl ] under nitrogen atmosphere]-amino group]-2-methoxy-5- (trifluoromethyl) -pyridine-3-carbonitrile (0.24 g,0.57 mmol) was dissolved in 5mL of toluene and the solution was cooled to-78 ℃. A solution of DIBAL-H (1.14 ml,1.14mmol in methylene chloride, 1M) was added dropwise over 15 minutes, and the reaction was allowed to warm to room temperature and stirred for an additional 30 minutes. The mixture was then cooled to 0deg.C and a mixture of 1M aqueous HCl and MeOH (1:1 (v/v), 10 mL) was added to quench the reaction. The resulting solution was warmed to room temperature and stirred vigorously for 1 hour, then diluted with EtOAc (10 mL) and basified with aqueous 2M NaOH solution. The mixture was then extracted with EtOAc (3×10 mL) and the combined organics were further washed with brine (10 mL), dried over sodium sulfate, then filtered and concentrated under reduced pressure. By flash chromatography (SiO ₂ The residue was purified with 0-10% EtOAc/hexanes to provide 6- [ [ (1S) -4-bromoindan-1-yl ]Amino group]-2-methoxy-5- (trifluoromethyl) pyridine-3-carbaldehyde (97 mg,41% yield). MS: m/z found 415,417[ M+H ]] ⁺ .

(e) (S) -2-methoxy-6- ((4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2, 3-dihydro-1H-inden-1-yl) amino) -5- (trifluoromethyl) nicotinaldehyde

6- [ [ (1S) -4-bromoindan-1-yl ] in sealed tube]Amino group]-2-methoxy-5- (trifluoromethyl) pyridine-3-carbaldehyde (30 mg,0.07 mmol), 4, 5-tetramethyl-2- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,3, 2-dioxaborane (37 mg,0.14 mmol), 1' -bis (biphenylphosphino) -ferrocene-palladium (II) dichloride dichloromethane complex (6 mg,0.01 mmol), and potassium carbonate (28 mg,0.20 mmol) are suspended in 2mL of 1, 4-dioxane. Nitrogen was bubbled through the reaction solution for 2 minutes, then the vessel was sealed and heated in microwaves at 115 ℃ for 2 hours. The reaction was cooled to room temperature andby passing throughThe mixture was filtered. The filtrate was concentrated under reduced pressure and purified by flash chromatography (SiO ₂ The residue was purified with 0-10% EtOAc/hexanes to provide 2-methoxy-6- [ [ (1S) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) indan-1-yl]Amino group]-5- (trifluoromethyl) pyridine-3-carbaldehyde (21 mg,63% yield). MS: m/z found 463[ M+H ] ] ⁺ .

(f) (3 ' -chloro-2 ' - ((S) -1- ((5-formyl-6-methoxy-3- (trifluoromethyl) -pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) - ((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

Pd (PPh) ₃ ) ₄ (15 mg,0.01 mmol), potassium carbonate (26 mg,0.19 mmol), 2-methoxy-6- [ [ (1S) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) indan-1-yl]Amino group]-5- (trifluoromethyl) pyridine-3-carbaldehyde (29 mg,0.06 mmol), and N- [ [6- (2, 3-dichloro-4-pyridinyl) -2-methoxy-3-pyridinyl)]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (45 mg,0.09 mmol) was suspended in 1, 4-dioxane/water (4:1 (v/v), 2 mL), and the solution was then heated at 105 ℃ for 20 min. The mixture was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×5 mL). The combined organics were concentrated under reduced pressure and purified by flash chromatography (SiO ₂ The residue was purified with 0-4% MeOH/methylene chloride to provide N- [ [6- [ 3-chloro-2- [ (1S) -1- [ [ 5-formyl-6-methoxy-3- (trifluoromethyl) -2-pyridinyl ]]Amino group]Indan-4-yl]-4-pyridinyl]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (25 mg,51% yield). MS: m/z found 781,783[ M+H ] ] ⁺ .

(g) 1- (((6- (((S) -4- (5- (((tert-Butoxycarbonyl) (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid methyl ester

N- [ [6- [ 3-chloro-2- [ (1S) -1- [ [ 5-formyl-6-methoxy-3- (trifluoromethyl) -2-pyridinyl ]]Amino group]Indan-4-yl]-4-pyridinyl]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Tert-butyl carbamate (25 mg,0.03 mmol), acetic acid (2 mg,0.03 mmol), and methyl 1-aminocyclopropane carboxylate (15 mg,0.10 mmol) were dissolved in MeOH/THF (1:1 (v/v), 1 mL) and the solution was stirred at 25℃for 16 hours. Sodium cyanoborohydride (4 mg,0.06 mmol) was added and the resulting mixture was stirred at 25℃for 3 hours. The mixture was then diluted with water (2 mL) and extracted with EtOAc (3×2 mL). The combined organics were further washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 1- [ [6- [ [ (1S) -4- [4- [5- [ [ tert-butoxycarbonyl- [ [ (2S) -5-oxopyrrolidin-2-yl ] as a yellow oil]Methyl group]Amino group]Methyl group]-6-methoxy-2-pyridinyl]-3-chloro-2-pyridinyl ]Indan-1-yl]Amino group]-2-methoxy-5- (trifluoromethyl) -3-pyridinyl]Methylamino group]Methyl cyclopropanecarboxylate (32 mg, crude). MS: m/z found 880,882[ M+H ]] ⁺ . The material was used in the next step without further purification.

(h) 1- (((6- (((S) -4- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) -methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid methyl ester

1- [ [6- [ [ (1S) -4- [4- [5- [ [ tert-butoxycarbonyl- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Amino group]Methyl group]-6-methoxy-2-pyridinyl]-3-chloro-2-pyridinyl]Indan-1-yl]Amino group]-2-methoxy-5- (trifluoromethyl) -3-pyridinyl]Methylamino group]Methyl cyclopropanecarboxylate (32 mg, 0)02mmol, crude) was dissolved in 1mL MeOH and a solution of 1, 4-dioxane (19 μl,0.08 mmol) in 4M HCl was added. The mixture was stirred at room temperature for 1h and the solvent was removed under reduced pressure. Purification of the residue by reverse phase HPLC to afford 1- [ [6- [ [ (1S) -4- [ 3-chloro-4- [ 6-methoxy-5- [ [ [ (2S) -5-oxopyrrolidin-2-yl]Methylamino group]Methyl group]-2-pyridyl group]-2-pyridyl group]Indan-1-yl]Amino group]-2-methoxy-5- (trifluoromethyl) -3-pyridinyl ]Methylamino group]Methyl cyclopropanecarboxylate (5 mg,35% yield) (formate) MS: m/z found 780,782[ M+H] ⁺ LC retention time = 2.40min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.60(d,1H),8.54(s,1H),7.81(d,1H),7.69(d,1H),7.60(s,1H),7.40(d,1H),7.38–7.27(m,3H),5.86(q,1H),5.78(d,1H),4.03(s,3H),3.90(s,3H),3.84(t,3H),3.73(s,2H),3.64(s,3H),2.83(dd,2H),2.67(m,3H),2.37–2.22(m,3H),2.11–1.98(m,1H),1.87–1.75(m,1H),1.24(q,2H),1.03(q,2H).

Example 142:1- (((6- (((S) -4- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid (164)

1- [ [6- [ [ (1S) -4- [ 3-chloro-4- [ 6-methoxy-5- [ [ (2S) -5-oxopyrrolidin-2-yl [ (2S) -amino ] carbonyl]Methylamino group]Methyl group]-2-pyridyl group]-2-pyridyl group]Indan-1-yl]Amino group]-2-methoxy-5- (trifluoromethyl) -3-pyridinyl]Methylamino group]Methyl cyclopropanecarboxylate (3 mg, 0.04 mmol) was dissolved in THF/MeOH/water (3:1:1, 0.5 mL) and lithium hydroxide monohydrate (1 mg,0.02 mmol) was added. The reaction was stirred at room temperature for 16 hours and the solvent was removed under reduced pressure. Purification of the crude material by reverse phase HPLC to afford 1- [ [6- [ [ (1S) -4- [ 3-chloro-4- [ 6-methoxy-5- [ [ (2S) -5-oxopyrrolidin-2-yl ] as a white solid (formate)]Methylamino group]Methyl group]-2-pyridyl group]-2-pyridyl group]Indan-1-yl]Amino group]-2-methoxy-5- (trifluoromethyl) -3-pyridinyl]Methylamino group]Cyclopropanecarboxylic acid (1.6 mg,54% yield) MS: m/z found 766,768[ M+H ] ] ⁺ Retention time = 2.30min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.60(d,1H),8.54(d,1H),7.81(d,2H),7.73–7.65(m,1H),7.40(d,1H),7.32(s,3H),6.13(d,1H),5.88(d,1H),4.16(s,2H),4.03(t,3H),3.92(s,3H),3.84(s,3H),2.83(d,2H),2.76–2.57(m,3H),2.39–2.21(m,3H),2.16–2.00(m,1H),1.81(d,1H),1.33(s,2H),1.11(s,2H).

Example 143:7- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((2-oxo-1, 7-diazaspiro [3.5] nonan-7-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1, 7-diazaspiro [3.5] nonan-2-one (353)

In a similar manner to that described with respect to example 11, 1, 7-diazaspiro [3.5] was used in step (b)]Preparation of 7- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((2-oxo-1, 7-diazaspiro [3.5 ]) by substituting (5S) -5- (aminomethyl) pyrrolidin-2-one with nonan-2-one]Nonan-7-yl-methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl-methyl) -1, 7-diazaspiro [3.5]Nonan-2-one. The product was obtained as a white solid (formate). LC/MS: m/z found 741,743[ M+H ]] ⁺ Retention time = 2.08min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.64(d,1H),8.43(s,1H),7.79(d,1H),7.72(d,1H),7.55(t,1H),7.50(d,1H),7.45(d,1H),7.41(d,1H),7.33(d,2H),7.28(d,1H),4.02(s,2H),4.00(t,3H),3.94(d,3H),3.71(s,2H),3.01(s,4H),2.75(d,4H),2.69(s,2H),2.62(s,2H),1.98(s,4H),1.89(s,4H).

Example 144: (R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (354)

In a similar manner to that described in connection with example 11, (5R) -5- (aminomethyl) pyrrolidine-2-carboxylic acid was used in step (b) Ketones instead of (5S) -5- (aminomethyl) pyrrolidin-2-one, (R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one is prepared. The product was obtained as a white solid (formate). LC/MS: m/z found 689,691[ M+H ]] ⁺ Retention time = 2.01min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.67–8.62(m,1H),8.43(s,1H),7.79(d,1H),7.73–7.68(m,1H),7.55(t,1H),7.47(dd,2H),7.43–7.40(m,1H),7.36(s,1H),7.32(d,1H),7.28(d,1H),4.18(d,2H),4.03(d,3H),3.97(t,6H),3.91(d,1H),3.02(d,2H),2.92–2.78(m,2H),2.43–2.27(m,6H),1.85(s,2H).

Example 145: (S) -4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-3-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (405)

In a similar manner as described with respect to example 11, (S) -4- (((2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-3-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one was prepared in step (b) using (S) -4- (aminomethyl) pyrrolidin-2-one instead of (5S) -5- (aminomethyl) pyrrolidin-2-one. The product was obtained as a white solid (formate). LC/MS: m/z found 689,691[ M+H ]] ⁺ Retention time = 1.98min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.65(dd,1H),8.47(s,2H),7.82(d,1H),7.71(d,1H),7.56(t,1H),7.51(d,1H),7.48–7.44(m,1H),7.42(d,1H),7.38(s,1H),7.32(dd,2H),4.24(d,2H),4.05(d,5H),3.98(d,3H),3.64–3.53(m,2H),3.20–3.10(m,4H),2.97(d,2H),2.87(m,2H),2.52(m,2H),2.26–2.13(m,2H).

Example 146: (S) -1- ((6- (2-chloro-3- (3-chloro-2- (4- (((S) -3-hydroxypyrrolidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) pyrrolidin-3-ol (435)

(S) -1- ((6- (2-chloro-3- (3-chloro-2- (4- (((S) -3-hydroxypyrrolidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) pyrrolidin-3-ol was prepared in step (b) using (3S) -3-methylpyrrolidine instead of (5S) -5- (aminomethyl) pyrrolidin-2-one in a similar manner to that described for example 11. The product was obtained as a white solid (formate). LC/MS: m/z found 635,637[ M+H ]] ⁺ Retention time = 2.07min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.68–8.61(m,1H),8.52(s,1H),7.84(d,1H),7.72(d,1H),7.59–7.51(m,2H),7.47(m,1H),7.45–7.41(m,1H),7.39(s,1H),7.35(d,1H),7.30(dd,1H),4.53(s,1H),4.45(s,1H),4.36(s,2H),4.08–4.01(m,5H),4.00–3.96(m,3H),3.50–3.41(m,1H),3.34(d,2H),3.15(t,3H),2.98(s,1H),2.88(d,1H),2.33–2.15(m,2H),2.02(s,1H),1.88(d,1H).

Example 147: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) pyrrolidin-2-one (472)

In a similar manner as described with respect to example 11 step (b), (S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-methyl) -amino) -methyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) pyrrolidin-2-one was prepared by first reacting 6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one with (5S) -5- (aminomethyl) pyrrolidin-2-one and then reacting with formaldehyde (1 pot). The product was obtained as a white solid (formate). LC/MS: m/z found 717,719[ M+H ] ] ⁺ Retention time = 2.04min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.62(d,1H),7.79(d,1H),7.71(dd,1H),7.54(t,1H),7.49–7.37(m,3H),7.31–7.23(m,3H),4.02–3.93(m,5H),3.92(d,3H),3.80(d,1H),3.73–3.61(m,2H),3.54(d,1H),2.68–2.45(m,4H),2.39–2.21(m,12H),1.78(d,2H).

Example 148: (R) -4- ((((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (((R) -5-oxopyrrolidin-3-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) pyrrolidin-2-one (473)

In a similar manner as described with respect to example 11 step (b), (R) -4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-methyl) -amino) -methyl) -pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one was prepared by first reacting 6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (((R) -5-oxopyrrolidin-3-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one with (4S) -4- (aminomethyl) pyrrolidin-2-one and then reacting with formaldehyde (1 pot). The product was obtained as a white solid (formate). LC/MS: m/z found 717,719[ M+H ]] ⁺ Retention time = 2.00min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.64(dd,1H),8.39(s,1H),7.78(d,1H),7.72(d,1H),7.58–7.49(m,2H),7.48–7.44(m,1H),7.43–7.38(m,1H),7.37–7.31(m,2H),7.26(d,1H),4.08(s,2H),4.00(t,3H),3.96(d,3H),3.70(s,2H),3.55(dd,2H),3.15(d,2H),3.00(s,3H),2.92–2.80(m,1H),2.66–2.44(m,7H),2.35(s,3H),2.24–2.10(m,2H).

Example 149:1- (3- ((((6- (3- (2- (4- (((1-acetylazetidin-3-yl) methyl) (methyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) azetidin-1-one (499)

(a) 3- (((6- (3- (2- (4- ((((1- (tert-butoxycarbonyl) azetidin-3-yl) -methyl) (methyl) amino) -methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) azetidine-1-carboxylic acid tert-butyl ester

6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (40 mg,0.08 mmol), acetic acid (10 mg,0.16 mmol), and tert-butyl 3- (aminomethyl) azetidine-1-carboxylate (39 mg,0.21 mmol) were dissolved in MeOH/THF (1:1, 2 mL) and the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (8 mg,0.13 mmol) was added and the resulting mixture was stirred at 25℃for 1 hour. Formaldehyde (37% in water) (0.03 ml,0.32 mmol) was then added and the resulting mixture was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure and the residue was suspended in 5mL of water and then extracted with dichloromethane (3×3 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide tert-butyl 3- (((6- (3- (2- (4- ((((1- (tert-butoxycarbonyl) azetidin-3-yl) methyl) (methyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) azetidine-1-carboxylate (70 mg, crude) as a white foam. MS: m/z found 861,863[ M+H ] ] ⁺ . The material was used in the next step without further purification.

(b) 1- (azetidin-3-yl) -N- ((6- (3- (2- (4- (((azetidin-3-ylmethyl) (methyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -N-methyl methylamine

3- ((((6- (3- (2- (4- (((1))Butoxycarbonyl) azetidin-3-yl) -methyl) (methyl) -amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl methyl) (methyl) amino) methyl) azetidine-1-carboxylic acid tert-butyl ester (70 mg,0.08mmol, crude) was dissolved in 1mL MeOH and added to a 4M HCl solution (81 μl,0.32 mmol) in 1, 4-dioxane. The reaction was stirred at room temperature for 60 min and the solvent was removed under reduced pressure to provide N- (azetidin-3-ylmethyl) -1- [4- [4- [3- [5- [ [ azetidin-3-ylmethyl (methyl) amino ] as a yellow oil]Methyl group]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]-2-methoxy-phenyl]-N-methyl-methylamine (53 mg, crude). MS: m/z found 661,663[ M+H ]] ⁺ . The material was used in the next step without further purification.

(c) 1- (3- ((((6- (3- (2- (4- (((1-acetylazetidin-3-yl) methyl) (methyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) azetidin-1-one

N- (azetidin-3-ylmethyl) -1- [4- [4- [3- [5- [ [ azetidin-3-ylmethyl (methyl) amino ] radical)]Methyl group]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]-2-methoxy-phenyl]N-methyl-methylamine (53 mg,0.08mmol, crude) and triethylamine (40.mg, 0.40 mmol) were suspended in 2mL of dichloromethane, and the solution was cooled to 0deg.C. Acetic anhydride (41 mg,0.40 mmol) was added dropwise over 2 minutes, and the resulting mixture was then warmed to room temperature and stirred for 18 hours. The reaction was diluted with water (7 mL) and the solution extracted with EtOAc (3X 5 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by reverse phase HPLC to afford 1- (3- ((((6- (3- (2- (4- (((1-acetylazetidin-3-yl) methyl) (methyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) azetidin-1-one (17 mg,28% yield) as a white powder (formate). LC/MS: m/z actual measurementValues 745,747[ M+H ]] ⁺ Retention time = 2.09min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.65(d,1H),8.36(s,1H),7.80(d,1H),7.72(d,1H),7.54(dd,2H),7.46(d,1H),7.44–7.32(m,3H),7.28(d,1H),4.34(m,2H),4.20–4.05(m,4H),4.01(d,3H),3.97(d,4H),3.89(dd,1H),3.76(s,2H),3.75–3.69(m,1H),3.69–3.63(m,1H),3.27(d,2H),3.20–3.08(m,1H),3.06–2.95(m,1H),2.90(d,2H),2.65(s,3H),2.40(s,3H),1.84(d,6H).

Example 150:2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6-methyl-7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -6-methyl-2, 6-diazaspiro [3.4] octane-7-one (571)

2- [ [4- [ 3-chloro-4- [ 2-chloro-3- [ 6-methoxy-5- [ (6-oxo-2, 7-diazaspiro [3.4 ]]Octan-2-yl) methyl]-2-pyridyl group]Phenyl group]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]-2, 7-diazaspiro [3.4 ]]Octan-6-one (example 2) (25 mg,0.04 mmol) was dissolved in 1mL DMF and the solution was cooled to 0 ℃. Sodium hydride (60% dispersion in mineral oil) (15 mg,0.14 mmol) was added and the solution stirred for 30 min. Methyl iodide (11 mg,0.08 mmol) was then added and the reaction stirred at room temperature for 3 hours. The reaction was diluted with 3mL of water and extracted with EtOAc (3X 2 mL). The combined organics were concentrated under reduced pressure and the crude sample was purified by reverse phase HPLC to afford 2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6-methyl-7-oxo-2, 6-diazaspiro [ 3.4)) as a white powder (formate salt)]Octan-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -6-methyl-2, 6-diazaspiro [3.4]Octan-7-one (6 mg,23% yield). LC/MS: m/z found 741,743[ M+H ]] ⁺ Retention time = 2.13min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.65(d,1H),8.40(s,2H),7.76(d,1H),7.70(d,1H),7.55(t,1H),7.48(dd,2H),7.41(d,1H),7.36(s,1H),7.33(d,1H),7.28(d,1H),4.30(s,2H),4.09–4.03(m,3H),4.03–4.00(m,4H),3.97(d,5H),3.73(dd,6H),3.67(s,2H),2.82(s,6H),2.76(s,2H),2.70(s,2H).

Example 151: n- (3- (((6- (3- (2- (4- (((3-acetamidopropyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) propyl) acetamide (358)

N- (3- (((6- (3- (2- (4- (((3-acetamidopropyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) propyl) acetamide was prepared in step (b) using N- (3-aminopropyl) acetamide instead of (S) -5- (aminomethyl) pyrrolidin-2-one in a similar manner to example 11. MS: m/z found 693[ M+H ]] ⁺ Retention time = 1.67min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.62(d,1H),8.49(s,2H),7.81(d,1H),7.68(dd,1H),7.58–7.25(m,7H),4.20(s,2H),4.05(d,5H),3.95(s,3H),3.25–3.20(m,3H),2.96(m,4H),1.92(d,8H),1.88–1.77(m,3H).

Example 152:4- (((6- (2-chloro-3- (3-chloro-2- (4- (((2, 6-dioxopiperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidine-2, 6-dione (359)

In a similar manner to example 11, 4- (((6- (2-chloro-3- (3-chloro-2- (4- (((2, 6-dioxopiperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidine-2, 6-dione was prepared in step (b) using 4-aminopiperidine-2, 6-dione instead of (S) -5- (aminomethyl) pyrrolidin-2-one. MS: m/z found 717[ M+H ]] ⁺ Retention time = 1.60min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.58(d,1H),8.45(s,1H),7.75–7.63(m,2H),7.50(t,1H),7.43–7.35(m,3H),7.22(d,3H),3.97(s,3H),3.87(d,5H),3.80(s,2H),2.79(dd,5H),2.58(dd,5H).

Example 153:5- (((6- (3- (2- (4- (((5-amino-5-oxopentyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) pentanoylalkane (373)

In a manner analogous to example 11, (S) -5- (aminomethyl) pyrrolidin-2-one was replaced with 5-aminopentanoyl alkane in step (b) to prepare 5- (((6- (3- (2- (4- (((5-amino-5-oxopentyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) pentanoyl alkane. MS: m/z found 693[ M+H ]] ⁺ Retention time = 1.64min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.62(d,1H),8.50(s,2H),7.77(d,1H),7.68(dd,1H),7.57–7.23(m,7H),4.17(s,3H),4.01(d,5H),3.94(s,3H),2.97(t,2H),2.86(s,3H),2.29–2.19(m,4H),1.66(q,4H),1.25(s,2H).

Example 154:1- ((R) -3- (((6- (3- (2- (4- ((((R) -1-acetylpyrrolidin-3-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-1-yl) ethane-1-one (374)

In a manner analogous to example 11, (R) -1- (3-aminopyrrolidin-1-yl) ethan-1-one was used in place of (S) -5- (aminomethyl) pyrrolidin-2-one in step (b) to prepare 1- ((R) -3- (((6- (3- (2- (4- ((((R) -1-acetylpyrrolidin-3-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-1-one. MS: m/z found 717[ M+H ]] ⁺ Retention time = 1.64min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.60(d,1H),8.49(s,2H),7.73(dd,1H),7.67(dd,1H),7.51(t,1H),7.45–7.34(m,3H),7.30–7.19(m,3H),4.02–3.88(m,8H),3.83(s,2H),3.77–3.56(m,4H),3.59–3.48(m,4H),3.45–3.32(m,2H),2.30–2.08(m,2H),2.05–1.90(m,7H),1.91–1.79(m,1H).

Example 155:4- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (morpholinomethyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) morpholine (411)

In a similar manner to example 11, 4- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (morpholinomethyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) morpholine was prepared in step (b) using morpholine instead of (S) -5- (aminomethyl) pyrrolidin-2-one. MS: m/z found 635[ M+H ]] ⁺ Retention time = 2.07min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.60(d,1H),8.35(s,1H),7.77(d,1H),7.67(dd,1H),7.55–7.44(m,2H),7.43–7.20(m,5H),4.03(s,2H),3.96(s,3H),3.90(s,3H),3.77(t,4H),3.74–3.67(m,6H),2.94(t,4H),2.67(t,4H).

Example 156:1- ((6- (2-chloro-3- (3-chloro-2- (4- ((4-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-ol (412)

In a similar manner to example 11, 1- ((6- (2-chloro-3- (3-chloro-2- (4- ((4-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-ol was prepared in step (b) using piperidin-4-ol instead of (S) -5- (aminomethyl) pyrrolidin-2-one. MS: m/z found 663[ M+H ]] ⁺ Retention time = 2.05min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.63(d,1H),8.46(s,2H),7.86(d,1H),7.70(dd,1H),7.54(t,2H),7.47–7.28(m,5H),4.30(s,2H),4.11(s,2H),4.02(s,3H),3.97–3.89(m,4H),3.84(s,1H),3.38(s,2H),3.27(m,2H),3.15(s,2H),2.95(s,2H),2.03–1.92(m,4H),1.79–1.74(m,4H).

Example 157: 3-chloro-4- (2-chloro-3- (6-methoxy-5- ((4-methoxypiperidin-1-yl) methyl) pyridin-2-yl) phenyl) -2- (3-methoxy-4- ((4-methoxypiperidin-1-yl) methyl) phenyl) pyridine (447)

3-chloro-4- (2-chloro-3- (6-methoxy-5- ((4-methoxypiperidin-1-yl) methyl) pyridin-2-yl) phenyl) -2- (3-methoxy-4- ((4-methoxypiperidin-1-yl) methyl) phenyl) pyridine was prepared in step (b) using 4-methoxypiperidine instead of (S) -5- (aminomethyl) pyrrolidin-2-one in a similar manner to example 11. MS: m/z found 691[ M+H ] ] ⁺ Retention time = 1.83min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.61(d,8.52(s,1H),7.78–7.66(m,2H),7.52(t,1H),7.48–7.35(m,3H),7.32–7.21(m,3H),3.97(s,3H),3.87(d,3.62(s,2H),3.34–3.29(m,6H),2.96(d,2H),2.84(d,2H),2.58(s,2H),2.38(t,2H),1.93(s,4H),1.73–1.57(m,5H).

Example 158: (1 s,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine (448)

(1S, 4S) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1S, 4S) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexan-1-amine was prepared in step (b) by substituting (1S, 4S) -4-methoxycyclohexan-1-amine for (S) -5- (aminomethyl) pyrrolidin-2-one in a manner similar to example 11. MS: m/z found 719[ M+H ]] ⁺ Retention time = 2.00min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.65(dd,1H),8.49(d,1H),7.82(d,1H),7.68(d,1H),7.53(t,1H),7.51–7.41(m,2H),7.43–7.38(m,1H),7.34–7.25(m,3H),4.22(s,3H),4.13(s,2H),4.03(d,3.94(d,4H),3.45(q,3H),3.33–3.23(m,4H),3.18–3.00(m,1H),2.05(d,5H),1.89(m,5H),1.70(m,5H),1.56–1.43(m,5H),0.69(s,1H).

Example 159: (1 r,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine (450)

(1 r,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexan-1-amine was prepared in step (b) by substituting (1 r,4 r) -4-methoxycyclohexan-1-amine for (S) -5- (aminomethyl) pyrrolidin-2-one in a similar manner to example 11. MS: m/z found 719[ M+H ] ] ⁺ Retention time = 1.87min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.60(d,1H),7.75–7.64(m,2H),7.52(t,1H),7.45–7.34(m,3H),7.31–7.19(m,3H),3.98(d,5H),3.92(s,3H),3.84(s,2H),3.33–3.28(m,9H),3.22–3.12(m,1H),2.68(s,1H),2.53(s,1H),2.11–2.00(m,9H),1.36–1.11(m,6H).

Example 160:4- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((3-oxopiperazin-1-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperazin-2-one (457)

In a manner analogous to example 11, in step (b) piperazine-2-one was used instead of (S) -5- (aminomethyl) pyrrolidin-2-one to prepare 4- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((3-oxopiperazin-1-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperazin-2-one. MS: m/z found 661[ M+H ]] ⁺ Retention time = 1.51min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.59(d,1H),8.15(s,1H),7.77(d,1H),7.69(d,1H),7.51(t,1H),7.48–7.34(m,3H),7.29–7.21(m,3H),3.97(s,2H),3.88(d,3H),3.75(s,2H),3.67(s,2H),3.34–3.29(m,4H),3.35–3.25(m,2H),3.16(d,3H),2.80–2.69(m,4H).

Example 161:2- (2- ((6- (2-chloro-3- (3-chloro-2- (4- ((6- (2-hydroxyethyl) -2, 6-diazaspiro [3.4] oct-2-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] oct-6-yl) ethan-1-ol (670)

(a) 2- ((6- (3- (2- (4- ((6- (tert-butoxycarbonyl) -2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octane-6-carboxylic acid tert-butyl ester

In a similar manner to example 11, 2, 6-diazaspiro [3.4] was used in step (b) ]Preparation of 2- ((6- (3- (2- (4- ((6- (tert-butoxycarbonyl) -2, 6-diazaspiro [ 3.4)) by substituting tert-butyl octane-6-carboxylate for (S) -5- (aminomethyl) pyrrolidin-2-one]Octane-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl-2-chlorophenyl) -2-methoxypyridin-3-yl methyl) -2, 6-diazaspiro [3.4]Octane-6-carboxylic acid tert-butyl ester. MS: m/z found 885[ M+H ]] ⁺ .

(b) 2- (2- ((6- (2-chloro-3- (3-chloro-2- (4- ((6- (2-hydroxyethyl) -2, 6-diazaspiro [3.4] oct-2-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] oct-6-yl) ethan-1-ol

With 2- ((6- (3- (2- (4- ((6- (tert-butoxycarbonyl) -2, 6-diazaspiro [ 3.4))]Octane-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl-2-chlorophenyl) -2-methoxypyridin-3-yl methyl) -2, 6-diazaspiro [3.4]Tert-butyl octane-6-carboxylate (0.05 g,0.06 mmol) pairThe vial was fed, then dichloromethane (3 ml) was added, then trifluoroacetic acid (1 ml) was added and the reaction stirred at room temperature for 30 minutes, then evaporated under reduced pressure and the residue was dried for 2 hours via a high vacuum pump. To the resulting TFA salt was added potassium carbonate (0.04 g, 0.30 mmol), 2-bromoethanol (0.03 g,0.25 mmol) and acetonitrile (3 mL), and the mixture was stirred at 90℃for 1 hour. By passing through The mixture was filtered and the filter cake was washed with ethyl acetate (3×15 mL). The combined filtrates were concentrated under reduced pressure and the residue was purified by reverse phase HPLC (containing 0.05% formic acid modifier) to afford 2- (2- ((6- (2-chloro-3- (3-chloro-2- (4- ((6- (2-hydroxyethyl) -2, 6-diazaspiro [ 3.4)) as a white solid (formate salt)]Octane-2-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) -2, 6-diazaspiro [3.4]Octane-6-yl) ethan-1-ol (6.8 mg,12% yield). MS: m/z found 773[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.60(d,1H),8.34(s,2H),7.73(d,1H),7.66(dd,1H),7.55–7.45(m,1H),7.48–7.19(m,6H),4.24(s,2H),4.13–3.83(m,11H),3.72–3.82(m,11H),3.47(d,4H),3.31–3.03(m,6H),2.33(t,3H),1.32–1.21(m,1H).

Example 162:1- (2- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octane-6-yl) ethan-1-one (671)

(a) 1- (2- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octane-6-yl) ethan-1-one

In a similar manner to that described with respect to example 161, 1- (2- ((6- (2- (4- ((6-acetyl-2, 6-diazaspiro [ 3.4)) was prepared in step (b) using acetyl chloride instead of 2-bromoethanol ]Octane-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl-2-chlorophenyl) -2-methoxypyridin-3-yl methyl) -2, 6-diazaspiro [3.4]Octan-6-yl) ethan-1-one. MS: m/z found 769[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.62(d,8.34(s,2H),7.84–7.76(m,1H),7.67(dd,1H),7.57–7.46(m,2H),7.43–7.25(m,5H),4.41(d,2H),4.25–4.09(m,4H),4.04–3.84(m,9H),3.72(dd,2H),3.63(d,3H),3.53(t 3H),3.41(t,2H),2.33–2.11(m,5H),2.01(d,6H).

Example 163:1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1-propionylpiperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) propan-1-one (344)

(a) 1- (4-aminopiperidin-1-yl) propan-1-one

A solution of tert-butyl N- (4-piperidinyl) carbamate (0.80 g,3.99 mmol) in 32mL DCM was cooled in an ice bath. Triethylamine (1.11 ml,7.99 mmol) was added. A solution of propionyl chloride (0.38 mL,4.39 mmol) in 8mL DCM was slowly added. After 15 min, the reaction mixture was diluted with 30mL of DCM and washed with saturated sodium bicarbonate solution (10 mL), 0.3M HCl (10 mL), and saturated sodium bicarbonate solution (10 mL). The organics were dried over sodium sulfate and concentrated under reduced pressure to give crude tert-butyl (1-propionylpiperidin-4-yl) carbamate (1.01 g, 99%) as a white solid. ¹ H NMR (400 MHz, chloroform-d) delta 4.44 (s, 1H), 3.66 (s, 1H), 2.91 (s, 3H), 2.35 (q, 2H), 1.98 (d, 2H), 1.44 (s, 9H), 1.35-1.23 (m, 2H), 1.27-1.10 (m, 3H).

To (1-propionylpiperidin-4-yl) carbamic acid tert-butyl esterA solution of the ester (0.75 g,2.93 mmol) in 10mL DCM was added trifluoroacetic acid (7.84 mL,102.40 mmol). After 3 hours, volatiles were removed in vacuo. To the resulting oil was added saturated sodium bicarbonate (15 mL). The mixture was extracted with 7×15mL of 10% MeOH in DCM. Evaporating the combined organics to provide 1- (4-aminopiperidin-1-yl) propan-1-one; (0.12 g, 26%). MS: m/z found 157.1[ M+H ]] ⁺ .

(b) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1-propionylpiperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one) propan-1-one

Formate was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (25 mg,0.05 mmol) and 1- (4-amino-1-piperidinyl) propan-1-one (32 mg,0.20 mmol) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1-propionylpiperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one (37% yield). LCMS: m/z found 773.2[ M+H ]] ⁺ Retention time = 3.03min, (method a); ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.63(m,1H),7.79–7.67(m,2H),7.55(m,1H),7.47–7.37(m,3H),7.32–7.22(m,4H),4.52(t,2H),3.96(d,7H),3.88(s,2H),3.18–3.04(m,3H),2.97–2.77(m,2H),2.69(q,2H),2.45–2.37(m,5H),2.04(s,6H),1.53–1.23(m,4H),1.11(t,6H).

Example 164: (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (cyclopropanecarbonyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (cyclopropyl) methanone (345)

(a) (4-aminopiperidin-1-yl) (cyclopropyl) methanone

A solution of tert-butyl N- (4-piperidinyl) carbamate (0.20 g,1.00 mmol) in 8mL DCM was cooled in an ice bath. Triethylamine (0.28 ml,2.00 mmol) was added. A solution of cyclopropanecarbonyl chloride (cyclopropanecarbonyl chloride) (0.10 mL,1.05 mmol) in 3mL DCM was slowly added. After 5 min, the reaction mixture was diluted with 30mL of DCM and washed with saturated sodium bicarbonate solution (10 mL), 0.3M HCl (10 mL), and saturated sodium bicarbonate solution (10 mL). The organics were dried over sodium sulfate and concentrated under reduced pressure to provide crude tert-butyl (1- (cyclopropanecarbonyl) piperidin-4-yl) carbamate (0.26 g, 97%). MS: m/z found 269.1[ M+H ]] ⁺ .

To tert-butyl (1- (cyclopropanecarbonyl) piperidin-4-yl) carbamate (0.26 g,0.97 mmol) was added 4M hydrogen chloride in 1, 4-dioxane (2.42 ml,9.69 mmol). After stirring at room temperature for 6 hours, volatiles were removed in vacuo. The crude material was triturated with 2x5mL of anhydrous diethyl ether and dried under vacuum to provide (4-aminopiperidin-1-yl) (cyclopropyl) methanone hydrochloride (0.20 g, 100%). MS m/z found 169.1[ M+H ] ] ⁺ .

(b) (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (cyclopropanecarbonyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (cyclopropyl) methanone

Following reductive amination procedure a, prepared from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (30 mg,0.06 mmol) and (4-aminopiperidin-1-yl) (cyclopropyl) methanone hydrochloride (34 mg,0.24 mmol) as formate salt (77% yield) from (4- (((2-chloro-3- (3-chloro-2- (4- (((1- (cyclopropanecarbonyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (cyclopropyl) methanone. LCMS: m/z found 797.3[ M+H ]] ⁺ Retention time = 3.20min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),7.79(d,1H),7.72(d,1H),7.60–7.38(m,4H),7.38–7.25(m,3H),4.67–4.35(m,4H),4.17(s,2H),4.04(s,3H),3.97(s,5H),3.28–3.18(m,3H),2.98(s,1H),2.74(s,2H),2.25–1.96(m,6H),1.59–1.29(m,4H),0.85(d,8H).

Example 165: (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (cyclobutanecarbonyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (cyclobutyl) methanone (352)

(a) (4-aminopiperidin-1-yl) (cyclobutyl) methanone

A solution of tert-butyl N- (4-piperidinyl) carbamate (0.80 g,3.99 mmol) in 32mL DCM was cooled in an ice bath. Triethylamine (1.11 ml,7.99 mmol) was added. A solution of cyclobutanecarbonyl chloride (0.50 mL,4.39 mmol) in 8mL DCM was slowly added. After 5 min, the reaction mixture was diluted with 30mL of DCM and washed with saturated sodium bicarbonate solution (10 mL), 0.3M HCl (10 mL), and saturated sodium bicarbonate solution (10 mL). The organics were dried over sodium sulfate and concentrated under reduced pressure to provide crude tert-butyl (1- (cyclobutanecarbonyl) piperidin-4-yl) carbamate (1.06 g,94.0% yield). ¹ H NMR (400 MHz, chloroform-d) delta 4.47 (d, 2H), 3.65 (d, 2H), 3.30-3.17 (m, 1H), 3.00 (t, 1H), 2.72 (t, 1H), 2.40-2.28 (m, 2H), 2.32-2.19 (m, 1H), 2.19-2.06 (m, 2H), 2.06-1.93 (m, 1H), 1.97-1.78 (m, 2H), 1.44 (s, 9H), 1.23 (s, 2H).

To tert-butyl (1- (cyclobutanecarbonyl) piperidin-4-yl) carbamate (0.26 g,0.97 mmol) was added 4M hydrogen chloride in 1, 4-dioxane (2.42 ml,9.69 mmol). After stirring at room temperature for 6 hours, volatiles were removed in vacuo. The crude material was triturated with 2x5mL anhydrous diethyl ether and under vacuumLower drying to provide (4-aminopiperidin-1-yl) (cyclobutyl) methanone hydrochloride (0.20 g,94% yield). MS: m/z found 183.1[ M+H ]] ⁺ .

(b) (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (cyclobutanecarbonyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (cyclobutyl) methanone

Formate was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (30 mg,0.06 mmol) and (4-aminopiperidin-1-yl) (cyclobutyl) methanone hydrochloride (34 mg,0.24 mmol) of (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (cyclobutanecarbonyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (cyclobutyl) methanone (37% yield). LCMS: m/z found 824.6[ M+H ] ] ⁺ Retention time = 3.51min, (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.54(s,1H),7.80–7.68(m,2H),7.55(t,1H),7.50–7.38(m,3H),7.36–7.23(m,3H),4.59–4.45(m,2H),4.10(s,2H),4.03(s,3H),3.97–3.75(m,9H),3.49–3.36(m,2H),3.15–2.99(m,4H),2.96–2.76(m,1H),2.74–2.63(m,3H),2.41–1.95(m,9H),1.83(d,3H),1.47–1.24(m,4H).

Example 166: n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (methylsulfonyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (methylsulfonyl) piperidin-4-amine (372)

(a) 1- (methylsulfonyl) piperidin-4-amine

A solution of tert-butyl N- (4-piperidinyl) carbamate (0.80 g,3.99 mmol) in 32mL DCM was cooled in an ice bath. Triethylamine (1.11 ml,7.99 mmol) was added. A solution of methanesulfonyl chloride (0.34 mL,4.39 mmol) in 8mL DCM was slowly added. After 3h, the reaction mixture was diluted with 10mL of DCM and washed with 0.3M HCl (10 mL), and saturated sodium bicarbonate solution (10 mL). The organics were dried over sodium sulfate and concentrated under reduced pressure to give crude tert-butyl (1- (methylsulfonyl) piperidin-4-yl) carbamate (1.04 g,94% yield) as a white solid. ¹ H NMR (400 MHz, chloroform-d) delta 3.75 (d, 2H), 3.57 (s, 1H), 2.78 (s, 3H), 2.84-2.73 (m, 2H), 2.05 (dd, 2H), 1.57-1.44 (m, 2H), 1.44 (s, 9H).

To tert-butyl (1- (methylsulfonyl) piperidin-4-yl) carbamate (0.40 g,1.44 mmol) was added 4M hydrogen chloride in 1, 4-dioxane (3.59 ml,14.37 mmol). After stirring at room temperature for 6 hours, volatiles were removed in vacuo. The crude material was triturated with 2×5mL anhydrous diethyl ether and dried under vacuum to provide 1- (methanesulfonyl) piperidin-4-amine hydrochloride (0.30 g,97% yield). MS: m/z found 179.1[ M+H ] ] ⁺ .

(b) N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (methylsulfonyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (methylsulfonyl) piperidin-4-amine

Formate was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (23 mg,0.05 mmol) and 1- (methylsulfonyl) piperidin-4-amine hydrochloride (35 mg,0.17 mmol) with N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (methylsulfonyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (methylsulfonyl) piperidin-4-amine (56% yield). LCMS: m/z found 817.1[ M+H ]] ⁺ Retention time = 3.05min, (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.63(d,1H),7.80–7.67(m,2H),7.55(t,1H),7.48–7.38(m,3H),7.35–7.23(m,3H),4.01(m,4H),3.95(s,3H),3.88(s,2H),3.73(m,5H),2.87–2.66(m,12H),2.23–1.98(m,4H),1.63–1.44(m,4H).

Example 167:1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (2-methoxyacetyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methoxyethane-1-one (397)

(a) 1- (4-aminopiperidin-1-yl) -2-methoxyethane-1-one

A solution of tert-butyl N- (4-piperidinyl) carbamate (0.80 g,3.99 mmol) in 32mL DCM was cooled in an ice bath. Triethylamine (1.11 ml,7.99 mmol) was added. A solution of 2-methoxyacetyl chloride (0.40 mL,4.39 mmol) in 8mL DCM was slowly added. After 10 min, the reaction mixture was diluted with 30mL of DCM and washed with saturated sodium bicarbonate solution (10 mL), 0.3M HCl (10 mL), and saturated sodium bicarbonate solution (10 mL). The organics were dried over sodium sulfate and concentrated under reduced pressure to give crude tert-butyl (1- (2-methoxyacetyl) piperidin-4-yl) carbamate (1.06 g,97% yield) as a white solid. MS: m/z found 273.1[ M+H ] ] ⁺ . To tert-butyl (1- (2-methoxyacetyl) piperidin-4-yl) carbamate (0.60 g,2.20 mmol) was added 4M hydrogen chloride in 1, 4-dioxane (8.26 ml,33.05 mmol). After stirring at room temperature for 6 hours, volatiles were removed in vacuo. The crude material was triturated with 2×5mL anhydrous diethyl ether and dried under vacuum to give 1- (4-aminopiperidin-1-yl) -2-methoxyethane-1-one hydrochloride (0.35 g,76% yield). MS: m/z found 173.1[ M+H ]] ⁺ 。

(b) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (2-methoxyacetyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methoxyethan-1-one

Formate was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (28 mg,0.06 mmol) and 1- (4-aminopiperidin-1-yl) -2-methoxyethane-1-one hydrochloride (42 mg,0.20 mmol) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((2-methoxyacetyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methoxyethane-1-one (49% yield). LCMS: m/z found 805.0[ M+H ] ] ⁺ Retention time = 2.66min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.54(s,1H),7.78(d,1H),7.71(dd,1H),7.55(t,1H),7.50–7.44(m,2H),7.41(dd,1H),7.36–7.24(m,3H),4.55–4.46(m,2H),4.21(m,2H),4.16–4.06(m,4H),4.03(s,3H),3.98–3.86(m,7H),3.40(d,6H),3.08(m,3H),2.89(s,1H),2.74(m,2H),2.16–2.04(m,4H),1.53–1.27(m,4H).

Example 168: n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (2, 2-trifluoroethyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (2, 2-trifluoroethyl) piperidin-4-amine (437)

Formate was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypolynicotinaldehyde (29 mg,0.06 mmol) and 1- (2, 2-trifluoroethyl) piperidin-4-amine dihydrochloride (53 mg,0.21 mmol) with N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (2, 2-trifluoroethyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (2, 2-trifluoroethyl) piperidin-4-amine (46% yield). LCMS: m/z found 825.0[ M+H ]] ⁺ Retention time = 3.71min, (method a). ¹ H NMR(400MHz, methanol-d ₄ ):δ8.63(d,1H),7.78–7.68(m,2H),7.55(t,1H),7.48–7.37(m,3H),7.34–7.22(m,3H),4.02(s,3H),4.02(s,2H),3.95(s,3H),3.87(s,2H),3.08(m,2H),3.02(s,5H),3.06–2.97(m,1H),2.74(s,1H),2.59(t,1H),2.41(t,4H),1.98(t,4H),1.65–1.42(m,4H).

Example 169:1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (2-hydroxyacetyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-hydroxyethan-1-one (443)

(a) 1- (4-aminopiperidin-1-yl) -2-hydroxyethan-1-one

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A mixture of ethyl 2-glycolate (0.91 ml,9.53 mmol) and tert-butyl N- (4-piperidinyl) carbamate (2.12 g,10.59 mmol) was irradiated in a Biotage Initiator microwave apparatus (Biotage Initiator microwave) to 160℃for 30 minutes. Vacuum removing volatiles and passing through normal phase SiO ₂ The residue was purified by chromatography (20-100% ethyl acetate/petroleum ether, visualized by iodine staining) to afford tert-butyl (1- (2-hydroxyacetyl) piperidin-4-yl) carbamate (1.01 g,37% yield) as a white solid. ¹ H NMR (400 MHz, chloroform-d) delta 4.48 (d, 2H), 4.15 (d, 2H), 3.69 (s, 1H), 3.52-3.42 (m, 1H), 3.08-3.00 (m, 1H), 2.92-2.80 (m, 1H), 2.08-1.95 (m, 1H), 1.44 (s, 9H), 1.38-1.33 (m, 2H). To tert-butyl (1- (2-hydroxyacetyl) piperidin-4-yl) carbamate (0.38 g,1.47 mmol) was added 4M hydrogen chloride in 1, 4-dioxane (5.52 ml,22.1 mmol). After stirring at room temperature for 3 hours, volatiles were removed in vacuo. The crude material was triturated with 2×4mL of anhydrous diethyl ether and dried under vacuum to give crude 1- (4-aminopiperidin-1-yl) -2-hydroxyethan-1-one hydrochloride (0.35 g). MS: m/z found 159.1[ M+H ]] ⁺ .

(b) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (2-hydroxyacetyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-hydroxyethan-1-one

Formate was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (29 mg,0.06 mmol) and 1- (4-aminopiperidin-1-yl) -2-hydroxyethan-1-one hydrochloride (40 mg,0.21 mmol) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxyacetyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-hydroxyethan-1-one (49% yield). LCMS: m/z found 777.2[ M+H ] ] ⁺ Retention time = 2.36min, (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),7.78(d,1H),7.71(dd,1H),7.55(t,1H),7.51–7.38(m,3H),7.37–7.28(m,2H),7.27(d,1H),4.59–4.44(m,2H),4.31–4.16(m,4H),4.13(s,2H),4.03(s,3H),3.95(d,5H),3.85–3.77(m,2H),3.17–3.03(m,3H),2.93(s,1H),2.77(q,2H),2.16–2.04(m,4H),1.54–1.27(m,4H).

Example 170:4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (methoxycarbonyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidine-1-carboxylic acid methyl ester (465)

Following reductive amination procedure a, methyl 4- (((2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (methoxycarbonyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypolynicotinaldehyde (29 mg,0.06 mmol) and methyl 4-aminopiperidin-1-carboxylate hydrochloride (40 mg,0.21 mmol) were reacted with methyl 4- (((2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (methoxycarbonyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidine-1-carboxylate(43% yield) to formate. LCMS: m/z found 777.2[ M+H ]] ⁺ Retention time = 3.08min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.63(d,1H),7.79–7.67(m,2H),7.55(t,1H),7.47–7.37(m,3H),7.33–7.22(m,3H),4.13(s,4H),4.01(m,5H),3.94(s,3H),3.88(s,2H),3.68(d,6H),2.95–2.72(m,6H),2.00(m,4H),1.45–1.26(m,4H).

Example 171: (3- (((6- (2-chloro-3- (3-chloro-2- (4- (((3- (hydroxymethyl) bicyclo [1.1.1] pentan-1-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) bicyclo [1.1.1] pentan-1-yl) methanol (591)

Following reductive amination procedure A, starting from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (30 mg,0.06 mmol) and (3-aminobicyclo [ 1.1.1.1) ]Pentane-1-yl) methanol (24 mg,0.21 mmol) was prepared by reacting (3- (((6- (2-chloro-3- (3-chloro-2- (4- (((3- (hydroxymethyl)) bicyclo [ 1.1.1))]Pentane-1-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) amino) bicyclo [1.1.1]Pentane-1-yl) methanol (45% yield) was prepared as formate salt. 45% yield. LCMS: m/z found 687.4[ M+H ]] ⁺ Retention time = 2.81min, (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.62(d,1H),7.78–7.67(m,2H),7.54(t,1H),7.46–7.37(m,3H),7.30–7.20(m,3H),4.02(s,3H),3.92(d,5H),3.81(s,2H),3.60(d,4H),1.81–1.71(m,12H).

Example 172:1- (6- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((6- (2-methoxyacetyl) -2, 6-diazaspiro [3.3] heptan-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -2-methoxyethane-1-one (594)

(a) 2-methoxy-1- (2, 6-diazaspiro [3.3] heptane-2-yl) ethan-1-one

To 2,6-diazaspiro [3.3]]Heptane-2-carboxylic acid tert-butyl ester hemi-oxalate (2, 6-diazaspira [3.3]]A mixture of heptane-2-carboxylic acid tert-butyl ester hemioxylate) (1.50 g,3.08 mmol) in 40mL DCM was added triethylamine (1.89 mL,13.56 mmol). The mixture was cooled in an ice bath. A solution of 2-methoxyacetyl chloride (0.62 mL,6.78 mmol) in 10mL DCM was slowly added. After 3 hours, the mixture was washed with 20mL of saturated sodium bicarbonate solution, 20mL of 0.2M HCl, and 20mL of saturated sodium bicarbonate solution. The organics were dried over sodium sulfate, concentrated under reduced pressure, and passed through normal phase SiO ₂ Chromatography (15% to 100% EtOAc/hexanes) purification provided 6- (2-methoxyacetyl) -2, 6-diazaspiro [3.3]Heptane-2-carboxylic acid tert-butyl ester (0.59 g,71% yield). ¹ H NMR (400 MHz, chloroform-d) delta 4.37 (s, 2H), 4.16 (s, 2H), 4.17-4.03 (m, 4H), 3.97 (s, 2H), 3.38 (s, 3H), 1.43 (s, 9H).

To 6- (2-methoxyacetyl) -2, 6-diazaspiro [3.3]A solution of tert-butyl heptane-2-carboxylate (0.20 g,0.74 mmol) in 7mL DCM at 0deg.C was added a solution of trifluoroacetic acid (1.85 mL,7.40 mmol) in 3mL DCM. After 10min, the ice bath was removed. After 30min, volatiles were removed in vacuo. The resulting oil was azeotroped twice with 5mL of toluene to provide crude 2-methoxy-1- (2, 6-diazaspiro [3.3] as a TFA salt]Heptane-2-yl) ethan-1-one (0.22 g). ¹ H NMR (400 MHz, methanol-d) ₄ ) Delta 4.47 (s, 2H), 4.23 (d, 6H), 3.97 (s, 2H), 3.37 (s, 3H) MS: m/z found 171.1[ M+H ]] ⁺ .

(b) 1- (6- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((6- (2-methoxyacetyl) -2, 6-diazaspiro [3.3] heptan-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -2-methoxyethane-1-one

2-methoxy-1- (2, 6-diazaspiro [3.3] at room temperature]A mixture of heptane-2-yl) ethane-1-one TFA salt (43 mg,0.15 mmol) and sodium acetate (17 mg,0.20 mmol) in 0.45mL DCM was stirred for 10 min. After addition of 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (25 mg,0.05 mmol), the mixture was stirred for 5 min. Sodium triacetoxyborohydride (32 mg,0.15 mmol) was added. After stirring overnight at room temperature, the reaction mixture was diluted with 2mL of MeOH and filtered through a syringe filter. The crude product was purified by reverse phase chromatography (gradient 5 to 65% acetonitrile in water, 0.05% formic acid) and the combined pure fractions were freeze-dried to provide 1- [6- [ [4- [ 3-chloro-4- [ 2-chloro-3- [ 6-methoxy-5- [ [2- (2-methoxyacetyl) -2, 6-diazaspiro [3.3] as formate salt ]Heptan-6-yl]Methyl group]-2-pyridyl group]Phenyl group]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]-2, 6-diazaspiro [3.3 ]]Heptane-2-yl]-2-methoxy-ethanone (12 mg, 28%). LCMS: m/z found 801.4[ M+H ]] ⁺ Retention time = 2.70min, (method a). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.65(d,1H),8.50(s,1H),7.75–7.67(m,2H),7.55(t,1H),7.49–7.38(m,3H),7.38–7.30(m,2H),7.27(d,1H),4.41(d,4H),4.20–4.11(m,6H),4.05–4.01(m,7H),3.96(s,7H),3.85(s,2H),3.72(s,4H),3.36(s,6H).

Example 173: n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine (298)

Formate was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypolynicotinaldehyde (30 mg,0.06 mmol) and tetrahydropyran-4-amine (25 mg,0.24 mmol) with N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine. 75% yield. LCMS: m/z found 663.2[ M+H ]] ⁺ Protecting and protectingRetention time = 1.80min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.54(s,2H),7.77(d,1H),7.71(dd,1H),7.55(t,1H),7.49–7.44(m,2H),7.41(dd,1H),7.35–7.22(m,3H),4.09(s,2H),4.03(s,3H),4.02–3.97(m,4H),3.96(s,3H),3.92(s,2H),3.43(t,4H),3.15–3.00(m,1H),2.91–2.78(m,1H),2.08–1.87(m,4H),1.68–1.39(m,4H).

Example 174:1, 1-Dioxid 4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) tetrahydro-2H-thiopyran (299)

Formate was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (30 mg,0.06 mmol) and 1, 1-dioxo-thian-4-amine (36 mg,0.24 mmol) with 1, 1-dioxo-4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1, 1-dioxotetrahydro-2H-thiapyran-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) tetrahydro-2H-thiapyran. 80% yield. LCMS: m/z found 759.2[ M+H ]] ⁺ Retention time = 1.68min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.44(s,2H),7.79(d,1H),7.71(dd,1H),7.55(t,1H),7.51–7.44(m,2H),7.41(dd,1H),7.35–7.29(m,2H),7.27(d,1H),4.10(s,2H),4.03(s,3H),3.96(s,3H),3.90(s,2H),3.26–3.14(m,7H),3.13–3.04(m,2H),3.01–2.93(m,1H),2.46–2.36(m,2H),2.36–2.27(m,2H),2.23–2.04(m,4H).

Example 175:1- (3- (((6- (3- (2- (4- (((1-acetylazetidin-3-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) azetidin-1-one (300)

Formate salt was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (30 mg,0.06 mmol) and 1- (3-aminoazetidin-1-yl) ethanone (28 mg,0.24 mmol) 1- (3- (((6- (3- (2- (4- (((1-acetylazetidin-3-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) azetidin-1-one. 83% yield. LCMS: m/z found 689.2[ M+H ] ] ⁺ Retention time = 1.59min (method D). 1H NMR (400 MHz, methanol-D4): delta 8.68-8.59 (m, 1H), 8.32 (s, 2H), 7.75 (D, 1H), 7.71 (D, 1H), 7.55 (t, 1H), 7.47-7.38 (m, 3H), 7.32-7.21 (m, 3H), 4.39-4.28 (m, 2H), 4.18-4.07 (m, 2H), 4.03 (s, 3H), 4.00-3.90 (m, 7H), 3.87-3.67 (m, 6H), 1.86 (s, 6H).

Example 176: (S) -1- (((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol (301)

Formate salt was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (30 mg,0.06 mmol) and (2S) -1-aminopropane-2-ol (18 mg,0.24 mmol) with (S) -1- (((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol. 85% yield. LCMS: m/z found 611.2[ M+H ]] ⁺ Retention time = 1.70min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),8.52(s,2H),7.84(d,1H),7.73(d,1H),7.57(t,1H),7.51(d,1H),7.48(d,1H),7.44(d,1H),7.39(s,1H),7.34(t,2H),4.28(s,2H),4.20–4.13(m,2H),4.10–4.01(m,5H),3.99(s,3H),3.05(d,1H),2.98(d,1H),2.90–2.74(m,2H),1.23(dd,6H).

Example 177:2- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((5-oxo-6-azaspiro [3.4] oct-2-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) -6-azaspiro [3.4] octan-5-one (302)

Following reductive amination procedure a, starting from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (30 mg,0.06 mmol) and 2-amino-6-azaspiro [3.4 ]]Octan-5-one (34 mg,0.24 mmol) was prepared from 2- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((5-oxo-6-azaspiro [3.4 ]))]Octane-2-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl amino) -6-azaspiro [3.4]The octane-5-ketone is prepared into formate, namely a mixture of isomers (axial chirality). 88% yield. LCMS: m/z found 741.3[ M+H ]] ⁺ Retention time = 1.73min,1.78min and 1.85min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.53(s,2H),7.76(t,1H),7.71(d,1H),7.56(t,1H),7.50–7.44(m,2H),7.42(d,1H),7.35(s,1H),7.32(d,1H),7.29–7.24(m,1H),4.10(s,1H),4.07–4.01(m,4H),4.01–3.95(m,3H),3.91–3.80(m,2H),3.77–3.63(m,1H),3.60–3.45(m,1H),3.28–3.21(m,4H),2.66–2.52(m,2H),2.46–2.35(m,2H),2.33–2.17(m,6H),2.17–2.09(m,1H),2.03–1.92(m,1H).

Example 178:1- (2- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((2- (2-oxopyrrolidin-1-yl) ethyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethyl) pyrrolidin-2-one (303)

Following reductive amination procedure A, 1- (2- (((2-chloro-3- (3-chloro-2- (3-methoxy-2- (2-oxo-pyrrolidin-1-yl) ethyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypolynicotinaldehyde (30 mg,0.06 mmol) and 1- (2-aminoethyl) pyrrolidin-2-one (31 mg,0.24 mmol) was reacted with 1- (2- (((2-chloro-3- (3-chloro-2- (3-methoxy-4- (((2- (2-oxo-pyrrolidin-1-yl) ethyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridine-3- Group) methyl) amino) ethyl) pyrrolidin-2-one. 87% yield. LCMS: m/z found 717.3[ M+H ]] ⁺ Retention time = 1.75min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),8.44(s,2H),7.82(d,1H),7.72(d,1H),7.57(t,1H),7.50(d,1H),7.47(d,1H),7.43(d,1H),7.39(s,1H),7.36–7.28(m,2H),4.28(s,2H),4.11(s,2H),4.06(s,3H),3.99(s,3H),3.63(t,2H),3.57(t,2H),3.50(t,4H),3.23(t,2H),3.10(t,2H),2.46–2.36(m,4H),2.14–2.02(m,4H).

Example 179: n- ((6- (2-chloro-3- (3-chloro-2- (4- (((1-isopropylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1-isopropylpiperidin-4-amine (326)

Formate was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (25 mg,0.05 mmol) and 1-isopropylpiperidin-4-amine (29 mg,0.20 mmol) with N- ((6- (2-chloro-3- (3-chloro-2- (4- (((1-isopropylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1-isopropylpiperidin-4-amine. 73% yield. LCMS: m/z found 745.4[ M+H ]] ⁺ Retention time = 1.51min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.47(s,4H),7.81(d,1H),7.71(dd,1H),7.56(t,1H),7.51–7.44(m,2H),7.42(dd,1H),7.35(d,1H),7.33–7.23(m,2H),4.12(s,2H),4.04(s,3H),3.99–3.91(m,5H),3.46–3.33(m,5H),3.29–3.22(m,1H),3.14–3.05(m,1H),3.03–2.91(m,3H),2.83(t,2H),2.31–2.15(m,4H),1.89–1.67(m,4H),1.31(d,6H),1.27(d,6H).

Example 180: n- ((6- (2-chloro-3- (3-chloro-2- (4- (((4, 4-difluorocyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4, 4-difluorocyclohexane-1-amine (327)

Formate was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (25 mg,0.05 mmol) and 4, 4-difluorocyclohexane-1-amine (27 mg,0.20 mmol) with N- ((6- (2-chloro-3- (3-chloro-2- (4- (((4, 4-difluorocyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4, 4-difluorocyclohexane-1-amine. 80% yield. LCMS: m/z found 731.3[ M+H ] ] ⁺ Retention time = 2.27min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.69–8.64(m,1H),8.51–8.46(m,2H),7.85(d,1H),7.75–7.69(m,1H),7.57(td,1H),7.54–7.50(m,1H),7.49–7.46(m,1H),7.44(d,1H),7.39(s,1H),7.33(t,2H),4.28(s,2H),4.13(s,2H),4.06(s,3H),3.99(s,3H),3.28–3.20(m,1H),3.17–3.05(m,1H),2.30–2.11(m,8H),2.05–1.82(m,4H),1.80–1.60(m,4H).

Example 181:2- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (2-hydroxyethyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-ol (328)

Formate salt was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (25 mg,0.05 mmol) and 2- (4-amino-1-piperidinyl) ethanol (29 mg,0.20 mmol) 2- (4- (((2-chloro-3- (3-chloro-2- (4- (((1- (2-hydroxyethyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-ol. 84% yield. LCMS: m/z found 749.3[ M+H ]] ⁺ Retention time = 1.38min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.69–8.63(m,1H),8.40(s,4H),7.85(d,1H),7.72(dt,1H),7.57(t,1H),7.52(d,1H),7.47(d,1H),7.45–7.40(m,1H),7.38(s,1H),7.33(t,2H),4.23(s,2H),4.09(s,2H),4.06(s,3H),3.98(s,3H),3.83–3.72(m,4H),3.45–3.32(m,4H),3.23–3.03(m,2H),2.94(t,2H),2.81(t,2H),2.71(t,2H),2.52(t,2H),2.27–2.15(m,4H),1.90–1.72(m,4H).

Example 182: n- (2- (((6- (3- (2- (4- (((2-acetamidoethyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) ethyl) acetamide (329)

Formate was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (30 mg,0.06 mmol) and N- (2-aminoethyl) acetamide (25 mg,0.24 mmol) with N- (2- (((6- (3- (2- (4- (((2-acetaminoethyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) ethyl) acetamide. Yield 74%. LCMS: m/z found 665.2[ M+H ] ] ⁺ Retention time = 1.63min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),8.43(s,2H),7.86(d,1H),7.72(dd,1H),7.58(t,1H),7.51(d,1H),7.48(d,1H),7.45(dd,1H),7.39(s,1H),7.37–7.31(m,2H),4.31(s,2H),4.23(s,2H),4.08(s,3H),4.00(s,3H),3.55–3.46(m,4H),3.23–3.09(m,4H),2.03–1.95(m,6H).

Example 183:1- (6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((tetrahydro-2H-pyran-4-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N- ((tetrahydro-2H-pyran-4-yl) methyl) methylamine (330)

Following reductive amination procedure A, 1- (6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypolynicotinaldehyde (30 mg,0.06 mmol) and tetrahydropyran-4-ylmethylamine (28 mg,0.24 mmol) was reacted with 1- (6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((tetrahydro-2H-pyran-4-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-(tetrahydro-2H-pyran-4-yl) methyl) methylamine is prepared as formate. Yield 76%. LCMS: m/z found 691.3[ M+H ]] ⁺ Retention time = 1.88min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(dd,1H),8.53–8.48(m,2H),7.84(d,1H),7.72(dd,1H),7.57(dd,1H),7.52(d,1H),7.49–7.45(m,1H),7.45–7.41(m,1H),7.39(s,1H),7.37–7.30(m,2H),4.26(s,2H),4.11(s,2H),4.06(s,3H),4.01–3.90(m,7H),3.51–3.37(m,4H),2.94(d,2H),2.83(d,2H),2.08–1.90(m,2H),1.77–1.65(m,4H),1.43–1.25(m,4H).

Example 184:1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1-isobutyrylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methylpropan-1-one (346)

Formate was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (30 mg,0.06 mmol) and 1- (4-amino-1-piperidinyl) -2-methyl-propan-1-one (41 mg,0.24 mmol) with 1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1-isobutyrylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methylpropan-1-one. Yield 72%. LCMS: m/z found 801.4[ M+H ] ] ⁺ Retention time = 2.00min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),8.46(s,2H),7.88(d,1H),7.72(dd,1H),7.57(t,1H),7.54(d,1H),7.47(d,1H),7.44(dd,1H),7.39(s,1H),7.34(t,2H),4.68(t,2H),4.31(s,2H),4.27–4.15(m,4H),4.07(s,3H),3.99(s,3H),3.50–3.40(m,1H),3.38–3.32(m,1H),3.20(t,2H),2.99(p,2H),2.69(t,2H),2.35–2.14(m,5H),1.67–1.39(m,4H),1.17–1.00(m,12H).

Example 185:4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1-methyl-2-oxopiperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylpiperidin-2-one (418)

Formate salt was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (30 mg,0.06 mmol) and 4-amino-1-methyl-piperidin-2-one (31 mg,0.24 mmol) with 4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1-methyl-2-oxopiperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylpiperidin-2-one. 83% yield. LCMS: m/z found 717.3[ M+H ]] ⁺ Retention time = 1.55min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(dd,1H),8.47(s,1H),7.79(d,1H),7.71(d,1H),7.56(t,1H),7.49(d,1H),7.46(d,1H),7.42(d,1H),7.35(s,1H),7.32(d,1H),7.27(d,1H),4.22–4.09(m,2H),4.03(s,3H),3.97(s,3H),3.96–3.92(m,2H),3.51–3.36(m,5H),3.23–3.14(m,1H),2.99–2.89(m,6H),2.82(dd,1H),2.73(dd,1H),2.46–2.16(m,4H),1.97–1.75(m,2H).

Example 186:4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (dimethylcarbamoyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -N, N-dimethylpiperidine-1-carboxamide (419)

Formate was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (30 mg,0.06 mmol) and 4-amino-N, N-dimethyl-piperidine-1-carboxamide (42 mg,0.24 mmol) with 4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (dimethylcarbamoyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -N, N-dimethylpiperidin-1-carboxamide. 82% yield. LCMS: m/z found 803.4[ M+H ] ] ⁺ Retention time = 1.82min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.68–8.61(m,1H),8.54(s,2H),7.81–7.75(m,1H),7.72(d,1H),7.56(t,1H),7.47(dd,2H),7.42(d,1H),7.34(s,1H),7.31(d,1H),7.27(d,1H),4.13(s,2H),4.03(s,3H),3.97(s,3H),3.94(s,2H),3.79–3.63(m,4H),3.10–3.00(m,1H),2.92–2.73(m,17H),2.13–1.93(m,4H),1.63–1.38(m,4H).

Example 187: n- ((6- (2-chloro-3- (3-chloro-2- (4- (((1- (2, 2-difluoroethyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (2, 2-difluoroethyl) piperidin-4-amine (420)

Formate was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (30 mg,0.06 mmol) and 1- (2, 2-difluoroethyl) piperidin-4-amine (40 mg,0.24 mmol) with N- ((6- (2-chloro-3- (3-chloro-2- (4- (((1- (2, 2-difluoroethyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (2, 2-difluoroethyl) piperidin-4-amine. 63% yield. LCMS: m/z found 789.3[ M+H ]] ⁺ Retention time = 2.29min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.54(s,2H),7.80(d,1H),7.72(dd,1H),7.56(t,1H),7.50(d,1H),7.47(d,1H),7.42(dd,1H),7.36(d,1H),7.33(dd,1H),7.29(d,1H),5.96(tt,2H),4.19(s,2H),4.04(s,3H),4.00(s,2H),3.98(s,3H),3.11–2.95(m,5H),2.84–2.68(m,5H),2.38–2.21(m,4H),2.14–1.96(m,4H),1.76–1.48(m,4H).

Example 188: (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (furan-2-carbonyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (furan-2-yl) methanone (421)

Following reductive amination procedure a, starting from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methyl)Oxyphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (30 mg,0.06 mmol) and (4-amino-1-piperidinyl) - (2-furanyl) methanone (47 mg,0.24 mmol) were prepared as formate salt from (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (furan-2-carbonyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino piperidin-1-yl) (furan-2-yl) methanone. 46% yield. LCMS: m/z found 849.3[ M+H ] ] ⁺ Retention time = 1.93min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.67–8.59(m,1H),8.55(s,2H),7.78(d,1H),7.74–7.66(m,3H),7.58–7.52(m,1H),7.48–7.43(m,2H),7.41(dd,1H),7.33–7.22(m,3H),7.02(t,2H),6.59(dq,2H),4.60–4.42(m,4H),4.09–3.99(m,5H),3.95(s,3H),3.90(s,2H),3.28–2.82(m,6H),2.21–2.04(m,4H),1.58–1.37(m,4H).

Example 189: (4- (((6- (3- (2- (4- (((1-benzoylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (phenyl) methanone (422)

Prepared as formate salt from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (30 mg,0.06 mmol) and (4-amino-1-piperidinyl) -phenyl-methanone (50 mg,0.24 mmol) of (4- (((6- (3- (2- (4- (((1-benzoylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (phenyl) methanone according to reductive amination procedure a. 45% yield. LCMS: m/z found 869.3[ M+H ]] ⁺ Retention time = 2.42min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.55(s,2H),7.78(d,1H),7.72(d,1H),7.55(t,1H),7.50–7.44(m,2H),7.43–7.38(m,1H),7.34–7.18(m,7H),7.03–6.95(m,4H),6.83(dt,2H),4.08(s,2H),4.04(s,3H),3.96(s,3H),3.93(s,2H),3.73(t,4H),2.97–2.87(m,1H),2.74(t,5H),2.18–2.05(m,4H),1.75–1.52(m,4H).

Example 190: n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1-phenylpiperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1-phenylpiperidin-4-amine (423)

Formate was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (30 mg,0.06 mmol) and 1-phenylpiperidin-4-amine (43 mg,0.24 mmol) with N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1-phenylpiperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1-phenylpiperidin-4-amine. 60% yield. LCMS: m/z found 813.3[ M+H ] ] ⁺ Retention time = 2.81min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.63(d,1H),8.54(s,2H),7.76(d,1H),7.71(dd,1H),7.55(t,1H),7.50–7.37(m,13H),7.33–7.22(m,3H),4.73–4.54(m,2H),4.02(s,3H),3.99(s,2H),3.94(s,3H),3.88(s,2H),3.82–3.69(m,2H),3.21–3.07(m,2H),3.01–2.79(m,4H),2.22–2.06(m,2H),2.03–1.90(m,2H),1.56–1.31(m,4H).

Example 191: n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (pyridin-4-yl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (pyridin-4-yl) piperidin-4-amine (424)

Formate was prepared according to reductive amination procedure A from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (30 mg,0.06 mmol) and 1- (4-pyridinyl) piperidin-4-amine (43 mg,0.24 mmol) with N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (pyridin-4-yl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (pyridin-4-yl) piperidin-4-amine. Yield 59%. LCMS: m/z found 815.3[ M+H ]] ⁺ Retention time = 2.10min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.49(s,2H),8.13(t,4H),7.83(d,1H),7.72(d,1H),7.56(t,1H),7.52(d,1H),7.47(d,1H),7.43(d,1H),7.37(s,1H),7.33(d,1H),7.30(d,1H),7.10(t,4H),4.38–4.16(m,6H),4.05(s,5H),3.98(s,3H),3.45–3.34(m,1H),3.21(q,5H),2.34–2.17(m,4H),1.76–1.44(m,4H).

Example 192:2- ((6- (3- (2- (4- ((7-oxa-2-azaspiro [3.5] nonan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -7-oxa-2-azaspiro [3.5] nonane (470)

Following reductive amination procedure A, starting from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (30 mg,0.06 mmol) and 7-oxa-2-azaspiro [3.5] ]Nonane (31 mg,0.24 mmol) was added to 2- ((6- (3- (2- (4- ((7-oxa-2-azaspiro) 3.5)]Nonan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl-2-chlorophenyl) -2-methoxypyridin-3-yl methyl) -7-oxa-2-azaspiro [3.5]Nonane is prepared as formate. Yield 69%. LCMS: m/z found 715.3[ M+H ]] ⁺ Retention time = 1.79min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.52(s,2H),7.77(d,1H),7.71(dd,1H),7.56(t,1H),7.51(d,1H),7.47(d,1H),7.42(dd,1H),7.39–7.31(m,2H),7.29(d,1H),4.33(s,2H),4.06–3.99(m,5H),3.97(s,3H),3.86(s,4H),3.66–3.58(m,8H),3.56(s,4H),1.92–1.77(m,8H).

Example 193: n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (pyridin-2-yl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (pyridin-2-yl) piperidin-4-amine (444)

Following reductive amination procedure a, starting from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl)-2-methoxy nicotinaldehyde (30 mg,0.06 mmol) and 1- (2-pyridinyl) piperidin-4-amine (43 mg,0.24 mmol) N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (pyridin-2-yl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (pyridin-2-yl) piperidin-4-amine was prepared as the formate salt. 61% yield. LCMS: m/z found 815.3[ M+H ]] ⁺ Retention time = 1.43min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(dd,1H),8.54(s,2H),8.09(t,2H),7.82(d,1H),7.72(dd,1H),7.61–7.53(m,3H),7.53–7.49(m,1H),7.47(dd,1H),7.42(d,1H),7.37(d,1H),7.35–7.27(m,2H),6.88(t,2H),6.73–6.62(m,2H),4.49–4.28(m,4H),4.23(s,2H),4.11–4.00(m,5H),3.98(s,3H),3.11–3.00(m,1H),2.93(t,4H),2.26–2.08(m,4H),1.72–1.47(m,4H).

Example 194: n- ((6- (2-chloro-3- (3-chloro-2- (4- (((1- (3-chloropyridin-2-yl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (3-chloropyridin-2-yl) piperidin-4-amine (445)

Formate was prepared according to reductive amination procedure A from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (30 mg,0.06 mmol) and 1- (3-chloro-2-pyridinyl) piperidin-4-amine (51 mg,0.24 mmol) with N- ((6- (2-chloro-3- (3-chloro-2- (4- (((1- (3-chloropyridin-2-yl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (3-chloropyridin-2-yl) piperidin-4-amine. Yield 56%. LCMS: m/z found 883.3[ M+H ]] ⁺ Retention time = 2.49min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(dt,1H),8.56–8.49(m,2H),8.21–8.13(m,2H),7.83(d,1H),7.77–7.69(m,3H),7.60–7.50(m,2H),7.47(dt,1H),7.45–7.40(m,1H),7.38(s,1H),7.34(d,1H),7.30(dd,1H),7.00–6.91(m,2H),4.25(s,2H),4.11–4.03(m,5H),3.99(t,3H),3.96–3.80(m,4H),3.21(d,1H),2.99(s,1H),2.90(q,4H),2.23(d,2H),2.16(d,2H),1.90–1.62(m,4H).

Example 195: n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((2-methoxyethyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2-methoxyethane-1-amine (446)

Formate was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (30 mg,0.06 mmol) and 2-methoxyethylamine (18 mg,0.24 mmol) with N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((2-methoxyethyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2-methoxyethan-1-amine. 54% yield. LCMS: m/z found 611.2[ M+H ] ] ⁺ Retention time = 1.67min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.72–8.63(m,1H),8.57–8.49(m,2H),7.82(d,1H),7.72(dd,1H),7.57(t,1H),7.52–7.45(m,2H),7.43(dd,1H),7.38(d,1H),7.36–7.29(m,2H),4.25(s,2H),4.10(s,2H),4.08–4.03(m,3H),3.98(s,3H),3.70–3.57(m,4H),3.42(s,3H),3.40(s,3H),3.18(t,2H),3.08(t,2H).

Example 196: (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (cyclohexanecarbonyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (cyclohexyl) methanone (456)

Formate salt was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (30 mg,0.06 mmol) and (4-amino-1-piperidinyl) -cyclohexyl-methanone (51 mg,0.24 mmol) with (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (cyclohexanecarbonyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (cyclohexyl) methanone. 75% yield. LCMS: m/z found 881.4[ M+H ]] ⁺ Retention time = 2.31min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.63(dd,1H),8.55(s,2H),7.76(d,1H),7.73–7.68(m,1H),7.58–7.51(m,1H),7.47–7.38(m,3H),7.35–7.19(m,3H),4.52(t,2H),4.12–4.03(m,2H),4.02(s,3H),3.99(s,2H),3.94(s,3H),3.88(s,2H),3.12(t,2H),2.99–2.88(m,1H),2.87–2.78(m,1H),2.74–2.57(m,4H),2.19–1.89(m,4H),1.88–1.62(m,10H),1.55–1.16(m,14H).

Example 197: n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-thiopyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-thiopyran-4-amine (484)

Formate was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (30 mg,0.06 mmol) and tetrahydrothiopyran-4-amine (29 mg,0.24 mmol) with N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-thiopyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-thiopan-4-amine. 71% yield. LCMS: m/z found 695.2[ M+H ] ] ⁺ Retention time = 2.12min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.63(d,1H),8.55(s,2H),7.74(d,1H),7.71(dd,1H),7.55(t,1H),7.47–7.37(m,3H),7.32–7.21(m,3H),4.02(s,3H),3.96(s,2H),3.94(s,3H),3.86(s,2H),2.78–2.59(m,9H),2.58–2.49(m,1H),2.35–2.20(m,4H),1.71–1.46(m,4H).

Example 198:1- (2- ((6- (3- (2- (4- ((7-acetyl-2, 7-diazaspiro [3.5] nonan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 7-diazaspiro [3.5] nonan-7-yl) ethan-1-one (485)

According to reductive aminationProcedure a, prepared from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (30 mg,0.06 mmol) and 1- (2, 7-diazaspiro [3.5]]Nonan-7-yl) ethanone (41 mg,0.24 mmol) was prepared from 1- (2- ((6- (3- (2- (4- ((7-acetyl-2, 7-diazaspiro [ 3.5))]Nonan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl-2-chlorophenyl) -2-methoxypyridin-3-yl methyl) -2, 7-diazaspiro [3.5]Nonan-7-yl) ethan-1-one to formate. 82% yield. LCMS: m/z found 797.3[ M+H ]] ⁺ Retention time = 1.77min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66–8.61(m,1H),8.54(s,2H),7.75–7.66(m,2H),7.58–7.51(m,1H),7.47–7.38(m,3H),7.33–7.28(m,2H),7.28–7.23(m,1H),4.07(s,2H),4.03–3.97(m,3H),3.96–3.90(m,3H),3.83(s,2H),3.62–3.41(m,12H),3.38–3.32(m,4H),2.13–2.04(m,6H),1.90–1.80(m,4H),1.81–1.73(m,4H).

Example 199: n- ((6- (2-chloro-3- (3-chloro-2- (4- ((cyclohexylamino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) cyclohexylamine (524)

Formate was prepared according to reductive amination procedure A from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (30 mg,0.06 mmol) and cyclohexylamine (24 mg,0.24 mmol) with N- ((6- (2-chloro-3- (3-chloro-2- (4- ((cyclohexylamino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) cyclohexylamine. Yield 62%. LCMS: m/z found 659.3[ M+H ] ] ⁺ Retention time = 2.37min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.63(d,1H),8.55(s,2H),7.73(dd,2H),7.55(t,1H),7.48–7.39(m,3H),7.35–7.20(m,3H),4.03(s,5H),3.95(s,3H),3.88(s,2H),2.78–2.67(m,1H),2.63–2.48(m,1H),2.09–1.96(m,4H),1.87–1.74(m,4H),1.74–1.61(m,2H),1.40–1.10(m,10H).

Example 200: (1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexane-1-ol (364)

Using reductive amination procedure A, (1 r,4 r) -4- (((6- (2-chloro-3- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypolyl-pyridin-3-yl) methyl) amino) cyclohexan-1-ol was prepared from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino, acetic acid (20 mg, 0.08 mmol), 4-aminocyclohexanol (18 mg,0.16 mmol) and sodium cyanoborohydride (7 mg,0.12 mmol). 13mg,48% yield. MS: m/z found 691.2[ M+H ]] ⁺ Retention time = 1.69min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.62(m,1H),7.77–7.67(m,2H),7.59–7.50(m,1H),7.47–7.36(m,3H),7.34–7.21(m,3H),4.02(q,5H),3.94(t,3H),3.87(s,2H),3.53(s,2H),2.72(s,1H),2.56(s,1H),2.16–1.90(m,8H),1.41–1.19(m,8H).

Example 201: n- (4- (4- (3- (5- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2-oxaspiro [3.3] heptan-6-amine (365)

Using reductive amination procedure A, starting from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (20 mg,0.04 mmol), acetic acid (5 uL,0.08 mmol), 2-oxaspiro [3.3] ]Heptane-6-amine; preparation of N- (4- (4- (3- (5- (((2-oxaspiro [3.3 ])) s) by hydrochloride (24 mg,0.16 mmol) and sodium cyanoborohydride (7 mg,0.12 mmol)]Heptane-6-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl-2-methoxyphenylmethyl) -2-oxaspiro [3.3]Heptane-6-amine. 7.3mg,27% yield. MS: m/z found 687.2[ M+H ]] ⁺ Retention time = 1.77min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.61(m,1H),7.69(d,2H),7.58–7.50(m,1H),7.45–7.34(m,3H),7.28–7.19(m,3H),4.69(d,4H),4.58(s,4H),4.00(t,3H),3.92(t,3H),3.78(s,2H),3.69(s,2H),3.25–3.11(m,2H),2.52(m,4H),2.01(q,4H).

Example 202: (1 r,3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol (385)

Using reductive amination procedure a, starting from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (20 mg,0.04 mmol), acetic acid (5 ul,0.08 mmol), 3-amino-1-methyl-cyclobutanol; (1 r,3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol) was prepared from hydrochloride (22 mg,0.16 mmol) and sodium cyanoborohydride (7 mg,0.12 mmol). 8.5mg,33% yield. MS: m/z found 663.2[ M+H ] ] ⁺ Retention time = 1.69min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.64(d,1H),7.75(d,1H),7.73–7.67(m,1H),7.55(t,1H),7.46(d,2H),7.43–7.39(m,1H),7.34(s,1H),7.31(d,1H),7.26(d,1H),4.06–4.01(m,5H),3.97(d,3H),3.84(s,2H),3.78(t,1H),3.65–3.57(m,1H),2.39–2.24(m,4H),2.09(t,2H),1.95(t,2H),1.35(dd,6H).

Example 203:2- ((6- (2-chloro-3- (3-chloro-2- (4- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2-azaspiro [3.3] heptan-6-ol (386)

From 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl using reductive amination procedure a) -2-methoxy nicotinaldehyde (20 mg,0.04 mmol), acetic acid (5 uL,0.08 mmol), 2-azaspiro [3.3]]Preparation of 2- ((6- (2-chloro-3- (3-chloro-2- (4- ((6-hydroxy-2-azaspiro [3.3 ]) by heptan-6-ol) (18 mg,0.16 mmol) and sodium cyanoborohydride (7 mg,0.12 mmol)]Heptane-2-yl) methyl) -3-methoxyphenyl) pyridin-4-yl-phenyl) -2-methoxypyridin-3-yl-methyl) -2-azaspiro [3.3]Heptane-6-ol. 4.3mg,16% yield. MS: m/z found 687.2[ M+H ]] ⁺ Retention time = 1.71min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.64(d,1H),7.78–7.67(m,2H),7.55(t,1H),7.50–7.39(m,3H),7.36(s,1H),7.34–7.25(m,2H),4.28(s,2H),4.11(q,2H),4.04–4.01(m,5H),4.00(s,4H),3.96(t,3H),3.74(d,4H),2.67–2.50(m,4H),2.19–2.00(m,4H).

Example 204:6- ((6- (3- (2- (4- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2-oxa-6-azaspiro [3.3] heptane (387)

Using reductive amination procedure A, starting from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (20 mg,0.04 mmol) \acetic acid (5 uL,0.08 mmol), 2-oxa-6-azaspiro [3.3 ]Preparation of 6- ((6- (3- (2- (4- ((2-oxa-6-azaspiro [3.3 ]) by heptane (16 mg,0.16 mmol)) and sodium cyanoborohydride (7 mg,0.12 mmol))]Heptane-6-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl-2-chlorophenyl) -2-methoxypyridin-3-yl methyl) -2-oxa-6-azaspiro [3.3]Heptane. 6.2mg,24% yield. MS: m/z found 659.2[ M+H ]] ⁺ Retention time = 1.70min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.61(dd,1H),7.67(dd,2H),7.53(t,1H),7.44–7.37(m,2H),7.34(d,1H),7.28–7.19(m,3H),4.74(dd,8H),3.98(t,3H),3.89(d,3H),3.73(s,2H),3.64(s,2H),3.56(s,4H),3.53(s,4H).

Example 205:1- ((6- (2-chloro-3- (3-chloro-2- (4- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -3-methylazetidin-3-ol (396)

Using reductive amination procedure a, starting from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (20 mg,0.04 mmol), acetic acid (5 ul,0.08 mmol), 3-methylazetidin-3-ol; hydrochloride (19 mg,0.16 mmol) and sodium cyanoborohydride (7 mg,0.12 mmol) 1- ((6- (2-chloro-3- (3-chloro-2- (4- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -3-methylazetidin-3-ol was prepared. 4.7mg,19% yield. MS: m/z found 635.1[ M+H ] ] ⁺ Retention time = 0.65min (method B). ¹ H NMR (400 MHz, methanol-d) ₄ ).δ8.65(d,1H),7.78(d,1H),7.73–7.68(m,1H),7.56(dd,1H),7.51–7.40(m,3H),7.37(s,1H),7.32(dd,2H),4.38(s,2H),4.09(s,2H),4.06–4.00(m,5H),3.97(t,3H),3.90(d,2H),3.79(d,2H),3.62(d,2H),1.51(q,6H).

Example 206:2- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((6-oxo-2, 5-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 5-diazaspiro [3.4] octan-6-one (398)

Using reductive amination procedure A, starting from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (20 mg,0.04 mmol), acetic acid (5 uL,0.08 mmol), 2, 5-diazaspiro [3.4]]Preparation of 2- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((6-oxo-2, 5-diazaspiro [3.4 ]) by octan-6-one (20 mg,0.16 mmol) and sodium cyanoborohydride (7 mg,0.12 mmol)]Octane-2-yl-methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl-methyl) -2, 5-diazaspiro [3.4]Octan-6-one. 5.7mg,20% yield. MS: m/z found 715.1[ M+H ]] ⁺ Retention time = 1.57min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ9.99(t,1H),9.07(t,2H),8.91(t,1H),8.84–8.74(m,3H),8.70–8.60(m,3H),5.41(s,2H),5.37(t,3H),5.30(d,3H),5.21(d,2H),5.16(s,2H),5.10(d,2H),5.01(d,2H),4.83(s,2H),3.80(d,4H),3.73(d,4H).

Example 207: (1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexane-1-ol (410)

Using reductive amination procedure A, (1 s,4 s) -4- (((6- (2-chloro-3- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypolyl-in-3-yl) methyl) amino) cyclohexan-1-ol was prepared from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino, acetic acid (20 mg, 0.08 mmol), 4-aminocyclohexanol (18 mg,0.16 mmol) and sodium cyanoborohydride (7 mg,0.12 mmol). 21mg,77% yield. MS: m/z found 691.2[ M+H ] ] ⁺ Retention time = 1.75min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.66(d,1H),7.90(d,1H),7.72(d,1H),7.61–7.51(m,2H),7.45(dd,2H),7.38(s,1H),7.34(dd,2H),4.29(d,4H),4.08(s,3H),3.98(s,3H),3.20(q,2H),2.05–1.82(m,14H),1.71–1.51(m,4H).

Example 208:1- (((6- (2-chloro-3- (3-chloro-2- (4- (((1-hydroxycyclopropyl) methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) cyclopropan-1-ol (504)

Using reductive amination procedure A, starting from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (20 mg,0.04 mmol), acetic acid (5 uL,0.08 mmol), 1- (aminomethyl) cyclopropanol (14 mg,0.16 mmol) and sodium cyanoborohydride (7 mg,0.12 m)mol) 1- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1-hydroxycyclopropyl) methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) cyclopropan-1-ol. 6.5mg,26% yield. MS: m/z found 635.3[ M+H ]] ⁺ Retention time = 1.73min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.66(m,1H),7.90(d,1H),7.75–7.69(m,1H),7.58(dd,1H),7.53(d,1H),7.49–7.42(m,2H),7.39(s,1H),7.37–7.32(m,2H),4.38(d,4H),4.08(t,3H),3.99(t,3H),3.19(s,2H),3.16(s,2H),0.90(d,4H),0.73(d,4H).

Example 209: n- ((6- (2-chloro-3- (3-chloro-2- (4- (((2, 2-difluoroethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 2-difluoroethane-1-amine (505)

N- ((6- (2-chloro-3- (3-chloro-2- (4- (((2, 2-difluoroethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 2-difluoroethan-1-amine was prepared from 6- (2-chloro-3- (3-chloro-2- (4- (((2, 2-difluoroethyl) amino) methyl) 3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 2-difluoroethan-1-amine (8 mg,0.12 mmol) using reductive amination procedure A. 11.6mg,46% yield. MS: m/z found 623.1[ M+H ] ] ⁺ Retention time = 1.78min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.66–8.59(m,1H),8.27(d,1H),7.70(dd,1H),7.58–7.49(m,1H),7.46–7.41(m,2H),7.41–7.37(m,1H),7.31(dd,2H),7.26(dd,1H),6.39–5.67(m,1H),4.66–4.59(m,1H),4.08(s,2H),4.01(m,3H),3.94(t,3H),3.91(m,2H),3.59(q,1H),3.16(dd,2H),3.09–2.95(m,1H).

Example 210: n- ((6- (2-chloro-3- (3-chloro-2- (4- ((isopropylamino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) propan-2-amine (514)

N- ((6- (2-chloro-3- (3-chloro-2- (4- ((isopropylamino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypolyl-pyridin-3-yl) methyl) propan-2-amine was prepared from 6- (2-chloro-3- (3-chloro-2- (4- ((isopropylamino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) propan-2-amine using reductive amination procedure A (20 mg,0.04 mmol), acetic acid (5 uL,0.08 mmol), propan-2-amine (13 mg,0.16 mmol) and sodium cyanoborohydride (8 mg,0.12 mmol). 9.8mg,42% yield. MS: m/z found 579.3[ M+H ]] ⁺ Retention time = 0.67min (method B). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.66(dd,1H),7.90(d,1H),7.76–7.68(m,1H),7.61–7.51(m,2H),7.48–7.42(m,2H),7.38(s,1H),7.34(dd,2H),4.26(d,4H),4.08(d,3H),3.99(d,3H),3.48(s,2H),1.42(m,12H).

Example 211:1- (1- ((6- (3- (2- (4- ((4-acetylpiperidin-1-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) ethan-1-one (536)

1- (1- ((6- (3- (2- (4- ((4-acetylpiperidin-1-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) ethan-1-one was prepared from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-4-yl) methyl) nicotinaldehyde (20 mg,0.04 mmol), acetic acid (5 ul,0.08 mmol), 1- (4-piperidinyl) ethanone (21 mg,0.16 mmol) and sodium cyanoborohydride (8 mg,0.12 mmol) using reductive amination procedure a. 5.3mg,18% yield. MS: m/z found 717.3[ M+H ] ] ⁺ Retention time = 2.33min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.67(d,1H),7.91(d,1H),7.74(d,1H),7.59–7.52(m,2H),7.49–7.45(m,1H),7.41(s,1H),7.37(d,2H),4.37(s,2H),4.25(s,2H),4.06(d,3H),3.98(d,3H),3.63–3.41(m,4H),3.21–2.97(m,4H),2.75(d,1H),2.20(t,5H),2.13(t,3H),1.85(s,3H),1.57(s,1H).

Example 212: n- (1- ((6- (3- (2- (4- ((4-acetamidopiperidin-1-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide (322)

N- (1- ((6- (3- (2- (4- ((4-acetamidopiperidin-1-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide was prepared in step (b) using N- (4-piperidinyl) -acetamide instead of (5S) -5- (aminomethyl) pyrrolidin-2-one in a similar manner as described for example 11. The product was obtained as a white solid (formate). LC/MS: m/z found 745,747[ M+H ]] ⁺ Retention time = 2.12min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.64(d,1H),8.49(s,1H),7.79(d,1H),7.72(d,1H),7.59–7.49(m,2H),7.46(d,1H),7.41(d,1H),7.39–7.31(m,2H),7.28(d,1H),4.09(s,2H),4.00(d,3H),3.95(d,3H),3.87–3.63(m,4H),3.06(d,2H),2.83(s,2H),2.44(t,2H),2.01(d,2H),1.95–1.86(m,8H),1.79–1.45(m,4H).

Example 213: n- (1- (4- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) piperidin-4-yl) acetamide (325)

(a) 1- (4- (((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl]-2-methoxy-pyridine-3-carbaldehyde (100 mg,0.25 mmol), acetic acid (15 mg,0.25 mmol), and 1- (4-amino-1-piperidinyl) ethanone (51 mg,0.36 mmol) were dissolved in MeOH/THF (1:1, 3 mL) and then The solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (24 mg,0.38 mmol) was added and the resulting mixture was stirred at 25 ℃ for 1 hour. The reaction was then diluted with water (10 mL) and extracted with EtOAc (3×5 mL). The combined organics were further washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 1- (4- (((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (132 mg, crude) as a yellow oil. MS: m/z found 519,521[ M+H ]] ⁺ . The material was used in the next step without further purification.

(b) (1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

1- (4- (((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (132 mg, crude), DMAP (6 mg,0.05 mmol), and diisopropylethylamine (66 mg,0.51 mmol) were dissolved in 5ml THF, and tert-butyl tert-butoxycarbonyl carbonate (111 mg,0.51 mmol) was then added in portions. The resulting mixture was stirred at room temperature for 18 hours. The reaction was diluted with water (10 mL) and the aqueous extracted with EtOAc (3×5 mL). Concentrating the combined organics under reduced pressure and passing through normal phase SiO ₂ The crude sample was purified by chromatography (0-100% EtOAc/hexanes) to provide tert-butyl (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (114 mg,72% yield) as a white foam. MS: m/z found 619,621[ M+H ]] ⁺ .

(c) (1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) -pyridin-4-yl) -phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

Tetrakis (triphenylphosphine) palladium (0) (43 mg,0.04 mmol), potassium carbonate (76 mg,0.55 mmol), tert-butyl (6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (114 mg,0.18 mmol) and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (72 mg,0.28 mmol) were suspended in 1, 4-dioxane/water (4:1, 4 ml) and the solution was heated at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×5 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (0-50% EtOAc/hexanes) to afford (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-3-methoxyphenyl) -pyridin-4-yl) -phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester (114 mg,86% yield) as a yellow foam. MS: m/z found 719,721M+H ] ⁺ .

(d) ((6- (3- (2- (4- ((4-Acetaminopiperidin-1-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) (1-acetylpiperidin-4-yl) carbamic acid tert-butyl ester

(1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) -pyridin-4-yl) -phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester (20 mg,0.03 mmol), acetic acid (3 mg,0.06 mmol), and N- (4-piperidinyl) acetamide (8 mg,0.06 mmol) were dissolved in MeOH/THF (1:1, 1 mL), and the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (7 mg,0.11 mmol) was added and the resulting mixture was stirred at 25℃for 1 hour. The reaction was then diluted with water (2 mL) and extracted with EtOAc (3×2 mL). The combined organics were further washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide tert-butyl ((6- (3- (2- (4- ((4-acetamidopiperidin-1-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) (1-acetylpiperidin-4-yl) carbamate (23 mg, crude) as a clear oil. MS: mActual z values 845,847[ M+H ]] ⁺ . The material was used in the next step without further purification.

(e) N- (1- (4- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) piperidin-4-yl) acetamide

Tert-butyl ((6- (3- (2- (4- ((4-acetamidopiperidin-1-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) (1-acetylpiperidin-4-yl) carbamate (23 mg,0.03mmol, crude) was dissolved in 1mL MeOH and a solution of 1, 4-dioxane (27 μl,0.11 mmol) in 4M HCl was added. The reaction was stirred at room temperature for 60 minutes and the solvent was removed under reduced pressure. The crude sample was purified by reverse phase HPLC to provide N- (1- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) piperidin-4-yl) acetamide (10 mg,49% yield) as a white solid (formate salt). LC/MS: m/z found 745,747[ M+H ]] ⁺ Retention time = 2.12min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.67–8.61(m,1H),8.48(s,1H),7.84(d,1H),7.71(d,1H),7.56(t,1H),7.50(d,1H),7.44(dd,2H),7.37–7.27(m,3H),4.58(d,1H),4.11(s,2H),4.05(t,3H),4.03(s,3H),3.94(s,3H),3.78(s,1H),3.25–3.12(m,4H),2.80–2.64(m,3H),2.23–2.06(m,5H),1.98(d,2H),1.92(t,3H),1.67(d,2H),1.47(dd,2H).

Example 214: (S) -4- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) dihydrofuran-2 (3H) -one (338)

In a similar manner to that described for example 213, intermediate N- (1-acetyl) was utilized in step (d)-4-piperidinyl) -N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]Tert-butyl carbamate and (S) -4- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) dihydrofuran-2 (3H) -one was prepared by substituting (S) -4-aminodihydrofuran-2 (3H) -one for N- (4-piperidinyl) -acetamide. The product was obtained as a tan solid (formate). LC/MS: m/z found 704,706[ M+H ]] ⁺ Retention time = 2.13min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.62(d,1H),8.48(s,2H),7.84(d,1H),7.71(d,1H),7.56(t,1H),7.42(t,3H),7.32(d,1H),7.26(d,2H),4.60(d,1H),4.41(t,1H),4.21(d,1H),4.14(s,2H),4.07–3.97(m,4H),3.92(s,3H),3.86(d,2H),3.67(s,1H),3.18(t,2H),2.83–2.64(m,2H),2.44(d,1H),2.12(s,5H),1.48(dd,2H).

Example 215: (S) -3- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) -4-hydroxybutyric acid methyl ester (339)

In the same manner as described for example 213, the intermediate N- (1-acetyl-4-piperidinyl) -N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl is utilized in step (d)]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]Tert-butyl carbamate and (S) -3- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) 6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) -4-hydroxybutyric acid methyl ester was prepared using (S) -3-amino-4-hydroxybutyric acid methyl ester instead of N- (4-piperidinyl) -acetamide. The product was obtained as a tan solid (formate). LC/MS: m/z found 736,738[ M+H ] ] ⁺ Retention time = 2.17min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.65(s,1H),8.49(s,2H),7.84(d,1H),7.71(d,1H),7.56(t,1H),7.52–7.40(m,3H),7.38–7.25(m,3H),4.58(d,1H),4.24(d,2H),4.13(d,2H),4.05(d,3H),3.98(s,3H),3.95–3.81(m,2H),3.72(s,3H),3.50(s,1H),3.18(t,3H),2.81–2.64(m,3H),2.12(s,5H),1.58–1.36(m,2H).

Example 216: (S) -3- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) dihydrofuran-2 (3H) -one (340)

In the same manner as described for example 213, the intermediate N- (1-acetyl-4-piperidinyl) -N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl is utilized in step (d)]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]Tert-butyl carbamate and (S) -3- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) dihydrofuran-2 (3H) -one was prepared by substituting (S) -3-aminodihydrofuran-2 (3H) -one for N- (4-piperidinyl) -acetamide. The product was obtained as a tan solid (formate). LC/MS: m/z found 704,706[ M+H ]] ⁺ Retention time = 2.13min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.62(d,1H),8.53(s,1H),7.78(d,1H),7.70(d,1H),7.56(d,1H),7.43(d,3H),7.28(s,3H),4.41(s,1H),4.03(s,3H),3.99–3.92(m,7H),3.62(s,1H),3.16(s,1H),2.10(s,6H).

Example 217: n- (1- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide (341)

(a) N- (1- ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide

6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl]-2-methoxy-pyridine-3-carbaldehyde (150 mg,0.38 mmol), N- (4-piperidinyl) acetamide (108 mg,0.76 mmol), and acetic acid (23 mg,0.38 mmol) were dissolved in MeOH/THF (1:1, 5 mL), and the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (48 mg,0.76 mmol) was added and the resulting mixture was stirred at 25 ℃ for 1 hour. The reaction was then diluted with water (10 mL) and extracted with EtOAc (3×5 mL). The combined organics were further washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide N- (1- ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide (198 mg, crude) as a yellow foam. MS: m/z found 519,521[ M+H ]] ⁺ . The material was used in the next step without further purification.

(b) N- (1- ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide

Tetrakis (triphenylphosphine) palladium (0) (88 mg,0.08 mmol), potassium carbonate (158 mg,1.14 mmol), N- (1- ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) -acetamide (198mg, 0.38mmol, crude), and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (150 mg,0.57 mmol) were suspended in 1, 4-dioxane/water (4:1, 6 ml) and the solution was heated at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×5 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (0-50% EtOAc/hexanes) to increase purity to provide N- [1- [ [6- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl ] as a yellow solid ]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-4-piperidinyl]Acetamide (235 mg, crude). MS: m/z found 619,621[ M+H ]] ⁺ . The material is used in the next step without further needAnd (5) purifying.

(c) N- (1- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide

N- [1- [ [6- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl ]]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-4-piperidinyl]Acetamide (25 mg,0.04mmol, crude), acetic acid (5 mg,0.08 mmol), and 1- (4-amino-1-piperidinyl) ethanone (12 mg,0.08 mmol) were dissolved in MeOH/THF (1:1, 1 mL) and the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (5 mg,0.08 mmol) was added and the resulting mixture was stirred at 25 ℃ for 1 hour. The reaction was then diluted with water (2 mL) and extracted with EtOAc (3×2 mL). The combined organics were further washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude sample was purified by reverse phase HPLC to provide N- (1- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide (8 mg,26% yield) as a white solid (formate salt). LC/MS: m/z found 745,747[ M+H ] ] ⁺ Retention time = 2.13min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.65(d,1H),8.48(s,2H),7.79(d,1H),7.72(d,1H),7.58–7.50(m,2H),7.47(d,1H),7.43–7.37(m,2H),7.34(d,1H),7.27(d,1H),4.65(d,1H),4.27(s,2H),4.06(d,1H),3.99(d,6H),3.73(s,3H),3.19(t,2H),3.04(d,2H),2.70(d,1H),2.41(t,2H),2.22(t,2H),2.13(s,3H),1.91(s,5H),1.68–1.44(m,4H).

Example 218: (S) -3- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) -4-hydroxybutyric acid (342)

(S) -4- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) dihydrofuran-2 (3H) -one (example 214) (5 mg,0.01 mmol) was dissolved in water/MeOH (1:1, 0.5 mL) and sodium hydroxide (71 uL,0.07mmol,1M in water) was added. The reaction was stirred at room temperature for 60 minutes and the solvent was removed under reduced pressure. The crude sample was purified by reverse phase HPLC to provide (S) -3- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) -4-hydroxybutyric acid (2 mg,29% yield) as a white solid (formate salt). LC/MS: m/z found 722,724[ M+H ]] ⁺ Retention time = 2.10min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.67–8.62(m,1H),8.46(s,2H),7.86(d,1H),7.71(d,1H),7.57(t,1H),7.52(d,1H),7.48–7.42(m,2H),7.37(s,1H),7.33(t,2H),4.62(d,1H),4.39(d,1H),4.30(d,1H),4.19(s,2H),4.07(d,3H),4.00(s,4H),3.94(d,1H),3.71–3.65(m,1H),3.45(s,1H),3.19(t,2H),2.70(t,1H),2.63–2.41(m,2H),2.16(d,5H),1.51(d,2H).

Example 219: (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -L-homoserine (343)

In a similar manner to that described for example 218, methyl (S) -3- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) -4-hydroxybutyrate (example 215) was used in place of methyl (S) -4- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -amino) -dihydrofuran-2 (3H) -one to prepare (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -3-chloropyridin-2-methoxybenzyl) -L-homoserine. Obtaining a tan solid (formate)The product is obtained. LC/MS: m/z found 722,724[ M+H ]] ⁺ Retention time = 2.12min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.65(d,1H),8.46(s,2H),7.85(d,1H),7.71(d,1H),7.56(t,1H),7.51–7.41(m,3H),7.37(s,1H),7.33(d,2H),4.61(d,1H),4.34(d,1H),4.28(d,1H),4.17(s,2H),4.06(s,3H),4.02(s,1H),3.98(s,3H),3.85(d,1H),3.78(d,1H),3.67(d,1H),3.19(t,2H),2.70(s,1H),2.15(d,6H).

Example 220: n- (1- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide (355)

In a similar manner to that described for example 217, the intermediate N- [1- [ [6- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl is utilized in step (c) ]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-4-piperidinyl]Acetamide combined with 2, 6-diazaspiro [3.4 ]]Preparation of N- (1- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [ 3.4)) by substituting 1- (4-amino-1-piperidinyl) ethanone with octan-7-one]Octan-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide. The product was obtained as a white solid (formate). LC/MS: m/z found 729,731[ M+H ]] ⁺ Retention time = 2.06min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.63(d,1H),8.48(d,1H),7.79(d,1H),7.71(d,1H),7.55(t,1H),7.43(dd,3H),7.35–7.23(m,3H),4.09(s,2H),4.00(t,3H),3.94(d,3H),3.80(s,4H),3.73(s,3H),3.62(d,2H),3.05(d,2H),2.64(d,2H),2.42(s,2H),1.91(t,5H),1.58(d,2H).

Example 221: (R) -N- (1- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide (356)

In a similar manner to that described for example 217, the intermediate N- [1- [ [6- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl is utilized in step (c)]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-4-piperidinyl]Acetamides and (5R) -5- (aminomethyl) pyrrolidin-2-one was used in place of 1- (4-amino-1-piperidinyl) ethanone to prepare (R) -N- (1- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide. The product was obtained as a white solid (formate). LC/MS: m/z found 717,719[ M+H ] ] ⁺ Retention time = 2.07min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.67–8.61(m,1H),8.44(s,1H),7.81(d,1H),7.72(d,1H),7.55(t,1H),7.47(t,2H),7.42(d,1H),7.32(dd,3H),4.14(s,2H),4.01(d,3H),3.97(d,4H),3.83(s,2H),3.73(s,1H),3.12(d,2H),2.99(s,2H),2.54(s,2H),2.36(s,3H),1.92(d,5H),1.85(s,1H),1.61(d,2H).

Example 222: (S) -N- (1- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide (357)

In a similar manner to that described for example 217, the intermediate N- [1- [ [6- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl is utilized in step (c)]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-4-piperidinyl]-acetamide and preparation of (S) -N- (1- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide with (5S) -5- (aminomethyl) pyrrolidin-2-one instead of 1- (4-amino-1-piperidinyl) ethanone. The product was obtained as a white solid (formate). LC/MS: m/z found 717,719[ M+H ]] ⁺ Retention time = 2.08min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.64(d,1H),8.45(s,1H),7.80(d,1H),7.72(d,1H),7.55(t,1H),7.47(d,2H),7.41(d,1H),7.36–7.27(m,3H),4.12(d,2H),4.01(d,3H),3.96(d,4H),3.79(s,2H),3.72(s,1H),3.09(d,2H),2.96(s,2H),2.49(s,2H),2.34(d,3H),1.92(s,5H),1.85(s,1H),1.60(d,2H).

Example 223: n- (1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] -octane-2-yl) methyl) pyridin-2-yl) -phenyl) pyridin-2-yl) -2-methoxybenzyl) piperidin-4-yl) acetamide (400)

(a) N- (1- (2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) piperidin-4-yl) acetamide

2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (200 mg,0.76 mmol), acetic acid (46 mg,0.76 mmol), and N- (4-piperidinyl) acetamide (141 mg,0.99 mmol) were dissolved in MeOH/THF (1:1, 6 mL), and the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (67 mg,1.07 mmol) was added in portions and the resulting mixture was stirred at 25 ℃ for 1 hour. The reaction was then diluted with water (15 mL) and extracted with EtOAc (3X 5 mL). The combined organics were further washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide N- (1- (2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) piperidin-4-yl) acetamide (182 mg, crude) as a yellow oil. MS: m/z found 389[ M+H ]] ⁺ . The material was used in the next step without further purification.

(b) N- (1- (4- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) piperidin-4-yl) acetamide

Tetrakis (triphenylphosphine) palladium (0) (70 mg,0.06 mmol), potassium carbonate (126 mg,0.91 mmol), 6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl ]-2-methoxy-pyridine-3-carbaldehyde (120 mg,0.30 mmol) and N- (1- (2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) piperidin-4-yl) acetamide (178 mg,0.46 mmol) were suspended in 1, 4-dioxane/water (4:1, 5 ml) and the solution was then heated at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×5 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (0-10% MeOH/DCM) to provide N- (1- (4- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) piperidin-4-yl) acetamide (82 mg,43% yield) as a pale yellow foam. MS: m/z found 619,621[ M+H ]] ⁺ .

(c) N- (1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] -octane-2-yl) methyl) pyridin-2-yl) -phenyl) pyridin-2-yl) -2-methoxybenzyl) piperidin-4-yl) acetamide

N- (1- (4- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) piperidin-4-yl) acetamide (20 mg,0.03 mmol), acetic acid (4 mg,0.06 mmol), and 2, 6-diazaspiro [3.4]]The octan-7-one (8 mg,0.06 mmol) was dissolved in MeOH/THF (1:1, 1 mL) and the solution was stirred at 25℃for 2 h. Sodium cyanoborohydride (4 mg,0.06 mmol) was added and the resulting mixture was stirred at 25 ℃ for 1 hour. The reaction was then diluted with water (2 mL) and extracted with EtOAc (3×2 mL). The combined organics were further washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude sample was purified by reverse phase HPLC to afford N- (1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [ 3.4)) as a white solid (formate salt) ]-octan-2-yl) methyl) pyridin-2-yl) -phenyl) pyridin-2-yl) -2-methoxybenzyl) Piperidin-4-yl) acetamide (10 mg,42% yield). LC/MS: m/z found 729,731[ M+H ]] ⁺ Retention time = 2.08min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.62(d,1H),8.53(s,1H),7.69(d,2H),7.54(t,1H),7.45(t,2H),7.40(d,1H),7.29(d,2H),7.24(d,1H),3.99(s,3H),3.91(s,3H),3.84(s,2H),3.73(s,3H),3.58(s,2H),3.44(s,4H),3.09(s,2H),2.58(s,2H),2.48(s,2H),1.91(s,5H),1.59(d,2H).

Example 224: n- (1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6-oxo-2, 5-diazaspiro [3.4] -octane-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) piperidin-4-yl) acetamide (401)

In a similar manner to that described for example 223, the intermediate N- (1- (4- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) piperidin-4-yl) acetamide was used in step (c) and 2, 5-diazaspiro [3.4]Octane-6-ketone substituted 2, 6-diazaspiro [3.4]]Preparation of N- (1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6-oxo-2, 5-diazaspiro [3.4 ])]-octan-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl piperidin-4-yl) acetamide. The product was obtained as a white solid (formate). LC/MS: m/z found 729,731[ M+H ]] ⁺ Retention time = 2.09min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.63(d,1H),8.51(s,1H),7.69(d,2H),7.54(t,1H),7.46(dd,2H),7.40(d,1H),7.30(d,2H),7.24(d,1H),3.99(t,3H),3.92(d,5H),3.73(s,4H),3.57(d,2H),3.38(d,2H),3.14(s,1H),2.59(s,2H),2.38(dd,4H),2.07–1.89(m,6H),1.62(d,1H).

Example 225: n- (1- (4- (4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) piperidin-4-yl) acetamide (402)

In a similar manner to that described for example 223, the intermediate N- (1- (4- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) piperidin-4-yl) acetamide was used in step (c) and 1- (2, 6-diazaspiro [3.3]Heptan-2-yl) -ethanone instead of 2, 6-diazaspiro [3.4]Preparation of N- (1- (4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3 ])) on-7-one]Heptane-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) piperidin-4-yl) acetamide. The product was obtained as a white solid (formate). LC/MS: m/z found 743,745[ M+H ]] ⁺ Retention time = 2.10min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.63(d,1H),8.51(s,1H),7.69(d,2H),7.54(t,1H),7.46(dd,2H),7.40(d,1H),7.35–7.28(m,2H),7.24(d,1H),4.30(s,2H),4.05(s,2H),3.99(t,4H),3.92(d,5H),3.73(s,4H),3.58(s,5H),3.16(s,1H),2.63(s,1H),1.98–1.90(m,5H),1.84(d,3H),1.63(d,1H).

Example 226: (S) -N- (1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) piperidin-4-yl) acetamide (403)

In a similar manner to that described for example 223, the intermediate N- (1- (4- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) piperidin-4-yl) acetamide was used in step (c) and (5S) -5- (aminomethyl) pyrrolidin-2-one was used instead of 2, 6-diazaspiro [3.4 ]Preparation of (S) -N- (1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) piperidin-4-yl) acetamide. The product was obtained as a white solid (formate). LC/MS: m/z found 717,719[ M+H ]] ⁺ Retention time = 2.08min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.63(d,1H),8.52(s,1H),7.75(d,1H),7.70(d,1H),7.54(t,1H),7.46(dd,2H),7.40(d,1H),7.30(d,2H),7.25(d,1H),4.02(t,3H),3.94–3.88(m,5H),3.85(d,3H),3.73(s,1H),3.15(d,2H),2.78–2.66(m,2H),2.57(s,2H),2.30(dd,3H),2.03–1.90(m,6H),1.62(d,2H).

Example 227:1- (4- (((6- (3- (2- (4- ((4-amino-4-methylpiperidin-1-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) -methyl) -amino) piperidin-1-yl) ethan-1-one (406)

In a similar manner to that described for example 213, the intermediate N- (1-acetyl-4-piperidinyl) -N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl is utilized in step (d)]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]Tert-butyl carbamate and 4-methylpiperidin-4-amine was used instead of N- (4-piperidinyl) -acetamide to prepare 1- (4- (((6- (3- (2- (4- ((4-amino-4-methylpiperidin-1-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) -methyl) -amino) piperidin-1-yl) ethan-1-one. The product was obtained as a tan solid (formate). LC/MS: m/z found 717,719[ M+H ] ] ⁺ Retention time = 2.07min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.63(d,1H),8.49(s,2H),7.83(d,1H),7.71(d,1H),7.56(t,1H),7.53–7.40(m,3H),7.29(q,3H),4.58(d,1H),4.10(s,2H),4.05(d,3H),4.01(d,1H),3.94–3.85(m,3H),3.73(s,2H),3.18(t,2H),2.83(d,2H),2.70(t,1H),2.52(s,2H),2.21–2.06(m,5H),1.98–1.70(m,4H),1.58–1.38(m,2H),1.36(d,3H).

Example 228: (S) -4- (((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) methyl) pyrrolidin-2-one (407)

To describe with respect to example 213In a similar manner, the intermediate N- (1-acetyl-4-piperidinyl) -N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl ] is utilized in step (d)]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]Tert-butyl carbamate and (4S) -4- (((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) methyl) pyrrolidin-2-one was prepared by substituting (4S) -4- (aminomethyl) pyrrolidin-2-one for N- (4-piperidinyl) -acetamide. The product was obtained as a tan solid (formate). LC/MS: m/z found 717,719[ M+H ]] ⁺ Retention time = 2.06min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.67–8.61(m,1H),8.50(s,1H),7.81(d,1H),7.74–7.68(m,1H),7.56(t,1H),7.51–7.39(m,3H),7.32(dd,3H),4.55(d,1H),4.14(s,2H),4.04(d,5H),3.97(d,4H),3.57(t,1H),3.17(t,2H),3.02(d,3H),2.92–2.79(m,1H),2.70(t,1H),2.52(dd,1H),2.22–2.04(m,6H),1.43(dd,2H).

Example 229: n- (1- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide (432)

In a similar manner to that described for example 217, the intermediate N- [1- [ [6- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl is utilized in step (c)]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-4-piperidinyl]Acetamides N- (1- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamides were prepared by replacing 1- (4-amino-1-piperidinyl) ethanone with tetrahydropyran-4-amine. The product was obtained as a white solid (formate). LC/MS: m/z found 704,706[ M+H ]] ⁺ Retention time = 2.12min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.66–8.62(m,1H),8.54(s,1H),7.76(d,1H),7.71(d,1H),7.54(t,1H),7.46(t,2H),7.40(d,1H),7.34(s,1H),7.31(d,1H),7.25(d,1H),4.11(s,2H),4.02(s,1H),3.99(d,4H),3.96(s,3H),3.63(d,3H),3.43(t,2H),3.11(s,1H),2.95(d,2H),2.25(t,2H),2.01(d,2H),1.91(d,3H),1.86(d,2H),1.57(dd,4H).

Example 230:2- (1- ((6- (2-chloro-3- (3-chloro-2- (4- ((3- (2-hydroxypropane-2-yl) azetidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) azetidin-2-ol (471)

In a similar manner as described with respect to example 11, 2- (1- ((6- (2-chloro-3- (4- ((3- (2-hydroxypropane-2-yl) azetidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypolynicotinaldehyde was prepared in step (b) using the intermediate 6- (2-chloro-3- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypolyl and replacing (5S) -5- (aminomethyl) pyrrolidin-2-one with 2- (azetidin-3-yl) propan-2-ol. The product was obtained as a white solid (formate). LC/MS: m/z found 691,693[ M+H ] ] ⁺ Retention time = 2.25min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.66(d,1H),8.52(s,1H),7.85–7.80(m,1H),7.72(d,1H),7.56(dd,1H),7.50(d,1H),7.47(d,1H),7.43(d,1H),7.35(dd,3H),4.39(s,2H),4.22(s,2H),4.13–4.03(m,7H),3.98(d,7H),2.83(m,2H),1.13(t,12H).

Example 231:2- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one (493)

(a) 2- ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one

6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl]-2-methoxy-pyridine-3-carbaldehyde (400 mg,1.02 mmol) \acetic acid (61 mg,1.02 mmol), and 2, 6-diazaspiro [3.4]]Octan-7-one (178 mg,1.42 mmol) was dissolved in MeOH/THF (1:1, 10 mL) and the solution was stirred at 25℃for 2 h. The reaction was cooled to 0deg.C and sodium cyanoborohydride (89 mg,1.42 mmol) was added in portions over 3 minutes. The resulting mixture was warmed to 25 ℃ and stirred for an additional 1 hour. The reaction was diluted with 15mL of water and extracted with EtOAc (3X 10 mL). The combined organics were washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide 2- ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] as a yellow oil ]Octan-7-one (520 mg, crude). MS: m/z found 503,505[ M+H ]] ⁺ . The material was used in the next step without further purification.

(b) 4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzaldehyde

Tetrakis (triphenylphosphine) palladium (0) (115 mg,0.10 mmol), potassium carbonate (205 mg,1.49 mmol), 2- ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4]Octane-7-one (250 mg,0.50mmol, crude), and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (169 mg,0.65 mmol) were suspended in 1, 4-dioxane/water (4:1, 12 ml), and the solution was then heated at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 20mL of water, and extracted with EtOAc (3×10 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (0-10% DCM/MeOH) to provide 4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [ 3.4)) as a yellow foam]Octane-2-yl) methyl esterYl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzaldehyde (157 mg,52% yield). MS: m/z found 603,605[ M+H ] ] ⁺ .

(c) 2- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one

4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4 ])]Octan-2-yl-methyl) pyridin-2-yl-phenyl) pyridin-2-methoxybenzaldehyde (19 mg,0.03 mmol), 1- (2, 6-diazaspiro [ 3.3)]Heptan-2-yl) ketene hydrochloride (11 mg,0.06 mmol), and N, N-diisopropylethylamine (12 mg,0.09 mmol) were dissolved in MeOH/THF (1:1, 1 mL) and the solution was stirred at 25℃for 18 h. Sodium cyanoborohydride (6 mg,0.09 mmol) was added and the resulting mixture was stirred at 25℃for 1 hour. The reaction was filtered through CELITE and the filtrate was concentrated under reduced pressure. The crude sample was purified by reverse phase HPLC to provide 2- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [ 3.3)) as a white powder (formate))]Heptane-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl-2-chlorophenyl) -2-methoxypyridin-3-yl methyl) -2, 6-diazaspiro [3.4]Octan-7-one (8 mg,33% yield). LC/MS: m/z found 727,729[ M+H ]] ⁺ Retention time = 2.09min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.64(d,1H),7.72(dd,2H),7.55(t,1H),7.47(d,2H),7.41(d,1H),7.39–7.30(m,2H),7.27(d,1H),4.35(s,2H),4.25(s,2H),4.12(s,5H),4.01(d,3H),3.96(d,3H),3.91(s,3H),3.68–3.62(m,4H),3.61(t,2H),2.62(d,2H),1.84(s,3H).

Example 232:2- ((6- (3- (2- (4- ((2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] -octan-7-one (494)

2- ((6- (3- (2- ((2, 6-diazaspiro [3.3 ]))]Heptane-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl-2-chlorophenyl) -2-methoxypyridin-3-yl methyl) -2, 6-diazaspiro [3.4]-octan-7-one was isolated as a by-product of reaction (c) in example 231. The compound was obtained as a white solid (formate). LC/MS: m/z found 685,687[ M+H ]] ⁺ Retention time = 2.19min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.63(d,1H),8.39(s,4H),7.78(d,1H),7.73–7.67(m,1H),7.55(t,1H),7.46–7.37(m,3H),7.29(d,3H),4.19(s,4H),4.03(d,5H),3.96(s,2H),3.92(s,3H),3.81(d,8H),3.63(s,2H),2.64(s,2H)

Example 233:2- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one (495)

In a similar manner to that described with respect to example 231, intermediate 4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [ 3.4) was utilized in step (c)]Octan-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzaldehyde and the replacement of 1- (2, 6-diazaspiro [3.3] with tetrahydropyran-4-amine ]Preparation of heptan-2-yl) ketene hydrochloride 2- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4]Octane-7-one. The product was obtained as a white solid (formate). LC/MS: m/z found 688,690[ M+H ]] ⁺ Retention time = 2.13min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.65(d,1H),8.51(s,1H),7.70(d,2H),7.58–7.49(m,2H),7.47(d,1H),7.43–7.37(m,2H),7.34(d,1H),7.27–7.21(m,1H),4.27(s,2H),4.04(d,2H),3.99(t,6H),3.75(s,2H),3.58(d,2H),3.46(d,6H),3.40(d,1H),2.58(s,2H),2.10(d,2H),1.70(d,2H).

Example 234:2- ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one (496)

In a similar manner to that described with respect to example 231, intermediate 4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [ 3.4) was utilized in step (c)]Octan-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzaldehyde and the replacement of 1- (2, 6-diazaspiro [3.3 ] with 3-amino-1-methyl-cyclobutanol]Preparation of heptan-2-yl) ketene hydrochloride 2- ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] ]Octane-7-one. The product was obtained as a white solid (formate). LC/MS: m/z found 688,690[ M+H ]] ⁺ Retention time = 2.06min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.65(d,1H),8.47(s,1H),7.71(t,2H),7.54(t,1H),7.48(dd,2H),7.40(d,2H),7.34(d,1H),7.25(d,1H),4.17(d,2H),3.99(t,6H),3.97–3.88(m,1H),3.82(s,2H),3.59(d,2H),3.55(s,4H),2.60(s,2H),2.43–2.33(m,2H),2.19(t,2H),1.38(d,3H).

Example 235:2- ((6- (2-chloro-3- (3-chloro-2- (4- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one (497)

In a similar manner to that described with respect to example 231, intermediate 4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [ 3.4) was utilized in step (c)]Octan-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzaldehyde and use of 2-azaspiro [3.3]Heptan-6-ol instead of 1- (2, 6-diazaspiro [3.3]]Heptane-2-yl) ethylenePreparation of 2- ((6- (2-chloro-3- (3-chloro-2- (4- ((6-hydroxy-2-azaspiro [3.3 ])]Heptane-2-yl) methyl) -3-methoxyphenyl) pyridin-4-yl phenyl) -2-methoxypyridin-3-yl methyl) -2, 6-diazaspiro [3.4]Octane-7-one. The product was obtained as a white solid (formate). LC/MS: m/z found 700,702[ M+H ]] ⁺ Retention time = 2.08min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.65(d,1H),8.43(s,2H),7.72(dd,2H),7.55(t,1H),7.48(dd,2H),7.43–7.37(m,2H),7.34(d,1H),7.26(d,1H),4.39(s,2H),4.14(d,5H),4.02–3.99(m,3H),3.97(d,3H),3.88(s,2H),3.61(d,6H),2.61(s,4H),2.15(t,2H).

Example 236:2- ((6- (2-chloro-3- (3-chloro-2- (4- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one (498)

In a similar manner to that described with respect to example 231, intermediate 4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [ 3.4) was utilized in step (c)]Octan-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzaldehyde and replacement of 1- (2, 6-diazaspiro [3.3 ] with 3-methylazetidin-3-ol]Preparation of heptan-2-yl) ketene hydrochloride 2- ((6- (2-chloro-3- (3-chloro-2- (4- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4]Octane-7-one. The product was obtained as a white solid (formate). LC/MS: m/z measured values 674,676[ M+H ]] ⁺ Retention time = 2.08min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.65(d,1H),8.46(s,1H),7.71(t,2H),7.54(t,1H),7.48(dd,2H),7.43–7.37(m,2H),7.34(d,1H),7.25(d,1H),4.40(s,2H),4.05(d,2H),4.00(t,3H),3.98–3.91(m,5H),3.82(d,2H),3.59(t,2H),3.55(s,4H),2.60(s,2H),1.52(d,3H).

Example 237:2- ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) -amino) -methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one (502)

In a similar manner to that described with respect to example 231, intermediate 4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [ 3.4) was utilized in step (c)]Octan-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzaldehyde and (1 r,4 r) -4-aminocyclohexane-1-ol was used instead of 1- (2, 6-diazaspiro [3.3 ] ]Preparation of heptan-2-yl) ketene hydrochloride 2- ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) -amino) -methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4]Octane-7-one. The product was obtained as a white solid (formate). LC/MS: m/z measured values 702,704[ M+H ]] ⁺ Retention time = 2.07min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.65(d,1H),8.45(s,2H),7.71(t,2H),7.58–7.49(m,2H),7.47(d,1H),7.40(d,2H),7.34(d,1H),7.25(d,1H),4.28(s,2H),3.99(dd,6H),3.85(s,2H),3.59(d,7H),3.15(s,1H),2.60(d,2H),2.23(d,2H),2.07(d,2H),1.53(q,2H),1.38(t,2H).

Example 238:2- ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) -amino) -methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one (503)

In a similar manner to that described with respect to example 231, intermediate 4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [ 3.4) was utilized in step (c)]Octan-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzaldehyde and (1 s,4 s) -4-aminocyclohexane-1-ol was used instead of 1- (2, 6-diazaspiro [3.3 ]]Preparation of heptan-2-yl) ketene hydrochloride 2- ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) -amino) -methyl) -3-methoxy)Phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) -2, 6-diazaspiro [3.4 ]Octane-7-one. The product was obtained as a white solid (formate). LC/MS: m/z measured values 702,704[ M+H ]] ⁺ Retention time = 2.13min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.65(d,1H),8.48(s,1H),7.73–7.67(m,2H),7.54(dd,2H),7.49–7.45(m,1H),7.40(d,2H),7.34(d,1H),7.25(d,1H),4.29(s,2H),4.03–3.94(m,7H),3.84–3.78(m,2H),3.59(s,2H),3.53(s,4H),3.18(s,1H),2.59(s,2H),1.92(d,6H),1.64(d,2H).

Example 239:2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 r,4 r) -4-hydroxycyclohexyl) -amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one (515)

(a) 2- (2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) -2, 6-diazaspiro [3.4] octan-7-one

2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (300 mg,1.14 mmol), acetic acid (69 mg,1.14 mmol), and 2, 6-diazaspiro [3.4]]Octan-7-one (188 mg,1.49 mmol) was dissolved in MeOH/THF (1:1, 10 mL) and the solution was stirred at 25℃for 2 h. The reaction was cooled to 0deg.C and sodium cyanoborohydride (144 mg,2.29 mmol) was added in portions over 3 minutes. The resulting mixture was warmed to 25 ℃ and stirred for an additional 1 hour. The reaction was concentrated under reduced pressure and the residue was dissolved in 15mL DCM. The organic solution was washed with water (2×15 mL) and brine solution, then dried over sodium sulfate. The solution was concentrated under reduced pressure to afford 2- (2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) -2, 6-diazaspiro [3.4] as a yellow oil ]Octan-7-one (423 mg, crude). MS m/z found 373[ M+H ]] ⁺ . The material is used in the next stepWithout further purification.

(b) 6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) -methyl) -phenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde

Tetrakis (triphenylphosphine) palladium (0) (176 mg,0.15 mmol), potassium carbonate (316 mg,2.29 mmol), 6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl]-2-methoxy-pyridine-3-carbaldehyde (300 mg,0.76 mmol), and 2- (2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) -2, 6-diazaspiro [3.4]]Octan-7-one (369 mg,0.99mmol, crude) was suspended in 1, 4-dioxane/water (4:1, 10 ml) and the solution was then heated at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 15mL of water, and extracted with EtOAc (3×10 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (2-20% DCM/MeOH) to provide 6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [ 3.4)) as a yellow oil]Octane-2-yl) -methyl) -phenyl) pyridin-4-yl-phenyl) -2-methoxy nicotinaldehyde (119 mg,26% yield). MS: m/z found 603,605[ M+H ] ] ⁺ .

(c) 2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 r,4 r) -4-hydroxycyclohexyl) -amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one

To 6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4 ])]Octane-2-yl) -methyl) -phenyl) -pyridin-4-yl-phenyl) -2-methoxynicotinaldehyde (19 mg,0.03 mmol), acetic acid (2 mg,0.03 mmol), and (1 r,4 r) -4-aminocyclohexane-1-ol (8 mg,0.06 mmol) were dissolved in MeOH/THF (1:1, 1 ml), and the solution was stirred at 25 ℃ for 2 hours. Sodium cyanoborohydride (4 mg,0.06 mmol) was added and the resulting mixture was stirred at 25 ℃ for 1 hour. By CEThe reaction was filtered off with LITE and the filtrate was concentrated under reduced pressure. The crude sample was purified by reverse phase HPLC to provide 2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 r,4 r) -4-hydroxycyclohexyl) -amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] as a white solid (formate salt)]Octan-7-one (13 mg,60% yield). LC/MS: m/z measured values 702,704[ M+H ]] ⁺ Retention time = 2.05min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.63(d,1H),8.49(s,2H),7.87(d,1H),7.71(d,1H),7.57(t,1H),7.43(t,3H),7.34(d,1H),7.29(d,2H),4.23(s,2H),4.07(d,3H),4.02(s,2H),3.92(d,3H),3.71(s,4H),3.60(s,3H),3.11(s,1H),2.62(d,2H),2.21(d,2H),2.07(d,2H),1.50(q,2H),1.38(t,2H).

Example 240:2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) -methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one (516)

In a similar manner to that described for example 239, intermediate 6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4 ]) was utilized in step (c)]Octane-2-yl) -methyl-phenyl) -pyridin-4-yl) -phenyl-2-methoxynicotinaldehyde and the preparation of 2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) -methyl) -6-methoxypyridin-2-yl) phenyl) -pyridin-2-methoxy benzyl) -2, 6-diazaspiro [3.4] with (1 s,4 s) -4-aminocyclohexane-1-ol instead of (1 r,4 r) -4-aminocyclohexane-1-ol]Octane-7-one. The product was obtained as a white solid (formate). LC/MS: m/z measured values 702,704[ M+H ]] ⁺ Retention time = 2.10min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.63(d,1H),8.50(d,1H),7.88(d,1H),7.71(d,1H),7.57(t,1H),7.43(dd,3H),7.35(d,1H),7.28(d,2H),4.25(s,2H),4.08(d,3H),3.98(d,3H),3.92(d,3H),3.65(s,4H),3.59(d,2H),3.17(s,1H),2.60(d,2H),1.91(d,6H),1.64(d,2H).

Example 241:2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) -amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one (517)

In a similar manner to that described for example 239, intermediate 6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4 ]) was utilized in step (c)]Preparation of 2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] by substituting 3-amino-1-methyl-cyclobutanol for (1 r,4 r) -4-aminocyclohexane-1-ol with octan-2-yl) -methyl) -phenyl) pyridin-4-yl-phenyl) -2-methoxynicotinaldehyde ]Octane-7-one. The product was obtained as a white solid (formate). LC/MS: m/z found 688,690[ M+H ]] ⁺ Retention time = 2.04min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.63(t,1H),8.51(d,1H),7.82(d,1H),7.74–7.68(m,1H),7.56(t,1H),7.48–7.37(m,3H),7.35–7.24(m,3H),4.06(t,3H),4.03(s,2H),3.95(s,2H),3.92(d,3H),3.80(d,1H),3.69–3.51(m,6H),2.61(d,2H),2.34(d,2H),2.11(d,2H),1.41–1.29(m,3H).

Example 242:2- (4- (3-chloro-4- (2-chloro-3- (5- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one (518)

In a similar manner to that described for example 239, intermediate 6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4 ]) was utilized in step (c)]Preparation of 2- (4- (3-chloro-4- (2-chloro-3- (5- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -6-methoxypyraldehyde) by substituting 3-methylazetidin-3-ol for (1 r,4 r) -4-aminocyclohexane-1-olPyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4]Octane-7-one. The product was obtained as a white solid (formate). LC/MS: m/z measured values 674,676[ M+H ]] ⁺ Retention time = 2.06min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.64(m,1H),8.46(d,2H),7.81(d,1H),7.71(m,1H),7.56(dd,1H),7.51–7.40(m,3H),7.33(dd,3H),4.21(s,4H),4.04(t,3H),3.97–3.87(m,9H),3.76(d,2H),3.64(d,2H),2.67(d,2H),1.51(d,3H).

Example 243:2- (4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one (519)

In a similar manner to that described for example 239, intermediate 6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4 ]) was utilized in step (c)]Octane-2-yl-methyl) -phenyl) -pyridin-4-yl-phenyl) -2-methoxynicotinaldehyde and use of 1- (2, 6-diazaspiro [3.3]Preparation of 2- (4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3 ]) by substituting (1 r,4 r) -4-aminocyclohexane-1-ol with heptan-2-yl) ethanone]Heptane-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl-2-methoxyphenylmethyl-2, 6-diazaspiro [3.4]Octane-7-one. The product was obtained as a white solid (formate). LC/MS: m/z found 727,729[ M+H ]] ⁺ Retention time = 2.06min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.65(d,1H),8.42(s,2H),7.75(d,1H),7.70(d,1H),7.55(t,1H),7.47(dd,2H),7.42(d,1H),7.37–7.30(m,2H),7.28(d,1H),4.33(s,2H),4.29(s,2H),4.08(s,2H),4.05–4.00(m,7H),3.97–3.94(m,5H),3.84(s,4H),3.65(s,2H),2.69(d,2H),1.84(d,3H).

Example 244:2- (4- (4- (3- (5- ((2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one (520)

2- (4- (3- (5- ((2, 6-diazaspiro [3.3 ]))]Heptane-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl-2-methoxyphenylmethyl-2, 6-diazaspiro [3.4]The octan-7-one was isolated as a by-product of reaction (c) in example 243. The compound was obtained as a white solid (formate). LC/MS: m/z found 685,687[ M+H ] ] ⁺ Retention time = 2.10min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.65(t,1H),8.39(s,3H),7.69(s,2H),7.58–7.48(m,2H),7.46(d,1H),7.43–7.39(m,1H),7.38–7.31(m,2H),7.25(dd,1H),4.34(s,2H),4.18(d,4H),4.09(d,4H),3.98(dd,6H),3.75(d,2H),3.65(dd,6H),2.70(d,2H).

Example 245:2- (4- (3-chloro-4- (2-chloro-3- (5- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one (521)

In a similar manner to that described for example 239, intermediate 6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4 ]) was utilized in step (c)]Octane-2-yl) -methyl-phenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde and use of 2-azaspiro [3.3]Preparation of 2- (4- (3-chloro-4- (2-chloro-3- (5- ((6-hydroxy-2-azaspiro [3.3 ]) by heptane-6-ol instead of (1 r,4 r) -4-aminocyclohexane-1-ol]Heptane-2-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl-2-methoxyphenylmethyl-2, 6-diazaspiro [3.4]Octane-7-one. The product was obtained as a white solid (formate). LC/MS: m/z found 700,702[ M+H ]] ⁺ Retention time = 2.07min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.63(t,1H),7.81(d,1H),7.70(d,1H),7.56(dd,1H),7.48–7.40(m,3H),7.36–7.25(m,3H),4.20(s,2H),4.15–4.09(m,1H),4.09–4.02(m,5H),4.01–3.91(m,7H),3.78(s,4H),3.62(d,2H),2.66–2.55(m,4H),2.13(d,2H).

Example 246:1- (4- ((6- (3- (2- (4- ((4-acetylpiperazin-1-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) piperazin-1-one (655)

In a similar manner to that described with respect to example 11, 1- (6- (3- (2- (4- ((4-acetylpiperazin-1-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) piperazin-1-one was prepared in step (b) using 1- (piperazin-1-yl) ethan-1-one instead of (5S) -5- (aminomethyl) pyrrolidin-2-one. The product was obtained as a white solid (formate). LC/MS: m/z found 717[ M+H ] ] ⁺ Retention time = 2.57min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.63(d,1H),8.40(brs),7.80(d,1H),7.72(dd,1H),7.55(dd,1H),7.50–7.46(m,1H),7.44(d,1H),7.41(dd,1H),7.31–7.25(m,3H),3.99(s,3H),3.90(s,3H),3.75(s,2H),3.64(s,2H),3.63–3.55(m,8H),2.70–2.48(m,8H),2.10(s,3H),2.09(s,3H).

Example 247:1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (morpholinomethyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (458)

(a) 1- (4- (((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one:

to 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (0.30 g,0.76 mmol), and 1- (4-aminopiperidin-1-yl) ethan-1-one (0.22 g,1.52 mmol) in 1:1THF/MeOHAcetic acid (0.09 g,1.52 mmol) and 4A molecular sieves (1 g) were added to the mixture in (10 mL). The mixture was stirred at room temperature for 3 hours. Sodium cyanoborohydride (0.12 g,1.91 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction was quenched by the addition of water (1 mL). The mixture was diluted with ethyl acetate (50 mL), then washed with saturated aqueous brine solution (30 mL), the aqueous layer was extracted with ethyl acetate (3×30 mL), then the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. By positive rapid SiO ₂ Chromatography using a linear gradient (0-5% MeOH/CH ₂ Cl ₂ ) The residue was purified to provide 1- (4- (((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (0.36 g,90% yield). MS: m/z found 519[ M+H ] ] ⁺ .

(b) (1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

The round bottom flask was charged with 1- (4- (((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (0.72 g,1.39 mmol) and di-tert-butyl dicarbonate (0.60 g,2.77 mmol). The flask was purged with nitrogen for 5 minutes then dry THF (30 mL) was added via syringe followed by N, N-diisopropylethylamine (0.72 mL,5.54 mmol). The reaction was stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate (50 mL), then washed with saturated aqueous brine solution (30 mL), then the aqueous layer was extracted with ethyl acetate (3 x30 mL), and the combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. By positive rapid SiO ₂ Chromatography using a linear gradient (0-5% MeOH/CH ₂ Cl ₂ ) The residue was purified to give tert-butyl (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (0.86 g,100% yield). MS: m/z found 619[ M+H ]] ⁺ .

(c) 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde

With 4-bromo-2-methoxybenzaldehyde (1 g,4.65 mmol), bis (pinacolato) diborane (1.30 g,5.12 mmol), potassium acetate (1.28 g,13.02 mmol), and [1,1' -bis (biphenylphosphino) ferrocene]A microwave vial was fed with a complex of palladium (II) dichloride and methylene chloride (0.38 g,0.47 mmol). The flask was purged with nitrogen for 5 minutes, then dried 1, 4-dioxane (2 mL) was added and the reaction was bubbled with nitrogen for 5 minutes. The mixture was then stirred at 90℃for 1 hour. By passing throughThe mixture was filtered and the filter cake was washed with ethyl acetate (3×40 mL). The combined organic layers were concentrated under reduced pressure and passed through normal phase flash SiO ₂ Chromatography using a gradient (0-10% methanol/CH ₂ Cl ₂ ) The residue was purified to provide 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (0.92 g,75% yield). MS: m/z found 263[ M+H ]] ⁺ .

(d) (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester:

the microwave vial was fed with tert-butyl 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (0.22 g,0.83 mmol), (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (0.47 g,0.76 mmol), cesium carbonate (0.74 g 2.27 mmol), and tetrakis (triphenylphosphine) palladium (0) (0.09 g,0.08 mmol). 1, 4-dioxane (2 mL) was added, and the reaction was bubbled with nitrogen, followed by the addition of water (0.3 mL). The mixture was stirred thermally at 90℃for 30 minutes and then passed through The mixture was filtered and the filter cake was washed with ethyl acetate (3×15 mL). The filtrate was concentrated under reduced pressure and passed through normal phase flash SiO ₂ Chromatography using a gradient (0-10% methanol/CH ₂ Cl ₂ ) The residue was purified to give tert-butyl (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (0.53 g,96% yield). MS: m/z found 719[ M+H ]] ⁺ .

(e) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (morpholinomethyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

To a mixture of tert-butyl (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (0.06 g,0.08 mmol) and morpholine (0.01 g,0.17 mmol) in 1:1THF/MeOH (10 mL) was added acetic acid (0.01 g,0.17 mmol) and 4A molecular sieve (1 g). The mixture was stirred at room temperature for 3 hours. Sodium cyanoborohydride (0.01 g,0.211 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction was quenched by the addition of water (1 mL). The mixture was diluted with ethyl acetate (50 mL), then washed with saturated aqueous brine solution (30 mL), the aqueous layer was extracted with ethyl acetate (3×30 mL), and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. By positive rapid SiO ₂ Chromatography using a linear gradient (0-5% MeOH/CH ₂ Cl ₂ ) The residue was purified to provide tert-butyl (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (morpholinomethyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate, MS: m/z found 790[ M+H ]] ⁺ . The protected amine was then diluted with dichloromethane (3 ml), trifluoroacetic acid (1 ml) was added and the reaction stirred for 20 minutes, then concentrated under reduced pressureAnd (5) shrinking. The residue was purified by reverse phase HPLC (0.05% formic acid modifier) to afford 1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (morpholinomethyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one 6.8mg (12%) as a white solid (formate salt). MS: m/z found 690[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.60(d,1H),8.44(s,1H),7.84(d,1H),7.68(d,1H),7.54(t,1H),7.48–7.37(m,3H),7.31(d,1H),7.29–7.21(m,2H),4.60(d,1H),4.18(s,2H),4.04(s,3H),4.02(d,1H),3.88(s,3H),3.78–3.67(m,6H),3.23–3.11(m,1H),2.73–2.62(m,5H),2.23–2.07(m,5H),1.63–1.39(m,2H).

Example 248:1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((4-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one) ethan-1-one (459)

In a manner similar to example 247, 1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((4-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one was prepared in step (e) using piperidin-4-ol instead of morpholine. MS: m/z found 704[ M+H ] ] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.61(d,1H),8.52(s,1H),7.75(d,1H),7.68(dd,1H),7.52(t,1H),7.49–7.35(m,3H),7.32–7.20(m,3H),4.47(d,1H),4.00(s,3H),3.89(d,6H),3.71(s,1H),3.12(t,1H),3.08–3.03(m,2H),2.87–2.82(m,2H),2.68(t,1H),2.60(s,2H),2.08(s,3H),2.00(d,2H),1.94–1.86(m,2H),1.69–1.64(m,2H),1.46–1.24(m,2H).

Example 249:4- (2- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) ethyl) piperazin-2-one (479)

In a manner similar to example 247, 4- (2-aminoethyl) piperazin-2-one was used in place of morpholine in step (e) to prepare 4- (2- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) ethyl) piperazin-2-one. MS: m/z found 746[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.63(d,1H),8.43(s,2H),7.84(d,1H),7.68(dd,1H),7.58–7.46(m,2H),7.47–7.34(m,3H),7.37–7.26(m,2H),4.60(d,1H),4.29(s,2H),4.19(s,2H),3.99(d,7H),3.36–3.27(m,3H),3.18–3.11(m,4H),2.75(t,2H),2.75–2.61(m,3H),2.24–2.07(m,5H),1.64–1.39(m,2H).

Example 250: (R) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((3-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (489)

(R) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((3-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one) was prepared in step (e) using (R) -piperidin-3-ol instead of morpholine in a similar manner to example 247. MS: m/z found 704[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.62(d,1H),8.49(s,1H),7.79(d,1H),7.68(dd,1H),7.58–7.45(m,2H),7.46–7.36(m,2H),7.36–7.24(m,3H),4.53(d,1H),4.02(d,7H),3.92(s,4H),3.86(s,1H),3.20–2.98(m,6H),2.68(t,3H),2.09(s,4H),1.97(s,1H),1.83(d,1H),1.68(s,1H),1.54–1.25(m,2H).

Example 251: (S) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((3-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (507)

(S) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((3-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one) was prepared in step (e) using (S) -piperidin-3-ol instead of morpholine in a similar manner to example 247. MS: m/z found 704[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.63(d,1H),8.41(s,2H),7.85(d,1H),7.68(dd,1H),7.58–7.48(m,2H),7.47–7.27(m,5H),4.61(d,1H),4.29(s,2H),4.21(s,2H),4.07–3.92(m,7H),3.41–3.33(m,1H),3.27(d,3H),3.16(t,4H),2.96(s,1H),2.67(t,1H),2.19(t,3H),2.09(s,3H),1.78–1.67(m,1H),1.66–1.52(m,1H),1.54–1.41(m,1H).

Example 252:1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((4- (hydroxymethyl) piperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (508)

In a similar manner to example 247, 1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((4- (hydroxymethyl) piperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one was prepared in step (e) using piperidin-4-yl instead of morpholinomethanol. MS: m/z found 718[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.63(d,1H),8.44(s,2H),7.84(d,1H),7.68(dd,1H),7.53(t,2H),7.47–7.30(m,4H),7.30(d,1H),4.59(d,1H),4.32(s,2H),4.17(s,2H),4.06–3.92(m,7H),3.46(dd,4H),3.22–3.10(m,1H),3.02(t,2H),2.67(t,1H),2.09(s,5H),1.94(d,2H),1.65-1.80(m,1H),1.63–1.37(m,4H).

Example 253:1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((4- (methoxymethyl) piperidin-1-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (509)

In a manner similar to example 247, 1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((4- (methoxymethyl) piperidin-1-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one was prepared in step (e) using 4- (methoxymethyl) piperidine instead of morpholine. MS: m/z found 732[ M+H ] ] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.63(d,1H),8.48(s,1H),7.81(d,1H),7.68(dd,1H),7.58–7.48(m,2H),7.47–7.24(m,5H),4.55(d,1H),4.26(s,2H),4.08(s,2H),3.98(dd,7H),3.44(d,2H),3.31–3.28(m,4H),3.14(t,2H),2.96(t,2H),2.67(t,1H),2.18–2.06(m,5H),1.89(t,3H),1.56–1.33(m,4H).

Example 254:1- (4- ((4- (3-chloro-4- (2-chloro-3- (5- ((4-hydroxypiperidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) amino) piperidin-1-yl) ethan-1-one (487)

(a) 1- (4- ((4-bromo-2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one

The scintillation vial was charged with 4-bromo-2-methoxybenzaldehyde (0.20 g,0.93 mmol), 1- (4-aminopiperidin-1-yl) ethan-1-one (0.26 g,1.86 mmol), followed by 1:1THF/MeOH solution (6 mL), acetic acid (0.11 g,1.86 mmol) and 4A molecular sieve (1 g). The mixture was stirred at room temperature for 3 hours. Sodium cyanoborohydride (0.15 g,2.33 mmol) was added and the mixture was stirred at room temperature for 1 hour, then the reaction was quenched by the addition of water (1 ml). The mixture was diluted with ethyl acetate (50 mL), then washed with saturated aqueous brine solution (30 mL), then the aqueous layer was extracted with ethyl acetate (3×30 mL), and the combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. By positive rapid SiO ₂ Chromatography using a linear gradient (0-10% MeOH/CH ₂ Cl ₂ ) The residue was purified to provide 1- (4- ((4-bromo-2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one. MS: m/z found 341[ M+H ] ] ⁺ .

(b) (1-Acetylpiperidin-4-yl) (4-bromo-2-methoxybenzyl) carbamic acid tert-butyl ester

The round bottom flask was charged with 1- (4- ((4-bromo-2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one (0.59 g,1.73 mmol) and di-tert-butyl dicarbonate (0.75 g,3.46 mmol). The flask was purged with nitrogen for 5 minutes then dry THF (20 mL) was added via syringe followed by N, N-diisopropylethylamine (1.2 mL,6.92 mmol). The reaction was stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate (50 mL), then washed with saturated aqueous brine solution (30 mL) and the aqueous layer was extracted with ethyl acetate (3×30 mL), and the combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. By positive rapid SiO ₂ Chromatography using a linear gradient (0-5% MeOH/CH ₂ Cl ₂ ) The residue was purified to give tert-butyl (1-acetylpiperidin-4-yl) (4-bromo-2-methoxybenzyl) carbamate (0.68 g,89% yield). MS: m/z actual measurement 441[ M+H ]] ⁺ .

(c) (1-Acetylpiperidin-4-yl) (2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) carbamic acid tert-butyl ester

With (1-acetylpiperidin-4-yl) (4-bromo-2-methoxybenzyl) carbamic acid tert-butyl ester (0.68 g,1.54 mmol), bis (pinacolato) diborane (0.43 g,1.69 mmol), potassium acetate (0.42 g,4.31 mmol), and [1,1' -bis (biphenylphosphino) ferrocene ]A microwave vial was fed with a complex of palladium (II) dichloride and methylene chloride (0.13 g,0.15 mmol). The flask was purged with nitrogen for 5 minutes and then 5mL of dry was addedDry 1, 4-dioxane and sparge the reaction with nitrogen for 5 minutes. Stirring the mixture at 90deg.C for 1hr and passingThe mixture was filtered and the filter cake was washed with ethyl acetate (3×40 mL). The filtrate was concentrated under reduced pressure and passed through normal phase flash SiO ₂ Chromatography using a gradient (0-5% methanol/CH ₂ Cl ₂ ) The residue was purified to give tert-butyl (1-acetylpiperidin-4-yl) (2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) carbamate (0.75 g,100% yield). MS: m/z found 489[ M+H ]] ⁺ .

(d) (1-Acetylpiperidin-4-yl) (4- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) carbamic acid tert-butyl ester

The microwave vial was charged with tert-butyl (1-acetylpiperidin-4-yl) (2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) carbamate (0.40 g,0.82 mmol), 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (0.40 g,0.74 mmol), cesium carbonate (0.72 g 2.22 mmol), and tetrakis (triphenylphosphine) palladium (0) (0.09 g,0.07 mmol). 1, 4-dioxane (4 ml) was added, and the reaction was bubbled with nitrogen, followed by the addition of water (1 ml). The mixture was stirred at 90℃for 30min and then passed through The mixture was filtered and the filter cake was washed with ethyl acetate (3×15 mL). The filtrate was concentrated under reduced pressure and passed through normal phase flash SiO ₂ Chromatography using a gradient (0-10% methanol/CH ₂ Cl ₂ ) The residue was purified to give tert-butyl (1-acetylpiperidin-4-yl) (4- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) carbamate (0.70 g,95% yield). MS: m/z found 719[ M+H ]] ⁺ .

(e) 1- (4- ((4- (3-chloro-4- (2-chloro-3- (5- ((4-hydroxypiperidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) amino) piperidin-1-yl) ethan-1-one

To a mixture of tert-butyl (1-acetylpiperidin-4-yl) (4- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) carbamate (0.12 g,0.17 mmol) and piperidin-4-ol (0.03 g,0.33 mmol) in 1:1THF/MeOH (6 mL) was added acetic acid (0.02 g,0.3 mmol) and 4A molecular sieve (1 g). The mixture was stirred at room temperature for 3 hours. Sodium cyanoborohydride (0.03 g,0.42 mmol) was then added and the mixture was stirred at room temperature for 1 hour. The reaction was then quenched by the addition of water (1 mL). The mixture was diluted with ethyl acetate (50 mL), then washed with saturated aqueous brine solution (30 mL) and the aqueous layer was extracted with ethyl acetate (3×30 mL), and the combined organic phases were dried over sodium sulfate, dried and concentrated under reduced pressure. By positive rapid SiO ₂ Chromatography using a linear gradient (0-5% MeOH/CH ₂ Cl ₂ ) The residue was purified to provide tert-butyl (1-acetylpiperidin-4-yl) (4- (3-chloro-4- (2-chloro-3- (5- ((4-hydroxypiperidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) carbamate. MS: m/z found 804[ M+H ]] ⁺ . The protected amine was then diluted with dichloromethane (3 ml), trifluoroacetic acid (1 ml) was added and the reaction mixture stirred for 20 min, then concentrated under reduced pressure, and the residue was purified by reverse phase HPLC (0.05% formic acid modifier) to afford 1- (4- ((4- (3-chloro-4- (2-chloro-3- (5- ((4-hydroxypiperidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one 8.9mg (34%) as a white solid (formate salt). MS: m/z found 804[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.64(d,1H),8.52(s,1H),7.80(d,1H),7.71(dd,1H),7.59–7.37(m,4H),7.38–7.24(m,3H),4.60(d,1H),4.18(s,2H),4.06–3.94(m,7H),3.79–3.66(m,3H),3.28–3.11(m,2H),3.04–2.96(m,2H),2.68(t,1H),2.52(s,2H),2.18(d,2H),2.11(s,3H),1.91(d,2H),1.67–1.63(m,3H),1.67–1.51(m,1H),1.52–1.38(m,1H).

Example 255:1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one (488)

1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one

In a similar manner to example 254, 1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one was prepared in step (e) using (1 r,4 r) -4-methoxycyclohexane-1-amine instead of piperidin-4-ol. MS: m/z found 732[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.60(d,1H),8.51(s,1H),7.75(d,1H),7.68(dd,1H),7.53(t,1H),7.45–7.35(m,3H),7.27(t,3H),4.49(d,1H),4.02–3.86(m,11H),3.23–3.06(m,2H),2.92–2.87(m,1H),2.65(t,2H),2.15–1.97(m,10H),1.28(m,5H).

Example 256:2- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-5-one (525)

In a similar manner to example 254, 2, 6-diazaspiro is used in step (e)[3.4]Preparation of 2- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] by substituting piperidin-4-ol with octan-5-one]Octane-5-one. MS: m/z found 729[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.63(s,1H),8.44(s,3H),7.78–7.64(m,2H),7.57–7.21(m,6H),4.63(d,1H),4.28(s,2H),4.09–3.97(m,1H),4.02–3.91(m,7H),3.79(d,2H),3.66(d,2H),3.45–3.35(m,1H),3.30(d,1H),3.17(t,1H),2.66(t,1H),2.48(t,2H),2.21(t,2H),2.10(s,3H),1.67–1.42(m,2H),1.26(s,1H).

Example 257:2- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) -2,5, 7-triazaspiro [3.4] octan-6-one (526)

In a similar manner to example 254, 2,5, 7-triazaspiro [3.4 ] was used in step (e)]Preparation of 2- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2,5, 7-triazaspiro [3.4 ] using octan-6-one instead of piperidin-4-ol]Octan-6-one. MS: m/z found 730[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.63(d,1H),8.39(s,2H),7.72–7.64(m,2H),7.52(t,2H),7.44(d,1H),7.42–7.29(m,3H),7.23(d,1H),4.64(d,1H),4.29(s,2H),4.05(d,1H),3.97(d,6H),3.79(s,2H),3.73–3.62(m,4H),3.52–3.37(m,2H),3.18(t,1H),2.67(t,1H),2.22(t,2H),2.11(s,3H),1.69–1.55(m,1H),1.58–1.44(m,1H).

Example 258: (R) -5- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-2-one (541)

(R) -5- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-2-one) was prepared in step (e) using (R) -5-aminopiperidin-2-one instead of piperidin-4-ol in a similar manner to example 254. MS: m/z found 717[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.61(d,1H),8.49(s,2H),7.74(d,1H),7.67(dd,1H),7.55–7.44(m,2H),7.43(d,1H),7.40–7.25(m,3H),7.21(d,1H),4.58(d,1H),4.18(s,2H),3.96(d,7H),3.85(q,2H),3.46(dd,1H),3.20–3.05(m,2H),3.05–2.95(m,1H),2.65(t,1H),2.49–2.36(m,1H),2.37–2.23(m,1H),2.18–2.02(m,7H),1.83–1.71(m,1H),1.58–1.41(m,2H).

Example 259: (S) -5- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-2-one (542)

(S) -5- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-2-one) was prepared in step (e) using (S) -5-aminopiperidin-2-one instead of piperidin-4-ol in a similar manner to example 254. MS: m/z found 717[ M+H ] ] ⁺ ； ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.63(d,1H),7.89(d,1H),7.68(dd,1H),7.59–7.46(m,2H),7.47–7.35(m,2H),7.39–7.28(m,3H),4.62(s,1H),4.40–4.27(m,4H),4.06(s,4H),3.96(s,3H),3.78–3.66(m,2H),3.50–3.39(m,2H),3.27(d,2H),3.18(t,1H),2.66(t,1H),2.47(t,2H),2.39–2.28(m,1H),2.22(t,2H),2.09–1.98(m,2H),1.70–1.43(m,2H).

Example 260:1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (methylsulfonyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (383)

Following reductive amination procedure B from (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester (31 mg,0.04 mmol) and 1- (methylsulfonyl) piperidin-4-amine HCl (23 mg,0.11 mmol), followed by the general Boc deprotection procedure 1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (methylsulfonyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one) was prepared as a formate salt. Yield 27%. LCMS: m/z found 781.1[ M+H ]] ⁺ Retention time = 2.91min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.54(s,1H),7.78(d,1H),7.75–7.68(m,1H),7.55(t,1H),7.50–7.38(m,3H),7.36–7.24(m,3H),4.50(d,1H),4.08(s,2H),4.03(s,3H),3.94(d,5H),3.78(d,2H),3.17(d,1H),3.01–2.65(m,9H),2.21–1.99(m,7H),1.59(dd,2H),1.49–1.23(m,2H).

Example 261:1- (4- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) piperidin-1-yl) -2-methoxyethan-1-one (413)

1- (4- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) piperidin-1-yl) -2-methoxyethan-1-one was prepared as a formate salt according to the reductive amination procedure B from (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester (31 mg,0.04 mmol) and 1- (4-aminopiperidin-1-yl) -2-methoxyethan-1-one HCl (22 mg,0.11 mmol) followed by the general Boc deprotection procedure. Yield 50%. LCMS: m/z found 775.2[ M+H ] ] ⁺ Reserved, reserveTime = 2.62min, (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.53(s,1H),7.80(d,1H),7.71(dd,1H),7.56(t,1H),7.52–7.44(m,2H),7.42(dd,1H),7.36(d,1H),7.36–7.25(m,2H),4.65–4.49(m,2H),4.26–4.08(m,5H),4.04(s,3H),3.98(d,5H),3.40(s,3H),3.27–3.05(m,4H),2.98(s,1H),2.72(q,2H),2.11(s,8H),1.69–1.25(m,4H).

Example 262:1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((piperidin-4-ylamino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (417)

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((piperidin-4-ylamino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one was prepared as a formate salt according to the reductive amination procedure B from tert-butyl (6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (32 mg,0.04 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (15 mg,0.07 mmol) followed by the general Boc deprotection procedure. Yield 35%. LCMS: m/z found 703.3[ M+H ]] ⁺ Retention time = 1.97min, (method C). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.49(s,2H),7.87(d,1H),7.72(dd,1H),7.57(t,1H),7.50–7.40(m,3H),7.36–7.27(m,3H),4.60(m,1H),4.18(s,2H),4.06(d,6H),3.95(s,3H),3.48–3.40(m,2H),3.31–3.14(m,2H),3.12–2.94(m,3H),2.77–2.65(m,1H),2.22(t,4H),2.13(s,3H),1.78–1.64(m,2H),1.68–1.51(m,1H),1.50–1.42(m,1H).

Example 263:1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methoxyethan-1-one (481)

(a) N- [ [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl ] -2-methoxy-3-pyridinyl ] methyl ] -N- [1- (2-methoxyacetyl) -4-piperidinyl ] carbamic acid tert-butyl ester

To sodium acetate (73 mg,0.89 mmol), 1- (4-amino-1-piperidinyl) -2-methoxy-ethanone hydrochloride (186 mg,0.89 mmol) and 6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl]Acetic acid (36 μl,0.64 mmol) was added to a mixture of 2-methoxy-pyridine-3-carbaldehyde (250 mg,0.64 mmol) in 1mL THF and 1mL MeOH. After stirring at room temperature for 3 hours, the mixture was cooled in an ice bath and sodium cyanoborohydride (80 mg,1.27 mmol) was added in 2 portions. After 3 hours, the mixture was partitioned between EtOAc (20 mL) and water (15 mL). The layers were separated and the aqueous layer was extracted with 2×10ml EtOAc. The combined organics were washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford crude 1- [4- [ [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl group]-2-methoxy-3-pyridinyl]Methylamino group]-1-piperidinyl group]-2-methoxy-ethanone (346 mg). MS: m/z found 549.0[ M+H ]] ⁺ .

Crude 1- [4- [ [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl]-2-methoxy-3-pyridinyl]Methylamino group]-1-piperidinyl group]2-methoxy-ethanone (346 mg,0.63 mmol), 4-dimethylaminopyridine (15 mg,0.13 mmol) and N, N-diisopropylethylamine (219. Mu.L, 1.26 mmol) were dissolved in 8ml THF. Di-tert-butyl dicarbonate (192 mg,0.88 mmol) was added in portions. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (7 mL) and the mixture extracted with EtOAc (3×5 mL). Concentrating the combined organics under reduced pressure and passing through normal phase SiO ₂ The crude sample was purified by chromatography (0-100% EtOAc/hexanes) to afford N- [ [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl ] as a white foam]-2-methoxy-3-pyridinyl]Methyl group]-N- [1- (2-methoxyacetyl) -4-piperidinyl]Tert-butyl carbamate (250 mg,61% yield). MS: m/z found 649.1[ M+H ]] ⁺ .

(b) N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl ] phenyl ] -2-methoxy-3-pyridinyl ] methyl ] -N- [1- (2-methoxyacetyl) -4-piperidinyl ] carbamic acid tert-butyl ester

Tetrakis (triphenylphosphine) palladium (0) (26 mg,0.02 mmol), potassium carbonate (116 mg,0.84 mmol), N- [ [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl]-2-methoxy-3-pyridinyl]Methyl group]-N- [1- (2-methoxyacetyl) -4-piperidinyl]Tert-butyl carbamate (182 mg,0.28 mmol), and (4-formyl-3-methoxy-phenyl) boronic acid (55 mg,0.31 mmol) were suspended in 1, 4-dioxane/water (4:1, 2 ml). The solution was irradiated to 100 ℃ for 30 minutes in a Biotage Initiator microwave apparatus. The reaction mixture was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×5 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by normal phase silica gel chromatography (0-8% MeOH/DCM) to provide N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl ] as a white foam ]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [1- (2-methoxyacetyl) -4-piperidinyl]Tert-butyl carbamate (168 mg,80% yield). MS: m/z found 749.2M+H] ⁺ .

(c) 1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methoxyethan-1-one

Following reductive amination procedure B consisting of tert-butyl ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (1- (2-methoxyacetyl) piperidin-4-yl) carbamate (32 mg,0.04 mmol) and 1- (4-aminopiperidin-1-yl) ethan-1-one (13 mg,0.09 mmol), followed by the general Boc deprotection procedure 1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl)) amino) p iperidin-4-yl)) amino group) Methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl methyl) amino) piperidin-1-yl) -2-methoxyethan-1-one to prepare the formate salt. Yield 35%. LCMS: m/z found 775.2[ M+H ]] ⁺ Retention time = 2.78min, (method C). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(dd,1H),8.54(s,1H),7.77(d,1H),7.71(dd,1H),7.55(t,1H),7.50–7.42(m,2H),7.41(dd,1H),7.36–7.27(m,2H),7.27(d,1H),4.62(s,1H),4.56(d,1H),4.48(d,1H),4.20(d,1H),4.12(d,1H),4.08(s,2H),4.03(s,2H),4.03(d,1H),3.96(s,3H),3.91(s,3H),3.40(s,2H),3.40(d,1H),3.34–3.28(m,1H),3.21–3.07(m,2H),3.06(s,1H),2.93–2.83(m,1H),2.81–2.64(m,2H),2.12(s,3H),2.05(d,3H),1.55–1.27(m,4H).

Example 264:2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((1- (2-methoxyacetyl) piperidin-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one (490)

According to the method of preparing a pharmaceutical composition comprising (i) a compound selected from the group consisting of tert-butyl ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (1- (2-methoxyacetyl) piperidin-4-yl) carbamate (30 mg,0.04 mmol) and 2, 6-diazaspiro [3.4 ]]Reductive amination procedure B of octan-7-one (11 mg,0.09 mmol) followed by general Boc deprotection procedure 2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((1- (2-methoxyacetyl) piperidin-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-methoxybenzyl) -2, 6-diazaspiro [ 3.4)]The preparation of formate from octane-7-ketone. 43% yield. LCMS: m/z found 759.0[ M+H ]] ⁺ Retention time = 2.66min, (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ) Delta 8.62 (d, 1H), 7.78 (d, 1H), 7.71 (dd, 1H), 7.55 (t, 1H), 7.46-7.36 (m, 3H), 7.28 (dd, 3H), 4.49 (d, 1H), 4.20 (d, 1H), 4.12 (d, 1H), 4.03 (s, 3H), 3.93 (d, 5H), 3.84 (s, 2H), 3.58 (s, 2H), 3.51 (s, 4H), 3.40 (s, 3H), 3.32 (1H, by CD ₃ OD cover), 3.09 (t, 1H), 2.92 (s, 1H), 2.75 (t, 1H), 2.58 (s, 2H), 2.07 (d, 2H), 1.47-1.37 (m, 1H), 1.39–1.27(m,1H).

Example 265:1- (4- (((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methoxyethane-1-one (491)

According to the method of preparing a pharmaceutical composition comprising (i) a compound selected from the group consisting of tert-butyl ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (1- (2-methoxyacetyl) piperidin-4-yl) carbamate (30 mg,0.04 mmol) and 1- (2, 6-diazaspiro [ 3.3)]Reductive amination procedure B of heptan-2-yl) ethanone (14 mg,0.10 mmol) followed by general Boc deprotection procedure was performed to provide 1- (4- (((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [ 3.3))]Heptane-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methoxyethan-1-one. 22% yield. LCMS: m/z found 773.2[ M+H ]] ⁺ Retention time = 2.74min, (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),7.83(d,1H),7.71(dd,1H),7.56(t,1H),7.48–7.39(m,3H),7.34–7.26(m,3H),4.55(d,1H),4.33(s,2H),4.22(d,1H),4.17–3.96(m,11H),3.94(s,3H),3.84(s,4H),3.40(s,3H),3.12(t,2H),2.75(t,1H),2.14(d,2H),1.84(s,3H),1.57–1.38(m,2H).

Example 266:1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((4-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methoxyethan-1-one (510)

According to the method of preparing a pharmaceutical composition comprising (i) a compound selected from the group consisting of ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (1- (2-methoxyacetyl) piperidin-4-yl) carbamic acid tert-butyl ester (31 mg,0.04 mmol) and Reductive amination procedure B of piperidin-4-ol (9 mg,0.09 mmol) followed by general Boc deprotection procedure 1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((4-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methoxyethan-1-one) was prepared as the formate salt. 33% yield. LCMS: m/z found 734.3[ M+H ]] ⁺ Retention time = 2.74min, (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.56(s,1H),7.79(d,1H),7.71(dd,1H),7.60–7.38(m,4H),7.37–7.24(m,3H),4.49(d,1H),4.20(d,1H),4.12(d,1H),4.03(s,3H),4.03(s,1H),3.94(s,4H),3.80(s,1H),3.40(s,3H),3.17(s,2H),3.09(t,1H),2.93(s,1H),2.80–2.70(m,3H),2.07(d,2H),2.00–1.92(m,2H),1.72(s,2H),1.47–1.29(m,4H).

Example 267:1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-hydroxyethan-1-one (533)

(a) (1- (2- ((tert-Butoxycarbonyl) oxy) acetyl) piperidin-4-yl) ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

To sodium acetate (58 mg,0.71 mmol), 1- (4-aminopiperidin-1-yl) -2-hydroxyethan-1-one (138 mg,0.71 mmol) and 6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl]Acetic acid (29 μl,0.51 mmol) was added to a mixture of 2-methoxy-pyridine-3-carbaldehyde (200 mg,0.51 mmol) in 1mL THF and 1mL MeOH. After stirring overnight at room temperature, the mixture was cooled in an ice bath and sodium cyanoborohydride (64 mg,1.02 mmol) was added in 2 portions. After 3 hours, the mixture was partitioned between EtOAc (20 mL) and water (15 mL). The layers were separated and the aqueous layer was extracted with 2×10ml EtOAc. Wash with brine (20 mL) The combined organics were dried over sodium sulfate and concentrated under reduced pressure. The crude material was triturated with diethyl ether (3×20 mL) followed by normal phase silica gel chromatography (1% to 10% MeOH/DCM) to give 1- [4- [ [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl ]]-2-methoxy-3-pyridinyl]Methylamino group]-1-piperidinyl group]-2-hydroxy-ethanone (85 mg, 31%). MS: m/z found 537.1[ M+H ]] ⁺ .

1- [4- [ [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl ]]-2-methoxy-3-pyridinyl]Methylamino group]-1-piperidinyl group]2-hydroxy-ethanone (80 mg,0.15 mmol), 4-dimethylaminopyridine (4 mg,0.03 mmol), and N, N-diisopropylethylamine (52. Mu.L, 0.30 mmol) were dissolved in 2ml THF and di-tert-butyl dicarbonate (46 mg,0.21 mmol) was added in portions. The resulting mixture was stirred at room temperature for 72 hours. The reaction mixture was diluted with water (7 mL) and the mixture extracted with EtOAc (3×5 mL). Concentrating the combined organics under reduced pressure and passing through normal phase SiO ₂ The crude sample was purified by chromatography (0-100% EtOAc/hexanes) to provide tert-butyl (1- (2- ((tert-butoxycarbonyl) oxy) acetyl) piperidin-4-yl) ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (90 mg,82% yield). MS: m/z found 737.2[ M+H ] ] ⁺ .

(b) (1- (2- ((tert-Butoxycarbonyl) oxy) acetyl) piperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

Tetrakis (triphenylphosphine) palladium (0) (7 mg,0.01 mmol), potassium carbonate (34 mg,0.24 mmol), N- [ [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl]-2-methoxy-3-pyridinyl]Methyl group]-N- [1- (2-methoxyacetyl) -4-piperidinyl]Tert-butyl carbamate (60 mg,0.08 mmol), and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (24 mg,0.09 mmol) were suspended in 1, 4-dioxane/water (4:1, 1 ml). The solution was irradiated to 100 ℃ for 30 minutes in a Biotage Initiator microwave apparatus. The reaction mixture was diluted with 5mL of water and extracted with EtOAc (3X 5 mL)Taking. The combined organics were concentrated under reduced pressure and the crude sample purified by normal phase silica gel chromatography (20% to 98% EtOAc/hexanes) to afford tert-butyl (1- (2- ((tert-butoxycarbonyl) oxy) acetyl) piperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (56 mg,82% yield). MS: m/z found 835.1[ M+H ]] ⁺ .

(c) 1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-hydroxyethan-1-one

Formate was prepared following reductive amination procedure B from tert-butyl (1- (2- ((tert-butoxycarbonyl) oxy) acetyl) piperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (27 mg,0.03 mmol) and 1- (4-aminopiperidin-1-yl) ethan-1-one (11 mg,0.08 mmol) followed by the general Boc deprotection procedure to prepare 1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-hydroxyethan-1-one. 52% yield. LCMS: m/z found 761.4[ M+H ]] ⁺ Retention time = 2.69min, (method C). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.54(s,1H),7.77(d,1H),7.71(dd,1H),7.55(t,1H),7.50–7.42(m,2H),7.41(dd,1H),7.36–7.27(m,2H),7.26(d,1H),4.56(d,1H),4.48(d,1H),4.23(d,2H),4.08(s,2H),4.03(s,3H),3.96(s,3H),3.91(s,2H),3.78(d,1H),3.17(d,1H),3.06(t,2H),2.93–2.63(m,3H),2.15–2.05(m,8H),1.56–1.27(m,4H).

Example 268:1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-hydroxyethan-1-one (539)

Formate was prepared following reductive amination procedure B from tert-butyl (1- (2- ((tert-butoxycarbonyl) oxy) acetyl) piperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (28 mg,0.03 mmol) and trans-4-aminocyclohexanol (10 mg,0.03 mmol), followed by the general Boc deprotection procedure to prepare 1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-hydroxyethan-1-one. Yield 37%. LCMS: m/z found 734.4[ M+H ] ] ⁺ Retention time = 2.69min, (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),8.52(s,1H),7.81(d,1H),7.72(dd,1H),7.60–7.26(m,7H),4.63(s,1H),4.52(d,1H),4.26(d,3H),4.23(s,1H),4.06–3.97(m,8H),3.82(d,1H),3.63-3.53(m,1H),3.13–3.02(m,3H),2.78(t,1H),2.23(d,2H),2.09(t,4H),1.60–1.27(m,5H).

Example 269:1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (3-methoxypropionyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -3-methoxypropane-1-one (546)

(a) 1- (4-aminopiperidin-1-yl) -3-methoxypropane-1-one hydrochloride

A solution of tert-butyl N- (4-piperidinyl) carbamate (0.80 g,3.99 mmol) in 32mL DCM was cooled in an ice bath. Triethylamine (1.11 ml,7.99 mmol) was added. A solution of 2-methoxyacetyl chloride (0.45 mL,4.39 mmol) in 8mL DCM was slowly added. 30 minutesAfter this time, the reaction mixture was diluted with 30mL of DCM and washed with saturated sodium bicarbonate solution (10 mL), 0.3M HCl (10 mL), and saturated sodium bicarbonate solution (10 mL). The organics were dried over sodium sulfate and concentrated under reduced pressure to afford crude N- [1- (3-methoxypropionyl) -4-piperidinyl as a white solid]Tert-butyl carbamate (1.04 g,91% yield). MS: m/z found 287.2[ M+H ]] ⁺ . To N- [1- (3-methoxypropionyl) -4-piperidinyl]Tert-butyl carbamate (0.58 g,2.03 mmol) was added 4M hydrogen chloride in 1, 4-dioxane (5.06 ml,20.25 mmol). After stirring at room temperature for 2 hours, volatiles were removed in vacuo. The crude material was triturated with 3X10mL dry diethyl ether and dried under vacuum to give 1- (4-aminopiperidin-1-yl) -3-methoxypropane-1-one hydrochloride (0.45 g) MS: m/z found 187.1[ M+H ] ⁺ .

(b) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (3-methoxypropionyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -3-methoxypropane-1-one

Formate was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (30 mg,0.06 mmol) and 1- (4-aminopiperidin-1-yl) -3-methoxypropane-1-one hydrochloride (44 mg,0.21 mmol) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (3-methoxypropionyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -3-methoxypropane-1-one. 44% yield. LCMS: m/z found 833.3[ M+H ]] ⁺ Retention time = 2.93min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.53(s,1H),7.81(d,1H),7.72(dd,1H),7.60–7.39(m,4H),7.39–7.26(m,3H),4.72–4.48(m,3H),4.21(s,2H),4.04(m,6H),4.00(d,5H),3.68–3.64(m,4H),3.34(dd,6H),3.26(d,1H),3.21–3.10(m,2H),3.03(s,1H),2.80–2.56(m,5H),2.25–1.98(m,4H),1.67–1.26(m,3H).

Example 270:1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -3-methoxypropane-1-one (607)

(a) N- [ [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl ] -2-methoxy-3-pyridinyl ] methyl ] -N- [1- (3-methoxypropionyl) -4-piperidinyl ] carbamic acid tert-butyl ester

To sodium acetate (64 mg,0.78 mmol), 1- (4-amino-1-piperidinyl) -3-methoxy-propan-1-one hydrochloride (173 mg,0.78 mmol) and 6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl]A mixture of 2-methoxy-pyridine-3-carbaldehyde (218 mg,0.55 mmol) in 1mL THF and 1mL MeOH was added acetic acid (32 μl,0.55 mmol). After stirring overnight at room temperature, the mixture was cooled in an ice bath and sodium cyanoborohydride (70 mg,1.11 mmol) was added in 2 portions. After 3 hours at room temperature, the mixture was partitioned between EtOAc (20 mL) and water (15 mL). The layers were separated and the aqueous layer was extracted with 2×10ml EtOAc. The combined organics were washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford crude 1- [4- [ [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl group]-2-methoxy-3-pyridinyl]Methylamino group]-1-piperidinyl group]-3-methoxy-propan-1-one (330 mg). MS found 563.2M+H] ⁺ .

To 1- [4- [ [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl ]]-2-methoxy-3-pyridinyl]Methylamino group]-1-piperidinyl group]A mixture of 3-methoxy-propan-1-one (0.33 g,0.59 mmol), 4-dimethylaminopyridine (14.30 mg,0.12 mmol), and N, N-diisopropylethylamine (0.20 mL,1.17 mmol) in 6mL THF was added di-tert-butyl dicarbonate (0.19 g,0.88 mmol) in portions. After stirring overnight at room temperature, the mixture was dissolved in 20mL EtOAc and washed with water (15 mL) and brine (15 mL). The organic matter is dried by sodium sulfate Dried and concentrated under reduced pressure. Purification of the crude sample by normal phase silica gel chromatography (15% to 100% EtOAc/hexanes) provided N- [ [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl]-2-methoxy-3-pyridinyl]Methyl group]-N- [1- (3-methoxypropionyl) -4-piperidinyl]Tert-butyl carbamate (0.25 g, 64%). MS found 664.3M+H] ⁺ .

(b) N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl ] phenyl ] -2-methoxy-3-pyridinyl ] methyl ] -N- [1- (3-methoxypropionyl) -4-piperidinyl ] carbamic acid tert-butyl ester

Tetrakis (triphenylphosphine) palladium (0) (27 mg,0.02 mmol), potassium carbonate (120 mg,0.87 mmol), N- [ [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl ]]-2-methoxy-3-pyridinyl]Methyl group]-N- [1- (3-methoxypropionyl) -4-piperidinyl]Tert-butyl carbamate (192 mg,0.29 mmol) and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (82 mg,0.31 mmol) were suspended in 1, 4-dioxane/water (4:1, 2 ml). The solution was irradiated to 100 ℃ for 30 minutes in a Biotage Initiator microwave apparatus. The reaction mixture was diluted with 10mL of water and extracted with EtOAc (3×5 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by normal phase silica gel chromatography (20-100% etoac/hexanes) to afford N- [ [6- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl ] as a white foam ]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N- [1- (3-methoxypropionyl) -4-piperidinyl]Tert-butyl carbamate (200 mg, 91%). MS: m/z found 763.3M+H] ⁺ .

(c) 1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -3-methoxypropane-1-one

According to the formula ((6- (2-chloro)-tert-butyl 3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (1- (3-methoxypropionyl) piperidin-4-yl) carbamate (32 mg,0.04 mmol) and 1- (4-aminopiperidin-1-yl) ethan-1-one (15 mg,0.10 mmol) followed by general Boc deprotection procedure to prepare 1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -3-methoxypropane-1-one. Yield 51%. LCMS: m/z found 789.3[ M+H ]] ⁺ Retention time = 2.82min, (method C). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),8.49(s,2H),7.87(d,1H),7.72(dd,1H),7.62–7.50(m,2H),7.50–7.41(m,2H),7.39(d,1H),7.37–7.30(m,2H),4.64(s,1H),4.30(s,2H),4.23–4.02(m,7H),3.99(s,3H),3.67(td,2H),3.46–3.36(m,1H),3.34(s,3H),3.36–3.11(m,3H),2.79–2.57(m,4H),2.30–2.11(m,5H),2.14(s,3H),1.71–1.41(m,4H).

Example 271:1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((4-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -3-methoxypropane-1-one (616)

Formate was prepared following reductive amination procedure B from ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (1- (3-methoxypropionyl) piperidin-4-yl) carbamic acid tert-butyl ester (31 mg,0.04 mmol) and piperidin-4-ol (10 mg,0.10 mmol) followed by the general Boc deprotection procedure to prepare 1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((4-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -3-methoxypropane-1-one. Yield 38%. LCMS: m/z found 748.3[ M+H ]] ⁺ Retention time = 2.79min, (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.54(s,1H),7.79(d,1H),7.71(dd,1H),7.60–7.39(m,4H),7.38–7.25(m,3H),4.55(d,1H),4.04(s,4H),3.98–3.94(m,5H),3.88–3.75(m,1H),3.66(t,2H),3.33(s,3H),3.28–3.09(m,3H),2.97(s,1H),2.85–2.58(m,6H),2.08(t,2H),2.02–1.92(m,2H),1.73(s,2H),1.56–1.25(m,2H).

Example 272:2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((1- (3-methoxypropionyl) piperidin-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one (625)

According to the method of preparing a pharmaceutical composition comprising (i) a compound selected from the group consisting of tert-butyl ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (1- (3-methoxypropionyl) piperidin-4-yl) carbamate (32 mg,0.04 mmol) and 2, 6-diazaspiro [3.4]]Reductive amination procedure B of octan-7-one (13 mg,0.10 mmol) followed by general Boc deprotection procedure 2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((1- (3-methoxypropionyl) piperidin-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-methoxybenzyl) -2, 6-diazaspiro [ 3.4) ]The preparation of formate from octane-7-ketone. 40% yield. LCMS: m/z found 773.4[ M+H ]] ⁺ Retention time = 2.71min, (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.59(s,2H),7.86(d,1H),7.72(dd,1H),7.57(t,1H),7.49–7.40(m,3H),7.36–7.28(m,3H),4.65(d,1H),4.16(d,4H),4.07(s,3H),3.95(s,3H),3.86(s,4H),3.69–3.64(m,2H),3.63(s,2H),3.34(m,4H),3.17(t,1H),2.78–2.68(m,2H),2.66(s,3H),2.64–2.60(m,1H),2.19(t,2H),1.65–1.40(m,2H).

Example 273:1- (4- (((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -3-methoxypropane-1-one (631)

According to the method described for preparing the composition from ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (1- (3-methoxypropionyl) piperidin-4-yl) carbamic acid tert-butyl ester (32 mg,0.04 mmol) and 1- (2, 6-diazaspiro [ 3.3)]Reductive amination procedure B of heptan-2-yl) ethan-1-one hydrochloride (19 mg,0.11 mmol) followed by general Boc deprotection procedure was performed to provide 1- (4- (((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [ 3.3))]Heptane-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -3-methoxypropane-1-one to prepare the formate salt. 34% yield. LCMS: m/z found 787.7[ M+H ]] ⁺ Retention time = 2.77min, (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.53(s,1H),7.85(d,1H),7.72(dd,1H),7.57(t,1H),7.48–7.40(m,3H),7.35–7.27(m,3H),4.62(d,1H),4.33(s,2H),4.15–4.04(m,10H),3.92(d,6H),3.67 -3.63(m,2H),3.34(s,3H),3.20(s,2H),3.15(d,1H),2.78–2.67(m,2H),2.66–2.58(m,1H),2.16(t,2H),1.84(s,3H),1.62–1.38(m,2H).

Example 274: (S) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -3-methoxypropane-1-one (632)

Following reductive amination procedure B from ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (1- (3-methoxypropionyl) piperidin-4-yl) carbamic acid tert-butyl ester (29 mg,0.04 mmol) and (S) -1-aminopropane-2-ol (7 mg,0.09 mmol), followed by the general Boc deprotection procedure, (S) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -3-methoxypropane-1-one was prepared as a formate salt. 46% yield. LCMS: m/z found 722.3[ M+H ]] ⁺ Retention time = 2.79min, (method a). ¹ H NMR(400MHz, methanol-d ₄ ):δ8.66(dd,1H),8.54(s,1H),7.79(d,1H),7.72(dd,1H),7.56(t,1H),7.52–7.45(m,2H),7.42(dd,1H),7.39–7.31(m,2H),7.27(dd,1H),4.54(d,1H),4.24(d,2H),4.10–4.02(m,1H),4.03(s,3H),3.97(d,5H),3.66(t,2H),3.35(s,3H),3.19–3.08(m,1H),3.05–2.88(m,3H),2.81(dd,1H),2.76–2.57(m,3H),2.07(t,2H),1.51–1.27(m,2H),1.22(dd,3H).

Example 275:1- (6- ((6- (2-chloro-3- (3-chloro-2- (4- ((6- (2-hydroxyacetyl) -2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -2-hydroxyethan-1-one (667)

(a) 1- (2, 6-diazaspiro [3.3] heptane-2-yl) -2-hydroxy-ethanone

To 2, 6-diazaspiro [3.3]]A mixture of heptane-2-carboxylic acid tert-butyl ester half-oxalate (0.75 g,1.54 mmol) in 40mL DCM was added triethylamine (0.94 mL,6.78 mmol). The mixture was cooled in an ice bath. A solution of (2-chloro-2-oxo-ethyl) acetate (0.36 mL,3.39 mmol) in 10mL DCM was slowly added. After 3h, the mixture was washed with 20mL of saturated sodium bicarbonate, 20mL of 0.2M HCl, and 20mL of saturated sodium bicarbonate. The organics were dried over sodium sulfate, concentrated under reduced pressure, and passed through normal phase SiO ₂ Chromatography (15% to 100% EtOAc/hexanes) purification provided 6- (2-acetoxyacetyl) -2, 6-diazaspiro [3.3]Heptane-2-carboxylic acid tert-butyl ester (0.59 g,61% yield). MS: m/z found 299.2[ M+H ]] ⁺ . ¹ H NMR (400 MHz, chloroform-d) delta 4.48 (s, 2H), 4.33 (s, 2H), 4.16 (d, 2H), 4.13-4.03 (m, 4H), 2.15 (s, 2H), 1.43 (s, 9H).

To 6- (2-acetoxyacetyl) -2, 6-diazaspiro [3.3]A mixture of tert-butyl heptane-2-carboxylate (142 mg,0.48 mmol) in 1.5mL dioxane was slowly added to lithium hydroxide hydrateA solution of the material (42 mg,1.00 mmol) in 1.5mL of water. After 10 minutes, the mixture was cooled in an ice bath and acidified to ph=6 with 1M HCl. The mixture was extracted with 4×10ml DCM. The combined organics were dried over sodium sulfate. Removal of organics in vacuo to afford 6- (2-hydroxyacetyl) -2, 6-diazaspiro [3.3 ]]Heptane-2-carboxylic acid tert-butyl ester (82 mg,68% yield). MS: m/z found 257.2[ M+H ]] ⁺ . ¹ H NMR (400 MHz, chloroform-d) delta 4.20 (d, 4H), 4.08 (d, 4H), 3.98 (s, 2H), 1.43 (s, 9H).

To 6- (2-hydroxyacetyl) -2, 6-diazaspiro [3.3 ]]A solution of tert-butyl heptane-2-carboxylate (82 mg,0.32 mmol) in 3mL DCM at 0deg.C was added trifluoroacetic acid (0.80 mL,3.19 mmol). After 10min, the ice bath was removed. After 30min, volatiles were removed in vacuo. The resulting oil was azeotroped twice with 5mL toluene to provide crude 1- (2, 6-diazaspiro [3.3 ] as a TFA salt ]Heptane-2-yl) -2-hydroxy-ethanone (86 mg). MS: m/z found 157.1[ M+H ]] ⁺ .

(b) 1- [6- [ [4- [ 3-chloro-4- [ 2-chloro-3- [5- [ [2- (2-hydroxyacetyl) -2, 6-diazaspiro [3.3] heptan-6-yl ] methyl ] -6-methoxy-2-pyridinyl ] phenyl ] -2-pyridinyl ] -2-methoxy-phenyl ] methyl ] -2, 6-diazaspiro [3.3] heptan-2-yl ] -2-hydroxy-ethanone

1- (2, 6-diazaspiro [3.3] at room temperature]A mixture of heptane-2-yl) -2-hydroxy-ethanone TFA salt (43 mg,0.16 mmol) and sodium acetate (19 mg,0.23 mmol) in 0.45mL DCM was stirred for 10 min. After addition of 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (28 mg,0.06 mmol), the mixture was stirred for 5 min. Sodium triacetoxyborohydride (35 mg,0.16 mmol) was added. After stirring overnight at room temperature, the reaction mixture was diluted with 2mL of MeOH and filtered through a syringe filter. The crude product was purified by reverse phase chromatography (gradient of 5 to 65% acetonitrile in water, 0.05% formic acid) and the combined pure fractions were freeze-dried to provide 1- [6- [ [4- [ 3-chloro-4- [ 2-chloro-3- [5- [ [2- (2-hydroxyacetyl) -2, 6-diazaspiro [3.3] as formate salt]Heptan-6-yl]Methyl group]-6-methoxy-2-pyridinyl ]Phenyl group]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]-2, 6-diazaspiro [3.3]]Heptane-2-yl]-2-hydroxy-ethanone (9 mg,19% yield). LCMS: m/z found 773.4[ M+H ]] ⁺ Retention time = 2.47min, (method a). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.65(d,1H),8.49(s,1H),7.75–7.67(m,2H),7.56(t,1H),7.51–7.38(m,3H),7.38–7.24(m,3H),4.41(d,4H),4.21–4.11(m,6H),4.07–3.99(m,11H),3.96(s,3H),3.85(s,2H),3.72(s,4H).

Example 276:1- (6- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((6- (3-methoxypropionyl) -2, 6-diazaspiro [3.3] heptan-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -3-methoxypropane-1-one (679)

(a) 1- (2, 6-diazaspiro [3.3] heptane-2-yl) -2-methoxy-ethanone

To 2, 6-diazaspiro [3.3]]A mixture of heptane-2-carboxylic acid tert-butyl ester half-oxalate (0.75 g,1.54 mmol) in 40mL DCM was added triethylamine (0.94 mL,6.78 mmol). The mixture was cooled in an ice bath. A solution of 2-methoxyacetyl chloride (0.62 mL,6.78 mmol) in 10mL DCM was slowly added. After 3 hours, the mixture was washed with 20mL of saturated sodium bicarbonate solution, 20mL of 0.2M HCl, and 20mL of saturated sodium bicarbonate solution. The organics were dried over sodium sulfate, concentrated under reduced pressure, and passed through normal phase SiO ₂ Purification by chromatography (15% to 100% EtOAc/hexanes) provided 6- (3-methoxypropionyl) -2, 6-diazaspiro [3.3 ]Heptane-2-carboxylic acid tert-butyl ester (0.59 g,67% yield). ¹ H NMR (400 MHz, chloroform-d) delta 4.26 (s, 2H), 4.11 (s, 2H), 4.05 (s, 4H), 3.65 (t, 2H), 3.33 (s, 3H), 2.32 (t, 2H), 1.43 (s, 9H).

To 6- (3-methoxypropionyl) -2, 6-diazaspiro [3.3]]Tert-butyl heptane-2-carboxylate (0.20 g,0.70 mmol) in 7mL DCM at 0deg.C was added a solution of trifluoroacetic acid (1.76 mL,7.03 mmol) in 3mL DCM. After 10min, the ice bath was removed. After 45min, volatiles were removed in vacuo. The resulting oil was azeotroped twice with 5mL toluene to provide crude 1- (2, 6-diazaspiro [3.3] as a TFA salt]Heptane-2-yl) -2-methoxy-ethanone (0.19 g). ¹ H NMR (400 MHz, methanol-d) ₄ ) Delta 4.41 (d, 2H), 4.24 (s, 4H), 4.16 (s, 2H), 3.62 (t, 2H), 3.31 (s, 3H,overlaps with CD3OD), 2.35 (t, 2H). MS: m/z found 185.1[ M+H ]] ⁺ .

(b) 1- [6- [ [4- [ 3-chloro-4- [ 2-chloro-3- [ 6-methoxy-5- [ [2- (3-methoxypropionyl) -2, 6-diazaspiro [3.3] heptan-6-yl ] methyl ] -2-pyridinyl ] phenyl ] -2-pyridinyl ] -2-methoxy-phenyl ] methyl ] -2, 6-diazaspiro [3.3] heptan-2-yl ] -3-methoxy-propan-1-one

1- (2, 6-diazaspiro [3.3] at room temperature]A mixture of heptane-2-yl) -3-methoxy-propan-1-one TFA salt (47 mg,0.16 mmol) and sodium acetate (19 mg,0.23 mmol) in 0.45mL DCM was stirred for 10 min. After addition of 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (28 mg,0.06 mmol), the mixture was stirred for 5 min. Sodium triacetoxyborohydride (35 mg,0.16 mmol) was added. After stirring overnight at room temperature, the reaction mixture was diluted with 2mL of MeOH and filtered through a syringe filter. The crude product was purified by reverse phase chromatography (gradient of 5 to 65% acetonitrile in water, 0.05% formic acid) and the combined pure fractions were freeze-dried to provide 1- [6- [ [4- [ 3-chloro-4- [ 2-chloro-3- [ 6-methoxy-5- [ [2- (3-methoxypropionyl) -2, 6-diazaspiro [3.3] as formate salt ]Heptan-6-yl]Methyl group]-2-pyridyl group]Phenyl group]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]-2, 6-diazaspiro [3.3 ]]Heptane-2-yl]-3-methoxy-propan-1-one (17 mg,36% yield). LCMS: m/z found 829.3[ M+H ]] ⁺ Retention time = 2.74min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.64(d,1H),8.52(s,1H),7.74–7.67(m,2H),7.55(t,1H),7.48–7.38(m,3H),7.36–7.23(m,3H),4.35(d,4H),4.13–4.06(m,6H),4.01(s,3H),3.94(d,7H),3.80(s,2H),3.68–3.57(m,8H),3.33–3.29(m,6H),2.36–2.32(m,4H).

Example 277: n- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) propan-2-amine (211)

(a) ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) carbamic acid tert-butyl ester

From 6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl]Reductive amination procedure B of-2-methoxy-pyridine-3-carbaldehyde (400 mg,1.02 mmol) and a solution of methylamine (33% wt in ethanol, 2.04 mmol) provides 1- [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl group]-2-methoxy-3-pyridinyl]-N-methyl-methylamine, which is used in the next step without further purification. LCMS: m/z found 408.0[ M+H ]] ⁺ Retention time = 0.78min (method B).

To crude 1- [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl]-2-methoxy-3-pyridinyl]A solution of N-methyl-methylamine in DCM was added di-tert-butyl dicarbonate (278 mg,1.27 mmol). The mixture was stirred for 5 hours, concentrated in vacuo, and purified on a silica gel column with MeOH in DCM (0 to 10% gradient) as eluent to afford tert-butyl ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) carbamate. 75% yield over two steps. MS: m/z found 508.1[ M+H ] ] ⁺ 。

(b) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) carbamic acid tert-butyl ester

By using Suzuki coupling procedure B, a reaction was performed using N- [ [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl ]]-2-methoxy-3-pyridinyl]Methyl group]Tert-butyl N-methyl-carbamate (110 mg,0.22 mmol) and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (57 mg,0.22 mmol) were synthesized as such. Yield 76%. LCMS: m/z found 608.1[ M+H ]] ⁺ Retention time = 1.21min (method B).

(c) N- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) propan-2-amine

From tert-butyl ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) carbamate (50 mg,0.08 mmol) and propane-2-amine (10 mg,0.16 mmol) reductive amination procedure B afforded N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [4- [ (isopropylamino) methyl ] as crude material]-3-methoxy-phenyl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]tert-butyl-N-methyl-carbamate, LCMS: m/z found 651.2[ M+H ]] ⁺ Retention time = 0.99min (method B), which is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 65% yield was obtained via two steps. LCMS: m/z found 551.2[ M+H ] ] ⁺ Retention time = 1.79min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.67(d,1H),8.49(s,2H),7.87(d,1H),7.73(d,1H),7.58(t,1H),7.53(d,1H),7.50–7.43(m,2H),7.39(d,1H),7.36(d,2H),4.27(s,2H),4.23(s,2H),4.09(s,3H),4.00(s,3H),3.48(p,1H),2.75(s,3H),1.42(d,6H).

Example 278:1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one (212)

The N- [ [6- [3- [2- [4- [ [ (1-acetyl-4-piperidinyl) amino ] as crude material was provided from tert-butyl ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) carbamate (example 277, step (B)) (35 mg,0.06 mmol) and 1- (4-amino-1-piperidinyl) ethanone (16 mg,0.12 mmol) of reductive amination procedure B]Methyl group]-3-methoxy-phenyl]-3-chloro-4-pyridinyl]-2-chloro-phenyl]-2-methoxy-3-pyridinyl]Methyl group]Tert-butyl N-methyl-carbamate, LCMS: m/z found 734.3[ M+H ]] ⁺ Retention time = 0.95min (method B), which is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 80% yield over two steps. LCMS: m/z found 634.2[ M+H ]] ⁺ Retention time = 1.68min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(dd,1H),8.47(s,2H),7.90–7.83(m,1H),7.76–7.68(m,1H),7.58(t,1H),7.53(d,1H),7.49–7.43(m,2H),7.39(s,1H),7.38–7.31(m,2H),4.66(d,1H),4.29(s,2H),4.24(s,2H),4.09(s,3H),3.99(s,3H),3.52–3.34(m,2H),3.20(t,1H),2.76(s,3H),2.69(t,1H),2.22(t,2H),2.13(s,3H),1.69–1.44(m,2H).

Example 279:2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one (213)

From ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) carbamic acid tert-butyl ester (example 277, step (b)) (35 mg,0.06 mmol) and 2, 6-diazaspiro [3.4 ]]Reductive amination procedure B of octan-7-one (15 mg,0.12 mmol) provides N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [ 3-methoxy-4- [ (6-oxo-2, 7-diazaspiro [3.4 ] as crude material]Octan-2-yl) methyl]Phenyl group]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]Tert-butyl N-methyl-carbamate, LCMS: m/z found 718.3[ M+H ]] ⁺ Retention time = 0.93min (method B), which is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Yield 78% through two steps. LCMS: m/z found 618.2[ M+H ]] ⁺ Retention time = 1.63min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.41(s,2H),7.90(d,1H),7.76–7.69(m,1H),7.58(t,1H),7.52(d,1H),7.47–7.41(m,2H),7.38–7.30(m,3H),4.33–4.18(m,4H),4.09(s,3H),4.05–3.98(m,4H),3.97(s,3H),3.66(s,2H),2.77(s,3H),2.68(s,2H).

Example 280: (S) -4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) -3-hydroxybutyric acid (220)

From tert-butyl ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) carbamate (example 277, step (B)) (30 mg,0.05 mmol) and (3S) -4-amino-3-hydroxy-butanoic acid (12 mg,0.10 mmol) reductive amination procedure B afforded (3S) -4- [ [4- [4- [3- [5- [ tert-butoxycarbonyl (methyl) amino) as crude material ]Methyl group]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]-2-methoxy-phenyl]Methylamino group]-3-hydroxy-butyric acid, MS: m/z found 711.2[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 40% yield through two steps. LCMS: m/z found 611.2[ M+H ]] ⁺ Retention time = 1.62min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.70–8.63(m,1H),8.41–8.35(m,2H),7.87(d,1H),7.76–7.69(m,1H),7.61–7.55(m,1H),7.55–7.50(m,1H),7.48–7.43(m,2H),7.40–7.31(m,3H),4.32(s,2H),4.25(s,2H),4.24–4.18(m,1H),4.09(s,3H),3.99(s,3H),3.20(d,1H),3.02(dd,1H),2.77(s,3H),2.47(d,2H).

Example 281:3- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) propanoic acid (221)

From tert-butyl ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) carbamate (example 277, step (B)) (30 mg,0.05 mmol) and 3-aminopropionic acid (9 mg,0.10 mmol) reductive amination procedure B afforded 3- [ [4- [4- [3- [5- [ [ tert-butoxycarbonyl (methyl) amino) as crude material]Methyl group]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]-2-methoxy-phenyl]Methylamino group]Propionic acid, LCMS: m/z found 681.2[ M+H ]] ⁺ Retention time = 0.96min (method B), which is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Yield 64% through two steps. LCMS: m/z found 581.2[ M+H ] ] ⁺ Retention time = 1.65min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),8.36(s,2H),7.87(d,1H),7.77–7.68(m,1H),7.58(t,1H),7.51(d,1H),7.46(dd,2H),7.41–7.29(m,3H),4.28(s,2H),4.26(s,2H),4.09(s,3H),4.01(s,3H),3.21(t,2H),2.77(s,3H),2.55(t,2H).

Example 282: (S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid (226)

From tert-butyl ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) carbamate (example 277, step (B)) (30 mg,0.05 mmol) and (3S) -pyrrolidine-3-carboxylic acid (11 mg,0.10 mmol) of reductive amination procedure B afforded (3S) -1- [ [4- [4- [3- [5 ] tert-butoxycarbonyl (methyl) amino ] as crude material]Methyl group]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]-2-methoxy-phenyl]Methyl group]Pyrrolidine-3-carboxylic acid, LCMS: m/z found 707.2[ M+H ]] ⁺ Retention time = 0.96min (method B), whichDeprotection and purification by a general Boc deprotection procedure provides the final product as formate. Yield 66% over two steps. LCMS: m/z found 607.2[ M+H ]] ⁺ Retention time = 2.02min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.67(d,1H),8.44(s,2H),7.87(d,1H),7.76–7.71(m,1H),7.62–7.50(m,2H),7.48–7.44(m,2H),7.43–7.31(m,3H),4.48(s,2H),4.25(s,2H),4.09(s,3H),4.01(s,3H),3.66–3.56(m,1H),3.43(d,3H),3.15–3.06(m,1H),2.77(s,3H),2.43–2.31(m,1H),2.32–2.17(m,1H).

Example 283:2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -2-azaspiro [3.3] heptane-6-carboxylic acid (227)

From ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) carbamic acid tert-butyl ester (example 277, step (b)) (30 mg,0.05 mmol) and 2-azaspiro [3.3 ]]Reductive amination procedure B of heptane-6-carboxylic acid (14 mg,0.10 mmol) provides 2- [ [4- [4- [3- [5- [ [ tert-butoxycarbonyl (methyl) amino ] as crude material]Methyl group]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]-2-methoxy-phenyl]Methyl group]-2-azaspiro [3.3]Heptane-6-carboxylic acid, LCMS: m/z found 733.3[ M+H ]] ⁺ Retention time = 0.97min (method B), which is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Yield 60% through two steps. LCMS: m/z found 633.2[ M+H ]] ⁺ Retention time = 2.09min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.70–8.58(m,1H),8.51(s,2H),7.86(d,1H),7.72(dt,1H),7.58(td,1H),7.52–7.42(m,3H),7.42–7.31(m,2H),7.32–7.23(m,1H),4.44–4.33(m,2H),4.22(s,2H),4.12(d,2H),4.09(s,3H),4.01–3.88(m,4H),2.90–2.82(m,1H),2.78(s,1H),2.75(s,3H),2.51–2.37(m,2H),2.36–2.27(m,1H),1.92–1.84(m,1H).

Example 284:3- (((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) bicyclo [1.1.1] pentane-1-carboxylic acid (228)

From tert-butyl ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) carbamate (example 277, step (b)) (30 mg,0.05 mmol) and 3- (aminomethyl) bicyclo [ 1.1.1.1) ]Reductive amination procedure B of pentane-1-carboxylic acid (14 mg,0.10 mmol) provides 3- [ [ [4- [4- [3- [5- [ [ tert-butoxycarbonyl (methyl) amino ] as crude material]Methyl group]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]-2-methoxyphenyl]Methylamino group]Methyl group]Bicyclo [1.1.1]Pentane-1-carboxylic acid, LCMS: m/z found 733.3[ M+H ]] ⁺ Retention time = 0.96min (method B), which is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Yield 61% over two steps. LCMS: m/z found 633.2[ M+H ]] ⁺ Retention time = 2.07min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.67(d,1H),8.42(s,2H),7.87(d,1H),7.76–7.70(m,1H),7.58(t,1H),7.52(d,1H),7.46(t,2H),7.40(s,1H),7.36(t,2H),4.30(s,2H),4.25(s,2H),4.09(s,3H),4.00(s,3H),3.17(s,2H),2.77(s,3H),2.05(s,6H).

Example 285: (S) -1- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) pyrrolidine-3-carboxylic acid (239)

(a) (1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

From 6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl]Reductive amination procedure B of-2-methoxy-pyridine-3-carbaldehyde (250 mg,0.64 mmol) and 1- (4-amino-1-piperidinyl) ethanone (181 mg,1.27 mmol) provides 1- [4- [ [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl ] ]-2-methoxy-3-pyridinyl]Methylamino group]-1-piperidinyl group]The ethanone, which is used in the next step without further purification. LCMS: m/z found 519.1[ M+H ]] ⁺ Retention time = 0.79min (method B).

To crude 1- [4- [ [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl ]]-2-methoxy-3-pyridinyl]Methylamino group]-1-piperidinyl group]A solution of ketene (330 mg,0.63 mmol) in DCM was added di-tert-butyl dicarbonate (153 mg,0.70 mmol) and DMAP (7 mg,0.06 mmol). The mixture was stirred for 2 hours, concentrated in vacuo, and purified on a silica gel column with MeOH in DCM (0 to 10% gradient) as eluent to afford tert-butyl (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (365 mg,0.59 mmol). 92% yield over two steps. LCMS: m/z found 619.2[ M+H ]] ⁺ Retention time = 1.15min (method B).

(b) (1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

This intermediate was synthesized using suzuki coupling procedure B from tert-butyl (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (280 mg,0.45 mmol) and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (118 mg,0.45 mmol) by stirring at 110 ℃ for 4 hours. 77% yield. LCMS: m/z found 719.2[ M+H ] ] ⁺ Retention time = 1.12min (method B).

(c) (S) -1- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) pyrrolidine-3-carboxylic acid

From tert-butyl (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (30 mg,0.04 mmol) and (3S) -pyrrolidine-3-carboxylic acid (10 mg,0.08 mmol) of reductive amination procedure B provided (S) -1- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) (tert-butoxycarbonyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) pyrrolidine-3-carboxylic acid as crude material with LCMS: m/z actual measurement 818.3[ M+H] ⁺ Retention time = 0.87min (method B), which is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 55% yield over two steps. LCMS: m/z found 718.3[ M+H ]] ⁺ Retention time = 1.72min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.67(d,1H),8.38(s,2H),7.92–7.81(m,1H),7.72(d,1H),7.62–7.51(m,2H),7.49–7.42(m,2H),7.41(s,1H),7.36(t,2H),4.66(d,1H),4.55–4.39(m,2H),4.26(s,2H),4.14–4.03(m,4H),4.01(s,3H),3.65–3.56(m,1H),3.52–3.35(m,3H),3.21(t,2H),3.14–3.07(m,1H),2.76–2.67(m,1H),2.44–2.32(m,1H),2.31–2.16(m,3H),2.14(s,3H),1.68–1.43(m,2H).

Example 286:1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (240)

From tert-butyl (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (example 285, step (B)) (35 mg,0.05 mmol) and methylamine solution (33% wt in ethanol, 0.10 mmol) of reductive amination procedure B was provided as crude materialN- (1-acetyl-4-piperidinyl) -N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [ 3-methoxy-4- (methylaminomethyl) phenyl ]]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]Tert-butyl carbamate, LCMS: m/z found 734.3[ M+H ]] ⁺ Retention time = 0.88min (method B), which is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Yield 60% through two steps. LCMS: m/z found 634.2[ M+H ]] ⁺ Retention time = 1.71min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.70–8.64(m,1H),8.47(s,2H),7.86(d,1H),7.72(d,1H),7.57(t,1H),7.51(d,1H),7.49–7.47(m,1H),7.44(d,1H),7.40(s,1H),7.38–7.28(m,2H),4.61(d,1H),4.27(s,2H),4.16(s,2H),4.10–3.95(m,7H),3.27–3.13(m,2H),2.79–2.60(m,4H),2.24–2.15(m,2H),2.13(s,3H),1.63–1.35(m,2H).

Example 287:2- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2-azaspiro [3.3] heptane-6-carboxylic acid (243)

From tert-butyl (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (example 285, step (b)) (30 mg,0.04 mmol) and 2-azaspiro [ 3.3.3 ] ]Reductive amination procedure B of heptane-6-carboxylic acid (12 mg,0.08 mmol) provides 2- [ [4- [4- [3- [5- [ [ (1-acetyl-4-piperidinyl) -t-butoxycarbonyl-amino ] as crude material]Methyl group]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]-2-methoxy-phenyl]Methyl group]-2-azaspiro [3.3]Heptane-6-carboxylic acid, LCMS: m/z found 844.3[ M+H ]] ⁺ Retention time = 0.89min (method B), which is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 48% yield over two steps. LCMS: m/z found 744.3[ M+H ]] ⁺ Retention time = 1.79min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),8.45(s,2H),7.87(d,1H),7.72(d,1H),7.57(t,1H),7.48(ddd,3H),7.41–7.28(m,3H),4.63(d,1H),4.47–4.33(m,2H),4.27–4.11(m,4H),4.09–4.00(m,5H),4.00–3.91(m,3H),3.36–3.26(m,2H),3.20(t,1H),2.89(t,1H),2.71(t,1H),2.57–2.31(m,3H),2.26–2.08(m,5H),1.92(d,1H),1.66–1.40(m,2H).

Example 288:2- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one (244)

From tert-butyl (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (example 285, step (b)) (30 mg,0.04 mmol) and 2, 6-diazaspiro [3.4]]Reductive amination procedure B of octan-7-one (11 mg,0.08 mmol) provides N- (1-acetyl-4-piperidinyl) -N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [ 3-methoxy-4- [ (6-oxo-2, 7-diazaspiro [3.4] as a crude material ]Octan-2-yl) methyl]Phenyl group]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]Tert-butyl carbamate, LCMS: m/z found 829.3[ M+H ]] ⁺ Retention time = 0.86min (method B), which is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Yield 30% through two steps. LCMS: m/z found 729.3[ M+H ]] ⁺ Retention time = 1.64min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.67–8.62(m,1H),8.45(s,2H),7.87(d,1H),7.72(d,1H),7.61–7.53(m,1H),7.50–7.41(m,3H),7.38–7.29(m,3H),4.71–4.53(m,1H),4.21(s,4H),4.12–4.00(m,4H),3.98–3.89(m,6H),3.64(s,2H),3.37–3.26(m,2H),3.20(t,1H),2.79–2.60(m,3H),2.27–2.08(m,5H),1.67–1.38(m,2H).

Example 289: (S) -1- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) pyrrolidine-3-carboxylic acid isopropyl ester (245)

The (3S) -1- [4- [3- [5- [ [ (1-acetyl-4-piperidinyl) -t-butoxycarbonyl-amino ] as crude material was provided from tert-butyl (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (example 285, step (B)) (35 mg,0.05 mmol) and isopropyl (3S) -pyrrolidine-3-carboxylate (15 mg,0.10 mmol) of reductive amination procedure B]Methyl group]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]-2-methoxy-phenyl]Methyl group]Pyrrolidine-3-carboxylic acid isopropyl ester, LCMS: m/z found 860.4[ M+H ] ] ⁺ Retention time = 0.96min (method B), which is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Yield 60% through two steps. LCMS: m/z found 760.3[ M+H ]] ⁺ Retention time = 2.07min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.51(s,2H),7.83(d,1H),7.72(d,1H),7.56(t,1H),7.50(d,1H),7.47–7.40(m,2H),7.36–7.28(m,3H),5.05–4.97(m,1H),4.57(d,1H),4.15–3.96(m,8H),3.95(s,3H),3.28–2.95(m,7H),2.71(t,1H),2.33–2.06(m,7H),1.57–1.35(m,2H),1.25(d,6H).

Example 290: (S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid isopropyl ester (278)

From tert-butyl ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) carbamate (example 277, step (B)) (50 mg,0.08 mmol) and isopropyl (3S) -pyrrolidine-3-carboxylate (26 mg,0.16 mmol) of reductive amination procedure B afforded (3S) -1- [ [4- [4- [3- [5 ] t-butoxycarbonyl (methyl) amino group as crude material]Methyl group]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]-2-methoxy-phenyl]Methyl group]Pyrrolidine-3-carboxylic acid isopropylEster, LCMS: m/z found 749.3[ M+H ]] ⁺ Retention time = 1.04min (method B), which is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 55% yield over two steps. LCMS: m/z found 649.3[ M+H ] ] ⁺ Retention time = 2.08min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65–8.60(m,1H),8.58–8.52(m,2H),7.79(d,1H),7.71(d,1H),7.56(t,1H),7.48–7.39(m,3H),7.34–7.21(m,3H),5.05–4.91(m,1H),4.05(s,3H),4.00(s,2H),3.91(s,3H),3.80(s,2H),3.09–3.00(m,1H),3.00–2.92(m,1H),2.87–2.75(m,2H),2.72–2.67(m,1H),2.15–2.05(m,2H),1.23(d,6H).

Example 291:3- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) propanoic acid isopropyl ester (279)

From tert-butyl ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) carbamate (example 277, step (B)) (50 mg,0.08 mmol) and isopropyl 3-aminopropionate (22 mg,0.16 mmol) reductive amination procedure B afforded 3- [ [4- [4- [3- [5- [ [ tert-butoxycarbonyl (methyl) amino ] as crude material]Methyl group]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]-2-methoxy-phenyl]Methylamino group]Isopropyl propionate, LCMS: m/z found 723.3[ M+H ]] ⁺ Retention time = 1.03min (method B), which is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 65% yield was obtained via two steps. LCMS: m/z found 623.2[ M+H ]] ⁺ Retention time = 2.05min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.67(s,1H),7.87(d,1H),7.76–7.70(m,1H),7.68–7.63(m,1H),7.63–7.55(m,2H),7.54–7.43(m,3H),7.42–7.32(m,2H),5.07(q,1H),4.34(s,2H),4.26(s,2H),4.09(s,3H),4.01(s,3H),3.34(t,2H),2.82–2.73(m,5H),1.27(d,6H).

Example 292: (S) -4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) -3-hydroxybutyric acid isopropyl ester (280)

From tert-butyl ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) carbamate (example 277, step (B)) (50 mg,0.08 mmol) and isopropyl (3S) -4-amino-3-hydroxy-butyrate (26 mg,0.16 mmol) of reductive amination procedure B afforded 3- [ [4- [4- [3- [5- [ tert-butoxycarbonyl (methyl) amino ] as crude material]Methyl group]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]-2-methoxy-phenyl]Methylamino group]Isopropyl propionate, LCMS: m/z found 753.3[ M+H ]] ⁺ Retention time = 1.02min (method B), which is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Yield 60% through two steps. LCMS: m/z found 653.2[ M+H ]] ⁺ Retention time = 1.96min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),8.52(s,2H),7.86(d,1H),7.73(d,1H),7.58(t,1H),7.52–7.42(m,3H),7.39–7.30(m,3H),5.06–4.96(m,1H),4.36–4.26(m,1H),4.24(s,2H),4.20(s,2H),4.08(s,3H),3.99(s,3H),3.11(d,1H),2.99–2.89(m,1H),2.73(s,3H),2.56–2.49(m,2H),1.24(d,6H).

Example 293: isopropyl 2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -2-azaspiro [3.3] heptane-6-carboxylate (281)

From ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) carbamic acid tert-butyl ester (example 277, step (b)) (50 mg,0.08 mmol) and 2-azaspiro [3.3] ]Reductive amination procedure B of isopropyl heptane-6-carboxylate (30 mg,0.16 mmol) provides 2- [ [4- [4- [3 ] as crude material- [5- [ [ tert-butoxycarbonyl (methyl) amino ]]Methyl group]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]-2-methoxy-phenyl]Methyl group]-2-azaspiro [3.3]Heptane-6-carboxylic acid isopropyl ester, LCMS: m/z found 775.3[ M+H ]] ⁺ Retention time = 1.05min (method B), which is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Yield 50% over two steps. LCMS: m/z found 675.2[ M+H ]] ⁺ Retention time = 2.17min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(dd,1H),8.52(s,2H),7.85(d,1H),7.73(d,1H),7.58(t,1H),7.50–7.42(m,3H),7.40–7.29(m,3H),5.03–4.93(m,1H),4.24(s,2H),4.19(s,2H),4.08(s,3H),4.02–3.93(m,7H),3.05–2.93(m,1H),2.73(s,3H),2.57–2.47(m,2H),2.47–2.38(m,2H),1.22(dt,6H).

Example 294:1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (315)

From tert-butyl (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (example 285, step (b)) (30 mg,0.04 mmol) and 1- [4- (methylamino) -1-piperidinyl)]Reductive amination procedure B of ethaneketone (13 mg,0.08 mmol) provides N- (1-acetyl-4-piperidinyl) -N- [ [6- [3- [2- [4- [ [ (1-acetyl-4-piperidinyl) -methyl-amino ] as crude material ]Methyl group]-3-methoxy-phenyl]-3-chloro-4-pyridinyl]-2-chloro-phenyl]-2-methoxy-3-pyridinyl]Methyl group]Tert-butyl carbamate, LCMS: m/z found 859.4[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 48% yield over two steps. LCMS: m/z found 759.3[ M+H ]] ⁺ Retention time = 1.73min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.67–8.61(m,1H),8.52(s,2H),7.81(d,1H),7.74–7.68(m,1H),7.56(td,1H),7.50(d,1H),7.47–7.39(m,2H),7.36–7.24(m,3H),4.68(d,1H),4.54(d,1H),4.14–3.88(m,12H),3.22–3.09(m,3H),3.07–2.95(m,1H),2.78–2.59(m,2H),2.53(s,3H),2.17–2.01(m,10H),1.82–1.54(m,2H),1.53–1.29(m,2H).

Example 295:2- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one (332)

(a) (1-Acetylpiperidin-4-yl) (2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) carbamic acid tert-butyl ester

Reductive amination procedure B from 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (400 mg,1.53 mmol) and 1- (4-amino-1-piperidinyl) ethanone (399mg, 2.75 mmol) provides 1- [4- [ [ 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl ]]Methylamino group]-1-piperidinyl group]The ethanone, which is used in the next step without further purification. LCMS: m/z found 389.3[ M+H ] ] ⁺ Retention time = 0.69min (method B).

To crude 1- [4- [ [ 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl ]]Methylamino group]-1-piperidinyl group]A solution of ethanone in DCM was added di-tert-butyl dicarbonate (333 mg,1.53 mmol) and DMAP (37 mg,0.31 mmol). The mixture was stirred for 2 hours, concentrated in vacuo, and purified on a silica gel column with MeOH in DCM (0 to 10% gradient) as eluent to afford tert-butyl (1-acetylpiperidin-4-yl) (2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) carbamate (399mg, 0.81mmol, 53% yield over two steps). LCMS: m/z found 489.3[ M+H ]] ⁺ Retention time = 1.06min (method B).

(b) (1-Acetylpiperidin-4-yl) (4- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) carbamic acid tert-butyl ester

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To 6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl]A mixture of tert-butyl 2-methoxy-pyridine-3-carbaldehyde (100 mg,0.25 mmol), (1-acetylpiperidin-4-yl) (2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) carbamate (124 mg,0.25 mmol) and potassium carbonate (105 mg,0.76 mmol) in degassed dioxane/water (6:1) was added tetrakis (triphenylphosphine) palladium (0) (29 mg,0.03 mmol) and the mixture stirred at 105℃for 30 min. Water was added and the mixture was extracted three times into EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column with 2% MeOH in DCM as eluent to afford tert-butyl (1-acetylpiperidin-4-yl) (4- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) carbamate (170 mg, 93%). LCMS: m/z found 719.2[ M+H ] ] ⁺ Retention time = 1.11min (method B).

(c) 2- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one

From (1-acetylpiperidin-4-yl) (4- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) carbamic acid tert-butyl ester (50 mg,0.07 mmol) and 2, 6-diazaspiro [3.4]]Reductive amination procedure B of octan-7-one (18 mg,0.14 mmol) provides N- (1-acetyl-4-piperidinyl) -N- [ [4- [ 3-chloro-4- [ 2-chloro-3- [ 6-methoxy-5- [ (6-oxo-2, 7-diazaspiro [3.4] as a crude material]Octan-2-yl) methyl]-2-pyridyl group]Phenyl group]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]Tert-butyl carbamate, LCMS: m/z found 829.3[ M+H ]] ⁺ Retention time = 0.84min (method B), which is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 82% yield was obtained in two steps. LCMS: m/z found 729.3[ M+H ]] ⁺ Retention time = 1.65min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.52(s,2H),7.70(d,2H),7.55(t,1H),7.51(d,1H),7.47(d,1H),7.41(d,1H),7.37(s,1H),7.33(d,1H),7.25(d,1H),4.73–4.54(m,1H),4.22(s,2H),4.05(d,1H),4.01–3.94(m,6H),3.75(s,2H),3.59(s,2H),3.51–3.41(m,4H),3.25–3.11(m,2H),2.69(t,1H),2.59(s,2H),2.25–2.14(m,2H),2.13(s,3H),1.66–1.40(m,2H).

Example 296:1- (4- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) piperidin-1-yl) ethan-1-one (333)

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From tert-butyl (1-acetylpiperidin-4-yl) (4- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) carbamate (example 295, step (b)) (50 mg,0.07 mmol) and 1- [4- (methylamino) -1-piperidinyl]Reductive amination procedure B of ethanone (22 mg,0.14 mmol) provides N- (1-acetyl-4-piperidinyl) -N- [ [4- [4- [3- [5- [ [ (1-acetyl-4-piperidinyl) -methyl-amino ] as a crude material]Methyl group]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]-2-methoxy-phenyl]Methyl group]Tert-butyl carbamate, LCMS: m/z found 859.3[ M+H ]] ⁺ Retention time = 0.84min (method B), which is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 75% yield over two steps. LCMS: m/z found 759.3[ M+H ]] ⁺ Retention time = 1.72min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),8.46(s,2H),7.82(d,1H),7.73(d,1H),7.59–7.51(m,2H),7.49–7.46(m,1H),7.44–7.38(m,2H),7.35(d,1H),7.31–7.26(m,1H),4.71–4.55(m,2H),4.30(s,2H),4.14–3.97(m,8H),3.84(s,2H),3.26–3.10(m,4H),2.77–2.58(m,2H),2.43(s,3H),2.29–2.17(m,2H),2.17–2.10(m,6H),2.08–1.96(m,2H),1.78–1.43(m,4H).

Example 297:1- (4- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) piperidin-1-yl) -2-methylpropan-1-one (371)

From tert-butyl (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (example 285, step (B)) (40 mg,0.06 mmol) and 1- (4-amino-1-piperidinyl) -2-methyl-propan-1-one (19 mg,0.11 mmol) of reductive amination procedure B afforded N- (1-acetyl-4-piperidinyl) -N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [ 3-methoxy-4- [ [1- (2-methylpropanoyl) -4-piperidinyl ] as crude material ]Amino group]Methyl group]Phenyl group]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]Tert-butyl carbamate, LCMS: m/z found 873.4[ M+H ]] ⁺ Retention time = 0.90min (method B), which is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 58% yield over two steps. LCMS: m/z found 773.3[ M+H ]] ⁺ Retention time = 1.87min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.74–8.59(m,1H),8.55–8.42(m,2H),7.82(d,1H),7.74–7.69(m,1H),7.56(dd,1H),7.51(d,1H),7.49–7.45(m,1H),7.45–7.40(m,1H),7.37(s,1H),7.34(d,1H),7.30(d,1H),4.66(d,1H),4.56(d,1H),4.24(s,2H),4.22–4.14(m,1H),4.08–3.95(m,9H),3.22–3.13(m,2H),3.11–3.02(m,1H),2.99–2.92(m,1H),2.77–2.67(m,2H),2.30–2.03(m,8H),1.63–1.26(m,4H),1.17–1.04(m,6H).

Example 298:1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methylpropan-1-one (382)

From tert-butyl (1-acetylpiperidin-4-yl) (4- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) carbamate (example 295, step (B)) (40 mg,0.06 mmol) and 1- (4-amino-1-piperidinyl) -2-methyl-propan-1-one (19 mg,0.11 mmol) of reductive amination procedure B gave N- (1-acetyl-4-piperidinyl) -N- [ [4- [ 3-chloro-4- [ 2-chloro-3- [ 6-methoxy-5- [ [1- (2-methylpropanoyl) -4-piperidinyl ] as crude material]Amino group]Methyl group]-2-pyridyl group]Phenyl group]-2-pyridyl group]-2-methoxy-phenyl ]Methyl group]Tert-butyl carbamate, LCMS: m/z found 873.4[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 85% yield was obtained in two steps. LCMS: m/z found 773.3[ M+H ]] ⁺ Retention time = 1.83min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),8.50(s,2H),7.82(d,1H),7.72(d,1H),7.60–7.49(m,2H),7.47(d,1H),7.43(d,1H),7.38(s,1H),7.32(dd,2H),4.61(t,2H),4.24(s,2H),4.18–4.10(m,1H),4.09–4.01(m,6H),3.98(s,3H),3.25–3.06(m,4H),3.02–2.93(m,1H),2.75–2.60(m,2H),2.26–2.05(m,7H),1.64–1.26(m,4H),1.16–1.02(m,6H).

Example 299: (S) -1- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) pyrrolidine-3-carboxylic acid (388)

The (3S) -1- [6- [3- [2- [4- [ (1-acetyl-4-piperidinyl) -t-butoxycarbonyl ]Amino group]Methyl group]-3-methoxy-phenyl]-3-chloro-4-pyridinyl]-2-chloro-phenyl]-2-methoxy-3-pyridinyl]Methyl group]Pyrrolidine-3-carboxylic acid, LCMS: m/z found 818.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Yield 71% over two steps. LCMS: m/z found 718.3[ M+H ] ] ⁺ Retention time = 1.69min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),8.49(s,2H),7.92(d,1H),7.74(d,1H),7.58(t,1H),7.53(d,1H),7.50–7.47(m,1H),7.45(d,1H),7.42–7.28(m,3H),4.76–4.58(m,1H),4.41(s,2H),4.28(s,2H),4.09(s,3H),4.07–4.02(m,1H),3.99(s,3H),3.56(dd,1H),3.50–3.33(m,3H),3.26–3.02(m,3H),2.76–2.67(m,1H),2.43–2.31(m,1H),2.30–2.17(m,3H),2.13(s,3H).

Example 300:3- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) propanoic acid (389)

From tert-butyl (1-acetylpiperidin-4-yl) (4- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) carbamate (example 295, step (B)) (40 mg,0.06 mmol) and 3-aminopropionic acid (10 mg,0.11 mmol) of reductive amination procedure B afforded 3- [ [6- [3- [2- [4- [ [ (1-acetyl-4-piperidinyl) -tert-butoxycarbonyl-amino ] as crude material]Methyl group]-3-methoxy-phenyl]-3-chloro-4-pyridinyl]-2-chloro-phenyl]-2-methoxy-3-pyridinyl]Methylamino group]Propionic acid, LCMS: m/z found 792.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Yield 78% through two steps. LCMS: m/z found 692.2[ M+H ]] ⁺ Retention time = 1.68min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),8.50(s,2H),7.87(d,1H),7.73(dd,1H),7.58(t,1H),7.53(d,1H),7.48(d,1H),7.44(dd,1H),7.39(s,1H),7.34(dt,2H),4.65(d,1H),4.33–4.23(m,4H),4.10(s,3H),4.07–4.02(m,1H),3.99(s,3H),3.43–3.33(m,1H),3.25–3.19(m,3H),2.75–2.65(m,1H),2.53(t,2H),2.27–2.16(m,2H),2.13(s,3H),1.69–1.42(m,2H).

Example 301:3- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) propanoic acid (390)

The reductive amination procedure B of (1-acetylpiperidin-4-yl) ((tert-butyl 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (example 285, step (B)) (45 mg,0.06 mmol) and 3-aminopropionic acid (11 mg,0.13 mmol) afforded 3- [ [4- [4- [3- [5- [ (1-acetyl-4-piperidinyl) -tert-butoxycarbonyl-amino ] as crude material]Methyl group]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]-2-methoxy-phenyl]Methylamino group]Propionic acid, LCMS: m/z found 792.3[ M+H ]] ⁺ Retention time = 0.87min (method B), which is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Yield 52% through two steps. LCMS: m/z found 692.2[ M+H ]] ⁺ Retention time = 1.68min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.44(s,2H),7.86(d,1H),7.71(d,1H),7.57(t,1H),7.50(d,1H),7.45(t,2H),7.38(s,1H),7.36–7.29(m,2H),4.62(d,1H),4.27(s,2H),4.19(s,2H),4.10–3.93(m,7H),3.26–3.09(m,4H),2.77–2.66(m,1H),2.53(t,2H),2.24–2.14(m,2H),2.12(s,3H),1.63–1.39(m,2H).

Example 302:1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one (391)

From (1-acetylpiperidin-4-yl) (4- (3-chloro-4- (2-chloro-3- (5)Tert-butyl (example 295, step (B)) (40 mg,0.06 mmol) and tetrahydropyran-4-amine (11 mg,0.11 mmol) reductive amination procedure B of-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-methoxybenzyl) -2-carbamate provides N- (1-acetyl-4-piperidinyl) -N- [ [4- [ 3-chloro-4- [ 2-chloro-3- [ 6-methoxy-5- [ (tetrahydropyran-4-ylamino) methyl ] as crude material ]-2-pyridyl group]Phenyl group]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]Tert-butyl carbamate, LCMS: m/z found 804.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product. Yield 64% through two steps. LCMS: m/z found 704.3[ M+H ]] ⁺ Retention time = 1.76min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.68(d,1H),7.91(d,1H),7.73(d,1H),7.59(t,1H),7.55(d,1H),7.50(d,1H),7.48–7.44(m,1H),7.41(s,1H),7.39–7.34(m,2H),4.69(d,1H),4.35(s,2H),4.31(s,2H),4.14–4.02(m,6H),4.00(s,3H),3.56–3.40(m,4H),3.22(t,1H),2.77–2.66(m,1H),2.33–2.19(m,2H),2.16–2.06(m,5H),1.83–1.46(m,4H).

Example 303:1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (392)

From tert-butyl (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (example 285, step (B)) (40 mg,0.06 mmol) and tetrahydropyran-4-amine (11 mg,0.11 mmol) of reductive amination procedure B afforded N- (1-acetyl-4-piperidinyl) -N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [ 3-methoxy-4- [ (tetrahydropyran-4-ylamino) methyl ] as crude material]Phenyl group]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]Tert-butyl carbamate, LCMS: m/z found 804.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Yield 70% through two steps. LCMS: m/z found 704.3[ M+H ] ] ⁺ Retention time = 2.79min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.70–8.60(m,1H),8.52(s,2H),7.80(d,1H),7.74–7.67(m,1H),7.56(t,1H),7.53–7.49(m,1H),7.49–7.45(m,1H),7.42(d,1H),7.38(s,1H),7.34(d,1H),7.29(dd,1H),4.53(d,1H),4.25(s,2H),4.09–3.90(m,12H),3.54–3.38(m,2H),3.21–3.09(m,1H),3.04–2.92(m,1H),2.71(t,1H),2.22–1.96(m,7H),1.78–1.62(m,2H),1.55–1.22(m,2H).

Example 304:1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methyl (tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one (436)

From tert-butyl (1-acetylpiperidin-4-yl) (4- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) carbamate (example 295, step (B)) (50 mg,0.07 mmol) and N-methyltetrahydropyran-4-amine (16 mg,0.14 mmol) of reductive amination procedure B provided N- (1-acetyl-4-piperidinyl) -N- [ [4- [ 3-chloro-4- [ 2-chloro-3- [ 6-methoxy-5- [ [ methyl (tetrahydropyran-4-yl) amino ] as crude material]Methyl group]-2-pyridyl group]Phenyl group]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]Tert-butyl carbamate, LCMS: m/z found 818.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product. 65% yield was obtained via two steps. LCMS: m/z found 718.3[ M+H ]] ⁺ Retention time = 1.68min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(dt,1H),8.51(s,2H),7.83(d,1H),7.73(d,1H),7.61–7.49(m,2H),7.47(dd,1H),7.42(d,1H),7.38(s,1H),7.37–7.25(m,2H),4.71–4.59(m,1H),4.26(s,2H),4.10–4.00(m,6H),4.02–3.96(m,3H),3.95–3.86(m,2H),3.45(t,2H),3.20(t,1H),3.07–2.94(m,1H),2.70(t,1H),2.48(s,3H),2.28–2.15(m,2H),2.13(s,3H),1.99–1.89(m,2H),1.85–1.71(m,2H),1.69–1.42(m,2H).

Example 305: n- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -N-methyltetrahydro-2H-pyran-4-amine (441)

(a) ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester

From 6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl]Reductive amination procedure B of-2-methoxy-pyridine-3-carbaldehyde (220 mg,0.56 mmol) and tetrahydropyran-4-amine (113 mg,1.12 mmol) provided N- [ [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl ]]-2-methoxy-3-pyridinyl]Methyl group]Tetrahydropyran-4-amine, which is used in the next step without further purification. LCMS: m/z found 478.1[ M+H ]] ⁺ Retention time = 0.80min (method B).

To crude N- [ [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl ]]-2-methoxy-3-pyridinyl]Methyl group]A solution of tetrahydropyran-4-amine (267 mg,0.56 mmol) in DCM was added di-tert-butyl dicarbonate (153 mg,0.70 mmol) and DMAP (7 mg,0.06 mmol). The mixture was stirred for 2 hours, concentrated in vacuo, and purified on a silica gel column with MeOH in DCM (0 to 10% gradient) as eluent to afford tert-butyl ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamate (210 mg,0.36mmol, 65%). LCMS: m/z found 578.1[ M+H ]] ⁺ Retention time = 1.23min (method B).

(b) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester

To a mixture of ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester (300 mg,0.52 mmol), 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzaldehyde (136 mg,0.52 mmol) and potassium carbonate (215 mg,1.55 mmol) in degassed dioxane/water (6:1) was added tetrakis (triphenylphosphine) palladium (0) (60 mg,0.05 mmol) and the mixture was stirred at 105℃for 30 min. Water was added and the mixture was extracted three times into EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column with 2% MeOH in DCM as eluent to afford tert-butyl ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamate (330 mg,0.49mmol, 94%). LCMS m/z found 678.2[ M+H ]] ⁺ Retention time = 1.20min (method B).

(c) N- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -N-methyltetrahydro-2H-pyran-4-amine

From tert-butyl ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamate (50 mg,0.07 mmol) and N-methyltetrahydropyran-4-amine (17 mg,0.15 mmol) of reductive amination procedure B afforded N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [ 3-methoxy-4- [ [ methyl (tetrahydropyran-4-yl) amino ] as crude material]Methyl group]Phenyl group]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N-tetrahydropyran-4-yl-carbamic acid tert-butyl ester, LCMS: m/z found 777.3[ M+H ]] ⁺ Retention time = 0.95min (method B), which is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Yield 47% over two steps. LCMS: m/z found 677.3[ M+H ]] ⁺ Retention time = 1.68min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.71–8.65(m,1H),8.47(s,2H),7.90(d,1H),7.75–7.70(m,1H),7.61–7.54(m,2H),7.51–7.41(m,3H),7.41–7.31(m,2H),4.42–4.28(m,2H),4.26(s,2H),4.16–4.02(m,7H),4.00(s,3H),3.58–3.34(m,6H),2.77(s,3H),2.16–2.06(m,4H),2.02–1.85(m,2H),1.81–1.62(m,2H).

Example 306:1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) (methyl) amino) piperidin-1-yl) ethan-1-one (442)

From ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester (example 305, step (b)) (50 mg,0.07 mmol) and 1- [4- (methylamino) -1-piperidinyl) ]Reductive amination procedure B of ethanone (23 mg,0.15 mmol) provides N- [ [6- [3- [2- [4- [ [ (1-acetyl-4-piperidinyl) -methyl-amino ] as crude material]Methyl group]-3-methoxy-phenyl]-3-chloro-4-pyridinyl]-2-chloro-phenyl]-2-methoxy-3-pyridinyl]Methyl group]-N-tetrahydropyran-4-yl-carbamic acid tert-butyl ester, LCMS: m/z found 818.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Yield 47% over two steps. LCMS: m/z found 718.3[ M+H ]] ⁺ Retention time = 1.61min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.67(dt,1H),8.48(s,2H),7.89(d,1H),7.72(dq,1H),7.62–7.52(m,2H),7.50–7.43(m,2H),7.40(d,1H),7.36(ddd,2H),4.74(d,1H),4.33–4.20(m,4H),4.17–4.01(m,6H),4.01–3.90(m,3H),3.53–3.34(m,4H),3.20(t,1H),2.78–2.58(m,4H),2.26–2.05(m,7H),1.95–1.79(m,1H),1.79–1.59(m,3H).

Example 307: n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -N-methyltetrahydro-2H-pyran-4-amine (468)

(a) (2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester

Reductive amination procedure B from 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (300 mg,1.14 mmol) and tetrahydropyran-4-amine (232 mg,2.29 mmol) provided N- (2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) tetrahydro-2H-pyran-4-amine which was used in the next step without further purification. LCMS: m/z found 348.2[ M+H ] ] ⁺ Retention time = 0.69min (method B).

To a solution of crude N- (2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) tetrahydro-2H-pyran-4-amine in DCM was added di-tert-butyl dicarbonate (248 mg,1.14 mmol) and DMAP (28 mg,0.23 mmol). The mixture was stirred for 2 hours, concentrated in vacuo, and purified on a silica gel column with MeOH in DCM (0 to 10% gradient) as eluent to afford tert-butyl (2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) (tetrahydro-2H-pyran-4-yl) carbamate (330 mg,0.74mmol, 65% over two steps). LCMS: m/z found 448.3[ M+H ]] ⁺ Retention time = 1.15min (method B).

(b) (4- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester

To 6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl]-2-methoxy-pyridine-3-carbaldehyde (250 mg,0.64 mmol), (2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) (tetrahydro-2H-pyran-4-yl) carbamide methylA mixture of t-butyl acrylate (284 mg,0.64 mmol) and potassium carbonate (263 mg,1.91 mmol) in degassed dioxane/water (6:1) was added tetrakis (triphenylphosphine) palladium (0) (73 mg,0.06 mmol) and the mixture stirred at 100℃for 30 min. Water was added and the mixture was extracted three times into EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column with 2% MeOH in DCM as eluent to afford tert-butyl (4- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) (tetrahydro-2H-pyran-4-yl) carbamate (350 mg, 81%). LCMS: m/z found 678.2[ M+H ] ] ⁺ Retention time = 1.18min (method B).

(c) N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -N-methyltetrahydro-2H-pyran-4-amine

From tert-butyl (4- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) (tetrahydro-2H-pyran-4-yl) carbamate (50 mg,0.07 mmol), N-methyltetrahydropyran-4-amine (17 mg,0.15 mmol) of reductive amination procedure B afforded N- [ [4- [ 3-chloro-4- [ 2-chloro-3- [ 6-methoxy-5- [ [ methyl (tetrahydropyran-4-yl) amino ] as crude material]Methyl group]-2-pyridyl group]Phenyl group]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]-N-tetrahydropyran-4-yl-carbamic acid tert-butyl ester, LCMS: m/z found 777.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Yield 61% over two steps. LCMS: m/z found 677.3[ M+H ]] ⁺ Retention time = 1.72min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.69–8.62(m,1H),8.51(s,2H),7.83(d,1H),7.73(d,1H),7.55(dd,2H),7.48(dd,1H),7.42(d,1H),7.39(s,1H),7.35(d,1H),7.30(d,1H),4.28(s,2H),4.16–3.96(m,10H),3.88(s,2H),3.51–3.35(m,5H),3.05–2.89(m,1H),2.45(s,3H),2.11(d,2H),1.94(d,2H),1.83–1.64(m,4H).

Example 308:1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) piperidin-1-yl) ethan-1-one (469)

From tert-butyl (4- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) (tetrahydro-2H-pyran-4-yl) carbamate (example 307, step (b)) (50 mg,0.07 mmol) and 1- [4- (methylamino) -1-piperidinyl]Reductive amination procedure B of ethanone (23 mg,0.15 mmol) provides N- [ [4- [4- [3- [5- [ [ (1-acetyl-4-piperidinyl) -methyl-amino ] as crude material]Methyl group]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]-2-methoxy-phenyl]Methyl group]-N-tetrahydropyran-4-yl-carbamic acid tert-butyl ester, LCMS: m/z found 818.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 62% yield over two steps. LCMS: m/z found 718.3[ M+H ]] ⁺ Retention time = 1.67min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.69–8.62(m,1H),8.53(s,2H),7.79(d,1H),7.72(d,1H),7.59–7.49(m,2H),7.47(d,1H),7.41(d,1H),7.38(s,1H),7.34(d,1H),7.29–7.22(m,1H),4.61(d,1H),4.24(s,2H),4.14–3.90(m,9H),3.71(s,2H),3.45(t,2H),3.36–3.33(m,1H),3.13(t,1H),2.82(t,1H),2.70–2.57(m,1H),2.34(s,3H),2.15–2.04(m,5H),1.99(t,2H),1.77–1.45(m,4H).

Example 309:1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (427)

From (1-acetylpiperidin-4-yl) phenyl ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl)) phenyl) Reductive amination procedure B of tert-butyl-2-methoxypyridin-3-yl) methyl carbamate (example 285, step (B)) (50 mg,0.07 mmol) and N-methyltetrahydropyran-4-amine (16 mg,0.14 mmol) provides N- (1-acetyl-4-piperidinyl) -N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [ 3-methoxy-4- [ [ methyl (tetrahydropyran-4-yl) amino ] as crude material ]Methyl group]Phenyl group]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]Tert-butyl carbamate, LCMS: m/z found 818.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Yield 72% through two steps. LCMS: m/z found 718.3[ M+H ]] ⁺ Retention time = 2.64min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.63(d,1H),8.54(s,2H),7.77(d,1H),7.71(d,1H),7.55(t,1H),7.50–7.43(m,2H),7.41(d,1H),7.34–7.22(m,3H),4.49(d,1H),4.09–4.00(m,5H),3.99–3.85(m,8H),3.43(t,2H),3.15(t,1H),2.95(s,1H),2.89–2.79(m,1H),2.76–2.65(m,1H),2.43(s,3H),2.11(s,3H),2.09–1.98(m,2H),1.94(d,2H),1.85–1.67(m,2H),1.49–1.22(m,2H).

Example 310:1- (4- (((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (482)

From tert-butyl (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (example 285, step (b)) (50 mg,0.07 mmol) and 1- (2, 6-diazaspiro [ 3.3:3)]Reductive amination procedure B of heptan-2-yl) ethanone (19 mg,0.14 mmol) provides N- [ [6- [3- [2- [4- [ (2-acetyl-2, 6-diazaspiro [3.3] as crude material]Heptane-6-yl) methyl]-3-methoxy-phenyl]-3-chloro-4-pyridinyl]-2-chloro-phenyl]-2-methoxy-3-pyridinyl]Methyl group]tert-butyl-N- (1-acetyl-4-piperidinyl) carbamate, LCMS: m/z found 843.3[ M+H ] ] ⁺ Retention time = 0.86min (method B), which was taken off by a general Boc deprotection procedureProtected and purified to provide the final product as formate. Yield 68% over two steps. LCMS: m/z found 743.3[ M+H ]] ⁺ Retention time = 1.68min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.63(d,1H),8.54(s,2H),7.81(d,1H),7.71(d,1H),7.56(t,1H),7.48–7.37(m,3H),7.33–7.22(m,3H),4.55(d,1H),4.31(s,2H),4.15–3.86(m,13H),3.81–3.66(m,4H),3.17(t,1H),3.08–2.94(m,1H),2.71(t,1H),2.22–1.98(m,5H),1.84(s,3H),1.57–1.29(m,2H).

Example 311:1- (4- ((4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) piperidin-1-yl) ethan-1-one (483)

From tert-butyl (1-acetylpiperidin-4-yl) (4- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) carbamate (example 295, step (b)) (50 mg,0.07 mmol) and 1- (2, 6-diazaspiro [ 3.3:3)]Reductive amination procedure B of heptan-2-yl) ethanone (19 mg,0.14 mmol) provides N- [ [4- [4- [3- [5- [ (2-acetyl-2, 6-diazaspiro [3.3] as crude material]Heptane-6-yl) methyl]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]-2-methoxy-phenyl]Methyl group]tert-butyl-N- (1-acetyl-4-piperidinyl) carbamate, LCMS: m/z found 843.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Yield 66% over two steps. LCMS: m/z found 743.3[ M+H ] ] ⁺ Retention time = 1.68min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(dd,1H),8.52(s,2H),7.70(dd,2H),7.59–7.49(m,2H),7.47(dd,1H),7.41(d,1H),7.37(s,1H),7.34(d,1H),7.25(dd,1H),4.63(d,1H),4.31(s,2H),4.23(s,2H),4.11–3.93(m,9H),3.74(s,2H),3.66–3.51(m,4H),3.27–3.09(m,2H),2.78–2.60(m,1H),2.28–2.06(m,5H),1.85(s,3H),1.69–1.38(m,2H).

Example 312:1- (6- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one (492)

From ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester (example 305, step (b)) (50 mg,0.07 mmol) and 1- (2, 6-diazaspiro [3.3]Reductive amination procedure B of heptan-2-yl) ethanone (21 mg,0.15 mmol) provides N- [ [6- [3- [2- [4- [ (2-acetyl-2, 6-diazaspiro [3.3] as crude material]Heptane-6-yl) methyl]-3-methoxy-phenyl]-3-chloro-4-pyridinyl]-2-chloro-phenyl]-2-methoxy-3-pyridinyl]Methyl group]-N-tetrahydropyran-4-yl-carbamic acid tert-butyl ester, LCMS: m/z found 802.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Yield 38% over two steps. LCMS: m/z found 702.3[ M+H ]] ⁺ Retention time = 1.75min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.61(d,1H),8.54(s,2H),7.76(d,1H),7.70(d,1H),7.54(t,1H),7.46–7.32(m,3H),7.30–7.22(m,3H),4.28(s,2H),4.06–4.00(m,5H),4.00–3.93(m,2H),3.93–3.86(m,5H),3.75(s,2H),3.57–3.36(m,6H),2.90–2.77(m,1H),1.99–1.90(m,2H),1.83(s,3H),1.57–1.42(m,2H).

Example 313:2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one (506)

From ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester (example 305, step (b)) (50 mg,0.07 mmol) and 2, 6-diazaspiro [3.4 ]]Reductive amination procedure B of octan-7-one (19 mg,0.15 mmol) provides N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [ 3-methoxy-4- [ (6-oxo-2, 7-diazaspiro [3.4 ] as crude material]Octan-2-yl) methyl]Phenyl group]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N-tetrahydropyran-4-yl-carbamic acid tert-butyl ester, LCMS: m/z found 788.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Yield 70% through two steps. LCMS: m/z found 688.2[ M+H ]] ⁺ Retention time = 1.69min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.49(s,2H),7.89(d,1H),7.72(d,1H),7.58(t,1H),7.50–7.40(m,3H),7.38–7.28(m,3H),4.25(s,2H),4.21(s,2H),4.11–4.06(m,4H),4.05–4.01(m,1H),3.98–3.87(m,7H),3.64(s,2H),3.47(t,2H),3.42–3.34(m,1H),2.71–2.62(m,2H),2.11(dd,2H),1.80–1.62(m,2H).

Example 314:1- (6- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one (511)

From tert-butyl (4- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) (tetrahydro-2H-pyran-4-yl) carbamate (example 307, step (b)) (50 mg,0.07 mmol) and 1- (2, 6-diazaspiro [3.3 ]Reductive amination procedure B of heptan-2-yl) ethanone (21 mg,0.15 mmol) provides N- [ [4- [4- [3- [5- [ (2-acetyl-2, 6-diazaspiro [3.3 ] as crude material]Heptane-6-yl) methyl]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]-2-methoxy-phenyl]Methyl group]-N-tetrahydropyran-4-yl-carbamic acid tert-butyl ester, LCMS: m/z found 802.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 62% yield over two steps. LCMS: m/z found 702.3[ M+H ]] ⁺ Retention time = 1.73min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.55(s,2H),7.69(t,2H),7.55(t,1H),7.49–7.43(m,2H),7.43–7.37(m,1H),7.35–7.27(m,2H),7.24(d,1H),4.30(s,2H),4.08–3.89(m,12H),3.68(s,2H),3.55–3.47(m,4H),3.42(t,2H),3.05–2.91(m,1H),1.98(d,2H),1.84(s,3H),1.64–1.48(m,2H).

Example 315: n- ((6- (3- (2- (4- ((7-oxa-2-azaspiro [3.5] nonan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine (530)

From ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester (example 305, step (b)) (50 mg,0.07 mmol) and 7-oxa-2-azaspiro [3.5]]Reductive amination procedure B of nonane (19 mg,0.15 mmol) provides N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [ 3-methoxy-4- (7-oxa-2-azaspiro [3.5] as crude material ]Nonan-2-ylmethyl) phenyl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]-N-tetrahydropyran-4-yl-carbamic acid tert-butyl ester, LCMS: m/z found 789.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Yield 66% over two steps. LCMS: m/z found 689.3[ M+H ]] ⁺ Retention time = 1.85min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.63(d,1H),8.54(s,2H),7.77(d,1H),7.71(dd,1H),7.55(t,1H),7.47–7.38(m,3H),7.34–7.21(m,3H),4.03(s,3H),3.98(t,4H),3.92(s,5H),3.60(t,4H),3.51–3.37(m,6H),2.94–2.80(m,1H),1.95(d,2H),1.80(t,4H),1.51(qd,2H).

Example 316: n- (4- (4- (3- (5- ((7-oxa-2-azaspiro [3.5] nonan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) tetrahydro-2H-pyran-4-amine (531)

From tert-butyl (4- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) (tetrahydro-2H-pyran-4-yl) carbamate (example 307, step (b)) (50 mg,0.07 mmol) and 7-oxa-2-azaspiro [3.5]]Reductive amination procedure B of nonane (19 mg,0.15 mmol) provides N- [ [4- [ 3-chloro-4- [ 2-chloro-3- [ 6-methoxy-5- (7-oxa-2-azaspiro [3.5] as crude material]Nonan-2-ylmethyl) -2-pyridinyl]Phenyl group]-2-pyridyl group]-2-methoxy-phenyl]Methyl group]-N-tetrahydropyran-4-yl-carbamic acid tert-butyl ester, LCMS: m/z found 789.3[ M+H ] ] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Yield 68% over two steps. LCMS: m/z found 689.3[ M+H ]] ⁺ Retention time = 1.84min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(dd,1H),8.59–8.51(m,2H),7.73–7.66(m,2H),7.55(t,1H),7.49–7.43(m,2H),7.41(d,1H),7.36–7.28(m,2H),7.25(dd,1H),4.09(s,2H),4.05–3.91(m,8H),3.79(s,2H),3.67–3.54(m,4H),3.51–3.35(m,5H),3.15–2.99(m,2H),2.00(d,2H),1.87–1.74(m,4H),1.66–1.51(m,2H).

Example 317:1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (360)

(a) (1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

Using reductive amination procedure B, a reaction mixture was prepared from (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2-))(4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamic acid tert-butyl ester (20 mg,0.03 mmol), acetic acid (3 uL,0.06 mmol), 4-aminocyclohexanol (6 mg,0.06 mmol) and sodium cyanoborohydride (3 mg,0.06 mmol) were prepared as (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxypyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester. 22mg,97% yield. MS: m/z found 818.3[ M+H ] ] ⁺ .

(b) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

Tert-butyl (22 mg,0.03 mmol) of (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4- (((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (22 mg,0.03 mmol) and trifluoroacetic acid (102 ul,1.34 mmol) was used to prepare 1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one. 6mg,32% yield. MS: m/z found 718.2[ M+H ]] ⁺ Retention time = 1.71min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.64(m,1H),7.77(d,1H),7.73–7.68(m,1H),7.58–7.51(m,1H),7.51–7.44(m,2H),7.43–7.38(m,1H),7.36(s,1H),7.32(dd,1H),7.28–7.23(m,1H),4.49(d,1H),4.20(s,2H),4.02(t,3H),3.97(t,4H),3.91(d,3H),3.56(s,1H),3.15(t,1H),3.01(s,1H),2.85(s,1H),2.70(t,1H),2.18(d,2H),2.10(t,3H),2.03(s,4H),1.57–1.24(m,6H).

Example 318:1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (361)

(a) (1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

Using reductive amination procedure B, starting from tert-butyl (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (20 mg,0.03 mmol), acetic acid (3 uL,0.06 mmol), 2-azaspiro [3.3]]Preparation of (1-acetylpiperidin-4-yl) by heptane-6-ol (6 mg,0.06 mmol) and sodium cyanoborohydride (3 mg,0.06 mmol) ((6- (2-chloro-3- (3-chloro-2- (4- ((6-hydroxy-2-azaspiro [ 3.3))]Heptane-2-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamic acid tert-butyl ester. 21mg,92%. MS: m/z found 816.2[ M+H ]] ⁺ .

(b) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

From (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4- ((6-hydroxy-2-azaspiro [ 3.3)) using the general Boc deprotection procedure]Preparation of tert-butyl heptan-2-yl-methyl) -3-methoxyphenyl-pyridin-4-yl-phenyl) -2-methoxypyridin-3-yl-methyl) carbamate (21 mg,0.03 mmol) and trifluoroacetic acid (98 uL,1.29 mmol) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((6-hydroxy-2-azaspiro [3.3 ]) -e) ]Heptane-2-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) amino group) Piperidin-1-yl) ethan-1-one. 2.5mg,14%. MS: m/z found 716.2[ M+H ]] ⁺ Retention time = 21.71min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.66(d,1H),7.89(d,1H),7.71(d,1H),7.57(t,1H),7.52–7.41(m,3H),7.38(s,1H),7.35(d,2H),4.66(d,1H),4.41(s,2H),4.28(s,2H),4.16(d,5H),4.08(t,5H),3.97(d,3H),3.21(t,1H),2.76–2.57(m,3H),2.33–2.08(m,7H),1.71–1.45(m,1H).

Example 319:1- (4- (((6- (3- (2- (4- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (379)

(a) ((6- (3- (2- (4- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) (1-acetylpiperidin-4-yl) carbamic acid tert-butyl ester

Using reductive amination procedure B, starting from tert-butyl (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (20 mg,0.03 mmol), acetic acid (3 uL,0.06 mmol), 2-oxaspiro [3.3]]Heptane-6-amine; preparation of hydrochloride (8 mg,0.06 mmol) and sodium cyanoborohydride (3 mg,0.06 mmol) (6- (3- (2- (4- (((2-oxaspiro [3.3 ]) 3)]Heptane-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl methyl) (1-acetylpiperidin-4-yl) carbamic acid tert-butyl ester. 13mg,57% yield. MS: m/z found 816.2[ M+H ] ] ⁺ .

(b) 1- (4- (((6- (3- (2- (4- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

The general Boc deprotection procedure was used, followed by ((6- (3- (2- (4- (((2-oxaspiro [3.3 ]) -3)]Heptan-6-yl) amino methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl-2-chlorophenyl) -2-methoxypyridin-3-yl methyl) (1-acetylpiperidin-4-yl) carbamic acid tert-butyl ester (13 mg,0.02 mmol) and trifluoroacetic acid (60 uL,0.80 mmol) produce 1- (4- (((6- (3- (2- (4- (((2-oxaspiro [3.3 ]) -3)]Heptane-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one. 2.2mg,19% yield. MS: m/z found 718.2[ M+H ]] ⁺ Retention time = 2.21min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ ).δ8.69–8.62(m,1H),7.85(d,1H),7.71(d,1H),7.56(t,1H),7.51–7.40(m,3H),7.38(s,1H),7.32(t,2H),4.73(s,1H),4.62(s,1H),4.58(s,1H),4.14(s,4H),4.11(s,1H),4.06(d,4H),3.99(d,4H),3.65(d,1H),3.24–3.12(m,2H),2.68(d,2H),2.35(s,1H),2.18(d,2H),2.12(d,5H),1.16(s,1H).

Example 320:1- (4- (((6- (3- (2- (4- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (380)

(a) ((6- (3- (2- (4- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) (1-acetylpiperidin-4-yl) carbamic acid tert-butyl ester

By reductive amination procedure B, starting from (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxy)Tert-butyl (20 mg,0.03 mmol) of alkylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl carbamate, acetic acid (3 uL,0.06 mmol), 2-oxa-6-azaspiro [3.3]]Preparation of heptane (5 mg,0.06 mmol) and sodium cyanoborohydride (3 mg,0.06 mmol) (6- (3- (2- (4- ((2-oxa-6-azaspiro [ 3.3))]Heptane-6-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl-2-chlorophenyl) -2-methoxypyridin-3-yl methyl) (1-acetylpiperidin-4-yl) carbamic acid tert-butyl ester. 14mg,63% yield. MS: m/z found 802.2[ M+H ]] ⁺ .

(b) 1- (4- (((6- (3- (2- (4- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

The general Boc deprotection procedure was used, followed by ((6- (3- (2- (4- ((2-oxa-6-azaspiro [3.3 ])]Heptan-6-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl-2-chlorophenyl) -2-methoxypyridin-3-yl methyl) (1-acetylpiperidin-4-yl) carbamic acid tert-butyl ester (14 mg,0.02 mmol) and trifluoroacetic acid (66 uL,0.87 mmol) were used to prepare 1- (4- (((6- (3- (2- (4- ((2-oxa-6-azaspiro [3.3 ]) -3.3) ]Heptane-6-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one. 3.3mg,27%. MS: m/z found 702.1[ M+H ]] ⁺ Retention time = 1.70min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ).δ8.67–8.62(m,1H),7.86(d,1H),7.71(d,1H),7.56(t,1H),7.44(dd,3H),7.37–7.29(m,3H),4.77(t,4H),4.61(d,1H),4.20(d,4H),4.14(s,4H),4.06(t,4H),4.00(d,1H),3.95(t,3H),3.19(t,1H),2.70(t,1H),2.19(t,2H),2.12(t,3H),1.66–1.40(m,1H).

Example 321:1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((3, 3-dimethylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (381)

(a) (1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

Using reductive amination procedure B, starting from tert-butyl (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (20 mg,0.03 mmol), acetic acid (3 ul,0.06 mmol), 3-amino-1-methyl-cyclobutanol; preparation of (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester with sodium cyanoborohydride (7 mg,0.06 mmol). 12mg,54% yield. MS: m/z found 804.2[ M+H ] ] ⁺ .

(b) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((3, 3-dimethylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

From N- (1-acetyl-4-piperidinyl) -N- [ [6- [ 2-chloro-3- [ 3-chloro-2- [4- [ [ (3-hydroxy-3-methyl-cyclobutyl) amino ] using the general Boc deprotection procedure]Methyl group]-3-methoxy-phenyl]-4-pyridinyl]Phenyl group]-2-methoxy-3-pyridinyl]Methyl group]Tert-butyl carbamate (12 mg,0.01 mmol) and trifluoroacetic acid (57 ul,0.75 mmol) to prepare 1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((3, 3-dimethylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one. 2.5mg,24% yield. MS: m/z realMeasurement value 704.2[ M+H ]] ⁺ Retention time = 1.71min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ).δ8.66(d,1H),7.86(d,1H),7.75–7.67(m,1H),7.57(t,1H),7.51–7.41(m,3H),7.38(s,1H),7.33(t,2H),4.61(d,1H),4.17(s,5H),4.06(t,4H),3.99(t,4H),3.92(t,1H),3.19(t,1H),2.75–2.62(m,1H),2.38(t,2H),2.25–2.15(m,4H),2.12(d,4H),1.62–1.42(m,2H).

Example 322:1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1-hydroxycyclopropyl) methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (512)

(a) (1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4- ((((1-hydroxycyclopropyl) methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

Tert-butyl (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (20 mg,0.03 mmol), acetic acid (3 ul,0.06 mmol), 1- (aminomethyl) cyclopropanol (5 mg,0.06 mmol) and sodium cyanoborohydride (3.50 mg,0.06 mmol) was prepared from tert-butyl (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4- ((((1-hydroxycyclopropyl) methyl) amino) methyl) -3-methoxypyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate using reductive amination procedure B. 14mg,48%. MS: m/z found 790.2[ M+H ]] ⁺ .

(b) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1-hydroxycyclopropyl) methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

To a solution of tert-butyl (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4- ((((1-hydroxycyclopropyl) methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (14 mg,0.02 mmol) in DCM (0.1 mL) was added trifluoroacetic acid (69 ul,0.90 mmol). The reaction was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was purified by reverse phase HPLC (acetonitrile: water) to afford 1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1-hydroxycyclopropyl) methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one (3.1 mg, 25%). MS: m/z found 690.3[ M+H ] ] ⁺ Retention time = 1.71min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ).δ8.66(d,1H),7.90(d,1H),7.72(d,1H),7.57(t,1H),7.52(d,1H),7.46(dd,2H),7.39(s,1H),7.35(d,2H),4.66(d,1H),4.39(s,2H),4.28(s,2H),4.08(s,3H),3.99(d,3H),3.15(s,2H),2.75–2.64(m,1H),2.24(t,2H),2.13(d,3H),1.67–1.49(m,1H),0.90(s,2H),0.72(s,2H).

Example 323:1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((2, 2-difluoroethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (513)

(a) (1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4- (((2, 2-difluoroethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

By reductive amination procedure B, starting from (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl)) Phenyl) -tert-butyl 2-methoxypyridin-3-yl methyl) carbamate (20 mg,0.03 mmol), 2-difluoroethylamine (5 mg,0.06 mmol), acetic acid (3 mg,0.06 mmol) and sodium cyanoborohydride (3 mg,0.06 mmol) tert-butyl (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4- (((2, 2-difluoroethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate was prepared. 15mg,69% yield. MS: m/z found 784.2[ M+H ]] ⁺ 。

(b) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((2, 2-difluoroethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

Using the general Boc deprotection procedure, 1- (4- (((6- (2-chloro-3- (4- (((2, 2-difluoroethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester (14 mg,0.02 mmol) and trifluoroacetic acid (69 ul,0.90 mmol) was prepared from (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4- (((2, 2-difluoroethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one. 4.9mg,40% yield. MS: m/z found 684.3[ M+H ]] ⁺ Retention time = 1.71min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.63(dd,1H),7.90(d,1H),7.71(d,1H),7.57(dd,1H),7.44(q,4H),7.38–7.34(m,1H),7.33–7.26(m,2H),4.67(d,1H),4.30(s,2H),4.08(t,4H),4.05(s,2H),3.94(d,3H),3.45(d,1H),3.26–3.07(m,3H),2.76–2.64(m,2H),2.25(t,2H),2.13(d,4H),1.68–1.50(m,1H).

Example 324: n- ((6- (2-chloro-3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -3-fluoropropane-1-amine (534)

Formate was prepared according to reductive amination procedure A from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (14 mg,0.02 mmol), 3-fluoropropane-1-amine (9 mg,0.11 mmol), acetic acid (3 μl,0.06 mmol) and sodium cyanoborohydride (3.5 mg,0.06 mmol) with N- ((6- (2-chloro-3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -3-fluoropropane-1-amine. 8.6mg,49% yield. MS: m/z found 615.2[ M+H ] ] ⁺ Retention time=1.87 min (method D) ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.66(d,1H),7.89(d,1H),7.72(d,1H),7.57(dd,1H),7.53(d,1H),7.48–7.42(m,2H),7.39(s,1H),7.35(d,2H),4.65(t,2H),4.53(t,2H),4.30(d,4H),4.08(d,3H),3.99(d,3H),3.24(q,4H),2.24–2.06(m,4H).

Example 325:1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (537)

(a) (1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

Using reductive amination procedure B, (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester (20 mg,0.03 mmol), acetic acid (3 ul,0.06 mmol), 3-fluoropropane-1-amine (4 mg,0.06 mmol) and sodium cyanoborohydride (3 mg,0.06 mmol) was prepared from (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acidAnd (3) tert-butyl ester. 14mg,65% yield. MS: m/z found 780.3[ M+H ]] ⁺ .

(b) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

1- (4- (((6- (2-chloro-3- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) amino) piperidin-1-yl) ethan-1-one was prepared from (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) using the general Boc deprotection procedure (14 mg,0.02 mmol) and trifluoroacetic acid (69 ul,0.90 mmol). 3.2mg,26% yield. MS: m/z found 680.3[ M+H ]] ⁺ Retention time = 1.77min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.70–8.62(m,1H),7.90(d,1H),7.57(t,1H),7.53(d,1H),7.46(dd,2H),7.39(s,1H),7.35(d,2H),4.64(t,2H),4.53(t,1H),4.30(d,4H),4.08(t,4H),3.99(t,3H),3.43(s,1H),3.23(t,3H),2.75–2.62(m,1H),2.31–2.17(m,3H),2.13(d,4H).

Example 326: (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -L-alanine (130)

(a) (4- (4- (3- (5- (((tert-butoxycarbonyl) (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -L-alanine

To a mixture of tert-butyl (S) - ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (example 80, step (a)) (150 mg,0.22 mmol) and (S) -2-aminopropionic acid (58 mg,0.65 mmol) in MeOH (5 mL) was added sodium acetate (53.4 mg,0.65 mmol) and the mixture was stirred at room temperature for 1.5 hours. Sodium cyanoborohydride (40.9 mg,0.65 mmol) was then added and the mixture was stirred at room temperature for 0.5 hours. The mixture was filtered and the filtrate was concentrated to give (4- (4- (3- (5- (((tert-butoxycarbonyl) (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -L-alanine (170 mg, crude). LCMS m/z found 764,766[ M+H ] ] ⁺ . The crude product was used in the next step without further purification.

(b) (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -L-alanine

To a solution of (4- (4- (3- (5- (((tert-butoxycarbonyl) (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -L-alanine (160 mg,0.21 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3 mL,40.5 mmol) and the mixture was concentrated under N ₂ The mixture was stirred at room temperature for 10 minutes. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-methoxybenzyl) -L-alanine (33.1 mg,22% yield) as a white solid (formate). MS: m/z found 664[ M+H ]] ⁺ Retention time = 2.64min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),7.81(d,1H),7.70(dd,1H),7.57-7.50(m,2H),7.45-7.41(m,2H),7.37(s,1H),7.34-7.29(m,2H),4.33-4.25(m,2H),4.06-4.02(m,5H),3.98(s,3H),9.95-3.94(m,1H),3.62-3.57(m,1H),3.00-2.90(m,2H),2.39-2.32(m,3H),1.88-1.82(m,1H),1.53(d,1H).

Example 327: (S) -1- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid isopropyl ester (135)

(a) 1-aminocyclopropane-1-carboxylic acid isopropyl ester

To a mixture of 1-aminocyclopropane carboxylic acid (1 g,9.89 mmol) and propan-2-ol (5.35 g,89.0 mmol) was added thionyl chloride (2.46 g,20.6 mmol) and under N ₂ The mixture was stirred at 95℃for 24 hours. The mixture was then concentrated to afford isopropyl 1-aminocyclopropane-1-carboxylate (1.2 g,68% yield) as a white solid, which was used in the next step without further purification.

(b) (S) -1- ((isopropyl 4- (4- (3- (5- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) cyclopropane-1-carboxylate

To a mixture of tert-butyl (S) - ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (example 80, step (a)) (300 mg,433 umol), isopropyl 1-aminocyclopropane-1-carboxylate (248 mg,1.74 mmol) in methanol (10 mL) was added sodium cyanoborohydride (81.7 mg,1.30 mmol) and sodium acetate (177 mg,2.17 mmol) andat N ₂ The mixture was stirred at room temperature for 3 hours. The mixture is then concentrated and passed through normal phase SiO ₂ Chromatography (100% ethyl acetate) purified the residue to afford (S) -1- ((isopropyl 4- (4- (3- (5- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) cyclopropane-1-carboxylate (210 mg,59% yield) as a white solid. MS: m/z found 818[ M+H ]] ⁺ .

(c) (S) -1- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid isopropyl ester

To a solution of (S) -1- ((4- (4- (3- (5- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid isopropyl ester (200 mg,244 umol) in dichloromethane (3 mL) was added trifluoroacetic acid (9.24 g,81.04mmol,6.00mL,332 eq) and under N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was then filtered, the filtrate was concentrated and the residue was purified by reverse phase HPLC to provide (S) -1- ((isopropyl 4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-methoxybenzyl) amino) cyclopropane-1-carboxylate (18.6 mg,10.6% yield) as a white solid (formate). MS: m/z found 718[ M+H ] ] ⁺ Retention time = 3.37min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),7.90(d,1H),7.72(dd,1H),7.58(t,1H),7.52(d,1H),7.47-7.44(m,2H),7.36-7.32(m,3H),5.17-5.13(m,1H),4.53(s,2H),4.35-4.34(m,2H),4.10(s,3H),4.08-4.04(m,1H),4.00(s,3H),3.26-3.25(m,2H),2.43-2.36(m,3H),1.92-1.89(m,1H),1.63-1.59(m,2H),1.50-1.47(m,2H),1.32(d,6H).

Example 328: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4, 5-dihydro-1H-imidazol-2-yl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (179)

(a) (S) - ((6- (2-chloro-3- (3-chloro-2- (4, 5-dihydro-1H-imidazol-2-yl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

To a mixture of tert-butyl (S) - ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (see example 80, step (a)) (200 mg,0.289 mmol) and ethane-1, 2-diamine (52.1 mg,0.867 mmol) in tert-butanol (10 mL) was added iodine (220 mg,0.867 umol) and potassium carbonate (239 mg,1.74 mmol) followed by N ₂ The mixture was stirred at 70℃for 3 hours. Water (10 mL) was then added and the mixture extracted with ethyl acetate (2X 5 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to afford tert-butyl (S) - ((6- (2-chloro-3- (3-chloro-2- (4, 5-dihydro-1H-imidazol-2-yl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (205 mg,53% yield) as a black solid. MS: m/z found 731[ M+H ] ] ⁺ . The crude product was used in the next step without further purification.

(b) (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4, 5-dihydro-1H-imidazol-2-yl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

To (S) - ((6)A solution of tert-butyl (2-chloro-3- (3-chloro-2- (4, 5-dihydro-1H-imidazol-2-yl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (200 mg, 0.279 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (67.53 mmol,5 mL) followed by N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was then filtered, the filtrate was concentrated and the residue was purified by reverse phase HPLC to afford (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4, 5-dihydro-1H-imidazol-2-yl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (81.9 mg,43% yield) as a white solid (formate). MS: m/z found 631[ M+H ]] ⁺ Retention time = 2.62min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.73(d,1H),7.91(d,1H),7.86(d,1H),7.75(dd,1H),7.64-7.53(m,4H),7.47(dd,1H),3.34(d,1H),4.16-3.97(m,12H),4.00-3.97(m,1H),3.05-3.02(m,2H),2.42-2.36(m,3H),1.91-1.88(m,1H).

Example 329: (S) -4- ((4- (3-chloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) amino) -3-hydroxybutyric acid (180)

(a) 2, 3-dichloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) pyridine

To a mixture of 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (example 1, step (a)) (2 g,5.08 mmol) and ethane-1, 2-diamine (916 mg,15.2 mmol) in t-butanol (15 mL) was added potassium carbonate (4.21 g,30.4 mmol) and iodine (3.87 g,15.2 mmol), followed by N ₂ The mixture was stirred at 70℃for 3 hours. Water (10 mL) was then added and the mixture extracted with ethyl acetate (2X 5 mL). The combined organic phases were dried over anhydrous sodium sulfate,filtered and concentrated to afford 2, 3-dichloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) pyridine (1.8 g,32% yield) as a yellow crude solid. MS: m/z found 433[ M+H ]] ⁺ . The crude product was used in the next step without further purification.

(b) 4- (3-chloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzaldehyde

To 2, 3-dichloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) pyridine (400 mg, 0.92mmol) and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzaldehyde (435 mg,1.66 mmol) in dioxane/H ₂ A mixture of O (5:1, 6 mL) was added [1,1' -bis (biphenylphosphino) ferrocene]Palladium (II) dichloride complex with dichloromethane (112 mg,0.138 mmol) and potassium carbonate (382 mg,2.77 mmol) then under N ₂ The mixture was stirred at 110℃for 1 hour. The mixture was filtered, the filtrate was diluted with water (5 mL) and then extracted with ethyl acetate (2 x5 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to afford 4- (3-chloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzaldehyde (500 mg,54% yield) as a black crude solid. MS: m/z found 533[ M+H ]] ⁺ . The crude product was used in the next step without further purification.

(c) (S) -4- ((4- (3-chloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) amino) -3-hydroxybutyric acid

To 4- (3-chloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzaldehyde (150 mg, 0)A mixture of 281 mmol) and isopropyl (S) -4-amino-3-hydroxybutyrate (100 mg,0.843 mmol) in methanol (2 mL) was added sodium acetate (115 mg,1.41 mmol) followed by N ₂ The mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (119 mg,0.562 mmol) was then added and added under N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was filtered, the filtrate was concentrated and the residue was purified by reverse phase HPLC to provide (S) -4- ((4- (3-chloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-methoxybenzyl) amino) -3-hydroxybutyric acid (10 mg,5% yield) as a white solid (formate). MS: m/z found 636[ M+H ]] ⁺ Retention time = 2.64min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.28(d,1H),7.78(dd,1H),7.61(m,1H),7.57(d,1H),7.56-7.52(m,2H),7.46(d,1H),7.37(s,1H),7.34-7.33(m,1H),4.30(s,2H),4.29-4.19(m,4H),4.10(s,4H),3.98(s,3H),3.19-3.15(m,1H),3.02-2.97(m,1H),2.45-2.43(m,2H).

Example 330: (S) -4- ((4- (3-chloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) amino) -3-hydroxybutyric acid isopropyl ester (209)

(a) (S) -4- ((4- (3-chloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) amino) -3-hydroxybutyric acid isopropyl ester

To a mixture of 4- (3-chloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzaldehyde (example 329, step (b)) (150 mg, 0.281mmol) and isopropyl (S) -4-amino-3-hydroxybutyrate (135 mg,0.843 mmol) in methanol (2 mL) was added sodium acetate (115 mg,1.41 mmol) and under N ₂ Mixing at room temperatureThe mixture was stirred for 2 hours. Sodium triacetoxyborohydride (119 mg,0.056 mmol) was then added and the mixture was taken up in N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was filtered, the filtrate was concentrated and the residue was purified by reverse phase HPLC to provide isopropyl (S) -4- ((4- (3-chloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-methoxybenzyl) amino) -3-hydroxybutyrate (16 mg,7.93% yield) as a white solid (formate). MS: m/z found 678[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),8.28(d,1H),7.78(dd,1H),7.64-7.56(m,2H),7.52-7.46(m,3H),7.37(s,1H),7.35-7.33(m,1H),5.02-4.99(m,1H),4.29-4.25(m,3H),4.25-4.24(m,3H),4.10(s,3H),3.98(s,3H),3.13-3.12(m,2H),2.98-2.93(m,1H),2.53-2.51(m,2H),1.24-1.22(m,6H).

Example 331: (S) -5- (((6- (3- (2- (4- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (237)

(a) (S) - ((6- (3- (2- (4- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

To tert-butyl (S) - ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (example 80, step (a)) (200 mg,289 umol) and 1- (6-amino-2-azaspiro [ 3.3) ]A mixture of heptan-2-yl) ethan-1-one (82.7 mg,433 umol) in methanol (8 mL) was added sodium acetate (71.1 mg,867 umol) and purified under N ₂ The mixture was stirred at room temperature for 12 hours.Sodium triacetoxyborohydride (183 mg,867 umol) was then added and added to the mixture at N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was filtered, the filtrate concentrated and passed through normal phase SiO ₂ The residue was purified by chromatography (15-25% ethyl acetate/methanol) to afford (S) - ((6- (3- (2- (4- (((2-acetyl-2-azaspiro [ 3.3)) as a white solid]Heptane-6-yl) amino methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (150 mg,41% yield). MS: m/z found 829[ M+H ]] ⁺ .

(b) (S) -5- (((6- (3- (2- (4- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

To (S) - ((6- (3- (2- (4- (((2-acetyl-2-azaspiro [ 3.3))]Heptan-6-yl) amino methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (140 mg,168 umol) in dichloromethane (3 mL) was added trifluoroacetic acid (4.62 mg,40.5 umol) and concentrated under N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was filtered, the filtrate was concentrated and the residue was purified by reverse phase HPLC to afford (S) -5- ((((6- (3- (2- (4- (((2-acetyl-2-azaspiro [ 3.3)) as a white solid (formate))]Heptane-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl methyl) amino) methyl) pyrrolidin-2-one (16 mg 12% yield). MS: m/z found 729[ M+H ]] ⁺ Retention time = 2.60min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.67(d,1H),7.81(d,1H),7.73(dd,1H),7.58(t,1H),7.52-7.49(m,2H),7.43-7.37(m,2H),7.36(d,1H),7.30(d,1H),4.30(s,1H),4.20-4.18(m,3H),4.06-3.76(m,10H),3.77-3.76(m,1H),3.32-3.26(m,3H),2.91-2.71(m,2H),2.70-2.64(m,2H),2.45-2.33(m,4H),1.86(d,3H).

Example 332: (S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (153)

(a) 6- (2-chloro-3- (3-chloro-2- (3-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde

Following suzuki coupling procedure a, 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (150 mg,0.38 mmol) and 3-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (100 mg,0.38 mmol) were provided 6- (2-chloro-3- (3-chloro-2- (3-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde in 85% yield. LCMS: m/z found 493.1[ M+H ] ] ⁺ Retention time = 1.10min (method B).

(b) (S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

This compound was prepared as formate salt according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (3-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (30 mg,0.06 mmol) and (5S) -5- (aminomethyl) pyrrolidin-2-one (28 mg,0.24 mmol). Yield 68%. LCMS: m/z found 689.2[ M+H ]] ⁺ Retention time = 1.65min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(dd,1H),8.46–8.39(m,2H),7.81(d,1H),7.72(dt,1H),7.56(td,1H),7.46(dd,1H),7.42(dd,1H),7.34–7.26(m,2H),7.22(d,1H),7.15(s,1H),4.09(d,2H),4.05(s,3H),4.04–4.01(m,2H),3.97–3.89(m,2H),3.88(s,3H),3.01–2.84(m,4H),2.42–2.25(m,6H),1.92–1.77(m,2H).

Example 333:1- (4- (((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -5-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

This compound was prepared as a formate salt according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (3-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (example 332, step (a)) (30 mg,0.06 mmol) and 1- (4-amino-1-piperidinyl) ethanone (35 mg,0.24 mmol). 80% yield. LCMS: m/z found 745.3[ M+H ]] ⁺ Retention time = 1.71min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.55–8.48(m,2H),7.82(d,1H),7.71(d,1H),7.56(t,1H),7.45(dd,1H),7.42(d,1H),7.32–7.27(m,2H),7.20(s,1H),7.15(s,1H),4.55(d,2H),4.08(s,2H),4.06–4.02(m,5H),4.02–3.93(m,2H),3.88(s,3H),3.22–3.00(m,4H),2.78–2.57(m,2H),2.21–2.00(m,10H),1.56–1.29(m,4H).

Example 334:1- (6- (2-chloro-3- (3-chloro-2- (3-methoxy-5- ((methylamino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine (155)

This compound was prepared as formate salt according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (3-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (example 332, step (a)) (30 mg,0.06 mmol) and methylamine solution (33% wt in ethanol, 0.24 mmol). Yield 35%. LCMS: m/z found 523.2[ M+H ]] ⁺ Retention time = 1.71min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(dt,1H),8.53(s,2H),7.86(dd,1H),7.75–7.69(m,1H),7.58(ddd,1H),7.50–7.40(m,2H),7.37–7.31(m,2H),7.29(d,1H),7.18(s,1H),4.20(s,4H),4.08(s,3H),3.90(s,3H),2.73(s,3H),2.71(s,3H).

Example 335:2- (((6- (2-chloro-3- (3-chloro-2- (3- (((2-hydroxyethyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethan-1-ol (156)

This compound was prepared as formate salt according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (3-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (example 332, step (a)) (30 mg,0.06 mmol) and 2-aminoethanol (15 mg,0.24 mmol). 60% yield. LCMS: m/z found 583.2[ M+H ]] ⁺ Retention time = 1.63min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(dt,1H),8.54–8.47(m,2H),7.89–7.83(m,1H),7.76–7.69(m,1H),7.58(ddd,1H),7.47(dt,1H),7.44(d,1H),7.37–7.31(m,2H),7.29(d,1H),7.20(s,1H),4.24(s,2H),4.22(s,2H),4.08(s,3H),3.90(s,3H),3.81(ddt,4H),3.11(t,4H).

Example 336: (S) -1- (((6- (2-chloro-3- (3-chloro-2- (3- ((((S) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol (157)

This compound was prepared as formate salt according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (3-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (example 332, step (a)) (30 mg,0.06 mmol) and (2S) -1-aminopropane-2-ol (18 mg,0.24 mmol). 73% yield. LCMS: m/z found 611.2[ M+H ]] ⁺ Retention time = 1.72min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(dd,1H),8.55–8.49(m,2H),7.85(d,1H),7.73(dd,1H),7.62–7.55(m,1H),7.50–7.45(m,1H),7.44(dd,1H),7.37–7.31(m,2H),7.28(d,1H),7.20(d,1H),4.26–4.14(m,4H),4.07(s,3H),4.05–3.96(m,2H),3.90(s,3H),3.01(d,2H),2.82(dd,2H),1.23(d,3H),1.20(d,3H).

Example 337: (S) -4- ((3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) amino) -3-hydroxybutyric acid (169)

(a) ((6- (2-chloro-3- (3-chloro-2- (3-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) carbamic acid tert-butyl ester

Following suzuki coupling procedure a, ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) carbamic acid tert-butyl ester (200 mg,0.39 mmol) and 3-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (103 mg,0.39 mmol) were provided as ((6- (2-chloro-3- (3-chloro-2- (3-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) carbamic acid tert-butyl ester in 87% yield. LCMS: m/z found 608.2[ M+H ] ] ⁺ Retention time = 1.21min (method B).

(b) (S) -4- ((3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) amino) -3-hydroxybutyric acid

Reduction from ((6- (2-chloro-3- (3-chloro-2- (3-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) carbamic acid tert-butyl ester (40 mg,0.07 mmol) and (3S) -4-amino-3-hydroxy-butyric acid (16 mg,0.13 mmol)Amination procedure B provides (3S) -4- [ [3- [4- [3- [5- [ [ tert-butoxycarbonyl (methyl) amino ] as crude material]Methyl group]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]-5-methoxy-phenyl]Methylamino group]3-hydroxy-butyric acid, LCMS: m/z found 711.2[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Yield 30% through two steps. LCMS: m/z found 611.2[ M+H ]] ⁺ Retention time = 1.68min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.54(s,2H),7.84(d,1H),7.76–7.67(m,1H),7.58(s,1H),7.51–7.41(m,2H),7.38–7.32(m,2H),7.27(s,1H),7.20(s,1H),4.23(s,2H),4.19–4.12(m,3H),4.12–4.02(m,3H),3.90(s,3H),3.17–3.06(m,1H),3.01–2.91(m,1H),2.70(s,3H),2.46–2.35(m,2H).

Example 338:3- ((3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) amino) propanoic acid (170)

From tert-butyl ((6- (2-chloro-3- (3-chloro-2- (3-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) carbamate (example 337, step (a)) (40 mg,0.07 mmol) and 3-aminopropionic acid (12 mg,0.13 mmol) reductive amination procedure B afforded 3- [ [3- [4- [3- [5- [ [ tert-butoxycarbonyl (methyl) amino ] as crude material ]Methyl group]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]-5-methoxy-phenyl]Methylamino group]Propionic acid, LCMS: m/z found 681.2[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 62% yield over two steps. LCMS: m/z found 581.2[ M+H ]] ⁺ Retention time = 1.73min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(dd,1H),8.54(s,2H),7.84(d,1H),7.72(dd,1H),7.57(t,1H),7.48–7.40(m,2H),7.37(d,1H),7.33(d,1H),7.28(d,1H),7.20(d,1H),4.26(s,2H),4.17–4.11(m,2H),4.07(s,3H),3.90(s,3H),3.19(t,2H),2.70(s,3H),2.50(t,2H).

Example 339: (S) -1- (3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) pyrrolidine-3-carboxylic acid (171)

From tert-butyl ((6- (2-chloro-3- (3-chloro-2- (3-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) carbamate (example 337, step (a)) (40 mg,0.07 mmol) and (3S) -pyrrolidine-3-carboxylic acid (15 mg,0.13 mmol) of reductive amination procedure B afforded (3S) -1- [ [3- [4- [3- [5 ] t-butoxycarbonyl (methyl) amino ] as crude material]Methyl group]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]-5-methoxy-phenyl]Methyl group]Pyrrolidine-3-carboxylic acid, LCMS: m/z found 707.2[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Yield was 63% over two steps. LCMS: m/z found 607.2[ M+H ] ] ⁺ Retention time = 1.73min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.54(s,2H),7.85(d,1H),7.72(dd,1H),7.57(t,1H),7.48–7.41(m,2H),7.38(s,1H),7.34(d,1H),7.27(d,1H),7.20(t,1H),4.35–4.21(m,2H),4.18(s,2H),4.08(s,3H),3.90(s,3H),3.42–3.34(m,2H),3.25(t,2H),3.05(p,1H),2.72(s,3H),2.35–2.15(m,2H).

Example 340:2- (1- (3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) azetidin-3-yl) acetic acid (172)

From tert-butyl ((6- (2-chloro-3- (3-chloro-2- (3-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) carbamate (example 337, step (a)) (40 mg,0.07 mmol) and 2- (azetidin-3-yl) acetic acid (15 mg,0.13 mmol) reductive amination procedure B provided 2- [1- [ as crude material[3- [4- [3- [5- [ [ tert-butoxycarbonyl (methyl) amino ]]Methyl group]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]-5-methoxy-phenyl]Methyl group]Azetidin-3-yl]Acetic acid, LCMS: m/z found 707.2[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 73% yield over two steps. LCMS: m/z found 607.2[ M+H ]] ⁺ Retention time = 1.75min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.62(d,1H),8.54(s,2H),7.84(d,1H),7.72(dd,1H),7.57(t,1H),7.48–7.39(m,2H),7.34(d,1H),7.23(s,1H),7.15–7.04(m,2H),4.44(dd,1H),4.15(s,2H),4.12–4.08(m,1H),4.08(s,3H),3.91–3.81(m,5H),2.83–2.58(m,7H),2.34(dd,1H).

Example 341:2- (3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) -2-azaspiro [3.3] heptane-6-carboxylic acid (173)

From ((6- (2-chloro-3- (3-chloro-2- (3-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) carbamic acid tert-butyl ester (example 337, step (a)) (25 mg,0.04 mmol) and 2-azaspiro [3.3 ]]Reductive amination procedure B of heptane-6-carboxylic acid (12 mg,0.08 mmol) provides 2- [ [3- [4- [3- [5- [ [ tert-butoxycarbonyl (methyl) amino ] as crude material]Methyl group]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]-5-methoxy-phenyl]Methyl group]-2-azaspiro [3.3]Heptane-6-carboxylic acid, LCMS: m/z found 733.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Yield was 35% over two steps. LCMS: m/z found 633.2[ M+H ]] ⁺ Retention time = 1.78min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.67–8.61(m,1H),8.47(s,2H),7.88(d,1H),7.76–7.69(m,1H),7.58(t,1H),7.46(dd,2H),7.36(d,1H),7.31(d,1H),7.27–7.06(m,2H),4.39(s,1H),4.29(s,1H),4.25(s,2H),4.11–4.03(m,5H),3.96–3.82(m,4H),2.92–2.81(m,1H),2.79(s,1H),2.77(s,3H),2.51–2.37(m,2H),2.32(t,1H),1.85(d,1H).

Example 342:3- ((3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) amino) bicyclo [1.1.1] pentane-1-carboxylic acid (174)

From ((6- (2-chloro-3- (3-chloro-2- (3-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) carbamic acid tert-butyl ester (example 337, step (a)) (20 mg,0.03 mmol) and 3-aminobicyclo [ 1.1.1.1) ]Reductive amination procedure B of pentane-1-carboxylic acid (8 mg,0.07 mmol) provides 3- [ [3- [4- [3- [5- [ [ tert-butoxycarbonyl (methyl) amino ] as crude material]Methyl group]-6-methoxy-2-pyridinyl]-2-chloro-phenyl]-3-chloro-2-pyridinyl]-5-methoxy-phenyl]Methylamino group]Bicyclo [1.1.1]Pentane-1-carboxylic acid, LCMS: m/z found 719.2[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 55% yield over two steps. LCMS: m/z found 619.2[ M+H ]] ⁺ Retention time = 1.76min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.61(d,1H),8.52(s,2H),7.86(d,1H),7.72(d,1H),7.57(t,1H),7.47–7.40(m,2H),7.36(d,1H),7.25(d,1H),7.10(s,2H),4.23(s,2H),4.09(s,3H),3.90–3.82(m,5H),2.76(s,3H),2.00(s,6H).

Example 343:3- (((3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) amino) methyl) bicyclo [1.1.1] pentane-1-carboxylic acid (175)

From tert-butyl ((6- (2-chloro-3- (3-chloro-2- (3-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) carbamate (example 337, step (a)) (20 mg,0.03 mmol) and 3- (aminomethyl) bicyclo [ 1.1.1.1)]Pentane-1-carboxylic acid (9 mg,0.07 mmol) alsoThe prochlorazation procedure B provided 3- [ [ [3- [4- [3- [5- [ [ tert-butoxycarbonyl (methyl) amino ] as crude material]Methyl group]-6-methoxy-2-pyridinyl]-2-chloro-phenyl ]-3-chloro-2-pyridinyl]-5-methoxy-phenyl]Methylamino group]Methyl group]Bicyclo [1.1.1]Pentane-1-carboxylic acid, LCMS: m/z found 733.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. Yield 43% over two steps. LCMS: m/z found 633.2[ M+H ]] ⁺ Retention time = 1.80min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.54(s,2H),7.84(d,1H),7.76–7.68(m,1H),7.57(t,1H),7.49–7.42(m,2H),7.31(d,2H),7.24(d,1H),7.14(s,1H),4.13(s,4H),4.07(s,3H),3.89(s,3H),3.03–2.94(m,2H),2.69(s,3H),1.95(s,6H).

Example 344:1- (6- (3- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine (395)

(a) 2- (3-bromo-2-methylphenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane

To a solution of 3-bromo-2-methylaniline (10 g,53.7 mmol) and HCl (1 mol/L,5 mL) in MeOH (150 mL) at 0deg.C was added dropwise H ₂ Sodium nitrite (4.08 g,59.12 mmol) in O (30 mL). The reaction mixture was stirred at 0 ℃ for 0.5 hours. Bis (pinacolato) diborane (40.9 g,161 mmol) in methanol (50 mL) was then added to the mixture at 0 ℃ and the mixture was stirred at room temperature for 1 hour. Water (20 mL) was added and the mixture extracted with ethyl acetate (2X 10 mL). The combined organic phases were dried over anhydrous sulphate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ Chromatography (100% DCM) purified the residue to provide 2- (3-bromo-2-methylphenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (4 g,10% as a yellow oilYield). MS: m/z found 297 and 299[ M+H ]] ⁺ .

(b) 6- (3-bromo-2-methylphenyl) -2-methoxynicotinaldehyde

To 2- (3-bromo-2-methylphenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (1.8 g,6.06 mmol) and 6-chloro-2-methoxynicotinaldehyde (866 mg,5.05 mmol) in dioxane/H ₂ A mixture of tetrakis (triphenylphosphine) palladium (0) (29 mg,0.252 mmol) and potassium carbonate (2.09 g,15.1 mmol) were added to a mixture of O (6:1, 35 mL) followed by N ₂ The mixture was stirred at 95℃for 3 hours. The mixture was filtered, the filtrate was concentrated, and the filtrate was purified by normal phase SiO ₂ The residue was purified by chromatography (0-25% ethyl acetate/petroleum ether) to afford 6- (3-bromo-2-methylphenyl) -2-methoxynicotinaldehyde as a yellow solid (2.8 g,65% yield). MS: m/z measured values 306 and 308[ M+H ]] ⁺ .

(c) 6- (3- (2, 3-dichloropyridin-4-yl) -2-methylphenyl) -2-methoxynicotinaldehyde

To 2, 3-dichloro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine (2.68 g,9.78 mmol) and 6- (3-bromo-2-methylphenyl) -2-methoxynicotinaldehyde (1.5 g,4.90 mmol) in H ₂ A mixture of O/THF (1:5, 60 mL) was added [1,1' -bis (di-tert-butylphosphino) ferrocene ]Palladium (II) dichloride (159 mg,0.244 mmol), potassium phosphate (3.12 g,14.7 mmol), then under N ₂ The mixture was stirred at 80℃for 4 hours. Water (20 mL) was added and the mixture extracted with ethyl acetate (2X 10 mL). The combined organic phases were dried over anhydrous sulphate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ The residue was purified by chromatography (20-30% ethyl acetate/petroleum ether) to afford 6- (3- (2, 3-dichloropyridin-4-yl) -2-methylphenyl) -2-methoxynicotinaldehyde (1.8 g,34% yield) as a yellow solid. MS m/z found 373[ M+H ]] ⁺ .

(d) 6- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -2-methoxynicotinaldehyde

To 6- (3- (2, 3-dichloropyridin-4-yl) -2-methylphenyl) -2-methoxynicotinaldehyde (1.7 g,4.55 mmol) and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (example 77, step (a)) (1.79 g,6.83 mmol) in dioxane/H ₂ A mixture of O (5:1, 48 mL) was added [1,1' -bis (biphenylphosphino) ferrocene]Palladium (II) dichloride complex with dichloromethane (185 mg,227 umol) and potassium carbonate (1.89 g,13.6 mmol) then under N ₂ The mixture was stirred at 95℃for 4 hours. Water (20 mL) was added and the mixture was extracted with ethyl acetate (2X 50 mL). The combined organic phases were dried over anhydrous sulphate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ The residue was purified by chromatography (20-30% ethyl acetate/petroleum ether) to afford 6- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -2-methoxy nicotinaldehyde (800 mg,19.4% yield) as a yellow solid. MS: m/z found 473[ M+H ]] ⁺ .

(e) 1- (6- (3- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine

To a mixture of 6- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -2-methoxynicotinaldehyde (150 mg,317 umol) and methylammonium chloride (64.2 mg,0.951 mmol) in MeOH (1 mL) was added sodium acetate (156 mg,1.90 mmol) followed by N ₂ The mixture was stirred at room temperature for 11.5 hours. Sodium triacetoxyborohydride (69.7 mg,1.11 mmol) was then added and added under N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was filtered, the filtrate concentrated and the residue purified by reverse phase HPLC to afford a white solid @Formate) 1- (6- (3- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine (36.3 mg,20% yield). MS: m/z found 503[ M+H ]] ⁺ Retention time = 2.56min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),7.87(d,1H),7.55-7.51(m,2H),7.46-7.44(m,3H),7.37(dd,1H),7.28(dd,1H),7.21(d,1H),4.27(s,2H),4.21(s,2H),4.07(s,3H),4.01(s,3H),2.75(s,6H),2.19(s,3H).

Example 345:1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (399)

To a mixture of 6- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -2-methoxynicotinaldehyde (example 344, step (d)) (150 mg,0.317 mmol) and 1- (4-aminopiperidin-1-yl) ethan-1-one (135 mg,951 mol) in MeOH (1 mL) was added sodium acetate (156 mg,1.9 mmol), followed by N ₂ The mixture was stirred at room temperature for 11.5 hours. Sodium cyanoborohydride (69.76 mg,1.11 mmol) was then added and the mixture was taken up in N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was then filtered, the filtrate was concentrated and the residue was purified by reverse phase HPLC to provide 1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (62.4 mg,24.9% yield) as a white solid (formate). MS: m/z found 725[ M+H ]] ⁺ Retention time = 2.64min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.57(d,1H),7.79(d,1H),7.45(t,2H),7.38-7.34(m,3H),7.29-7.27(m,1H),7.19(d,1H),7.11(d,1H),4.61-4.53(m,2H),4.22(s,2H),4.08(s,2H),3.97-3.93(m,8H),3.17-3.11(m,4H),2.66-2.62(m,2H),2.2-2.07(m,13H),1.58-1.41(m,4H).

Example 346:2- ((6- (3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one (408)

To 6- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -2-methoxynicotinaldehyde (example 344, step (d)) (150 mg,0.317 umol) and 2, 6-diazaspiro [3.4 ]]Sodium acetate (156 mg,1.9 mmol) was added to a mixture of octan-7-one (154 mg,0.951 mol) in MeOH (5 mL) followed by N ₂ The mixture was stirred at room temperature for 11.5 hours. Sodium cyanoborohydride (69.7 mg,1.11 mmol) was then added and the mixture was taken up in N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was filtered, the filtrate was concentrated and the residue was purified by reverse phase HPLC to afford 2- ((6- (3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [ 3.4)) as a white solid (formate salt)]Octane-2-yl) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl methyl) -2, 6-diazaspiro [3.4]Octan-7-one (38 mg,15% yield). MS: m/z found 693[ M+H ]] ⁺ Retention time = 2.30min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),7.77(d,1H),7.53-7.34(m,6H),7.26-7.25(m,1H),7.14(d,2H),4.30(s,2H),4.05-3.96(m,12H),3.71(s,4H),3.67(s,2H),3.64(s,2H),2.71(s,2H),2.65(s,2H),2.18(s,3H).

Example 347:1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one (409)

To 6- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -2-methoxynicotinaldehyde (example 344, step (d)) (150 mg,0.317 mmol) and 1- (2, 6-diazaspiro [3.3] ]Heptane (heptane)A mixture of-2-yl) ethan-1-one (241 mg,0.951 mmol) in MeOH (6 mL) was added sodium acetate (156 mg,1.9 mmol) followed by N ₂ The mixture was stirred at room temperature for 11.5 hours. Sodium cyanoborohydride (69.7 mg,1.11 mmol) was then added and the mixture was taken up in N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was filtered, the filtrate was concentrated and the residue was purified by reverse phase HPLC to afford 1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [ 3.3)) as a white solid (formate))]Heptane-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl-2-methylphenyl) -2-methoxypyridin-3-yl methyl) -2, 6-diazaspiro [3.3]Heptane-2-yl) ethan-1-one (91.1 mg,36% yield). MS: m/z found 721[ M+H ]] ⁺ Retention time = 2.52min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),7.78(d,1H),7.53-7.35(m,6H),7.27-7.25(m,1H),7.16(d,1H),4.39-4.36(m,6H),4.33(s,4H),4.19(s,2H),4.18(s,2H),4.01(d,8H),3.88(s,4H),2.18(s,3H),1.87(s,6H).

Example 348: n- ((6- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine (426)

To a mixture of 6- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -2-methoxynicotinaldehyde (example 344, step (d)) (45 mg,95.1 mol) and tetrahydro-2H-pyran-4-amine (28.87 mg, 284 mol) in MeOH (2 mL) was added sodium acetate (46.8 mg,570 mol) followed by N ₂ The mixture was stirred at room temperature for 10 hours. Sodium triacetoxyborohydride (40.3 mg,190 umol) was then added and added to the mixture under N ₂ The mixture was stirred at room temperature for 2 hours. The mixture was filtered, the filtrate was concentrated and the residue was purified by reverse phase HPLC to provide N- ((6- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine (19 mg,28% yield) as a white solid (formate salt). MS: m/z actual measurementValue 643[ M+H ]] ⁺ Retention time = 2.54min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),7.87(d,1H),7.56-7.46(m,2H),7.45-7.41(m,3H),7.36(d,1H),7.28(d,1H),7.19(d,1H),4.30(s,2H),4.19(s,2H),4.08-4.05(m,7H),4.01(s,3H),3.51-3.40(m,4H),3.33-3.26(m,2H),2.19(s,3H),2.14-2.06(m,4H),1.78-1.64(m,4H).

Example 349: n- (1- ((6- (3- (2- (4- ((4-acetamidopiperidin-1-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide (467)

To a mixture of 6- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -2-methoxynicotinaldehyde (example 344, step (d)) (40 mg,84.5 mol) and N- (piperidin-4-yl) acetamide (36.0 mg, 255 mol) in MeOH (2 mL) was added sodium acetate (41.6 mg,507 mol) followed by N ₂ The mixture was stirred at room temperature for 11.5 hours. Sodium cyanoborohydride (21.2 mg,338 umol) was then added and the mixture was taken up in N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was filtered, the filtrate was concentrated and the residue was purified by reverse phase HPLC to provide N- (1- ((6- (3- (2- (4- ((4-acetamidopiperidin-1-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide (13 mg,18% yield) as a white solid (formate salt). MS: m/z found 725[ M+H ]] ⁺ Retention time = 2.67min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.58(d,1H),7.87-7.28(m,1H),7.51-7.47(m,2H),7.40-7.30(m,4H),7.12(d,1H),7.10-7.09(m,1H),4.24(s,2H),4.20-3.83(m,8H),3.78-3.76(m,2H),3.41-3.37(m,2H),3.24-3.22(m,2H),3.07-3.06(m,2H),2.80-2.75(m,2H),2.12(s,3H),2.05-1.97(m,4H),1.88(s,6H),1.69-1.54(m,4H).

Example 350:2- ((2-methoxy-6- (3- (2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) phenyl) -3-methylpyridin-4-yl) -2-methylphenyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one (415)

(a) 2-methoxy-6- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) nicotinaldehyde

6- (3-bromo-2-methylphenyl) -2-methoxynicotinaldehyde (example 344, step (b)) (1.95 g,6.37 mmol), bis (pinacolato) diborane (3.23 g,12.74 mmol), potassium acetate (1.88 g,19.11 mmol) and [1,1' -bis (biphenylphosphino) ferrocene]A mixture of palladium (II) dichloride (463 mg,637 umol) in 1, 4-dioxane (30 mL) was degassed and N ₂ Purging three times, then at N ₂ The mixture was stirred at 100℃for 3 hours. The mixture was combined with another batch at 50mg scale. By adding H ₂ O (30 mL) quenched the reaction mixture and extracted with ethyl acetate (3X 25 mL). The combined organic extracts were washed with saturated aqueous brine solution (2×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide a residue. By normal phase SiO ₂ The residue was purified by chromatography (0-20% ethyl acetate/petroleum ether) to afford 2-methoxy-6- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) nicotinaldehyde (1.9 g,84% yield) as a yellow solid. ¹ H NMR(400MHz,CDCl ₃ -d):δ＝10.42(s,1H),8.17(d,1H),7.85(dd,1H),7.47(dd,1H),7.31-7.27(m,1H),7.11(d,1H),4.09(s,3H),2.59(s,3H),1.38(s,12H).

(b) 6- (3- (2-chloro-3-methylpyridin-4-yl) -2-methylphenyl) -2-methoxynicotinaldehyde

2-methoxy-6- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) nicotinaldehyde (1.9 g,5.38 mmol), 2-chloro-4-iodo-3-methylpyridine (2.73 g,10.76 mmol), potassium carbonate (2.23 g,16.14 mmol) and [1,1' -bis (biphenylphosphino) -ferrocene]Palladium (II) dichloride complex with dichloromethane (439 mg, 538. Mu. Mol) in 1, 4-dioxane/H ₂ The mixture in O (10:1, 33 mL) was degassed and N ₂ Purging three times, then at N ₂ The mixture was stirred at 95℃for 3 hours. The mixture was combined with another batch at 50mg scale. By adding H ₂ O (30 mL) quenched the reaction mixture and extracted with ethyl acetate (3X 25 mL). The combined organic extracts were washed with saturated aqueous brine solution (2×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide a residue. By normal phase SiO ₂ The residue was purified by chromatography (10-50% ethyl acetate/petroleum ether) to afford 6- (3- (2-chloro-3-methylpyridin-4-yl) -2-methylphenyl) -2-methoxynicotinaldehyde as a yellow oil (1 g,52% yield). ¹ H NMR(400MHz,CDCl ₃ -d):δ＝10.43(s,1H),8.29(d,1H),8.21(d,1H),7.52(dd,1H),7.39(t,1H),7.20-7.14(m,2H),7.09(d,1H),4.11(s,3H),2.19(s,3H),2.11(s,3H).

(c) 6- (3- (2- (4-formyl-3-methoxyphenyl) -3-methylpyridin-4-yl) -2-methylphenyl) -2-methoxynicotinaldehyde

6- (3- (2-chloro-3-methylpyridin-4-yl) -2-methylphenyl) -2-methoxynicotinaldehyde (0.95 g,2.69 mmol), 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (1.76 g,6.73 mmol), potassium phosphate (1.71 g,8.08 mmol) and [1,1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) dichloride (175 mg, 269. Mu. Mol) in 1, 4-dioxane/H ₂ The mixture in O (10:1, 22 mL) was degassed and N ₂ Purging three times, then at N ₂ The mixture was stirred at 95℃for 2 hours. The mixture was combined with another batch on a 20mg scale. By adding H ₂ O (30 mL) quenched the reaction mixture and extracted with ethyl acetate (3X 25 mL). The combined organic extracts were washed with saturated aqueous brine solution (2×15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to giveFor residue. By normal phase SiO ₂ The residue was purified by chromatography (10-50% ethyl acetate/petroleum ether) to afford 6- (3- (2- (4-formyl-3-methoxyphenyl) -3-methylpyridin-4-yl) -2-methoxyphenyl) -2-methoxynicotinaldehyde (1 g,82% yield) as a white solid. ¹ H NMR(400MHz,CDCl ₃ -d):δ10.53(s,1H),10.43(s,1H),8.61(d,1H),8.22(d,1H),7.92(d,1H),7.52(dd,1H),7.41(t,1H),7.24-7.19(m,5H),4.11(s,3H),4.03-3.99(m,3H),2.18(s,3H),2.11(s,3H).

(d) 2- ((2-methoxy-6- (3- (2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) -3-methylpyridin-4-yl) -2-methylphenyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one

At N ₂ 6- (3- (2- (4-formyl-3-methoxyphenyl) -3-methylpyridin-4-yl) -2-methylphenyl) -2-methoxynicotinaldehyde (150 mg,0.3 mmol), 2, 6-diazaspiro [3.4] at room temperature]A mixture of octan-7-one hydrochloride (162 mg,1 mmol) and sodium acetate (163 mg,2 mmol) in MeOH (1.5 mL) was stirred for 3 hours. Sodium cyanoborohydride (73 mg,1.2 mmol) was then added and the mixture was taken up in N ₂ The mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered, the filtrate was concentrated and the residue was purified by reverse phase HPLC to afford 2- ((2-methoxy-6- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [ 3.4) as a white solid]Octane-2-yl) methyl) phenyl) -3-methylpyridin-4-yl) -2-methylphenyl pyridin-3-yl methyl) -2, 6-diazaspiro [3.4]Octane-7-one (50.2 mg,22% yield). MS: m/z found 673[ M+H ]] ⁺ Retention time = 1.84min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ.8.40-8.35(m,1H),7.57(d,1H),7.40-7.35(m,1H),7.32-7.26(m,2H),7.16(d,1H),7.11(d,1H),7.02-6.98(m,3H),3.87(s,3H),3.81(s,3H),3.67(s,2H),3.61(s,2H),3.49(d,4H),3.32(d,8H),2.49-2.47(m,4H),2.02(s,3H),1.98(s,3H).

Example 351:1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one (416)

At N ₂ 6- (3- (2- (4-formyl-3-methoxyphenyl) -3-methylpyridin-4-yl) -2-methylphenyl) -2-methoxynicotinaldehyde (150 mg,0.3 mmol) (example 35, step c), 1- (2, 6-diazaspiro [3.3 ] at room temperature]A mixture of heptan-2-yl) ethan-1-one trifluoroacetate (255 mg,1.0 mmol) and sodium acetate (163 mg,2.0 mmol) in MeOH (1.5 mL) was stirred for 3 hours. Sodium cyanoborohydride (73 mg,1.2 mmol) was then added and the mixture was taken up in N ₂ The mixture was stirred at room temperature for 12 hours. The reaction mixture was then filtered, the filtrate was concentrated and the residue was purified by reverse phase HPLC to afford 1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [ 3.3)) as a white solid]Heptane-2-yl) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl methyl) -2, 6-diazaspiro [3.3]Heptane-2-yl) ethan-1-one (64.4 mg,27% yield). MS: m/z found 701[ M+H ]] ⁺ Retention time = 2.00min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ.8.37(d,1H),7.58(d,1H),7.38-7.36(m,1H),7.31(d,1H),7.28-7.25(m,1H),7.17-7.15(m,1H),7.12-7.10(m,1H),7.02(s,1H),6.99(d,2H),4.20(d,4H),3.95(d,4H),3.87(s,3H),3.81(s,3H),3.64(s,2H),3.58(s,2H),3.43-3.42(m,8H),2.02(s,3H),1.97(s,3H),1.76(s,3H),1.75(s,3H).

Example 352: n- (2-methoxy-4- (4- (3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) -2-methylphenyl) -3-methylpyridin-2-yl) benzyl) tetrahydro-2H-pyran-4-amine (425)

To 6- (3- (2- (4-formyl-3-methoxyphenyl) -3-methylpyridin-4-yl) -2-methylphenyl) -2-methoxyphenylnicotinaldehyde (150 mg,0.3 mmol) (example 35, step c) (15) A solution of 0mg, 332. Mu. Mol) in MeOH (5 mL) was added tetrahydro-2H-pyran-4-amine (50 mg, 497. Mu. Mol) and sodium acetate (109 mg,1.33 mmol) and the mixture was stirred at room temperature for 12 hours. Sodium cyanoborohydride (42 mg, 663. Mu. Mol) was then added and the solution was stirred at room temperature for 1 hour. The reaction was then concentrated under reduced pressure and the residue was purified by reverse phase HPLC to afford N- (2-methoxy-4- (4- (3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) -2-methylphenyl) -3-methylpyridin-2-yl) benzyl) tetrahydro-2H-pyran-4-amine (51.5 mg,23% yield) as a white solid (formate). MS: m/z found 623[ M+H ]] ⁺ Retention time = 1.95min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ＝8.52-8.48(m,3H),7.88(d,1H),7.54-7.48(m,2H),7.42(t,1H),7.29(d,1H),7.25-7.16(m,4H),4.30(s,2H),4.24(s,2H),4.07-4.05(m,7H),3.99(s,3H),3.50-3.38(m,6H),2.13-2.07(m,10H),1.76-1.69(m,4H).

Example 353:2- (4- (4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) pyridin-2-yl) phenyl) -3-fluoropyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one (324)

(a) 6- (2-chloro-3-fluoropyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde

2-chloro-3-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine (150 mg,0.58 mmol), 6- (3-bromo-2-chlorophenyl) -2-methoxynicotinaldehyde (228 mg,0.70 mmol), [1,1' -bis (biphenylphosphino) ferrocene ]The palladium (II) dichloride complex with dichloromethane (48 mg,0.06 mmol), and potassium carbonate (201 mg,1.46 mmol) were suspended in 1, 4-dioxane/water (4:1, 5 ml) and the solution was then heated at 105 ℃ for 60 minutes. The reaction was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×5 mL). Concentrating the combined organics under reduced pressure and introducingThe crude sample was purified by silica gel chromatography (0-30% EtOAc/hexanes) to afford 6- (2-chloro-3-fluoropyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (54 mg,25% yield) as a yellow solid. MS: m/z found 377,379[ M+H ]] ⁺ 。

(b) 6- (2-chloro-3- (3-fluoro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde

Tetrakis (triphenylphosphine) palladium (0) (33 mg,0.03 mmol), potassium carbonate (59 mg,0.43 mmol), 6- (2-chloro-3-fluoropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (54 mg,0.14 mmol), and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (56 mg,0.21 mmol) were suspended in 1, 4-dioxane/water (4:1, 3 ml), and the solution was then heated at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×5 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (0-35% etoac/hexanes) to afford 6- (2-chloro-3- (3-fluoro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde as a white solid (29 mg,43% yield). MS: m/z found 477,479[ M+H ] ] ⁺ 。

(c) 2- (4- (4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) -pyridin-2-yl) phenyl) -3-fluoropyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one

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6- (2-chloro-3- (3-fluoro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (15 mg,0.03 mmol), acetic acid (4 mg,0.06 mmol) and 2, 6-diazaspiro [3.4]]The octan-7-one (16 mg,0.13 mmol) was dissolved in MeOH/THF (1:1, 1 mL) and the solution was stirred at 25℃for 2 h. Sodium cyanoborohydride (8 mg,0.13 mmol) was added and the resulting mixture was stirred at 25℃for 1 hour. Then using waterThe reaction was diluted with (2 mL) and extracted with EtOAc (3X 2 mL). The combined organics were further washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude sample was purified by reverse phase HPLC to afford 2- (4- (4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4 ]) as a white solid (formate salt)]Octane-2-yl) methyl pyridin-2-yl phenyl) -3-fluoropyridin-2-yl-2-methoxybenzyl) -2, 6-diazaspiro [3.4]Octan-7-one (12 mg,55% yield). LC/MS: m/z found 697,699[ M+H ]] ⁺ Retention time = 2.00min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.59(d,1H),8.40(s,2H),7.79(d,1H),7.71(d,1H),7.65(s,1H),7.60–7.54(m,2H),7.51(d,2H),7.47(s,1H),7.28(d,1H),4.33(s,2H),4.09(s,4H),4.04(s,2H),4.03(d,3H),3.99(d,3H),3.81(s,4H),3.64(d,4H),2.70(s,2H),2.65(s,2H).

Example 354:1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-fluoropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (337)

In the same manner as described for example 353, intermediate 6- (2-chloro-3- (3-fluoro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde was utilized in step (c) and 1- (4-amino-1-piperidinyl) ethanone was substituted for 2, 6-diazaspiro [3.4]]Octan-7-one preparation of 1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-fluoropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one. The product was obtained as a tan solid (formate). LC/MS: m/z found 729,731[ M+H ]] ⁺ Retention time = 2.10min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.63–8.55(m,1H),8.48(s,2H),7.87(d,1H),7.72(d,1H),7.67(s,1H),7.61–7.51(m,4H),7.50–7.45(m,1H),7.32(d,1H),4.63(t,2H),4.29(s,2H),4.19(s,2H),4.06(s,4H),4.01(s,4H),3.38(d,1H),3.19(t,2H),2.77–2.61(m,2H),2.21(m,5H),2.12(s,6H),1.55(m,4H).

Example 355:2- (4- (3-chloro-4- (2-fluoro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-methoxy benzyl) -2, 6-diazaspiro [3.4] octane-7-one (438)

(a) 4- (3-bromo-2-fluorophenyl) -2, 3-dichloropyridine

1, 3-dibromo-2-fluoro-benzene (649 mg,2.56 mmol), 2, 3-dichloro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine (500 mg,1.83 mmol), [1,1' -bis (biphenylphosphino) ferrocene, were placed in a sealed tube ]The palladium (II) dichloride complex with dichloromethane (149 mg,0.18 mmol), and potassium carbonate (704 mg,5.11 mmol) were suspended in 10mL of 1, 4-dioxane. Nitrogen was bubbled through the reaction solution for 2 minutes, then the vessel was sealed and heated at 75 ℃ for 18 hours. The reaction was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×10 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (0-40% EtOAc/hexanes) to afford 4- (3-bromo-2-fluorophenyl) -2, 3-dichloropyridine (290 mg,50% yield) as a white solid. MS: m/z found 321,323[ M+H ]] ⁺ .

(b) 4- (4- (3-bromo-2-fluorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzaldehyde

Tetrakis (triphenylphosphine) palladium (0) (108 mg,0.09 mmol), potassium carbonate (193 mg,1.40 mmol), 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (123 mg,0.47 mmol), and 4- (3-bromo-2-fluorophenyl) -2, 3-dichloropyridine (150 mg,0.47 mmol) were suspended in 1, 4-dioxane/water (4:1, 6 ml), and the solution was heated at 105 ℃ for 20 min. Make the opposite directionShould be cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×5 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (0-45% EtOAc/hexanes) to afford 4- (4- (3-bromo-2-fluorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzaldehyde (74 mg,38% yield) as a yellow solid. MS: m/z found 420,422[ M+H ] ] ⁺ 。

(c) 4- (3-chloro-4- (2-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -pyridin-2-yl) -2-methoxybenzaldehyde

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4- (4- (3-bromo-2-fluorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzaldehyde (74 mg,0.18 mmol), bis (pinacolato) diborane (63 mg,0.25 mmol) and [1,1' -bis (biphenylphosphino) ferrocene were introduced into a sealed tube]A complex of palladium (II) dichloride with dichloromethane (14 mg,0.02 mmol), and potassium acetate (48 mg,0.49 mmol) were suspended in 4mL of 1, 4-dioxane. Nitrogen was bubbled through the reaction solution for 2 minutes, then the vessel was sealed and heated at 95 ℃ for 3 hours. The reaction was cooled to room temperature and the mixture was filtered through CELITE. The filtrate was concentrated under reduced pressure and the crude oil was purified by silica gel chromatography (5-50% EtOAc/hexanes) to afford 4- (3-chloro-4- (2-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -pyridin-2-yl) -2-methoxybenzaldehyde (80 mg,97% yield) as a yellow oil. MS: m/z found 468,470[ M+H ]] ⁺ 。

(d) 6- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2-fluorophenyl) -2-methoxynicotinaldehyde

Tetrakis (triphenylphosphine) palladium (0) (62 mg,0.05 mmol), potassium carbonate (109 mg,0.79 mmol), 4- (3-chloro-4- (2-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -pyridin-2-yl) -2-methoxybenzaldehyde (80 mg,0.17 mmol), and 6-chloro-2-methoxynicotinaldehyde (44 mg,0.26 mmol) were suspended in 1,4 Dioxane/water (4:1, 4 ml) and then heating the solution at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 10mL of water, and 5mL of EtOAc was also added. The sample was sonicated and the insoluble solids filtered, washed with EtOAc/hexanes, and dried to provide 6- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2-methoxyphenyl) -2-methoxynicotinaldehyde (43 mg,53% yield) as a white solid. MS: m/z found 477,479[ M+H ]] ⁺ .

(e) 2- (4- (3-chloro-4- (2-fluoro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one

6- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2-fluorophenyl) -2-methoxynicotinaldehyde (16 mg,0.03 mmol), acetic acid (4 mg,0.07 mmol), and 2, 6-diazaspiro [3.4]]Octan-7-one (13 mg,0.10 mmol) was dissolved in MeOH/THF (1:1, 1 mL) and the solution was stirred at 25℃for 2 h. Sodium cyanoborohydride (6 mg,0.10 mmol) was added and the resulting mixture was stirred at 25 ℃ for 1 hour. The reaction was filtered through CELITE and the filtrate was concentrated under reduced pressure. The crude sample was purified by reverse phase HPLC to afford 2- (4- (3-chloro-4- (2-fluoro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [ 3.4)) as a white solid (formate salt) ]Octan-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl-2, 6-diazaspiro [3.4]Octan-7-one (10 mg,45% yield). LC/MS: m/z found 697,699[ M+H ]] ⁺ Retention time = 2.04min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.65(dd,1H),8.41(s,1H),8.22(s,1H),7.74(d,1H),7.53(dd,1H),7.51–7.42(m,4H),7.36(s,1H),7.33(d,1H),4.30(s,2H),4.10–4.02(m,7H),3.96(d,5H),3.71(s,4H),3.65(d,2H),3.61(d,2H),2.69(d,2H),2.62(d,2H).

Example 356:1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-fluorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (439)

In a similar manner to that described with respect to example 355, the intermediate 6- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2-fluorophenyl) -2-methoxynicotinaldehyde was utilized in step (e) and 1- (4-amino-1-piperidinyl) ketene was substituted for 2, 6-diazaspiro [ 3.4)]Octan-7-one preparation of 1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-fluorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one. The product was obtained as a white solid (formate). LC/MS: m/z found 729,731[ M+H ]] ⁺ Retention time = 2.18min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.66(dd,1H),8.51(d,1H),8.22(d,1H),7.83–7.76(m,1H),7.56–7.48(m,3H),7.45(d,2H),7.37(s,1H),7.33(d,1H),4.59(dd,2H),4.23(s,2H),4.12–4.08(m,3H),4.04(s,4H),4.00–3.94(m,4H),3.17(q,2H),3.05(d,1H),2.69(t,2H),2.12(dd,10H),1.69–1.20(m,4H).

Example 357: n- ((6- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) -methyl) phenyl) pyridin-4-yl) -2-fluorophenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine (440)

In a similar manner to that described with respect to example 355, the intermediate 6- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2-fluorophenyl) -2-methoxynicotinaldehyde was utilized in step (e) and tetrahydropyran-4-amine was substituted for 2, 6-diazaspiro [3.4 ]]Preparation of N- ((6- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) -methyl) phenyl) pyridin-4-yl) -2-fluorophenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine from octan-7-one. The product was obtained as a white solid (formate). LC/MS: m/z found 647,649[ M+H ]] ⁺ Retention time = 2.23min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.69–8.63(m,1H),8.50(s,2H),8.24(s,1H),7.83(d,1H),7.53(t,3H),7.47(d,2H),7.39(s,1H),7.36–7.31(m,1H),4.27(s,2H),4.12(q,5H),4.08–3.96(m,7H),3.50–3.33(m,5H),3.19(s,1H),2.07(dd,4H),1.67(dd,4H).

Example 358:1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-fluoropyridin-4-yl) -2-fluorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (449)

(a) 4- (3-bromo-2-fluorophenyl) -2-chloro-3-fluoropyridine

1, 3-dibromo-2-fluoro-benzene (1013 mg,3.99 mmol), (2-chloro-3-fluoropyridin-4-yl) boronic acid (500 mg,2.85 mmol) and [1,1' -bis (biphenylphosphino) ferrocene were introduced into a sealed tube]A complex of palladium (II) dichloride with dichloromethane (233 mg,0.29 mmol), and potassium carbonate (1100 mg,7.98 mmol) are suspended in 25mL of 1, 4-dioxane. Nitrogen was bubbled through the reaction solution for 2 minutes, then the vessel was sealed and heated at 75 ℃ for 18 hours. The reaction was cooled to room temperature, diluted with 30mL of water, and extracted with EtOAc (3×15 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (0-20% EtOAc/hexanes) to afford 4- (3-bromo-2-fluorophenyl) -2-chloro-3-fluoropyridine as a white solid (3411 mg,39% yield). MS: m/z found 304,306[ M+H ] ] ⁺ .

(b) 4- (4- (3-bromo-2-fluorophenyl) -3-fluoropyridin-2-yl) -2-methoxybenzaldehyde

Tetrakis (triphenylphosphine) palladium (0) (190 mg,0.16 mmol), potassium carbonate (340 mg,2.46 mmol), 2-methoxy-4- (4,4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (215 mg,0.82 mmol), and 4- (3-bromo-2-fluorophenyl) -2-chloro-3-fluoropyridine (250 mg,0.82 mmol) were suspended in 1, 4-dioxane/water (4:1, 7 ml), and the solution was then heated at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×5 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (0-30% EtOAc/hexanes) to afford 4- (4- (3-bromo-2-fluorophenyl) -3-fluoropyridin-2-yl) -2-methoxybenzaldehyde as a yellow solid (155 mg,47% yield). MS: m/z found 404,406[ M+H ]] ⁺ .

(c) 4- (3-fluoro-4- (2-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -phenyl) -pyridin-2-yl) -2-methoxybenzaldehyde

4- (4- (3-bromo-2-fluorophenyl) -3-fluoropyridin-2-yl) -2-methoxybenzaldehyde (155 mg,0.38 mmol), bis (pinacolato) diborane (136 mg,0.54 mmol) and [1,1' -bis (biphenylphosphino) -ferrocene were introduced into a sealed tube]The palladium (II) dichloride complex with dichloromethane (31 mg,0.04 mmol), and potassium acetate (105 mg,1.07 mmol) were suspended in 6ml of 1, 4-dioxane. Nitrogen was bubbled through the reaction solution for 2 minutes, then the vessel was sealed and heated at 95 ℃ for 3 hours. The reaction was cooled to room temperature and the mixture was filtered through CELITE. The filtrate was concentrated under reduced pressure and the crude oil was purified by silica gel chromatography (5-50% EtOAc/hexanes) to afford 4- (3-fluoro-4- (2-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -phenyl) -pyridin-2-yl) -2-methoxybenzaldehyde (130 mg,75% yield) as a yellow oil. MS: m/z found 452[ M+H ] ] ⁺ .

(d) 6- (2-fluoro-3- (3-fluoro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde

Tetrakis (triphenylphosphine) palladium (0) (67 mg,006 mmol), potassium carbonate (119 mg,0.86 mmol), 4- (3-fluoro-4- (2-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -phenyl) -pyridin-2-yl) -2-methoxybenzaldehyde (130 mg,0.29 mmol), and 6-chloro-2-methoxynicotinaldehyde (124 mg,0.72 mmol) were suspended in 1, 4-dioxane/water (4:1, 4 ml) and the solution was heated at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 10mL of water, and 5mL of EtOAc was also added. The sample was sonicated and the insoluble solids filtered, washed with EtOAc/hexanes, and dried to provide 6- (2-fluoro-3- (3-fluoro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (48 mg,36% yield) as a white solid. MS: m/z found 461[ M+H ]] ⁺ .

(e) 1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-fluoropyridin-4-yl) -2-fluorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

6- (2-fluoro-3- (3-fluoro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (16 mg,0.03 mmol), acetic acid (4 mg,0.07 mmol), and 1- (4-amino-1-piperidinyl) ethanone (15 mg,0.10 mmol) were dissolved in MeOH/THF (1:1, 1 mL) and the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (7 mg,0.10 mmol) was added and the resulting mixture was stirred at 25 ℃ for 1 hour. The reaction was filtered through CELITE and the filtrate was concentrated under reduced pressure. The crude sample was purified by reverse phase HPLC to provide 1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-fluoropyridin-4-yl) -2-methoxyphenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (15 mg,60% yield) as a white solid (formate salt). LC/MS: m/z found 713[ M+H ] ] ⁺ Retention time = 2.14min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.64–8.58(m,1H),8.43(s,2H),8.25(t,1H),7.86(d,1H),7.68(s,1H),7.64–7.53(m,5H),7.49(t,1H),4.64(t,2H),4.31(s,2H),4.21(d,2H),4.13(t,3H),4.11–3.98(m,5H),3.36(d,2H),3.19(t,2H),2.69(t,2H),2.21(q,4H),2.13(q,6H),1.70–1.40(m,4H).

Example 359:2- (4- (3-fluoro-4- (2-fluoro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-methoxy benzyl) -2, 6-diazaspiro [3.4] octane-7-one (451)

In a similar manner to that described for example 358, intermediate 6- (2-fluoro-3- (3-fluoro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde was used in step (e) and 2, 6-diazaspiro [3.4]]Preparation of 2- (4- (3-fluoro-4- (2-fluoro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4 ]) using octan-7-one instead of 1- (4-amino-1-piperidinyl) ethanone]Octan-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl-2, 6-diazaspiro [3.4]Octane-7-one. The product was obtained as a white solid (formate). LC/MS: m/z found 681[ M+H ]] ⁺ Retention time = 2.04min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.60(d,1H),8.36(s,2H),8.23(t,1H),7.78(d,1H),7.66(s,1H),7.58(d,3H),7.54–7.45(m,3H),4.36(s,2H),4.12(s,4H),4.10–4.07(m,5H),4.00(d,3H),3.85(s,4H),3.64(dd,4H),2.70(d,2H),2.65(d,2H).

Example 360: n- ((6- (2-fluoro-3- (3-fluoro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine (452)

In a similar manner to that described for example 358, N- ((6- (2-fluoro-3- (3-fluoro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) was prepared in step (e) using the intermediate 6- (2-fluoro-3- (3-fluoro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde and tetrahydropyran-4-amine instead of 1- (4-amino-1-piperidinyl) ethanone ) Phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine. The product was obtained as a white solid (formate). LC/MS: m/z actual measurement 631[ M+H ]] ⁺ Retention time = 2.19min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.61(d,1H),8.49(s,2H),8.25(t,1H),7.85(d,1H),7.67(s,1H),7.63–7.52(m,5H),7.49(t,1H),4.28(s,2H),4.16(s,2H),4.13(t,3H),4.08–4.00(m,7H),3.50–3.34(m,5H),3.24(s,1H),2.08(t,4H),1.80–1.56(m,4H).

Example 361:1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (528)

(a) 6- (3-bromo-2- (trifluoromethyl) phenyl) -2-methoxynicotinaldehyde

To 1, 3-dibromo-2- (trifluoromethyl) benzene (10 g,32.9 mmol) and 2-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) nicotinaldehyde (example 376, step (a)) (26 g,98.7 mmol) in 1, 4-dioxane/H ₂ Potassium carbonate (11.4 g,82 mmol) and tetrakis (triphenylphosphine) palladium (0) (3.80 g,3.29 mmol) were added to a mixture in O (9:1, 200 mL) followed by N ₂ The mixture was stirred at 95℃for 3 hours. Water (50 mL) was added and the mixture extracted with ethyl acetate (2X 100 mL). The combined organic extracts were dried over anhydrous sulfate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ The residue was purified by chromatography (0-10% EtOAc/petroleum ether) to afford 6- (3-bromo-2- (trifluoromethyl) phenyl) -2-methoxynicotinaldehyde as a yellow solid (8 g,67% yield). ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.29(s,1H),8.22(d,1H),8.03(d,1H),7.67(t,1H),7.55(d,1H),7.32(d,1H),3.98(s,3H).

(b) 2-methoxy-6- (3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2- (trifluoromethyl) phenyl) nicotinaldehyde

To a mixture of 6- (3-bromo-2- (trifluoromethyl) phenyl) -2-methoxynicotinaldehyde (9 g,25.0 mmol) and bis (pinacolato) diborane (12.7 g,49.9 mmol) in 1, 4-dioxane (100 mL) was added potassium acetate (7.36 g,75.1 mmol) and [1,1' -bis (biphenylphosphino) ferrocene]Complexes of palladium (II) dichloride with dichloromethane (2.04 g,2.50 mmol), then under N ₂ The mixture was stirred at 95℃for 3 hours. The mixture was combined with another batch on a 1.0g scale. The mixture was filtered, the filtrate concentrated and passed through normal phase SiO ₂ The residue was purified by chromatography (0-15% EtOAc/petroleum ether) to afford 2-methoxy-6- (3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2- (trifluoromethyl) phenyl) nicotinaldehyde as a yellow solid (9 g,88% yield). ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.31(s,1H),8.23(d,1H),7.80-7.67(m,3H),7.35(d,1H),4.01(s,3H),1.34(s,12H).

(c) 6- (3- (2, 3-dichloropyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxynicotinaldehyde

To 2-methoxy-6- (3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2- (trifluoromethyl) phenyl) nicotinaldehyde (3 g,7.37 mmol) and 2, 3-dichloro-4-iodopyridine (1.01 g,3.68 mmol) in 1, 4-dioxane/H ₂ A mixture of O (5:1, 90 mL) was added [1,1' -bis (di-tert-butylphosphino) ferrocene ]Palladium (II) dichloride (0.24 g,0.37 mmol) and potassium phosphate (2.35 g,11 mmol) then under N ₂ The mixture was stirred at 95℃for 2 hours. The mixture was combined with another batch on a 1.1g scale. Concentrating the mixture and passing through normal phase SiO ₂ The residue was purified by chromatography (0-20% EtOAc/petroleum ether) to afford 6- (3- (2, 3-dichloropyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxynicotinaldehyde as a yellow oil (1.6 g,78% yield). ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.31(s,1H),8.51(d,1H),8.25(d,1H),7.92(t,1H),7.76(d,1H),7.64-7.59(m,2H),7.39(d,1H),4.04(s,3H).

(d) 6- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxynicotinaldehyde

To a mixture of 6- (3- (2, 3-dichloropyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxynicotinaldehyde (1.5 g,3.51 mmol), 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (1.38 g,5.27 mmol) in 1, 4-dioxane/water (5:1, 24 mL) was added potassium carbonate (1.46 g,10.5 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.40 g,0.35 mmol) followed by N ₂ The mixture was stirred at 95℃for 1 hour. Concentrating the mixture to provide a residue, which is purified by normal phase SiO ₂ Chromatography (0-50% EtOAc/petroleum ether) was purified to provide 6- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxynicotinaldehyde (1.5 g,79% yield) as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.39(s,1H),10.28(s,1H),8.72(d,1H),8.22(d,1H),7.91-7.87(m,1H),7.80(d,1H),7.72(d,1H),7.62(d,1H),7.57(d,1H),7.47(s,1H),7.37(d,2H),4.00(s,3H),3.96(s,3H).

(e) 1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

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To a mixture of 6- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxynicotinaldehyde (200 mg,0.38 mmol) and 1- (4-aminopiperidin-1-yl) ethan-1-one (162 mg,1.14 mmol) in MeOH/THF (1:1, 10 mL) was added sodium acetate (124 mg,1.52 mmol) and the mixture was stirred at room temperatureStirring is carried out for 1 hour. Sodium cyanoborohydride (95.4 mg,1.52 mmol) was then added and the mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide 1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (37.8 mg,12% yield) as a white solid (formate salt). MS: m/z found 779[ M+H ]] ⁺ Retention time = 2.68min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),8.48(br s,2H),7.90(d,1H),7.82(t,1H),7.65(d,1H),7.56(d,1H),7.51-7.49(m,2H),7.41(s,1H),7.37(d,1H),7.21(d,1H),4.70-4.63(m,2H),4.33(s,2H),4.22(s,2H),4.11-4.02(m,8H),3.47-3.41(m,2H),3.26-3.19(m,2H),2.75-2.69(m,2H),2.29-2.15(m,10H),1.67-1.52(m,4H).

Example 362: n- ((6- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine (529)

(a) N- ((6- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine

To a mixture of 6- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxynicotinaldehyde (example 361, step (d)) (200 mg,0.38 mmol) and tetrahydro-2H-pyran-4-amine (115 mg,1.14 mmol) in MeOH/THF (1:1, 10 mL) was added sodium acetate (124 mg,1.52 mmol) and the mixture stirred at room temperature for 1 hour. Sodium cyanoborohydride (95.4 mg,1.52 mmol) was then added and the mixture was stirred at room temperature for 0.5 hours. The mixture was then concentrated and passed through a reverse reactionThe residue was purified by phase HPLC to provide N- ((6- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine (54.8 mg,19% yield) as a white solid (formate salt). MS: m/z found 697[ M+H ]] ⁺ Retention time = 2.89min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),7.88(d,1H),7.82(t,1H),7.65(d,1H),7.55(d,1H),7.51-7.49(m,2H),7.41(s,1H),7.36(d,1H),7.20(d,1H),4.30(s,2H),4.16(s,2H),4.09-4.01(m,10H),3.51-3.45(m,4H),3.26-3.23(m,2H),2.14-2.06(m,4H),1.78-1.65(m,4H).

Example 363:2- ((6- (3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one (576)

(a) 2- ((6- (3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one

To a solution of 6- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxynicotinaldehyde (example 361, step (d)) (100 mg,190 umol) in MeOH (2 mL) was added sodium acetate (93 mg,1.14 mmol) and 2, 6-diazaspiro [3.4]Octane-7-one trifluoroacetate salt (228 mg,949 umol) and the solution was stirred at room temperature for 12 hours. Sodium cyanoborohydride (36 mg,569 umol) was then added and the solution was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure and the residue was purified by reverse phase HPLC to afford 2- ((6- (3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4 ]) as a white solid (formate salt)]Octane-2-yl) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl methyl) -2, 6-diazaspiro [3.4]Octan-7-one (25.1 mg,16 yield). MS: m/z found 747[ M+H ]] ⁺ Retention time = 2.37min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.63(d,1H),8.42(s,1H),7.81-7.77(m,2H),7.62(d,1H),7.51-7.46(m,3H),7.37-7.33(m,2H),7.15-7.14(m,1H),4.32(s,2H),4.08(br s,4H),3.98(m,8H),3.75(s,4H),3.65(br d,4H),2.70(s,2H),2.64(s,2H).

Example 364:1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one (577)

(a) 1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one

To a solution of 6- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxynicotinaldehyde (example 361, step (d)) (90 mg,171 umol) in MeOH (2 mL) was added sodium acetate (56 mg,683 umol) and 1- (2, 6-diazaspiro [ 3.3)]Heptane-2-yl) ethan-1-one hydrochloride (91 mg,512 umol) and the solution was stirred at room temperature for 12 hours. Sodium cyanoborohydride (2 mg,342 umol) was then added and the solution was stirred at room temperature for 1 hour. The reaction was then concentrated under reduced pressure and the residue was purified by reverse phase HPLC to afford 1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3 ])) as a white solid (formate))]Heptane-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl methyl) -2, 6-di-n-Azaspiro [3.3]Heptane-2-yl) ethan-1-one (23.5 mg,16% yield). MS: m/z found 775[ M+H ]] ⁺ Retention time = 2.52min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.62(d,1H),8.46(br s,1H),7.80-7.72(m,2H),7.62(d,1H),7.46(m,3H),7.35-7.32(m,2H),7.12(d,1H),4.34(d,4H),4.19(s,2H),4.11(s,2H),4.06(d,6H),3.98(s,3H),3.97(s,3H),3.85(s,2H),3.72(m,4H),1.85(s,6H).

Example 365:6- (4- (4- (3- (5- ((2-oxa-6-azaspiro [3.3] heptane-6-yl) methyl) -6-methoxypyridin-2-yl) -2- (trifluoromethyl) phenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2-oxa-6-azaspiro [3.3] heptane (578)

(a) 6- (4- (4- (3- (5- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -6-methoxypyridin-2-yl) -2- (trifluoromethyl) phenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2-oxa-6-azaspiro [3.3] heptane

To 6- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxynicotinaldehyde (example 361, step (d)) (0.1 g,0.2 mmol) and 2-oxa-6-azaspiro [3.3]]A solution of heptane (0.05 g,0.47 mmol) in a THF/MeOH mixture (1:1, 4 mL) was added sodium acetate (0.03 g,0.38 mmol) and the mixture stirred at room temperature for 1 hour. Sodium cyanoborohydride (0.036 g,0.57 mmol) was then added and the mixture was stirred at room temperature for 1hr. The mixture was then concentrated and the residue purified by reverse phase HPLC to afford 6- (4- (4- (3- (5- ((2-oxa-6-azaspiro [3.3 ]) as a white solid (formate))]Heptane-6-yl) methyl) -6-methoxypyridin-2-yl) -2- (trifluoromethyl) phenyl) -3-chloropyridin-2-yl-2-methoxyphenylmethyl-2-oxa-6-azaspiro [3.3 ]Heptane (23.3 mg,98% yield). MS: m/z found 693[ M+H ]] ⁺ Retention time = 2.61min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.64(d,1H),7.82-7.78(m,1H),7.73(br d,1H),7.64(d,1H),7.48-7.45(m,3H),7.35-7.32(m,2H),7.14(d,1H),4.79-4.78(m,8H),4.12(s,2H),4.02-3.97(m,10H),3.82(s,2H),3.73(s,4H).

Example 366: (S) -1- (((6- (3- (3-chloro-2- (4- ((((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol (580)

(a) (S) -1- (((6- (3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol

A mixture of 6- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxynicotinaldehyde (example 361, step (d)) (100 mg,189 mol), (S) -1-aminopropane-2-ol (71 mg,949 mol) and sodium acetate (62 mg,759 mol) in MeOH/THF (1:1, 14 mL) was stirred at room temperature for 1h. Sodium cyanoborohydride (95 mg,1.52 mmol) was then added and the mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide (S) -1- (((6- (3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol (31.9 mg,24% yield) as a white solid (formate). MS: m/z found 645[ M+H ] ] ⁺ Retention time = 2.53min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),7.87-7.80(m,2H),7.65(d,1H),7.54-7.49(m,3H),7.41-7.35(m,2H),7.20(d,1H),4.30(s,2H),4.17(s,2H),4.08-4.01(m,8H),3.09-3.05(m,1H),3.00-2.96(m,1H),2.89-2.81(m,2H),1.26-1.24(m,6H).

Example 367: n- ((6- (3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) -3-fluoropropane-1-amine (587)

(a) N- ((6- (3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) 3-fluoropropane-1-amine

To a mixture of 6- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxynicotinaldehyde (example 361, step (d)) (95 mg, 180. Mu. Mol) and 3-fluoropropane-1-amine hydrochloride (61 mg, 540. Mu. Mol) in tetrahydrofuran/methanol (1:1, 2 mL) was added sodium acetate (59 mg, 321. Mu. Mol) and N ₂ The mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (45 mg, 321 umol) was then added and the mixture was taken up in N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was filtered, the filtrate was concentrated and the residue was purified by reverse phase HPLC to provide N- ((6- (3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) -3-fluoropropane-1-amine (42 mg,31% yield) as a white solid (formate salt). MS: m/z found 649[ M+H ] ] ⁺ Retention time = 2.85min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),7.87-7.80(m,2H),7.65(d,1H),7.55-7.49(m,3H),7.41(d,1H),7.36(dd,1H),7.20(d,1H),4.68-4.62(m,2H),4.56-4.52(m,2H),4.29(s,2H),4.14(s,2H),4.05(s,3H),4.01(s,3H),3.23-3.19(m,2H),3.12-3.08(m,2H),2.20-2.04(m,4H).

Example 368: (1 r,4 r) -4- (((6- (3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol (588)

(a) (1 r,4 r) -4- (((6- (3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol

To a mixture of 6- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxynicotinaldehyde (example 361, step (d)) (95 mg, 180. Mu. Mol) and (1 r,4 r) -4-aminocyclohexane-1-ol (73 mg, 631. Mu. Mol) in THF/MeOH (1:1, 2 mL) was added sodium acetate (59 mg, 321. Mu. Mol) and N ₂ The mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (45 mg, 321 umol) was then added and the mixture was taken up in N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was filtered, the filtrate was concentrated and the residue was purified by reverse phase HPLC to provide (1 r,4 r) -4- (((6- (3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol as a white solid (formate salt) (17 mg,12% yield). MS: m/z found 725[ M+H ] ] ⁺ Retention time = 2.70min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),7.87(d,1H),7.84-7.80(m,1H),7.65(d,1H),7.55-7.49(m,3H),7.40(d,1H),7.36(dd,1H),7.21(d,1H),4.28(s,2H),4.18(s,2H),4.06(s,3H),4.01(s,3H),3.61-3.58(m,2H),3.16-3.01(m,2H),2.25-2.22(m,4H),2.13-2.07(m,4H),1.56-1.39(m,8H).

Example 369:1- (4- (((6- (3- (3-chloro-2- (3-methoxy-4- (((1- (2-methoxyacetyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methoxyethane-1-one (602)

(a) 1- (4- (((6- (3- (3-chloro-2- (3-methoxy-4- (((1- (2-methoxyacetyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methoxyethane-1-one

To a mixture of 6- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxynicotinaldehyde (example 361, step (d)) (150 mg,0.284 mmol) and 1- (4-aminopiperidin-1-yl) -2-methoxyethan-1-one hydrochloride (149 mg,0.711 mmol) in methanol/tetrahydrofuran (1:1, 6 mL) was added sodium acetate (140 mg,1.71 mmol) and N ₂ The mixture was stirred at room temperature for 11.5 hours. Sodium triacetoxyborohydride (362 mg,1.71 mmol) was then added and added under N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was then filtered, the filtrate was concentrated and the residue was purified by reverse phase HPLC to afford 1- (4- (((6- (3- (3-chloro-2- (3-methoxy-4- (((1- (2-methoxyacetyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methoxyethan-1-one (37 mg,15% yield) as a white solid (formate). MS: m/z found 839[ M+H ] ] ⁺ Retention time = 2.52min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),7.89-7.87(m,1H),7.82(t,1H),7.64(d,1H),7.55(d,1H),7.51-7.49(m,2H),7.41(d,1H),7.36(dd,1H),7.20(d,1H),4.67-4.59(m,3H),4.31(s,2H),4.27-4.26(m,2H),4.17-4.16(m,4H),4.05(s,3H),4.03(s,3H),3.50-3.43(m,7H),3.32-3.16(m,2H),3.15-3.12(m,2H),2.80-2.73(m,2H),2.27-2.18(m,4H),1.66-1.50(m,4H).

Example 370: n- ((6- (3- (2- (4- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) -2-oxaspiro [3.3] heptan-6-amine (604)

(a) N- ((6- (3- (2- (4- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) -2-oxaspiro [3.3] heptan-6-amine

To 6- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxynicotinaldehyde (example 361, step (d)) (0.1 g,0.19 mmol) and 2-oxaspiro [3.3]]A mixture of heptane-6-amine (0.07 g,0.47 mmol) in a THF/MeOH mixture (1:1, 4 mL) was added sodium acetate (0.09 g,1.14 mmol) in one portion and under N ₂ The mixture was stirred at room temperature for 2 hours under an atmosphere. Sodium triacetoxyborohydride (0.24 g,1.14 mmol) was then added and the mixture was stirred at room temperature for 1 hour. The mixture was then concentrated and the residue was purified by reverse phase HPLC to provide N- ((6- (3- (2- (4- ((2-oxaspiro [3.3 ]) as a white solid (formate))]Heptane-6-ylamino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl methyl) -2-oxaspiro [3.3 ]Heptane-6-amine (68.4 mg,46% yield). MS: m/z found 721[ M+H ]] ⁺ Retention time = 2.72min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),7.86-7.80(m,2H),7.65(d,1H),7.52-7.49(m,3H),7.39-7.34(m,2H),7.19(d,1H),4.75(s,4H),4.65(d,4H),4.14(s,2H),4.05(s,3H),4.01-4.01(m,5H),3.70-3.50(m,2H),2.72-2.66(m,4H),2.42-2.30(m,4H).

Example 371: (S) -5- (((6- (3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (610)

(a) (S) -5- (((6- (3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

To a mixture of 6- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxynicotinaldehyde (example 361, step (d)) (100 mg,189 mol), (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride (86 mg,569 mol) in THF/MeOH (1:1, 8 ml) was added sodium acetate (62 mg,759 mol) and the mixture was stirred at room temperature for 0.5 h. Sodium triacetoxyborohydride (161 mg, 759. Mu. Mol) was then added and added to the mixture under N ₂ The mixture was stirred at room temperature for 2.5 hours. The mixture was then concentrated and the residue was purified by reverse phase HPLC to afford (formate) (S) -5- (((6- (3- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one (67.2 mg,45% yield) as a yellow solid. MS: m/z found 723[ M+H ] ] ⁺ Retention time = 2.46min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.39(br s),7.84-7.79(m,2H),7.65(d,1H),7.53-7.48(m,3H),7.39-7.35(m,2H),7.17(d,1H),4.25-4.24(m,2H),4.06-3.98(m,10H),3.12-3.08(m,2H),2.93-2.87(m,2H),2.46-2.30(m,6H),1.93-1.83(m,2H).

Example 372:2- (((6- (3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethan-1-ol (612)

(a) 2- (((6- (3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethan-1-ol

At N ₂ To a mixture of 6- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxynicotinaldehyde (example 361, step (d)) (0.09 g,0.17 mmol) and 2-aminoethanol (0.05 g,0.85 mmol) in a THF/methanol mixture (4:3, 3.5 ml) was added sodium acetate (0.08 g,1.02 mmol) at one time under an atmosphere. The mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.22 g,1.02 mmol) was then added and the mixture was stirred at room temperature for 1 hour. The mixture was combined with another batch on a 10mg scale. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 2- (((6- (3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethan-1-ol (22.2 mg,21% yield) as a pink solid. MS: m/z found 617[ M+H ] ] ⁺ Retention time = 2.33min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):8.62(d,1H),7.81-7.45(m,2H),7.63(d,1H),7.47-7.41(m,3H),7.30-7.27(m,2H),7.12(d,1H),4.01(s,3H),3.95(s,3H),3.91(s,2H),3.85(s,2H),3.73-3.70(m,4H),2.79-2.76(m,4H).

Example 373:1- (6- (3- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine (613)

To a mixture of 6- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxynicotinaldehyde (example 361, step (d)) (100 mg,0.19 mmol) and methylamine hydrochloride (38.4 mg,0.569 mmol) in methanol/THF (1:1, 3 ml) was added sodium acetate (108 mg,1.33 mmol) and under N ₂ Lower in the chamberThe mixture was stirred at temperature for 3.5 hours. Sodium triacetoxyborohydride (160 mg,0.76 mmol) was then added and added to the mixture at N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was filtered, the filtrate was concentrated and the residue was purified by reverse phase HPLC to provide 1- (6- (3- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine (35 mg,30% yield) as a white solid (formate salt). MS: m/z found 557[ M+H ]] ⁺ Retention time = 2.55min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),8.55(brs,2H),7.88(d,1H),7.84-7.81(m,1H),7.65(d,1H),7.54-7.49(m,3H),7.41(m,1H),7.36(dd,1H),7.22(d,1H),4.27(s,2H),4.25(s,2H),4.07(s,3H),4.02(s,3H),2.76-2.74(m,6H).

Example 374: n- ((6- (3- (3-chloro-2- (3-methoxy-4- (((2-methoxyethyl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) -2-methoxyethane-1-amine (614)

To a mixture of 6- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxynicotinaldehyde (example 361, step (d)) (100 mg,0.189 mmol) and 2-methoxyethane-1-amine (42.7 mg,0.569 mmol) in methanol (1.5 mL) and THF (1.5 mL) was added sodium acetate (62.2 mg,0.759 mmol) and under N ₂ The mixture was stirred at room temperature for 4 hours. Sodium cyanoborohydride (47.7 mg,0.759 mmol) was then added and the mixture was taken up in N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was filtered, the filtrate was concentrated and the residue was purified by reverse phase HPLC to provide N- ((6- (3- (3-chloro-2- (3-methoxy-4- (((2-methoxyethyl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) -2-methoxyethane-1-amine (26 mg,19% yield) as a white solid (formate salt). MS: m/z found 645[ M+H ]] ⁺ Retention time = 2.85min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.63(d,1H),8.57(brs,1H),7.82-7.76(m,2H),7.64(d,1H),7.48-7.45(m,3H),7.35-7.30(m,2H),7.13(d,1H),4.07(s,2H),4.02(s,3H),4.00(s,3H),3.90(s,2H),3.62-3.56(m,4H),3.40(s,3H),3.38(s,3H),3.01-3.00(m,2H),2.89-2.86(m,2H).

Example 375:1- (6- (((6- (3- (2- (4- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -2-azaspiro [3.3] heptan-2-yl) ethan-1-one (651)

(a) 6- (((benzyloxy) carbonyl) amino) -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester

To 6-amino-2-azaspiro [3.3]]A mixture of tert-butyl heptane-2-carboxylate (1 g,4.71 mmol) and benzyl chloroformate (1.21 g,7.07 mmol) in dichloromethane (15 mL) was added N, N-diisopropylethylamine (1.8 g,14.1 mmol) and concentrated in N ₂ The mixture was stirred at room temperature for 2 hours. Water (10 mL) was added and the mixture extracted with ethyl acetate (2X 10 mL). The combined organic phases were dried over anhydrous sulphate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ The residue was purified by chromatography (22-25% ethyl acetate/petroleum ether) to afford 6- (((benzyloxy) carbonyl) amino) -2-azaspiro [3.3] as a yellow oil]Heptane-2-carboxylic acid tert-butyl ester (1.4 g, crude). ¹ H NMR(400MHz,DMSO-d ₆ ):δ7.51-7.49(m,1H),7.32-7.27(m,5H),4.94(s,2H),3.80-3.78(m,3H),3.76-3.68(m,2H),2.36-3.34(m,2H),2.02-1.99(m,2H),1.33(s,9H).

(b) (2-Azaspiro [3.3] heptan-6-yl) carbamic acid benzyl ester

6- (((Benzylmethoxy)Carbonyl) amino) -2-azaspiro [3.3]A solution of tert-butyl heptane-2-carboxylate (1 g,2.89 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5.56 mL,75.0 mmol) and taken up in N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was filtered and concentrated to provide (2-azaspiro [3.3] as a yellow oil]Benzyl heptan-6-yl) carbamate (2 g, crude). MS: m/z found 247[ M+H ] ] ⁺ . The crude product was used in the next step without further purification.

(c) (2-acetyl-2-azaspiro [3.3] heptan-6-yl) carbamic acid benzyl ester

To (2-azaspiro [3.3]]A mixture of benzyl heptan-6-yl) carbamate (1.9 g,8.00 mmol) and acetic anhydride (1.2 g,12.0 mmol) in dichloromethane (20 mL) was added triethylamine (2.4 g,23.9 mmol) and under N ₂ The mixture was stirred at room temperature for 2 hours. The mixture was filtered and concentrated to provide (2-acetyl-2-azaspiro [3.3] as a yellow oil]Benzyl heptan-6-yl) carbamate (900 mg, crude). The crude product was used in the next step without further purification. ¹ H NMR(400MHz,DMSO-d ₆ ):δ7.58-7.57(m,1H),7.37-7.32(m,5H),5.00(s,2H),4.12(s,1H),3.91(s,1H),3.87-3.85(m,2H),3.72(s,1H),3.14(s,3H),2.44-2.43(m,2H),2.09-2.08(m,2H).

(d) 1- (6-amino-2-azaspiro [3.3] heptan-2-yl) ethan-1-one

To (2-acetyl-2-azaspiro [3.3]]A mixture of benzyl heptan-6-yl) carbamate (400 mg,1.39 mmol) in ethanol/methanol (1:1, 10 mL) was added palladium on carbon (10%, 1.00 g), and the mixture was stirred under hydrogen (50 psi) at 80℃for 12 hours. The mixture was filtered and concentrated to provide 1- (6-amino-2-azaspiro [3.3] as a white oil]Heptane-2-yl) ethan-1-one (200 mg, crude). MS: m/z found 155[ M+H ]] ⁺ . The crude product was used in the next step without further purification.

(e) 1- (6- (((6- (3- (2- (4- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -2-azaspiro [3.3] heptan-2-yl) ethan-1-one

To 1- (6-amino-2-azaspiro [3.3]]A mixture of heptan-2-yl) ethan-1-one (105 mg,0.68 mmol) and 6- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxynicotinaldehyde (example 361, step (d)) (120 mg,0.23 mmol) in methanol (5 mL) was added sodium acetate (112 mg,1.37 mmol) followed by N ₂ The mixture was stirred at room temperature for 11.5 hours. Sodium triacetoxyborohydride (289 mg,1.37 mmol) was added and the mixture was taken up in N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was filtered, the filtrate was concentrated and the residue was purified by reverse phase HPLC to afford 1- (6- (((6- (3- (2- (4- ((2-acetyl-2-azaspiro [ 3.3)) as a white solid (formate))]Heptane-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl methyl) amino) -2-azaspiro [3.3]Heptane-2-yl) ethan-1-one (31 mg,16% yield). MS: m/z found 803[ M+H ] ] ⁺ Retention time = 2.57min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.45(brs,1H),7.85-7.79(m,2H),7.64(d,1H),7.52-7.35(m,5H),7.18(d,1H),4.28(d,2H),4.20-4.15(m,4H),4.05-3.93(m,10H),3.96(d,2H),3.77-3.59(m,2H),2.70-2.67(m,4H),2.42-2.28(m,4H),1.87(s,3H),1.86(s,3H).

Example 376:2- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -6- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) benzonitrile (615)

(a) 2-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) nicotinaldehyde

To a solution of 6-bromo-2-methoxynicotinaldehyde (50 g,29 mmol) in 1, 4-dioxane (1L) was added bis (pinacolato) diborane (81.4 g,320 mmol), potassium acetate (80 g,815 mmol) and [1,1' -bis (biphenylphosphino) ferrocene]Palladium (II) dichloride (9.52 g,11.6 mmol) and under N ₂ The mixture was stirred at 95℃for 3 hours. The reaction mixture was cooled to room temperature and passed throughThe mixture was filtered. The filtrate was concentrated and the residue was dissolved in a petroleum ether/ethyl acetate mixture (2:1,600 ml) and stirred for 15 minutes. The mixture was filtered and the filtrate concentrated in vacuo to afford 2-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) nicotinaldehyde (120 g,86% purity) as a black oil (120 g,86% purity). ¹ H NMR(400MHz,CDCl ₃ ):δ10.40(s,1H),8.05(d,1H),7.54(d,1H),4.15(s,3H),1.38(s,12H).

(b) 2-bromo-6- (5-formyl-6-methoxypyridin-2-yl) benzonitrile

To 2-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) nicotinaldehyde (1.5 g,5.70mmol,86% purity), 2, 6-dibromobenzonitrile (1.93 g,7.41 mmol), and [ (2-dicyclohexylphosphino-3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) -2- (2 '-amino-1, 1' -biphenyl) ]A mixture of palladium (II) mesylate (0.26 g,0.29 mmol) in THF (56 mL) was added to potassium phosphate (2.42 g,11.4 mmol) in water (14 mL) followed by N ₂ The mixture was stirred at 80℃for 12 hours. The reaction mixture (3 batches) was cooled to room temperature and cooled to room temperatureThe reaction mixture was concentrated under reduced pressure to remove THF. To the residue was added water and the mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (3×5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to provide 2-bromo-6- (5-formyl-6-methoxypyridin-2-yl) benzonitrile (2.4 g,34% yield) as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.29(s,1H),8.28(d,1H),8.06(d,1H),8.00(d,1H),7.77(t,1H),7.67(d,1H),4.15(s,3H).

(c) 2- (2, 3-dichloropyridin-4-yl) -6- (5-formyl-6-methoxypyridin-2-yl) benzonitrile

To a mixture of 2-bromo-6- (5-formyl-6-methoxypyridin-2-yl) benzonitrile (0.3 g,0.95 mmol) and 2, 3-dichloro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.52 g,1.89 mmol) in 1, 4-dioxane/water (5:1, 12 mL) was added potassium carbonate (0.4 g,2.84 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.11 g,0.95 mol), followed by a reaction under N ₂ The mixture was stirred at 95℃for 2 hours. The reaction mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (2×20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-35% ethyl acetate/petroleum ether) to give 2- (2, 3-dichloropyridin-4-yl) -6- (5-formyl-6-methoxypyridin-2-yl) benzonitrile (300 mg,82% yield) as a white solid. MS: m/z found 384[ M+H ]] ⁺ .

(d) 2- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -6- (5-formyl-6-methoxypyridin-2-yl) benzonitrile

To 2- (2, 3-dichloropyridin-4-yl) -6- (5-formyl-6-methoxypyridin-2-yl) benzonitrile (0.25 g,0.65 mmol) and 2-methoxy-4- (4, 5-tetramethylene)A mixture of base-1, 3, 2-dioxaborane-2-yl) benzaldehyde (0.26 g,0.98 mmol) in 1, 4-dioxane/water (5:1, 12 mL) was added potassium carbonate (0.27 g,1.95 mmol) and tetrakis (triphenylphosphine) palladium (0) (75.2 mg, 65.07. Mu. Mol) followed by N ₂ The mixture was stirred at 95℃for 2 hours. The reaction mixture was cooled to room temperature, water (10 mL) was added and the mixture was extracted with ethyl acetate (2×30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-60% ethyl acetate/petroleum ether) to afford the product as a white solid (130 mg). The product was further purified by preparative TLC to provide 2- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -6- (5-formyl-6-methoxypyridin-2-yl) benzonitrile (40 mg,22% yield) as a white solid. MS: m/z found 484[ M+H ] ] ⁺ .

(e) 2- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -6- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) benzonitrile

At N ₂ A mixture of 2- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -6- (5-formyl-6-methoxypyridin-2-yl) benzonitrile (35 mg, 72.33. Mu. Mol), 1- (4-aminopiperidin-1-yl) ethan-1-one (38.7 mg,0.22 mmol) and sodium acetate (35.6 mg,0.43 mmol) in dichloromethane (2 mL) was stirred at room temperature for 3 hours. Sodium cyanoborohydride (13.6 mg,0.22 mmol) was then added and the mixture was taken up in N ₂ The mixture was stirred at room temperature for 30 minutes. The reaction mixture was purified by reverse phase HPLC to afford 2- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -6- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) benzonitrile (7.3 mg,13% yield) as a white solid. MS: m/z found 736[ M+H ]] ⁺ Retention time = 2.50min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.69(d,1H),8.01(d,1H),7.89(t,1H),7.85(d,1H),7.61(d,1H),7.53(d,1H),7.48(d,1H),7.43(d,1H),7.31-7.28(m,2H),4.51-4.44(m,2H),4.1(s,3H),3.98-3.89(m,7H),3.87(s,2H),3.15-3.13(m,2H),2.79-2.68(m,4H),2.10(s,6H),2.05-1.97(m,4H),1.43-1.24(m,4H).

Example 377:2- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -6- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) benzonitrile (636)

(a) 2- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -6- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) benzonitrile

To 2- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -6- (5-formyl-6-methoxypyridin-2-yl) benzonitrile (example 376, step (d)) (70 mg,145 umol) and 1- (2, 6-diazaspiro [3.3]A mixture of heptan-2-yl) ethanone hydrochloride (63.9 mg,362 umol) in dichloromethane (5 mL) was added sodium acetate (59.3 mg, 323 umol) followed by N ₂ The mixture was stirred at room temperature for 12 hours. Sodium triacetoxyborohydride (92 mg, 433. Mu. Mol) was then added and added to the mixture at N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 2- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3 ]) as a white solid (formate salt)]Heptane-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -6- (5- ((6-acetyl-2, 6-diazaspiro [ 3.3)]Heptane-2-yl) methyl) -6-methoxypyridin-2-yl benzonitrile (15.1 mg,13% yield). MS: m/z found 732. ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.73(d,1H),8.42(br s,2H),8.04(d,1H),7.92(t,1H),7.85(d,1H),7.64(d,1H),7.58(d,1H),7.53-7.50(m,2H),7.42(s,1H),7.39(d,1H),4.38(s,2H),4.35(s,2H),4.33(s,2H),4.20(s,4H),4.15-4.11(m,7H),3.99(s,3H),3.96(s,2H),3.82(s,4H),1.86(s,6H).

Example 378:2- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -6- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) benzonitrile (652)

(a) 2- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -6- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) benzonitrile

To a mixture of 2- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -6- (5-formyl-6-methoxypyridin-2-yl) benzonitrile (example 376, step (d)) (60 mg,124 umol) and tetrahydropyran-4-amine (37.6 mg,372 umol) in dichloromethane (5 mL) was added sodium acetate (50.8 mg,620 umol) followed by N ₂ The mixture was stirred at room temperature for 12 hours. Sodium triacetoxyborohydride (78.8 mg, 332. Mu. Mol) was then added and added to the mixture at N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide 2- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -6- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) benzonitrile (6.3 mg,7% yield) as a white solid (formate). MS: m/z found 654[ M+H ]] ⁺ Retention time = 2.58min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.73(d,1H),8.53(br s,2H),8.05(d,1H),7.95-7.91(m,2H),7.65(d,1H),7.59-7.53(m,3H),7.42-7.37(m,2H),4.28(s,2H),4.15(s,3H),4.12-4.01(m,9H),3.56-3.43(m,5H),3.15-3.10(m,1H),2.13-2.02(m,4H),1.77-1.60(m,4H).

Example 379:2- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) phenyl) pyridin-4-yl) -6- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) pyridin-2-yl) benzonitrile (653)

(a) 2- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) -6- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) benzonitrile

To 2- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -6- (5-formyl-6-methoxypyridin-2-yl) benzonitrile (example 376, step (d)) (60 mg,0.12 mmol), 2, 6-diazaspiro [3.4]]Sodium acetate (102 mg,1.24 mmol) was added to a mixture of octan-7-one trifluoroacetate salt (238 mg,0.99 mmol) in dichloromethane/methanol (2:1, 7.5 mL) followed by N ₂ The mixture was stirred at room temperature for 12 hours. Sodium triacetoxyborohydride (78.8 mg,0.37 mmol) was then added and added under N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 2- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [ 3.4) as a white solid (formate salt)]Octan-2-yl) methyl) phenyl) pyridin-4-yl) -6- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [ 3.4)]Octane-2-yl) methyl pyridin-2-yl benzonitrile (6.4 mg,6% yield). MS: m/z found 704[ M+H ]] ⁺ Retention time = 2.20min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.73(d,1H),8.41(br s,2H),8.03(d,1H),7.92(t,1H),7.84(d,1H),7.63(d,1H),7.57(d,1H),7.51(d,2H),7.40-7.36(m,2H),4.28(s,2H),4.11(s,3H),4.02(s,4H),3.99(s,3H),3.88(s,2H),3.67(s,2H),3.62-3.60(m,6H),2.70(s,2H),2.63(s,2H).

Example 380:2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) nicotinonitrile (404)

(a) 2-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) nicotinic acid carbonitrile

Tetrakis (triphenylphosphine) palladium (0) (31 mg,0.03 mmol), potassium carbonate (55 mg,0.40 mmol), 2-chloro-4-iodonicotinonitrile (46 mg,0.17 mmol), and 6- (2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -2-methoxynicotinaldehyde (50 mg,0.13 mmol) were suspended in 1, 4-dioxane/water (4:1, 3 ml) and the solution was heated at 110 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×5 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (0-40% EtOAc/hexanes) to provide 2-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) nicotinic carbonitrile (49 mg,95% yield) as a yellow oil. MS: m/z found 384,386[ M+H ]] ⁺ .

(b) 4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) -2- (4-formyl-3-methoxyphenyl) nicotinic carbonitrile

Tetrakis (triphenylphosphine) palladium (0) (30 mg,0.03 mmol), potassium carbonate (53 mg,0.38 mmol), 2-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) nicotinic carbonitrile (49 mg,0.13 mmol), and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (50 mg,0.19 mmol) were suspended in 1, 4-dioxane/water (4:1, 3 mL) and the solution was heated at 105℃for 20 min. The reaction was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×5 mL). The combined organics were concentrated under reduced pressure and purified by silica gel chromatography The crude sample was purified (0-100% EtOAc/hexanes) to provide 4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) -2- (4-formyl-3-methoxyphenyl) nicotinic carbonitrile (31 mg,50% yield) as a yellow foam. MS: m/z found 484,486[ M+H ]] ⁺ 。

(c) 2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) nicotinic carbonitrile

4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) -2- (4-formyl-3-methoxyphenyl) -nicotinic carbonitrile (31 mg,0.06 mmol), acetic acid (8 mg,0.13 mmol), and 1- (4-amino-1-piperidinyl) ethanone (27 mg,0.19 mmol) were dissolved in MeOH/THF (1:1, 1 mL) and the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (12 mg,0.19 mmol) was added and the resulting mixture was stirred at 25℃for 1 hour. The reaction was then diluted with water (3 mL) and extracted with EtOAc (3×2 mL). The combined organics were further washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude sample was purified by reverse phase HPLC to provide 2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) nicotinonitrile (22 mg,48% yield) as a white solid (formate). LC/MS: m/z found 736,739[ M+H ] ] ⁺ Retention time = 2.04min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.93(d,1H),7.77(d,2H),7.56(m,6H),7.28(d,1H),4.47(d,2H),4.02(d,3H),3.98(d,5H),3.92(s,2H),3.88(s,2H),3.14(t,2H),2.93–2.76(m,2H),2.69(q,2H),2.10(d,6H),2.03(s,4H),1.45–1.26(m,4H).

Example 381:4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) pyridin-2-yl) phenyl) -2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) phenyl) nicotinonitrile (433)

In a similar manner to that described for example 380, the intermediate 4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) -2- (4-formyl-3-methoxyphenyl) -nicotinic carbonitrile was used in step (c) and with 2, 6-diazaspiro [3.4]Preparation of 4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [ 3.4) by substituting octane-7-one for 1- (4-amino-1-piperidinyl) ethanone]Octan-2-yl) methyl pyridin-2-yl) phenyl) -2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [ 3.4)]Octane-2-yl) methyl) phenyl) nicotinonitrile. The product was obtained as a white solid (formate). LC/MS: m/z found 704,706[ M+H ]] ⁺ Retention time = 1.94min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.98–8.92(m,1H),8.45(s,1H),7.76(t,2H),7.63–7.57(m,3H),7.57–7.51(m,3H),7.29(d,1H),4.21(s,2H),4.03–4.00(m,3H),3.99(t,3H),3.93(d,6H),3.66(s,4H),3.63(t,2H),3.61(d,2H),2.67(d,2H),2.62(d,2H).

Example 382:4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) -2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) nicotinonitrile (434)

In a similar manner as described for example 380, 4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) -2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) nicotinonitrile was prepared in step (c) using the intermediate 4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) -2- (4-formyl-3-methoxyphenyl) -nicotinonitrile and replacing 1- (4-amino-1-piperidinyl) ethanone with tetrahydropyran-4-amine. The product was obtained as a white solid (formate). LC/MS: m/z found 654,656[ M+H ]] ⁺ Retention time = 2.10min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.95(m,1H),8.53(s,1H),7.78(dd,2H),7.63–7.58(m,3H),7.57–7.52(m,3H),7.32–7.26(m,1H),4.12(s,2H),4.03(t,3H),4.01–3.97(m,6H),3.95(s,3H),3.43(t,4H),3.10(s,1H),2.91(s,1H),2.05–1.91(m,4H),1.67–1.46(m,4H).

Example 383:1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (271)

(a) 6- (2-chloro-3- (2- (4-formyl-3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxynicotinaldehyde

2-chloro-3-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine (100 mg,0.39 mmol), 6- (3-bromo-2-chlorophenyl) -2-methoxynicotinaldehyde (155 mg,0.47 mmol), [1,1' -bis (biphenylphosphino) ferrocene ]The palladium (II) dichloride complex with dichloromethane (32 mg,0.04 mmol), and potassium carbonate (136 mg,0.99 mmol) were suspended in 1, 4-dioxane/water (4:1, 3 mL) and the solution was then heated at 105℃for 2 hours. LC/MS showed complete conversion to the intermediate 6- (2-chloro-3-methylpyridin-4-yl) phenyl) -2-methoxynicotinaldehyde. 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (145 mg,0.55 mmol) was added to the reaction mixture and the resulting solution was stirred at 105℃for an additional 18 hours. The reaction was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×5 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (0-50% EtOAc/hexanes) to afford 6- (2-chloro-3- (2- (4-formyl-3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (30 mg,16% yield) as a yellow film. MS: m/z found 473[ M+H ]] ⁺ .

(b) 1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

6- (2-chloro-3- (2- (4-formyl-3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (10 mg,0.02 mmol), acetic acid (3 mg,0.04 mmol) and 1- (4-amino-1-piperidinyl) ethanone (12 mg,0.08 mmol) were dissolved in MeOH/THF (1:1, 1 mL) and the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (5 mg,0.08 mmol) was added and the resulting mixture was stirred at 25 ℃ for 1 hour. The reaction was then diluted with water (2 mL) and extracted with EtOAc (3×2 mL). The combined organics were further washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude sample was purified by reverse phase HPLC to provide 1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (8 mg,54% yield) as a white solid (formate salt). LC/MS: m/z found 725,727[ M+H ] ] ⁺ Retention time = 2.01min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.52(s,1H),8.46(s,2H),7.85(d,1H),7.68(d,1H),7.54(dd,2H),7.40(d,1H),7.32(d,2H),7.23(s,1H),7.16(d,1H),4.63(t,2H),4.29(s,2H),4.16(s,2H),4.06(s,5H),3.98(s,3H),3.41(s,1H),3.17(d,3H),2.67(d,2H),2.20(d,4H),2.14–2.07(m,9H),1.74–1.30(m,4H).

Example 384: (S) -1- (((6- (2-chloro-3- (2- (4- ((((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -phenyl) -2-methoxypyridin-3-yl) -methyl) -amino) propan-2-ol (274)

In the same manner as described for example 383, intermediate 6- (2-chloro-3- (2- (4-formyl-3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypolynicotinaldehyde was used in step (b)And (S) -1- (((6- (2-chloro-3- (2- (4- ((((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -phenyl) -2-methoxypyridin-3-yl) -methyl) -amino) propan-2-ol) was prepared using (S) -1-aminopropane-2-ol instead of 1- (4-amino-1-piperidinyl) -ethanone. The product was obtained as a white solid (formate). LC/MS: m/z found 591,593[ M+H ]] ⁺ Retention time = 1.98min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.53(d,1H),7.85(d,1H),7.69(d,1H),7.56(t,1H),7.50(d,1H),7.40(d,1H),7.32(t,2H),7.23(s,1H),7.16(d,1H),4.29(s,2H),4.20(s,2H),4.06(d,5H),3.98(s,3H),3.04(t,2H),2.84(q,2H),2.12(s,3H),1.22(d,6H).

Example 385.1- (6- (2-chloro-3- (2- (3-methoxy-4- ((methylamino) methyl) phenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methylamine (334)

(a) 6- (2-chloro-3-methylpyridin-4-yl) phenyl) -2-methoxynicotinaldehyde

To a solution of 6- (2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -2-methoxynicotinaldehyde (6 g,16.1 mmol) and 2-chloro-4-iodo-3-methylpyridine (4.07 g,16.1 mmol) in a 1, 4-dioxane/water mixture (10:1, 120 mL) was added potassium carbonate (6.66 g,48.2 mmol) and [1,1' -bis (biphenylphosphino) ferrocene ]Palladium (II) dichloride complex with dichloromethane (0.39 g,0.48 mmol) and the mixture was stirred at 95 ℃ for 4 hours. The reaction was filtered, concentrated and diluted with water (50 mL). The aqueous layer was extracted with ethyl acetate (2×40 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ Chromatography (0-20% ethyl acetate/petroleum ether) purified the residue to afford 6- (2-chloro-3-methylpyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (4.7 g,78% yield). ¹ H NMR (400 MHz, chloroform-d): delta 10.36 (s, 1H), 8.25 (m),1H),8.14(d,1H),7.65(d,1H),7.45(t,1H),7.35(d,1H),7.19(s,1H),7.09(d,1H),4.06(s,3H),2.15(s,3H).

(b) 6- (2-chloro-3- (2- (4-formyl-3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxynicotinaldehyde

To a solution of 6- (2-chloro-3-methylpyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (1.5 g,4.02 mmol) and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (2.11 g,8.04 mmol) in a 1, 4-dioxane/water mixture (10:1, 33 mL) was added potassium phosphate (2.56 g,12.1 mmol) and [1,1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) dichloride (0.13 g,0.2 mmol) and the mixture was stirred at 95℃for 4 hours. The mixture was concentrated, after which water (10 mL) was added. The aqueous layer was extracted with ethyl acetate (2×15 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ Chromatography (0-100% ethyl acetate/petroleum ether) purified the residue to afford 6- (2-chloro-3- (2- (4-formyl-3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (0.23 g,12% yield). ¹ H NMR (400 MHz, chloroform-d): delta 10.41 (s, 2H), 7.77-7.74 (m, 2H), 7.48-7.46 (m, 2H), 6.97-6.91 (m, 5H), 3.86 (s, 6H), 1.97 (s, 3H).

(c) 1- (6- (2-chloro-3- (2- (3-methoxy-4- ((methylamino) methyl) phenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methylamine

To a mixture of 6- (2-chloro-3- (2- (4-formyl-3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (0.17 g,0.95 mmol) in methanol (0.5 mL) and THF (0.5 mL) was added sodium acetate (0.19 g,2.28 mmol) and methylamine hydrochloride. The mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (0.096 g,1.52 mmol) was added to the mixture and the mixture was stirred at room temperature for 30 minutes. Will beThe mixture was concentrated and the residue was purified by reverse phase HPLC to provide 1- (6- (2-chloro-3- (2- (3-methoxy-4- ((methylamino) methyl) phenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methylamine (25.4 mg,9% yield) as a white solid (formate). MS: m/z found 503[ M+H ] ] ⁺ Retention time = 1.88min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.52(d,1H),8.51(m,2H),7.85(d,1H),7.69(dd,1H),7.57(t,1H),7.49(d,1H),7.41(dd,1H),7.35-7.31(m,2H),7.24(d,1H),7.16(dd,1H),4.25(s,2H),4.21(s,2H),4.08(s,3H),3.98(s,3H),2.73(s,6H),2.11(s,3H).

Example 386:2- ((6- (2-chloro-3- (2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) phenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one (368)

To 6- (2-chloro-3- (2- (4-formyl-3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (example 385, step (b)) (0.15 g,0.32 mmol) and 2, 6-diazaspiro [3.4]]Sodium acetate (0.16 g,1.9 mmol) was added as a mixture of octan-7-one hydrochloride (0.11 g,0.7 mmol) in a THF/MeOH mixture (1:1, 1 mL). The mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (0.08 g,1.27 mmol) was added to the mixture and the mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide 2- ((6- (2-chloro-3- (2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4 ]) as a yellow solid (formate salt)]Octane-2-yl) methyl) phenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) -2, 6-diazaspiro [3.4]Octan-7-one (47.5 mg,16% yield). MS: m/z found 693[ M+H ]] ⁺ Retention time = 1.85min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.54(d,1H),8.42(br s,2H),7.81(d,1H),7.70(dd,1H),7.57(t,1H),7.52(d,1H),7.41(dd,1H),7.34-7.30(m,2H),7.24(s,1H),7.18(dd,1H),4.39(s,2H),4.15(s,4H),4.10(s,2H),4.05(s,3H),3.99(s,3H),3.87(m,4H),3.68(d,4H),2.73-2.68(m,4H),2.13(s,3H).

Example 387:1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one (369)

To 6- (2-chloro-3- (2- (4-formyl-3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (example 385, step (b)) (0.1 g,0.21 mmol) and 1- (2, 6-diazaspiro [3.3]]A mixture of heptan-2-yl) ethan one trifluoroacetate (0.11 g,0.42 mmol) in a THF/methanol mixture (1:1, 4 mL) was added sodium acetate (0.1 g,1.27 mmol) and the mixture stirred at room temperature for 1 hour. Sodium cyanoborohydride (0.05 g,0.85 mmol) was added to the mixture and the mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [ 3.3)) as a white solid (formate))]Heptane-2-yl) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl methyl) -2, 6-diazaspiro [3.3]Heptane-2-yl) ethan-1-one (48 mg,25% yield). MS: m/z found 721[ M+H ]] ⁺ Retention time = 2.05min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.55(d,1H),8.38(br s,1H),7.81(d,1H),7.70(dd,1H),7.58(t,1H),7.51(d,1H),7.42(dd,1H),7.34-7.31(m,2H),7.26(s,1H),7.19(d,1H),4.40(s,2H),4.37(s,4H),4.26(s,4H),4.16-4.10(m,6H),4.03(s,3H),4.00-3.97(m,7H),2.13(s,3H),1.87(s,6H).

Example 388: (S) -5- (((6- (2-chloro-3- (2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (414)

To a mixture of 6- (2-chloro-3- (2- (4-formyl-3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (example 385, step (b)) (0.18 g,0.38 mmol) and (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride (0.14 g,0.95 mmol) in THF/water mixture (1:3, 4 ml) was added sodium acetate (0.19 g,2.28 mmol) and the mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (0.1 g,1.52 mmol) was added to the mixture and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford (S) -5- ((((6- (2-chloro-3- (2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one (27.5 mg,10% yield) as a white solid (formate). MS: m/z found m/z 669[ M+H ]] ⁺ Retention time = 1.87min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.53(d,1H),8.35(br s,2H),7.81(d,1H),7.68(dd,1H),7.55(t,1H),7.50(d,1H),7.39(dd,1H),7.32-7.28(m,2H),7.23(d,1H),7.15(dd,1H),4.28-4.21(m,2H),4.04-3.98(m,9H),3.93-3.92(m,1H),3.14-3.09(m,2H),2.93-2.89(m,2H),2.41-2.32(m,6H),2.12(s,3H),1.90-1.85(m,2H).

Example 389: n- ((6- (2-chloro-3- (2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine

To a mixture of 6- (2-chloro-3- (2- (4-formyl-3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (example 385, step (b)) (0.11 g,0.23 mmol) and tetrahydro-2H-pyran-4-amine (0.06 g,0.58 mmol) in a THF/MeOH mixture (1:1, 2 mL) was added sodium acetate (0.08 g,0.93 mmol) and the mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (0.07 g,1.05 mmol) was added and the mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide N- ((6- (2-chloro-3- (2- (3-methoxy-4- (((tetrahydro- -)) as a white solid (formate))2H-pyran-4-yl) amino) methyl) phenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) tetrahydro-2H-pyran-4-amine (43.4 mg,26% yield). MS: m/z found 643[ M+H ]] ⁺ Retention time = 2.18min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.55(d,1H),8.50(br s,2H),7.88(d,1H),7.71(dd,1H),7.61-7.53(m,2H),7.43(dd,1H),7.36-7.33(m,2H),7.26(s,1H),7.19(d,1H),4.31(s,2H),4.20(s,2H),4.09-4.04(m,7H),4.01(s,3H),3.51-3.42(m,6H),2.14-2.08(m,7H),1.76-1.67(m,4H).

Example 390: (1 r,4 r) -4- (((6- (2-chloro-3- (2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexane-1-ol (463)

To a mixture of 6- (2-chloro-3- (2- (4-formyl-3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (example 385, step (b)) (0.1 g,0.21 mmol) and (1 r,4 r) -4-aminocyclohexanol (0.06 g,0.49 mmol) in a THF/MeOH mixture (1:1, 2 ml) was added sodium acetate (0.07 g,0.85 mmol) and the mixture was stirred at room temperature for 12 hours. Sodium cyanoborohydride (0.06 g,0.95 mmol) was added and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide (1 r,4 r) -4- (((6- (2-chloro-3- (2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol (31.6 mg,19% yield) as a white solid (formate). MS: m/z found m/z 671[ M+H ]] ⁺ Retention time = 2.04min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.53(d,1H),8.49(br s,2H),7.87(d,1H),7.68(dd,1H),7.56(t,1H),7.51(d,1H),7.41(dd,1H),7.34-7.31(m,2H),7.23(d,1H),7.16(dd,1H),4.28(s,2H),4.22(s,2H),4.07(s,3H),3.98(s,3H),3.61-3.54(m,2H),3.14-3.05(m,2H),2.23-2.20(m,4H),2.11-2.03(m,7H),1.58-1.49(m,4H),1.41-1.32(m,4H).

Example 391:6- (4- (4- (3- (5- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-methylpyridin-2-yl) -2-methoxyphenylmethyl) -2-oxa-6-azaspiro [3.3] heptane (464)

To 6- (2-chloro-3- (2- (4-formyl-3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (example 385, step (b)) (0.11 g,0.23 mmol) and 2-oxa-6-azaspiro [ 3.3) ]A mixture of heptane (0.05 g,0.53 mmol) in a THF/methanol mixture (1:1, 1 mL) was added sodium acetate (0.08 g,0.93 mmol) and the mixture stirred at room temperature for 0.5 h. Sodium cyanoborohydride (0.07 g,1.05 mmol) was added and the mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 6- (4- (4- (3- (5- ((2-oxa-6-azaspiro [3.3 ]) as a yellow solid (formate))]Heptane-6-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-methylpyridin-2-yl-2-methoxyphenylmethyl) -2-oxa-6-azaspiro [3.3]Heptane (13.5 mg,8% yield). MS: m/z found 639[ M+H ]] ⁺ Retention time = 2.01min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.52(d,1H),8.39(br s,2H),7.76-7.74(m,1H),7.68(dd,1H),7.55(t,1H),7.46(d,1H),7.38(dd,1H),7.32-7.28(m,2H),7.22(s,1H),7.15(d,1H),4.78-4.74(m,8H),4.32-4.23(m,6H),4.15-4.13(m,1H),4.02-3.89(m,10H),3.70-3.67(m,1H),2.11(s,3H).

Example 392: n- (1- ((6- (3- (2- (4- ((4-acetamidopiperidin-1-yl) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide (466)

To 6- (2-chloro-3- (2- (4-formyl-3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (example 385, step (b)) (0.1 g,0.21 mmol) and N- (piperidin-4-yl) acetamide (0.09 g,0.63 mmol) in a THF/methanol mixture (2:3Sodium acetate (0.07 g,0.85 mmol) was added to the mixture in 5 mL) and the mixture was stirred at room temperature for 8 hours. Sodium triacetoxyborohydride (0.22 g,1.06 mmol) was added to the mixture and the mixture was stirred at room temperature for 8 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide N- (1- ((6- (3- (2- (4- ((4-acetamidopiperidin-1-yl) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide (29.6 mg,17% yield) as a yellow solid (formate salt). MS: m/z found 725[ M+H ] ] ⁺ Retention time = 2.03min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):8.56(d,1H),8.41(br s,2H),7.85(d,1H),7.72(d,1H),7.60-7.54(m,2H),7.42(d,1H),7.35-7.32(m,2H),7.26(s,1H),7.20(d,1H),4.28(s,2H),4.05(s,3H),3.99(s,3H),3.92(m,3H),3.82-3.76(m,1H),3.45(m,1H),3.21-3.05(m,4H),2.68-2.62(m,2H),2.15-2.09(m,6H),2.00-1.95(m,8H),1.82-1.65(m,4H).

Example 393:1- (2-methoxy-4- (4- (3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) -2-methylphenyl) -3-methylpyridin-2-yl) phenyl) -N-methyl methylamine (362)

(a) 2-methoxy-6- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) nicotinaldehyde

6- (3-bromo-2-methylphenyl) -2-methoxynicotinaldehyde (example 344, step (b)) (1.95 g,6.37 mmol), bis (pinacolato) diborane (3.23 g,12.74 mmol), potassium acetate (1.88 g,19.11 mmol) and [1,1' -bis (biphenylphosphino) ferrocene]A mixture of palladium (II) dichloride (463 mg,637 umol) in 1, 4-dioxane (30 mL) was degassed and N ₂ Purging three times, then at N ₂ The mixture was stirred for 3 hours at 100 ℃ under an atmosphere. The mixture was combined with another batch at 50mg scale. The reaction mixture was quenched by the addition of water (30 mL)Quench and extract with ethyl acetate (3×25 mL). The combined organic layers were washed with saturated aqueous brine solution (2×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ The residue was purified by chromatography (0-20% ethyl acetate/petroleum ether) to afford 2-methoxy-6- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) nicotinaldehyde (1.9 g,84% yield) as a yellow solid. ¹ H NMR(400MHz,CDCl ₃ ):δ10.42(s,1H),8.17(d,1H),7.85(dd,1H),7.47(dd,1H),7.31-7.27(m,1H),7.11(d,1H),4.09(s,3H),2.59(s,3H),1.38(s,12H),1.27(s,9H).

(b) 6- (3- (2-chloro-3-methylpyridin-4-yl) -2-methylphenyl) -2-methoxynicotinaldehyde

2-methoxy-6- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) nicotinaldehyde (1.9 g,5.38 mmol), 2-chloro-4-iodo-3-methylpyridine (2.73 g,10.76 mmol), potassium carbonate (2.23 g,16.14 mmol) and [1,1' -bis (biphenylphosphino) ferrocene]A mixture of a complex of palladium (II) dichloride with dichloromethane (439 mg,538 umol) in 1, 4-dioxane/water (10:1, 33 mL) was degassed and N ₂ Purging three times, then at N ₂ The mixture was stirred under an atmosphere at 95 ℃ for 3 hours. The mixture was combined with another batch at 50mg scale. The reaction mixture was quenched by the addition of water (30 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with saturated aqueous brine solution (2×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ The residue was purified by chromatography (10-50% ethyl acetate/petroleum ether) to afford 6- (3- (2-chloro-3-methylpyridin-4-yl) -2-methylphenyl) -2-methoxynicotinaldehyde as a yellow oil (1 g,52% yield). ¹ H NMR(400MHz,CDCl ₃ ):δ10.43(s,1H),8.29(d,1H),8.21(d,1H),7.52(dd,1H),7.39(t,1H),7.20-7.14(m,2H),7.09(d,1H),4.11(s,3H),2.19(s,3H),2.11(s,3H).

(c) 6- (3- (2- (4-formyl-3-methoxyphenyl) -3-methylpyridin-4-yl) -2-methylphenyl) -2-methoxynicotinaldehyde

6- (3- (2-chloro-3-methylpyridin-4-yl) -2-methylphenyl) -2-methoxynicotinaldehyde (0.95 g,2.69 mmol), 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (1.76 g,6.73 mmol), potassium phosphate (1.71 g,8.08 mmol) and [1,1' -bis (di-tert-butylphosphino) ferrocene]A mixture of palladium (II) dichloride (175.5 mg, 263 umol) in 1, 4-dioxane/water (10:1, 22 mL) was degassed and N ₂ Purging three times, then at N ₂ The mixture was stirred under an atmosphere at 95 ℃ for 2 hours. The mixture was combined with another batch on a 20mg scale. The reaction mixture was quenched by the addition of water (30 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with saturated aqueous brine solution (2×15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ The residue was purified by chromatography (10-50% ethyl acetate/petroleum ether) to afford 6- (3- (2- (4-formyl-3-methoxyphenyl) -3-methylpyridin-4-yl) -2-methoxyphenyl) -2-methoxynicotinaldehyde (1 g,82% yield) as a white solid. ¹ H NMR(400MHz,CDCl ₃ ):δ10.53(s,1H),10.43(s,1H),8.61(d,1H),8.22(d,1H),7.92(d,1H),7.52(dd,1H),7.41(t,1H),7.24-7.19(m,5H),4.11(s,3H),4.03-3.99(m,3H),2.18(s,3H),2.11(s,3H).

(d) 1- (2-methoxy-4- (4- (3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) -2-methylphenyl) -3-methylpyridin-2-yl) phenyl) -N-methyl methylamine

To a solution of 6- (3- (2- (4-formyl-3-methoxyphenyl) -3-methylpyridin-4-yl) -2-methylphenyl) -2-methoxynicotinaldehyde (150 mg,331.5 mol) in MeOH (5 mL) were added methylamine hydrochloride (68.5 mg,994.5 mol) and sodium acetate (108.8 mg,1.33 mmol) and the solution was stirred at room temperature for 12 hours. Sodium triacetoxyborohydride (140.5 mg,663 umo) was then added l) and the resulting solution was stirred at 20℃for 1 hour. The reaction was concentrated under reduced pressure and the residue was purified by reverse phase HPLC to provide 1- (2-methoxy-4- (4- (3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) -2-methylphenyl) -3-methylpyridin-2-yl) phenyl) -N-methylamine (24.2 mg,15% yield) as a white solid (formate). MS: m/z found 483.3[ M+H ]] ⁺ Retention time = 1.70min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.52-8.50(m,3H),7.87(d,1H),7.51-7.49(m,2H),7.42(t,1H),7.29(d,1H),7.26-7.23(m,2H),7.21-7.17(m,2H),4.26(s,2H),4.22(s,2H),4.06(s,3H),3.99(s,3H),2.74(d,6H),2.13(s,3H),2.08(s,3H).

Example 394 1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethane-1-one (363)

To a solution of 6- (3- (2- (4-formyl-3-methoxyphenyl) -3-methylpyridin-4-yl) -2-methylphenyl) -2-methoxynicotinaldehyde (example 393, step (c)) (150 mg,331.5 mol) and 1- (4-amino-1-piperidinyl) ethanone (177.7 mg,994.5 mol) as the hydrochloride salt in methanol (3 mL) was added sodium acetate (108.8 mg,1.33 mmol) and the solution was stirred at room temperature for 12 hours. Sodium triacetoxyborohydride (70.3 mg,331.5 mol) was then added and the solution was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure and the residue was purified by reverse phase HPLC to provide 1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (80 mg,34% yield) as a white solid (formate salt). MS: m/z found 705.4[ M+H ] ] ⁺ Retention time = 2.02min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.51-8.49(m,2H),7.88(d,1H),7.54-7.48(m,2H),7.41(t,1H),7.29(d,1H),7.25-7.16(m,4H),4.68-4.62(m,2H),4.31(s,2H),4.22(s,2H),4.08-4.05(m,5H),3.99(s,3H),3.45-3.34(m,2H),3.24-3.17(m,2H),2.75-2.67(m,2H),2.28-2.18(m,4H),2.14(d,9H),2.07(s,3H),1.70-1.45(m,4H).

EXAMPLE 395N- (1- ((6- (3- (2- (4- ((4-acetamidopiperidin-1-yl) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide (461)

To a solution of 6- (3- (2- (4-formyl-3-methoxyphenyl) -3-methylpyridin-4-yl) -2-methylphenyl) -2-methoxynicotinaldehyde (example 393, step (c)) (140 mg,309.4 umol) and N- (piperidin-4-yl) acetamide (132 mg,928 umol) in methanol (10 mL) was added sodium acetate (101.5 mg,1.24 mmol) and the solution was stirred at room temperature for 12 hours. Sodium cyanoborohydride (77.8 mg,1.24 mmol) was then added and the solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC to provide N- (1- ((6- (3- (2- (4- ((4-acetamidopiperidin-1-yl) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide (51.7 mg,22% yield) as a white solid (formate). MS: m/z found 705.3[ M+H ]] ⁺ Retention time = 1.95min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.51(d,1H),8.44(br s,2H),7.86(d,1H),7.55-7.49(m,2H),7.41(t,1H),7.29(d,1H),7.25-7.17(m,4H),4.29(s,2H),4.01(s,5H),3.97(s,3H),3.92-3.79(m,2H),3.44(d,2H),3.26(s,2H),3.09(t,2H),2.79(br t,2H),2.14(s,3H),2.09(s,5H),2.01(d,2H),1.94(d,6H),1.82-1.66(m,4H).

Example 396: (S) -5- ((((6- (3- (2- (4- ((S) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (335)

(a) (S) -N- ((S) -1- (4-bromo-2-methoxyphenyl) ethyl) -2-methylpropane-2-sulfinamide

At N ₂ To a mixture of 1- (4-bromo-2-methoxyphenyl) ethanone (0.2 g,0.87 mmol) and (S) -2-methylpropane-2-sulfinamide (0.21 g,1.75 mmol) in THF (10 mL) was added titanium (IV) tetraethoxide (2 mL,2.62 mmol) in one portion. The mixture was stirred at 80℃for 48 hours to give (S) -N- (1- (4-bromo-2-methoxyphenyl) ethylene) -2-methylpropane-2-sulfinamide (MS: m/z found 332 and 334[ M+H ] as a white suspension] ⁺ ). The mixture was cooled to-35 ℃ and cooled to N ₂ Sodium cyanoborohydride (0.17 g,4.37 mmol) was added in the next portion. The mixture was stirred at-35℃for 30 min. The mixture was combined with another batch on a 0.5g scale. Water (50 mL) was then added and the combined mixture was extracted with ethyl acetate (2X 25 mL). The combined organic phases were washed with saturated aqueous brine solution (2×25 mL), dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-30% ethyl acetate/petroleum ether) to afford (S) -N- ((S) -1- (4-bromo-2-methoxyphenyl) ethyl) -2-methylpropane-2-sulfinamide as a white solid (0.4 g,2 steps 40% yield). ¹ H NMR(400MHz,CDCl ₃ ):δ7.09(d,1H),7.01(dd,1H),6.93(d,1H),4.72-4.65(m,1H),3.77(s,3H),3.62(d,1H),1.38(d,,3H),1.14(s,9H).

(b) (S) -N- ((S) -1- (2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) ethyl) -2-methylpropan-2-sulfinamide

At N ₂ To a mixture of (S) -N- ((S) -1- (4-bromo-2-methoxyphenyl) ethyl) -2-methylpropane-2-sulfinamide (0.3 g,0.9 mmol) and bis (pinacolato) diborane (0.46 g,1.79 mmol) in 1, 4-dioxane (3 mL) was added at one time [1,1' -bis (biphenylphosphino) ferrocene]Complex of palladium (II) dichloride with dichloromethane (0.07 g,0.09 mmol) and ethylPotassium acid (0.26 g,2.69 mmol) and the mixture was stirred at 100deg.C for 12 hours. Concentrating the mixture and passing through normal phase SiO ₂ The residue was purified by chromatography (0-25% ethyl acetate/petroleum ether) to afford (S) -N- ((S) -1- (2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) ethyl) -2-methylpropan-2-sulfinamide as a yellow oil (0.3 g,66% yield). ¹ H NMR(400MHz,CDCl ₃ ):δ7.34(d,1H),7.25-7.19(m,2H),4.82(d,1H),3.82(s,3H),3.72(d,1H),1.38(d,3H),1.26(s,12H).1.14(s,9H).

(c) (6- (3- (2- (4- ((S) -1- (((S) -tert-butylsulfinyl) amino) ethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

At N ₂ To a mixture of (S) -N- ((S) -1- (2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) ethyl) -2-methylpropane-2-sulfinamide (0.3 g,0.79 mmol) and tert-butyl (5-oxopyrrolidin-2-yl) methyl) carbamate (0.3 g,0.51 mmol) in 1, 4-dioxane/water mixture (6:1, 3.5 mL) was added potassium phosphate (0.32 g,1.52 mmol) and [1,1' -bis (di-tert-butylphosphino) ferrocene at one time ]Palladium (II) dichloride (0.03 g,0.05 mmol) and the mixture is stirred at 100℃for 12 hours. To the mixture was added water (50 mL) and the mixture was extracted with ethyl acetate (2×25 mL). The combined organic phases were washed with saturated aqueous brine solution (2×15 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (silica gel, petroleum ether: ethyl acetate=0:1) to afford tert-butyl ((6- (3- (2- (4- ((S) -1- (((S) -tert-butylsulfinyl) amino) ethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (0.18 g,27% yield) as a white solid. MS: m/z found 810[ M+H ]] ⁺ .

(d) (S) -5- ((((6- (3- (2- (4- ((S) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

At N ₂ To a mixture of tert-butyl ((6- (3- (2- (4- ((S) -1- (((S) -tert-butylsulfinyl) amino) ethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) ((((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (0.18 g,0.22 mmol) in dichloromethane (0.3 mL) was added trifluoroacetic acid (3 mL,0.03 mmol) at one time and the mixture was stirred at 45 ℃ for 3 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford (S) -5- ((((6- (3- (2- (4- ((S) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (7.1 mg,5% yield) as a white solid (formate). MS: m/z measured values 606 and 608[ M+H ] ] ⁺ Retention time = 2.69min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.67(d,1H),8.44(br s,2H),7.81(d,1H),7.73(dd,1H),7.58(t,1H),7.52-7.48(m,2H),7.45-7.38(m,3H),7.30(d,1H),4.75(q,1H),4.06(s,3H),4.01(s,3H),3.98(d,2H),3.94-3.87(m,1H),2.90-2.80(m,2H),2.40-2.28(m,3H),1.91-1.82(m,1H),1.70(d,3H).

Example 397: (S) -1- (6- (3- (2- (4- ((S) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethan-1-amine (393)

(a) (S) -N- ((E) - (6- (3- (2- (4- ((E) - (((S) -tert-butylsulfinyl) imino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methylene) -2-methylpropan-2-sulfinamide

At N ₂ To a mixture of 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (0.3 g,0.61 mmol) and (S) -2-methylpropan-2-sulfinamide (0.16 g,1.34 mmol) in THF (6 mL) was added titanium tetraethoxide (IV) (0.6 mL,2.89 mmol) at one time under atmosphere and the mixture was stirred at 80 ℃ for 12 hours. To the mixture was added water (5 mL), the mixture was filtered, and the filtrate was concentrated. To the residue was added water (5 mL) and saturated aqueous brine solution (5 mL) and the mixture was extracted with ethyl acetate/THF mixture (1:1, 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (20-50% ethyl acetate/petroleum ether) to afford (S) -N- ((E) - (6- (3- (2- (4- ((E) - (((S) -tert-butylsulfinyl) imino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methylene) -2-methylpropan-2-sulfinamide as a yellow solid (0.32 g,75% yield). MS: m/z found 699[ M+H ] ] ⁺ .

(b) (S) -N- ((S) -1- (6- (3- (2- (4- ((S) -1- (((S) -tert-butylsulfinyl) amino) ethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethyl) -2-methylpropan-2-sulfinamide

At N ₂ To a mixture of (S) -N- ((E) - (6- (3- (2- (4- ((E) - ((S) -tert-butylsulfinyl) imino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methylene) -2-methylpropan-2-sulfinamide (0.29 g,0.41 mmol) in dichloromethane (10 mL) was added dropwise methyl magnesium bromide (3 m,0.55 mL) at 0 ℃ under an atmosphere and the mixture was stirred at room temperature for 2 hours. To the mixture was added methyl magnesium bromide (3 m,0.28 ml) dropwise and the mixture was stirred at room temperature for 14 hours. Water (5 mL) was added to the mixture at 0deg.C to quench the methyl magnesium bromide. The mixture was filtered and the filtrate was concentrated. To the disabledTo the residue was added water (10 mL) and saturated aqueous brine solution (50 mL) and the mixture was extracted with ethyl acetate/THF mixture (1:1, 20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (silica gel, 100% ethyl acetate/petroleum ether) to provide (S) -N- ((S) -1- (6- (3- (2- (4- ((S) -1- (((S) -tert-butylsulfinyl) amino) ethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethyl) -2-methylpropan-2-sulfinamide as a yellow solid (125 mg,32% yield). MS: m/z measured values 731 and 733[ M+H ] ] ⁺ .

(c) (S) -1- (6- (3- (2- (4- ((S) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethan-1-amine

To a mixture of (S) -N- ((S) -1- (6- (3- (2- (4- ((S) -1- (((S) -tert-butylsulfinyl) amino) ethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethyl) -2-methylpropan-2-sulfinamide (122 mg,0.17 mmol) in acetonitrile (1 mL) was added HCl solution (6 m,0.5 mL) in one portion. The mixture was stirred at room temperature for 1 hour. The mixture was purified directly by reverse phase HPLC to afford (S) -1- (6- (3- (2- (4- ((S) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethan-1-amine (54.7 mg,56% yield) as a white solid (formate). MS: m/z found 523[ M+H ]] ⁺ Retention time = 2.57min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.67(d,1H),8.56(br s,1H),7.87(d,1H),7.74(dd,1H),7.59(t,1H),7.52-7.46(m,3H),7.40-7.36(m,3H),4.75(q,1H),4.65(q,1H),4.10(s,3H),4.01(s,3H),1.69(t,6H).

Example 398:1- (4- (((S) -1- (6- (3- (2- (4- ((S) -1- ((1-acetylpiperidin-4-yl) amino) ethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethyl) amino) piperidin-1-yl) ethan-1-one (599)

(a) (S) -1- (6- (3- (2- (4- ((S) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethan-1-amine

To a mixture of (S) -N- ((S) -1- (6- (3- (2- (4- ((S) -1- (((S) -tert-butylsulfinyl) amino) ethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethyl) -2-methylpropan-2-sulfinamide (example 397, step (b)) 0.09g,0.12 mmol) in THF (2 mL) was added aqueous HCl solution (12 m,0.06 mL) (about 2 drops) at a time. The mixture was stirred at room temperature for 12 hours. The mixture was concentrated to provide crude (S) -1- (6- (3- (2- (4- ((S) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethan-1-amine hydrochloride (110 mg, crude) as a yellow solid. MS: m/z found 523[ M+H ]] ⁺ .

(b) 1- (4- (((S) -1- (6- (3- (2- (4- ((S) -1- ((1-acetylpiperidin-4-yl) amino) ethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethyl) amino) piperidin-1-yl) ethan-1-one

At N ₂ A mixture of (S) -1- (6- (3- (2- (4- ((S) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethan-1-amine hydrochloride (0.11 g,0.2 mmol), sodium acetate (0.08 g,0.98 mmol), triethylamine (0.08 mL,0.59 mmol) and 1-acetylpiperidin-4-one (0.07 g,0.49 mmol) in methanol (3 mL) was stirred at room temperature for 12 hours. Sodium cyanoborohydride (0.05 g,0.79 mmol) was then added and the mixture was stirred at room temperature for 1 hour. The mixture was combined with another batch at 40mg scale. Purification of the mixture directly by reverse phase HPLC provided the mixture as white Solid 1- (4- (((S) -1- (6- (3- (2- (4- ((S) -1- ((1-acetylpiperidin-4-yl) amino) ethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethyl) amino) piperidin-1-yl) ethan-1-one (20.4 mg,10% yield). MS: m/z found 773[ M+H ]]Retention time = 2.94min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),7.82(d,1H),7.74(dd,1H),7.57(t,1H),7.48-7.42(m,3H),7.33-7.30(m,3H),4.47-4.42(m,3H),4.32(q,1H),3.94(s,3H),3.92-3.88(m,5H),3.12-2.94(m,2H),2.68-2.52(m,4H),2.09-1.99(m,8H),1.86-1.79(m,2H),1.43-1.22(m,10H).

Example 399: (S) -2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-fluoro-6-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one (145)

(a) (S) - ((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To tert-butyl (S) - ((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (example 95, step a) (200 mg,282 umol) and 2, 6-diazaspiro [ 3.4)]A mixture of octan-7-one (71 mg,563 umol) in dichloromethane/methanol (2:1, 9 mL) was added sodium acetate (69 mg,845 umol) and sodium triacetoxyborohydride (178 mg,845 umol) followed by N ₂ The mixture was stirred at room temperature for 3 hours. The mixture was filtered, the filtrate concentrated and passed through normal phase SiO ₂ Chromatography (100% ethyl acetate/petroleum ether) purification of the residue to afford (S) - ((6- (2-chloro)) as a white solid-3- (3-chloro-2- (3-fluoro-5-methoxy-4- ((7-oxo-2, 6-diazaspiro [ 3.4)]Octan-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (155 mg,32% yield). MS: m/z found 819[ M+H ]] ⁺ .

(b) (S) -2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-fluoro-6-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one

At N ₂ (S) - ((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4 ]) was reacted at room temperature]A mixture of tert-butyl (5-oxopyrrolidin-2-yl) methyl) carbamate (150 mg, 0.183umol) in trifluoroacetic acid (50.6 mmol,3.75 mL) was stirred for 0.5 h. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford (S) -2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-fluoro-6-methoxybenzyl) -2, 6-diazaspiro [3.4] as a white solid (formate salt) ]Octan-7-one (101 mg,72% yield). MS: m/z found 719[ M+H ]] ⁺ Retention time = 2.58min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.67(d,1H),7.89(d,1H),7.73-7.68(m,1H),7.57(t,1H),7.50-7.45(m,2H),7.36(d,1H),7.24-7.21(m,2H),4.58(s,2H),4.34-4.33(m,5H),4.09-4.04(m,4H),4.01(s,3H),3.68(s,2H),3.25-3.22(m,2H),2.73(m,2H),2.43-2.33(m,4H),1.92-1.89(m,1H).

Example 400: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (146)

(a) (S) - ((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

To tert-butyl (S) - ((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (example 95, step a) (200 mg, 0.281mmol) and 2-azaspiro [ 3.3)]A mixture of heptane-6-ol (84.3 mg,0.563 mmol) in dichloromethane/MeOH (1:1, 6 mL) was added sodium acetate (115 mg,1.41 mmol) followed by N ₂ The mixture was stirred at room temperature for 3 hours. Sodium triacetoxyborohydride (178 mg,0.846 mmol) was then added and the mixture was taken up in N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was filtered, the filtrate concentrated and passed through normal phase SiO ₂ Chromatography (0 to 100% ethyl acetate/petroleum ether) purification of the residue to afford (S) - ((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((6-hydroxy-2-azaspiro [3.3 ]) as a white solid]Heptane-2-yl) methyl) -5-methoxyphenyl pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (155 mg,54% yield). MS: m/z found 806[ M+H ]] ⁺ .

(b) (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

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To (S) - ((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((6-hydroxy-2-azaspiro [3.3 ])]Heptane-2-yl) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridineA solution of tert-butyl (5-oxopyrrolidin-2-yl) methyl) carbamate (150 mg,185 mol) in dichloromethane (5 mL) was added trifluoroacetic acid (67.5 mmol,5 mL) and taken up in N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was then concentrated and the residue was purified by reverse phase HPLC to afford (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((6-hydroxy-2-azaspiro [3.3 ])) as a white solid (formate)) ]Heptane-2-yl) methyl) -5-methoxyphenyl pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) amino) methyl) pyrrolidin-2-one (88.5 mg,61% yield). MS: m/z found 706[ M+H ]] ⁺ Retention time = 2.75min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.67(d,1H),7.90(d,1H),7.72(dd,1H),7.57(t,1H),7.48(d,1H),7.45(dd,1H),7.37(d,1H),7.27(s,1H),7.21(dd,1H),4.50(s,2H),4.38-4.34(m,2H),4.21-4.14(m,5H),4.12(s,3H),4.07-4.05(m,1H),4.01(s,3H),3.25-3.21(m,2H),2.66-2.59(m,2H),2.43-2.37(m,3H),2.18-2.13(m,2H),1.92-1.89(m,1H).

Example 401: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- (((3-fluoropropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (147)

In a similar manner to example 400, 3-fluoropropane-1-amine hydrochloride was used in place of 2-azaspiro [3.3 ] in step (a)]Preparation of (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- (((3-fluoropropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (formate salt) from heptane-6-ol. MS: m/z found 670[ M+H ]] ⁺ Retention time = 2.79min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.68(d,1H),8.44(brs,1H),7.81(d,1H),7.74-7.70(m,1H),7.57(t,1H),7.50(d,1H),7.44-7.40(m,1H),7.31-7.26(m,2H),7.21(d,1H),4.65(t,1H),4.53(t,1H),4.35(s,2H),4.05(s,3H),4.02(s,5H),3.97-3.89(m,1H),3.27-3.22(m,2H),2.96-2.82(m,2H),2.40-2.29(m,3H),2.22-2.07(m,2H),1.91-1.79(m,1H).

Example 402: (S) -5- ((((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (148)

In a similar manner to example 400, 1- (4-aminopiperidin-1-yl) ethan-1-one was used in place of 2-azaspiro [3.3 ] in step (a) ]Preparation of (S) -5- ((((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one from heptane-6-ol. MS: m/z found 735[ M+H ]] ⁺ Retention time = 2.72min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.64(d,1H),7.76-7.70(m,2H),7.55(t,1H),7.46(d,1H),7.40(dd,1H),7.25(d,1H),7.17(s,1H),7.11(d,1H),4.49(br d,1H),4.02(s,5H),3.96(s,3H),3.94-3.89(m,1H),3.89-3.78(m,3H),3.19-3.10(m,1H),2.85(br t,1H),2.76-2.62(m,3H),2.38-2.22(m,3H),2.13-1.98(m,5H),1.88-1.75(m,1H),1.48-1.22(m,2H).

Example 403: (S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((S) -oxetan-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (181)

In a similar manner to example 400, 2-azaspiro [3.3] was replaced in step (a) with (S) -oxetan-2-ylmethylamine]Preparation of ((S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((S) -oxetan-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (formate) MS: m/z found 680[ M+H] ⁺ Retention time = 2.68min (method a). ¹ H NMR ((400 MHz, methanol-d) ₄ ):δ.8.67(d,1H),8.39(s,2H),7.81(d,1H),7.73-7.71(m,1H),7.56(t,1H),7.49(d,1H),7.44-7.41(m,1H),7.30(d,1H),7.25(s,1H),7.21-7.18(m,1H),5.13-5.08(m,1H),4.76-4.71(m,1H),4.66-4.61(m,1H),4.37-4.30(m,2H),4.05-4.03(m,5H),4.01(s,3H),3.93(br s,1H),3.49-3.44(m,1H),3.25-3.21(m,1H),2.97-2.80(m,3H),2.56-2.49(m,1H),2.39-2.28(m,3H),1.91-1.82(m,1H).

Example 404: (S) -5- (((6- (3- (2- (4- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (210)

In a similar manner to example 400, 1- (6-amino-2-azaspiro [3.3 ] was used in step (a)]Heptan-2-yl) ethan-1-one hydrochloride instead of 2-azaspiro [3.3]Preparation of (S) -5- ((((6- (3- (2- (4- (((2-acetyl-2-azaspiro [ 3.3))]Heptane-6-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl-methyl) amino) methyl) pyrrolidin-2-one (formate salt). MS: m/z found 747[ M+H ]] ⁺ Retention time = 2.66min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.67(d,1H),8.38(brs,2H),7.81(d,1H),7.71(dd,1H),7.56(t,1H),7.49(d,1H),7.41(dd,1H),7.29(d,1H),7.25(s,1H),7.19(d,1H),4.27(s,1H),4.18(s,3H),4.06-3.98(m,9H),3.93(s,2H),3.77-3.73(m,1H),2.96-2.91(m,2H),2.70-2.62(m,2H),2.40-2.32(m,5H),1.84(d,1H).

Example 405:1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (285)

(a) 6- (2-chloro-3- (3-chloro-2- (3-fluoro-4-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde

Following suzuki coupling procedure a, 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (325 mg,0.83 mmol) and (3-fluoro-4-formyl-5-methoxyphenyl) boronic acid (163 mg,0.83 mmol) were provided in 90% yield from 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde. LCMS: m/z found 511.2[ M+H ] ] ⁺ Retention time = 1.08min (method B).

(b) 1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

Following reductive amination procedure a, starting from 6- (2-chloro-3- (3-chloro-2- (3-fluoro-4-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (50 mg,0.10 mmol) and 1- (4-amino-1-piperidinyl) ethanone (56 mg,0.39 mmol) afforded 1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one (formate) in 80% yield. LCMS: m/z found 763.3[ M+H ]] ⁺ Retention time = 1.82min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),8.53(s,2H),7.80(d,1H),7.72(d,1H),7.56(t,1H),7.48(d,1H),7.42(d,1H),7.29(d,1H),7.20(s,1H),7.14(d,1H),4.59–4.47(m,2H),4.12(s,2H),4.04(s,3H),4.02–3.93(m,7H),3.17(t,2H),3.07–2.96(m,2H),2.70(t,2H),2.19–2.00(m,10H),1.57–1.29(m,4H).

Example 406:1- (6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine (286)

Formate was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (3-fluoro-4-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (example 405, step (a)) (50 mg,0.10 mmol) and methylamine solution (33% wt in ethanol, 0.39 mmol) 1- (6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methylamine. Yield 76%. LCMS: m/z found 541.2[ M+H ] ] ⁺ Retention time = 1.79min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.68(d,1H),8.53(s,2H),7.85(d,1H),7.73(d,1H),7.58(t,1H),7.50(d,1H),7.45(dd,1H),7.34(d,1H),7.26(s,1H),7.20(d,1H),4.27(s,2H),4.17(s,2H),4.08(s,3H),4.01(s,3H),2.71(s,6H).

Example 407:2- ((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one (287)

Following reductive amination procedure a, starting from 6- (2-chloro-3- (3-chloro-2- (3-fluoro-4-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (example 405, step (a)) (50 mg,0.10 mmol) and 2, 6-diazaspiro [3.4]]Octan-7-one (49 mg,0.39 mmol) was prepared from 2- ((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy) -4- ((7-oxo-2, 6-diazaspiro [ 3.4)]Octane-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) -2, 6-diazaspiro [3.4]The preparation of formate from octane-7-ketone. Yield 56%. LCMS: m/z found 731.2[ M+H ]] ⁺ Retention time = 1.67min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.47(s,2H),7.72(t,2H),7.55(t,1H),7.47(d,1H),7.41(d,1H),7.27(d,1H),7.19(s,1H),7.13(d,1H),4.01(s,5H),3.95(s,3H),3.85(s,2H),3.66(s,4H),3.63–3.54(m,8H),2.63–2.54(m,4H).

Example 408: (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (cyclopropanecarbonyl) piperidin-4-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (cyclopropyl) methanone (316)

Formate was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (3-fluoro-4-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (example 405, step (a)) (25 mg,0.05 mmol) and (4-aminopiperidin-1-yl) (cyclopropyl) methanone (33 mg,0.20 mmol) with (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (cyclopropanecarbonyl) piperidin-4-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (cyclopropyl) methanone. 63% yield. LCMS: m/z found 815.3[ M+H ] ] ⁺ Retention time = 3.25min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.68–8.63(m,1H),8.55–8.49(m,2H),7.80(d,1H),7.72(d,1H),7.60–7.52(m,1H),7.50–7.46(m,1H),7.42(d,1H),7.28(d,1H),7.20(s,1H),7.13(d,1H),4.52(d,2H),4.39(d,2H),4.09(s,2H),4.04(s,3H),4.00–3.91(m,5H),3.26–3.16(m,2H),3.06–2.91(m,2H),2.82–2.66(m,2H),2.19–2.10(m,2H),2.09–2.02(m,2H),1.98(d,2H),1.53–1.41(m,2H),1.40–1.27(m,2H),0.89–0.76(m,8H).

Example 409:1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((1-propionylpiperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one (331)

Following reductive amination procedure a, starting from 6- (2-chloro-3- (3-chloro-2- (3-fluoro-4-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (actualEXAMPLE 405, step (a)) (25 mg,0.05 mmol) and 1- (4-aminopiperidin-1-yl) propan-1-one (31 mg,0.20 mmol) 1- (4- (((6- (2-chloro-3- (3-chloro-5-methoxy-4- (((1-propionylpiperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one was prepared as the formate salt. 83% yield. LCMS: m/z found 791.3[ M+H ]] ⁺ Retention time = 1.88min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.67(d,1H),8.49(s,2H),7.83(d,1H),7.72(d,1H),7.57(t,1H),7.49(d,1H),7.43(d,1H),7.31(d,1H),7.23(s,1H),7.17(d,1H),4.61(d,2H),4.22(s,2H),4.13–4.03(m,7H),4.00(s,3H),3.20–3.10(m,4H),2.70(t,2H),2.44(q,4H),2.23–2.08(m,4H),1.57–1.36(m,4H),1.12(t,6H).

Example 410:1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- (((1-isobutyrylpiperidin-4-yl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methylpropan-1-one (347)

Formate was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (3-fluoro-4-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (example 405, step (a)) (30 mg,0.06 mmol) and 1- (4-aminopiperidin-1-yl) -2-methylpropan-1-one (40 mg,0.23 mmol) with 1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- (((1-isobutyrylpiperidin-4-yl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methylpropan-1-one. 73% yield. LCMS: m/z found 819.4[ M+H ] ] ⁺ Retention time = 2.05min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.69–8.63(m,1H),8.50(s,2H),7.82(d,1H),7.71(d,1H),7.56(t,1H),7.47(d,1H),7.42(d,1H),7.30(d,1H),7.21(s,1H),7.15(d,1H),4.68–4.53(m,2H),4.21–4.10(m,4H),4.09–4.02(m,5H),3.98(s,3H),3.21–3.09(m,4H),3.02–2.92(m,2H),2.76–2.61(m,2H),2.24–2.05(m,4H),1.54–1.31(m,4H),1.16–0.98(m,12H).

Example 411: n- ((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine (348)

Formate was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (3-fluoro-4-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (example 405, step (a)) (30 mg,0.06 mmol) and tetrahydropyran-4-amine (24 mg,0.23 mmol) with N- ((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine. Yield 70%. LCMS: m/z found 681.2[ M+H ]] ⁺ Retention time = 1.83min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(dd,1H),8.55–8.50(m,2H),7.77(d,1H),7.71(d,1H),7.55(dd,1H),7.46(dt,1H),7.41(d,1H),7.26(d,1H),7.18(s,1H),7.11(d,1H),4.07–4.01(m,5H),4.00–3.97(m,2H),3.97–3.94(m,5H),3.92(s,2H),3.48–3.36(m,4H),2.93–2.82(m,2H),2.00–1.88(m,4H),1.57–1.44(m,4H).

Example 412:1, 1-Dioxid 4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) tetrahydro-2H-thiopyran (349)

Following reductive amination procedure a, 1-dioxido 4- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4-formyl-5-methoxyphenyl) pyridin-4-yl) methyl) -3-fluoro-5-methoxyphenyl) pyridin-4-yl) phenyl) was reacted with 6- (2-chloro-2- (3-chloro-2- (4- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) pyridin-4-yl) phenyl) from 6- (2-chloro-3- (3-chloro-2- (3-fluoro-4-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) (example 405, step (a)) (30 mg,0.06 mmol) and 1, 1-dioxido-2H-thiopyran (35 mg,0.23 mmol) 2-methoxypyridin-3-yl) methyl) amino) tetrahydro-2H-thiopyran. Yield 70%. LCMS: m/z found 777.2[ M+H ]] ⁺ Retention time = 1.70min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.68–8.61(m,1H),8.45(s,2H),7.79(d,1H),7.71(d,1H),7.55(td,1H),7.49–7.45(m,1H),7.41(d,1H),7.27(d,1H),7.18(s,1H),7.12(d,1H),4.03(s,5H),3.96(s,3H),3.90(s,2H),3.26–3.16(m,4H),3.16–3.03(m,4H),3.03–2.94(m,2H),2.38–2.26(m,4H),2.18–2.03(m,4H).

Example 413: (S) -5- (((6- (3- (2- (2- ((1R, 3S, 4S) -2-azabicyclo [2.2.1] heptan-3-yl) -1H-benzo [ d ] imidazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (152)

Following Suzuki coupling procedure A, a reaction is carried out from (1R, 3S, 4S) -3- (6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-benzo [ d ]]Imidazol-2-yl) -2-azabicyclo [2.2.1]Tert-butyl heptane-2-carboxylate (40 mg,0.09 mmol) and tert-butyl (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (54 mg,0.09 mmol) provide (1R, 3S, 4S) -3- (6- (4- (3- (5- (((tert-butoxycarbonyl) (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -1H-benzo [ d)]Imidazol-2-yl) -2-azabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester, LCMS: m/z found 868.3[ M+H ]] ⁺ It is deprotected and purified by a general Boc deprotection procedure to provide the final product as formate. 90% yield over two steps. LCMS: m/z found 668.2[ M+H ] ] ⁺ Retention time = 1.69min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.63(d,1H),8.50(s,2H),7.90(d,1H),7.76(d,1H),7.70(dd,2H),7.61–7.52(m,2H),7.43(dd,2H),7.27(d,1H),4.48(s,1H),4.08–3.95(m,4H),3.91–3.80(m,3H),2.95(s,1H),2.81–2.68(m,2H),2.40–2.21(m,3H),1.97–1.71(m,6H),1.61(d,1H).

Example 414: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (177)

(a) 2- ((3-bromophenyl) thio) ethane-1-amine

To a mixture of 3-bromothiophenol (2.7 ml,26.4 mmol) and 2-chloroethane-1-amine hydrochloride (6.8 g,58.2 mmol) in a THF/water mixture (1:1, 50 mL) was added sodium hydroxide (2.6 g,66.1 mmol) and the mixture was stirred at 80℃for 12 hours. The reaction was quenched with water (50 mL) and the mixture extracted with ethyl acetate (2×25 mL). The combined organic phases were washed with brine (2×25 mL), dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-50% MeOH in ethyl acetate) to afford 2- ((3-bromophenyl) thio) ethan-1-amine (6.1 g,99% yield) as a white solid. ¹ H NMR (400 MHz, methanol-d) ₄ ):δ7.66-7.65(m,1H),7.48-7.44(m,2H),7.32-7.30(m,1H),3.28-3.24(m,2H),3.16-3.11(m,2H).

(b) N- (2- ((3-bromophenyl) thio) ethyl) acetamide

To a mixture of 2- ((3-bromophenyl) thio) ethan-1-amine (3.6 g,15.7 mmol) in ethyl acetate (30 mL) was added acetic anhydride (1.8 mL,18.8 mmol) and triethylamine (3.3 mL,23.5 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (50 mL) and the mixture extracted with ethyl acetate (2×25 mL). The combined organic phases were washed with brine (2×25 mL), dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ Purification of the residue by chromatography (0-90% MeOH/ethyl acetate)To afford N- (2- ((3-bromophenyl) thio) ethyl) acetamide (2 g,47% yield) as a white solid. ¹ H NMR (400 MHz, methanol-d) ₄ ):δ7.56(s,1H),7.38-7.34(m,2H),7.24-7.22(m,1H),3.41-3.32(m,2H),3.10-3.07(m,2H)1.92(s,3H).

(c) 1- (8-bromo-2, 3-dihydrobenzo [ f ] [1,4] thiazepin-4 (5H) -yl) ethan-1-one

To a mixture of N- (2- ((3-bromophenyl) thio) ethyl) acetamide (2 g,7.29 mmol) in toluene (10 mL) was added paraformaldehyde (0.11 g,3.65 mmol), methanesulfonic acid (0.62 mL,8.75 mmol) and acetic anhydride (0.89 g,8.75 mmol) and at N ₂ The mixture was stirred at 70 °. Additional paraformaldehyde (0.55 g,18.2 mmol) was added and reacted under N ₂ The mixture was stirred at 100℃for 3 hours. The reaction was quenched with water (10 mL) and the mixture extracted with ethyl acetate (2×15 mL). The combined organic phases were washed with saturated aqueous brine solution (2×15 mL), dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ Chromatography (0-90% MeOH/ethyl acetate) of the residue to afford 1- (8-bromo-2, 3-dihydrobenzo [ f ] as a white solid][1,4]Thioazepine-4 (5H) -yl) ethan-1-one (0.85 g,41% yield). ¹ H NMR (400 MHz, chloroform-d): delta 7.67 (d, 1H), 7.42-7.40 (d, 1H), 7.13 (d, 1H), 4.62-4.59 (m, 2H), 4.04-3.92 (m, 2H), 2.83-2.81 (m, 2H), 1.84-1.81 (m, 3H).

(d) 1- (8-bromo-1, 1-dioxo-2, 3-dihydrobenzo [ f ] [1,4] thiazepin-4 (5H) -yl) ethan-1-one

To 1- (8-bromo-2, 3-dihydrobenzo [ f ]][1,4]A mixture of thiozepine-4 (5H) -yl) ethan-1-one (0.8 g,2.8 mmol) in formic acid (5 mL) and water (5 mL) was added hydrogen peroxide (2.3 mL,28 mmol) and the mixture was stirred at room temperature for 12H. To the mixture was added a saturated aqueous sodium sulfite solution (10 mL) and the mixture was extracted with ethyl acetate (2×10 mL). By usingThe combined organic phases were washed with brine (2×5 mL), dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ Chromatography (0-100% ethyl acetate/petroleum ether) of the residue to afford 1- (8-bromo-1, 1-dioxo-2, 3-dihydrobenzo [ f ] as a white solid][1,4]Thioazepine-4 (5H) -yl) ethan-1-one (0.35 g, 39%). MS: m/z found 318 and 320[ M+H ]] ⁺ .

(e) 1, 1-dioxido 8-bromo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepine

To 1- (8-bromo-1, 1-dioxo-2, 3-dihydrobenzo [ f ]][1,4]A mixture of the thiozepine-4 (5H) -yl) ethan-1-one (0.35 g,1.1 mmol) in ethanol (3 mL) was added to an aqueous HCl solution (12M, 8 mL) and the mixture was stirred at 100deg.C for 12 hours. To the mixture was added saturated aqueous sodium bicarbonate solution (50 mL) and the mixture was extracted with ethyl acetate (2×25 mL). The combined organic phases were washed with brine (2×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ Chromatography (0-100% ethyl acetate/petroleum ether) of the residue to afford 1, 1-dioxido 8-bromo-2, 3,4, 5-tetrahydrobenzo [ f ] as a white solid][1,4]Sulfur azepine (0.17 g, 56%). ¹ H NMR (400 MHz, chloroform-d): delta 8.13 (d, 1H), 7.58 (dd, 1H), 7.11 (d, 1H), 4.17 (s, 2H), 3.50-3.42 (m, 2H), 3.22-3.20 (m, 2H).

(f) 1, 1-Dioxid 8-bromo-2, 3-dihydrobenzo [ f ] [1,4] sulfadiazine-4 (5H) -carboxylic acid tert-butyl ester

To 1, 1-dioxide 8-bromo-2, 3,4, 5-tetrahydrobenzo [ f][1,4]A mixture of a thioazepine (0.4 g,1.45 mmol) in THF (5 mL) was added di-tert-butyl dicarbonate (0.41 g,1.88 mmol) and triethylamine (0.2 mL,1.45 mmol) and the mixture was stirred at room temperature for 0.5 h. The mixture was concentrated, then water (5 mL) and brine (5 mL) were added and the mixture was extracted with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. General purpose medicinePassing normal phase SiO ₂ Chromatography (0-15% ethyl acetate/petroleum ether) of the residue to afford 1, 1-dioxo 8-bromo-2, 3-dihydrobenzo [ f ] as a yellow solid][1,4]Thioazepine-4 (5H) -carboxylic acid tert-butyl ester (0.45 g, 82%). ¹ H NMR (400 MHz, chloroform-d): delta 8.16-8.13 (m, 1H), 7.63-7.61 (m, 1H), 7.36-7.18 (m, 1H), 4.61 (s, 2H), 4.03 (br s, 2H), 3.28-3.20 (m, 2H), 1.32 (s, 9H).

(g) 1, 1-Dioxid 8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2, 3-dihydrobenzo [ f ] [1,4] thiazepine-4 (5H) -carboxylic acid tert-butyl ester

To 1, 1-dioxido 8-bromo-2, 3-dihydrobenzo [ f][1,4]A mixture of a thioazepine-4 (5H) -carboxylic acid tert-butyl ester (0.42 g,1.12 mmol) and bis (pinacolato) diborane (0.43 g,1.67 mmol) in 1, 4-dioxane (8 mL) was added [1,1' -bis (biphenylphosphino) ferrocene]Palladium (II) dichloride complex with dichloromethane (0.04 g,0.04 mmol) and potassium acetate (0.33 g,3.35 mmol) and the mixture was stirred at 110 ℃ for 6 hours. The mixture was concentrated and passed through normal phase SiO ₂ Chromatography (0-20% ethyl acetate/petroleum ether) of the residue to afford 1, 1-dioxo 8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2, 3-dihydrobenzo [ f ] as a white solid][1,4]Thioazepine-4 (5H) -carboxylic acid tert-butyl ester (0.45 g, 95%). ¹ H NMR (400 MHz, chloroform-d): delta 8.44-8.43 (m, 1H), 7.90 (d, 1H), 7.48-7.19 (m, 1H), 4.66 (s, 2H), 4.04 (br s, 2H), 3.25-3.18 (m, 2H), 1.30-1.27 (m, 21H).

(h) (S) -1, 1-Dioxid 8- (4- (3- (5- (((tert-Butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2, 3-dihydrobenzo [ f ] [1,4] thiazepine-4 (5H) -carboxylic acid tert-butyl ester

To 1, 1-Dioxid 8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2, 3-dihydrobenzo [ f][1,4]Sulfur azepine-4 (5H) A mixture of tert-butyl carboxylate (0.2 g,0.47 mmol) and tert-butyl (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (0.2 g,0.34 mmol) in 1, 4-dioxane/water (10:1, 5.5 mL) was added potassium phosphate (0.22 g,1.01 mmol) and [1,1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) dichloride (0.02 g,0.03 mmol) and the mixture was stirred at 110℃for 16 hours. The mixture was concentrated, water (5 mL) and brine (5 mL) were added and the mixture was extracted with an ethyl acetate/THF mixture (1:1, 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (silica gel, ethyl acetate: meoh=10:1) to afford (S) -1, 1-dioxo 8- (4- (3- (5- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2, 3-dihydrobenzo [ f) as a pale yellow solid][1,4]Thioazepine-4 (5H) -carboxylic acid tert-butyl ester (0.2 g, 54%). MS: m/z found 852[ M+H ]] ⁺ .

(i) (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] sulfan-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

To (S) -1, 1-dioxo 8- (4- (3- (5- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2, 3-dihydrobenzo [ f][1,4]A mixture of the thioazepine-4 (5H) -carboxylic acid tert-butyl ester (0.2 g,0.23 mmol) in methylene chloride (0.5 mL) was added trifluoroacetic acid (2 mL,27 mmol) and the mixture stirred at room temperature for 15 min. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f)) as a white solid (formate))][1,4]Thioazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl-methyl) amino-methyl) pyrrolidin-2-one (73.2 mg, 44%). MS: m/z found 652[ M+H ]] ⁺ Retention time = 2.53min (method a). ¹ H NMR(400MHz,MeOD):δ8.72(d,1H),8.42(d,1H),8.08(dd,1H),7.93(d,1H),7.77-7.72(m,2H),7.61(t,1H),7.52-7.48(m,2H),7.40(d,1H),4.57(s,2H),4.39-4.30(m,2H),4.12-4.05(m,4H),3.71-3.70(m,2H),3.61-3.60(m,2H),3.31-3.22(m,2H),2.48-2.34(m,3H),1.99-1.88(m,1H).

Example 415: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4-methyl-1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (561)

(a) 1, 1-Dioxo 8- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2, 3-dihydrobenzo [ f ] [1,4] thiazepine-4 (5H) -carboxylic acid tert-butyl ester

To 1, 1-Dioxid 8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2, 3-dihydrobenzo [ f ][1,4]A mixture of sulfan-4 (5H) -carboxylic acid tert-butyl ester (example 414, step (g) (2.9 g,6.86 mmol) and 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (1.5 g,3.81 mmol) in water (6 mL) and toluene (36 mL) was added potassium phosphate (2.43 g,11.4 mmol) and chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl)]Palladium (II) (0.24 g,0.31 mmol) and the mixture was stirred at 100deg.C for 1 hour. To the mixture was added water (200 mL) and the mixture was extracted with ethyl acetate (2 x100 mL). The combined organic phases were washed with brine (2×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ Chromatography (0-30% ethyl acetate/petroleum ether) of the residue to afford 1, 1-dioxo 8- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2, 3-dihydrobenzo [ f][1,4]Thioazepine-4 (5H) -carboxylic acid tert-butyl ester (1.6 g, 56%). ¹ H NMR (400 MHz, chloroform-d): delta 10.36 (s, 1H), 8.63 (m, 1H), 8.45-8.42 (m, 1H), 8.14 (d, 1H), 7.96-7.93(m,1H),7.67(d,1H),7.45(m,2H),7.35-7.34(m,1H),7.31-7.29(m,2H),4.74(s,2H),4.07(s,3H),3.31-3.30(m,2H),1.72-1.70(m,2H),1.17(s,9H).

(b) 6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] sulfazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde

To 1, 1-dioxo 8- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2, 3-dihydrobenzo [ f ][1,4]A mixture of the thioazepine-4 (5H) -carboxylic acid tert-butyl ester (1.6 g,2.44 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (10 mL,135 mmol) and the mixture was stirred at room temperature for 12 hours. To the mixture was added aqueous HCl solution (12 m,3 ml) and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated and saturated aqueous sodium carbonate (50 mL) was added to the residue. The mixture was extracted with ethyl acetate (2×25 mL). The combined organic phases were washed with brine (2×5 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford 6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ])][1,4]Thioazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (1 g,56% yield). MS: m/z observed values 554 and 556[ M+H ]] ⁺ .

(c) 1, 1-dioxo 8- (3-chloro-4- (2-chloro-3- (5- (hydroxymethyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -4-methyl-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepine

To 6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f)][1,4]A mixture of thiozepine-8-yl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (0.25 g,0.45 mmol) in THF (3 mL) was added paraformaldehyde (0.03 g,0.9 mmol) and sodium acetate (0.11 g,1.35 mmol) and the mixture stirred at room temperature for 12 h. Sodium triacetoxyborohydride (0.38 g,1.8 mmol) was added and the mixture was stirred at room temperature for 1 hour. Into the mixture Water (5 mL) was added and the mixture extracted with ethyl acetate (2X 5 mL). The combined organic phases were washed with brine (2×5 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (silica gel, ethyl acetate: meoh=5:1) to afford 8- (3-chloro-4- (2-chloro-3- (5- (hydroxymethyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -4-methyl-2, 3,4, 5-tetrahydrobenzo [ f ] as a white solid][1,4]Sulfur azepine 1, 1-dioxide (0.18 g, 55%). MS: m/z found 570[ M+H ]] ⁺ .

(d) 6- (2-chloro-3- (3-chloro-2- (4-methyl-1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde

To 8- (3-chloro-4- (2-chloro-3- (5- (hydroxymethyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -4-methyl-2, 3,4, 5-tetrahydrobenzo [ f][1,4]A mixture of the thioazepine 1, 1-dioxide (0.18 g,0.32 mmol) in methylene chloride (2 mL) was added to the dess-Martin periodate (0.27 g,0.63 mmol) and the mixture was stirred at room temperature for 12 hours. The mixture was filtered, the filtrate was concentrated, and the residue was purified by preparative TLC (silica gel, ethyl acetate: meoh=10:1) to afford 6- (2-chloro-3- (3-chloro-2- (4-methyl-1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f) as a white solid][1,4]Thioazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (0.11 g, 46%). ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.32(s,1H),8.78(d,1H),8.24(d,2H),8.06(dd,1H),7.80(dd,1H),7.68-7.61(m,4H),7.51(d,1H),4.28-4.24(m,2H),4.08(s,3H),3.59-3.56(m,2H),3.35-3.34(m,2H),2.20(s,3H).

(e) (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4-methyl-1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

To 6- (2-chloro-3- (3-chloro-2- (4-methyl)-1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f][1,4]A mixture of sulfan-8-yl pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (0.14 g,0.25 mmol) and (S) -5- (aminomethyl) -2-pyrrolidone hydrochloride (0.06 g,0.37 mmol) in methanol (3 mL) was added sodium acetate (0.08 g,0.99 mmol) and the mixture stirred at room temperature for 12 hours. Sodium cyanoborohydride (0.05 g,0.74 mmol) was added and the mixture was stirred at room temperature for 1 hour. The mixture was filtered, the filtrate was concentrated and the residue was purified by reverse phase HPLC to afford (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4-methyl-1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f)) as a white solid (formate salt)][1,4]Thiozepine-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) amino) methyl) pyrrolidin-2-one (0.04 g, 24%). MS: m/z found 666[ M+H ]] ⁺ Retention time = 2.54min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.62(d,1H),8.28(d,1H),7.94(dd,1H),7.73(d,1H),7.66(dd,1H),7.57(d,1H),7.50(t,1H),7.43-7.37(m,2H),7.23(d,1H),4.40-4.16(m,2H),3.98(s,3H),3.95-3.80(m,3H),3.45-3.42(m,4H),2.84-2.75(m,2H),2.33-2.24(m,6H),1.81-1.76(m,1H).

Example 416: (S) -5- (((6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-4- (((S) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] sulfan-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one (582)

(a) (S) -6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-4- ((5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde

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To 6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f)][1,4]Thioazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (example 415, step (b)) (0.27 g,487 mmol) and methanesulfonic acid (S)) A mixture of- (5-oxopyrrolidin-2-yl) methyl ester (0.28 g,1.46 mmol) in acetonitrile (6 mL) was added potassium carbonate (0.27 g,1.95 mmol) and the mixture was stirred at 100℃for 12 hours. The mixture was filtered, the filtrate concentrated and passed through normal phase SiO ₂ Chromatography (0-10% MeOH in ethyl acetate) purification of the residue afforded (S) -6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-4- ((5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydrobenzo [ f) as a yellow oil][1,4]Thioazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (0.15 g, 23%). MS: m/z found m/z 651[ M+H ]] ⁺ .

(b) (S) -5- (((6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-4- (((S) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] sulfan-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

To (S) -6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-4- ((5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydrobenzo [ f)][1,4]A mixture of sulfan-8-yl pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (0.14 g,215 mmol) and (S) -5- (aminomethyl) -2-pyrrolidone hydrochloride (0.05 g,0.32 mmol) in MeOH (4 mL) was added sodium acetate (0.05 g,0.64 mmol) and the mixture stirred at room temperature for 12 hours. Sodium cyanoborohydride (0.04 g,0.64 mmol) was added and the mixture was stirred at room temperature for 1 hour. The mixture was filtered, the filtrate was concentrated and the residue was purified by reverse phase HPLC to afford (S) -5- (((6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-4- (((S) -5-oxopyrrolidin-2-yl)) methyl) -2,3,4, 5-tetrahydrobenzo [ f) as a white solid][1,4]Thioazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl-methyl) amino-methyl) pyrrolidin-2-one (12.3 mg, 8%). MS: m/z found 749[ M+H ]] ⁺ Retention time = 3.01min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.30(d,1H),7.94(dd,1H),7.79-7.75(m,1H),7.68-7.66(m,1H),7.57(d,1H),7.52(t,1H),7.43-7.39(m,2H),7.29-7.24(m,1H),4.46-4.36(m,2H),4.05-4.01(m,5H),3.90-3.85(m,2H),3.56-3.54(m,2H),3.43-3.37(m,2H),2.95-2.93(m,2H),2.45-2.27(m,7H),2.19-2.13(m,1H),1.86-1.81(m,1H),1.68-1.66(m,1H).

Example 417: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((S) -2-hydroxypropyl) -1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (611)

(a) (S) -6- (2-chloro-3- (3-chloro-2- (4- (2-hydroxypropyl) -1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde

To 6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ]) in a sealed tube][1,4]A mixture of sulfan-8-yl pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (example 415, step (b)) (150 mg,0.27 mmol) and triethylamine (151 uL,1.08 mmol) in dichloromethane/DMA (1:1, 1 mL) was added benzenesulfonic acid (S) -2-hydroxypropyl 4-methyl ester (249 mg,1.08 mmol) and the mixture was stirred at 90℃for 12 hours. The mixture was diluted with brine (20 mL) and extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ Chromatography (0-100% EtOAc/petroleum ether) of the residue afforded (S) -6- (2-chloro-3- (3-chloro-2- (4- (2-hydroxypropyl) -1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f) as a pale yellow solid][1,4]Thioazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (135 mg, 34%). MS: m/z measured values 612 and 614[ M+H ]] ⁺ . ¹ H NMR (400 MHz, chloroform-d): delta 10.36 (s, 1H), 8.62 (d, 1H), 8.45 (d, 1H), 8.14 (d, 1H), 7.92 (d, 1H), 7.67 (dd, 1H), 7.43 (t, 1H), 7.35 (d, 1H), 7.30 (dd, 1H), 7.25 (d, 1H), 4.07 (s, 3H), 3.98 (br s, 1H), 3.31-3.23 (m, 2H), 2.95 (s, 2H), 2.87 (s, 1H), 2.37 (d, 1H), 2.08 (d, 1H), 1.03-1.01 (m, 3H).

(b) (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((S) -2-hydroxypropyl) -1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

To (S) -6- (2-chloro-3- (3-chloro-2- (4- (2-hydroxypropyl) -1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f)][1,4]A mixture of sulfan-8-yl pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (130 mg,0.21 mmol) in MeOH/dichloromethane (6 ml, 1/1) was added (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride (48 mg,0.32 mmol) and sodium acetate (87 mg,1.06 mmol) and the mixture stirred at room temperature for 2 hours. Sodium cyanoborohydride (26 mg,0.42 mmol) was added and the mixture was stirred for an additional 10 hours. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC to afford (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((S) -2-hydroxypropyl) -1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f)) as a white solid (formate salt)][1,4]Thioazepine-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) amino) methyl) pyrrolidin-2-one (66 mg,41% yield). MS: m/z found 710 and 712[ M+H ]] ⁺ Retention time = 2.63min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.70(d,1H),8.37(d,1H),8.00(dd,1H),7.80(d,1H),7.74(dd,1H),7.62-7.56(m,2H),7.50(d,1H),7.46(d,1H),7.31(d,1H),4.44(br s,2H),4.06(s,3H),4.02-3.92(m,4H),3.65-3.64(m,2H),3.50-3.45(m,2H),2.87-2.84(m,2H),2.42-2.33(m,5H),1.89-1.84(m,1H),1.11(d,3H).

Example 418:5- (3-chloro-4- (2-chloro-3- (5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one (142)

(a) 5-bromo-2- (2, 2-dimethoxyethyl) isoindolin-1-one

At N ₂ To a mixture of methyl 4-bromo-2- (bromomethyl) benzoate (3 g,9.74 mmol) in methanol (60 mL) was added 2, 2-dimethoxyethylamine (5.31 mL,48.7 mmol) in one portion. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated. To the residue were added water (30 mL) and a saturated aqueous brine solution (30 mL). The mixture was extracted with ethyl acetate/THF mixture (1:1, 100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-50% ethyl acetate/petroleum ether) to afford 5-bromo-2- (2, 2-dimethoxyethyl) isoindolin-1-one (2.7 g,92% yield) as a white solid.

(b) 2- (5-bromo-1-oxoisoindolin-2-yl) acetaldehyde

To a mixture of 5-bromo-2- (2, 2-dimethoxyethyl) isoindolin-1-one (1.3 g,4.33 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (6.50 mL,87.8 mmol) and water (1 mL) in one portion. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated directly under vacuum to provide 2- (5-bromo-1-oxoisoindolin-2-yl) acetaldehyde trifluoroacetate as a yellow oil (1.8 g) which was used in the next step without further purification.

(c) (S) -5-bromo-2- (2- (((5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one

To a mixture of 2- (5-bromo-1-oxoisoindolin-2-yl) acetaldehyde (1.8 g,7.08 mmol) in dichloromethane/methanol (1:1, 40 mL) was added triethylamine (9.86 mL,70.8 mmol), followed by (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride (1.07 g,7.08 mmol) and sodium cyanoborohydride (1.34 g,21.2 mmol). The mixture was stirred at room temperature for 12 hours. A crude pale yellow suspension of (S) -5-bromo-2- (2- (((5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one (2.5 g) in dichloromethane/methanol (1:40 mL) was used in the next step.

(d) (S) - (2- (5-bromo-1-oxoisoindolin-2-yl) ethyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To a solution of crude (S) -5-bromo-2- (2- (((5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one (2.5 g,7.10 mmol) in dichloromethane/methanol (1:1 40 mL) was added di-tert-butyl dicarbonate (3.10 g,14.2 mmol) and the reaction stirred at room temperature for 2 hours. The mixture was concentrated under vacuum, water (30 mL) was added and the mixture extracted with THF/ethyl acetate (1/3, 100 mL), dried over anhydrous sodium sulfate and filtered. Concentrating the filtrate and passing through normal phase SiO ₂ The residue was purified by chromatography (0-100% ethyl acetate/petroleum ether to 0-20% methanol/ethyl acetate) to give tert-butyl (S) - (2- (5-bromo-1-oxoisoindolin-2-yl) ethyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (1.5 g,44% yield) as pale yellow oil.

(e) (S) - (2- (1-oxo-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) isoindolin-2-yl) ethyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To a mixture of tert-butyl (S) - (2- (5-bromo-1-oxoisoindolin-2-yl) ethyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (1 g,2.21 mmol) and bis (pinacolato) diborane (1.68 g,6.63 mmol) in 1, 4-dioxane (20 mL) was added potassium acetate (404 mg,4.42 mmol) followed by [1,1' -bis (biphenylphosphino) ferrocene]Palladium (II) dichloride complex with dichloromethane (181 mg,0.22 mmol). The reaction was stirred at 130℃for 3 hours. After cooling, the mixture was filtered and washed with ethyl acetate (100 mL). Under reduced pressureThe filtrate was concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-100% ethyl acetate/petroleum ether to 0-20% methanol/ethyl acetate) to afford tert-butyl (S) - (2- (1-oxo-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl) ethyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (0.41 g,37% yield) as an orange solid. ¹ H NMR (400 MHz, methanol-d) ₄ ):δ7.93(s,1H),7.90-7.84(m,1H),7.81-7.73(m,1H),4.61(d,2H),3.98(s,1H),3.82(s,2H),3.68-3.57(m,2H),3.37(s,2H),2.40-2.24(m,3H),1.84(br,1H),1.39(s,12H),1.22(s,9H).

(f) (S) - (2- (5- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1-oxoisoindolin-2-yl) ethyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To a mixture of 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (100 mg,0.25 mmol) and tert-butyl (5-oxopyrrolidin-2-yl) ethyl) (5-oxopyrrolidin-2-yl) carbamate (178 mg,0.36 mmol) in THF/water (5/1, 6 ml) was added followed by [1,1' -bis (di-tert-butylphosphino) ferrocene ] dichloropalladium (II) (16.6 mg,0.03 mmol) and the reaction was stirred at 85 ℃ for 12 hours. After cooling, water (10 mL) was added and the mixture was extracted with ethyl acetate (200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (20% methanol/ethyl acetate) to give tert-butyl (S) - (2- (5- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1-oxoisoindolin-2-yl) ethyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (0.06 g,24% yield) as a white solid.

(g) (2- (5- (3-chloro-4- (2-chloro-3- (5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1-oxoisoindolin-2-yl) ethyl) carbamic acid tert-butyl ester (((S) -5-oxopyrrolidin-2-yl) methyl)

To a mixture of tert-butyl (S) - (2- (5- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1-oxoisoindolin-2-yl) ethyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (53 mg,0.07 mmol) in dichloromethane/methanol (1/1, 4 mL) was added sodium acetate (17.9 mg,0.22 mmol) and (S) -1-aminopropane-2-ol (6.54 mg,0.09 mmol). The mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (13.7 mg,0.22 mmol) was then added and the mixture was stirred for an additional 13 hours. The mixture was concentrated under reduced pressure to provide tert-butyl (2- (5- (3-chloro-4- (2-chloro-3- (5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1-oxoisoindolin-2-yl) ethyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (63 mg) as a yellow solid, which was used in the next step without further purification.

(h) 5- (3-chloro-4- (2-chloro-3- (5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one

To a mixture of tert-butyl (2- (5- (3-chloro-4- (2-chloro-3- (5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1-oxoisoindolin-2-yl) ethyl) ((((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (63 mg,0.08 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL,13.5 mmol) and the mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC to provide 5- (3-chloro-4- (2-chloro-3- (5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one as a white solid (formate salt) 16mg,26% yield). MS: m/z found 689[ M+H ]] ⁺ Retention time 2.54min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.67(d,1H),8.45(br s,1H),7.91-7.80(m,4H),7.72(dd,1H),7.57(t,1H),7.48-7.44(m,2H),7.35(d,1H),4.67(s,2H),4.24(s,2H),4.08-4.04(m,4H),3.83-3.78(m,3H),3.06-3.02(m,3H),2.87-2.76(m,3H),2.34-2.25(m,3H),1.82-1.80(m,1H),1.23(d,3H).

Example 419: (S) -5- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (2- (((5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one (143)

(S) -5- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (2- (((5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one (27.3 mg,20% yield) was prepared in analogy to example 418 using (S) - (tert-butyl 2- (5- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1-oxoisoindolin-2-yl) ethyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid and 1- (4-aminopiperidin-1-yl) ethanone. MS: m/z measured values 756 and 758[ M+H ]] ⁺ Retention time = 2.57min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.70(d,1H),8.37(br s,1H),7.94-7.90(m,3H),7.85(dd,1H),7.74(dd,1H),7.60(t,1H),7.51-7.47(m,2H),7.38(d,1H),4.71(s,2H),4.66(s,1H),4.28(s,2H),4.11(s,3H),4.08(s,1H),3.92-3.87(m,3H),3.43-3.33(m,1H),3.18-3.15(m,3H),2.96-2.92(m,2H),2.73-2.70(m,1H),2.39-2.21(m,5H),2.15(s,3H),1.89-1.84(m,1H),1.66-1.51(m,2H).

Example 420: (S) -5- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (2- (((5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one (144)

In a similar manner to example 418, tert-butyl (S) - (2- (5- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1-oxoisoindolin-2-yl) ethyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate and 1- (2, 6-diazaspiro [ 3.3)]Preparation of (S) -5- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3 ]) by heptan-2-yl) ethanone trifluoroacetate salt]Heptane-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (2- (((5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one (17.6 mg,12% yield). MS: m/z found 754 and 756[ M+H ]] ⁺ Retention time=2.48 (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.70(d,1H),8.32(br s,2H),7.95-7.92(m,2H),7.86-7.81(m,2H),7.74(dd,1H),7.60(t,1H),7.50(d,1H),7.47(dd,1H),7.34(d,1H),4.71(s,2H),4.38(s,2H),4.14(d,4H),4.07(s,3H),4.05(s,4H),3.94-3.91(m,3H),3.24-3.22(m,2H),3.02-3.00(m,2H),2.41-2.32(m,3H),1.91-1.87(m,4H).

Example 421:5- (3-chloro-4- (2-chloro-3- (4-fluoro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one (178)

(a) 6- (3-bromo-2-chlorophenyl) -4-fluoro-2-methoxy nicotinaldehyde

To a solution of 2- (3-bromo-2-chlorophenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (4 g,12.7 mmol), 6-chloro-4-fluoro-2-methoxynicotinaldehyde (3 g,15.8 mmol) and potassium carbonate (4.37 g,31.7 mmol) in a 1, 4-dioxane/water mixture (6:1, 35 mL) was added tetrakis (triphenylphosphine) palladium (0) (0.9 g,0.8 mmol) and under N ₂ Under the atmosphere at 95 DEG CThe mixture was stirred for 1 hour. To the mixture was added water (50 mL) and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated aqueous brine solution (2×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-2% ethyl acetate/petroleum ether) to afford 6- (3-bromo-2-chlorophenyl) -4-fluoro-2-methoxynicotinaldehyde as a yellow solid (3.3 g,58% yield). MS: m/z found 344[ M+H ]] ⁺ .

(b) 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -4-fluoro-2-methoxynicotinaldehyde

At N ₂ To 6- (3-bromo-2-chlorophenyl) -4-fluoro-2-methoxynicotinaldehyde (2.3 g,6.62 mmol) in 1, 4-dioxane/H under an atmosphere ₂ A mixture of potassium carbonate (2.74 g,19.9 mmol) and [1,1' -bis (biphenylphosphino) ferrocene were added in one portion to a mixture of O mixtures (6:1, 14 mL)]Palladium (II) dichloride complex with dichloromethane (0.27 g,0.33 mmol). (2, 3-dichloropyridin-4-yl) boronic acid (1.27 g,6.62 mmol) in 1, 4-dioxane (8 mL) was added dropwise to the mixture at 95℃for 2 hours. To the mixture was added water (5 mL) and the mixture was extracted with ethyl acetate (2×5 mL). The combined organic phases were washed with saturated aqueous brine solution (2×5 mL), dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-30% ethyl acetate/petroleum ether) to afford 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -4-fluoro-2-methoxynicotinaldehyde as a yellow oil (1.25 g,45% yield). MS: m/z measured values 411 and 413[ M+H ]] ⁺ .

(c) (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

6- (2-chloro-3- (2, 3-dichloropyridine) -4) at room temperatureA solution of phenyl) -4-fluoro-2-methoxynicotinaldehyde (1.28 g,3.11 mmol), (S) -5- (aminomethyl) -2-pyrrolidone hydrochloride (0.7 g,4.66 mmol) and sodium acetate (0.89 g,10.9 mmol) in a dichloromethane/MeOH mixture (1:1, 20 mL) and trimethyl orthoformate (3 mL) was stirred for 12 h. Sodium cyanoborohydride (0.59 g,9.33 mmol) was then added and the mixture was stirred at room temperature for 0.5h to afford (S) -5- ((((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (observed MS: m/z found 509 and 511[ M+H ])] ⁺ )。

Di-tert-butyl dicarbonate (1.8 ml,7.65 mmol) and triethylamine (0.64 ml,4.59 mmol) were then added and the mixture was stirred at room temperature for 20 minutes. To the mixture was added water (5 mL) and the mixture was extracted with ethyl acetate (2×5 mL). The combined organic phases were washed with saturated aqueous brine solution (2×5 mL), dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-100% ethyl acetate/petroleum ether) to give tert-butyl (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (1.5 g, two steps 80% yield) as a yellow solid. (MS: m/z found 609[ M+H ]] ⁺ .

(d) (6- (3- (2- (2- (2- ((tert-Butoxycarbonyl) ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) -1-oxoisoindolin-5-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) ((((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

At N ₂ To tert-butyl (S) - (2- (1-oxo-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) isoindolin-2-yl) ethyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (example 418, step (e)) (0.1 g,0.2 mmol) and tert-butyl (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (0.11 g,0.18 mmol) under an atmosphereA mixture of 1, 4-dioxane/water mixture (7.5:1, 3.4 mL) was added potassium carbonate (0.07 g,0.54 mmol) and [1,1' -bis (biphenylphosphino) ferrocene at one time]Palladium (II) dichloride complex with dichloromethane (15 mg,18 umol) and the mixture was stirred at 110 ℃ for 3 hours. The mixture was concentrated. To the residue were added water (5 mL) and a saturated aqueous brine solution (5 mL). The mixture was extracted with ethyl acetate/THF mixture (1:1, 10 ml), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (silica gel, ethyl acetate: meoh=4:1) to afford tert-butyl ((6- (3- (2- (2- ((tert-butoxycarbonyl) (((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) -1-oxoisoindolin-5-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamate as a yellow solid (0.06 g,40% yield). MS: m/z found 946[ M+H ] ] ⁺ .

(e) 5- (3-chloro-4- (2-chloro-3- (4-fluoro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one

To a mixture of ((6- (3- (2- (2- (2- ((tert-butoxycarbonyl) (((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) -1-oxoisoindolin-5-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (57 mg,0.06 mmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (1.5 mL,20 mmol) at one time and the mixture was stirred at room temperature for 15 minutes. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 5- (3-chloro-4- (2-chloro-3- (4-fluoro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one (7.3 mg,15% yield) as a pale yellow solid (formate). MS: m/z found 746[ M+H ]] ⁺ Retention time = 2.48min (squareMethod a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.70(d,1H),7.95-7.92(m,2H),7.85(d,1H),7.76(dd,1H),7.60(t,1H),7.51-7.47(m,2H),7.19(d,1H),4.71(s,2H),4.09(s,3H),4.02(s,2H),3.94-3.88(m,4H),3.23-3.22(m,2H),3.03-2.96(m,2H),2.86-2.81(m,2H),2.43-2.31(m,6H),1.91-1.80(m,2H).

Example 422:5- (3-chloro-4- (2-chloro-3 '-fluoro-5' -methoxy-4 '- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,1' -biphenyl ] -3-yl) pyridin-2-yl) -2- (2- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one (242)

(a) 3' -bromo-2 ' -chloro-3-fluoro-5-methoxy- [1,1' -biphenyl ] -4-carbaldehyde

To a mixture of 2- (3-bromo-2-chlorophenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (2.7 g,8.5 mmol) and 4-bromo-2-fluoro-6-methoxybenzaldehyde (1.8 g,7.7 mmol) in a 1, 4-dioxane/water mixture (6:1, 60 mL) was added potassium carbonate (3.2 g,23 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.4 g,0.3 mmol) and the mixture was stirred at 95℃for 3 hours. The mixture was concentrated, water (20 mL) was added to the residue, and the mixture was extracted with EtOAc (2×40 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ Chromatography (0-10% EtOAc/petroleum ether) of the residue afforded 3' -bromo-2 ' -chloro-3-fluoro-5-methoxy- [1,1' -biphenyl as a yellow solid]-4-Formaldehyde (2.1 g,79% yield). ¹ H NMR(400MHz,CDCl ₃ ):δ10.39(s,1H),7.64-7.62(m,1H),7.20-7.14(m,2H),6.73-6.69(m,2H),3.89(s,3H).

(b) 2' -chloro-3 ' - (2, 3-dichloropyridin-4-yl) -3-fluoro-5-methoxy- [1,1' -biphenyl ] -4-carbaldehyde

At N ₂ Downward 3' -bromo-2 ' -chloro-3-fluoro-5-methoxy- [1,1' -biphenyl]A mixture of 4-formaldehyde (1.5 g,4.4 mmol) in a 1, 4-dioxane/water mixture (6:1, 18 mL) was added at once potassium carbonate (1.8 g,13 mmol) and [1,1' -bis (biphenylphosphino) ferrocene]Palladium (II) dichloride complex with dichloromethane (0.2 g,0.22 mmol). (2, 3-dichloropyridin-4-yl) boronic acid (0.9 g,4.8 mmol) in 1, 4-dioxane (10 mL) was added dropwise to the mixture at 95℃for 4 hours. The mixture was concentrated. To the residue was added water (5 mL) and the mixture was extracted with EtOAc (2×5 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ Chromatography (20-25% etoac/petroleum ether) of the residue afforded 2' -chloro-3 ' - (2, 3-dichloropyridin-4-yl) -3-fluoro-5-methoxy- [1,1' -biphenyl) as a yellow solid]-4-Formaldehyde (0.6 g,33% yield). MS: m/z measured values 410 and 412[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.35(s,1H),8.54(d,1H),7.64-7.63(m,2H),7.58-7.55(m,2H),7.15(s,1H),7.07-7.04(d,1H),3.99(s,3H).

(c) (S) - ((2 ' -chloro-3 ' - (2, 3-dichloropyridin-4-yl) -3-fluoro-5-methoxy- [1,1' -biphenyl ] -4-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

2' -chloro-3 ' - (2, 3-dichloropyridin-4-yl) -3-fluoro-5-methoxy- [1,1' -biphenyl ] at room temperature]A mixture of 4-formaldehyde (0.9 g,2.2 mmol), (S) -5- (aminomethyl) -2-pyrrolidone hydrochloride (0.4 g,2.6 mmol) and sodium acetate (0.54 g,6.6 mmol) in dichloromethane (30 mL) and trimethyl orthoformate (3 mL) was stirred for 12 hours. Sodium triacetoxyborohydride (0.93 g,4.4 mmol) was then added and the mixture stirred at room temperature for 0.5 hours to afford (S) -5- ((((2 ' -chloro-3 ' - (2, 3-dichloropyridin-4-yl) -3-fluoro-5-methoxy- [1,1' -biphenyl) for 0.5 hours]-4-yl-methyl) amino) methyl) pyrrolidin-2-one (MS: m/z found 508 and 510[ M+H ]] ⁺ ).

Triethylamine (0.45 m) was then addedl,3.24 mmol) and di-tert-butyl dicarbonate (0.94 g,4.32 mmol) and the mixture is stirred at room temperature for 0.5 h. Water (10 mL) was added and the mixture extracted with EtOAc (2X 5 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (silica gel, etOAc: meoh=10:1) to afford (S) - ((2 ' -chloro-3 ' - (2, 3-dichloropyridin-4-yl) -3-fluoro-5-methoxy- [1,1' -biphenyl) as a yellow solid ]-4-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (0.9 g,67% yield). MS: m/z found 552 and 554[ M-tert-butyl ]] ⁺ ).

(d) ((3 ' - (2- (2- (2- ((tert-Butoxycarbonyl) ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) -1-oxoisoindolin-5-yl) -3-chloropyridin-4-yl) -2' -chloro-3-fluoro-5-methoxy- [1,1' -biphenyl ] -4-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To (S) - ((2 ' -chloro-3 ' - (2, 3-dichloropyridin-4-yl) -3-fluoro-5-methoxy- [1,1' -biphenyl)]-4-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (0.2 g,0.33 mmol) and (S) - (2- (1-oxo-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl) ethyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (0.2 g,0.4 mmol) in 1, 4-dioxane/water mixture (10:1, 13 mL) was added [1,1' -bis (biphenylphosphino) ferrocene]Palladium (II) dichloride in combination with dichloromethane (0.01 g,0.02 mmol) and potassium carbonate (0.14 g,1 mmol) and the mixture was stirred at 110 ℃ for 3 hours. To the mixture was added water (5 mL) and the mixture was then extracted with EtOAc (2×10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (silica gel, etOAc: meoh=3:1) to afford ((3 ' - (2- (2- ((tert-butoxycarbonyl) (((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) -1-oxoisoindolin-5-yl) -3-chloropyridin-4-yl) -2' -chloro-3-fluoro-5-methoxy- [1,1' -biphenyl) as a yellow solid ]-4-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (0.2 g,61% yield). M is MS: m/z found 945[ M+H ]] ⁺ .

(e) 5- (3-chloro-4- (2-chloro-3 '-fluoro-5' -methoxy-4 '- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,1' -biphenyl ] -3-yl) pyridin-2-yl) -2- (2- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one

((3 ' - (2- (2- ((tert-butoxycarbonyl) ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) -1-oxoisoindolin-5-yl) -3-chloropyridin-4-yl) -2' -chloro-3-fluoro-5-methoxy- [1,1' -biphenyl) at room temperature]A mixture of tert-butyl 4-yl) methyl (((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (0.19 g,0.2 mmol) in trifluoroacetic acid (1.5 mL) and dichloromethane (0.5 mL) was stirred for 10 min. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 5- (3-chloro-4- (2-chloro-3 '-fluoro-5' -methoxy-4 '- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,1' -biphenyl) as a white solid (formate)]-3-yl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one (32.5 mg,20% yield). MS: m/z found 745[ M+H ]]Retention time = 2.55min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.70(d,1H),8.34(s,1H),7.95-7.91(m,2H),7.85(d,1H),7.61-7.56(m,2H),7.50-7.46(m,2H),7.02(s,1H),6.97(d,1H),4.71(s,2H),4.23(s,2H),4.00(s,3H),3.97-3.92(m,4H),3.26-3.24(m,2H),3.05-3.04(m,4H),2.42-2.33(m,6H),1.89-1.87(m,2H).

Example 423:1- (6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine (159)

(a) 5- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) isoindoline-2-carboxylic acid tert-butyl ester

Following suzuki coupling procedure a, 5- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) isoindoline-2-carboxylic acid tert-butyl ester was provided in 71% yield from 5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) isoindoline-2-carboxylic acid tert-butyl ester (150 mg,0.43 mmol) and 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypoly-nicotinaldehyde (171 mg,0.43 mmol). LCMS: m/z found 576.1[ M+H ]] ⁺ Retention time = 1.20min (method B).

(b) 5- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) isoindoline-2-carboxylic acid tert-butyl ester

Following reductive amination procedure B, tert-butyl 5- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) isoindoline-2-carboxylate (40 mg,0.07 mmol) and methylamine solution (33% wt in methanol, 0.14 mmol) afforded 5- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) isoindoline-2-carboxylate which was used in the next step without further purification. LCMS: m/z found 591.2[ M+H ] ] ⁺ Retention time = 0.92min (method B).

(c) 1- (6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine

A solution of crude tert-butyl 5- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) isoindoline-2-carboxylate (25 mg,0.04 mmol) in dichloromethane/trifluoroacetic acid (2:1) was stirred for 30 min, concentrated and purified by preparative HPLC to afford 1- (6- [ - ]2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine (formate) was produced in 62% yield by two steps. LCMS: m/z found 491.1[ M+H ]] ⁺ Retention time = 1.54min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.71–8.59(m,1H),8.53(s,2H),7.86(d,1H),7.76–7.65(m,3H),7.61–7.50(m,2H),7.48–7.41(m,2H),7.35(d,1H),4.62(s,4H),4.19(s,2H),4.08(s,3H),2.73(s,3H).

Example 424:2- (((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethan-1-ol (160)

Following reductive amination procedure B, tert-butyl 5- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) isoindoline-2-carboxylate (40 mg,0.07 mmol) and 2-aminoethanol (9 mg,0.14 mmol) were provided as crude 5- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxyethyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) isoindoline-2-carboxylate as tert-butyl 5- (3-chloro-3- (5- (((2-hydroxyethyl) amino) methyl) 6-methoxypyridin-2-yl) phenyl) isoindoline-2-carboxylate, LCMS: m/z found 621.2[ M+H ] ] ⁺ It was deprotected and purified by a general Boc deprotection procedure to afford 2- (((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethan-1-ol (formate) in 74% yield over two steps. LCMS: m/z found 521.1[ M+H ]] ⁺ Retention time = 1.52min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.52(s,2H),7.85(d,1H),7.75–7.67(m,3H),7.62–7.52(m,2H),7.48–7.40(m,2H),7.33(d,1H),4.64(s,4H),4.19(s,2H),4.07(d,3H),3.81(t,2H),3.08(t,2H).

Example 425: (S) -1- (((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol (161)

Following reductive amination procedure B, tert-butyl 5- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) isoindoline-2-carboxylate (40 mg,0.07 mmol) and (2S) -1-aminopropane-2-ol (10 mg,0.14 mmol) were provided as crude (S) -5- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) isoindoline-2-carboxylate, LCMS: m/z found 635.2[ M+H ]] ⁺ It was deprotected and purified by a general Boc deprotection procedure to afford (S) -1- (((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol (formate) in 78% yield over two steps. LCMS: m/z found 535.1[ M+H ] ] ⁺ Retention time = 1.58min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.53(s,2H),7.84(d,1H),7.75–7.67(m,3H),7.56(q,2H),7.48–7.41(m,2H),7.32(d,1H),4.63(s,4H),4.21–4.10(m,2H),4.07(s,3H),4.04–3.96(m,1H),2.97(dd,1H),2.85–2.74(m,1H),1.22(d,3H).

Example 426:1- (4- (((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (162)

Following reductive amination procedure B, tert-butyl 5- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) isoindoline-2-carboxylate (40 mg,0.07 mmol) and 1- (4-amino-1-piperidinyl) ethanone (20 mg,0.14 mmol) were provided as crude 5- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) isoindoline-2-carboxylate LCMS: m/z found 702.3[ M+H ]] ⁺ It was deprotected and purified by a general Boc deprotection procedure to afford 1- (4- (((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (formate) in 80% yield over two steps. LCMS (liquid Crystal Module)M/z found 602.2[ M+H ]] ⁺ Retention time = 1.58min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.50(s,2H),7.87–7.79(m,1H),7.71(d,3H),7.56(t,2H),7.45(dd,2H),7.31(d,1H),4.67(s,4H),4.57(d,1H),4.09(s,2H),4.05(d,3H),4.01(d,1H),3.23–3.09(m,2H),2.71(t,1H),2.12(d,5H),1.59–1.33(m,2H).

Example 427:1- (4- (((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) piperidin-1-yl) ethan-1-one (163)

Following reductive amination procedure B, starting from 5- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) isoindoline-2-carboxylic acid tert-butyl ester (40 mg,0.07 mmol) and 1- [4- (methylamino) -1-piperidinyl]Ethaneone (22 mg,0.14 mmol) afforded 5- (4- (3- (5- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) isoindoline-2-carboxylic acid speed ester as crude material, LCMS: m/z found 716.3[ M+H] ⁺ It was deprotected and purified by a general Boc deprotection procedure to afford 1- (4- (((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) piperidin-1-yl) ethan-1-one (formate) in 40% yield over two steps. LCMS: m/z found 616.2[ M+H ]] ⁺ Retention time = 1.59min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.51(s,2H),7.80(d,1H),7.72(dt,3H),7.56(dt,2H),7.46(d,1H),7.41(dd,1H),7.27(d,1H),4.67(s,4H),4.65–4.57(m,1H),4.08–4.02(m,1H),4.01(s,3H),3.79(s,2H),3.14(t,1H),2.91(t,1H),2.65(t,1H),2.39(s,3H),2.12(s,3H),2.07–1.93(m,2H),1.74–1.46(m,2H).

Example 428:2- ((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one (230)

Following reductive amination procedure B, starting from 5- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) isoindoline-2-carboxylic acid speed ester (50 mg,0.09 mmol) and 2, 6-diazaspiro [3.4] ]Octan-7-one (22 mg,0.17 mmol) afforded 5- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4 ]) as crude material]Octan-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) isoindoline-2-carboxylic acid tert-butyl ester, LCMS: m/z found 686.2[ M+H ]] ⁺ Which is deprotected and purified by a general Boc deprotection procedure to provide 2- ((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4 ]]Octane-7-one (formate) was produced in 78% yield through two steps. LCMS: m/z found 586.2[ M+H ]] ⁺ Retention time = 1.52min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.47(s,2H),7.76–7.67(m,4H),7.59–7.51(m,2H),7.47(d,1H),7.41(d,1H),7.25(d,1H),4.68(s,4H),4.00(s,3H),3.79(s,2H),3.60(s,2H),3.55–3.44(m,4H),2.60(s,2H).

Example 429: (S) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (167)

(a) 6-bromo-1-methyl-1H-indazole-3-carbaldehyde

To a solution of 6-bromo-1H-indazole-3-carbaldehyde (0.60 g,2.67 mmol) in 6mL THF was added methyl iodide (0.20 mL,3.20 mmol) and potassium carbonate (0.55 g,4.00 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was transferred to a Biotage MW vessel, capped, and heated to 50 ℃ for 4 hours, then 60 ℃ for 4 hours. The reaction mixture was diluted with 15mL EtOAc and filtered through a CELITE pad. The filtrate was concentrated and the resulting crude product was purified by normal phase silica gel chromatography (0% to 30% EtOAc/hexanes) to afford 6-bromo-1-methyl-1H-indazole-3-carbaldehyde (0.37 g,58% yield). ¹ H NMR (400 MHz, chloroform-d) δ10.19 (s, 1H), 8.16 (d, 1H), 7.67-7.66 (m, 1H), 7.48-7.44 (m, 1H), 4.21-4.07 (s, 3H).

(b) 1-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-indazole-3-carbaldehyde

6-bromo-1-methyl-1H-indazole-3-carbaldehyde (151 mg,0.63 mmol), bis (pinacolato) diborane (224 mg,0.88 mmol), potassium acetate (173 mg,1.77 mmol) and [1,1' -bis (biphenylphosphino) ferrocene were weighed out]A mixture of palladium (II) dichloride complex with dichloromethane (52 mg,0.06 mmol) was placed in a Biotage microwave vial. Anhydrous 1, 4-dioxane (4 mL) was added. The mixture was degassed with nitrogen for 2 minutes. The vessel was capped and irradiated in a Biotage Initiator microwave apparatus to 95 ℃ for 75 minutes. The mixture was diluted with 10mL EtOAc and filtered through a CELITE pad. The CELITE pad was washed with 20mL EtOAc. The combined filtrates were concentrated under reduced pressure and the crude material was purified by normal phase silica gel chromatography (0% to 28% etoac/hexanes) to afford 1-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-indazole-3-carbaldehyde (157 mg,87% yield). ¹ H NMR (400 MHz, chloroform-d) δ10.23 (s, 1H), 8.29 (dd, 1H), 7.97 (d, 1H), 7.78 (dd, 1H), 4.22 (s, 3H), 1.39 (s, 12H).

(c) (S) - ((6- (2-chloro-3- (3-chloro-2- (3-formyl-1-methyl-1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

To (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl)A solution of tert-butyl (5-oxopyrrolidin-2-yl) methyl) carbamate (192 mg,0.32 mmol), 1-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-indazole-3-carbaldehyde (102 mg,0.36 mmol) and potassium carbonate (134 mg,0.97 mmol) in degassed 1, 4-dioxane/water (6:1, 3.7 mL) was added tetrakis (triphenylphosphine) palladium (0) (37 mg,0.03 mmol). The mixture was irradiated to 105 ℃ in a Biotage Initiator microwave apparatus for 25 minutes. Water (10 mL) was added and the mixture extracted into EtOAc (3X 12 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by normal phase silica gel chromatography (0% to 8% MeOH/DCM) to afford tert-butyl (S) - ((6- (2-chloro-3- (3-chloro-2- (3-formyl-1-methyl-1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (203 mg,88% yield). MS: m/z found 715.2[ M+H ] ] ⁺ .

(d) (S) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

Formate is prepared according to the reductive amination procedure B from tert-butyl (S) - ((6- (2-chloro-3- (3-chloro-2- (3-formyl-1-methyl-1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (32 mg,0.04 mmol) and 1- (4-aminopiperidin-1-yl) ethan-1-one (13 mg,0.09 mmol) followed by the general Boc deprotection procedure to prepare (S) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one. Yield 38%. LCMS: m/z found 742.6[ M+H ]] ⁺ Retention time = 2.72min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.67(d,1H),8.51(s,1H),7.97(dd,1H),7.87(t,1H),7.79–7.68(m,2H),7.56(t,1H),7.53–7.46(m,2H),7.43(dd,1H),7.27(d,1H),4.56(d,1H),4.44(s,2H),4.13(s,3H),4.03(s,3H),3.98(s,1H),3.85(dd,3H),3.17(s,2H),2.80–2.65(m,3H),2.39–2.30(m,2H),2.34–2.22(m,1H),2.18(d,2H),2.12(s,3H),1.89–1.76(m,1H),1.58–1.37(m,2H).

Example 430: (S) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (168)

Formate salt was prepared following reductive amination procedure B from (S) - ((6- (2-chloro-3- (3-chloro-2- (3-formyl-1-methyl-1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (38 mg,0.05 mmol) and 1- (4- (methylamino) piperidin-1-yl) ethan-1-one (10 mg,0.03 mmol) followed by the general Boc deprotection procedure to give (S) -5- (((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one. 46% yield. LCMS: m/z found 755.1[ M+H ] ] ⁺ Retention time = 2.77 minutes, (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.67(d,1H),8.44(s,1H),7.98(dd,1H),7.86(t,1H),7.79(d,1H),7.72(dd,1H),7.57(t,1H),7.52–7.41(m,3H),7.29(d,1H),4.64(d,1H),4.27(s,2H),4.12(s,3H),4.04(s,4H),3.97–3.85(m,3H),3.35(s,2H),3.21–2.98(m,1H),2.90–2.76(m,2H),2.50(s,3H),2.41–2.26(m,3H),2.13(s,5H),1.92–1.46(m,3H).

Example 431: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (183)

According to the formula (S) - ((6- (2-chloro-3- (3))-tert-butyl chloro-2- (3-formyl-1-methyl-1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl ((5-oxopyrrolidin-2-yl) methyl) carbamate (34 mg,0.05 mmol) and (S) -5- (aminomethyl) pyrrolidin-2-one (10 mg,0.03 mmol) reductive amination procedure B followed by a general Boc deprotection procedure prepared as formate salt from (S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indazol-6-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one. Yield 56%. LCMS: m/z found 714.8[ M+H ]] ⁺ Retention time = 2.62min, (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.67(d,1H),7.97(dd,1H),7.85(t,1H),7.79(d,1H),7.72(dd,1H),7.57(t,1H),7.52–7.41(m,3H),7.29(d,1H),4.40–4.28(m,2H),4.12(s,3H),4.04(s,3H),4.02–3.85(m,4H),2.99–2.76(m,4H),2.43–2.23(m,6H),1.89–1.77(m,2H).

Example 432: (S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((((S) -oxetan-2-yl) methyl) amino) methyl) -1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (235)

Formate is prepared following reductive amination procedure B from (S) - ((6- (2-chloro-3- (3-chloro-2- (3-formyl-1-methyl-1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (37 mg,0.05 mmol) and (S) -oxetan-2-ylmethylamine (10 mg,0.03 mmol) followed by the general Boc deprotection procedure, (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((((S) -oxetan-2-yl) methyl) amino) methyl) -1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one. Yield 50%. LCMS: m/z found 686.4[ M+H ]] ⁺ Retention time = 2.77min, (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.67(d,1H),8.48(s,1H),7.96(dd,1H),7.93–7.86(m,1H),7.77(d,1H),7.72(dd,1H),7.56(t,1H),7.55–7.47(m,2H),7.44(dd,1H),7.28(d,1H),5.12–5.04(m,1H),4.75–4.68(m,1H),4.63–4.59(m,1H),4.51(s,2H),4.14(s,3H),4.03(s,3H),3.97–3.84(m,3H),3.39(dd,1H),3.32–3.16(m,1H),2.86–2.71(m,3H),2.56–2.48(m,1H),2.42–2.23(m,3H),1.90–1.77(m,1H).

Example 433: (S) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (((2-hydroxyethyl) (methyl) amino) methyl) -1-methyl-1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (247)

Formate was prepared following reductive amination procedure B from (S) - ((6- (2-chloro-3- (3-chloro-2- (3-formyl-1-methyl-1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (30 mg,0.04 mmol) and 2- (methylamino) ethan-1-ol (6 mg,0.08 mmol) followed by the general Boc deprotection procedure, (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-hydroxyethyl) (methyl) amino) methyl) -1-methyl-1H-indazol-6-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one. Yield 41%. LCMS: m/z found 674.0[ M+H ] ] ⁺ Retention time = 2.64min, (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.68(d,1H),8.48(s,1H),8.00(d,1H),7.90(s,1H),7.77(d,1H),7.72(dd,1H),7.61–7.46(m,3H),7.44(dd,1H),7.28(d,1H),4.46(s,2H),4.15(s,2H),4.03(s,3H),3.98–3.82(m,5H),3.08(t,2H),2.85–2.72(m,2H),2.71(s,3H),2.40–2.32(m,1H),2.36–2.23(m,2H),1.88–1.77(m,1H).

Example 434:1- (4- (((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (263)

(a) 6- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-indazole-3-carbaldehyde

To a mixture of 1-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-indazole-3-carbaldehyde (34 mg,0.12 mmol), 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (46 mg,0.12 mmol) and potassium carbonate (49 mg,0.35 mmol) in degassed 1, 4-dioxane/water (6:1, 1.15 ml) was added tetrakis (triphenylphosphine) palladium (0) (14 mg,0.01 mmol). The mixture was irradiated to 105 ℃ in a Biotage Initiator microwave apparatus for 25 minutes. Water (7 mL) was added and the mixture extracted into EtOAc (3X 15 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by normal phase silica gel chromatography (15% to 80% EtOAc/hexanes) to afford 6- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-indazole-3-carbaldehyde (41 mg,67% yield). ¹ H NMR (400 MHz, chloroform-d) δ10.43 (d, 1H), 10.26 (s, 1H), 8.71 (d, 1H), 8.39 (dd, 1H), 8.21 (d, 1H), 7.89 (t, 1H), 7.81-7.71 (m, 2H), 7.53 (t, 1H), 7.46-7.36 (m, 2H), 7.33 (d, 1H), 4.25 (s, 3H), 4.14 (s, 3H).

(b) 1- (4- (((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

Following reductive amination procedure a, 1- (4- (((6- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) is methylphenidated from 6- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-indazol-3-carbaldehyde (38 mg,0.07 mmol) and 1- (4-aminopiperidin-1-yl) ethan-1-one (41 mg,0.29 mmol) with 1- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl) -1H-indazol-6-yl) -3-chloropyridin-4-yl) methyl) amino)Pyridin-1-yl) ethan-1-one to formate. Yield 50%. LCMS: m/z found 769.3[ M+H ]] ⁺ Retention time = 2.81min, (method a). ¹ H NMR(400MHz,DMSO-d ₆ ):δ9.55(d,1H),9.02(s,1H),8.79(d,1H),8.70–8.63(m,2H),8.54(dd,1H),8.45–8.29(m,3H),8.20(dd,1H),8.09(d,1H),4.98–4.88(m,4H),4.84(s,3H),4.73(s,3H),4.55(s,4H),3.92–3.80(m,1H),3.56–3.43(m,4H),2.79(d,6H),2.69(d,3H),2.62(s,1H),2.07(s,3H),2.01–1.91(m,2H).

Example 435: (S) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-indazol-3-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one (288)

According to the method of preparing a pharmaceutical composition comprising (S) - ((6- (2-chloro-3- (3-chloro-2- (3-formyl-1-methyl-1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester (33 mg,0.05 mmol) and 2, 6-diazaspiro [3.4 ]]Reductive amination procedure B of octan-7-one hydrochloride (15 mg,0.09 mmol) followed by general Boc deprotection procedure (S) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-indazol-3-yl) methyl) -2, 6-diazaspiro [ 3.4)]The preparation of formate from octane-7-ketone. Yield 41%. LCMS: m/z found 725.0[ M+H ]] ⁺ Retention time = 2.64min, (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.67(dd,1H),7.95(dd,1H),7.85(dd,1H),7.79(dd,1H),7.72(dd,1H),7.57(t,1H),7.52–7.45(m,2H),7.45–7.42(m,1H),7.29(dd,1H),4.25(s,2H),4.11(s,2H),4.04(s,3H),3.95(s,3H),3.93–3.85(m,1H),3.68(s,4H),3.59(d,2H),2.89–2.76(m,2H),2.60(d,2H),2.40–2.24(m,3H),1.89–1.78(m,1H).

Example 436: (S) -5- (((6- (3- (2- (3- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (308)

According to the method of preparing a pharmaceutical composition comprising (S) - ((6- (2-chloro-3- (3-chloro-2- (3-formyl-1-methyl-1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tert-butyl (5-oxopyrrolidin-2-yl) methyl) carbamate (33 mg,0.05 mmol) and 1- (2, 6-diazaspiro [3.3] ]Reductive amination procedure B of heptan-2-yl) ethan-1-one (8 mg,0.09 mmol) followed by general Boc deprotection procedure was performed to isolate (S) -5- (((6- (3- (2- (3- ((6-acetyl-2, 6-diazaspiro [ 3.3))]Heptane-2-yl) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl-methyl) amino) methyl) pyrrolidin-2-one was prepared as a formate salt. Yield 30%. LCMS: m/z found 740.6[ M+H ]] ⁺ Retention time = 2.70min, (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.67(d,1H),7.94(dd,1H),7.84(t,1H),7.77(d,1H),7.72(dd,1H),7.56(t,1H),7.52–7.40(m,3H),7.28(d,1H),4.30(s,2H),4.15(d,2H),4.11(s,3H),4.04(d,5H),3.91(d,2H),3.87(s,2H),3.71(s,4H),2.82–2.74(m,2H),2.40–2.25(m,3H),1.83(s,3H).

Example 437: (S) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-indazol-3-yl) methyl) pyrrolidine-3-carboxylic acid (309)

Following reductive amination procedure B from (S) - ((6- (2-chloro-3- (3-chloro-2- (3-formyl-1-methyl-1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (35 mg,0.05 mmol) and (S) -pyrrolidine-3-carboxylic acid (11 mg,0.10 mmol), followed by the general Boc deprotection procedure, (S) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) benzene) Base) pyridin-2-yl) -1-methyl-1H-indazol-3-yl) methyl) pyrrolidine-3-carboxylic acid was prepared as formate salt. Yield 35%. LCMS: m/z found 714.0[ M+H ]] ⁺ Retention time = 2.75min, (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.68(d,1H),8.00(d,1H),7.92(s,1H),7.80–7.68(m,2H),7.60–7.52(m,2H),7.49(d,1H),7.44(dd,1H),7.27(d,1H),4.82–4.69(m,2H),4.17(s,3H),4.03(s,3H),3.88(dd,3H),3.68–3.59(m,1H),3.54(d,1H),3.44(s,2H),3.10(d,1H),2.83–2.69(m,2H),2.39–2.22(m,5H),1.88–1.76(m,1H).

Example 438:1- (6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((methylamino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine (276)

(a) 6- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-indole-3-carbaldehyde

Following the suzuki coupling procedure a, 6- [ 3-chloro-4- [ 2-chloro-3- (5-formyl-6-methoxy-2-pyridinyl) phenyl ] from 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (65 mg,0.17 mmol) and 1-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-indole-3-carbaldehyde (47 mg,0.17 mmol) was provided 6- [ 3-chloro-4- [ 2-chloro-3- (5-formyl-6-methoxy-2-pyridinyl) phenyl]-2-pyridyl group]-1-methyl-indole-3-carbaldehyde (75 mg, 88%). LCMS: m/z found 516.1[ M+H ]] ⁺ Retention time = 1.02min (method B).

(b) 1- (6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((methylamino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine

According to the reductive amination processSequence A, consisting of 6- [ 3-chloro-4- [ 2-chloro-3- (5-formyl-6-methoxy-2-pyridinyl) phenyl ]-2-pyridyl group]-1-methyl-indole-3-carbaldehyde (30 mg,0.06 mmol) and a solution of methylamine (33% wt in methanol, 0.23 mmol) provided 1- (6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((methylamino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine (formate) in 78% yield. LCMS: m/z found 546.2[ M+H ]] ⁺ Retention time = 1.72min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(dd,1H),8.54(s,2H),7.87–7.80(m,2H),7.79(s,1H),7.72(d,1H),7.58(dd,1H),7.55–7.48(m,2H),7.48–7.41(m,2H),7.34(d,1H),4.41(s,2H),4.11(s,2H),4.07(s,3H),3.91(s,3H),2.73(s,3H),2.67(s,3H).

Example 439:1- (4- (((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-indol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (277)

Following reductive amination procedure A, starting from 6- [ 3-chloro-4- [ 2-chloro-3- (5-formyl-6-methoxy-2-pyridinyl) phenyl]-2-pyridyl group]-1-methyl-indole-3-carbaldehyde (30 mg,0.06 mmol) and 1- (4-amino-1-piperidinyl) ethanone (33 mg,0.23 mmol) provide 1- (4- (((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-indol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (formate) in 92% yield. LCMS: m/z found 768.3[ M+H ]] ⁺ Retention time = 1.76min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.53(s,2H),7.86–7.75(m,3H),7.72(dd,1H),7.56(t,1H),7.52(s,1H),7.50(dd,1H),7.46–7.41(m,2H),7.29(d,1H),4.65(d,1H),4.53(d,1H),4.43(s,2H),4.11–4.02(m,4H),4.01–3.93(m,3H),3.91(s,3H),3.45–3.34(m,1H),3.18(q,2H),3.02–2.89(m,1H),2.70(q,2H),2.24(t,2H),2.16–1.98(m,8H),1.67–1.28(m,4H).

Example 440: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- ((S) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (184)

(a) (S) -5- ((((S) -6-bromo-1, 2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one

(S) -6-bromo-1, 2,3, 4-tetrahydronaphthalen-1-amine (75 mg,0.33 mmol), methanesulfonic acid (S) - (5-oxopyrrolidin-2-yl) methyl ester (77 mg,0.40 mmol), and potassium carbonate (137 mg,1.00 mmol) were suspended in 3mL acetonitrile. The reaction mixture was then heated at 80 ℃ for 18 hours. The reaction was cooled to room temperature, diluted with water (6 mL) and extracted with EtOAc (3×5 mL). The combined organics were washed with water (5 mL), brine (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide (S) -5- ((((S) -6-bromo-1, 2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one (104 mg) as a pale brown oil. MS: m/z found 323,325[ M+H ]] ⁺ . The material was used in the next step without further purification.

(b) (S) -5- ((((S) -6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one

(S) -5- ((((S) -6-bromo-1, 2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one (50 mg,0.15 mmol), bis (pinacolato) diborane (55 mg,0.22 mmol) and [1,1' -bis (biphenylphosphino) ferrocene were introduced into a sealed tube]A complex of palladium (II) dichloride with dichloromethane (13 mg,0.02 mmol), and potassium carbonate (60 mg,0.43 mmol) were suspended in 2mL of 1, 4-dioxane. Nitrogen was bubbled through the reaction solution for 2 minutes, then the vessel was sealed and at 1Heating at 00 deg.C for 18 hr. The reaction was cooled to room temperature and the mixture was filtered through CELITE. The filtrate was concentrated under reduced pressure and the crude oil was purified by reverse phase HPLC to afford (S) -5- ((((S) -6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one (12 mg,21% yield) as a white solid. MS: m/z found 289[ M+H ]] ⁺ (boric acid fragments).

(c) (S) -5- (((6- (2-chloro-3- (3-chloro-2- ((S) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

In the same manner as described in relation to example 48, the intermediate (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester was used in step (b) and (S) -5- ((((S) -6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one was used in place of (S) -1- (8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2, 3-dihydrobenzo [ f ] ][1,4]Oxazepin-4 (5H) -yl) propan-2-ol to prepare (S) -5- (((6- (2-chloro-3- (3-chloro-2- ((S) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one. The product was obtained as a white solid (formate). LC/MS: m/z found 699,701[ M+H ]] ⁺ Retention time = 2.11min, (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.61(d,1H),8.44(s,1H),7.80(d,1H),7.70(d,1H),7.60–7.49(m,3H),7.49–7.37(m,3H),7.2(d,1H),4.18(s,1H),4.03(d,5H),3.91(s,2H),3.08–2.81(m,6H),2.35(q,6H),2.07(s,3H),1.85(d,3H).

Example 441: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (185)

(a) (S) -5- ((((R) -6-bromo-1, 2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one

(R) -6-bromo-1, 2,3, 4-tetrahydronaphthalen-1-amine (75 mg,0.33 mmol), methanesulfonic acid (S) - (5-oxopyrrolidin-2-yl) methyl ester (77 mg,0.40 mmol), and potassium carbonate (137 mg,1.00 mmol) were suspended in 3mL acetonitrile. The reaction mixture was then heated at 80 ℃ for 18 hours. The reaction was cooled to room temperature, diluted with water (6 mL) and extracted with EtOAc (3×5 mL). The combined organics were washed with water (5 mL), brine (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide (S) -5- ((((R) -6-bromo-1, 2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one (107 mg, crude) as a pale brown oil. MS: m/z found 323,325[ M+H ] ] ⁺ . The material was used in the next step without further purification.

(b) (R) -6-bromo-1, 2,3, 4-tetrahydronaphthalen-1-yl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

(S) -5- ((((R) -6-bromo-1, 2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one (107 mg,0.33mmol, crude) and N, N-diisopropylethylamine (85 mg,0.66 mmol) were dissolved in 5mL THF and di-tert-butyl dicarbonate (145 mg,0.66 mmol) was added in portions. The resulting mixture was stirred at room temperature for 18 hours. To the crude mixture was added EtOAc (15 mL) and the resulting solution was washed with saturated aqueous sodium bicarbonate (2×10 mL) and brine (2×10 mL). The organic layer was concentrated under reduced pressure and the crude sample was purified by reverse phase HPLC to afford the base ((R) -6-bromo-1, 2,3, 4-tetrahydronaphthalen-1-yl) ((S) -5-oxopyrrolidin-2-Tert-butyl methyl) carbamate (39 mg,28% yield). MS: m/z found 423,425[ M+H ]] ⁺ 。

(c) ((S) -5-Oxopyrrolidin-2-yl) methyl) ((R) -6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) carbamic acid tert-butyl ester

Tert-butyl ((R) -6-bromo-1, 2,3, 4-tetrahydronaphthalen-1-yl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (39 mg,0.09 mmol), bis (pinacolato) diborane (33 mg,0.13 mmol), [1,1' -bis (biphenylphosphino) ferrocene ]A complex of palladium (II) dichloride with dichloromethane (8 mg,0.01 mmol), and potassium carbonate (36 mg,0.26 mmol) were suspended in 2mL of 1, 4-dioxane. Nitrogen was bubbled through the reaction solution for 2 minutes, then the vessel was sealed and heated at 100 ℃ for 18 hours. The reaction was cooled to room temperature and the mixture was filtered through CELITE. The filtrate was concentrated under reduced pressure and the crude oil was purified by reverse phase HPLC to afford (((S) -5-oxopyrrolidin-2-yl) methyl) ((R) -6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) carbamic acid tert-butyl ester (17 mg,39% yield) as a white solid. MS: m/z found 471[ M+H ]] ⁺ .

(d) (S) -5- (((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

In the same manner as described in relation to example 48, the intermediate tert-butyl (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate was used in step (b) in combination with (((S) -5-oxopyrrolidin-2-yl) methyl) ((R) -6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,2,3, 4-tetrahydronaphthalene-1 -group) carbamate instead of (S) -1- (8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2, 3-dihydrobenzo [ f)][1,4]Oxazepin-4 (5H) -yl) propan-2-ol to prepare (S) -5- (((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one. The product was obtained as a white solid (formate). LC/MS: m/z found 699,701[ M+H ]] ⁺ Retention time = 2.10min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.61(d,1H),8.44(s,1H),7.80(d,1H),7.70(d,1H),7.60–7.49(m,3H),7.49–7.37(m,3H),7.2(d,1H),4.18(s,1H),4.03(d,5H),3.91(s,2H),3.08–2.81(m,6H),2.35(q,6H),2.07(s,3H),1.85(d,3H).

Example 442:2- ((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((S) -5-oxopyrrolidin-2-yl) -methyl) -amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one (255)

(a) (R) -6- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (188 mg,0.48 mmol), tetrakis (triphenylphosphine) palladium (0) (74 mg,0.06 mmol), potassium carbonate (132 mg,0.96 mmol), and (((S) -5-oxopyrrolidin-2-yl) methyl) ((R) -6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) carbamic acid tert-butyl ester (example 441, step (c)) (150 mg,0.32 mmol) were suspended in 1, 4-dioxane/water (4:1, 5 mL) and the solution was then heated at 105℃for 20 min. The reaction was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×5 mL). Concentrating under reduced pressure The combined organics were condensed and the crude sample purified by silica gel chromatography (0-4% MeOH/DCM) to afford tert-butyl ((R) -6- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) ((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (26 mg,55% yield) as a yellow oil. MS: m/z found 701,703[ M+H ]] ⁺ 。

(b) (R) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

Tert-butyl ((R) -6- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (20 mg,0.03 mmol), 2, 6-diazaspiro [ 3.4)]Octan-7-one (7 mg,0.04 mmol), and acetic acid (3 mg,0.06 mmol) were dissolved in MeOH/THF (1:1, 1 mL) and the solution was stirred at 25℃for 4 h. Sodium cyanoborohydride (4 mg,0.06 mmol) was added and the resulting mixture was stirred at 25 ℃ for 2 hours. The reaction was then diluted with water (3 mL) and extracted with EtOAc (3×2 mL). The combined organics were further washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford ((R) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [ 3.4)) as a yellow oil ]Octan-2-yl) methyl pyridin-2-yl) phenyl pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (23 mg, crude). MS: m/z found 811,813[ M+H ]] ⁺ . The material was used in the next step without further purification.

(c) 2- ((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one

To ((R) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4 ])]Tert-butyl (23 mg,0.03 mmol) of octan-2-yl-methyl) pyridin-2-yl-phenyl) -1,2,3, 4-tetrahydronaphthalen-1-yl (((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (23 mg,0.03 mmol) was dissolved in 1mL MeOH and a solution of 1, 4-dioxane (28.33. Mu.L, 0.11 mmol) in 4M HCl was added dropwise. The reaction was stirred at room temperature for 60 minutes and the solvent was removed under reduced pressure. The crude sample was purified by reverse phase HPLC to provide 2- ((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] as a white solid (formate salt) ]Octan-7-one (5 mg,25% yield). LC/MS: m/z found 711,713[ M+H ]] ⁺ Retention time = 2.11min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.61(d,1H),8.43(s,1H),7.76(d,1H),7.69(d,1H),7.59–7.48(m,3H),7.46(s,1H),7.44–7.38(m,2H),7.28(d,1H),4.17(s,1H),4.02(d,3H),3.99(s,2H),3.88(s,1H),3.75(s,4H),3.62(s,2H),3.08–2.77(m,4H),2.63(s,2H),2.33(d,3H),2.04(d,3H),1.93–1.76(m,2H).

Example 443: (S) -5- ((((R) -6- (3-chloro-4- (2-chloro-3- (5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one (256)

In the same manner as described for example 442, intermediate ((R) -6- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester was used in step (b) and (S) -1-aminopropane-2-ol was used instead of 2, 6-diazaspiro- [ 3.4)]Octan-7-one to prepare (S) -5- (((R) -6- (3-chloro-4- (2-chloro-3- (5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one. The product was obtained as a white solid (formate). LC/MS: m/z found 660,662[ M+H ]] ⁺ Retention time = 2.12min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.61(d,1H),8.46(s,1H),7.89–7.82(m,1H),7.74–7.68(m,1H),7.55(d,2H),7.49(d,1H),7.43(q,3H),7.37–7.30(m,1H),4.26(s,2H),4.13–3.98(m,5H),3.85(s,1H),3.09(d,1H),2.88(m,5H),2.40–2.24(m,3H),2.03(s,3H),1.86(dd,2H),1.27–1.13(m,3H).

Example 444: (S) -5- ((((R) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one (257)

In the same manner as described for example 442, intermediate ((R) -6- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester was used in step (b) and (S) -3-aminodihydrofuran-2 (3H) -one was used instead of 2, 6-diazaspiro [ 3.4)]Octan-7-one to prepare (S) -5- (((R) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -2-oxotetrahydrofuranl-3-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one. The product was obtained as a white solid (formate). LC/MS: m/z found 686,688[ M+H ]] ⁺ Retention time = 2.20min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.60(d,1H),7.77(d,7.70(d,1H),7.53(t,2H),7.48(d,1H),7.44–7.36(m,3H),7.25(d,1H),4.41(t,1H),4.23(q,1H),4.02(d,4H),3.94(d,2H),3.83(s,1H),3.66(m,1H),2.98–2.73(m,4H),2.56(m,1H),2.39–2.22(m,3H),2.19–2.08(m,1H),2.03(d,3H),1.85(d,2H).

Example 445: ((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -L-homoserine (265)

In the same manner as described for example 442, intermediate ((R) -6- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester was used in step (b) and L-homoserine was used instead of 2, 6-diazaspiro [ 3.4) ]Octan-7-one to prepare ((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -L-homoserine. The product was obtained as a white solid (formate). LC/MS: m/z found 704,706[ M+H ]] ⁺ Retention time = 2.14min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.65–8.58(m,1H),8.35(s,1H),7.85(d,1H),7.71(d,1H),7.56(t,3H),7.48(s,1H),7.43(d,2H),7.33(d,1H),4.27(d,3H),4.07(d,3H),3.95–3.75(m,3H),3.69(d,1H),3.08(s,1H),3.03–2.83(m,3H),2.36(m,3H),2.06(d,5H),1.89(s,2H).

Example 446: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (3-hydroxy-3-methylbutyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (208)

(a) 4- (6-bromo-8-chloro-3, 4-dihydroisoquinolin-2 (1H) -yl) -2-methylbutan-2-ol

A mixture of 6-bromo-8-chloro-1, 2,3, 4-tetrahydroisoquinoline (0.5 g,2.03 mmol), 4-bromo-2-methylbutan-2-ol (0.51 g,3.04 mmol) and potassium carbonate (0.56 g,4.06 mmol) in acetonitrile (6 mL) was degassed and N ₂ Purging three times, then at N ₂ The mixture was stirred under an atmosphere at 100 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent and the mixture was poured into ethyl acetate (15 mL). The mixture was filtered and the filtrate was concentrated to give 4- (6-bromo-8-chloro-3, 4-dihydroisoquinolin-2 (1H) -yl) -2-methylbutan-2-ol (0.72 g, crude) as a yellow oil. MS: m/z found 332[ M+H ] ] ⁺ .

(b) 4- (8-chloro-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -2-methylbutan-2-ol

At N ₂ To a mixture of 4- (6-bromo-8-chloro-3, 4-dihydroisoquinolin-2 (1H) -yl) -2-methylbutan-2-ol (0.7 g,2.1 mmol) and bis (pinacolato) diborane (0.8 g,3.16 mmol) in 1, 4-dioxane (8 mL) was added potassium acetate (0.41 g,4.21 mmol) and [1,1' -bis (biphenylphosphino) ferrocene at one time under an atmosphere]Complex of palladium (II) dichloride with dichloromethane (0.09 g,0.11 mmol) and stirring the mixture at 110℃for 12 hours. Concentrating the mixture and passing through normal phase SiO ₂ Chromatography (0-100% ethyl acetate/petroleum ether to 10% MeOH/ethyl acetate) purified the residue to afford 4- (8-chloro-6- (4, 5-tetramethyl-1, 3, 2-dioxaborin-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -2-methylbutan-2-ol (0.57 g,71% yield) as a yellow gum. ¹ H NMR (400 MHz, methanol-d) ₄ ):δ7.42(s,1H),7.36(s,1H),3.76(s,2H),2.92-2.82(m,6H),1.76-1.71(m,2H),1.23(s,12H),1.15(s,6H).

(c) (S) - ((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (3-hydroxy-3-methylbutyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

At N ₂ To 4- (8-chloro-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) under an atmosphere ) A mixture of (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-methylbutan-2-ol (0.25 g,0.66 mmol) and (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (0.18 g,0.30 mmol) in a 1, 4-dioxane/water mixture (10:1, 6.6 mL) was added at once [1,1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) dichloride (0.02 g,0.03 mmol) and potassium phosphate (0.19 g,0.91 mmol). The mixture was stirred at 110℃for 1.5 hours. The mixture was combined with another batch on the same scale. The mixture was concentrated. To the residue was added water (5 mL) and saturated aqueous brine solution (5 mL) and the mixture was extracted with ethyl acetate/THF mixture (1:1, 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ Chromatography (0-100% 30% THF in ethyl acetate/petroleum ether) purified the residue to provide 0.2g of product, which was further purified by preparative TLC (silica gel, ethyl acetate: meoh=4:1) to provide tert-butyl (6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (3-hydroxy-3-methylbutyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate as a pale yellow solid (0.09 g,14% yield). MS: m/z found 808[ M+H ] ] ⁺ .

(d) (S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (3-hydroxy-3-methylbutyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

To a mixture of tert-butyl (S) - ((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (3-hydroxy-3-methylbutyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (95 mg,0.12 mmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (1.4 mL,19 mmol) at one time and the mixture was stirred at room temperature for 15 minutes. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford (S) -5- ((((6- (2-chloro)) as a pale yellow solid (formate salt)-3- (3-chloro-2- (8-chloro-2- (3-hydroxy-3-methylbutyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl-methyl) amino) methyl) pyrrolidin-2-one (31.6 mg,34% yield). MS: m/z found 708 and 710[ M+H ]] ⁺ Retention time = 2.98min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.67(d,1H),8.31(br s,1H),7.87(d,1H),7.74(dd,1H),7.66(d,1H),7.59(t,1H),7.55(s,1H),7.48(d,1H),7.45(dd,1H),7.35(d,1H),4.27-4.15(m,4H),4.09(s,3H),4.06-4.01(m,1H),3.32-3.30(m,2H),3.26-3.18(m,4H),3.10-3.08(m,2H),2.48-2.32(m,3H),1.98-1.84(m,3H),1.32(s,6H).

Example 447: (S) -5- ((((6- (3- (2- (2- ((1-acetylpiperidin-4-yl) methyl) -8-chloro-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (289)

(S) -5- ((((6- (3- (2- (2- ((1-acetylpiperidin-4-yl) methyl) -8-chloro-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (15 mg,28% yield) was prepared in step (a) using 6-bromo-8-chloro-1, 2,3, 4-tetrahydroisoquinoline and 1- (4- (bromomethyl) piperidin-1-yl) ethane-1-one in a manner similar to example 446. MS: m/z found 761 and 763[ M+H ]] ⁺ Retention time = 3.01min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),7.83(d,1H),7.73(dd,1H),7.60-7.56(m,2H),7.46-7.43(m,3H),7.33(d,1H),4.60-4.53(m,1H),4.08(m,5H),3.98-3.95(m,2H),3.79(s,2H),3.18-3.15(m,1H),3.05-2.98(m,4H),2.87(m,2H),2.74-2.68(m,1H),2.58(d,2H),2.42-2.35(m,3H),2.12(s,3H),2.04-1.85(m,4H),1.31-1.11(m,2H).

Example 448: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (oxetan-3-ylmethyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (307)

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (oxetan-3-ylmethyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (0.9 mg,1.8% yield, formate) was prepared in step (a) using 6-bromo-8-chloro-1, 2,3, 4-tetrahydroisoquinoline and 3- (bromomethyl) oxetane in analogy to example 446. MS: m/z found 692[ M+H ]] ⁺ Retention time = 0.64min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.61(d,1H),7.74-7.68(m,2H),7.53(t,2H),7.44-7.40(m,3H),7.24(d,1H),4.60(s,2H),4.51(t,2H),4.01(s,3H),3.83-3.82(m,3H),3.69-3.64(m,2H),3.00-2.74(m,7H),2.69-2.68(m,3H),2.35-2.31(m,3H).

Example 449: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (131)

(a) (R) -1- (6-bromo-8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol

At N ₂ N, N-diisopropylethylamine (1.9 mL,10.8 mmol) and (2R) -2-methyl ethylene oxide (1 mL,14.4 mmol) were added in one portion to a mixture of 6-bromo-8-methoxy-1, 2,3, 4-tetrahydroisoquinoline hydrochloride (0.5 g,1.8 mmol) in EtOH (6 mL) under an atmosphere. The mixture was stirred at room temperature for 12 hours. The mixture was then concentrated to provide (R) -1- (6-bromo-8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (0.6 g, crude) as a yellow gum. MS: m/z found 300 and 302[ M+H ]] ⁺ .

(b) (R) -1- (8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol

At N ₂ To a mixture of (R) -1- (6-bromo-8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (0.6 g,2 mmol) and bis (pinacolato) diborane (1.02 g,4 mmol) in 1, 4-dioxane (15 mL) was added at once [1,1' -bis (biphenylphosphino) ferrocene]Palladium (II) dichloride in combination with dichloromethane (0.065 g,0.08 mmol) and potassium acetate (0.39 g,4 mmol). The mixture was stirred at 115℃for 12 hours. Concentrating the mixture and passing through normal phase SiO ₂ Chromatography (0-100% 30% THF in ethyl acetate/petroleum ether to 5% MeOH in ethyl acetate) purified the residue to afford (R) -1- (8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol as a yellow gum (0.45 g,55% yield). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ7.20(s,1H),7.14(s,1H),4.17-4.12(m,1H),3.87(s,3H),3.24-2.90(m,6H),2.82-2.80(m,2H),1.36(s,12H),1.24-1.22(m,3H).

(c) (6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester (((S) -5-oxopyrrolidin-2-yl) methyl)

At N ₂ To a mixture of (R) -1- (8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (0.17 g,0.5 mmol) and (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (0.18 g,0.29 mmol) in a 1, 4-dioxane/water mixture (8:1, 4.5 mL) was added at once [1,1' -bis (biphenylphosphino) ferrocene]Palladium (II) dichloride and methyl dichlorideAlkane complex (0.024 g,0.03 mmol) and potassium carbonate (0.12 g,0.88 mmol). The mixture was stirred at 110℃for 12 hours. The mixture was concentrated. To the residue was added water (5 mL) and saturated aqueous brine solution (5 mL) and the mixture was extracted with ethyl acetate/THF mixture (1:1, 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ Chromatography (30% 25% THF in ethyl acetate/petroleum ether to ethyl acetate/THF/meoh=10/3/1) purified the residue to afford tert-butyl ((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (0.175 g,50% yield) as a green gum. MS: m/z found 794[ M+H ]] ⁺ .

(d) (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

To a mixture of tert-butyl ((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (0.17 g,0.21 mmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (1.8 mL) at one time. The mixture was stirred at room temperature for 20 minutes and then the mixture was concentrated. The residue was purified by reverse phase HPLC to provide (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (52.1 mg,32% yield) as a pale yellow solid (formate). MS: m/z found 694[ M+H ] ] ⁺ Retention time = 2.73min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),7.76(dd,1H),7.60(t,1H),7.48-7.40(m,2H),7.20-7.19(m,3H),4.47-4.39(m,2H),4.30(m,1H),4.09-4.06(m,5H),3.95-3.91(m,4H),3.60-3.59(m,2H),3.28-3.17(m,4H),2.88-2.83(m,2H),2.42-2.30(m,3H),1.88-1.81(m,1H),1.30(d,3H).

Example 450: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (132)

(a) 6-bromo-2- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinoline

At N ₂ To a mixture of 6-bromo-8-methoxy-1, 2,3, 4-tetrahydroisoquinoline (0.4 g,1.65 mmol) and (2-bromoethoxy) (tert-butyl) dimethylsilane (0.59 g,2.48 mmol) in acetonitrile (8 mL) was added triethylamine (1.4 mL,9.91 mmol) in one portion under an atmosphere and the mixture was stirred at 100deg.C for 12 hours. The mixture was concentrated. To the residue were added water (5 mL) and a saturated aqueous brine solution (5 mL). The mixture was extracted with ethyl acetate/THF mixture (1:1, 20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-30% ethyl acetate/petroleum ether) to provide 6-bromo-2- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinoline (0.45 g,62% yield) as a yellow gum. ¹ H NMR(400MHz,CDCl ₃ ):δ6.80(s,1H),6.70(s,1H),3.79-3.76(m,2H),3.71(s,3H),3.50(m,2H),2.76-2.65(m,6H),0.84(s,9H),0.00(s,6H).

(b) 2- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,2,3, 4-tetrahydroisoquinoline

At N ₂ Potassium acetate (0.21 g,2.1 mmol) and [1,1' -bis (biphenylphosphino) ferrocene were added in one portion to a mixture of 6-bromo-2- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinoline (0.42 g,1.05 mmol) and bis (pinacolato) diborane (0.45 g,1.78 mmol) in 1, 4-dioxane (5 mL) under an atmosphere]Palladium (II) dichloride complex with dichloromethane (0.04 g,0.05 mmol) and the mixture was stirred at 110 ℃ for 12 hours. Concentrating the mixture and passing through normal phase SiO ₂ The residue was purified by chromatography (0-30% THF in ethyl acetate/petroleum ether) to provide 2- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,2,3, 4-tetrahydroisoquinoline as a yellow gum (0.4 g,78% yield). ¹ H NMR(400MHz,CDCl ₃ ):δ7.13(s,1H),6.98(s,1H),3.85-3.71(m,5H),3.67-3.58(m,2H),2.83(m,2H),2.75-2.70(m,4H),1.27(s,12H),0.83(s,9H),0.00(s,6H).

(c) (S) - ((6- (3- (2- (2- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

At N ₂ To a mixture of tert-butyl 2- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,2,3, 4-tetrahydroisoquinoline (0.18 g,0.41 mmol) and (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (0.18 g,0.3 mmol) in a 1, 4-dioxane/water mixture (9:1, 5 ml) was added potassium carbonate (0.12 g,0.89 mmol) and [1,1' -bis (biphenylphosphino) ferrocene at one time under an atmosphere ]Palladium (II) dichloride complex with dichloromethane (0.024 g,0.03 mmol) and the mixture was stirred at 110 ℃ for 12 hours. The mixture was concentrated. To the residue was added water (5 mL) and saturated aqueousBrine solution (5 mL) and the mixture was extracted with ethyl acetate/THF mixture (1:1, 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-70% 25% THF in ethyl acetate/petroleum ether to 15% 30% THF in MeOH/ethyl acetate) to afford tert-butyl (5-oxopyrrolidin-2-yl) methyl) carbamate (0.27 g,54% yield) MS: m/z found 894[ m+h ] as a brown gum] ⁺ .

(d) (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

To a mixture of tert-butyl (6- (3- (2- (2- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (0.265 g,0.3 mmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (3.5 mL) at one time and the mixture stirred at room temperature for 5 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (35.4 mg,15% yield) as a yellow solid (formate). MS: m/z found 680[ M+H ] ] ⁺ Retention time = 2.61min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),7.75(dd,1H),7.59(t,1H),7.47-7.45(m,2H),7.17-7.15(m,3H),4.27-4.25(m,2H),4.08(s,3H),3.95-3.93(m,7H),3.89-3.85(m,1H),3.44-3.42(m,2H),3.29-3.27(m,2H),3.19(m,2H),2.80-2.72(m,2H),2.38-2.27(m,3H),1.87-1.79(m,1H).

Example 451: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (176)

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (27.8 mg,29% yield, formate) was prepared in step (a) using 6-bromo-8-methoxy-1, 2,3, 4-tetrahydroisoquinoline and (S) -2-methyl oxirane in analogy to example 449. MS: m/z found 694[ M+H ]] ⁺ Retention time = 2.58min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),7.76(dd,1H),7.60(t,1H),7.48-7.45(m,2H),7.19-7.17(m,3H),4.43-4.27(m,3H),4.09(s,3H),4.01(s,2H),3.95(s,3H),3.93-3.88(m,1H),3.58-3.53(m,2H),3.26-3.13(m,4H),2.85-2.77(m,2H),2.39-2.29(m,3H),1.87-1.80(m,1H),1.29(d,3H).

Example 452: (S) -1- (((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol (214)

(a) (R) -1- (6-bromo-8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol

The scintillation vial was charged with 6-bromo-8-methoxy-1, 2,3, 4-tetrahydroisoquinoline hydrochloride (0.5 g,1.79 mmol), (R) -2-methyl oxirane (1.04 g,17.95 mmol), and N, N-diisopropylethylamine (0.94 ml,5.38 mmol). Then add Ethanol (15 mL) and the reaction was stirred at 85 ℃ for 1 hour. By passing throughThe mixture was filtered and the filter cake was washed with ethyl acetate (3×40 mL). The filtrate was concentrated under reduced pressure. By positive rapid SiO ₂ Chromatography, purification of the residue using a gradient (0-60% ethyl acetate/hexanes) provided (R) -1- (6-bromo-8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (0.4 g,74% yield). MS: m/z found 300[ M+H ]] ⁺ .

(b) (R) -1- (8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol

The microwave vial was charged with (R) -1- (6-bromo-8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (0.40 g,1.33 mmol), bis (pinacolato) diborane (0.37 g,1.47 mmol), potassium acetate (0.37 g,3.73 mmol), and 1,1' -bis (biphenylphosphino) ferrocene-palladium (II) dichloromethane complex (0.08 g,0.09 mmol). The flask was purged with nitrogen for 5 minutes, then dried dioxane (2 mL) was added and the reaction was bubbled with nitrogen for 5 minutes. The mixture was stirred thermally at 90℃for 1 hour. By passing throughThe mixture was filtered and the filter cake was washed with ethyl acetate (3×40 mL). The filtrate was concentrated under reduced pressure. By positive rapid SiO ₂ Chromatography using a gradient (0-10% methanol/CH ₂ Cl ₂ ) The residue was purified to provide (R) -1- (8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (0.36 g,78% yield). MS: m/z found 348[ M+H ]] ⁺ .

(c) (R) -6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde

The microwave vial was charged with (R) -1- (8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (0.36 g,1.04 mmol), 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (0.41 g,1.04 mmol), cesium carbonate (1.01 g,3.11 mmol), and tetrakis (triphenylphosphine) palladium (0) (0.08 g,0.07 mmol). 1, 4-dioxane (2 ml) was added, and the reaction was bubbled with nitrogen, followed by the addition of water (0.3 ml). The mixture was stirred thermally at 90℃for 1 hour. By passing throughThe mixture was filtered and the filter cake was washed with ethyl acetate (3×15 mL). The filtrate was concentrated under reduced pressure. By positive rapid SiO ₂ Chromatography, purification of the residue using a gradient (0-5% methanol DCM) provided (R) -6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (0.35 g,58% yield). MS: m/z found 578[ M+H ] ] ⁺ .

(d) (S) -1- (((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol

To a mixture of (R) -6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (0.07 g,0.11 mmol), and (S) -1-aminopropane-2-ol (0.02 g,0.22 mmol) in 1:1THF/MeOH (6 mL) was added acetic acid (0.01 g,0.22 mmol) and 4A molecular sieve (1 g). The mixture was stirred at room temperature for 3 hours. Sodium cyanoborohydride (0.02 g,0.28 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction was quenched by the addition of water (1 mL). The mixture was diluted with ethyl acetate (50 mL), then washed with saturated aqueous brine solution (30 mL), thenThe aqueous layer was extracted with ethyl acetate (3×30 mL), and the combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to provide (S) -1- (((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol (15 mg,21% yield) as a white solid (formate salt). MS: m/z found 637[ M+H ] ] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.58(d,1H),8.50(s,1H),7.79(d,1H),7.68(dd,1H),7.53(t,1H),7.43–7.36(m,2H),7.29(d,1H),7.04(d,2H),4.15–4.00(m,6H),4.03–3.93(m,1H),3.85(s,5H),3.00(s,4H),2.91(d,1H),2.79–2.67(m,3H),1.19(dd,6H).

Example 453: (1R, 3R) -3- (((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol (215)

(1R, 3R) -3- (((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol) was prepared in a similar manner to example 452 by substituting (1R, 3R) -3-amino-1-methylcyclobutan-1-ol for (S) -1-aminopropane-2-ol in step (d). MS: m/z found 663[ M+H ]] ⁺ ； ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.58(d,1H),8.50(s,1H),7.77(d,1H),7.67(dd,1H),7.53(t,1H),7.39(d,2H),7.27(d,1H),7.04(d,2H),4.14–4.05(m,1H),4.03(s,3H),3.94(s,2H),3.88(s,1H),3.85(s,4H),3.76–3.65(m,1H),3.01(s,4H),2.72(d,2H),2.31(t,2H),2.03(d,2H),1.33(s,3H),1.19(d,3H).

Example 454: (R) -1- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (216)

(R) -1- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -tetrahydrofuranyl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol was prepared in step (d) using (S) - (tetrahydrofuran-2-yl) methylamine instead of (S) -1-aminopropane-2-ol in a similar manner to example 452. MS: m/z found 663[ M+H ] ] ⁺ ； ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.57(d,1H),8.50(s,1H),7.75(d,1H),7.68(dd,1H),7.52(t,1H),7.42–7.35(m,2H),7.26(d,1H),7.02(d,2H),4.00(d,6H),3.85(s,4H),3.80–3.70(m,2H),2.95(d,5H),2.88(dd,1H),2.77(t,1H),2.64(s,2H),2.11–1.98(m,1H),1.96–1.83(m,2H),1.62–1.48(m,1H),1.18(d,3H).

Example 455: (R) -1- ((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -3-methylazetidin-3-ol (217)

(R) -1- ((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -3-methylazetidin-3-ol was prepared in analogy to example 452 using 3-methylazetidin-3-ol instead of (S) -1-aminopropane-2-ol in step (d). MS: m/z found 649[ M+H ]] ⁺ ； ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.59(d,1H),8.44(s,1H),7.75(d,1H),7.68(dd,1H),7.52(t,1H),7.44–7.35(m,2H),7.28(d,1H),7.10(s,2H),4.20–4.15(m,3H),4.08(s,3H),4.00(s,3H),3.88(s,3H),3.78(d,3H),3.64–3.59(m,3H),3.11(s,2H),3.00–2.92(m,2H),1.48(s,3H),1.22(d,3H).

Example 456: (R) - ((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) glycine methyl ester (218)

In a similar manner to example 452, (R) - ((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) glycine methyl ester was prepared in step (d) using glycine methyl ester instead of (S) -1-aminopropane-2-ol. MS: m/z found 651[ M+H ]] ⁺ ； ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.57(d,1H),8.50(s,1H),7.68(t,2H),7.51(t,1H),7.42–7.33(m,2H),7.21(d,1H),7.03(d,2H),4.13–4.03(m,1H),3.98(s,3H),3.82(d,7H),3.67(s,3H),3.41(s,2H),2.98(s,4H),2.66(s,2H),1.18(d,3H).

Example 457: (R) - ((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) glycine (229)

(a) (R) - ((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) glycine

The vial was fed with (R) - ((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) glycine methyl ester (example 456) (0.01 g,0.02 mmol) followed by the addition of 1, 4-dioxane (1.5 ml). Separately, another vial was fed with lithium hydroxide monohydrate (0.002g, 0.05 mmol) and then dissolved in water (0.5 ml). The solutions were combined and stirred at room temperature for 1 hour, then purified directly by reverse phase HPLC (0.05% formic acid modifier) to afford (R) - ((6- (2-chloro-3- (3-chloro-2)) as a white solid (formate salt)- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) glycine (8 mg,50% yield). MS: m/z found 637[ M+H ]] ⁺ ； ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.59(d,1H),8.49(s,1H),7.84(d,1H),7.70(dd,1H),7.54(t,1H),7.44–7.37(m,2H),7.31(d,1H),7.07(d,2H),4.26(s,2H),4.19–4.09(m,1H),4.06(s,3H),4.04–3.92(m,2H),3.87(s,3H),3.51(s,2H),3.20–3.11(m,2H),3.06(s,2H),2.90–2.81(m,2H),1.21(d,3H).

Example 458:1- (6- ((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one (249)

(a) 6-bromo-2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinoline

The scintillation vial was charged with 6-bromo-8-methoxy-1, 2,3, 4-tetrahydroisoquinoline hydrochloride (0.5 g,1.79 mmol), 1-bromo-3-fluoropropane (0.73 g,3.59 mmol), and potassium carbonate (0.74 ml,5.38 mmol). Acetonitrile (15 ml) was then added and the reaction stirred at room temperature for 2 hours. By passing throughThe mixture was filtered and the filter cake was washed with ethyl acetate (3×40 mL). The filtrate was concentrated under reduced pressure. By positive rapid SiO ₂ Chromatography, purification of the residue using a gradient (0-60% ethyl acetate/hexane) provided 6-bromo-2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinoline (0.41 g,74% yield). MS: m/z found 302[ M+H ]] ⁺ .

(b) 2- (3-fluoropropyl) -8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,2,3, 4-tetrahydroisoquinoline

With 6-bromo-2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinoline (0.41 g,1.36 mmol), bis (pinacolato) diborane (0.38 g,1.49 mmol), potassium acetate (0.37 g,3.80 mmol), and [1,1' -bis (biphenylphosphino) ferrocene]A microwave vial was fed with a complex of palladium (II) dichloride and dichloromethane (0.08 g,0.09 mmol). The flask was purged with nitrogen for 5 minutes, then dried 1, 4-dioxane (2 mL) was added and the reaction was bubbled with nitrogen for 5 minutes. The mixture was stirred thermally at 90℃for 1 hour. By passing through The mixture was filtered and the filter cake was washed with ethyl acetate (3×40 mL). The filtrate was concentrated under reduced pressure. By positive rapid SiO ₂ Chromatography using a gradient (0-10% methanol/CH ₂ Cl ₂ ) The residue was purified to give 2- (3-fluoropropyl) -8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 4-tetrahydroisoquinoline (0.45 g,96% yield). MS: m/z found 350[ M+H ]] ⁺ .

(c) 6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde

The microwave vial was charged with 2- (3-fluoropropyl) -8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,2,3, 4-tetrahydroisoquinoline (0.25 g,0.72 mmol), 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (0.28 g,0.72 mmol), cesium carbonate (0.70 g,2.15 mmol), and tetrakis (triphenylphosphine) palladium (0) (0.06 g,0.05 mmol). 1, 4-dioxane (2 ml) was added, and the reaction was bubbled with nitrogen, followed by the addition of water (0.3 ml). The mixture was stirred thermally at 90℃for 1 hour. By passing throughThe mixture was filtered and the filter cake was washed with ethyl acetate (3×15 mL). The filtrate was concentrated under reduced pressure. By positive rapid SiO ₂ Chromatography using a gradient (0-5% methanol/CH ₂ Cl ₂ ) The residue was purified to provide 6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (0.41 g,100% yield). MS: m/z found 580[ M+H ] ] ⁺ .

(d) 1- (6- ((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one

To 6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (0.08 g,0.14 mmol) and 1- (2, 6-diazaspiro [3.3]]A mixture of heptane-2-yl) and ethan-1-one (0.05 g,0.28 mmol) in 1:1THF/MeOH (6 mL) was added acetic acid (0.02 g,0.28 mmol) and 4A molecular sieve (1 g). The mixture was stirred at room temperature for 3 hours. Sodium cyanoborohydride (0.02 g,0.34 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction was quenched by the addition of water (1 mL). The mixture was diluted with ethyl acetate (50 mL), washed with saturated aqueous brine solution (30 mL), then the aqueous layer was extracted with ethyl acetate (3×30 mL), and the combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (containing 0.05% formic acid modifier) to afford 1- (6- ((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] as a white solid (formate salt) ]Heptane-2-yl) ethan-1-one (7.5 mg,8% yield). MS: m/z found 704[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.58(d,1H),8.43(s,1H),7.72(d,1H),7.67(dd,1H),7.52(t,1H),7.43–7.34(m,2H),7.25(d,1H),7.08(d,2H),4.87(s,1H),4.60(t,1H),4.48(t,1H),4.30(s,2H),4.05(s,2H),4.02–3.90(m,7H),3.89–3.73(m,7H),3.14–2.98(m,6H),2.19–2.01(m,1H),1.81(s,3H).

Example 459:2- ((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one (250)

In a manner analogous to example 458, 2, 6-diazaspiro [3.4] is used in step (d)]Octane-7-ketone substituted 1- (2, 6-diazaspiro [3.3]]Preparation of 2- ((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] ethan-1-one]Octane-7-one. MS: m/z found 690[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.59(d,1H),8.40(s,1H),7.75(d,1H),7.67(dd,1H),7.52(t,1H),7.43–7.34(m,2H),7.26(d,1H),7.09(s,2H),4.61(t,1H),4.49(t,1H),4.06–3.97(m,7H),3.88(s,3H),3.76(s,4H),3.60(s,2H),3.20(t,2H),3.15–3.06(m,4H),2.61(s,2H),2.22–2.04(m,2H).

Example 460: n- ((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2-oxaspiro [3.3] heptane-6-amine (251)

In a manner analogous to example 458, 2-oxaspiro [3.3] is used in step (d)]Heptan-6-amine replaces 1- (2, 6-diazaspiro [3.3]]Preparation of N- ((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2-oxaspiro [3.3] ethan-1-one ]Heptane-6-amine. MS: m/z found 677[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.58(d,1H),8.48(s,1H),7.77(d,1H),7.67(dd,1H),7.53(t,1H),7.43–7.34(m,2H),7.27(d,1H),7.06–7.02(m,2H),4.69(s,2H),4.59(d,3H),4.46(t,1H),4.02(s,3H),3.82(d,6H),3.53–3.40(m,1H),2.99(d,2H),2.96–2.88(m,2H),2.84(t,3H),2.61(t,2H),2.21(t,2H),2.13–1.95(m,1H).

Example 461: (1- ((((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) cyclopropyl) methanol (252)

In a similar manner to example 458, 1- (2, 6-diazaspiro [3.3 ] was replaced with (1- (aminomethyl) cyclopropyl) methanol in step (d)]Heptane-2-yl) ethan-1-one preparation (1- ((((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) cyclopropyl) methanol. MS: m/z found 665[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.58(d,1H),8.49(s,1H),7.81(d,1H),7.69(dd,1H),7.54(t,1H),7.44–7.36(m,2H),7.32(d,1H),7.03(d,2H),4.57(t,1H),4.46(t,1H),4.21(s,2H),4.05(s,3H),3.85(s,3H),3.72(s,2H),3.55(s,2H),3.13(s,2H),2.98(t,2H),2.87(t,2H),2.79(t,2H),2.12–1.94(m,2H),0.64(d,4H).

Example 462: (S) -3- (6- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propanoic acid methyl ester (272)

(a) 3- (6-bromo-8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propionic acid methyl ester

With 6-bromo-8-methylThe scintillation vials were charged with oxy-1, 2,3, 4-tetrahydroisoquinoline hydrochloride (0.05 g,0.18 mmol), methyl 3-bromopropionate (0.04 g,0.27 mmol), and potassium carbonate (0.07 ml,0.54 mmol). Acetonitrile (15 ml) was then added and the reaction stirred at room temperature for 2 hours. By passing through The mixture was filtered and the filter cake was washed with ethyl acetate (3×40 mL). The filtrate was concentrated under reduced pressure. By positive rapid SiO ₂ Chromatography, purification of the residue using a gradient (0-60% ethyl acetate/hexanes) provided methyl 3- (6-bromo-8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propionate (0.16 g,75% yield). MS: m/z found 328[ M+H ]] ⁺ .

(b) 3- (8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) propionic acid methyl ester

Methyl 3- (6-bromo-8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propionate (0.16 g,0.49 mmol), bis (pinacolato) diborane (0.14 g,0.54 mmol), potassium acetate (0.13 g,1.37 mmol), and [1,1' -bis (biphenylphosphino) ferrocene]A microwave vial was fed with a complex of palladium (II) dichloride and dichloromethane (0.04 g,0.05 mmol). The flask was purged with nitrogen for 5 minutes, then dried 1, 4-dioxane (2 mL) was added and the reaction was bubbled with nitrogen for 5 minutes. The mixture was stirred thermally at 90℃for 1 hour. By passing throughThe mixture was filtered and the filter cake was washed with ethyl acetate (3×40 mL). The filtrate was concentrated under reduced pressure and passed through normal phase flash SiO ₂ Chromatography using a gradient (0-5% methanol/CH ₂ Cl ₂ ) The residue was purified to give methyl 3- (8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) propionate (0.16 g,88% yield). MS: m/z found 376[ M+H ] ] ⁺ .

(c) 3- (6- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propionic acid methyl ester

The microwave vial was charged with methyl 3- (8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) propionate (0.15 g,0.40 mmol), 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (0.16 g,0.40 mmol), cesium carbonate (0.39 g,1.20 mmol), and tetrakis (triphenylphosphine) palladium (0) (0.05 g,0.04 mmol). 1, 4-dioxane (2 mL) was added, and the reaction was bubbled with nitrogen, followed by the addition of water (0.3 mL). The mixture was stirred thermally at 90℃for 1 hour. By passing throughThe mixture was filtered and the filter cake was washed with ethyl acetate (3×15 mL). The filtrate was concentrated under reduced pressure. By positive rapid SiO ₂ Chromatography using a gradient (0-5% methanol/CH ₂ Cl ₂ ) The residue was purified to give methyl 3- (6- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propanoate (0.24 g,100% yield). MS: m/z found 606[ M+H ]] ⁺ .

(d) (S) -3- (6- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propanoic acid methyl ester

To a mixture of methyl 3- (6- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propanoate (0.12 g,0.20 mmol) and (S) -1-aminopropane-2-ol (0.03 g,0.40 mmol) in 1:1THF/MeOH (6 mL) was added acetic acid (0.02 g,0.40 mmol) and 4A molecular sieve (1 g). The mixture was stirred at room temperature for 3 hours. AddingSodium cyanoborohydride (0.03 g,0.49 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction was quenched by the addition of water (1 ml). The mixture was diluted with ethyl acetate (50 mL), then washed with saturated aqueous brine solution (30 mL), then the aqueous layer was extracted with ethyl acetate (3×30 mL), and the combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (0.05% formic acid modifier) to afford methyl (S) -3- (6- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propanoate (20 mg,15% yield) as a white solid (formate). MS: m/z found 665[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.57(d,1H),7.76–7.64(m,2H),7.52(t,1H),7.42–7.34(m,2H),7.25(d,1H),7.01(d,2H),4.87(s,1H),4.01(s,3H),3.99–3.83(m,6H),3.65(d,5H),2.98–2.86(m,4H),2.77(t,2H),2.72–2.54(m,3H),1.16(d,3H).

Example 463:3- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propanoic acid methyl ester (273)

(a) 3- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propanoic acid methyl ester

In a similar manner to example 462, 2, 6-diazaspiro [3.4] was used in step (d)]Preparation of 3- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4 ]) by substituting (S) -1-aminopropane-2-ol with octan-7-one]Octan-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propionic acid methyl ester. MS: m/z realMeasured value 716[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.57(d,1H),8.50(s,1H),7.71–7.63(m,2H),7.51(t,1H),7.38(t,2H),7.22(d,1H),7.02(d,2H),3.97(s,3H),3.86(s,3H),3.73(s,2H),3.67(d,5H),3.56(s,2H),3.45(s,4H),2.92(d,2H),2.80(t,2H),2.66(t,2H),2.56(s,2H).

Example 464: (S) -3- (6- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propanoic acid (293)

(a) (S) -3- (6- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propanoic acid

The vial was charged with methyl (S) -3- (6- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propanoate (example 462) (0.01 g,0.02 mmol) followed by 1, 4-dioxane (1.5 ml). Separately, another vial was fed with lithium hydroxide monohydrate (0.002g, 0.05 mmol) and then dissolved in water (0.5 ml). The solutions were combined and stirred at room temperature for 1 hour, then purified directly by reverse phase HPLC (0.05% formic acid modifier) to afford (S) -3- (6- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propanoic acid (8 mg,50% yield) as a white solid (formate). MS: m/z found 651[ M+H ] ] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.59(d,1H),8.50(s,1H),7.78(d,1H),7.68(dd,1H),7.53(t,1H),7.43–7.35(m,2H),7.28(d,1H),7.10(d,2H),4.12(s,2H),4.07(d,2H),4.02–3.91(m,1H),3.88(s,3H),3.27(m,6H),3.11(t,2H),2.88(dd,1H),2.72(t,1H),2.60(t,2H),1.18(dd,3H).

Example 465:3- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propanoic acid (294)

In a similar manner to example 464, 3- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4 ]) was used in step (a)]Octane-2-yl) methyl pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propanoic acid methyl ester (example 463) was substituted for (S) -3- (6- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propanoic acid methyl ester to prepare 3- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [ 3.4)]Octan-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propionic acid. MS: m/z found 702[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.60(d,1H),8.45(s,1H),7.74–7.64(m,2H),7.52(t,1H),7.45–7.34(m,2H),7.24(d,1H),7.14(s,2H),4.29(s,2H),3.99(s,3H),3.88(d,5H),3.59(d,6H),3.50–3.36(m,4H),3.17(t,2H),2.69–2.56(m,4H).

Example 466: (S) -2- (6- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) acetamide (275)

In a similar manner to example 462, using 6-bromo-8-methoxy-1, 2,3, 4-tetrahydroisoquinoline hydrochloride and 2-bromoacetamide in step (a) and (S) -1-aminopropane-2-ol in step (d) to prepare (S) -2- (6- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- 3, 4-dihydroisoquinolin-2 (1H) -yl) acetamide. MS: m/z found 636[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.58(d,1H),8.52(s,1H),7.79(d,1H),7.69(dd,1H),7.53(t,1H),7.44–7.36(m,2H),7.29(d,1H),7.02(d,2H),4.87(s,3H),4.04(s,4H),3.84(s,3H),3.69(s,2H),3.23(s,2H),2.97(t,2H),2.88(dd,1H),2.82(t,2H),2.72(t,1H),1.19(d,3H).

Example 467:1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) cyclopropane-1-carboxylic acid methyl ester (295)

In a similar manner to example 462, 6-bromo-8-methoxy-1, 2,3, 4-tetrahydroisoquinoline hydrochloride and methyl 1- (bromomethyl) cyclopropane-1-carboxylate are used in step (a) and 2, 6-diazaspiro [3.4] is used in step (d)]Preparation of 1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4 ])]Octan-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) cyclopropane-1-carboxylic acid methyl ester. MS: m/z found 742[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.60(d,1H),8.40(s,1H),7.74(d,1H),7.68(dd,1H),7.52(t,1H),7.44–7.35(m,2H),7.26(d,1H),7.10(s,2H),4.13(s,2H),4.02–3.93(m,5H),3.88(s,3H),3.73–3.65(m,7H),3.60(s,2H),3.11(t,2H),2.61(s,2H),1.46–1.38(m,2H),1.14–1.06(m,2H).

Example 468:2- ((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoro-2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one (296)

In a similar manner to example 462, 6-bromo-8-methoxy was used in step (a)-1,2,3, 4-tetrahydroisoquinoline hydrochloride and 1-chloro-3-fluoropropane-2-ol and using 2, 6-diazaspiro [3.4] in step (d) ]Preparation of 2- ((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoro-2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4]Octane-7-one. MS: m/z found 706[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.59(d,1H),8.42(s,2H),7.70(dd,2H),7.52(t,1H),7.44–7.35(m,2H),7.26(d,1H),7.07(d,2H),4.55–4.41(m,1H),4.43–4.29(m,1H),4.27–4.13(m,1H),4.01(d,5H),3.94(s,2H),3.87(s,3H),3.69(s,4H),3.59(s,2H),3.18(t,2H),3.11–3.04(m,2H),3.05–2.91(m,2H),2.61(s,2H).

Example 469:1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) cyclopropane-1-carboxylic acid (297)

In a similar manner to example 464, 1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4 ]) was used in step (a)]Octane-2-yl) methyl pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) cyclopropane-1-carboxylic acid methyl ester (example 467) was used instead of (S) -3- (6- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propionic acid methyl ester to prepare 1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [ 3.4)]Octan-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) cyclopropane-1-carboxylic acid. MS: m/z found 728[ M+H ] ] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.60(d,1H),8.47(s,1H),7.68(t,2H),7.52(t,1H),7.45–7.34(m,2H),7.23(d,1H),7.15(s,2H),4.39(s,2H),3.94(d,6H),3.81(s,2H),3.56(d,9H),3.34–3.29(m,3H),2.58(s,2H),1.30(s,2H),0.78(s,2H).

Example 470:2- (3- (6- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) -2-oxopyrrolidin-1-yl) acetic acid (480)

(a) 2- (3- (6-bromo-8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) -2-oxopyrrolidin-1-yl) acetic acid tert-butyl ester

The scintillation vial was charged with 6-bromo-8-methoxy-1, 2,3, 4-tetrahydroisoquinoline hydrochloride (0.15 g,0.54 mmol), tert-butyl 2- (3-bromo-2-oxopyrrolidin-1-yl) acetate (0.15 g,0.54 mmol) and potassium carbonate (0.22 g,1.62 mmol). Acetonitrile (2 ml) was then added and the reaction stirred at 80℃for 2 hours. By passing throughThe mixture was filtered and the filter cake was washed with ethyl acetate (3×40 mL). The filtrate was concentrated under reduced pressure. By positive rapid SiO ₂ Chromatography using a gradient (0-5% MeOH/CH ₂ Cl ₂ ) The residue was purified to give tert-butyl 2- (3- (6-bromo-8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) -2-oxopyrrolidin-1-yl) acetate (0.23 g,100% yield). MS: m/z found 439[ M+H ]] ⁺ .

(b) 2- (3- (8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -2-oxopyrrolidin-1-yl) acetic acid tert-butyl ester

With tert-butyl 2- (3- (6-bromo-8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) -2-oxopyrrolidin-1-yl) acetate (0.31 g,0.71 mmol), bis (pinacolato) diborane (0.2)0g,0.78 mmol), potassium acetate (0.19 g,1.98 mmol), and [1,1' -bis (biphenylphosphino) ferrocene]A microwave vial was fed with a complex of palladium (II) dichloride and methylene chloride (0.06 g,0.07 mmol). The flask was purged with nitrogen for 5 minutes, then dried 1, 4-dioxane (2 mL) was added and the reaction was bubbled with nitrogen for 5 minutes. The mixture was stirred at 95℃for 30 minutes. By passing throughThe mixture was filtered and the filter cake was washed with ethyl acetate (3×40 mL). The filtrate was concentrated under reduced pressure. By positive rapid SiO ₂ Chromatography using a gradient (0-5% methanol/CH ₂ Cl ₂ ) The residue was purified to give tert-butyl 2- (3- (8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -2-oxopyrrolidin-1-yl) acetate (0.29 g,85% yield). MS: m/z found 487[ M+H ]] ⁺ .

(c) 2- (3- (6- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) -2-oxopyrrolidin-1-yl) acetic acid tert-butyl ester

The microwave vial was charged with tert-butyl 2- (3- (8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) -2-oxopyrrolidin-1-yl) acetate (0.29 g,0.60 mmol), 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (0.23 g,0.60 mmol), cesium carbonate (0.58 g,1.79 mmol), and tetrakis (triphenylphosphine) palladium (0) (0.07 g,0.06 mmol). 1, 4-dioxane (2 ml) was added, the reaction was bubbled with nitrogen, and then water (0.3 ml) was added. The mixture was stirred at 95℃for 30 minutes. By passing through The mixture was filtered and the filter cake was washed with ethyl acetate (3×15 mL). The filtrate was concentrated under reduced pressure. By positive rapid SiO ₂ Chromatography using a gradient (0-5% methanol/CH ₂ Cl ₂ ) The residue was purified to give tert-butyl 2- (3- (6- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) -2-oxopyrrolidin-1-yl) acetate (0.25 g,59% yield). MS: m/z found 717[ M+H ]] ⁺ .

(d) 2- (3- (6- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) -2-oxopyrrolidin-1-yl) acetic acid tert-butyl ester

To a mixture of tert-butyl 2- (3- (6- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) -2-oxopyrrolidin-1-yl) acetate (0.12 g,0.17 mmol) and 1- (4-aminopiperidin-1-yl) ethan-1-one (0.05 g,0.33 mmol) in 1:1THF/MeOH (2 mL) was added acetic acid (0.02 g,0.33 mmol) and 4A molecular sieve (1 g). The mixture was stirred at room temperature for 3 hours. Sodium cyanoborohydride (0.03 g,0.42 mmol) was added and the mixture was stirred at room temperature for 1 hour, then the reaction was quenched by the addition of water (1 ml). The mixture was diluted with ethyl acetate (50 mL), washed with saturated aqueous brine solution (30 mL), and the aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure to provide tert-butyl 2- (3- (6- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) -2-oxopyrrolidin-1-yl) acetate. MS: m/z found 843[ M+H ] ] ⁺ . The crude product was used in the next step without further purification.

(e) 2- (3- (6- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) -2-oxopyrrolidin-1-yl) acetic acid

The crude tert-butyl 2- (3- (6- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) -2-oxopyrrolidin-1-yl) acetate was diluted with dichloromethane (6 ml) and treated with trifluoroacetic acid (2 ml). The reaction mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure, and the residue was purified by reverse phase HPLC (containing 0.05% formic acid modifier) to afford 2- (3- (6- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) -2-oxopyrrolidin-1-yl) acetic acid (23 mg,81% yield) as a white solid (formate). MS: m/z found 787[ M+H ]] ⁺ ； ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.55(d,1H),8.35(s,1H),7.85(d,1H),7.67(dd,1H),7.52(t,1H),7.42–7.33(m,2H),7.31(d,1H),7.03–6.96(m,2H),4.63(d,1H),4.24(s,2H),4.12–3.95(m,5H),3.88(t,1H),3.85–3.73(m,5H),3.55–3.35(m,2H),3.27(q,2H),3.23–3.08(m,2H),2.90(d,3H),2.67(t,1H),2.31–2.14(m,3H),2.10(s,3H),1.67–1.41(m,2H).

Example 471: (S) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2,1-f ] [1,2,4] triazin-2-yl) methyl) azetidine-3-carboxylic acid methyl ester (182)

(a) (S) -1- ((6- (4- (3- (5- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2,1-f ] [1,2,4] triazin-2-yl) methyl) azetidine-3-carboxylic acid methyl ester

To (S) - ((6- (2-chloro-3- (3-chloro-2- (2- (hydroxymethyl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2, 1-f)][1,2,4]A solution of t-butyl triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (33 mg,0.04 mmol) in dichloromethane (0.4 mL) was added methanesulfonyl chloride (4. Mu.L, 0.05 mmol) and triethylamine (19. Mu.L, 0.13 mmol). The reaction was stirred at room temperature for 1 hour. LCMS indicated the formation of the desired mesylate. The solvent was evaporated and the residue taken in DMF (0.4 mL). Potassium carbonate (19 mg,0.13 mmol) and azetidine-3-carboxylic acid methyl ester hydrochloride (20 mg,0.13 mmol) were added, and the reaction was stirred at room temperature for 12 hours. LCMS indicated the formation of the desired product. The solvent was evaporated and the residue was suspended in water. The precipitate formed is collected to provide (S) -1- ((6- (4- (3- (5- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2, 1-f) ][1,2,4]Triazin-2-yl) methyl azetidine-3-carboxylic acid methyl ester (31 mg, 83%). The material was used as such without any purification. MS: m/z found 831[ M+H ]] ⁺ .

(b) (S) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2,1-f ] [1,2,4] triazin-2-yl) methyl) azetidine-3-carboxylic acid methyl ester

From (S) -1- ((6- (4- (3- (5- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2, 1-f) using the general Boc deprotection procedure][1,2,4]Preparation of (S) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((5-oxopyrrolidine) wafer-size)) with methyl triazin-2-yl) methyl) azetidine-3-carboxylate (31 mg,0.04 mmol) and trifluoroacetic acid (57. Mu.L, 0.75 mmol)2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2,1-f][1,2,4]Triazin-2-yl) methyl) azetidine-3-carboxylic acid methyl ester. 11mg,40% yield. MS: m/z found 731.1[ M+H ]] ⁺ Retention time = 1.72min (method D). 1H NMR (400 MHz, methanol-D) ₄ )δ8.62–8.56(m,1H),8.17(d,1H),7.80(d,1H),7.70(d,1H),7.66(s,1H),7.54(t,1H),7.38(d,1H),7.29(t,2H),4.04(t,3H),4.02(s,2H),3.92(s,1H),3.77(s,2H),3.71(q,5H),3.60–3.54(m,5H),3.41(p，1H),2.91(t,2H),2.43–2.26(m,3H),1.86(d,1H).

Example 472:6- (3-chloro-4- (2-chloro-3- (5- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one (231)

From 6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2, 1-f) using reductive amination procedure B][1,2,4]Triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (15 mg,0.02 mmol), acetic acid (3 μl,0.05 mmol), 3-methylazetidin-3-ol; preparation of 6- (3-chloro-4- (2-chloro-3- (5- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2, 1-f) with sodium cyanoborohydride (6 mg,0.05 mmol)][1,2,4]Triazin-4 (3H) -one. 4.9mg,29% yield. MS: m/z found 676[ M+H ]] ⁺ Retention time = 1.67min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.60(d,1H),8.44(s,1H),8.19(d,1H),7.84(d,1H),7.71(d,1H),7.67(q,1H),7.58–7.50(m,1H),7.41(d,1H),7.34(d,1H),7.28(d,1H),4.32(s,2H),4.06(t,3H),4.02(d,2H),3.90(s,1H),3.87(s,3H),3.61–3.56(m,3H),3.54(d,2H),1.51(d,6H).

Example 473:6- (3-chloro-4- (2-chloro-3- (5- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one (222)

(a) 6-bromo-2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one

To 6-bromo-2- (hydroxymethyl) -3-methylpyrrolo [2,1-f ][1,2,4]A solution of triazin-4 (3H) -one (200 mg,0.77 mmol) in dichloromethane (0.5 mL) was added triethylamine (216. Mu.L, 1.55 mmol) and methanesulfonyl chloride (66. Mu.L, 0.85 mmol). The reaction was stirred at room temperature for 1h. LCMS indicated the formation of the desired mesylate. The solvent was evaporated and the residue was suspended in DMF (2 mL) followed by the addition of potassium carbonate (211 mg,1.55 mmol) and 3-methylazetidin-3-ol hydrochloride (192 mg,1.55 mmol). The mixture was stirred at room temperature for 12 hours. The solvent was evaporated and the residue was suspended in water. Collecting the precipitate formed to provide 6-bromo-2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f][1,2,4]Triazin-4 (3H) -one (203 mg, 80%). MS: m/z found 326.9[ M+H ]] ⁺ .

(b) 2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one

6-bromo-2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f][1,2,4]Triazin-4 (3H) -one (200 mg,0.61 mmol), bis (pinacolato) diborane (217 mg,0.86 mmol), potassium acetate (180 mg,1.83 mmol) and [1,1' -bis (biphenylphosphino) di-Ferrocene iron]The complex of palladium (II) dichloride with dichloromethane (50 mg,0.06 mmol) was suspended in 1, 4-dioxane (5 ml). Nitrogen was bubbled through the reaction for 2 minutes. The reaction was heated at 95℃for 3 hours. The reaction was concentrated and the residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to afford 2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyrrolo [2,1-f ][1,2,4]Triazin-4 (3H) -one (115 mg, 50%). MS: m/z found 375.1[ M+H ]] ⁺ .

(c) 6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2,1-f ] [1,2,4] triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde

To 2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyrrolo [2,1-f][1,2,4]A mixture of triazin-4 (3H) -one (114 mg,0.30 mmol) and 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (100 mg,0.25 mmol) in 1, 4-dioxane/water (4:1, 3 mL) was added potassium carbonate (105 mg,0.76 mmol). Nitrogen was bubbled through the mixture for two minutes. Tetrakis (triphenylphosphine) palladium (0) (59 mg,0.05 mmol) was added and the reaction stirred at 100 ℃ for 30 min. To the reaction mixture was added water (15 mL) followed by extraction with EtOAc (3×15 mL). The combined organic layers were washed with saturated aqueous brine solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by normal phase silica gel chromatography (0-5% MeOH in DCM) to provide 6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2, 1-f) ][1,2,4]Triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (104 mg, 68%). MS: m/z found 605.1[ M+H ]] ⁺ .

(d) 6- (3-chloro-4- (2-chloro-3- (5- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one

From 6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2, 1-f) using reductive amination procedure B][1,2,4]Triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (15 mg,0.02 mmol), acetic acid (3. Mu.L, 0.05 mmol), 2-azaspiro [3.3]]Preparation of 6- (3-chloro-4- (2-chloro-3- (5- ((6-hydroxy-2-azaspiro [3.3 ]) by heptane-6-ol hydrochloride (7 mg,0.05 mmol) and sodium cyanoborohydride (3 mg,0.05 mmol)]Heptane-2-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl-2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f][1,2,4]Triazin-4 (3H) -one. 14mg,79% yield. MS: m/z found 702.1[ M+H ]] ⁺ Retention time = 1.67min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.24–8.07(m,1H),7.85–7.69(m,1H),7.27(s,3H),7.11(d,1H),6.97(s,1H),6.85(dd,2H),3.69(s,1H),3.60(m,3H),3.52(s,2H),3.41–3.32(m,2H),3.17(m,4H),3.09–2.96(m,2H),2.95–2.68(m,8H),2.12(s,2H),1.65(s,2H),1.12–1.00(m,3H).

Example 474:6- (3-chloro-4- (2-chloro-3- (5- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one (232)

From 6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2, 1-f) using reductive amination procedure B][1,2,4]Triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (15 mg,0.02 mmol), acetic acid (3. Mu.L, 0.05 mmol), 3-amino-1-methyl-cyclobutanol hydrochloride (7 mg,0.05 mmol) and cyanoSodium borohydride (3 mg,0.05 mmol) preparation of 6- (3-chloro-4- (2-chloro-3- (5- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrpyrrolo [2, 1-f)][1,2,4]Triazin-4 (3H) -one. 5.1mg,30% yield. MS: m/z found 690.3[ M+H ]] ⁺ Retention time = 1.67min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.59(m,1H),8.52(s,1H),8.18(q,1H),7.81(d,1H),7.72–7.68(m,1H),7.66(q,1H),7.55(dd,1H),7.40(d,1H),7.34–7.25(m,2H),4.07(t,3H),4.02(s,2H),3.79(s,3H),3.59(t,3H),3.47(d,2H),3.22(d,2H),2.35(t,2H),2.09(t,2H),1.48(s,3H),1.36(t,3H).

Example 475:6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one (233)

From 6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2, 1-f) using reductive amination procedure B][1,2,4]Triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (15 mg,0.02 mmol), acetic acid (3. Mu.L, 0.05 mmol), propane-2-amine (3 mg,0.05 mmol) and sodium cyanoborohydride (3 mg,0.05 mmol) to prepare 6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ][1,2,4]Triazin-4 (3H) -one. 5.3mg,33% yield. MS: m/z found 650.1[ M+H ]] ⁺ Retention time = 1.78min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.59(dd,1H),8.54(d,1H),8.18(d,1H),7.81(d,1H),7.70(d,1H),7.66(d,1H),7.54(m,1H),7.39(d,1H),7.33–7.25(m,2H),4.07–4.05(m,3H),4.03(s,2H),3.78(s,2H),3.61–3.56(m,3H),3.45(d,2H),3.19(dd,3H),1.48(s,3H),1.28(d,6H).

Example 476:6- (3-chloro-4- (2-chloro-3- (5- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one (234)

From 6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2, 1-f) using reductive amination procedure B][1,2,4]Triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (15 mg,0.02 mmol), acetic acid (3. Mu.L, 0.05 mmol), (1 r,4 r) -4-aminocyclohexane-1-ol (6 mg,0.05 mmol) and sodium cyanoborohydride (3 mg,0.05 mmol) to prepare 6- (3-chloro-4- (2-chloro-3- (5- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f][1,2,4]Triazin-4 (3H) -one. 7.1mg,41% yield. MS: m/z found 704[ M+H ]] ⁺ Retention time = 1.67min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )。δ8.64–8.57(m,1H),8.53(s,1H),8.17(q,1H),7.83(d,1H),7.72–7.68(m,1H),7.66(q,1H),7.55(t,1H),7.40(dd,1H),7.35–7.25(m,2H),4.13(s,2H),4.06(t,3H),3.78(d,2H),3.59(t,3H),3.55(d,1H),3.46(d,2H),3.21(d,2H),2.95(d,1H),2.17(d,2H),2.04(d,2H),1.48(s,3H),1.46–1.28(m,4H).

Example 477: (S) - (2- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxy-4-oxopyrrolo [2,1-f ] [1,2,4] triazin-3 (4H) -yl) ethyl) glycine (460)

(a) 1-amino-4-bromo-1H-pyrrole-2-carboxylic acid methyl ester

A1.0M solution of lithium bis (trimethylsilyl) amide in THF (53.92 mL,53.92 mmol) was slowly added to a mixture of methyl 4-bromo-1H-pyrrole-2-carboxylate (10 g,49.0 mmol) suspended in DMF (400 mL) under nitrogen at-10deg.C. After stirring for 1 hour, O- (biphenylphosphinyloxy) hydroxylamine (11.4 g,49.0 mmol) was added. The resulting reaction mixture was allowed to warm to room temperature and stirred for 11 hours. The reaction (total of 6 batches) was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (2L). The combined organic layers were washed with water (1L) and brine, dried over sodium sulfate, and concentrated by evaporation. By normal phase SiO ₂ The residue was purified by chromatography (0-30% EtOAc/petroleum ether) to give methyl 1-amino-4-bromo-1H-pyrrole-2-carboxylate (38.3 g,59% yield) as a yellow solid. ¹ H NMR(400MHz,CDCl ₃ ):δ6.88(d,1H),6.74(d,1H),5.51-5.41(m,2H),3.76(s,3H).

(b) 1- (((benzyloxy) carbonyl) amino) -4-bromo-1H-pyrrole-2-carboxylic acid methyl ester

To a mixture of methyl 1-amino-4-bromo-1H-pyrrole-2-carboxylate (15.3 g,69.9 mmol) in 1, 4-dioxane (40 mL) was added water (40 mL) and sodium bicarbonate (8.80 g,105 mmol). Benzyl chloroformate (10.9 ml,76.8 mmol) was then added dropwise. The reaction was stirred at room temperature for 12 hours. To the mixture (3 batches total) was added ethyl acetate (500 mL) and the mixture was washed with water (600 mL) and concentrated in vacuo. By normal phase SiO ₂ The residue was purified by chromatography (0-50% EtOAc/petroleum ether) to afford methyl 1- (((benzyloxy) carbonyl) amino) -4-bromo-1H-pyrrole-2-carboxylate (80 g, crude) as a dark yellow oil. The product was used in the next step without further purification.

(c) 6-bromopyrrolo [2,1-f ] [1,2,4] triazine-2, 4 (1H, 3H) -dione

To methyl 1- (((benzyloxy) carbonyl) amino) -4-bromo-1H-pyrrole-2-carboxylate (10 g,28.3 mmol) was added 28% ammonium hydroxide solution (30 ml,218 mmol) in a sealed tube and the mixture was heated to 120 ℃ for 4 hours. The combined mixture was then concentrated directly under vacuum (7 batches). Ethanol (150 mL) was added to the residue, and the mixture was stirred at room temperature for 1 hour, then filtered, and washed with ethanol (60 mL). The filter cake was dried under reduced pressure to provide 6-bromopyrrolo [2,1-f ] [1,2,4] triazine-2, 4 (1H, 3H) -dione (15 g,32% yield) as a yellow solid.

(d) 6-bromo-2, 4-dichloropyrrolo [2,1-f ] [1,2,4] triazine

To 6-bromopyrrolo [2,1-f][1,2,4]To a mixture of triazine-2, 4 (1H, 3H) -dione (7 g,30.4 mmol) and triethylamine hydrochloride (12.6 g,91.3 mmol) was added phosphorus oxychloride (phosphoryl trichloride) (48.1 ml,517 mmol). The solution was then heated at 105 ℃ for 12 hours. After cooling to 0 ℃, the mixture (2 batches) was slowly quenched with saturated aqueous sodium bicarbonate to pH 8 and extracted with EtOAc (300 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Pure through normal phase SiO ₂ Chromatography (0-10% EtOAc/petroleum ether) of the residue afforded 6-bromo-2, 4-dichloropyrrolo [2,1-f as a white solid][1,2,4]Triazine (13 g,80% yield). ¹ H NMR(400MHz,DMSO-d6):δ8.62(d,1H),7.46(d,1H).

(e) 6-bromo-2-chloropyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one

To 6-bromo-2, 4-dichloropyrrolo [2,1-f][1,2,4]A solution of triazine (12 g,45 mmol) in THF (80 mL) was added sodium hydroxide (3.96 g,98.9 mmol) and water (80 mL). The mixture was stirred at room temperature for 12 hours. To the mixture was added 1N HCl to pH 3, and the mixture was extracted with ethyl acetate (100 mL). Wash the organic layer with brine (200 mL)Dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 6-bromo-2-chloropyrrolo [2,1-f ] as a white solid][1,2,4]Triazin-4 (3H) -one (10 g,89% yield) was used directly without further purification. ¹ H NMR(400MHz,DMSO-d ₆ ):δ13.07(br s,1H),7.91(s,1H),7.09(d,1H).

(f) 3-allyl-6-bromo-2-chloropyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one

To 6-bromo-2-chloropyrrolo [2,1-f][1,2,4]A mixture of triazin-4 (3H) -one (3 g,12.1 mmol) in DMF (30 mL) was added potassium tert-butoxide (2.03 g,18.1 mmol) and 3-iodoprop-1-ene (1.65 mL,18.1 mmol) and the reaction stirred at room temperature for 24 hours. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (60 mL). The organic layer was washed with brine (80 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ Chromatography (0-10% EtOAc/petroleum ether) purified the residue to afford 3-allyl-6-bromo-2-chloropyrrolo [2,1-f ] as a pale yellow solid][1,2,4]Triazin-4 (3H) -one (3 g,86% yield).

(g) 3-allyl-6-bromo-2-methoxypyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one

3-allyl-6-bromo-2-chloropyrrolo [2,1-f ] at 0deg.C][1,2,4]A mixture of triazin-4 (3H) -one (2 g,6.93 mmol) in THF (50 mL) was added as a 30% solution of sodium methoxide in methanol (1.19 g,6.59 mmol). The mixture was then allowed to warm to room temperature and stirred for 1 hour. Water (1 mL) was added to the reaction and the mixture was concentrated. To the residue was added water (20 mL) and the mixture was extracted with dichloromethane (50 mL). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. By normal phase SiO ₂ Chromatography (0-20% EtOAc/petroleum ether) of the residue afforded 3-allyl-6-bromo-2-methoxypyrazole as a yellow solidPyrrolo [2,1-f][1,2,4]Triazin-4 (3H) -one (1.41 g,69% yield). ¹ H NMR(400MHz,DMSO-d ₆ ):δ7.67(d,1H),6.94(d,1H),5.94-5.87(m,1H),5.17-5.11(m,2H),4.55-4.52(m,2H),3.99(s,3H).

(h) 2- (6-bromo-2-methoxy-4-oxopyrrolo [2,1-f ] [1,2,4] triazin-3 (4H) -yl) acetaldehyde

To 3-allyl-6-bromo-2-methoxypyrrolo [2,1-f ] at 0 DEG C][1,2,4]A solution of triazin-4 (3H) -one (1.4 g,4.93 mmol) in THF/water (1/1, 20 mL) was added to a 0.16M solution of osmium tetroxide in water (12.3 mL) followed by sodium periodate (6.96 g,32.5 mmol). The reaction was allowed to warm to room temperature and stirred for 12 hours. The reaction was quenched with saturated aqueous sodium sulfite (200 mL) and extracted with dichloromethane (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to afford 2- (6-bromo-2-methoxy-4-oxopyrrolo [2, 1-f) as a yellow solid ][1,2,4]Triazin-3 (4H) -yl) acetaldehyde (1 g, crude) was used in the next step without further purification. ¹ H NMR(400MHz,CDCl ₃ ):δ9.62(s,1H),7.81(s,1H),7.03(s,1H),4.87(s,2H),3.93(s,3H).

(i) N- (2- (6-bromo-2-methoxy-4-oxopyrrolo [2,1-f ] [1,2,4] triazin-3 (4H) -yl) ethyl) -N- (tert-butoxycarbonyl) glycine tert-butyl ester

To 2- (6-bromo-2-methoxy-4-oxopyrrolo [2, 1-f)][1,2,4]A mixture of triazin-3 (4H) -yl) acetaldehyde (0.75 g,2.62 mmol) in methanol (30 mL) was added tert-butyl glycinate (516 mg,3.93 mmol) and sodium acetate (640 mg,7.86 mmol) and the mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (494 mg,7.86 mmol) was then added and stirring continued for an additional 2 hours to provide (2- (6-bromo-2-methoxy-4-oxopyrrolo [2, 1-f)][1,2,4]Triazin-3 (4H) -yl) ethyl) glycine tert-butyl ester. Triethylamine (1.04 mL 7.48 mmol) and then were addedDi-tert-butyl dicarbonate (2.72 g,12.5 mmol) and the reaction stirred at room temperature for 12 hours. The mixture was concentrated under reduced pressure and passed through normal phase SiO ₂ Chromatography (0-10% EtOAc/petroleum ether) of the residue afforded N- (2- (6-bromo-2-methoxy-4-oxopyrrolo [2, 1-f) as a yellow oil][1,2,4]Triazin-3 (4H) -yl) ethyl) -tert-butyl N- (tert-butoxycarbonyl) glycine (0.75 g,57% yield). ¹ H NMR(400MHz,CDCl ₃ ):δ7.18(dd,1H),6.91(dd,1H),4.11-1.07(m,2H),3.98(d,3H),3.85(s,1H),3.75(s,1H),3.54-3.48(m,2H),1.42(d,9H),1.28(s,9H).

(j) N- (tert-Butoxycarbonyl) -N- (2- (2-methoxy-4-oxo-6- (4, 5-tetramethyl-1, 3, 2-dioxabor-en-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-3 (4H) -yl) ethyl) glycine tert-butyl ester

To N- (2- (6-bromo-2-methoxy-4-oxopyrrolo [2, 1-f)][1,2,4]A mixture of triazin-3 (4H) -yl) ethyl) -tert-butyl N- (tert-butoxycarbonyl) glycine (245 mg,0.49 mmol) and bis (pinacolato) diborane (372 mg,1.47 mmol) in 1, 4-dioxane (5 mL) was added potassium acetate (95.9 mg,0.98 mmol) followed by [1,1' -bis (biphenylphosphino) ferrocene]Palladium (II) dichloride complex with dichloromethane (39.9 mg,0.05 mmol) then the reaction was stirred at 110 ℃ for 5 hours. After cooling, the mixture was combined with another batch at 300mg scale, and water (10 mL) was added and the mixture extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. By normal phase SiO ₂ The residue was purified twice by chromatography (0-30% EtOAc/petroleum ether) to afford N- (tert-butoxycarbonyl) -N- (2- (2-methoxy-4-oxo-6- (4, 5-tetramethyl-1, 3, 2-dioxaboran-2-yl) pyrrolo [2, 1-f) as a yellow oil][1,2,4]Triazin-3 (4H) -yl) ethyl) glycine tert-butyl ester (270 mg total). MS: m/z found 571[ M+Na ]] ⁺ .

(k) (S) -N- (tert-Butoxycarbonyl) -N- (2- (6- (4- (3- (5- (((tert-Butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxy-4-oxopyrrolo [2,1-f ] [1,2,4] triazin-3 (4H) -yl) ethyl) glycine tert-butyl ester

At N ₂ Downward N- (tert-Butoxycarbonyl) -N- (2- (2-methoxy-4-oxo-6- (4, 5-tetramethyl-1, 3, 2-dioxaboran-2-yl) pyrrolo [2, 1-f)][1,2,4]A mixture of t-butyl triazin-3 (4H) -yl) ethyl glycinate (104 mg,0.18 mmol) and t-butyl (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (example 45, step (c)) (80 mg,0.13 mmol) in THF/water (4/1, 5 mL) was added at one time potassium phosphate (86.1 mg,0.4 mmol) and chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl)]Palladium (II) (XPhos Pd G2) (10.6 mg,0.01 mmol). The mixture was stirred at 80℃for 12 hours. Water (20 mL) was added to the reaction and the mixture was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated and passed through normal phase SiO ₂ Chromatography (0-100% EtOAc/petroleum ether) purification of the residue to afford (S) -N- (tert-butoxycarbonyl) -N- (2- (6- (4- (3- (5- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxy-4-oxopyrrolo [2, 1-f) as a yellow solid ][1,2,4]Triazin-3 (4H) -yl) ethyl) glycine tert-butyl ester (210 mg,43% yield).

(l) (S) - (2- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxy-4-oxopyrrolo [2,1-f ] [1,2,4] triazin-3 (4H) -yl) ethyl) glycine

To (S) -N- (tert-butoxycarbonyl) -N- (2- (6- (4- (3- (5- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl)) amino) methyl)) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxy-4-oxopyrrolo [2,1-f][1,2,4]A mixture of t-butyl triazin-3 (4H) -yl) ethyl glycinate (200 mg,205 mmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (3.00 mL,40.5 mmol) and the reaction stirred at room temperature for 12 hours. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC to afford (S) - (2- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-methoxy-4-oxopyrrolo [2, 1-f) as a white solid (formate salt)][1,2,4]Triazin-3 (4H) -yl) ethyl) glycine (16.4 mg,10% yield). MS: m/z found 721 and 723[ M+H ]] ⁺ Retention time = 2.76min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.58(d,1H),8.33(s,1H),8.13(d,1H),7.80(d,1H),7.71-7.69(m,2H),7.55(t,1H),7.39(dd,1H),7.31(d,1H),7.27(d,1H),4.39-4.36(m,2H),4.12(s,3H),4.05(s,3H),4.04-4.03(m,2H),3.94-3.89(m,1H),3.52(s,2H),3.36-3.33(m,2H),2.93-2.91(m,2H),2.36-2.32(m,4H).

Example 478: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (555)

(a) (2- (6-bromo-2-methoxy-4-oxopyrrolo [2,1-f ] [1,2,4] triazin-3 (4H) -yl) ethyl) (methyl) carbamic acid tert-butyl ester

To 2- (6-bromo-2-methoxy-4-oxopyrrolo [2, 1-f)][1,2,4]A mixture of triazin-3 (4H) -yl) acetaldehyde (850 mg,2.97 mmol) (example 477, step (H)) in methanol (10 mL) was added methylamine hydrochloride (1.00 g,14.9 mmol) and sodium acetate (1.46 g,17.8 mmol) and the mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (560 mg,8.91 mmol) and the mixture was stirred for a further 10 hours. Triethylamine (2.07 ml,14.9 mmol) and di-tert-butyl dicarbonate (3.89 g,17.8 mmol) were then added and the mixture was stirred at room temperature for 2 hours. The mixture was combined with another batch at 316mg scale, and water (15 mL) was added and the mixture extracted with dichloromethane (60 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-30% EtOAc/petroleum ether) to afford (2- (6-bromo-2-methoxy-4-oxopyrrolo [2, 1-f) as a yellow solid ][1,2,4]Triazin-3 (4H) -yl) ethyl) (methyl) carbamic acid tert-butyl ester (770 mg,85% purity). MS: m/z measured values 423 and 425[ M+Na ]] ⁺ .

(b) (2- (2-methoxy-4-oxo-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-3 (4H) -yl) ethyl) (methyl) carbamic acid tert-butyl ester

(2- (6-bromo-2-methoxy-4-oxopyrrolo [2, 1-f) at room temperature][1,2,4]Triazin-3 (4H) -yl) ethyl) (methyl) carbamic acid tert-butyl ester (400 mg,1.0 mmol), bis (pinacolato) diborane (1.01 g,4.0 mmol), potassium acetate (254 mg,2.99 mmol) and [1,1' -bis (biphenylphosphino) -ferrocene]A mixture of palladium (II) dichloride (72.9 mg,99.7 mmol) in 1, 4-dioxane (4 mL) was degassed for 0.3 hours. The reaction mixture was then stirred at 85 ℃ for 12 hours. After cooling, water (15 mL) was added and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ The residue was purified by chromatography (0-30% etoac/petroleum ether) twice to afford (2- (2-methoxy-4-oxo-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyrrolo [2, 1-f) as a yellow oil][1,2,4]Triazin-3 (4H) -yl) ethyl) (methyl) carbamic acid tert-butyl ester (180 mg,15% yield).

(c) (S) - ((6- (3- (2- (3- (2- ((tert-butoxycarbonyl) (methyl) amino) ethyl) -2-methoxy-4-oxo-3, 4-dihydropyrrolo [2,1-f ] [1,2,4] triazin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

At N ₂ Downward (2- (2-methoxy-4-oxo-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyrrolo [2, 1-f)][1,2,4]A mixture of t-butyl triazin-3 (4H) -yl) ethyl) (methyl) carbamate (45.4 mg,0.10 mmol) and t-butyl (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (example 45, step (c)) (50 mg,0.08 mmol) in ethanol/water (4/1, 1.25 mL) was added at one time potassium phosphate (35.9 mg,0.17 mmol) and chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl)]Palladium (II) (XPhos Pd G2) (6.65 mg,8.45 μmol). The mixture was stirred at 80℃for 12 hours. Water (5 mL) was added and the mixture extracted with ethyl acetate (40 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated and passed through normal phase SiO ₂ The residue was purified by chromatography (0-30% ethyl acetate/petroleum ether) to provide a yellow oil. By normal phase SiO ₂ Chromatography (100% EtOAc first, 10% methanol/ethyl acetate second) purified the oil twice to afford (S) - ((6- (3- (2- (3- (2- ((tert-butoxycarbonyl) (methyl) amino) ethyl) -2-methoxy-4-oxo-3, 4-dihydropyrrolo [2, 1-f) as a yellow oil][1,2,4]Triazin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (120 mg,40% yield). MS: m/z found 877 and 879[ M+H ]] ⁺ .

(d) (S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxy-3- (2- (methylamino) ethyl) pyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one

(S) - ((6- (3- (2- (3- (2- ((tert-butoxycarbonyl) (methyl) amino) ethyl) -2-methoxy-4-oxo-3, 4-dihydropyrrolo [2, 1-f) at room temperature][1,2,4]A mixture of tert-butyl triazin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (110 mg,0.13 mmol) and trifluoroacetic acid (2 mL,27.0 mmol) in dichloromethane (1 mL) was stirred for 0.5 h. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC to afford (S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-methoxy-3- (2- (methylamino) ethyl) pyrrolo [2, 1-f) as a brown solid (formate salt) ][1,2,4]Triazin-4 (3H) -one (4.6 mg,4.8% yield). MS: m/z found 677 and 679[ M+H ]] ⁺ Retention time = 2.79min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.62(d,1H),8.17(d,1H),7.93(d,1H),7.74(dd,2H),7.60(t,1H),7.45(dd,1H),7.41(d,1H),7.31(d,1H),4.40-4.37(m,4H),4.14-4.07(m,7H),3.39-3.37(m,2H),3.29(s,2H),2.77(s,3H),2.46-2.39(m,3H),1.96-1.92(m,1H).

Example 479: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one (258)

Using reductive amination procedure B, a reaction mixture was prepared from (S) - ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxy- [1,2, 4))]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (example 480, step (b)) (15 mg,0.02 mmol), acetic acid (2. Mu.L, 0.04 mmol), (5S) -5- (aminomethyl) pyrrolidin-2-one (5 mg,0.04 mmol) and sodium cyanoborohydride (3 mg,0.04 mmol) were prepared ((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) benzeneMethyl) -2-methoxypyridin-3-yl) methyl (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester. Using the general Boc deprotection procedure, the reaction mixture was prepared from ((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,2, 4) ]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester and trifluoroacetic acid (24. Mu.L, 0.31 mmol) preparation of (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one. 5.6mg,37% yield. MS: m/z found 730.2[ M+H ]] ⁺ Retention time = 1.51min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.85(s,1H),8.06(s,1H),7.92(s,1H),7.73(s,1H),7.60(s,1H),7.53(s,1H),7.50(s,2H),4.62(s,2H),4.35(s,2H),4.13(s,4H),4.10(d,4H),3.38(s,2H),2.41(s,6H).

Example 480: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (259)

(a) (S) - ((6- (2-chloro-3- (3-chloro-2- (2- (hydroxymethyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

To (2- (hydroxymethyl) -8-methoxy- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) boronic acid (53 mg,0.24 mmol) and tert-butyl (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate 100mg,0.16 mmol) in 1, 4-dioxane/water (4:1, 3 mL) was added potassium carbonate (65 mg,0.47 mmol). Nitrogen was bubbled through the mixture for two minutes. Tetrakis (triphenylphosphine) palladium (0) (36 mg,0.03 mmol) was added and the reaction stirred at 100 ℃ for 30 min. The reaction mixture was diluted with water (30 mL) and the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by normal phase silica gel chromatography (0-5% MeOH in DCM) to provide (S) - ((6- (2-chloro-3- (3-chloro-2- (2- (hydroxymethyl) -8-methoxy- [1,2, 4))]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (109 mg,94% yield). MS: m/z found 734[ M+H ]] ⁺ .

(b) (S) - ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

To (S) - ((6- (2-chloro-3- (3-chloro-2- (2- (hydroxymethyl) -8-methoxy- [1,2, 4))]Triazolo [1,5-a ]]A solution of tert-butyl pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (109 mg,0.15 mmol) in dichloromethane (3 mL) was added to dessert-butyl periodate (126 mg,0.30 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was purified by normal phase silica gel chromatography (0-5% MeOH in DCM) to provide (S) - ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxy- [1,2, 4)) ]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (92 mg,85% yield). MS: m/z found 731.9[ M+H ]] ⁺ .

(c) (S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

Using reductive amination procedure B, a reaction mixture was prepared from (S) - ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxy- [1,2, 4))]Triazolo [1,5-a ]]Preparation of (S) - ((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -8-methoxy- [1,2, 4) methyl) carbamic acid tert-butyl ester (15 mg,0.02 mmol), acetic acid (2. Mu.L, 0.04 mmol), 3-methylazetidin-3-ol hydrochloride (5 mg,0.04 mmol) and sodium cyanoborohydride (3 mg,0.04 mmol)]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester. Using the general Boc deprotection procedure, a reaction was performed from (S) - ((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl)) 8-methoxy- [1,2, 4) ]Triazolo [1,5-a ]]Preparation of (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl)) methyl) -8-methoxy- [1,2, 4) with tert-butyl (5-oxopyrrolidin-2-yl) methyl) carbamate and trifluoroacetic acid (21. Mu.L, 0.27 mmol)]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one. 4.2mg,29% yield. MS: m/z found 703[ M+H ]] ⁺ Retention time = 1.55min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.82(s,1H),8.72(d,1H),8.27(s,1H),7.86(d,1H),7.73(d,1H),7.58(t,1H),7.52(d,1H),7.46(d,2H),7.34(d,1H),4.54(s,2H),4.20(s,2H),4.11(d,4H),4.07(t,4H),4.00(s,1H),3.95(d,2H),3.09(t,2H),2.35(d,3H),1.88(d,1H),1.53(s,3H).

Example 481: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (260)

Using reductive amination procedure B, a reaction mixture was prepared from (S) - ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxy- [1,2, 4))]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (15 mg,0.02 mmol), acetic acid (2. Mu.L, 0.04 mmol), (1 r,4 r) -4-aminocyclohexane-1-ol (5 mg,0.04 mmol) and sodium cyanoborohydride (3 mg,0.04 mmol) preparation ((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2, 4) ]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester. Using the general Boc deprotection procedure, the reaction mixture was prepared from ((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2, 4)]Triazolo [1,5-a ]]Preparation of (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2, 4) by using pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester and trifluoroacetic acid (24. Mu.L, 0.31 mmol)]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one. 2.6mg,17% yield. MS: m/z found 731[ M+H ]] ⁺ Retention time = 1.53min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )。δ8.82(s,1H),8.72(d,1H),7.77(d,1H),7.72(d,1H),7.60–7.51(m,2H),7.46(s,1H),7.43(d,1H),7.27(d,1H),4.37(s,2H),4.12(d,3H),4.02(d,3H),3.97–3.84(m,3H),2.85–2.72(m,2H),2.31(q,4H),2.17(d,2H),2.02(d,2H),1.83(s,1H),1.51–1.26(m,4H).

Example 482: (S) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) azetidine-3-carboxylic acid (261)

Using reductive amination procedure B, a reaction mixture was prepared from (S) - ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxy- [1,2, 4)) ]Triazolo [1,5-a ]]Preparation of (S) -1- ((6- (4- (3- (5- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-methoxy- [1,2,4 ] methyl ] carbamic acid tert-butyl ester (15 mg,0.02 mmol), acetic acid (2. Mu.L, 0.04 mmol), azetidine-3-carboxylic acid (4 mg,0.04 mmol) and sodium cyanoborohydride (3 mg,0.04 mmol)]Triazolo [1,5-a ]]Pyridin-2-yl) methyl) azetidine-3-carboxylic acid. Using the general Boc deprotection procedure, from (S) -1- ((6- (4- (3- (5- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-methoxy- [1,2,4]Triazolo [1,5-a ]]Preparation of (S) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2, 4) by pyridin-2-yl) methyl azetidine-3-carboxylic acid and trifluoroacetic acid (26. Mu.L, 0.34 mmol)]Triazolo [1,5-a ]]Pyridin-2-yl) methyl) azetidine-3-carboxylic acid. 3.3mg,22% yield. MS: m/z found 717[ M+H ] ] ⁺ Retention time = 1.53min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.83(s,1H),8.75–8.70(m,1H),7.89(d,1H),7.73(d,1H),7.59(t,1H),7.52(d,1H),7.47(s,2H),7.37(d,1H),4.66(s,2H),4.37(t,4H),4.30(s,2H),4.11(d,3H),4.09(t,3H),4.04(s,1H),3.54(t,1H),3.20(d,2H),2.41(d,3H),1.91(s,1H).

Example 483: (S) -1- (2- (((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) ethyl) cyclopropane-1-carboxylic acid (262)

Using reductive amination procedure B, a reaction mixture was prepared from (S) - ((6- (2-chloro)-3- (3-chloro-2- (2-formyl-8-methoxy- [1,2, 4)]Triazolo [1,5-a ]]Preparation of (S) -1- (2- (((6- (4- (5- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-methoxy- [1,2, 4) by tert-butyl pyridin-6-yl pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (15 mg,0.02 mmol), acetic acid (2. Mu.L, 0.04 mmol), 1- (2-aminoethyl) cyclopropanecarboxylic acid (5 mg,0.04 mmol) and sodium cyanoborohydride (3 mg,0.04 mmol)]Triazolo [1,5-a ]]Pyridin-2-yl) methyl) amino) ethyl) cyclopropane-1-carboxylic acid. From (S) -1- (2- (((6- (4- (3- (5- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-methoxy- [1,2, 4) using the general Boc deprotection procedure ]Triazolo [1,5-a ]]Preparation of (S) -1- (2- (((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2, 4) by pyridin-2-yl) methyl) amino) ethyl cyclopropane-1-carboxylic acid and trifluoroacetic acid (27. Mu.L, 0.36 mmol)]Triazolo [1,5-a ]]Pyridin-2-yl) methyl) amino) ethyl) cyclopropane-1-carboxylic acid. 2.2mg,14% yield. MS: m/z found 745[ M+H ]] ⁺ Retention time = 0.61min (method B). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.83(s,1H),8.72(d,1H),7.82(d,1H),7.72(d,1H),7.57(t,1H),7.52(d,1H),7.49–7.41(m,2H),7.31(d,1H),4.51(s,2H),4.11(s,3H),4.10(s,2H),4.05(d,3H),3.96(s,1H),3.34(s,2H),2.98(d,2H),2.35(s,3H),1.88(d,3H),1.20(s,2H),0.71(s,2H).

Example 484: (S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one (370)

Using reductive amination procedure B, a reaction mixture was prepared from (S) - ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxy- [1,2, 4))]Triazolo [1,5-a ]]Pyridin-6-yl) pyridines-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (15 mg,0.02 mmol), acetic acid (2. Mu.L, 0.04 mmol), 3-amino-1-methyl-cyclobutanol hydrochloride (6 mg,0.04 mmol) and sodium cyanoborohydride (3 mg,0.04 mmol) were prepared ((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2, 4) ]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester. Using the general Boc deprotection procedure, from ((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester and trifluoroacetic acid (28. Mu.L, 0.36 mmol) preparation of (S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one. 3.7mg,25% yield. MS: m/z found 717.1[ M+H ]] ⁺ Retention time = 1.92min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.84(s,1H),8.73(d,1H),7.91(d,1H),7.74(d,1H),7.59(t,1H),7.53(d,1H),7.48(d,2H),7.38(d,1H),4.46(s,2H),4.35(s,2H),4.12(s,4H),4.10(t,4H),4.07(d,2H),3.25(d,2H),2.41(t,6H),2.26(t,2H).

Example 485:1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one (595)

(a) (1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- (hydroxymethyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

To tert-butyl (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (417 mg,0.67 mmol) and (2- (hydroxymethyl) -8-methoxy- [1,2, 4)]Triazolo [1,5-a ]]A mixture of pyridin-6-yl) boronic acid (150 mg,0.67 mmol) in 1, 4-dioxane/water (4:1, 3 mL) was added potassium carbonate (279 mg,2.02 mmol). Nitrogen was bubbled through the mixture for two minutes. Tetrakis (triphenylphosphine) palladium (0) (78 mg,0.07 mmol) was added and the reaction stirred at 100 ℃ for 30 min. The reaction mixture was diluted with water (30 mL) and the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by normal phase silica gel chromatography (0-5% MeOH in DCM) to provide (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- (hydroxymethyl) -8-methoxy- [1,2, 4))]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamic acid tert-butyl ester (399 mg,66% yield). MS: m/z found 762.2[ M+H ]] ⁺ .

(b) (1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

To (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- (hydroxymethyl) -8-methoxy- [1,2, 4)]Triazolo [1,5-a ]]A solution of tert-butyl pyridin-6-yl) pyridin-4-yl-phenyl) -2-methoxypyridin-3-yl methyl) carbamate (399 mg,0.44 mmol) in dichloromethane (3 mL) was added to dess Martin periodate (377 mg,0.89 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was purified by normal phase silica gel chromatography (0-5% MeOH in DCM) to provide (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxy- [1,2, 4))]Triazolo [1,5 ]a]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamic acid tert-butyl ester (145 mg,43% yield). MS: m/z found 760.4[ M+H ]] ⁺ .

(c) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

Using reductive amination procedure B, starting from (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxy- [1,2, 4)]Triazolo [1,5-a ]]Preparation of (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2, 4) by using tert-butyl pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamate (20 mg,0.03 mmol), acetic acid (3. Mu.L, 3.16mg,0.05 mmol), (1 r,4 r) -4-aminocyclohexane-1-ol (6 mg,0.05 mmol) and sodium cyanoborohydride (3 mg,0.05 mmol) ]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester. From (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl)) methyl) -8-methoxy- [1,2, 4) using the general Boc deprotection procedure]Triazolo [1,5-a ]]Preparation of tert-butyl pyridin-6-yl) pyridin-4-yl phenyl) -2-methoxypyridin-3-yl methyl) carbamate and trifluoroacetic acid (32 μl,0.42 mmol) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) 8-methoxy- [1,2, 4) methyl)]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one. 5.8mg,29% yield. MS: m/z found 761.1[ M+H ]] ⁺ Retention time = 1.57min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.84(s,1H),8.73(d,1H),7.91(d,1H),7.73(d,1H),7.59(t,1H),7.48(s,2H),7.37(d,1H),4.68(d,1H),4.57(s,2H),4.33(s,2H),4.12(s,4H),4.09(d,4H),3.51(s,1H),3.22(t,1H),2.72(d,1H),2.65(d,1H),2.26(s,4H),2.13(s,4H),2.07(d,2H),1.55(q,3H),1.43–1.26(m,2H).

Example 486:1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one (596)

Using reductive amination procedure B, starting from (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxy- [1,2, 4) ]Triazolo [1,5-a ]]Preparation of (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2, 4) by using tert-butyl pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamate (20 mg,0.03 mmol), acetic acid (3. Mu.L, 0.05 mmol), (1 r,3 r) -3-amino-1-methylcyclobutan-1-ol hydrochloride (7 mg,0.05 mmol) and sodium cyanoborohydride (3 mg,0.05 mmol)]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester. From (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl)) 8-methoxy- [1,2, 4) using the general Boc deprotection procedure]Triazolo [1,5-a ]]Preparation of tert-butyl pyridin-6-yl) pyridin-4-yl phenyl) -2-methoxypyridin-3-yl methyl) carbamate and trifluoroacetic acid (0.07 ml,0.89 mmol) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one. 6mg,31% yield. MS: m/z found 747.3[ M+H ] ] ⁺ Retention time = 1.55min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.83(d,1H),8.73(d,1H),7.91(d,1H),7.73(d,1H),7.59(t,1H),7.55–7.50(m,1H),7.48(t,2H),7.36(d,1H),4.67(d,1H),4.39(d,2H),4.30(s,2H),4.12(d,3H),4.08(d,4H),3.45(d,1H),3.21(t,1H),2.70(t,1H),2.39(t,2H),2.30–2.18(m,4H),2.13(s,4H),1.72–1.59(m,1H),1.54(dd,1H),1.38(d,3H).

Example 487:1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

Using reductive amination procedure B, starting from (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxy- [1,2, 4)]Triazolo [1,5-a ]]Preparation of (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -8-methoxy- [1,2, 4) by tert-butyl pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl carbamate (20 mg,0.03 mmol), acetic acid (3. Mu.L, 0.05 mmol), 3-methylazetidin-3-ol hydrochloride (7 mg,0.05 mmol) and sodium cyanoborohydride (3 mg,0.05 mmol)]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester. From (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl)) 8-methoxy- [1,2, 4) using the general Boc deprotection procedure]Triazolo [1,5-a ]]Preparation of tert-butyl pyridin-6-yl) pyridin-4-yl phenyl) -2-methoxypyridin-3-yl methyl) carbamate (15 mg,0.02 mmol) and trifluoroacetic acid (0.07 ml,0.89 mmol) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) 8-methoxy- [1,2, 4) methyl) ]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one. 4.6mg,24% yield. MS: m/z found 731.4[ M+H ]] ⁺ Retention time = 1.57min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.78(d,1H),8.71(d,1H),8.52(d,1H),7.81(d,1H),7.72(d,1H),7.57(t,1H),7.51(d,1H),7.46–7.39(m,2H),7.29(d,1H),4.54(d,1H),4.11(d,3H),4.04(d,3H),4.02(s,2H),4.00(s,3H),3.53(d,2H),3.35(d,3H),3.17(t,1H),3.03(s,1H),2.70(t,1H),2.11(s,3H),1.47(s,4H),1.37(d,1H).

Example 488: (R) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxypropyl) amino) methyl) 8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (638)

Using reductive amination procedure B, starting from (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxy- [1,2, 4)]Triazolo [1,5-a ]]Preparation of (R) - (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxypropyl) amino) methyl) -8-methoxy- [1,2, 4) by using tert-butyl pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamate (20 mg,0.03 mmol), acetic acid (3. Mu.L, 0.05 mmol), (2R) -1-aminopropane-2-ol (4 mg,0.05 mmol) and sodium cyanoborohydride (3 mg,0.05 mmol)]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester. From (R) - (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxypropyl) amino) methyl)) 8-methoxy- [1,2, 4) using the general Boc deprotection procedure ]Triazolo [1,5-a ]]Preparation of (R) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxypropyl) amino) methyl)) 8-methoxy- [1,2, 4) by tert-butyl pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate and trifluoroacetic acid (0.06 ml,0.79 mmol)]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one. 4.6mg,24% yield. MS: m/z found 719.3[ M+H ]] ⁺ Retention time = 1.55min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.79(s,1H),8.71(d,1H),8.53(s,1H),7.80(d,1H),7.72(d,1H),7.57(t,1H),7.51(d,1H),7.44(d,2H),7.28(d,1H),4.52(d,1H),4.17(d,2H),4.11(s,3H),4.03(d,3H),3.98(s,3H),3.95(s,2H),3.16(t,1H),2.97(s,1H),2.86–2.78(m,1H),2.70(t,2H),2.11(s,4H),2.06(d,1H),1.48–1.32(m,1H),1.18(d,3H).

Example 489:1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((isopropylamino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (644)

Using reductive amination procedure B, starting from (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxy- [1,2, 4)]Triazolo [1,5-a ]]Preparation of (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- ((isopropylamino) methyl) -8-methoxy- [1,2, 4) by using tert-butyl pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamate (20 mg,0.03 mmol), acetic acid (3. Mu.L, 0.05 mmol), propane-2-amine (3 mg,0.05 mmol) and sodium cyanoborohydride (3 mg,0.05 mmol) ]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester. From (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- ((isopropylamino) methyl) -8-methoxy- [1,2, 4) using the general Boc deprotection procedure]Triazolo [1,5-a ]]Preparation of tert-butyl pyridin-6-yl) pyridin-4-yl phenyl) -2-methoxypyridin-3-yl methyl) carbamate and trifluoroacetic acid (0.07 ml,0.89 mmol) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((isopropylamino) methyl) -8-methoxy- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one. 8.4mg,46% yield. MS: m/z found 705.4[ M+H ]] ⁺ Retention time = 2.06min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.84(s,1H),8.73(d,1H),8.07(s,1H),7.91(d,1H),7.73(d,1H),7.59(t,1H),7.53(d,1H),7.47(d,2H),7.36(d,1H),4.68(d,1H),4.55(s,2H),4.33(s,2H),4.12(s,4H),4.08(s,4H),3.54–3.45(m,1H),3.22(t,1H),2.76–2.61(m,1H),2.26(t,2H),2.13(s,4H),1.70–1.52(m,1H),1.43(d,6H).

Example 490:1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxyethyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (654)

Using reductive amination procedure B, starting from (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxy- [1,2, 4)]Triazolo [1,5-a ]]Preparation of (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxyethyl) amino) methyl) -8-methoxy- [1,2, 4) by using tert-butyl pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamate (20 mg,0.03 mmol), acetic acid (3. Mu.L, 0.05 mmol), 2-aminoethanol (3.21 mg,0.05 mmol) and sodium cyanoborohydride (3 mg,0.05 mmol) ]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester. From (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxyethyl) amino) methyl)) 8-methoxy- [1,2, 4) using the general Boc deprotection procedure]Triazolo [1,5-a ]]Preparation of tert-butyl pyridin-6-yl) pyridin-4-yl phenyl) -2-methoxypyridin-3-yl methyl) carbamate (15 mg,0.02 mmol) and trifluoroacetic acid (0.07 ml,0.89 mmol) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((2-hydroxyethyl) amino) methyl) 8-methoxy- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one. 7mg,50% yield. MS: m/z found 705.6[ M+H ]] ⁺ Retention time = 1.98min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.84(s,1H),8.73(d,1H),7.91(d,1H),7.73(d,1H),7.59(t,1H),7.53(dd,1H),7.47(d,2H),7.36(d,1H),4.67(d,1H),4.54(s,2H),4.30(s,2H),4.12(d,3H),4.08(d,4H),3.86(t,2H),3.51–3.41(m,1H),3.21(t,1H),2.76–2.62(m,1H),2.25(t,2H),2.13(d,3H),1.71–1.46(m,1H).

Example 491:2- ((6- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one (659)

Using reductive amination procedure B, starting from (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxy- [1,2, 4)]Triazolo [1,5-a ] ]Pyridin-6-yl) pyridin-4-yl) phenyl-2-methoxypyridin-3-yl) methyl-carbamic acid tert-butyl ester (20 mg,0.03 mmol), acetic acid (3. Mu.L, 0.05 mmol), 2, 6-diazaspiro [3.4 ]]Preparation of (1-acetylpiperidin-4-yl) from (9 mg,0.05 mmol) of octan-7-one hydrochloride and sodium cyanoborohydride (3 mg,0.05 mmol) ((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((7-oxo-2, 6-diazaspiro [ 3.4))]Octan-2-yl) methyl) - [1,2,4]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester. From (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((7-oxo-2, 6-diazaspiro [ 3.4)) using the general Boc deprotection procedure]Octan-2-yl) methyl) - [1,2,4]Triazolo [1,5-a ]]Preparation of tert-butyl pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamate and trifluoroacetic acid (0.06 ml,0.80 mmol) 2- ((6- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-methoxy- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-2-yl) methyl) -2, 6-diazaspiro [3.4]Octane-7-one. 8.2mg,40% yield. MS: m/z found 770.4[ M+H ]] ⁺ Retention time = 1.49min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.78(d,1H),8.72(dd,1H),8.45(s,1H),7.88(d,1H),7.73(d,1H),7.58(t,1H),7.51(dd,1H),7.48–7.44(m,1H),7.42(s,1H),7.34(d,1H),4.63(d,1H),4.22(s,2H),4.10(d,3H),4.07(d,3H),4.04(s,1H),3.99(d,2H),3.58(s,2H),3.56(s,3H),3.36(d,1H),3.20(t,1H),2.70(t,1H),2.58(s,2H),2.21(t,2H),2.13(s,3H),1.66–1.42(m,1H).

Example 492:1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (660)

Using reductive amination procedure B, starting from (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxy- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamic acidTert-butyl ester (20 mg,0.03 mmol), acetic acid (3. Mu.L, 0.05 mmol), 2-azaspiro [3.3]]Preparation of (1-acetylpiperidin-4-yl) from heptane-6-ol hydrochloride (8 mg,0.05 mmol) and sodium cyanoborohydride (3 mg,0.05 mmol) ((6- (2-chloro-3- (3-chloro-2- (2- ((6-hydroxy-2-azaspiro [3.3 ]))]Heptane-2-yl) methyl) -8-methoxy- [1,2,4]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester. From (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- ((6-hydroxy-2-azaspiro [ 3.3)) using the general Boc deprotection procedure]Heptane-2-yl) methyl) -8-methoxy- [1,2,4]Triazolo [1,5-a ]]Preparation of tert-butyl pyridin-6-yl) pyridin-4-yl phenyl) -2-methoxypyridin-3-yl methyl) carbamate and trifluoroacetic acid (0.06 ml,0.76 mmol) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((6-hydroxy-2-azaspiro [ 3.3)) ]Heptane-2-yl) methyl) -8-methoxy- [1,2,4]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one. 6.4mg,32% yield. MS: m/z found 757.4[ M ]] ⁺ Retention time = 1.54min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )。δ8.79(s,1H),8.72(d,1H),8.48(s,1H),7.86(d,1H),7.73(d,1H),7.58(t,1H),7.52(d,1H),7.45(d,2H),7.33(d,1H),4.61(d,1H),4.20(s,2H),4.17(s,2H),4.11(s,3H),4.06(d,3H),4.02(s,1H),3.81(s,2H),3.78(s,2H),3.19(t,1H),2.70(t,1H),2.54(t,2H),2.20(d,2H),2.12(s,3H),2.07(t,2H),1.63–1.39(m,1H).

Example 493:1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxyethyl) amino) methyl) -4-methoxypyrrolo [2,1-f ] [1,2,4] triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one (661)

(a) 6-bromo-4-chloropyrrolo [2,1-f ] [1,2,4] triazine-2-carboxylic acid ethyl ester

6-Bromide-4-oxo-3, 4-dihydropyrrolo [2,1-f][1,2,4]A mixture of triazine-2-carboxylic acid ethyl ester (100 mg,0.35 mmol) and phosphorus oxychloride (0.49 mL,5.24 mmol) in toluene (3 mL) was heated at reflux for 18 hours. The mixture was concentrated and the residue was diluted with dichloromethane (10 mL) and sodium bicarbonate solution (10 mL). The resulting mixture was stirred at room temperature for 10 minutes. The separated organic layer was washed with cold brine (30 mL), dried, and concentrated under reduced pressure. Purification of the crude material by chromatography on silica gel eluting with dichloromethane provided 6-bromo-4-chloropyrrolo [2,1-f][1,2,4]Triazine-2-carboxylic acid ethyl ester (76 mg,71% yield). MS: m/z found 306[ M+H ] ] ⁺ .

(b) 6-bromo-4-methoxypyrrolo [2,1-f ] [1,2,4] triazine-2-carboxylic acid methyl ester

To 0 ℃ 6-bromo-4-chloropyrrolo [2,1-f][1,2,4]A solution of triazine-2-carboxylic acid ethyl ester (175 mg,0.57 mmol) in THF (2 mL) was added sodium methoxide in methanol (25% w/w,37mg,0.69 mmol). The reaction was stirred at 0deg.C for 1h. Additional sodium methoxide in methanol (25% w/w,37mg,0.69 mmol) was added and the reaction was stirred for an additional 1 hour. The reaction was diluted with ethyl acetate (15 mL), washed with ammonium chloride solution and brine. The organic layer was dried, concentrated and the residue purified by chromatography on silica gel (eluting with 50% ethyl acetate in hexanes) to afford 6-bromo-4-methoxypyrrolo [2,1-f][1,2,4]Triazine-2-carboxylic acid methyl ester (85 mg,52% yield). MS: m/z found 288[ M+H ]] ⁺ .

(c) (6-bromo-4-methoxypyrrolo [2,1-f ] [1,2,4] triazin-2-yl) methanol

To 0 ℃ 6-bromo-4-methoxypyrrolo [2,1-f][1,2,4]A solution of methyl triazine-2-carboxylate (85 mg,0.30 mmol) in THF/MeOH (1:1, 1 mL) was added sodium borohydride (34 mg,0.89 mmol). The mixture was stirred at 20℃for 2 hours. LCMS indicated conversion to the desiredThe expected product. The reaction was quenched by the addition of water (5 mL) and extracted with EtOAc (3X 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. By SiO ₂ Chromatography (0-5% MeOH in DCM) of the residue to afford (6-bromo-4-methoxypyrrolo [2, 1-f)][1,2,4]Triazin-2-yl) methanol (39 mg,51% yield). MS: m/z found 260.0[ M+H ]] ⁺ .

(d) (4-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-2-yl) methanol

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(6-bromo-4-methoxypyrrolo [2, 1-f)][1,2,4]Triazin-2-yl) methanol (55 mg,0.21 mmol), bis (pinacolato) diborane (81 mg,0.32 mmol), potassium acetate (42 mg,0.43 mmol) and [1,1' -bis (biphenylphosphino) ferrocene]A mixture of palladium (II) dichloride and dichloromethane (17 mg,0.02 mmol) in 3ml 1, 4-dioxane was degassed and heated at 95℃for 3 hours. The reaction was concentrated and the residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to afford (4-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyrrolo [2,1-f][1,2,4]Triazin-2-yl) methanol (29 mg,45% yield). MS: m/z found 306.2[ M+H ]] ⁺ .

(e) (1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- (hydroxymethyl) -4-methoxypyrrolo [2,1-f ] [1,2,4] triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

To (4-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyrrolo [2, 1-f) ][1,2,4]Triazin-2-yl) methanol (28 mg,0.09 mmol) and (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester (57 mg,0.09 mmol) in 1, 4-dioxane-A mixture of potassium carbonate (38 mg,0.28 mmol) and tetrakis (triphenylphosphine) palladium (0) (11 mg,0.01 mmol) was added to a mixture of water (4:1, 1 mL). The mixture was stirred at 110℃for 30 minutes. The solvent was evaporated and the residue was purified by silica gel chromatography (0-10% MeOH in DCM) to give (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- (hydroxymethyl) -4-methoxypyrrolo [2, 1-f))][1,2,4]Triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamic acid tert-butyl ester (31 mg,44% yield). MS: m/z found 762.4[ M+H ]] ⁺ .

(f) (1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxyethyl) amino) methyl) -4-methoxypyrrolo [2,1-f ] [1,2,4] triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

To (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- (hydroxymethyl) -4-methoxypyrrolo [2, 1-f))][1,2,4]A solution of tert-butyl triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl carbamate (30 mg,0.04 mmol) in dichloromethane (0.5 mL) was added triethylamine (11. Mu.L, 0.08 mmol) and methanesulfonyl chloride (6. Mu.L, 0.08 mmol). The reaction was stirred at room temperature for 1 hour. LCMS indicated the formation of the desired mesylate. The solvent was evaporated and the residue was suspended in DMF (0.4 mL) followed by the addition of potassium carbonate (11 mg,0.08 mmol) and 2-aminoethanol (5 mg,0.08 mmol). The mixture was stirred at room temperature for 12 hours. The solvent was evaporated and the residue was suspended in water. The precipitate formed was collected to afford (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxyethyl) amino) methyl)) methyl) -4-methoxypyrrolo [2, 1-f) ][1,2,4]Triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamic acid tert-butyl ester (4 mg,13% yield). MS: m/z found 805.4[ M+H ]] ⁺ .

(g) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxyethyl) amino) methyl) -4-methoxypyrrolo [2,1-f ] [1,2,4] triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

From (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxyethyl) amino) methyl)) methyl) -4-methoxypyrrolo [2, 1-f) using the general Boc deprotection procedure][1,2,4]Triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamic acid tert-butyl ester (4 mg,0.005 mmol) preparation 1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxyethyl) amino) methyl)) methyl) -4-methoxypyrrolo [2, 1-f)][1,2,4]Triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one. 1.6mg,46% yield. MS: m/z found 707.2[ M+H ]] ⁺ Retention time = 2.13min (method C). ¹ H NMR (400 MHz, methanol-d 4) delta 8.64 (d, 1H), 8.52 (s, 1H), 7.90 (d, 1H), 7.72 (d, 1H), 7.59 (d, 2H), 7.43 (d, 1H), 7.39-7.33 (m, 2H), 4.65 (s, 1H), 4.36 (s, 2H), 4.30 (s, 2H), 4.23 (d, 3H), 4.09 (s, 4H), 3.89 (s, 2H), 2.24 (s, 2H), 2.13 (d, 3H).

Example 494:1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one (583)

(a) (6-bromo-8-ethoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methanol

To a suspension of 2,4, 6-trimethylbenzene-1-sulfonic acid urethane (2, 4, 6-trimethylbenzenesulfonylhydroxylamine, amino 2,4, 6-trimethyllbenzene-1-sulfonate) (195 mg,0.92 mmol) in dichloromethane (110 mL) was added 5-bromo-3-ethoxy-pyridin-2-amine (200 mg,0.92 mmol) at 0-5 ℃. After 10 minutes the ice bath was removed and the reaction was allowed to proceed at room temperatureThe mixture was stirred for 1 hour. The suspension was diluted with diethyl ether (100 mL), filtered, washed with diethyl ether, and dried under reduced pressure to afford 5-bromo-3-ethoxy-2-imino-pyridin-1-amine 2,4, 6-trimethylbenzenesulfonic acid (124 mg,32% yield). To a solution of 5-bromo-3-ethoxy-2-imino-pyridin-1-amine 2,4, 6-trimethylbenzenesulfonic acid (124 mg,0.30 mmol) in ethanol (2 mL) was added sodium hydroxide (24 mg,0.59 mmol). The mixture was heated to 60 ℃ for 1 hour. Methyl 2-glycolate (53 mg,0.59 mmol) was added and the mixture was heated to 80℃for 3 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was washed with water (10 mL) to afford (6-bromo-8-ethoxy- [1,2, 4) ]Triazolo [1,5-a ]]Pyridin-2-yl) methanol (36 mg,45% yield). MS: m/z found 272[ M+H ]] ⁺ .

(b) [ 8-ethoxy-2- (hydroxymethyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] boronic acid

(6-bromo-8-ethoxy- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-2-yl) methanol (36 mg,0.13 mmol), bis (pinacolato) diborane (50 mg,0.20 mmol), potassium acetate (39 mg,0.40 mmol) and [1,1' -bis (biphenylphosphino) ferrocene]The complex of palladium (II) dichloride and dichloromethane (11 mg,0.01 mmol) was suspended in 10ml of 1, 4-dioxane. Nitrogen was bubbled through the reaction for 2 minutes, and then the reaction was heated at 95 ℃ for 3 hours. The reaction was concentrated to afford [ 8-ethoxy-2- (hydroxymethyl) - [1,2,4]]Triazolo [1,5-a ]]Pyridin-6-yl]Boric acid (30.00 mg,96% yield). The material was used in the next step without further purification. MS: m/z found 238.1[ M+H ]] ⁺ .

(c) (1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- (hydroxymethyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

To tert-butyl (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (78 mg,0.13 mmol) and [ 8-ethoxy-2- (hydroxymethyl) - [1,2,4] ]Triazolo [1,5-a ]]Pyridin-6-yl]A mixture of boric acid (30 mg,0.13 mmol) in 1, 4-dioxane/water (4:1, 3 mL) was added potassium carbonate (52 mg,0.38 mmol). Nitrogen was bubbled through the mixture for two minutes. Tetrakis (triphenylphosphine) palladium (0) (29 mg,0.03 mmol) was added and the reaction stirred at 100 ℃ for 30 min. The reaction mixture was diluted with water (30 mL) and the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by normal phase silica gel chromatography (0-5% MeOH in DCM) to provide (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- (hydroxymethyl) - [1,2, 4))]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamic acid tert-butyl ester (89 mg,91% yield). MS: m/z found 776.2[ M+H ]] ⁺ .

(d) (1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2-formyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

To (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- (hydroxymethyl) - [1,2, 4)]Triazolo [1,5-a ]]A solution of tert-butyl pyridin-6-yl) pyridin-4-yl-phenyl) -2-methoxypyridin-3-yl methyl) carbamate (89 mg,0.11 mmol) in dichloromethane (3 mL) was added to dess-martin periodate (97 mg,0.23 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was purified by normal phase silica gel chromatography (0-5% MeOH in DCM) to provide (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2-formyl- [1,2, 4)) ]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamic acid tert-butyl ester (71 mg, 80%). MS: m/z found 774[ M+H ]] ⁺ .

(e) (1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

Using reductive amination procedure B, starting from (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2-formyl- [1,2, 4)]Triazolo [1,5-a ]]Preparation of (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) - [1,2, 4) with tert-butyl pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) carbamate (15 mg,0.02 mmol), acetic acid (2 μl,0.04 mmol), (1 r,4 r) -4-aminocyclohexane-1-ol (4 mg,0.04 mmol) and sodium cyanoborohydride (2 mg,0.04 mmol)]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester. 13mg,77% yield. MS: m/z found 875.0[ M+H ]] ⁺ .

(f) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

Using the general Boc deprotection procedure, from (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- (((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) - [1,2, 4)]Triazolo [1,5-a ]]Preparation of tert-butyl pyridin-6-yl) pyridin-4-yl phenyl) -2-methoxypyridin-3-yl methyl) carbamate (13 mg,0.01 mmol) and trifluoroacetic acid (23. Mu.L, 0.30 mmol) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- (((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) - [1,2, 4) methyl)]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) amino) piperidin-1-yl) ethane-1-one. 9.4mg,82% yield. MS: m/z found 774.3[ M+H ]] ⁺ Retention time = 1.67min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.77(s,1H),8.67(d,1H),7.87(d,1H),7.68(d,1H),7.54(t,1H),7.48(d,1H),7.42(s,2H),7.31(d,1H),4.62(d,2H),4.49(s,2H),4.32(d,2H),4.28(s,2H),4.03(s,5H),3.60–3.39(m,2H),2.65(t,2H),2.20(s,5H),2.02(d,3H),1.63(s,1H),1.50(d,7H).

Example 495:1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one (584)

Using reductive amination procedure B, starting from (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2-formyl- [1,2, 4)]Triazolo [1,5-a ]]Preparation of (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- (((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) - [1,2, 4) by using tert-butyl pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamate (example 494, step (d)) (15 mg,0.02 mmol), acetic acid (2. Mu.L, 0.04 mmol), (1 r,3 r) -3-amino-1-methylcyclobutan-1-ol hydrochloride (5 mg,0.04 mmol) and sodium cyanoborohydride (2 mg,0.04 mmol) ]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester. Using the general Boc deprotection procedure, from (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- (((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) - [1,2, 4)]Triazolo [1,5-a ]]Preparation of tert-butyl pyridin-6-yl) pyridin-4-yl phenyl) -2-methoxypyridin-3-yl methyl) carbamate and trifluoroacetic acid (0.07 ml,0.10g,0.86 mmol) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- (((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) - [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one. 4.6mg,31% yield. MS: m/z found 761.1[ M+H ]] ⁺ Retention time = 1.67min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.80(s,1H),8.72(d,1H),7.90(d,1H),7.73(d,1H),7.59(t,1H),7.54–7.50(m,1H),7.49–7.42(m,2H),7.35(d,1H),4.66(d,1H),4.41–4.34(m,2H),4.33(s,2H),4.28(s,2H),4.08(d,4H),3.96(t,1H),3.43(s,1H),3.21(t,1H),2.78–2.62(m,1H),2.38(t,2H),2.30–2.16(m,4H),2.13(d,4H),1.63(d,1H),1.57–1.49(m,4H),1.38(d,3H).

Example 496:1- (4- (((6- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-ethoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) piperidin-1-yl) ethan-1-one (585)

Using reductive amination procedure B, starting from (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2-formyl- [1,2, 4) ]Triazolo [1,5-a ]]Preparation of (1-acetylpiperidin-4-yl) ((6- (3- (2- (((1-acetylpiperidin-4-yl) amino) methyl) -8-ethoxy- [1,2, 4) with tert-butyl pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamate (example 494, step (d)) (20 mg,0.03 mmol), acetic acid (3. Mu.L, 0.05 mmol), 1- (4-amino-1-piperidinyl) ethanone (7 mg,0.05 mmol) and sodium cyanoborohydride (3 mg,0.05 mmol)]Triazolo [1,5-a ]]Pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl-methyl) carbamic acid tert-butyl ester. Using the general Boc deprotection procedure, from (1-acetylpiperidin-4-yl) ((6- (3- (2- (2- (((1-acetylpiperidin-4-yl) amino)) methyl) -8-ethoxy- [1,2, 4)]Triazolo [1,5-a ]]Preparation of tert-butyl pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl methyl) carbamate and trifluoroacetic acid (76 μl,1.00 mmol) 1- (4- (((6- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-ethoxy- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-2-yl) methyl) amino) piperidin-1-yl) ethan-1-one. 9mg,44% yield. MS: m/z found 800.3[ M+H ]] ⁺ Retention time = 1.67min (method D). ¹ H NMR (400 MHz, A)Alcohol-d ₄ )δ8.82(s,1H),8.72(d,1H),7.91(d,1H),7.73(d,1H),7.59(t,1H),7.53(d,1H),7.48(s,1H),7.46(s,1H),7.37(d,1H),4.68(d,2H),4.62(s,2H),4.38(q,2H),4.33(s,2H),4.09(s,5H),3.67–3.45(m,2H),3.22(t,2H),2.72(d,2H),2.27(s,5H),2.13(s,7H),1.72–1.62(m,2H),1.53(d,3H).

Example 497:2- ((6- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-ethoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one (586)

Using reductive amination procedure B, starting from (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2-formyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamic acid tert-butyl ester (example 494, step (d)) (20 mg,0.03 mmol), acetic acid (3. Mu.L, 0.05 mmol) and 2, 6-diazaspiro [3.4]]Preparation of (1-acetylpiperidin-4-yl) from (6 mg,0.05 mmol) octan-7-one and sodium cyanoborohydride (3 mg,0.05 mmol) ((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((7-oxo-2, 6-diazaspiro [ 3.4))]Octan-2-yl) methyl) - [1,2,4]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester. From (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((7-oxo-2, 6-diazaspiro [ 3.4)) using the general Boc deprotection procedure]Octan-2-yl) methyl) - [1,2,4]Triazolo [1,5-a ]]Preparation of tert-butyl pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamate and trifluoroacetic acid (56 μl,0.73 mmol) 2- ((6- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-ethoxy- [1,2, 4) ]Triazolo [1,5-a ]]Pyridin-2-yl) methyl) -2, 6-diazaspiro [3.4]Octane-7-one. 2mg,10% yield. MS: m/z found 784.2[ M+H ]] ⁺ Retention time = 1.63min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.77(s,1H),8.72(d,1H),7.90(d,1H),7.73(d,1H),7.59(t,1H),7.51(d,1H),7.47(d,1H),7.41(s,1H),7.37(d,1H),4.36(t,2H),4.31(s,3H),4.25(s,2H),4.09(s,5H),3.85(s,5H),3.63(s,2H),3.21(s,1H),2.65(d,3H),2.25(s,2H),2.13(s,4H),1.53(d,3H).

Example 498: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) imidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (310)

Using reductive amination procedure B, a reaction mixture was prepared from (S) - ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxyimidazo [1, 2-a))]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (example 499, step (c)) (20 mg,0.03 mmol), acetic acid (3. Mu.L, 0.05 mmol), (5S) -5- (aminomethyl) pyrrolidin-2-one (6 mg,0.05 mmol) and sodium cyanoborohydride (3 mg,0.05 mmol) preparation ((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) imidazo [1, 2-a)]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester. Imidazo [1,2-a ] was prepared from ((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) using the general Boc deprotection procedure ]Preparation of (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) imidazo) 1, 2-a) with tert-butyl pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid and trifluoroacetic acid (39. Mu.L, 0.51 mmol)]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one. 10mg,50% yield. MS: m/z found 729.1[ M+H ]] ⁺ Retention time = 0.62min (method B). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.72(d,1H),8.22(s,1H),8.06(t,1H),7.91(d,1H),7.77–7.71(m,1H),7.59(t,1H),7.52(d,1H),7.46(d,1H),7.36(dd,1H),7.33(s,1H),4.50(s,2H),4.34(s,2H),4.12(t,3H),4.10–4.02(m,6H),3.27–3.24(m,2H),2.39(q,7H),1.91(s,2H).

Example 499: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (312)

(a) [2- (hydroxymethyl) -8-methoxy-imidazo [1,2-a ] pyridin-6-yl ] boronic acid

(6-bromo-8-methoxyimidazo [1, 2-a)]Pyridin-2-yl) methanol (161 mg,0.63 mmol), bis (pinacolato) diborane (318 mg,1.25 mmol), potassium acetate (184 mg,1.88 mmol) and [1,1' -bis (biphenylphosphino) ferrocene]The palladium (II) dichloride complex with dichloromethane (51 mg,0.06 mmol) was suspended in 5ml 1, 4-dioxane. Nitrogen was bubbled through the suspension for 2 minutes, and the mixture was then heated at 95 ℃ for 3 hours. The reaction was concentrated and the residue was purified by silica gel chromatography (0-50% MeOH in DCM) to provide (2- (hydroxymethyl) -8-methoxyimidazo [1, 2-a) ]Pyridin-6-yl) boronic acid (131 mg, 69%). MS: m/z found 223[ M+H ]] ⁺ .

(b) (S) - ((6- (2-chloro-3- (3-chloro-2- (2- (hydroxymethyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To (2- (hydroxymethyl) -8-methoxyimidazo [1, 2-a)]Pyridin-6-yl) boronic acid (130.8 mg,0.59 mmol) and (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) amino groupA mixture of tert-butyl formate (250 mg,0.39 mmol) in 1, 4-dioxane/water (4:1, 3 mL) was added potassium carbonate (163 mg,1.18 mmol). Nitrogen was bubbled through the mixture for two minutes. Tetrakis (triphenylphosphine) palladium (0) (45 mg,0.04 mmol) was added and the reaction stirred at 100 ℃ for 30 min. The reaction mixture was diluted with water (30 mL) and the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by normal phase silica gel chromatography (0-5% MeOH in DCM). Purifying the residue to provide (S) - ((6- (2-chloro-3- (3-chloro-2- (2- (hydroxymethyl) -8-methoxyimidazo [1, 2-a))]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (255 mg,89% yield). MS: m/z found 733.2[ M+H ] ] ⁺ .

(c) (S) - ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To (S) - ((6- (2-chloro-3- (3-chloro-2- (2- (hydroxymethyl) -8-methoxyimidazo [1, 2-a))]A solution of tert-butyl pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (255 mg,0.35 mmol) in dichloromethane (3 mL) was added to dessert-butyl periodate (254 mg,0.70 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was purified by normal phase silica gel chromatography (0-5% MeOH in DCM) to provide (S) - ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxyimidazo [1, 2-a))]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (233 mg,36% yield). MS: m/z found 731[ M+H ]] ⁺ .

(d) (S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

Using reductive amination procedure B, a reaction mixture was prepared from (S) - ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxyimidazo [1, 2-a))]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (20 mg,0.03 mmol), acetic acid (3. Mu.L, 0.05 mmol), (1 r,3 r) -3-amino-1-methylcyclobutan-1-ol hydrochloride (7 mg,0.05 mmol) and sodium cyanoborohydride (3 mg,0.05 mmol) were prepared to ((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxyimidazo [1, 2-a)]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester. Using the general Boc deprotection procedure, the reaction mixture was prepared from ((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxyimidazo [1, 2-a)]Preparation of (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxyimidazo [1, 2-a) t-butyl pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamate and trifluoroacetic acid (0.07 ml,0.86 mmol)]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one. 5mg,26% yield. MS: m/z found 716.0[ M+H ] ] ⁺ Retention time = 1.53min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.71–8.65(m,1H),8.52(s,1H),7.95(d,1H),7.73(dd,2H),7.55(t,1H),7.49(d,1H),7.41(d,1H),7.28–7.21(m,1H),7.06(s,1H),4.11–4.05(m,5H),4.01(t,3H),3.85(d,3H),3.83–3.73(m,1H),2.80–2.62(m,2H),2.33(d,4H),2.29–2.21(m,1H),2.06(t,2H),1.81(d,1H),1.36(d,3H).

Example 500: (S) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one (314)

Using reductive amination procedure B, a reaction mixture was prepared from (S) - ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxyimidazo [1, 2-a))]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (example 499, step (c)) (20 mg,0.03 mmol), acetic acid (3. Mu.L, 0.05 mmol), 2, 6-diazaspiro [3.4]]Octan-7-one; preparation of (S) - ((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((7-oxo-2, 6-diazaspiro [3.4 ]) with sodium cyanoborohydride (3 mg,0.05 mmol) (9 mg,0.05 mmol)]Octane-2-yl) methyl) imidazo [1,2-a]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester. Using the general Boc deprotection procedure, a reaction mixture was prepared from (S) - ((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((7-oxo-2, 6-diazaspiro [3.4 ]))]Octane-2-yl) methyl) imidazo [1,2-a ]Preparation of (S) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxo-pyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] with tert-butyl (5-oxo-pyrrolidin-2-yl) methyl) carbamate and trifluoroacetic acid (50. Mu.L, 0.65 mmol)]Pyridin-2-yl) methyl) -2, 6-diazaspiro [3.4]Octane-7-one. 4.1mg,20% yield. MS: m/z found 741.2[ M+H ]] ⁺ Retention time = 1.45min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.68(dd,1H),8.49(s,1H),7.98(s,1H),7.83(d,1H),7.72(d,1H),7.57(t,1H),7.51–7.46(m,1H),7.43(d,1H),7.31(d,1H),7.06(s,1H),4.23(s,2H),4.10(s,2H),4.07–4.02(m,6H),3.94(s,4H),3.62(s,2H),2.99(t,2H),2.65(d,2H),2.34(d,3H),1.86(s,1H).

Example 501: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (317)

Using reductive amination procedure B, a reaction mixture was prepared from (S) - ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxyimidazo [1, 2-a))]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (example 499, step (c)) (20 mg,0.03 mmol), acetic acid (3. Mu.L, 0.05 mmol), 3-methylazetidin-3-ol hydrochloride (7 mg,0.05 mmol) and sodium cyanoborohydride (11 mg,0.05 mmol) preparation of (S) - ((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -8-methoxyimidazo [1, 2-a) ]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester. Using the general Boc deprotection procedure, a sequence of (S) - ((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl)) 8-methoxyimidazo [1, 2-a)]Preparation of (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -8-methoxyimidazo [1, 2-a)) methyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester and trifluoroacetic acid (57 μl,0.75 mmol)]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one. 7.6mg,72% yield. MS: m/z found 702.1[ M+H ]] ⁺ Retention time = 1.55min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.73–8.68(m,1H),8.55(d,1H),8.14(s,1H),7.91(d,1H),7.73(d,1H),7.59(t,1H),7.51(d,1H),7.48–7.43(m,1H),7.38(d,1H),7.17(d,1H),4.56(s,2H),4.35(s,2H),4.20(d,2H),4.11–4.07(m,7H),3.26(t,2H),2.45–2.34(m,3H),1.92(d,1H),1.52(s,3H).

Example 502: (S) -5- ((((6- (3- (2- (2- (((1-acetylpiperidin-4-yl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (318)

Using reductive amination procedure B, a reaction mixture was prepared from (S) - ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxyimidazo [1, 2-a)) ]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (example 499, step (c)) (20 mg,0.03 mmol), acetic acid (3. Mu.L, 0.05 mmol), 1- (4-amino-1-piperidinyl) ethanone (8 mg,0.05 mmol) and sodium cyanoborohydride (3 mg,0.05 mmol) preparation of (S) - ((6- (3- (2- (2- (((1-acetylpiperidin-4-yl) amino) methyl) -8-methoxyimidazo [1, 2-a))]Pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester. Using the general Boc deprotection procedure, a sequence consisting of (S) - ((6- (3- (2- (2- (((1-acetylpiperidin-4-yl) amino) methyl)) methyl) -8-methoxyimidazo [1, 2-a)]Preparation of (S) -5- ((((6- (3- (2- (((1-acetylpiperidin-4-yl) amino) methyl) -8-methoxyimidazo [1, 2-a)) using pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester and trifluoroacetic acid (67. Mu.L, 0.87 mmol)]Pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl-methyl) amino) methyl) pyrrolidin-2-one. 7.2mg,35% yield. MS: m/z found 757.1[ M+H ]] ⁺ Retention time = 1.53min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.71–8.65(m,1H),8.49(d,2H),7.98(s,1H),7.77(d,1H),7.73–7.69(m,1H),7.56(t,1H),7.51–7.46(m,1H),7.44–7.39(m,1H),7.27(dd,1H),7.06(d,1H),4.57(d,1H),4.23(s,2H),4.07(t,3H),4.02(t,3H),3.97(d,1H),3.92–3.83(m,3H),3.25–3.11(m,2H),2.80(m,2H),2.68(t,1H),2.39–2.24(m,3H),2.16(d,2H),2.11(t,3H),1.60–1.32(m,1H).

Example 503: (S) -5- (((6- (3- (2- (2- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (319)

By means of returnProchlorazation procedure B, prepared from (S) - ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxyimidazo [1, 2-a))]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (example 499, step (c)) (20 mg,0.03 mmol), acetic acid (3. Mu.L, 0.05 mmol), 1- (2, 6-diazaspiro [ 3.3)]Preparation of (S) - ((6- (3- (2- (2- ((6-acetyl-2, 6-diazaspiro [3.3 ]) by using heptan-2-yl) ethan-1-one hydrochloride (10 mg,0.05 mmol) and sodium cyanoborohydride (3 mg,0.05 mmol)]Heptane-2-yl) methyl) -8-methoxyimidazo [1,2-a]Pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester. Using the general Boc deprotection procedure, a reaction mixture was prepared from (S) - ((6- (3- (2- (2- ((6-acetyl-2, 6-diazaspiro [3.3 ])]Heptane-2-yl) methyl) -8-methoxyimidazo [1,2-a]Preparation of (S) -5- ((((6- (3- (2- (2- ((6-acetyl-2, 6-diazaspiro [3.3 ])) S-3) using pyridin-6-yl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester and trifluoroacetic acid (49. Mu.L, 0.64 mmol) ]Heptane-2-yl) methyl) -8-methoxyimidazo [1,2-a]Pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl-methyl) amino) methyl) pyrrolidin-2-one. 2.7mg,13% yield. MS: m/z found 755[ M+H ]] ⁺ Retention time = 1.54min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.68(d,1H),8.48(d,1H),7.92(s,1H),7.79(d,1H),7.72(d,1H),7.56(t,1H),7.48(d,1H),7.43(d,1H),7.28(d,1H),7.05(s,1H),4.32(s,2H),4.10–4.01(m,11H),3.98(d,2H),3.87(s,4H),2.86(t,2H),2.42–2.24(m,3H),1.83(s,4H).

Example 504: (S) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) -2, 5-diazaspiro [3.4] octan-6-one (320)

Using reductive amination procedure B, a reaction mixture was prepared from (S) - ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxymi-ne)Azolo [1,2-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (example 499, step (c)) (20 mg,0.03 mmol), acetic acid (3. Mu.L, 0.05 mmol), 2, 5-diazaspiro [3.4]]Preparation of (S) - ((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((6-oxo-2, 5-diazaspiro [3.4 ])) by means of (9 mg,0.05 mmol) and sodium cyanoborohydride (3 mg,0.05 mmol)]Octane-2-yl) methyl) imidazo [1,2-a]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester. Using the general Boc deprotection procedure, a reaction mixture was prepared from (S) - ((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((6-oxo-2, 5-diazaspiro [3.4 ])) ]Octane-2-yl) methyl) imidazo [1,2-a]Preparation of (S) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxo-pyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] with tert-butyl (5-oxo-pyrrolidin-2-yl) methyl) carbamate and trifluoroacetic acid (59 μl,0.77 mmol)]Pyridin-2-yl) methyl) -2, 5-diazaspiro [3.4]Octan-6-one. 6.3mg,31% yield. MS: m/z found 741.1[ M+H ]] ⁺ Retention time = 1.53min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.67(dd,1H),8.44(d,1H),7.86(s,1H),7.79(d,1H),7.71(d,1H),7.59–7.52(m,1H),7.47(dd,1H),7.42(d,1H),7.28(dd,1H),7.02(s,1H),4.04(m,6H),3.99(s,2H),3.95(s,2H),3.90(d,1H),3.69(d,2H),3.55(d,2H),2.93–2.81(m,2H),2.41(d,2H),2.38–2.25(m,4H),1.85(t,1H).

Example 505: (S) -5- (((6- (3- (2- (2- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (321)

Using reductive amination procedure B, a reaction mixture was prepared from (S) - ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxyimidazo [1, 2-a))]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridine-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (example 499, step (c)) (20 mg,0.03 mmol), acetic acid (3. Mu.L, 0.05 mmol), 2-oxaspiro [3.3]]Preparation of (S) - ((6- (3- (2- (2- (((2-oxaspiro [3.3 ])) 3) ]Heptane-6-yl) amino) methyl) -8-methoxyimidazo [1,2-a]Pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester. Using the general Boc deprotection procedure, the reaction mixture was prepared from (S) - ((6- (3- (2- (2- (((2-oxaspiro [3.3 ])]Heptane-6-yl) amino) methyl) -8-methoxyimidazo [1,2-a]Preparation of (S) -5- ((((6- (3- (2- (2- (((2-oxaspiro [3.3 ])) 2- (((2-oxopyrrolidin-2-yl)) methyl)) carbamic acid tert-butyl ester and trifluoroacetic acid) (64. Mu.L, 0.84 mmol))]Heptane-6-yl) amino) methyl) -8-methoxyimidazo [1,2-a]Pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl-methyl) amino) methyl) pyrrolidin-2-one. 4.7mg,24% yield. MS: m/z found 730.1[ M+H ]] ⁺ Retention time = 1.64min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.68(d,1H),7.99(s,1H),7.77(d,1H),7.72(d,1H),7.56(t,1H),7.49(d,1H),7.42(d,1H),7.26(d,1H),7.07(s,1H),4.14(s,2H),4.07(s,3H),4.02(t,3H),3.93–3.82(m,3H),3.71(d,1H),3.68(s,2H),3.62(s,2H),2.78(t,2H),2.31(q,5H),2.01–1.91(m,2H),1.83(s,1H).

Example 506: (S) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) azetidine-3-carboxylic acid (350)

Using reductive amination procedure B, a reaction mixture was prepared from (S) - ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxyimidazo [1, 2-a)) ]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (example 499, step (c)) (20 mg,0.03 mm)Preparation of (S) -1- ((6- (4- (3- (5- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-methoxyimidazo [1, 2-a)]Pyridin-2-yl) methyl) azetidine-3-carboxylic acid. Using the general Boc deprotection procedure, from S) -1- ((6- (4- (3- (5- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-methoxyimidazo [1,2-a]Preparation of (S) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1, 2-a) with pyridine-2-yl methyl) azetidine-3-carboxylic acid and trifluoroacetic acid (70. Mu.L, 0.92 mmol)]Pyridin-2-yl) methyl) azetidine-3-carboxylic acid. 8.1mg,41% yield. MS: m/z found 716[ M+H ]] ⁺ Retention time = 1.50min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.68(m,1H),8.50(q,1H),8.07(s,1H),7.80(d,1H),7.73–7.66(m,1H),7.55(dd,1H),7.47(m,1H),7.42(m,1H),7.28(d,1H),7.07(d,1H),4.45(s,2H),4.29–4.17(m,4H),4.05(t,3H),4.03(d,3H),4.02(s,1H),3.93(s,1H),3.39(m,1H),2.98–2.84(m,2H),2.41–2.26(m,3H),1.84(m,1H).

Example 507: (S) -1- (2- (((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) amino) ethyl) cyclopropane-1-carboxylic acid (351)

Using reductive amination procedure B, a reaction mixture was prepared from (S) - ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxyimidazo [1, 2-a))]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (example 499, step (c)) (20 mg,0.03 mmol), acetic acid (3. Mu.L, 0.05 mmol), 1- (2-aminoethyl) cyclopropane-1-carboxylic acid (7 mg,0.05 mmol) and sodium cyanoborohydride (3 mg, 0)05 mmol) preparation of (S) -1- (2- (((6- (4- (3- (5- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-methoxyimidazo [1, 2-a)]Pyridin-2-yl) methyl) amino) ethyl) cyclopropane-1-carboxylic acid. From (S) -1- (2- (((6- (4- (3- (5- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-methoxyimidazo [1, 2-a) using the general Boc deprotection procedure ]Preparation of (S) -1- (2- (((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1, 2-a) with (68. Mu.L, 0.89 mmol) pyridine-2-yl methyl) amino) ethyl cyclopropane-1-carboxylic acid and trifluoroacetic acid]Pyridin-2-yl) methyl) amino) ethyl) cyclopropane-1-carboxylic acid. 3.7mg,18% yield. MS: m/z found 744[ M+H ]] ⁺ Retention time = 1.66min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.68(d,1H),8.51(s,1H),8.07(s,1H),7.82(d,1H),7.71(d,1H),7.57(t,1H),7.48(d,1H),7.43(d,1H),7.30(d,1H),7.08(s,1H),4.34(s,2H),4.15(s,2H),4.06(s,3H),4.04(s,3H),4.00(s,1H),3.26(t,2H),3.06(t,2H),2.40–2.31(m,3H),1.86(d,3H),1.17(s,2H),0.70(s,2H).

Example 508: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (384)

Using reductive amination procedure B, a reaction mixture was prepared from (S) - ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxyimidazo [1, 2-a))]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (example 499, step (c)) (20 mg,0.03 mmol), acetic acid (3. Mu.L, 0.05 mmol), (1 r,4 r) -4-aminocyclohexane-1-ol (6 mg,0.05 mmol) and sodium cyanoborohydride (3 mg,0.05 mmol) preparation ((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-) Methoxy imidazo [1,2-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester. Using the general Boc deprotection procedure, the reaction mixture was prepared from ((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1, 2-a)]Preparation of (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1, 2-a) with tert-butyl pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamate and trifluoroacetic acid (24 μl,0.31 mmol)]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one. 4.7mg,24% yield. MS: m/z found 730.2[ M+H ]] ⁺ Retention time = 1.50min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.69(d,1H),8.51(s,1H),8.07(s,1H),7.84(d,1H),7.77–7.68(m,1H),7.57(t,1H),7.50(d,1H),7.44(d,1H),7.32(d,1H),7.09(s,1H),4.38(s,2H),4.13(d,2H),4.08(d,3H),4.06(t,3H),3.98(s,1H),3.57(s,1H),3.16(d,1H),3.02(t,2H),2.34(d,3H),2.24(d,2H),2.06(d,2H),1.87(d,1H),1.51(q,2H),1.36(q,2H).

Example 509:1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (morpholinomethyl) imidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (475)

(a) (1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- (hydroxymethyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

To (2- (hydroxymethyl) -8-methoxyimidazo [1, 2-a)]Pyridin-6-yl) boronic acid (example 499, step (a)) (140.7 mg,0.63 mmol) and (1-acetylpiperidin-4-yl) ((6- (2)A mixture of tert-butyl chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl carbamate (262 mg,0.42 mmol) in 1, 4-dioxane/water (4:1, 3 mL) was added potassium carbonate (175 mg,1.27 mmol). Nitrogen was bubbled through the mixture for two minutes. Tetrakis (triphenylphosphine) palladium (0) (49 mg,0.04 mmol) was added and the reaction stirred at 100 ℃ for 30 min. The reaction mixture was diluted with water (30 mL) and the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by normal phase silica gel chromatography (0-5% MeOH in DCM) to give (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- (hydroxymethyl) -8-methoxyimidazo [1, 2-a))]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamic acid tert-butyl ester (110 mg,34% yield). MS: m/z found 761.1[ M+H ]] ⁺ .

(b) (1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

To (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- (hydroxymethyl) -8-methoxyimidazo [1, 2-a))]A solution of tert-butyl pyridin-6-yl) pyridin-4-yl-phenyl) -2-methoxypyridin-3-yl methyl) carbamate (110 mg,0.14 mmol) in dichloromethane (3 mL) was added to dess-martin periodate (122 mg,0.29 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was purified by normal phase silica gel chromatography (0-5% MeOH in DCM) to give (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxyimidazo [1, 2-a))]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamic acid tert-butyl ester (91 mg,83% yield). MS: m/z found 759[ M+H ]] ⁺ .

(c) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (morpholinomethyl) imidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

By reductive amination procedure B, starting from (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxyimidazo [1, 2-a))]Preparation of (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (morpholinomethyl) imidazo [1,2-a ]) with tert-butyl pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamate (15 mg,0.02 mmol), acetic acid (2. Mu.L, 0.04 mmol), morpholine (3 mg,0.04 mmol) and sodium cyanoborohydride (3 mg,0.04 mmol) ]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester. From (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (morpholinomethyl) imidazo [1, 2-a)) using the general Boc deprotection procedure]Preparation of tert-butyl pyridin-6-yl) pyridin-4-yl phenyl) -2-methoxypyridin-3-yl methyl) carbamate and trifluoroacetic acid (55. Mu.L, 0.72 mmol) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (morpholinomethyl) imidazo [1, 2-a))]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one. 4.7mg,33% yield. MS: m/z found 730.1[ M+H ]] ⁺ Retention time = 1.46min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.69(d,1H),8.48(s,1H),7.94(s,1H),7.90(d,1H),7.72(d,1H),7.58(t,1H),7.47(t,2H),7.36(d,1H),7.04(s,1H),4.67(d,1H),4.30(s,2H),4.13–4.02(m,8H),3.91(s,2H),3.75(s,4H),3.46(s,1H),3.21(t,1H),2.77(s,4H),2.74–2.62(m,1H),2.25(t,2H),2.13(s,3H),1.77–1.44(m,1H).

Example 510:1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((3, 3-difluoropyrrolidin-1-yl) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (476)

By means of returnProchlorazation procedure B was performed using (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxyimidazo [1, 2-a))]Preparation of (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- ((3, 3-difluoropyrrolidin-1-yl) methyl) -8-methoxyimidazo [1,2-a ]) with tert-butyl pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl (example 509, step (b)) (15 mg,0.02 mmol), acetic acid (2. Mu.L, 0.04 mmol), 3-difluoropyrrolidine (4 mg,0.04 mmol) and sodium cyanoborohydride (3 mg,0.04 mmol) ]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester. From (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- ((3, 3-difluoropyrrolidin-1-yl) methyl) -8-methoxyimidazo [1, 2-a) using the general Boc deprotection procedure]Preparation of tert-butyl pyridin-6-yl) pyridin-4-yl phenyl) -2-methoxypyridin-3-yl methyl) carbamate and trifluoroacetic acid (58 μl,0.76 mmol) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((3, 3-difluoropyrrolidin-1-yl) methyl) -8-methoxyimidazo [1, 2-a) preparation]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one. 3.4mg,23% yield. MS: m/z found 750.1[ M+H ]] ⁺ Retention time = 2.26min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.74(d,1H),8.71(s,1H),8.19(s,1H),7.91(d,1H),7.73(d,1H),7.59(t,1H),7.54(d,2H),7.47(d,1H),7.37(d,1H),4.68(d,1H),4.33(s,2H),4.17(s,6H),4.09(t,5H),3.51(s,1H),3.17(t,3H),2.75–2.61(m,1H),2.43(m,2H),2.32–2.19(m,2H),2.14(d,4H).

Example 511:1- ((6- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) -3-methylazetidine-3-carbonitrile (477)

By reductive amination procedure B, starting from (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxyimidazo [1, 2-a))]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamic acid tert-butyl ester (example 509, step Preparation of (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- ((3-cyano-3-methylazetidin-1-yl) methyl) -8-methoxyimidazo [1, 2-a) (15 mg,0.02 mmol), acetic acid (2. Mu.L, 0.04 mmol), 3-methylazetidine-3-carbonitrile (4 mg,0.04 mmol) and sodium cyanoborohydride (3 mg,0.04 mmol)) (15 mg,0.02 mmol)]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester. From (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- ((3-cyano-3-methylazetidin-1-yl) methyl)) 8-methoxyimidazo [1, 2-a) using the general Boc deprotection procedure]Preparation of tert-butyl pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamate and trifluoroacetic acid (50 μl,0.65 mmol) 1- ((6- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-methoxyimidazo [1, 2-a)]Pyridin-2-yl) methyl) -3-methylazetidine-3-carbonitrile. 3.9mg,27% yield. MS: m/z found 739.2[ M+H ]] ⁺ Retention time = 2.17min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.72(d,1H),8.62(s,1H),8.15(s,1H),7.91(d,1H),7.73(d,1H),7.59(t,1H),7.52(d,1H),7.46(d,1H),7.35(d,1H),4.74–4.61(m,1H),4.36(s,1H),4.33(s,2H),4.30(s,1H),4.13(s,3H),4.09(d,4H),3.97(d,2H),3.49(d,1H),3.25–3.14(m,1H),2.70(t,1H),2.33–2.18(m,2H),2.13(s,3H),1.70(s,3H),1.63(s,1H),1.52(s,1H).

Example 512:1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2, 2-difluoroethyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (478)

By reductive amination procedure B, starting from (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxyimidazo [1, 2-a))]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamic acid tert-butyl ester (example 509, step (b)) (15 mg,0.02 mmol), acetic acid (2. Mu.L, 0.04 mmol), 2-difluoroethylamine (5 mg,0.04 mmol) and sodium cyanoborohydride (3 mg,0.04 m)mol) preparation of (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- (((2, 2-difluoroethyl) amino) methyl) -8-methoxyimidazo [1, 2-a)]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester. From (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- (((2, 2-difluoroethyl) amino) methyl)) 8-methoxyimidazo [1, 2-a) using the general Boc deprotection procedure]Preparation of tert-butyl pyridin-6-yl) pyridin-4-yl phenyl) -2-methoxypyridin-3-yl methyl) carbamate and trifluoroacetic acid (56 μl,0.73 mmol) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((2, 2-difluoroethyl) amino) methyl) -8-methoxyimidazo [1, 2-a) preparation]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one. 1.6mg,11% yield. MS: m/z found 724.2[ M+H ] ] ⁺ Retention time = 1.59min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.71(d,1H),8.56(s,1H),8.11(s,1H),7.91(d,1H),7.73(d,1H),7.59(s,1H),7.51(d,1H),7.46(d,1H),7.37(d,1H),7.21(s,1H),4.67(s,1H),4.43(s,2H),4.33(s,2H),4.10(d,9H),3.55(d,3H),3.22(s,1H),2.70(s,1H),2.26(s,2H),2.13(s,4H).

Example 513: (1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol (453)

(a) 6- (2-chloro-3- (3-chloro-2- (2- (hydroxymethyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde

To (2- (hydroxymethyl) -8-methoxyimidazo [1, 2-a)]Pyridine-6-yl) boronic acid (example 499, step (a)) (76 mg,0.34 mmol) and 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (100 mg,0.23 mmol) in 1, 4-dioxane/water (4:1)Potassium carbonate (95 mg,0.68 mmol) was added to the mixture in 3 mL. Nitrogen was bubbled through the mixture for two minutes. Tetrakis (triphenylphosphine) palladium (0) (26 mg,0.02 mmol) was added and the reaction stirred at 100 ℃ for 30 min. The reaction mixture was diluted with water (30 mL) and the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by normal phase silica gel chromatography (0-5% MeOH in DCM) to provide 6- (2-chloro-3- (3-chloro-2- (2- (hydroxymethyl) -8-methoxyimidazo [1, 2-a) ]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (91 mg,75% yield). MS: m/z found 535.1[ M+H ]] ⁺ .

(b) 6- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridine-2-carbaldehyde

To 6- (2-chloro-3- (3-chloro-2- (2- (hydroxymethyl) -8-methoxyimidazo [1, 2-a)]A solution of pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (91 mg,0.17 mmol) in dichloromethane (3 mL) was added with dess martin periodate (144 mg,0.34 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was purified by normal phase silica gel chromatography (0-5% MeOH in DCM) to provide 6- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a]Pyridine-2-carbaldehyde (88 mg,97% yield). MS: m/z found 533[ M+H ]] ⁺ .

(c) (1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol

From 6- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxy) using reductive amination procedure APyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ]Preparation of (1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) 8-methoxyimidazo [1, 2-a)) by pyridine-2-carbaldehyde (15 mg,0.03 mmol), acetic acid (3. Mu.L, 0.06 mmol), (1 r,4 r) -4-aminocyclohexane-1-ol (13 mg,0.11 mmol) and sodium cyanoborohydride (5 mg,0.08 mmol)]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexane-1-ol. 8.4mg,41% yield. MS: m/z found 731.2[ M+H ]] ⁺ Retention time = 1.49min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.73–8.67(m,1H),8.51(d,1H),8.07(s,1H),7.89(d,1H),7.76–7.68(m,1H),7.58(t,1H),7.50(dd,1H),7.48–7.42(m,1H),7.35(d,1H),7.09(s,1H),4.38(s,2H),4.27(s,2H),4.08(t,6H),3.57(s,2H),3.18(t,2H),2.24(d,4H),2.06(s,4H),1.53(p，4H),1.38(d,4H).

Example 514:2- ((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((6-oxo-2, 5-diazaspiro [3.4] oct-2-yl) methyl) imidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 5-diazaspiro [3.4] octan-6-one (454)

From 6- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a using reductive amination procedure a]Pyridine-2-carbaldehyde (example 513, step (b)) (15 mg,0.03 mmol), acetic acid (3. Mu.L, 0.06 mmol) and 2, 5-diazaspiro [3.4]]Preparation of 2- ((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((6-oxo-2, 5-diazaspiro [3.4 ]) by means of octan-6-one hydrochloride (18 mg,0.11 mmol) and sodium cyanoborohydride (5 mg,0.08 mmol) ]Octane-2-yl) methyl) imidazo [1,2-a]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) -2, 5-diazaspiro [3.4]Octan-6-one. 3.5mg,17% yield. MS: m/z found 753.1[ M+H ]] ⁺ Retention time = 1.46min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )8.69(d,1H),8.49(s,1H),7.98(s,1H),7.80(d,1H),7.72(d,1H),7.57(t,1H),7.51–7.46(m,1H),7.44(d,1H),7.31(d,1H),7.07(d,1H),4.23(s,2H),4.12(s,2H),4.07(s,3H),4.04(d,5H),4.00(d,3H),3.95(d,2H),3.89(d,2H),2.45(s,4H),2.38(d,4H).

Example 515:1- ((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -3-methylazetidin-3-ol (455)

From 6- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a using reductive amination procedure a]Pyridine-2-carbaldehyde (example 513, step (b)) (15 mg,0.03 mmol), acetic acid (3. Mu.L, 0.06 mmol), 3-methylazetidin-3-ol hydrochloride (14 mg,0.11 mmol) and sodium cyanoborohydride (5 mg,0.08 mmol) was used to prepare 1- ((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -8-methoxyimidazo [1, 2-a)]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -3-methylazetidin-3-ol. 3.5mg,18% yield. MS: m/z found 675.2[ M+H ]] ⁺ Retention time = 1.46min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.70(d,1H),8.51(d,1H),8.08(s,1H),7.88(d,1H),7.73(d,1H),7.58(t,1H),7.50(d,1H),7.45(d,1H),7.36(d,1H),7.09(s,1H),4.48(s,2H),4.42(s,2H),4.13(d,4H),4.07(dd,6H),4.02(t,4H),1.52(d,6H).

Example 516:2- ((6- (2-chloro-3- (3-chloro-2- (2- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2-azaspiro [3.3] heptan-6-ol (474)

From 6- (3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a using reductive amination procedure a]Pyridine-2-carbaldehyde (example 513, step (b)) (15 mg, 0).03 mmol), acetic acid (3. Mu.L, 0.06 mmol), 2-azaspiro [3.3]]Preparation of heptane-6-ol hydrochloride (17 mg,0.11 mmol) and sodium cyanoborohydride (5 mg,0.08 mmol) 2- ((6- (2-chloro-3- (3-chloro-2- (2- ((6-hydroxy-2-azaspiro [3.3 ]))]Heptane-2-yl) methyl) -8-methoxyimidazo [1,2-a]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) -2-azaspiro [3.3]Heptane-6-ol. 3.4mg,17% yield. MS: m/z found 727.2[ M+H ]] ⁺ Retention time = 0.56min (method B). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.72(d,1H),8.62(s,1H),8.15(s,1H),7.91(d,1H),7.73(d,1H),7.59(t,1H),7.52(d,1H),7.46(d,1H),7.35(d,1H),4.74–4.61(m,1H),4.36(s,1H),4.33(s,2H),4.30(s,1H),4.13(s,3H),4.09(d,4H),3.97(d,2H),3.49(d,1H),3.25–3.14(m,1H),2.70(t,1H),2.33–2.18(m,2H),2.13(s,3H),1.70(s,3H),1.63(s,1H),1.52(s,1H).

Example 517: (S) -N- (1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-3-yl) methyl) piperidin-4-yl) acetamide (377)

(a) 1-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrrolo [3,2-b ] -pyridine-3-carbaldehyde

6-bromo-1-methyl-pyrrolo [3,2-b ] in a sealed tube]Pyridine-3-carbaldehyde (457 mg,1.91 mmol), bis (pinacolato) diborane (680 mg,2.68 mmol), [1,1' -bis (biphenylphosphino) ferrocene]A complex of palladium (II) dichloride with dichloromethane (156 mg,0.19 mmol), and potassium acetate (525 mg,5.35 mmol) were suspended in 15mL of 1, 4-dioxane. Nitrogen was bubbled through the reaction solution for 2 minutes, then the vessel was sealed and heated at 95 ℃ for 3 hours. The reaction was filtered through CELITE and the filtrate was concentrated under reduced pressure. The dark crude oil was dissolved in 5mL EOAc and slowly addedHexane was added until the catalyst precipitated out of solution. The solid was filtered and the filtrate concentrated to provide a pale brown oil. After standing for 15 minutes, a portion of the oil was allowed to solidify. The whole sample was suspended in 10mL of hexane and sonicated until refined solids formed. The solid was filtered and dried to provide 1-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrrolo [3,2-b ] as a yellow solid]Pyridine-3-carbaldehyde (401 mg,73% yield). MS: m/z found 205[ M+H ]] ⁺ (boric acid fragments).

(b) (S) - ((6- (2-chloro-3- (3-chloro-2- (3-formyl-1-methyl-1H-pyrrolo [3,2-b ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

Tetrakis (triphenylphosphine) palladium (0) (20 mg,0.02 mmol), potassium carbonate (35 mg,0.25 mmol), N- [ [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl]-2-methoxy-3-pyridinyl]Methyl group]-N- [ [ (2S) -5-oxopyrrolidin-2-yl]Methyl group]Carbamic acid tert-butyl ester (50 mg,0.08 mmol), and 1-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrrolo [3,2-b]Pyridine-3-carbaldehyde (36 mg,0.13 mmol) was suspended in 1, 4-dioxane/water (4:1, 2 mL) and the solution was then heated at 105℃for 20 min. The reaction was cooled to room temperature, diluted with 5mL of water, and extracted with EtOAc (3×3 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (0-6% meoh/DCM) to provide (S) - ((6- (2-chloro-3- (3-chloro-2- (3-formyl-1-methyl-1H-pyrrolo [3, 2-b)) as a yellow oil]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (50 mg,83% yield). MS: m/z found 715, 717[ M+H ] ] ⁺ .

(c) (S) - ((6- (3- (2- (3- ((4-acetamidopiperidin-1-yl) methyl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

(S) - ((6- (2-chloro-3- (3-chloro-2- (3-formyl-1-methyl-1H-pyrrolo [3, 2-b))]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (25 mg,0.03 mmol), acetic acid (4 mg,0.07 mmol), and N- (4-piperidinyl) acetamide (20 mg,0.14 mmol) were dissolved in MeOH/THF (1:1, 1 mL) and the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (9 mg,0.14 mmol) was added and the resulting mixture was stirred at 25℃for 1 hour. The reaction was then diluted with water (3 mL) and extracted with EtOAc (3×3 mL). The combined organics were further washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford (S) - ((6- (3- (2- (3- ((4-acetamidopiperidin-1-yl) methyl) -1-methyl-1H-pyrrolo [3, 2-b)) as a yellow oil]Pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (29 mg, crude). MS: m/z found 841,843[ M+H ] ] ⁺ . The material was used in the next step without further purification.

(d) (S) -N- (1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-3-yl) methyl) piperidin-4-yl) acetamide

(S) - ((6- (3- (2- (3- ((4-acetamidopiperidin-1-yl) methyl) -1-methyl-1H-pyrrolo [3, 2-b)]Tert-butyl pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (29 mg,0.03mmol, crude) was dissolved in 1mL MeOH and 4M HCl solution in 1, 4-dioxane (27 μl,0.11 mmol) was added. The reaction was stirred at room temperature for 60 minutes and the solvent was removed under reduced pressure. Purification of crude samples by reverse phase HPLC to afford white(S) -N- (1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-pyrrolo [3, 2-b) of a color solid (formate)]Pyridin-3-yl) methyl piperidin-4-yl) acetamide (7 mg,29% yield). LC/MS: m/z found 741,743[ M+H ]] ⁺ Retention time = 2.08min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.79(s,1H),8.71(s,1H),8.35–8.30(m,1H),7.88(s,1H),7.80(d,1H),7.72(d,1H),7.57(t,1H),7.49(d,1H),7.44(d,1H),7.29(d,1H),4.55–4.46(m,2H),4.04(s,4H),3.97(s,5H),3.90(s,2H),3.51(s,2H),3.12(s,1H),2.84(d,2H),2.32(d,3H),2.09(d,2H),1.92(s,3H),1.80(d,2H).

Example 518: (S) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one (378)

In a similar manner to that described for example 517, intermediate (S) - ((6- (2-chloro-3- (3-chloro-2- (3-formyl-1-methyl-1H-pyrrolo [3, 2-b)) was used in step (c)]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester and 2, 6-diazaspiro [3.4]Preparation of (S) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-pyrrolo [3, 2-b) using octane-7-one instead of N- (4-piperidinyl) acetamide]Pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4]Octane-7-one. The product was obtained as a white solid (formate). LC/MS: m/z found 725,727[ M+H ]] ⁺ Retention time = 2.01min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.78(d,1H),8.71(d,1H),8.45(s,1H),8.30(d,1H),7.84–7.75(m,2H),7.72(d,1H),7.56(t,1H),7.49(d,1H),7.44(d,1H),7.31–7.23(m,1H),4.48(s,2H),4.07(s,4H),4.03(d,3H),3.94(dd,5H),3.88(s,1H),3.61(s,2H),2.79(d,2H),2.64(s,2H),2.33(q,3H),1.83(s,1H).

Example 519:1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-fluorophenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (282)

(a) 6- (2-chloro-3- (3-chloro-2- (3-fluoro-4-formylphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde

Following suzuki coupling procedure a, 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (200 mg,0.51 mmol) and 2-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (127 mg,0.51 mmol) was provided 6- (2-chloro-3- (3-chloro-2- (3-fluoro-4-formylphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (220 mg,90% yield). LCMS: found 481.1[ M+H ] m/z ] ⁺ Retention time = 1.10min (method B).

(b) 1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-fluorophenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

This compound was prepared as formate salt according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (3-fluoro-4-formylphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (50 mg,0.10 mmol) and 1- (4-amino-1-piperidinyl) ethanone (59 mg,0.42 mmol). Yield 66%. LCMS: m/z found 733.3[ M+H ]] ⁺ Retention time = 1.64min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.54(s,2H),7.78(d,1H),7.71(dd,1H),7.63–7.51(m,3H),7.49–7.38(m,3H),7.28(d,1H),4.50(t,2H),4.03(s,3H),4.00–3.88(m,6H),3.20–3.10(m,2H),2.87(dd,2H),2.71(t,2H),2.12–2.09(m,6H),2.09–1.98(m,4H),1.49–1.22(m,4H).

Example 520:1- (6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((methylamino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine (283)

Formate was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (3-fluoro-4-formylphenyl) pyridin-4-yl) phenyl) -2-methoxy nicotinaldehyde (example 519, step (a)) (50 mg,0.10 mmol) and methylamine solution (33% wt in ethanol, 0.42 mmol) 1- (6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((methylamino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methylamine. Yield 38%. LCMS: m/z found 511.1[ M+H ] ] ⁺ Retention time = 1.60min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.71–8.63(m,1H),8.54(s,2H),7.84(d,1H),7.77–7.68(m,1H),7.65–7.52(m,4H),7.49–7.42(m,2H),7.34(d,1H),4.16(s,4H),4.08(s,3H),2.71(s,3H),2.65(s,3H).

Example 521:2- ((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one (284)

Following reductive amination procedure a, starting from 6- (2-chloro-3- (3-chloro-2- (3-fluoro-4-formylphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (example 519, step (a)) (50 mg,0.10 mmol) and 2, 6-diazaspiro [3.4]]Octan-7-one (52 mg,0.42 mmol) was prepared from 2- ((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((7-oxo-2, 6-diazaspiro [3.4 ])]Octane-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) -2, 6-diazaspiro [3.4]The preparation of formate from octane-7-ketone. 42% yield. LCMS: m/z found 701.2[ M+H ]] ⁺ Retention time = 1.59min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.68–8.60(m,1H),8.49(s,2H),7.71(t,2H),7.58–7.49(m,3H),7.48–7.35(m,3H),7.26(d,1H),4.01(s,3H),3.82(s,4H),3.62–3.51(m,8H),3.49–3.40(m,4H),2.63–2.53(m,4H).

Example 522:1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3- (difluoromethoxy) phenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (394)

(a) 6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4-formylphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde

To a mixture of 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (150 mg,0.38 mmol), (3- (difluoromethoxy) -4-formylphenyl) boronic acid (82 mg,0.38 mmol) and potassium carbonate (158 mg,1.14 mmol) in degassed 1, 4-dioxane/water (6:1) was added tetrakis (triphenylphosphine) palladium (0) (44 mg,0.04 mmol) and the mixture was stirred at 100 ℃ for 30 min. Water was added and the mixture was extracted three times into EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column with 2% MeOH in DCM as eluent to afford 6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4-formylphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (190 mg, 94%). LCMS: m/z found 529.1[ M+H ]] ⁺ Retention time = 1.11min (method B).

(b) 1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3- (difluoromethoxy) phenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

Formate salt was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4-formylphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (20 mg,0.04 mmol) and 1- (4-amino-1-piperidinyl) ethanone (21 mg,0.15 mmol) with 1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3- (difluoromethoxy) phenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one. 58% yield. LCMS: m/z found 781.3[ M+H ] ] ⁺ Retention time = 1.75min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.67(d,1H),8.51–8.42(m,2H),7.86(d,1H),7.72(d,1H),7.65(q,2H),7.60–7.53(m,2H),7.50–7.41(m,2H),7.33(dd,1H),7.03(t,1H),4.67–4.51(m,2H),4.17(s,4H),4.07(s,3H),4.05–3.96(m,1H),3.26–3.08(m,4H),2.71(t,2H),2.25–2.05(m,10H),1.66–1.31(m,4H).

Example 523:2- ((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one (597)

Following reductive amination procedure a, starting from 6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4-formylphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (example 522, step (a)) (60 mg,0.11 mmol) and 2, 6-diazaspiro [3.4]]Octan-7-one (57 mg,0.45 mmol) was prepared from 2- ((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- ((7-oxo-2, 6-diazaspiro [ 3.4))]Octane-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) -2, 6-diazaspiro [3.4]The preparation of formate from octane-7-ketone. Yield 47%. LCMS: m/z found 749.2[ M+H ]] ⁺ Retention time = 2.65min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.73–8.59(m,1H),8.40(s,2H),7.78(d,1H),7.71(d,1H),7.66–7.49(m,4H),7.48–7.39(m,2H),7.30(d,1H),6.97(t,1H),4.09–4.00(m,5H),3.97(s,2H),3.81(s,4H),3.66–3.56(m,8H),2.65(s,2H),2.61(s,2H).

Example 524:1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3- (difluoromethoxy) phenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one (598)

Following reductive amination procedure a, starting from 6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4-formylphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (example 522, step (a)) (60 mg,0.11 mmol) and 1- (2, 6-diazaspiro [3.3 ]]Heptan-2-yl) ethanone (64 mg,0.45 mmol) was prepared from 1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [ 3.3))]Heptane-2-yl) methyl) -3- (difluoromethoxy) phenyl) -3-chloropyridin-4-yl-2-chlorophenyl) -2-methoxypyridin-3-yl methyl) -2, 6-diazaspiro [3.3]Heptane-2-yl) ethan-1-one to form formate. Yield 51%. LCMS: m/z found 777.3[ M+H ]] ⁺ Retention time = 2.78min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.46(s,2H),7.74(d,1H),7.71(dd,1H),7.62–7.51(m,4H),7.46(d,1H),7.42(dd,1H),7.29(d,1H),6.96(t,1H),4.40–4.23(m,4H),4.12–4.04(m,4H),4.02(s,3H),3.92(s,2H),3.88(s,2H),3.84–3.74(m,4H),3.68–3.59(m,4H),1.85(s,6H).

Example 525: (S) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (617)

Following reductive amination procedure A, starting from 6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4-formylphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (example 522, step (a)) (50 mg,0.09 mmol) and (S) method5- (aminomethyl) pyrrolidin-2-one (43 mg,0.38 mmol) was prepared as formate salt of (S) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one. Yield 38%. LCMS: m/z found 725.2[ M+H ] ] ⁺ Retention time = 2.67min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),8.41(s,2H),7.80(d,1H),7.72(dd,1H),7.66–7.51(m,4H),7.46(d,1H),7.43(dd,1H),7.30(d,1H),6.98(t,1H),4.05(s,3H),4.03–3.95(m,4H),3.95–3.82(m,2H),2.96–2.72(m,4H),2.44–2.22(m,6H),1.94–1.73(m,2H).

Example 526: n- ((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine (618)

Formate was prepared according to reductive amination procedure A from 6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4-formylphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (example 522, step (a)) (50 mg,0.09 mmol) and tetrahydropyran-4-amine (38 mg,0.38 mmol) with N- ((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine. 40% yield. LCMS: m/z found 699.2[ M+H ]] ⁺ Retention time = 3.01min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),8.53(s,2H),7.81(d,1H),7.72(d,1H),7.67–7.51(m,4H),7.46(d,1H),7.43(dd,1H),7.30(d,1H),7.00(t,1H),4.10–3.88(m,11H),3.43(tt，4H),3.12–2.87(m,2H),1.99(t,4H),1.67–1.43(m,4H).

Example 527:4- (((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((1-methyl-2-oxopiperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylpiperidin-2-one (619)

Racemic and formate salt was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4-formylphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (example 522, step (a)) (50 mg,0.09 mmol) and 4-amino-1-methyl-piperidin-2-one (48 mg,0.38 mmol) with 4- (((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((1-methyl-2-oxopiperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylpiperidin-2-one). 42% yield. LCMS: m/z found 753.3[ M+H ] ] ⁺ Retention time = 2.73min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),8.46(s,2H),7.80(d,1H),7.71(dd,1H),7.67–7.58(m,2H),7.58–7.50(m,2H),7.46(d,1H),7.42(dd,1H),7.29(d,1H),6.98(t,1H),4.04(s,3H),4.03–3.92(m,4H),3.50–3.42(m,2H),3.42–3.34(m,2H),3.27–3.06(m,2H),2.98–2.84(m,6H),2.81–2.60(m,2H),2.37–2.14(m,4H),1.90–1.73(m,2H).

Example 528:2- (4- (((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((1- (2-hydroxyethyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-ol (620)

Formate salt was prepared according to reductive amination procedure a from 6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4-formylphenyl) pyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (example 522, step (a)) (50 mg,0.09 mmol) and 2- (4-amino-1-piperidinyl) ethanol (54 mg,0.38 mmol) 2- (4- (((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((1- (2-hydroxyethyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-ol. 34% yield. LCMS: m/z found 785.3[ M+H ]] ⁺ Retention time = 2.23min (method a). ¹ H NMR(400MHzMethanol-d ₄ ):δ8.67(d,1H),8.44(s,4H),7.83(d,1H),7.72(dd,1H),7.68–7.60(m,2H),7.60–7.53(m,2H),7.47(d,1H),7.44(dd,1H),7.31(d,1H),7.01(t,1H),4.15–4.01(m,7H),3.86–3.73(m,4H),3.50–3.41(m,2H),3.41–3.34(m,3H),3.10–2.94(m,4H),2.94–2.75(m,3H),2.74–2.55(m,2H),2.26–2.11(m,4H),1.85–1.65(m,4H).

Example 529:2- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3- (difluoromethoxy) phenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one (662)

(a) 2- ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one

To 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (example 1, step (a)) (600 mg,1.52 mmol) and 2, 6-diazaspiro [3.4 ]]A mixture of octan-7-one trifluoroacetate (1.46 g,6.10 mmol) in methanol (10 mL) was added sodium acetate (1.25 g,15.2 mmol) and under N ₂ The mixture was stirred at room temperature for 3 hours. Sodium triacetoxyborohydride (1.62 g,7.62 mmol) was then added and added under N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was filtered, concentrated and passed through normal phase SiO ₂ Chromatography (0-45% ethyl acetate/petroleum ether) purification of the residue to afford 2- ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4 ] as a white solid]Octan-7-one (480 mg,56% yield). MS: m/z found 503[ M+H ]] ⁺ .

(b) 2- (difluoromethoxy) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde

To a mixture of 4-bromo-2- (difluoromethoxy) benzaldehyde (300 mg,1.20 mmol) and bis (pinacolato) diborane (284 mg,1.55 mmol) in 1, 4-dioxane (3 mL) was added potassium acetate (234 mg,2.39 mmol), [1,1' -bis (biphenylphosphino) ferrocene]Complex of palladium (II) dichloride with dichloromethane (97.6 mg,0.119 mmol) and under N ₂ The mixture was stirred at 100℃for 1 hour. To the mixture was added water (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phases were dried over anhydrous sulphate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ The residue was purified by chromatography (0-15% ethyl acetate/petroleum ether) to provide 2- (difluoromethoxy) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (230 mg, crude) as a yellow oil. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.37(s,1H),7.92(d,1H),7.75-7.73(m,1H),7.68-7.32(m,2H),1.34(s,12H).

(c) 4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (difluoromethoxy) benzaldehyde

To 2- ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4]A mixture of octan-7-one (200 mg,0.397 mmol) and 2- (difluoromethoxy) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (177 mg,0.59 mmol) in THF/water (5:1, 6 mL) was added potassium phosphate (252 mg,1.19 mmol) and [1,1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) dichloride (25.8 mg,0.04 mmol) in N ₂ And the mixture was stirred at 80℃for 2 hours. Water (10 mL) was added and the mixture extracted with ethyl acetate (10 mL x 2). The combined organic phases were dried over anhydrous sulphate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ The residue was purified by chromatography (0-60% ethyl acetate/petroleum ether) to afford 4- (3-chloro-4- (2-chloro-3- (6-)) as a white solidMethoxy-5- ((7-oxo-2, 6-diazaspiro [ 3.4)]Octan-2-yl) methyl pyridin-2-yl) phenyl pyridin-2-yl) -2- (difluoromethoxy) benzaldehyde (130 mg,24% yield). MS: m/z found 639[ M+H ]] ⁺ .

(d) 2- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3- (difluoromethoxy) phenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one

To 4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4 ])]Octan-2-yl-methyl) pyridin-2-yl-phenyl) pyridin-2-yl-2- (difluoromethoxy) benzaldehyde (200 mg,0.31 mmol) and 1- (2, 6-diazaspiro [ 3.3)]A mixture of heptan-2-yl) ethan-1-one hydrochloride (82.9 mg,0.47 mmol) in dichloromethane (10 mL) was added sodium acetate (77 mg,0.94 mmol) and taken up in N ₂ The mixture was stirred at room temperature for 1.5 hours. Sodium triacetoxyborohydride (199mg, 0.94 mmol) was then added and the mixture was taken up in N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was then concentrated and the residue was purified by reverse phase HPLC to afford 2- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [ 3.3)) as a white solid (formate salt) ]Heptane-2-yl) methyl) -3- (difluoromethoxy) phenyl) -3-chloropyridin-4-yl-2-chlorophenyl) -2-methoxypyridin-3-yl methyl) -2, 6-diazaspiro [3.4]Octan-7-one (15.1 mg,6% yield). MS: m/z found 763[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₆ ):δ8.67(d,1H),8.32(brs,2H),7.81(d,1H),7.73(dd,1H),7.62-7.56(m,4H),7.48-7.44(m,2H),7.32(d,1H),6.99(t,1H),4.34(s,2H),4.10-4.08(m,4H),4.06(s,3H),3.99(s,2H),3.91-3.90(m,4H),3.77-3.75(m,4H),3.65(s,2H),2.67(s,2H),1.86(s,3H).

Example 530:1- (6- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (difluoromethoxy) benzyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one (663)

(a) N- ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine

To a mixture of 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (example 1, step (a)) (600 mg,1.52 mmol) and tetrahydro-2H-pyran-4-amine (308 mg,3.05 mmol) in dichloromethane (10 mL) was added sodium acetate (375 mg,4.57 mmol) and the mixture was concentrated under N ₂ The mixture was stirred at room temperature for 2.5 hours. Sodium triacetoxyborohydride (969 mg,4.57 mmol) was then added and added under N ₂ The mixture was stirred at room temperature for 0.5H to afford N- ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine (730 mg, crude), MS: m/z found 478[ M+H ] ⁺ . The crude mixture was used in the next step without further purification.

(b) ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester

To a solution of N- ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine in dichloromethane (10 mL) was added di-tert-butyl dicarbonate (665 mg,3.05 mmol) followed by triethylamine (463 mg,4.57 mmol) and N ₂ The mixture was stirred at room temperature for 5 hours. The mixture was then filtered and concentrated and passed through normal phase SiO ₂ The residue was purified by chromatography (0-40% ethyl acetate/petroleum ether) to afford ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamic acid as a white solidTert-butyl ester (700 mg,79% yield). ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.52(d,1H),7.76(d,1H),7.74-7.58(m,3H),7.49(d,1H),7.29(d,1H),4.32(s,2H),3.96(s,3H),3.89-3.86(m,3H),3.82-3.79(m,2H),1.78-1.76(m,2H),1.69-1.66(m,2H),1.39-1.35(m,9H).

(c) ((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4-formylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester

To a mixture of tert-butyl ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamate (600 mg,1.04 mmol) and 2- (difluoromethoxy) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (example 529, step (b)) (463 mg,1.55 mmol) in THF/water (5:1, 12 mL) was added potassium phosphate (660 mg,3.11 mmol) and [1,1' -bis (di-tert-butylphosphino) ferrocene ]Palladium (II) dichloride (67.5 mg,0.10 mmol) and under N ₂ The mixture was stirred at 80℃for 1 hour. Water (20 mL) was added and the mixture extracted with ethyl acetate (2X 30 mL). The combined organic phases were dried over anhydrous sulphate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ The residue was purified by chromatography (0-50% ethyl acetate/petroleum ether) to give tert-butyl ((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4-formylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamate (600 mg,81% yield) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.30(s,1H),8.75(d,1H),7.95(d,1H),7.76-7.74(m,1H),7.70(d,1H),7.66(s,1H),7.61-7.43(m,5H),7.25(d,1H),4.27(s,2H),3.91(s,3H),3.84-3.58(m,2H),3.57-3.55(m,4H),1.74-1.70(m,4H),1.32-1.22(m,9H).

(d) ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3- (difluoromethoxy) phenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester

To ((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4-formylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester (200 mg,0.28 mmol) and 1- (2, 6-diazaspiro [ 3.3)]A mixture of heptan-2-yl) ethan-1-one hydrochloride (74.2 mg,0.42 mmol) in dichloromethane (10 mL) was added sodium acetate (68.9 mg,0.84 mmol) and taken under N ₂ The mixture was stirred at room temperature for 1.5 hours. Sodium triacetoxyborohydride (178 mg,0.84 mmol) was then added and added under N ₂ The mixture was stirred at room temperature for 1.5 hours. The mixture was filtered, the filtrate was concentrated and purified by preparative thin layer chromatography (SiO ₂ EtOAc: meoh=5:1) the residue was purified to provide ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [ 3.3)) as a white solid]Heptane-2-yl) methyl) -3- (difluoromethoxy) phenyl) -3-chloropyridin-4-yl-2-chlorophenyl) -2-methoxypyridin-3-yl methyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester (95 mg,40% yield). MS: m/z found 838[ M+H ]] ⁺ .

(e) 1- (6- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (difluoromethoxy) benzyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one

To ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [ 3.3))]Heptan-2-yl) methyl) -3- (difluoromethoxy) phenyl) -3-chloropyridin-4-yl-2-chlorophenyl) -2-methoxypyridin-3-yl methyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester (90 mg,0.11 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (3 mL,40.5 mmol) and concentrated under N ₂ The mixture was stirred at room temperature for 20 minutes. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 1- (6- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5-)) as a white solid (formate salt) (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (difluoromethoxy) benzyl) -2, 6-diazaspiro [3.3]Heptane-2-yl) ethan-1-one (29.3 mg,35% yield). MS: m/z found 738[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₆ ):δ8.59(d,1H),7.80(d,1H),7.64-7.57(m,4H),7.49(t,1H),7.40-7.35(m,2H),7.26(d,1H),7.01(t,1H),4.45(s,2H),4.40-4.32(m,6H),4.21(s,2H),4.07(brs,2H),3.99-3.95(m,5H),3.41-3.38(m,3H),2.05-2.02(m,2H),1.78(s,3H),1.75-1.59(m,2H).

Example 531:1- (4- (((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3- (difluoromethoxy) phenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (664)

In a similar manner to that described for example 530, 1- (4- (((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [ 3.3))]Heptane-2-yl) methyl) -3- (difluoromethoxy) phenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one. MS: m/z found 779[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₆ ):δ8.71(d,1H),7.93(d,1H),7.75-7.69(m,4H),7.61(t,1H),7.51(d,1H),7.47(dd,1H),7.39(d,1H),7.12(t,1H),4.56(s,2H),4.43-4.35(m,8H),4.18-4.12(m,6H),3.54-3.50(m,1H),3.27-3.15(m,1H),2.75-2.70(m,1H),2.32-2.24(m,2H),2.16(s,3H),1.87(s,3H),1.71-1.55(m,2H),1.43-1.30(m,1H).

Example 532:2- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3- (difluoromethoxy) phenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one (665)

In a similar manner to that described for example 529, 1- (2, 6-diazaspiro [ 3.3) was replaced with 1- (4-aminopiperidin-1-yl) ethan-1-one in step (d) ]Preparation of heptan-2-yl) ethan-1-one hydrochloride 2- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3- (difluoromethoxy) phenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4]Octane-7-one. MS: m/z found 765[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₆ ):δ8.67(d,1H),8.52(brs),7.72(dd,2H),7.65-7.64(m,2H),7.58-7.54(m,2H),7.48(d,1H),7.43(dd,1H),7.27(d,1H),7.02(t,1H),4.60-4.51(m,1H),4.09-3.97(m,6H),3.78(s,2H),3.61(s,2H),3.50-3.40(m,4H),3.22-3.15(m,1H),2.78-2.71(m,1H),2.61(s,2H),2.13-2.06(m,5H),1.48-1.31(m,3H).

Example 533:2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (difluoromethoxy) benzyl) -2, 6-diazaspiro [3.4] octane-7-one (683)

In a similar manner to that described with respect to example 530, 2, 6-diazaspiro [3.4] was used in step (d)]Octane-7-ketone trifluoro acetate replaces 1- (2, 6-diazaspiro [3.3 ]]Preparation of 2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (difluoromethoxy) benzyl) -2, 6-diazaspiro [3.4] heptan-2-yl) ethan-1-one hydrochloride]Octane-7-one (formate). MS: m/z found 724[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.68(d,1H),8.35(brs,1H),7.91(d,1H),7.74(dd,1H),7.64-7.55(m,4H),7.48-7.46(m,2H),7.38(d,1H),6.99(t,1H),4.31(s,2H),4.11(s,3H),4.09-4.06(m,2H),4.00(s,2H),3.66(s,4H),3.63(s,2H),3.52-3.47(m,3H),2.64(s,2H),2.16-2.13(m,2H),1.80-1.73(m,2H).

Example 534:2- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (difluoromethoxy) benzyl) -2, 6-diazaspiro [3.4] octan-7-one (684)

In a similar manner to that described for example 530, tetrahydro-2H-pyran-4-amine was replaced with 1- (4-aminopiperidin-1-yl) ethan-1-one in step (a) and 2, 6-diazaspiro [3.4 ] in step (d)]Octane-7-ketone substituted 1- (2, 6-diazaspiro [3.3 ]]Heptane-2-yl) ethan-1-one hydrochloride to prepare 2- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (difluoromethoxy) benzyl) -2, 6-diazaspiro [3.4]Octane-7-one (formate). MS: m/z found 765[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.68(d,1H),8.24(brs,1H),7.91(d,1H),7.74(dd,1H),7.65-7.57(m,4H),7.48-7.46(m,2H),7.38(d,1H),7.00(t,1H),4.72-4.71(m,2H),4.35(s,2H),4.11(s,3H),4.07(s,2H),3.69(s,4H),3.64(s,2H),3.33-3.24(m,2H),2.76-2.73(m,3H),2.31-2.26(m,2H),2.23(s,3H),1.57-1.52(m,2H).

Example 535:1- (4- (((5- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -3-methoxypyrazin-2-yl) methyl) amino) piperidin-1-yl) ethan-1-one (311)

1- (4- (((5- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -3-methoxypyrazin-2-yl) methyl) amino) piperidin-1-yl) ethan-1-one was prepared according to reductive amination procedure a from 5- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -3-methoxypyrazine-2-carbaldehyde (15 mg,0.03 mmol) and 1- (4-amino-1-piperidinyl) ethan-one (17 mg,0.12 mmol). Formate, 65% yield. LCMS: m/z found 746.3[ M+H ] ] ⁺ Retention time = 1.63min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.68(d,1H),8.50(s,2H),8.42(s,2H),7.78(d,1H),7.63(t,1H),7.57–7.47(m,3H),7.40(s,1H),7.36(d,1H),4.65(t,2H),4.38(s,2H),4.32(s,2H),4.14–4.01(m,5H),4.00(s,3H),3.49–3.33(m,2H),3.20(t,2H),2.70(t,2H),2.31–2.15(m,4H),2.15–2.09(m,6H),1.72–1.43(m,4H).

Example 536:1- (4- (((5- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -3-methoxypyridin-2-yl) methyl) amino) piperidin-1-yl) ethan-1-one (565)

(a) 5- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -3-methoxy Pi Kaolin aldehyde

3-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) Pi Kaolin aldehyde (187 mg,0.71 mmol), tetrakis (triphenylphosphine) palladium (0) (137 mg,0.12 mmol), potassium carbonate (245 mg,1.78 mmol), and 4- (3-bromo-2-chloro-phenyl) -2, 3-dichloro-pyridine (200 mg,0.59 mmol) were suspended in 1, 4-dioxane/water (4:1, 5 ml), and the solution was then heated at 105℃for 20 min. The reaction was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×10 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (5-100% EtOAc/hexanes) to afford 5- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -3-methoxy Pi Kaolin aldehyde as a yellow oil (50 mg,21% yield). MS: m/z found 393,395[ M+H ]] ⁺ .

(b) 5- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -3-methoxy Pi Kaolin aldehyde

Tetrakis (triphenylphosphine) palladium (0) (48 mg,0.04 mmol),Potassium carbonate (85 mg,0.62 mmol), 5- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -3-methoxy Pi Kaolin aldehyde (81 mg,0.21 mmol), and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (70 mg,0.27 mmol) were suspended in 1, 4-dioxane/water (4:1, 3 mL) and the solution was heated at 105℃for 20 min. The reaction was cooled to room temperature, diluted with 5mL of water, and extracted with EtOAc (3×5 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (10-80% EtOAc/hexanes) to afford 5- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -3-methoxy Pi Kaolin aldehyde (23 mg,23% yield) as a yellow foam. MS: m/z found 493,495[ M+H ]] ⁺ .

(c) 1- (4- (((5- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -3-methoxypyridin-2-yl) methyl) amino) piperidin-1-yl) ethan-1-one

5- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -3-methoxy Pi Kaolin aldehyde (12 mg,0.02 mmol), acetic acid (3 mg,0.05 mmol), and 1- (4-amino-1-piperidinyl) ethanone (10 mg,0.07 mmol) were dissolved in MeOH/THF (1:1, 1 mL) and the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (4 mg,0.07 mmol) was added and the resulting mixture was stirred at 25 ℃ for 1 hour. The reaction was filtered through CELITE and the filtrate was concentrated under reduced pressure. The crude sample was purified by reverse phase HPLC to provide 1- (4- (((5- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -3-methoxypyridin-2-yl) methyl) amino) piperidin-1-yl) ethan-1-one (8 mg,48% yield) as a white solid (formate salt). LC/MS: m/z found 745,747[ M+H ] ] ⁺ Retention time = 2.08min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.66(d,1H),8.47(s,2H),8.27(s,1H),7.59(d,3H),7.52(d,1H),7.46(d,2H),7.38(s,1H),7.34(d,1H),4.62(d,2H),4.36(s,2H),4.27(s,2H),4.05(d,2H),3.98(s,6H),3.35(s,2H),3.19(t,2H),2.69(t,2H),2.21(t,4H),2.13(s,6H),1.56(dd,4H).

Example 537:2- (4- (3-chloro-4- (2-chloro-3- (5-methoxy-6- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) pyridin-3-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octane-7-one (566)

In a similar manner to that described for example 536, the intermediate 5- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -3-methoxy Pi Kaolin aldehyde was used in step (c) and 2, 6-diazaspiro [3.4]Preparation of 2- (4- (3-chloro-4- (2-chloro-3- (5-methoxy-6- ((7-oxo-2, 6-diazaspiro [3.4 ]) using octan-7-one instead of 1- (4-amino-1-piperidinyl) ethanone]Octan-2-yl) methyl) pyridin-3-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl-2, 6-diazaspiro [3.4]Octane-7-one. The product was obtained as a white solid (formate). LC/MS: m/z found 713,715[ M+H ]] ⁺ Retention time = 1.99min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.65(d,1H),8.43(s,2H),8.23(d,1H),7.58(dd,3H),7.50–7.43(m,3H),7.36–7.30(m,2H),4.43(s,2H),4.24(s,2H),4.10(s,4H),3.98(s,4H),3.96(d,6H),3.68(s,2H),3.64(d,2H),2.71(d,2H),2.67(d,2H).

Example 538:1- (4- ((4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3',3 "-dichloro-6-methoxy- [2,4':2',4" -terpyridin ] -2 "-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one (668)

(a) 2',3' -dichloro-6-methoxy- [2,4' -bipyridine ] -5-carbaldehyde

6-chloro-2-methoxynicotinaldehyde (1.13 g, 6)57 mmol), tetrakis (triphenylphosphine) palladium (0) (0.38 g,0.33 mmol), potassium carbonate (1.36 g,9.86 mmol), and 2, 3-dichloro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine (0.90 g,3.29 mmol) were suspended in 1, 4-dioxane/water (4:1, 20 ml), and the solution was then heated at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 40mL of water, and extracted with dichloromethane (3×30 mL). The combined organics were dried over sodium sulfate and concentrated under reduced pressure. The crude solid was suspended in 4:1 hexane/EtOAc (50 mL) and sonicated, then filtered and further washed with hexane. Drying the filter cake to provide 2',3' -dichloro-6-methoxy- [2,4' -bipyridine as a white solid]5-Formaldehyde (0.50 g,54% yield). MS: m/z found 283,285[ M+H ]] ⁺ .

(b) 2',3' -trichloro-6-methoxy- [2,4':2', 4' -terpyridine ] -5-carbaldehyde

2',3' -dichloro-6-methoxy- [2,4' -bipyridine]-5-Formaldehyde (150 mg,0.53 mmol), tetrakis (triphenylphosphine) palladium (0) (61 mg,0.05 mmol), potassium carbonate (219 mg,1.59 mmol), and 2, 3-dichloro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine (145 mg,0.53 mmol) were suspended in 1, 4-dioxane/water (4:1, 6 ml), and the solution was then heated at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 10mL of water, and extracted with dichloromethane (3×5 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (0-50% EtOAc/hexanes) to afford 2",3',3" -trichloro-6-methoxy- [2,4':2',4 "-terpyridine as a yellow oil ]-5-Formaldehyde (76 mg,36% yield). MS: m/z found 394, 396[ M+H ]] ⁺ .

(c) 3', 3' -dichloro-2 '- (3-formyl-4-methoxyphenyl) -6-methoxy- [2,4':2', 4' -terpyridine ] -5-carbaldehyde

Tetrakis (triphenylphosphine) palladium (0) (44 mg,0.04 mmol),Potassium carbonate (79 mg,0.57 mmol), 2', 3' -trichloro-6-methoxy- [2,4':2', 4' -terpyridine]-5-Formaldehyde (76 mg,0.19 mmol), and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (75 mg,0.29 mmol) were suspended in 1, 4-dioxane/water (4:1, 3 ml), and the solution was then heated at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×5 mL). The combined organics were concentrated under reduced pressure and the crude sample was purified by silica gel chromatography (0-70% etoac/hexanes) to afford 3',3 "-dichloro-2" - (3-formyl-4-methoxyphenyl) -6-methoxy- [2,4':2',4 "-terpyridine as a tan solid]-5-Formaldehyde (86 mg,91% yield). MS: m/z found 494,496[ M+H ]] ⁺ .

(d) 1- (4- ((4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3',3 "-dichloro-6-methoxy- [2,4':2',4" -terpyridin ] -2 "-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one

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3', 3' -dichloro-2 '- (3-formyl-4-methoxyphenyl) -6-methoxy- [2,4':2', 4' -terpyridine ]5-Formaldehyde (20 mg,0.04 mmol), acetic acid (5 mg,0.08 mmol), and 1- (4-amino-1-piperidinyl) ethanone (17 mg,0.12 mmol) were dissolved in MeOH/THF (1:1, 1 mL), and the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (8 mg,0.12 mmol) was added and the resulting mixture was stirred at 25 ℃ for 1 hour. The reaction was filtered through CELITE and the filtrate was concentrated under reduced pressure. The crude sample was purified by reverse phase HPLC to provide 1- (4- ((4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3',3 "-dichloro-6-methoxy- [2,4':2',4" -terpyridine) as a white solid (formate salt)]-2 "-yl) -2-methoxybenzyl-amino) piperidin-1-yl) ethan-1-one (15 mg,49% yield). LC/MS: m/z found 746,748[ M+H ]] ⁺ Retention time = 1.95min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.75–8.70(m,2H),8.46(s,2H),7.91(d,1H),7.82(d,1H),7.55(dd,2H),7.48(d,1H),7.41(s,1H),7.36(d,1H),4.62(dd,2H),4.30(s,2H),4.12(s,2H),4.07(s,4H),3.99(s,4H),3.19(d,4H),2.71(d,2H),2.28–2.09(m,10H),1.52(m,4H).

Example 539:2- (4- (3 ',3 "-dichloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) - [2,4':2',4" -terpyridin ] -2 "-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one (669)

In a similar manner to that described for example 538, intermediate 3',3 "-dichloro-2" - (3-formyl-4-methoxyphenyl) -6-methoxy- [2,4':2',4 "-terpyridine was used in step (d) ]-5-Formaldehyde in combination with 2, 6-diazaspiro [3.4 ]]Preparation of 2- (4- (3 ', 3' -dichloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [ 3.4) by substituting 1- (4-amino-1-piperidinyl) ethanone with octan-7-one]Octane-2-yl) methyl) - [2,4':2', 4' -terpyridine]-2 "-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4]Octane-7-one. The product was obtained as a white solid (formate). LC/MS: m/z measured values 714,716[ M+H ]] ⁺ Retention time = 1.85min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.71(dd,2H),8.35(s,2H),7.87–7.79(m,2H),7.56(d,1H),7.52(d,1H),7.45(d,1H),7.40(s,1H),7.36(d,1H),4.40(s,2H),4.17(s,4H),4.07–4.00(m,5H),3.98(d,3H),3.77(s,4H),3.67(d,2H),3.63(s,2H),2.71(s,2H),2.64(d,2H).

Example 540: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indol-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (141)

(a) 7-bromo-5-methyl-1, 3,4, 5-tetrahydro-2H-pyrido [4,3-b ] indole-2-carboxylic acid tert-butyl ester

7-bromo-1, 3,4, 5-tetrahydro-2H-pyrido [4,3-b ] in an ice bath under nitrogen]A solution of tert-butyl indole-2-carboxylate (242 mg,0.69 mmol) in 3mL anhydrous DMF was cooled. 60% sodium hydride in mineral oil (41 mg,1.03 mmol) was added in 2 portions. The ice bath was removed and the mixture was stirred at room temperature for 1 hour. Methyl iodide (64. Mu.L, 1.03 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled in an ice bath and ice water (15 mL) was slowly added. The resulting precipitate was collected, washed with 2mL of water, and dried in vacuo to afford 7-bromo-5-methyl-3, 4-dihydro-1H-pyrido [4,3-b ] ]Indole-2-carboxylic acid tert-butyl ester (162 mg, 57%). ¹ H NMR(400MHz,DMSO-d ₆ )δ7.68(d,1H),7.39(d,1H),7.12(dd,1H),4.51(s,2H),3.71(t,2H),3.62(s,3H),2.78(t,2H),1.43(s,9H).

(b) 5-methyl-7- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,3,4, 5-tetrahydro-2H-pyrido [4,3-b ] indole-2-carboxylic acid tert-butyl ester

A mixture of 7-bromo-5-methyl-3, 4-dihydro-1H-pyrido [4,3-b ] indole-2-carboxylic acid tert-butyl ester (50 mg,0.14 mmol), bis (pinacolato) diborane (42 mg,0.16 mmol), potassium acetate (38 mg,0.38 mmol), and [1,1' -bis (biphenylphosphino) ferrocene ] dichloropalladium (II) complex with dichloromethane (9 mg,0.01 mmol) was weighed into a Biotage microwave vial. Anhydrous 1, 4-dioxane (1 mL) was added and the mixture was bubbled with nitrogen for 2 min. The vessel was capped and placed in a 95 ℃ heating block for 2 hours. The mixture was diluted with 10mL EtOAc and filtered through a CELITE pad. The CELITE pad was washed with 20mL EtOAc. The combined filtrates were concentrated under reduced pressure and the crude material was purified by normal phase silica gel chromatography (0% to 6% MeOH/DCM) to give tert-butyl 5-methyl-7- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydro-1H-pyrido [4,3-b ] indole-2-carboxylate (27 mg, 48%).

(c) (S) -7- (4- (3- (5- (((tert-Butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -5-methyl-1, 3,4, 5-tetrahydro-2H-pyrido [4,3-b ] indole-2-carboxylic acid tert-butyl ester

To tert-butyl (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (38 mg,0.06 mmol), 5-methyl-7- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydro-1H-pyrido [4, 3-b)]A mixture of tert-butyl indole-2-carboxylate (26 mg,0.06 mmol) and potassium carbonate (27 mg,0.19 mmol) in degassed 1, 4-dioxane/water (6:1, 2.1 mL) was added tetrakis (triphenylphosphine) palladium (0) (7 mg,0.01 mmol) and the mixture was irradiated to 105℃for 25 min in a Biotage Initiator microwave apparatus. Water (8 mL) was added and the mixture extracted into EtOAc (3X 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by normal phase silica gel chromatography (0% to 5% MeOH/DCM) to afford (S) -7- (4- (3- (5- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -5-methyl-1, 3,4, 5-tetrahydro-2H-pyrido [4, 3-b)]Indole-2-carboxylic acid tert-butyl ester (51 mg, 94%). MS: m/z found 841.0[ M+H ]] ⁺ .

(d) (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indol-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

Following the general Boc deprotection procedure, (S) -7- (4- (3- (5- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -5-methyl-1, 3,4, 5-tetrahydro-2H-pyrido [4,3-b]Conversion of indole-2-carboxylic acid tert-butyl ester to (S) -5- (((6- (2-chloro-3- (3-chloro-2- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4, 3-b))]Indol-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) amino) methyl) pyrroleAn alkyl-2-ketoformate. Yield 27%. LCMS: m/z found 641.2[ M+H ]] ⁺ Retention time = 2.77min, (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.62(d,1H),8.54(s,1H),7.78–7.67(m,3H),7.59–7.51(m,2H),7.45–7.37(m,3H),7.26(d,1H),4.37(s,2H),4.02(d,3H),3.93–3.81(m,3H),3.76(s,3H),3.55(t,2H),3.11(d,2H),2.77–2.63(m,2H),2.39–2.21(m,3H),1.88–1.75(m,1H).

Example 541: (S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indol-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (158)

(a) 7-bromo-5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indole

7-bromo-5-methyl-1, 3,4, 5-tetrahydro-2H-pyrido [4,3-b]A solution of tert-butyl indole-2-carboxylate (112 mg,0.31 mmol) in 1.5mL dichloromethane/0.75 mL trifluoroacetic acid was stirred for 10 min. Volatiles were removed in vacuo and the material was azeotroped with 2mL toluene. Drying the resulting material under vacuum to provide 7-bromo-5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] as trifluoroacetate salt ]Indole (150 mg). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.04(s,2H),7.76(d,1H),7.46(d,1H),7.19(dd,1H),4.33(d,2H),3.67(s,3H),3.53(m,2H),3.04(t,2H).

(b) 2- (7-bromo-5-methyl-1, 3,4, 5-tetrahydro-2H-pyrido [4,3-b ] indol-2-yl) ethan-1-ol

To 7-bromo-5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b]Indole trifluoroacetate (74 mg,0.20 mmol) at 1Potassium carbonate (54 mg,0.39 mmol) was added to a solution of 5mL of acetonitrile. The mixture was stirred for 3 minutes. 2-Bromoethanol (42. Mu.L, 0.59 mmol) was added and the reaction vessel was capped. After stirring at room temperature for 16 hours, the mixture was irradiated to 60 ℃ for 45 minutes in a Biotage Initiator microwave apparatus, followed by further irradiation at 65 ℃ for 30 minutes. The reaction mixture was diluted with 10mL EtOAc, filtered through CELITE, and evaporated to dryness. Purification of the crude material by normal phase silica gel chromatography (0.5% to 10% MeOH/DCM) provided 2- (7-bromo-5-methyl-1, 3,4, 5-tetrahydro-2H-pyrido [4, 3-b)]Indol-2-yl) ethane-1-ol (53 mg, 88%). ¹ H NMR (400 MHz, methanol-d) ₄ )δ7.52(d,1H),7.30(d,1H),7.13(dd,1H),3.94(s,2H),3.85(t,2H),3.64(s,3H),3.17(t,2H),2.96(t,4H).

(c) 2- (5-methyl-7- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,3,4, 5-tetrahydro-2H-pyrido [4,3-b ] indol-2-yl) ethan-1-ol

2- (7-bromo-5-methyl-1, 3,4, 5-tetrahydro-2H-pyrido [4,3-b ] is weighed out]Indol-2-yl) ethan-1-ol (48 mg,0.15 mmol), bis (pinacolato) diborane (51 mg,0.20 mmol), potassium acetate (42 mg,0.43 mmol) and [1,1' -bis (biphenylphosphino) ferrocene ]A mixture of palladium (II) dichloride complex with dichloromethane (10 mg,0.01 mmol) was placed in a Biotage microwave vial. Anhydrous 1, 4-dioxane (1 mL) was added and the mixture was degassed with nitrogen for 2 min. The vessel was capped and irradiated to 95 ℃ in a Biotage Initiator microwave apparatus for 65 minutes. Adding another part of [1,1' -bis (biphenylphosphino) ferrocene]Complexes of palladium (II) dichloride with dichloromethane (2 mg) and bis (pinacolato) diborane (10 mg,0.04 mmol). The mixture was irradiated to 95 ℃ for 60 minutes. The mixture was diluted with 10mL EtOAc and filtered through a CELITE pad. The CELITE pad was washed with 20mL EtOAc and 5mL acetonitrile. The combined filtrates were concentrated under reduced pressure and the resulting crude material was purified by normal phase silica gel chromatography (2% to 10% MeOH/DCM) to afford 2- (5-methyl-7- (4, 5-tetramethyl-1, 3, 2-dioxaboran-2-yl) -1,3,4, 5-tetrahydro-2H-pyrido [4, 3-b)]Indol-2-yl) ethan-1-ol24mg,44％)。 ¹ H NMR (400 MHz, chloroform-d) delta 7.79 (s, 1H), 7.56 (d, 1H), 7.39 (d, 1H), 4.27 (s, 2H), 3.95 (q, 2H), 3.69 (s, 3H), 3.43 (d, 2H), 3.12 (dt, 4H), 1.38 (s, 12H).

(d) (S) - ((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indol-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

To tert-butyl (S) - ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (38 mg,0.06 mmol), 2- (5-methyl-7- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,3,4, 5-tetrahydro-2H-pyrido [4, 3-b)]A mixture of indol-2-yl) ethane-1-ol (23 mg,0.06 mmol) and potassium carbonate (27 mg,0.19 mmol) in degassed 1, 4-dioxane/water (6:1, 1.15 mL) was added tetrakis (triphenylphosphine) palladium (0) (7 mg,0.01 mmol). The mixture was irradiated to 105 ℃ in a Biotage Initiator microwave apparatus for 25 minutes. Water was added and the mixture was extracted into EtOAc (3X 15 mL) followed by MeOH/DCM (10%, 2X10 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by normal phase silica gel chromatography (0 to 20% MeOH/DCM) to afford (S) - ((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4, 3-b)]Indol-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (46 mg, 91%). MS: m/z found 785.1[ M+H ]] ⁺ .

(e) (S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indol-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

According to general BoDeprotection procedure (S) - ((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4, 3-b)]Indol-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester is converted to (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4, 3-b))]Indol-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one. 55% yield. LCMS: m/z found 685.1[ M+H ]] ⁺ Retention time = 2.75min, (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.62(dd,1H),8.50(s,1H),7.77(dd,1H),7.72–7.69(m,2H),7.60–7.51(m,2H),7.46–7.37(m,3H),7.27(dd,1H),4.31(s,2H),4.03(s,3H),3.98–3.83(m,5H),3.76(d,3H),3.50(s,2H),3.26–3.12(m,4H),2.82–2.68(m,2H),2.39–2.24(m,3H),1.88–1.78(m,1H).

Example 542: (S) -5- (((4- (3-chloro-4- (2-chloro-3- (8-chloro-6- ((((S) -2-hydroxypropyl) amino) methyl) -5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one (206)

(a) 4- (3-bromo-2-chlorophenyl) -2, 3-dichloropyridine

2, 3-dichloro-4-iodo-pyridine (15 g,54.8 mmol), 2- (3-bromo-2-chlorophenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (26.1 g,82.1 mmol), potassium carbonate (22.7 g,164 mmol), and [1,1' -bis (biphenylphosphino) ferrocene]A mixture of palladium (II) dichloride complex with dichloromethane (447 mg,0.55 mmol) in 1, 4-dioxane/water (5/1, 240 mL) was degassed and N ₂ The mixture was purged and then stirred at 100 ℃ for 12 hours. The reaction mixture was concentrated and passed through normal phase SiO ₂ Chromatography (0-10% EtOAc/petroleum ether) of the residue afforded 4- (3-bromo-2-chlorophenyl) -2, 3-dichloropyrazole as a white solidPyridine (17 g,91% yield).

(b) 2, 3-dichloro-4- (2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) pyridine

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4- (3-bromo-2-chlorophenyl) -2, 3-dichloropyridine (12 g,35.6 mmol), bis (pinacolato) diborane (27.1 g,107 mmol), and [1,1' -bis (biphenylphosphino) ferrocene]A mixture of palladium (II) dichloride with dichloromethane (2.90 g,3.56 mmol), potassium acetate (10.5 g,107 mmol) in 1, 4-dioxane (150 mL) was degassed and N ₂ The mixture was purged and then stirred at 100 ℃ for 12 hours. The reaction mixture was filtered, concentrated and passed through normal phase SiO ₂ The residue was purified by chromatography (0-10% EtOAc/petroleum ether) to afford 2, 3-dichloro-4- (2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) pyridine (3 g,22% yield) as a white solid.

(c) 4-amino-5-chloro-2-methoxybenzoic acid

To a mixture of methyl 4-acetamido-5-chloro-2-methoxybenzoate (100 g, 3838 mmol) in ethanol/water (2:1,600 mL) was added sodium hydroxide (62.1 g,1.55 mol). The mixture was stirred at 80℃for 12 hours. The mixture was diluted with water and treated with concentrated HCl. The resulting precipitate was filtered, washed with water and dried to provide 4-amino-5-chloro-2-methoxybenzoic acid (120 g, crude).

(d) 8-chloro-5-methoxyquinoline-6-carboxylic acid methyl ester

To 4-amino-5-chloro-2-methoxybenzoic acid (20 g,99.2 mmol) in concentrated H ₂ SO ₄ /H ₂ Glycerin (41.1 g, 4476 mmol) and 3-nitro were added to a mixture of O (5:1, 96 mL)Sodium phenyl sulfonate (44.7 g, 198mmol). The mixture was stirred at 100℃for 3h and 140℃for 1 h. The mixture was cooled to 60 ℃, methanol (40 mL) was added, and the mixture was stirred at 60 ℃ for 10 hours. The solution was evaporated and the residue was poured into an ice-water mixture and basified with saturated aqueous ammonium hydroxide. The mixture was diluted with ethyl acetate (2L) and filtered. The organic layer was separated, dried and evaporated. By normal phase SiO ₂ Chromatography (0-100% EtOAc/petroleum ether) purified the residue to afford methyl 8-chloro-5-methoxyquinoline-6-carboxylate (4 g,16% yield). ¹ H NMR(400MHz,DMSO-d ₆ ):δ9.15(dd,1H),8.70(dd,1H),8.16(s,1H),7.78(dd,1H),4.00(m,3H),3.93(m,3H).

(e) 8-chloro-5-methoxyquinoline-6-carboxylic acid

To a mixture of methyl 8-chloro-5-methoxyquinoline-6-carboxylate (7 g,27.8 mmol) in methanol/water (7:2, 90 mL) was added lithium hydroxide monohydrate (3.50 g,83.4 mmol). The mixture was stirred at 15 ℃ for 15hr and then concentrated under reduced pressure to provide a residue. Water (30 mL) was added and the mixture extracted with EtOAc (3X 30 mL). The aqueous phase was treated with concentrated HCl (to ph=3) and the resulting suspension was filtered to provide 8-chloro-5-methoxyquinoline-6-carboxylic acid (7 g, crude) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ9.07(dd,1H),8.64(dd,1H),8.10(s,1H),7.66(dd,1H),3.95(s,3H).

(f) 5-Methoxyquinoline-6-carboxylic acid

To a mixture of 8-chloro-5-methoxyquinoline-6-carboxylic acid (1 g,4.21 mmol) in ethanol (80 mL) was added hydrazine hydrate (1.05 g,21 mmol) and 10% Pd/C (1 g). The mixture was then stirred at 80℃for 14 hours. The reaction mixture was filtered and concentrated under reduced pressure to afford 5-methoxyquinoline-6-carboxylic acid (5 g, crude) as a red solid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.86(dd,1H),8.50(d,1H),7.80(d,1H),7.66(d,1H),7.53(dd,1H),4.00(s,3H).

(g) 5-Methoxyquinoline-6-carboxylic acid methyl ester

To a mixture of 5-methoxyquinoline-6-carboxylic acid (5 g,24.6 mmol) in methanol (20 mL) was added thionyl chloride (4.39 g,36.9 mmol) and the mixture was stirred at 70℃for 4 h. The reaction mixture was concentrated under reduced pressure, water (30 mL) was added and the mixture extracted with EtOAc (3×30 mL). The combined organic layers were washed with saturated aqueous brine solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide a residue. By normal phase SiO ₂ Chromatography (0-100% EtOAc/petroleum ether) purified the residue to afford methyl 5-methoxyquinoline-6-carboxylate (5 g,93% yield) as a yellow solid.

(h) 1-oxo-5-methoxy-6- (methoxycarbonyl) quinoline

To a mixture of methyl 5-methoxyquinoline-6-carboxylate (5 g,23 mmol) in dichloromethane (5 mL) was added 3-chloroperbenzoic acid (5.96 g,34.5 mmol) and the mixture stirred at 15℃for 12 hours. Saturated sodium sulfite solution (50 mL) was added and the mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with saturated aqueous brine solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide a residue. By normal phase SiO ₂ The residue was purified by chromatography (0-100% EtOAc/petroleum ether to 0-100% ethyl acetate/MeOH) to afford 1-oxo-5-methoxy-6- (methoxycarbonyl) quinoline (3 g,55% yield) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.71(dd,1H),8.34(d,1H),8.11(d,1H),8.04(d,1H),7.60-7.56(m,1H),4.02(s,3H),3.95(m,3H).

(i) 2-bromo-5-methoxyquinoline-6-carboxylic acid methyl ester

To a mixture of 1-oxo 5-methoxy-6- (methoxycarbonyl) quinoline (3 g,12.86 mmol) in chloroform (10 mL) was added phosphorus tribromooxide (11.1 g,38.6 mmol) and the mixture was stirred at 50℃for 4 hours. Water (90 mL) was added and the mixture extracted with dichloromethane (3X 90 mL). The combined organic layers were washed with saturated aqueous brine solution (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide a residue. By normal phase SiO ₂ The residue was purified by chromatography (0-100% EtOAc/petroleum ether to 0-100% ethyl acetate/MeOH) to afford methyl 2-bromo-5-methoxyquinoline-6-carboxylate (3 g,79% yield) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.58(dd,1H),8.11(d,1H),7.88-7.84(m,2H),4.05(s,3H),3.98(m,3H).

(j) 2, 8-dichloro-5-methoxyquinoline-6-carboxylic acid methyl ester

To a mixture of methyl 2-bromo-5-methoxyquinoline-6-carboxylate (0.6 g,2.03 mmol) in DMF (10 mL) was added N-chlorosuccinimide (1.08 g,8.1 mmol) and glacial acetic acid (0.01 g,0.2 mmol). The mixture was stirred at 80℃for 12 hours. Water (8 mL) was added to the reaction mixture, and the resulting solid was collected by filtration to give methyl 2, 8-dichloro-5-methoxyquinoline-6-carboxylate (0.75 g, crude). ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.70(d,1H),8.20(s,1H),7.81(d,1H),3.99(s,3H),3.93(s,3H).

(k) (2, 8-dichloro-5-methoxyquinolin-6-yl) methanol

To a mixture of methyl 2, 8-dichloro-5-methoxyquinoline-6-carboxylate (0.4 g,1.4 mmol) in THF (5 mL) was added lithium aluminum hydride (0.06 g,1.68 mmol) and the mixture was admixed at 20 ℃The mixture was stirred for 1 hour. To the reaction mixture was added water (5 mL) at 0 ℃, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ The residue was purified by chromatography (0-100% EtOAc/petroleum ether) to afford (2, 8-dichloro-5-methoxyquinolin-6-yl) methanol (0.22 g) as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.53(d,1H),8.02(s,1H),7.69(d,1H),5.47(br,1H),4.69(s,2H),3.88(s,3H).

(l) 2, 8-dichloro-5-methoxyquinoline-6-carbaldehyde

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To a mixture of (2, 8-dichloro-5-methoxyquinolin-6-yl) methanol (0.2 g,0.77 mmol) in dichloromethane (2 mL) was added manganese dioxide (0.67 g,7.75 mmol) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to afford 2, 8-dichloro-5-methoxyquinoline-6-carbaldehyde (0.2 g, crude). ¹ H NMR (400 MHz, chloroform-d): delta 10.43 (s, 1H), 8.46 (d, 1H), 8.17 (s, 1H), 7.50 (d, 1H), 4.09 (s, 3H).

(m) 8-chloro-2- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -5-methoxyquinoline-6-carbaldehyde

To a mixture of 2, 8-dichloro-5-methoxyquinoline-6-carbaldehyde (400 mg,1.56 mmol) and 2, 3-dichloro-4- (2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) pyridine (901 mg,2.34 mmol) in 1, 4-dioxane/water (12 ml, 5/1) was added potassium carbonate (648 mg,4.69 mmol) followed by [1,1' -bis (biphenylphosphino) ferrocene ]Complexes of palladium (II) dichloride with dichloromethane (128 mg,0.16 mmol). The reaction was stirred at 110℃for 3 hours. The mixture was filtered and washed with EtOAc (50 mL). Concentrating the filtrate and passing through normal phase SiO ₂ The residue was purified by chromatography (0-50% EtOAc/petroleum ether) to give 8-chloro-2- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -5-methoxyquinoline-6-carbaldehyde (516 mg) as a yellow solid.MS: m/z found 479[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.49(s,1H),8.58(d,1H),8.32(d,1H),8.19(s,1H),7.97(d,1H),7.87(dd,1H),7.51(t,1H),7.30(d,1H),7.16(d,1H),4.14(s,3H),1.17(s,1H).

(n) (S) -5- (((4-bromo-2-methoxybenzyl) amino) methyl) pyrrolidin-2-one

To a mixture of 4-bromo-2-methoxybenzaldehyde (3 g,13.9 mmol) and (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride (2.52 g,16.7 mmol) in methanol (40 mL) was added sodium acetate (3.43 g,41.8 mmol) and the mixture was stirred at room temperature for 12 hours. Sodium cyanoborohydride (1.75 g,27.9 mmol) was added and the mixture was stirred at room temperature for 0.5 h. To the mixture was added water (50 mL) and the mixture was extracted with ethyl acetate (2 x100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to provide (S) -5- (((4-bromo-2-methoxybenzyl) amino) methyl) pyrrolidin-2-one (4 g, crude) as a yellow oil which was used in the next step without further purification.

(o) (S) - (4-bromo-2-methoxybenzyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

A mixture of (S) -5- (((4-bromo-2-methoxybenzyl) amino) methyl) pyrrolidin-2-one (3.9 g,12.5 mmol), di-tert-butyl dicarbonate (8.15 g,37.4 mmol) and triethylamine (5.20 mL,37.4 mmol) in dichloromethane (40 mL) was degassed and purged with nitrogen. At N ₂ The mixture was stirred at room temperature for 3 hours under an atmosphere. The mixture was concentrated and passed through normal phase SiO ₂ The residue was purified by chromatography (0-100% EtOAc/petroleum ether) to give tert-butyl (S) - (4-bromo-2-methoxybenzyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (4.2 g,81% yield) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ7.73(s,1H),7.19-7.13(m,2H),6.93(s,1H),4.38-4.27(m,2H),3.83(s,3H),3.71(s,1H),3.21-3.16(m,2H),2.15-1.99(m,3H),1.13(s,1H),1.42-1.31(m,9H).

(p) (S) - (2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To a mixture of tert-butyl (S) - (4-bromo-2-methoxybenzyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (4.1 g,9.92 mmol), bis (pinacolato) diborane (7.56 g,29.8 mmol) in 1, 4-dioxane (40 mL) was added potassium acetate (2.92 g,29.8 mmol) and [1,1' -bis (biphenylphosphino) ferrocene]Complexes of palladium (II) dichloride with dichloromethane (810 mg,0.99 mmol). At N ₂ The mixture was stirred at 95℃for 12 hours. The mixture was filtered, the filtrate concentrated and passed through normal phase SiO ₂ The residue was purified by chromatography (0-100% EtOAc/petroleum ether) to give tert-butyl (S) - (2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (2.6 g,56% yield) as a black solid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ7.72(s,1H),7.27(d,1H),7.18(s,1H),7.01(d,1H),4.41-4.39(m,2H),3.93(s,3H),3.72(s,1H),3.21-3.17(m,2H),2.17-2.04(m,3H),1.75-1.71(m,1H),1.43-1.30(m,21H).

(q) (S) - (4- (3-chloro-4- (2-chloro-3- (8-chloro-6-formyl-5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To 8-chloro-2- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -5-methoxyquinoline-6-carbaldehyde (260 mg,0.54 mmol) and tert-butyl (275 mg) of (S) -2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl ((5-oxopyrrolidin-2-yl) methyl) carbamateA mixture of 0.60 mmol) in 1, 4-dioxane/water (6 ml, 5:1) was added potassium carbonate (225 mg,1.63 mmol) followed by 1,1' -bis (biphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (44.4 mg,0.05 mmol). The reaction was stirred at 110℃for 3 hours. After cooling, the mixture was diluted with water (20 mL) and extracted with EtOAc (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-100% EtOAc/petroleum ether to 0-20% MeOH/EtOAc) to afford tert-butyl (S) - (4- (3-chloro-4- (2-chloro-3- (8-chloro-6-formyl-5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (320 mg,43% yield) as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.60(s,1H),8.72-7.69(m,2H),8.31(s,1H),8.10(d,1H),7.98(d,1H),7.63(t,1H),7.48(d,2H),7.42(d,2H),7.32(s,1H),4.60-4.56(m,3H),4.25(s,3H),3.95(s,3H),3.37-3.32(m,3H),2.24-2.19(m,2H),1.80-1.77(m,2H),1.50(m,9H).

(r) (4- (3-chloro-4- (2-chloro-3- (8-chloro-6- (((S) -2-hydroxypropyl) amino) methyl) -5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) ((((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To a mixture of tert-butyl (S) - (4- (3-chloro-4- (2-chloro-3- (8-chloro-6-formyl-5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (60 mg,0.07 mmol) in methanol (2 mL) was added (S) -1-aminopropane-2-ol (12.00 mg,0.16 mmol) and sodium acetate (19.0 mg,0.23 mmol). The mixture was stirred at room temperature for 11 hours. Sodium cyanoborohydride (15 mg,0.23 mmol) was added and the mixture was stirred for an additional 1 hour. The residue was purified by preparative TLC (20% MeOH/ethyl acetate) to give tert-butyl (4- (3-chloro-4- (2-chloro-3- (8-chloro-6- ((((S) -2-hydroxypropyl) amino) methyl) -5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) ((((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (50 mg,61% yield) as a pale yellow solid.

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (8-chloro-6- ((((S) -2-hydroxypropyl) amino) methyl) -5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one

A mixture of tert-butyl (4- (3-chloro-4- (2-chloro-3- (8-chloro-6- ((((S) -2-hydroxypropyl) amino) methyl) -5-methoxyquinolin-2-yl) phenyl) pyridin-2-methoxybenzyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (50 mg,0.06 mmol) and trifluoroacetic acid (1.00 mL,13.5 mmol) in dichloromethane (0.5 mL) was stirred at room temperature for 0.5 hours. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC to provide (S) -5- (((4- (3-chloro-4- (2-chloro-3- (8-chloro-6- ((((S) -2-hydroxypropyl) amino) methyl) -5-methoxyquinolin-2-yl) phenyl) pyridin-2-methoxybenzyl) amino) methyl) pyrrolidin-2-one (8.9 mg, 18%) as a white solid (formate). MS: m/z measured values 734 and 736[ M+H ]] ⁺ Retention time = 3.02min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.70-7.67(m,2H),8.55(br s,1H),8.06(s,1H),7.98(d,1H),7.85(dd,1H),7.67(t,1H),7.55(dd,1H),7.51(d,1H),7.45(d,1H),7.33-7.30(m,2H),4.22(s,2H),4.07(s,3H),4.00-3.96(m,6H),3.90-3.87(m,1H),2.83-2.73(m,4H),2.38-2.30(m,3H),1.85-1.80(m,1H),1.22(d,3H).

Example 543: (S) -5- (((4- (3-chloro-4- (2-chloro-3- (8-chloro-6- (((2-hydroxyethyl) amino) methyl) -5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one (238)

(a) (S) - (4- (3-chloro-4- (2-chloro-3- (8-chloro-6- (((2-hydroxyethyl) amino) methyl) -5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To a mixture of tert-butyl (S) - (4- (3-chloro-4- (2-chloro-3- (8-chloro-6-formyl-5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (example 542, step (q)) (0.07 g,0.09 mmol) in a dichloromethane/methanol mixture (1:1, 0.6 mL) was added 2-aminoethanol (17 mg,0.27 mmol) and sodium acetate (0.04 g,0.45 mmol). After 2 hours, sodium cyanoborohydride (0.02 g,0.27 mmol) was added and the mixture was stirred at room temperature for a further 10 hours. The reaction mixture was purified by preparative TLC (20% MeOH in ethyl acetate) to afford tert-butyl (S) - (4- (3-chloro-4- (2-chloro-3- (8-chloro-6- (((2-hydroxyethyl) amino) methyl) -5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (70 mg, 70%) as a yellow solid. MS: m/z found 820 and 822[ M+H ]] ⁺ .

(b) (S) -5- (((4- (3-chloro-4- (2-chloro-3- (8-chloro-6- (((2-hydroxyethyl) amino) methyl) -5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one

A mixture of tert-butyl (S) - (4- (3-chloro-4- (2-chloro-3- (8-chloro-6- (((2-hydroxyethyl) amino) methyl) -5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (0.07 g,0.09 mmol) and trifluoroacetic acid (3 mL,40.5 mmol) in dichloromethane (1 mL) was stirred at room temperature for 0.5 h. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide (formate) (S) -5- (((4- (3-chloro-4- (2-chloro-3- (8-chloro-6- (((2-hydroxyethyl) amino) methyl) -5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one (17 mg, 26%) as a pale yellow solid. MS: m/z actual measurement values 720 and 720[ M+H ] ] ⁺ Retention time = 2.90min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.71-8.66(m,2H),8.42(br s,2H),8.06(s,1H),8.00(d,1H),7.83(dd,1H),7.66(t,1H),7.55-7.48(m,3H),7.37-7.33(m,2H),4.43(s,2H),4.22-4.14(m,2H),4.09(s,3H),3.98(m,4H),3.83(t,2H),3.16(t,2H),3.06-2.99(m,2H),2.45-2.31(m,3H),1.91-1.80(m,1H).

Example 544: (S) -5- (((4- (4- (3- (6- (((1-acetylpiperidin-4-yl) amino) methyl) -8-chloro-5-methoxyquinolin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one (241)

(a) (S) - (4- (4- (3- (6- (((1-acetylpiperidin-4-yl) amino) methyl) -8-chloro-5-methoxyquinolin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To a mixture of tert-butyl (S) - (4- (3-chloro-4- (2-chloro-3- (8-chloro-6-formyl-5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (example 542, step (q)) (60 mg,0.08 mmol) in methanol (0.5 mL) was added 1- (4-aminopiperidin-1-yl) ethanone (33 mg,0.23 mmol) and sodium acetate (32 mg,0.39 mmol). The mixture was stirred at room temperature for 11 hours. Sodium cyanoborohydride (15 mg,0.23 mmol) was added and the mixture was stirred for an additional 1 hour. The reaction mixture was concentrated and the residue was purified by preparative TLC (20% MeOH in ethyl acetate) to give tert-butyl (S) - (4- (4- (3- (6- (((1-acetylpiperidin-4-yl) amino) methyl) -8-chloro-5-methoxyquinolin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (49 mg, 63%) as a yellow solid. MS: m/z found 901 and 903[ M+H ] ] ⁺ .

(b) (S) -5- (((4- (4- (3- (6- (((1-acetylpiperidin-4-yl) amino) methyl) -8-chloro-5-methoxyquinolin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one

To a mixture of tert-butyl (S) - (4- (4- (3- (6- (((1-acetylpiperidin-4-yl) amino) methyl) -8-chloro-5-methoxyquinolin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (49 mg,0.05 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (2 mL,27 mmol) and the mixture was stirred at room temperature for 0.5 h. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide (formate) (S) -5- (((4- (4- (3- (6- (((1-acetylpiperidin-4-yl) amino) methyl) -8-chloro-5-methoxyquinolin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one (23.7 mg,46% yield) as a pale yellow solid. MS: m/z measured values 801 and 803[ M+H ]] ⁺ Retention time = 3.01min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.68-8.65(m,2H),8.45(br s,1H),8.06(s,1H),7.95(d,1H),7.82(dd,1H),7.65(t,1H),7.54-7.50(m,2H),7.46(d,1H),7.35-7.31(m,2H),4.60(s,1H),4.53-4.50(m,1H),4.19(s,2H),4.08(s,2H),4.04(s,3H),3.96-3.92(m,5H),3.13(m,1H),2.99-2.92(m,3H),2.73-2.68(m,1H),2.38-2.28(m,3H),2.14-2.07(m,5H),1.89-1.85(m,1H),1.49-1.42(m,1H).

Example 545: (S) -5- ((((8-chloro-2- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5-methoxyquinolin-6-yl) methyl) amino) methyl) pyrrolidin-2-one (207)

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(a) (4- (3-chloro-4- (2-chloro-3- (8-chloro-5-methoxy-6- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) quinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) carbamic acid tert-butyl ester

To a mixture of tert-butyl (S) - (4- (3-chloro-4- (2-chloro-3- (8-chloro-6-formyl-5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (example 542, step (q)) (60 mg,0.08 mmol) in MeOH (0.5 mL) was added (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride (18 mg,0.12 mmol) and sodium acetate (32 mg,0.39 mmol) and the mixture was stirred at room temperature for 11 hours. Sodium cyanoborohydride (15 mg,0.23 mmol) was added and the mixture was stirred for an additional 1 hour. The reaction was concentrated and the residue was purified by preparative TLC (20% MeOH in ethyl acetate) to give tert-butyl (4- (3-chloro-4- (2-chloro-3- (8-chloro-5-methoxy-6- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) quinolin-2-yl) phenyl) pyridin-2-methoxybenzyl) ((((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (50 mg,56% yield) as a yellow solid.

(b) (S) -5- ((((8-chloro-2- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5-methoxyquinolin-6-yl) methyl) amino) pyrrolidin-2-one

To a mixture of tert-butyl (4- (3-chloro-4- (2-chloro-3- (8-chloro-5-methoxy-6- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) quinolin-2-yl) phenyl) pyridin-2-methoxybenzyl) ((((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (50 mg,0.06 mmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (1 mL,13.5 mmol) and the mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide (S) -5- ((((8-chloro-2- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5-methoxyquinoline) as a white solid (formate salt)-6-yl-methyl) amino) methyl) pyrrolidin-2-one (14.5 mg,30% yield). MS: m/z observed values 773 and 775[ M+H ]] ⁺ Retention time = 2.97min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.69-8.66(m,2H),8.07(s,1H),7.94(d,1H),7.84(dd,1H),7.66(t,1H),7.56-7.52(m,2H),7.48(d,1H),7.36-7.32(m,2H),4.08(s,4H),4.03(s,3H),3.98(s,3H),3.95-3.93(m,1H),3.88-3.85(m,1H),2.92-2.89(m,2H),2.79-2.73(m,2H),2.40-2.29(m,6H),1.88-1.83(m,2H).

Example 546: (S) -5- ((((8-chloro-2- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5-methoxyquinolin-6-yl) methyl) amino) methyl) pyrrolidin-2-one (236)

(a) 8-chloro-2- (2-chloro-3- (3-chloro-2- (3-fluoro-4-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -5-methoxyquinoline-6-carbaldehyde

To a mixture of 8-chloro-2- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -5-methoxyquinoline-6-carbaldehyde (100 mg, 209. Mu. Mol) (see example 542, step (m)) and 2-fluoro-6-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (117 mg, 418. Mu. Mol) in tetrahydrofuran (3 mL) and water (0.6 mL) was added potassium phosphate (133.18 mg, 627. Mu. Mol) and [1,1' -bis (biphenylphosphino) ferrocene]Complex of palladium (II) dichloride with dichloromethane (13.6 mg, 20.9. Mu. Mol) then under N ₂ The mixture was stirred at 85℃for 1 hour. The mixture was filtered, the filtrate was concentrated and the residue was purified by reverse phase HPLC to provide the compound 8-chloro-2- (2-chloro-3- (3-chloro-2- (3-fluoro-4-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -5-methoxyquinoline-6-carbaldehyde (50 mg,31.0% yield) as a white solid. MS: m/z found 595[ M+H ]] ⁺ .

(b) (S) -5- ((((8-chloro-2- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5-methoxyquinolin-6-yl) methyl) amino) methyl) pyrrolidin-2-one

To a mixture of 8-chloro-2- (2-chloro-3- (3-chloro-2- (3-fluoro-4-formyl-5-methoxyphenyl) pyridin-4-yl) phenyl) -5-methoxyquinoline-6-carbaldehyde (40 mg, 67.1. Mu. Mol) and (S) -5- (aminomethyl) pyrrolidin-2-one (40.4 mg, 268. Mu. Mol) in methanol (1.5 mL) was added sodium acetate (33.0 mg, 402. Mu. Mol) followed by N ₂ The mixture was stirred at room temperature for 12 hours. Sodium cyanoborohydride (25.3 mg, 402. Mu. Mol) was then added and the mixture was taken up in N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was filtered, the filtrate was concentrated and the residue was purified by reverse phase HPLC to provide the compound (S) -5- ((((8-chloro-2- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5-methoxyquinolin-6-yl) methyl) amino) pyrrolidin-2-one (10 mg,17% yield) as a white solid (formate). MS: m/z found 791[ M+H ]] ⁺ Retention time = 3.03min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.71-8.67(m,2H),8.39(brs),8.08(s,1H),7.96(d,1H),7.85(dd,1H),7.67(t,1H),7.56-7.54(m,2H),7.24(s,1H),7.19-7.17(m,1H),4.19-4.09(m,4H),4.04-4.01(m,6H),3.94-3.87(m,2H),2.95-2.77(m,4H),2.40-2.28(m,6H),1.88-1.82(m,2H).

Example 547:6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) -1, 2-dihydro-3H-pyrrolo [3,4-c ] pyridin-3-one (290)

(a) 4- (bromomethyl) -6-chloronicotinic acid methyl ester

At N ₂ N-bromosuccinimide (4.99 g,28 mmol) and 2,2' -azobis (2-methylpropanenitrile) (0.35 g,2.16 mmol) were added in one portion to a mixture of methyl 6-chloro-4-methylnicotinate (4 g,21 mmol) in chloroform (90 mL) under an atmosphere. The mixture was stirred at 70 ° for 16 hours. To the mixture was added water (5 mL), the organic phase was separated, washed with saturated aqueous brine solution (2×5 mL), dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-10% ethyl acetate/petroleum ether) to provide methyl 4- (bromomethyl) -6-chloronicotinate (7 g,37% purity) as a colourless oil (7 g,37% purity). MS: m/z measured values 264 and 266[ M+H ]] ⁺ .

(b) 6-chloro-2- (2, 2-dimethoxyethyl) -1, 2-dihydro-3H-pyrrolo [3,4-c ] pyridin-3-one

At N ₂ To a mixture of methyl 4- (bromomethyl) -6-chloronicotinate (7 g,37% purity, 10.6 mmol) in methanol (40 mL) was added 2, 2-dimethoxyethane-1-amine (3.5 mL,31.8 mmol) in one portion under an atmosphere. The mixture was stirred at room temperature for 1 hour, and then the mixture was concentrated. To the residue was added water (20 mL) and saturated aqueous brine solution (5 mL) and the mixture was extracted with ethyl acetate/THF mixture (1:1, 20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ Chromatography (0-40% ethyl acetate/petroleum ether) of the residue to afford 6-chloro-2- (2, 2-dimethoxyethyl) -1, 2-dihydro-3H-pyrrolo [3,4-c ] as a white solid]Pyridin-3-one (1.2 g,44% yield). ¹ H NMR(400MHz,CDCl ₃ ):δ8.79(s,1H),7.38(s,1H),4.49(s,2H),4.47(t,1H),3.65(d,2H),3.36(s,6H).

(c) 2- (6-chloro-3-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridin-2-yl) acetaldehyde

To 6-chloro-2- (2, 2-dimethoxyethyl) -1, 2-dihydro-3H-pyrrolo [3,4-c]A mixture of pyridin-3-one (0.4 g,1.56 mmol) in dichloromethane (2 mL) was added at once trifluoroacetic acid (2 mL,27.0 mmol) and water (0.08 mL,4.44 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was then concentrated to provide 2- (6-chloro-3-oxo-1, 3-dihydro-2H-pyrrolo [3, 4-c) as a yellow gum ]Pyridin-2-yl) acetaldehyde (0.35 g, crude). MS: m/z found 211[ M+H ]] ⁺ . The crude product was used in the next step without further purification.

(d) (S) -6-chloro-2- (2- (((5-oxopyrrolidin-2-yl) methyl) amino) ethyl) -1, 2-dihydro-3H-pyrrolo [3,4-c ] pyridin-3-one

At N ₂ To 2- (6-chloro-3-oxo-1H-pyrrolo [3, 4-c) under atmosphere]A mixture of pyridin-2 (3H) -yl) acetaldehyde (0.35 g,1.66 mmol) and (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride (0.3 g,1.99 mmol) in a dichloromethane/methanol mixture (1:1, 4 mL) was added triethylamine (0.46 ml,3.32 mmol) in one portion. The mixture was stirred at room temperature for 0.5 hours. Sodium triacetoxyborohydride (0.7 g,3.32 mmol) was then added and the mixture was stirred at room temperature for 2.5 hours. (S) -6-chloro-2- (2- (((5-oxopyrrolidin-2-yl) methyl) amino) ethyl) -1, 2-dihydro-3H-pyrrolo [3, 4-c)]Pyridin-3-one (MS: m/z found 309[ M+H)] ⁺ ) The crude pale yellow suspension in methylene chloride/methanol mixture was used in the next step without purification.

(e) (S) - (2- (6-chloro-3-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridin-2-yl) ethyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

At N ₂ To (S) -6-chloro-2- (2- (((5-oxopyrrolidin-2-yl) methyl) amino) ethyl) -1, 2-dihydro-3H-pyrrolo [3, 4-c) under an atmosphere ]Di-tert-butyl dicarbonate (0.72 g,3.32 mmol) was added in one portion to a crude mixture of pyridin-3-one in dichloromethane/methanol (step d). The mixture was stirred at room temperature for 0.5 hours, then water (5 mL) was added and the mixture was extracted with dichloromethane (2 x10 mL). The combined organic phases were washed with saturated aqueous brine solution (2×5 mL), dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ Chromatography (0-100% ethyl acetate/petroleum ether to 10% meoh/ethyl acetate) of the residue to afford (S) - (2- (6-chloro-3-oxo-1, 3-dihydro-2H-pyrrolo [3, 4-c) as a yellow gum]Pyridin-2-yl) ethyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (0.32 g,41% yield). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64-8.58(m,1H),7.63(m,1H),4.59-4.53(m,2H),3.89-3.79(m,1H),3.68(m,2H),3.54-3.41(m,2H),3.31-3.25(m,2H),2.28-2.16(m,3H),1.75-1.71(m,1H),1.23-1.11(m,9H).

(f) (S) - (2- (6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -3-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridin-2-yl) ethyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To (S) - (2- (6-chloro-3-oxo-1, 3-dihydro-2H-pyrrolo [3, 4-c)]Pyridin-2-yl) ethyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (60 mg, 95.0. Mu. Mol) and 2, 3-dichloro-4- (2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) pyridine (example 542, step (b)) (87.5 mg, 190. Mu. Mol) in 1, 4-dioxane/water (1:1, 5 ml) were added potassium carbonate (39.4 mg, 285. Mu. Mol) and [1,1' -bis (biphenylphosphino) ferrocene ]Complex of palladium (II) dichloride with dichloromethane (7.77 mg, 9.51. Mu. Mol) and under N ₂ The mixture was stirred at 110℃for 4 hours. The mixture was filtered and the filtrate was concentrated to provide (S) - (2- (6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -3-oxo-1, 3-dihydro-2H-pyrrolo [3, 4-c) as a yellow solid]Pyridin-2-yl) ethyl) ((5-oxopyri-dine)Pyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (80 mg,39% yield). MS: m/z found 630[ M+H ]] ⁺ .

(g) (4- (4- (3- (2- (2- ((tert-Butoxycarbonyl) ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) -3-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To (S) - (2- (6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -3-oxo-1, 3-dihydro-2H-pyrrolo [3, 4-c)]Pyridin-2-yl) ethyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (60 mg, 95.09. Mu. Mol) and (S) - (2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (example 542, step (p)) (87.5 mg, 190. Mu. Mol) in 1, 4-dioxane/water (1:1, 5 mL) was added potassium carbonate (39.4 mg, 285. Mu. Mol) and [1,1' -bis (biphenylphosphino) ferrocene ]Complex of palladium (II) dichloride with dichloromethane (7.77 mg, 9.51. Mu. Mol) then under N ₂ The mixture was stirred at 110℃for 4 hours. Anhydrous sodium sulfate was added to dryness and the mixture was filtered and concentrated to afford (4- (4- (3- (2- (2- ((tert-butoxycarbonyl) (((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) -3-oxo-2, 3-dihydro-1H-pyrrolo [3, 4-c) as a yellow solid]Pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (77 mg,25% yield). MS: m/z found 928[ M+H ]] ⁺ .

(h) 6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) -1, 2-dihydro-3H-pyrrolo [3,4-c ] pyridin-3-one

To (4- (4- (3- (2- (2- ((tert-butoxycarbonyl) (((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) -3-oxo-2, 3-dihydro-1H-pyrrolo [3, 4-c)]Tert-butyl pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (70 mg, 0.756. Mu. Mol) in dichloromethane (5 mL) was added trifluoroacetic acid (0.675 mmol,5.00 mL) and added to a mixture of dichloromethane (5 mL) and N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide 6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) -1, 2-dihydro-3H-pyrrolo [3, 4-c) as a white solid (formate salt)]Pyridin-3-one (5 mg,8% yield). MS: m/z found 728[ M+H ]] ⁺ Retention time = 2.23min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ9.06(s,1H),8.68(d,1H),7.96(d,1H),7.71-7.68(m,1H),7.63(t,1H),7.53-7.48(m,3H),7.41(s,1H),7.36(d,1H),4.34(m,2H),4.04-3.94(m,8H),3.30-3.29(m,2H),3.21-3.20(m,2H),3.13-3.12(m,2H),2.43-2.33(m,7H),1.90-1.88(m,2H).

Example 548: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) imidazo [1,2-a ] pyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one (291)

(a) 6-Bromoimidazo [1,2-a ] pyrazine-2-carboxylic acid ethyl ester

At N ₂ A mixture of 5-bromopyrazin-2-amine (10 g,57.5 mmol) and ethyl 3-bromo-2-oxopropionate (12.3 g,63.2 mmol) in 1, 4-dioxane (50 mL) was stirred at 95℃for 12 hours. Triethylamine (9.6 ml,69.0 mmol) was then added and the mixture was stirred atN ₂ The mixture was stirred at 15℃for 1 hour. The mixture was filtered and washed with dichloromethane/ethanol (9/1, 200 mL). The filtrate was concentrated, petroleum ether (10 mL) was added to the residue, and the mixture was concentrated under reduced pressure. Water (100 mL) was then added and the mixture was filtered through normal phase SiO ₂ Purification of the solid cake by chromatography (0-40% ethyl acetate/petroleum ether) to afford 6-bromoimidazo [1,2-a ] as a yellow solid]Pyrazine-2-carboxylic acid ethyl ester (1.9 g,12% yield). ¹ H NMR(400MHz,DMSO-d ₆ ):δ9.11(s,1H),8.99(s,1H),8.64(s,1H),4.43-4.38(m,2H),1.40-1.37(m,3H).

(b) 6-bromoimidazo [1,2-a ] pyrazine-2-carbaldehyde

At N ₂ At 78 ℃ to 6-bromoimidazo [1,2-a ]]A mixture of pyrazine-2-carboxylic acid ethyl ester (1 g,3.70 mmol) in THF (10 mL) was added diisobutylaluminum hydride (9.26 mL,1mol/L,9.26 mmol) and the mixture was stirred at-78℃for 2 hours. A saturated aqueous ammonium chloride solution (50 mL) was then added and the mixture extracted with ethyl acetate (2X 100 mL). The combined organic phases were dried over anhydrous sulfate, filtered and concentrated under reduced pressure to afford 6-bromoimidazo [1,2-a ] as a yellow solid]Pyrazine-2-carbaldehyde (400 mg, crude). ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.18(s,1H),9.18(s,1H),9.07(d,1H),8.72(s,1H).

The crude product was used in the next step without further purification.

(c) 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) imidazo [1,2-a ] pyrazine-2-carbaldehyde

To 6-bromoimidazo [1,2-a ]]A mixture of pyrazine-2-carbaldehyde (250 mg,1.11 mmol) and 2, 3-dichloro-4- (2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) pyridine (example 542, step (b)) (595 mg,1.55 mmol) in 1, 4-dioxane/water (5:1, 12 mL)Potassium carbonate (459 mg,3.32 mmol) and [1,1' -bis (biphenylphosphino) ferrocene were added ]Complexes of palladium (II) dichloride with dichloromethane, then in N ₂ The mixture was stirred at 110℃for 1 hour. The mixture was filtered, the filtrate concentrated and passed through normal phase SiO ₂ Chromatography (0-60% ethyl acetate/petroleum ether) of the residue to afford 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) imidazo [1,2-a ] as a yellow solid]Pyrazine-2-carbaldehyde (200 mg,44% yield). ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.17(s,1H),9.39(s,1H),9.02(s,1H),8.83(s,1H),8.54(d,1H),7.84(dd,1H),7.68(t,1H),7.60(d,1H),7.59-7.57(m,1H).

(d) 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) imidazo [1,2-a ] pyrazine-2-carbaldehyde

To 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) imidazo [1,2-a]A mixture of pyrazine-2-carbaldehyde (150 mg,0.37 mmol) and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (see example 77, step (a)) (195 mg,0.74 mmol) in THF/water (5:1, 6 mL) was added potassium phosphate (237 mg,1.11 mmol) and [1,1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) dichloride (24.2 mg,0.04 mmol) then under N ₂ The mixture was stirred at 80℃for 1 hour. The mixture was filtered, the filtrate was concentrated and purified by preparative TLC (SiO ₂ Petroleum ether ethyl acetate=1:3) purification of the residue to afford 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) imidazo [1,2-a as a yellow solid ]Pyrazine-2-carbaldehyde (80 mg,42% yield). MS: m/z found 503[ M+H ]] ⁺ .

(e) (S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) imidazo [1,2-a ] pyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one

To 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) imidazo [1,2-a]A mixture of pyrazine-2-carbaldehyde (75 mg, 149. Mu. Mol), (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride (89.8 mg, 596. Mu. Mol) in methanol (5 mL) was added sodium acetate (73.3 mg, 894. Mu. Mol) followed by N ₂ The mixture was stirred at room temperature for 3 hours. Sodium cyanoborohydride (46.8 mg, 745. Mu. Mol) was then added and the mixture was taken up in N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) imidazo [1, 2-a) as a white solid (formate salt)]Pyrazin-2-yl) methyl) pyrrolidin-2-one (15.1 mg,13% yield). MS: m/z found 699[ M+H ]] ⁺ Retention time = 2.10min (method a). ¹ H NMR (400 MHz, methanol-d) ₆ ):δ9.05(s,1H),8.78(d,1H),8.67(d,1H),8.31(brs,2H),8.08(s,1H),7.76(dd,1H),7.61(t,1H),7.51-7.47(m,3H),7.40-7.34(m,2H),4.29-4.13(m,4H),4.01-4.00(m,4H),3.89-3.87(m,1H),3.13-3.09(m,2H),2.87-2.83(m,2H),2.41-2.28(m,6H),1.89-1.84(m,2H).

Example 549: (S) -2- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one (219)

From (S) - (4- (3-chloro-4- (2-chloro-3- (3-formyl-1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (60 mg,0.08 mmol) and 2, 6-diazaspiro [3.4]]Reductive amination procedure B of octan-7-one (21 mg,0.17 mmol) provides (S) - (4- (3-chloro-4- (2-chloro-3- (1-methyl-3- ((7-oxo-2, 6-diazaspiro [3.4 ]) as crude material]Octane-2-yl) methyl) -1H-pyrrolo [2,3-b]Pyridin-6-yl) phenyl) pyridin-2-yl)-2-Methoxybenzyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester, MS: m/z found 824.3[ M+H ]] ⁺ Which is deprotected and purified by a general Boc deprotection procedure to provide (S) -2- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2, 3-b) as formate salt]Pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4 ]Octane-7-one. The yield was 67% over two steps. LCMS: m/z found 724.3[ M+H ]] ⁺ Retention time = 1.61min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(dd,1H),8.43(s,2H),8.23(d,1H),7.75–7.68(m,1H),7.65–7.55(m,2H),7.51–7.42(m,4H),7.37(s,1H),7.33(d,1H),4.31(s,2H),4.23–4.11(m,2H),4.01–3.95(m,4H),3.92(s,3H),3.89(s,4H),3.62(s,2H),3.08–2.95(m,2H),2.65(s,2H),2.42–2.28(m,3H),1.94–1.80(m,1H).

Example 550:1- (4- ((4- (4- (3- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one (246)

(a) 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridine-3-carbaldehyde

To 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b]A mixture of pyridine-3-carbaldehyde (100 mg,0.24 mmol), 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (63 mg,0.24 mmol) and potassium carbonate (100 mg,0.72 mmol) in degassed 1, 4-dioxane/water (6:1) was added tetrakis (triphenylphosphine) palladium (0) (28 mg,0.02 mmol) and the mixture stirred at 105℃for 30 min. Water was added and the mixture was extracted three times into EtOAc. Combined organic layersDried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to provide 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2, 3-b) ]Pyridine-3-carbaldehyde (60 mg, 48%). LCMS: m/z found 516.1[ M+H ]] ⁺ Retention time = 1.01min (method B).

(b) 1- (4- ((4- (4- (3- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one

Following reductive amination procedure a, starting from 6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b]Pyridine-3-carbaldehyde (40 mg,0.08 mmol) and 1- (4-amino-1-piperidinyl) ethanone (44 mg,0.31 mmol) were prepared by reacting 1- (4- ((4- (4- (3- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [2, 3-b) with 1- (4- (3- (((1-acetylpiperidin-4-yl)) amino)) methyl)]Pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one to prepare the formate salt. Yield 76%. LCMS: m/z found 768.3[ M+H ]] ⁺ Retention time = 1.74min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.67(d,1H),8.50(s,2H),8.25(d,1H),7.72(d,1H),7.67(s,1H),7.60(t,1H),7.53(d,1H),7.51–7.44(m,3H),7.39(s,1H),7.35(dd,1H),4.65(d,2H),4.43(s,2H),4.27(s,2H),4.06(d,2H),3.99(s,3H),3.94(s,3H),3.44–3.37(m,2H),3.25–3.11(m,2H),2.69(t,2H),2.29–2.15(m,4H),2.13(s,6H),1.69–1.42(m,4H).

Example 551:1- (4- ((4- (4- (3- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one (264)

(a) (1-Acetylpiperidin-4-yl) (4- (3-chloro-4- (2-chloro-3- (3-formyl-1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) carbamic acid tert-butyl ester

To 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b]A mixture of pyridine-3-carbaldehyde (140 mg,0.34 mmol), (1-acetylpiperidin-4-yl) (2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) carbamic acid tert-butyl ester (164 mg,0.34 mmol) and potassium carbonate (139 mg,1.01 mmol) in degassed 1, 4-dioxane/water (6:1) was added tetrakis (triphenylphosphine) palladium (0) (39 mg,0.03 mmol) and the mixture stirred at 110℃for 30 min. Water was added and the mixture was extracted three times into EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column with 2% MeOH in dichloromethane as eluent to afford (1-acetylpiperidin-4-yl) (4- (3-chloro-4- (2-chloro-3- (3-formyl-1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl-carbamic acid tert-butyl ester (130 mg, 52%). LCMS: m/z found 742.3[ M+H ]] ⁺ Retention time = 1.05min (method B).

(b) 1- (4- ((4- (4- (3- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one

From (1-acetylpiperidin-4-yl) (4- (3-chloro-4- (2-chloro-3- (3-formyl-1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-6-yl) phenyl) pyridin-2-yl-2-methoxybenzyl-carbamic acid tert-butyl ester (100 mg,0.13 mmol) and 1- [4- (methylamino) -1-piperidinyl]Reductive amination procedure B of ethanone (42 mg,0.27 mmol) provides (1-acetylpiperidin-4-yl) (4- (4- (3- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl)) methyl) -1 as a crude material-methyl-1H-pyrrolo [2,3-b]Pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl-carbamic acid tert-butyl ester, MS: m/z found 882.4[ M+H ]] ⁺ Which is deprotected and purified by a general Boc deprotection procedure to provide 1- (4- ((4- (4- (3- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-pyrrolo [2, 3-b)) as formate salt]Pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one. The yield was 28% over two steps. LCMS: m/z found 782.3[ M+H ]] ⁺ Retention time = 1.74min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.70–8.64(m,1H),8.52–8.39(m,2H),8.23(d,1H),7.72(d,1H),7.69–7.56(m,2H),7.53(d,1H),7.51–7.43(m,3H),7.41–7.38(m,1H),7.38–7.33(m,1H),4.71–4.60(m,2H),4.38–4.24(m,3H),4.20–3.78(m,9H),3.48–3.31(m,2H),3.27–3.07(m,2H),2.79–2.53(m,5H),2.36–2.03(m,10H),1.88–1.40(m,4H).

Example 552:1- (4- ((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one (556)

(a) 6- (3-bromo-2-chlorophenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridine-3-carbaldehyde

At N ₂ Downward (3-formyl-1-methyl-pyrrolo [2, 3-b)]Pyridin-6-yl) boronic acid (9.40 g,46.1 mmol) and 1, 3-dibromo-2-chlorobenzene (18.70 g,69.1 mmol) in THF/H ₂ A mixture of tetrakis (triphenylphosphine) palladium (0) (5.32 g,4.61 mmol) and potassium carbonate (19.10 g,138 mmol) were added in one portion to a mixture of O (5/1, 120 mL). The mixture was stirred at 85℃for 3 hours. To the mixture was added saturated aqueous brine solution (100 mL). The mixture was extracted with ethyl acetate (300 mL). Organic layer warpDried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ Chromatography (0-100% ethyl acetate/petroleum ether) of the residue to afford 6- (3-bromo-2-chlorophenyl) -1-methyl-1H-pyrrolo [2,3-b]Pyridine-3-carbaldehyde (6.10 g,38% yield).

(b) 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridine-3-carbaldehyde

At N ₂ Downward 6- (3-bromo-2-chlorophenyl) -1-methyl-1H-pyrrolo [2,3-b]Pyridine-3-carbaldehyde (4.10 g,11.3 mmol) and 2, 3-dichloro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine (3.86 g,14.1 mmol) in 1, 4-dioxane/H ₂ Potassium phosphate (7.47 g,35.2 mmol) and [1,1' -bis (di-tert-butylphosphino) ferrocene were added in one portion to a mixture of O (5/1, 48 mL) ]Palladium (II) dichloride (764 mg,1.17 mmol). The mixture was stirred at 85℃for 3 hours. The mixture was combined with another batch on a 540mg scale. Water (30 mL) was added and the mixture extracted with ethyl acetate (130 mL). The organic layer was concentrated. By normal phase SiO ₂ Chromatography (0-10% ethyl acetate/petroleum ether) of the residue to afford 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] as a yellow solid]Pyridine-3-carbaldehyde (2.20 g,40% yield). ¹ H NMR (400 MHz, chloroform-d): delta 9.94 (s, 1H), 8.56 (d, 1H), 8.31 (d, 1H), 7.84 (s, 1H), 7.66 (dd, 1H), 7.55 (t, 1H), 7.44 (t, 1H), 7.22 (dd, 1H), 7.17 (d, 1H), 3.95 (s, 3H).

(c) (1-Acetylpiperidin-4-yl) (4- (3-chloro-4- (2-chloro-3- (3-formyl-1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) carbamic acid tert-butyl ester

At N ₂ Downward 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b]Pyridine-3-carbaldehyde (400 mg,0.96 mmol) and (1-acetylPiperidin-4-yl) (tert-butyl 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) carbamate (563 mg,1.15 mmol) in EtOH/toluene/H ₂ Potassium phosphate (408 mg,1.92 mmol) and [1,1' -bis (di-t-butylphosphino) ferrocene were added in one portion to a mixture of O (2/2/1, 5 mL) ]Palladium (II) dichloride (63 mg,0.10 mmol). The mixture was stirred at 85℃for 12 hours. The mixture was combined with 200mg of another batch. Water (20 mL) was added and the mixture extracted with ethyl acetate (100 mL). The organic layer was concentrated under vacuum. By normal phase SiO ₂ The residue was purified by chromatography (0-100% ethyl acetate/petroleum ether) twice to give (1-acetylpiperidin-4-yl) (4- (3-chloro-4- (2-chloro-3- (3-formyl-1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl-carbamic acid tert-butyl ester (340 mg,63% purity). MS: m/z found 742[ M+H ]] ⁺ .

(d) 1- (4- ((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one

According to the method of preparing (1-acetylpiperidin-4-yl) (4- (3-chloro-4- (2-chloro-3- (3-formyl-1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl carbamate tert-butyl ester (75 mg,0.10 mmol) and tetrahydro-2H-pyran-4-amine (31 mg,0.30 mmol) reductive amination procedure B followed by general Boc deprotection procedure to provide 1- (4- ((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2, 3-B) amino) methyl ]Pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl-amino) piperidin-1-yl) ethan-1-one to prepare formate salt. 18% yield. LCMS: m/z found 727.1[ M+H ]] ⁺ Retention time = 2.86min, (method a); ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.68(d,1H),8.53(br s,1H),8.25(d,1H),7.74(dd,1H),7.66(s,1H),7.61(t,1H),7.52–7.47(m,4H),7.38(s,1H),7.35(d,1H),4.60(s,2H),4.42(s,2H),4.18(s,2H),4.09-4.02(m,3H),3.99(s,3H),3.96(s,3H),3.51–3.45(m,3H),3.23–3.15(m,2H),2.71–2.68(m,1H),2.18–2.11(m,7H),1.72–1.67(m,1H),1.57–1.44(m,2H).

example 553:1- (4- ((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- ((((tetrahydro-2H-pyran-4-yl) methyl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one (557)

According to the method of preparing (1-acetylpiperidin-4-yl) (4- (3-chloro-4- (2-chloro-3- (3-formyl-1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl carbamate (example 552, step (c)) (75 mg,0.10 mmol) and (tetrahydro-2H-pyran-4-yl) methylamine (35 mg,0.20 mmol) reductive amination procedure B followed by the general Boc deprotection procedure to provide 1- (4- ((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- ((((tetrahydro-2H-pyran-4-yl) methyl) amino) methyl) -1H-pyrrolo [2, 3-B)]Pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl-amino) piperidin-1-yl) ethan-1-one to prepare formate salt. Yield 6%. LCMS: m/z found 742.4[ M+H ]] ⁺ Retention time = 2.90min, (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.68(d,1H),8.52(br s,2H),8.27(d,1H),7.74(dd,1H),7.69(s,1H),7.61(t,1H),7.53-7.47(m,4H),7.39(s,1H),7.35(d,1H),4.64(s,1H),4.60(s,3H),4.44(s,2H),4.22(s,2H),4.08–4.03(m,1H),3.98(d,7H),3.50–3.41(m,3H),3.24–3.15(m,1H),2.98(d,2H),2.74–2.68(m,1H),2.23–2.14(m,5H),2.00–1.98(m,1H),1.72(d,2H),1.47–1.32(m,2H).

Example 554:1- (4- ((4- (3-chloro-4- (2-chloro-3- (3- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one (558)

According to the method of preparing (1-acetylpiperidin-4-yl) (4- (3-chloro-4- (2-chloro-3- (3-formyl-1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl carbamate (example 552, step (c)) (75 mg,0.10 mmol) and 1, 1-Di-4-aminotetrahydro-2H-thiopyran hydrochloride (28 mg,0.15 mmol) reductive amination procedure B followed by the general Boc deprotection procedure followed by 1- (4- ((4- (3-chloro-4- (2-chloro-3- (3- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [2, 3-B) amino) methyl]Pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl-amino) piperidin-1-yl) ethan-1-one to prepare formate salt. 16% yield. LCMS: m/z found 775.3[ M+H ]] ⁺ Retention time = 2.74min (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.68(d,1H),8.49(br s,1H),8.21(d,1H),7.73(dd,1H),7.60(t,1H),7.54(d,1H),7.51(d,1H),7.48(s,1H),7.46(dd,1H),7.41–7.35(m,3H),4.68–4.65(m,1H),4.60(s,1H),4.28(s,2H),4.11–4.06(m,3H),4.01(s,3H),3.91(s,3H),3.50(t,1H),3.25–3.19(m,3H),3.16–3.07(m,4H),2.74–2.67(m,1H),2.38–2.33(m,2H),2.23–2.10(m,7H).

Example 555:1- (4- ((4- (3-chloro-4- (2-chloro-3- (3- (((2-hydroxyethyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one (559)

According to the method of preparing (1-acetylpiperidin-4-yl) (4- (3-chloro-4- (2-chloro-3- (3-formyl-1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl carbamate tert-butyl ester (example 552, step (c)) (75 mg,0.10 mmol) and 2-aminoethan-1-ol (12 mg,0.20 mmol) reductive amination procedure B followed by general Boc deprotection procedure to provide 1- (4- ((4- (3-chloro-4- (2-chloro-3- (3- (((2-hydroxyethyl) amino) methyl) -1-methyl-1H-pyrrolo [2, 3-B) 1- (3-chloro-4- (2-chloro-3-hydroxy-ethyl) amino) methyl) 1-methyl-1H-pyrrolo [2,3-B ] methyl-ethyl-methyl-phenyl-carbamate]Pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl-amino) piperidin-1-yl) ethan-1-one to prepare formate salt. 10% yield. LCMS: m/z found 688.9[ M+H ]] ⁺ Retention time=2.65 min (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.88(d,1H),8.52(br s,2H),8.27(d,1H),7.74(dd,1H),7.69(s,1H),7.61(t,1H),7.53–7.45(m,4H),7.39(s,1H),7.35(d,1H),4.65–4.60(m,1H),4.47(s,2H),4.22(s,2H),4.07–4.05(m,2H),4.00(s,3H),3.96(s,3H),3.84(m,2H),3.24–3.15(m,4H),2.75–2.68(m,1H),2.23–2.19(m,2H),2.14(s,3H),1.60–1.58(m,1H),1.50–1.46(m,1H).

Example 556:1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (560)

(a) (1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) carbamic acid tert-butyl ester

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At N ₂ Downward 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ]Pyridine-3-carbaldehyde (0.30 g,0.72 mmol) and 1- (4-aminopiperidin-1-yl) ethanone (0.13 g,0.94 mmol) in CH ₂ Cl ₂ Sodium acetate (0.18 g,2.16 mmol) and sodium triacetoxyborohydride (0.46 g,2.16 mmol) were added in one portion to the mixture (40 mL). The mixture was stirred at room temperature for 6 hours. At N ₂ To the above solution were added di-tert-butyl dicarbonate (0.47 g,2.16 mmol) and triethylamine (1.00 ml,0.72 mmol) in one portion. The mixture was stirred at room temperature for 1 hour. Water (20 mL) was added to the mixture. By CH ₂ Cl ₂ (100 mL) the mixture was extracted. The organic phase was washed with saturated aqueous brine solution (2×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ Chromatography (0-100% ethyl acetate/petroleum ether) of the residue to afford (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (2, 3-dichloropyrazine)Pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b]Pyridin-3-yl) methyl) carbamic acid tert-butyl ester (0.80 g). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.29(d,1H),8.03(d,1H),7.60(dd,1H),7.46(t,1H),7.32–7.27(m,3H),7.22(d,1H),4.42–4.39(m,2H),3.89–3.83(m,1H),3.76(s,3H),3.73–3.61(m,4H),2.42–2.36(m,2H),2.18–2.10(m,2H),1.98(s,3H),1.40(s,9H).

(b) (1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) carbamic acid tert-butyl ester

At N ₂ Downset (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2, 3-b) ]Pyridin-3-yl) methyl carbamic acid tert-butyl ester (0.79 g,1.23 mmol) and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (0.39 g,1.47 mmol) in 1, 4-dioxane/H ₂ A mixture of O (10:1, 22 mL) was added in one portion [1,1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) dichloride (0.06 g,0.09 mmol) and potassium phosphate (0.78 g,3.69 mmol). The mixture was stirred at 100℃for 12 hours. The mixture was combined with another batch at 50mg scale. The mixture was concentrated. To the residue were added water (50 mL) and a saturated aqueous brine solution (50 mL). The mixture was extracted with ethyl acetate/THF mixture (1:1, 100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ Chromatography (20-100% ethyl acetate/petroleum ether) purification of the residue to afford (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2, 3-b) as a yellow solid]Pyridin-3-yl) methyl) carbamic acid tert-butyl ester (0.38 g,35% yield). MS: m/z found 742.3[ M+H ]] ⁺ .

(c) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

According to the method of preparing (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2, 3-b)]Tert-butyl pyridin-3-yl) methyl carbamate (120 mg,0.16 mmol) and 1- (4-amino-1-piperidinyl) propan-1-one (30 mg,0.48 mmol) reductive amination procedure B followed by general Boc deprotection procedure to deprotect 1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2, 3-B)]Pyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one. 17% yield. LCMS: m/z found 688.4[ M+H ]] ⁺ Retention time = 2.59min (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.68(d,1H),8.22(d,1H),7.74–7.72(dd,1H),7.61(t,1H),7.54–7.46(m,4H),7.42(d,1H),7.39(s,1H),7.36–7.34(m,1H),4.58–4.54(m,1H),4.22–4.20(m,4H),4.00–3.98(m,4H),3.92(s,3H),3.82(t,2H),3.21–3.13(m,1H),3.08–3.05(m,3H),2.75–2.69(m,5H),1.50-1.37(m,2H).

Example 557:1- (4- (((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (564)

According to the method of preparing (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2, 3-b)]Tert-butyl pyridin-3-yl) methyl carbamate (example 556, step (b)) (120 mg,0.16 mmol) and 1- (2, 6-diazaspiro [ 3.3) ]Reductive amination procedure B of heptan-2-yl) ethanone trifluoroacetate (0.05 g,0.19 mmol) followed by a general Boc deprotection procedure to prepare 1- (4- (((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [ 1))3.3]Heptane-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl-2-chlorophenyl) -1-methyl-1H-pyrrolo [2,3-b]Pyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one. 16% yield. LCMS: m/z found 767.4[ M+H ]] ⁺ Retention time = 2.71min, (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.67(d,1H),8.27(d,1H),7.74(dd,1H),7.69(s,1H),7.61(t,1H),7.50–7.45(m,4H),7.36–7.33(m,2H),4.69–4.66(m,1H),4.51(s,2H),4.36(s,2H),4.13–4.07(m,5H),4.02–3.96(m,10H),3.45–3.41(m,1H),3.25–3.22(m,1H),2.75–2.66(m,1H),2.31–2.24(m,2H),2.15(s,3H),1.86(m,3H),1.65–1.50(m,2H).

Example 558:2- (4- (4- (3- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one (579)

According to the method of preparing (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2, 3-b)]Tert-butyl pyridin-3-yl) methyl carbamate (example 556, step (b)) (120 mg,0.16 mmol) and 2, 6-diazaspiro [3.4]]Reductive amination procedure B of octan-7-one trifluoroacetate (0.05 g,0.16 mmol) followed by general Boc deprotection procedure followed by 2- (4- (4- (3- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl) -1H-pyrrolo [2, 3-B) ]Pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl-2-methoxybenzyl) -2, 6-diazaspiro [3.4]The preparation of formate from octane-7-ketone. 8% yield. LCMS: m/z found 752.4[ M+H ]] ⁺ Retention time = 2.71min (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.20(d,1H),7.72(dd,1H),7.60(t,1H),7.47–7.45(m,3H),7.40–7.37(m,2H),7.28–7.27(m,2H),4.52–4.48(m,1H),4.07(s,2H),3.98–3.90(m,7H),3.77(s,2H),3.59(s,2H),3.44–3.40(m,4H),3.19–3.12(m,1H),2.92–2.85(m,1H),2.74–2.68(m,1H),2.58(s,2H),2.12–2.03(m,5H),1.46–1.31(m,2H).

Example 559:1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) (methyl) amino) piperidin-1-yl) ethan-1-one (600)

(a) 1- (4- (((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) (methyl) amino) piperidin-1-yl) ethan-1-one

To 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b]Sodium acetate (295 mg,3.60 mmol) was added to a mixture of pyridine-3-carbaldehyde (500 mg,1.20 mmol), 1- (4-amino-1-piperidinyl) ethanone (255 mg,1.80 mmol) in dichloromethane (5 mL). At N ₂ The mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (1.02 g,4.80 mmol) was added and the mixture was taken up in N ₂ The mixture was stirred at room temperature for 1 hour. Concentrating the mixture and passing through normal phase SiO ₂ The resulting residue was purified by chromatography (45-65% EtOAc/petroleum ether) to afford 1- (4- (((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2, 3-b)) ]Pyridin-3-yl) methyl) (methyl) amino piperidin-1-yl) ethan-1-one (780 mg). MS: m/z found 556.2[ M+H ]] ⁺ .

(b) 4- (4- (3- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzaldehyde

To 1- (4- (((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) methylA mixture of (meth) amino) piperidin-1-yl) ethan-1-one (500 mg,0.90 mmol) and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (352 mg,1.35 mmol) in dioxane/water (5:1, 18 mL) was added potassium carbonate (372 mg,2.69 mmol) and 1,1' -bis (biphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (73 mg,0.09 mmol). At N ₂ The mixture was stirred at 120℃for 4 hours. Water (10 mL) was added to the mixture. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The resulting residue was purified by chromatography (47-55% MeOH in ethyl acetate) to afford 4- (4- (3- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-pyrrolo [2, 3-b) ]Pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzaldehyde (350 mg,50% yield). MS: m/z found 656[ M+H ]] ⁺ 。

(c) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) (methyl) amino) piperidin-1-yl) ethan-1-one

To 4- (4- (3- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-pyrrolo [2, 3-b)]Sodium acetate (37 mg,0.46 mmol) was added to a mixture of pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl-2-methoxybenzaldehyde (100 mg,0.15 mmol) and tetrahydro-2H-pyran-4-amine (23 mg,0.23 mmol) in MeOH (1 mL). At N ₂ The mixture was stirred at room temperature for 5.5 hours. Sodium triacetoxyborohydride (129 mg,0.61 mmol) was added and the mixture was stirred at N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was filtered and the filtrate was concentrated. The resulting residue was purified by reverse phase HPLC to provide 1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) methyl) (methyl) amino piperidin-1-yl) ethan-1-one (54 mg,44% yield). L (L) CMS: m/z found 742.5[ M+H ]] ⁺ Retention time = 2.82min (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.68(d,1H),8.23(d,1H),7.73(dd,1H),7.63–7.59(m,2H),7.58(d,1H),7.51(d,1H),7.48–7.38(m,4H),4.68–4.60(m,2H),4.35–4.32(m,4H),4.13–4.06(m,3H),4.05(s,3H),3.95(s,3H),3.51–3.45(m,2H),3.31–3.16(m,2H),2.60–2.61(m,4H),2.15–2.12(m,7H),1.75–1.73(m,4H).

Example 560:1- (4- (((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) (methyl) amino) piperidin-1-yl) ethan-1-one (601)

According to the method of preparing a compound comprising 4- (4- (3- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzaldehyde (example 559, step (b)) (100 mg,0.15 mmol) and 1- (2, 6-diazaspiro [3.3]]Heptan-2-yl) ethanone trifluoroacetate (58 mg,0.23 mmol) was then purified by reverse phase HPLC to convert 1- (4- (((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [ 3.3))]Heptane-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl-2-chlorophenyl) -1-methyl-1H-pyrrolo [2,3-b]Pyridin-3-yl) methyl) (methyl) amino) piperidin-1-yl) ethan-1-one to form formate salt. 28% yield. LCMS: m/z found 780.3[ M+H ]] ⁺ Retention time = 2.70min (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),8.22(d,1H),7.75–7.72(m,1H),7.63–7.59(m,2H),7.49–7.43(m,4H),7.35–7.32(m,2H),4.63–4.60(m,1H),4.35(s,2H),4.24(s,2H),4.11–4.02(m,5H),3.96–3.91(m,10H),3.21–3.17(m,2H),2.69–2.57(m,4H),2.15–2.10(m,5H),1.86(s,3H),1.77–1.63(m,2H).

Example 561:2- (4- (4- (3- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one (603)

To 4- (4- (3- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzaldehyde (example 559, step (b)) (100 mg,0.15 mmol) and 2, 6-diazaspiro [3.4]]A mixture of octan-7-one trifluoroacetate (183 mg,0.76 mmol) in MeOH (5 mL) was added sodium acetate (63 mg,0.76 mol). At N ₂ The mixture was stirred at room temperature for 1.5 hours. Sodium triacetoxyborohydride (161 mg,0.76 mmol) was added to the mixture. At N ₂ After stirring at room temperature for 0.5 hours, the mixture was concentrated. The resulting residue was purified by reverse phase HPLC to provide 2- (4- (4- (3- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-pyrrolo [2, 3-b) as formate salt]Pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl-2-methoxybenzyl) -2, 6-diazaspiro [3.4]Octan-7-one (30 mg,23% yield). LCMS: m/z found 766.4[ M+H ]] ⁺ Retention time = 2.68min (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.67(d,1H),8.24(d,1H),7.74(dd,1H),7.68(s,1H),7.61(t,1H),7.50–7.47(m,4H),7.37–7.33(m,2H),4.84–4.81(m,2H),4.71(s,1H),4.39(s,2H),4.22(s,2H),4.13–4.10(m,1H),4.04–3.96(m,10H),3.68(s,2H),3.19–3.15(m,1H),2.73–2.65(m,6H),2.16(m,5H),1.84–1.68(m,2H).

Example 562:2- (4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one (605)

(a) ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester

To 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b]A mixture of pyridine-3-carbaldehyde (0.50 g,1.20 mmol) and tetrahydropyran-4-amine (0.60 g,6.00 mmol) in DCM/MeOH (1:1, 20 mL) was added sodium acetate (0.29 g,3.60 mmol) and 4A molecular sieves (0.10 g,1.20 mmol). After stirring at room temperature for 12 hours, sodium cyanoborohydride (1.51 g,24.0 mmol) was added. After stirring at room temperature for an additional 12 hours, the mixture was diluted with MeOH (5 mL). Di-tert-butyl dicarbonate (1.57 g,7.17 mmol) and triethylamine (0.73 g,7.17 mmol) were added. At N ₂ After stirring at room temperature for 4 hours, the mixture was concentrated. By normal phase SiO ₂ The resulting residue was purified by chromatography (0-30% etoac/petroleum ether) to afford ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2, 3-b) as a yellow solid]Pyridin-3-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester (0.55 g,76% yield). ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.53(d,1H),8.14(d,1H),7.75(d,1H),7.64–7.60(m,2H),7.52–7.48(m,2H),7.37(d,1H),4.57(s,2H),3.83(s,5H),3.25–3.22(m,2H),1.85–1.83(m,2H),1.46(m,11H).

(b) ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester

To ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester (500 mg,0.83 mmol) and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (435 mg,1.66 mmol) in dioxane/H ₂ A mixture in O (5:1, 12 mL) was added 1,1' -bis (biphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (68 mg,0.08 mmol)) And potassium carbonate (344 mg,2.49 mmol). At N ₂ The mixture was stirred at 120℃for 12 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc (2×30 mL). The combined organic phases were dried over anhydrous sulphate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ The resulting residue was purified by chromatography (0-75% EtOAc/petroleum ether) to afford ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester (514 mg,80% yield). ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.44(s,1H),8.78(d,1H),8.15(d,1H),7.84–7.82(m,1H),7.76–7.73(m,1H),7.64-7.61(m,2H),7.54–7.52(m,3H),7.43–7.37(m,2H),4.57(s,2H),4.09–4.03(m,1H),3.83–3.81(m,4H),3.63–3.60(m,6H),3.28–3.22(m,2H),1.85–1.79(m,2H),1.46(s,9H).

(c) 2- (4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one

According to the formula (I) consisting of ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester (100 mg,0.14 mmol) and 2, 6-diazaspiro [3.4 ]]Reductive amination procedure B of octan-7-one trifluoroacetate (171 mg,0.71 mmol) followed by general Boc deprotection procedure followed by 2- (4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2, 3-B) amino)]Pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4]The preparation of formate from octane-7-ketone. 43% yield. LCMS: m/z found 711.3[ M+H ]] ⁺ Retention time = 2.72min (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.69(d,1H),8.27(d,1H),7.73–7.72(m,2H),7.62(t,1H),7.56(d,1H),7.52–7.47(m,3H),7.43(s,1H),7.40–7.38(m,1H),4.34–4.29(m,6H),4.11–4.05(m,3H),4.02(s,3H),3.97(s,3H),3.72–3.70(m,3H),3.51–3.47(m,3H),2.76(d,2H),2.19–2.15(m,2H),1.80–1.70(m,2H).

Example 563:2- ((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) ethan-1-ol (606)

To ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2, 3-b)]Sodium acetate (70.1 mg,0.86 mmol) was added as a mixture of tert-butyl pyridin-3-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamate (example 562, step (b)) (150 mg,0.21 mol) and 2-aminoethanol (39 mg,0.64 mmol) in MeOH (3 mL). After stirring at room temperature for 2 hours, sodium triacetoxyborohydride (181 mg,0.86 mmol) was added to the mixture. After 30 min, the mixture was diluted with DCM (5 mL) and trifluoroacetic acid (2 mL) was added. The mixture was concentrated and the resulting residue was purified by reverse phase HPLC to provide 2- ((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2, 3-b) as formate salt ]Pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl-amino) ethan-1-ol (17 mg,12% yield). LCMS: m/z found 646.3[ M+H ]] ⁺ Retention time = 2.58min, (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.69(d,1H),8.26(d,1H),7.75–7.73(dd,1H),7.69(s,1H),7.62(t,1H),7.55–7.47(m,4H),7.41(s,1H),7.38–7.36(dd,1H),4.46(s,2H),4.32(s,2H),4.09–4.05(m,2H),4.01(s,3H),3.96(s,3H),3.85(t,2H),3.51–3.45(m,3H),3.16(t,2H),2.19–2.14(m,2H),1.77–1.67(m,2H).

Example 564:1- (6- (4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one (609)

To ((6- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester (example 562, step (b)) (100 mg,0.14 mmol) and 1- (2, 6-diazaspiro [3.3]]A mixture of heptan-2-yl) ethanone hydrochloride (33 mg,0.19 mmol) in MeOH (3 mL) was added sodium acetate (47 mg,0.57 mmol). After stirring at room temperature for 2.5 hours, sodium triacetoxyborohydride (121 mg,0.57 mmol) was added. The mixture was stirred at room temperature for 30 minutes. Water (20 mL) was added and the mixture extracted with EtOAc (2X 30 mL). The combined organic phases were dried over anhydrous sulphate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ Chromatography (0-50% EtOAc/petroleum ether) was used to purify the residue to afford ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [ 3.3)) ]Heptane-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl-2-chlorophenyl) -1-methyl-1H-pyrrolo [2,3-b]Pyridin-3-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester (107 mg,91% yield). MS: m/z found 825.4[ M+H ]] ⁺ .

To ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [ 3.3))]Heptane-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl-2-chlorophenyl) -1-methyl-1H-pyrrolo [2,3-b]To a mixture of tert-butyl pyridin-3-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamate (100 mg,0.12 mmol) in DCM (5 mL) was added trifluoroacetic acid (2 mL). After stirring at room temperature for 30 minutes, the mixture was concentrated. The resulting residue was purified by reverse phase HPLC to provide 1- (6- (4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2, 3-b) as formate salt]Pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.3]Heptane-2-yl) ethan-1-one (7.6 mg,8% yield). LCMS: m/z found 725.4[ M+H ]] ⁺ Retention time = 2.80min (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),8.26(d,1H),7.75–7.72(dd,1H),7.68(s,1H),7.61(t,1H),7.51–7.47(m,3H),7.42(d,1H),7.33–7.30(m,2H),4.46(s,2H),4.34(s,2H),4.13–4.05(m,4H),3.96–3.91(m,8H),3.77(s,4H),3.52–3.41(m,3H),2.16–2.13(m,2H),1.86(s,3H),1.77–1.67(m,2H).

Example 565: n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) -N-methyltetrahydro-2H-pyran-4-amine (635)

At N ₂ Downward 4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2, 3-b)]A mixture of tert-butyl pyridin-6-yl) phenyl-pyridin-2-yl) -2-methoxybenzyl (tetrahydro-2H-pyran-4-yl) carbamate (example 566, step (d)) (0.50 g,0.64 mmol) in THF (5 mL) was added paraformaldehyde (0.06 g,1.91 mmol) and sodium acetate (0.16 g,1.91 mmol) at one time. The mixture was stirred at room temperature for 12 hours. At N ₂ Sodium triacetoxyborohydride (0.54 g,2.54 mmol) was added in one portion to the mixture. The mixture was stirred at room temperature for 0.5 hours. The mixture was filtered. The filtrate was concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-90% MeOH/ethyl acetate) to afford 0.45g of the imine intermediate. To a solution of 0.45g of the imine intermediate in THF (5 mL) was added sodium borohydride (0.17 g,4.5 mmol). The mixture was stirred at 20℃for 12 hours. Water (3 mL) was added. The resulting mixture was purified by reverse phase HPLC to afford 4- (3-chloro-4- (2-chloro-3- (1-methyl-3- ((methyl (tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2, 3-b) as a white solid]Pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester (45 mg,10% yield). MS: m/z found 800.3[ M+H ] ] ⁺ .

To 4- (3-chloro-4- (2-chloro-3- (1-methyl-3- ((methyl (tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2, 3-b)]A mixture of tert-butyl pyridin-6-yl) phenyl-pyridin-2-yl) -2-methoxybenzyl (tetrahydro-2H-pyran-4-yl) carbamate (40 mg,0.05 mmol) in 1, 4-dioxane (1.5 mL) was added in one portion to an aqueous HCl solution (12M, 0.3 mL). The mixture was stirred at room temperature for 2 hours. The mixture was combined with 5mg scaleIs combined with another batch of material. The combined mixture was purified by reverse phase HPLC to afford N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2, 3-b) as a white solid]Pyridin-3-yl) methyl) -N-methyltetrahydro-2H-pyran-4-amine (6 mg,5% yield). LCMS: m/z found 700.3[ M+H ]] ⁺ Retention time = 2.94min (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.69(d,1H),8.23(d,1H),7.74(dd,1H),7.68–7.59(m,2H),7.55–7.45(m,4H),7.41(s,1H),7.37(d,1H),4.38–4.29(m,4H),4.12–4.06(m,4H),4.05(s,3H),4.01(s,3H),3.53–3.40(m,6H),2.72–2.59(m,3H),2.13–2.04(m,4H),1.86–1.64(m,4H).

Example 566: n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine (563)

(a) 4-bromo-2-methoxybenzyl (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester

At N ₂ To a mixture of 4-bromo-2-methoxy-benzaldehyde (1.50 g,6.98 mmol) and tetrahydropyran-4-amine (0.99 g,9.77 mmol) in MeOH/DCM (1:1, 16 mL) was added sodium acetate (1.14 g,14 mmol) in one portion. The mixture was stirred at room temperature for 12 hours. At N ₂ Sodium triacetoxyborohydride (4.44 g,20.9 mmol) was added in one portion to the mixture. The mixture was stirred at room temperature for 1 hour. The above solution was diluted with THF (20 mL). At N ₂ Di-tert-butyl dicarbonate (4.00 ml,17.4 mmol) and triethylamine (0.97 ml,6.96 mmol) were added in the next portion. The mixture was stirred at room temperature for 1 hour. Water (500 mL) was added to the mixture. The mixture was extracted with ethyl acetate (2×250 mL). Washed with saturated aqueous brine solution (2X 200 mL)The combined organic phases were washed, dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The resulting residue was purified by chromatography (0-10% ethyl acetate/petroleum ether) to give tert-butyl 4-bromo-2-methoxybenzyl (tetrahydro-2H-pyran-4-yl) carbamate (1.8 g, 60%) as a colourless oil. MS: m/z found 300[ M-tert-butyl ]] ⁺ .

(b) 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester

At N ₂ To a mixture of tert-butyl 4-bromo-2-methoxybenzyl (tetrahydro-2H-pyran-4-yl) carbamate (1.60 g,4.00 mmol) and bis (pinacolato) diborane (1.83 g,7.19 mmol) in 1, 4-dioxane (15 mL) was added 1,1' -bis (biphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (0.1 g,0.12 mmol) and potassium acetate (1.18 g,12 mmol) at once. The mixture was stirred at 100℃for 3 hours. The mixture was concentrated. By normal phase SiO ₂ The resulting residue was purified by chromatography (0-30% ethyl acetate/petroleum ether) to give tert-butyl 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl (tetrahydro-2H-pyran-4-yl) carbamate (2.00 g,87% yield) as a white solid. ¹ H NMR (400 MHz, chloroform-d): delta 7.30 (d, 1H), 7.17 (s, 1H), 7.07 (d, 1H), 4.32 (m, 2H), 3.86-3.82 (m, 6H), 3.38-3.28 (m, 2H), 1.52-1.49 (m, 4H), 1.27-1.17 (m, 21H).

(c) 4- (3-chloro-4- (2-chloro-3- (3-formyl-1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester

At N ₂ Downward 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b]Pyridine-3-carbaldehyde (0.15 g,0.36 mmol) and 2-methoxy-tert-butyl 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl (tetrahydro-2H-pyran-4-yl) carbamate (0.29 g,0.65 mmol) in 1, 4-dioxane/H ₂ A mixture of O mixture (4:1, 5 mL) was added in one portion [1,1' -bis (di-t-butylphosphino) ferrocene]Palladium (II) dichloride (0.02 g,0.04 mmol) and potassium phosphate (0.23 g,1.08 mmol). The mixture was stirred at 100℃for 12 hours. Water (50 mL) was added to the mixture. The mixture was extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with saturated aqueous brine solution (2×25 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by preparative TLC (silica gel, petroleum ether: ethyl acetate=2:1) to afford 4- (3-chloro-4- (2-chloro-3- (3-formyl-1-methyl-1H-pyrrolo [2, 3-b) as a white solid ]Pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester (0.15 g,55% yield). MS: m/z found 701[ M+H ]] ⁺ .

(d) 4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester

At N ₂ Downward 4- (3-chloro-4- (2-chloro-3- (3-formyl-1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester (0.10 g,0.14 mmol) and tetrahydro-2H-pyran-4-amine (0.03 g,0.29 mmol) in CH ₂ Cl ₂ Sodium acetate (0.04 g,0.43 mmol) was added in one portion to the mixture of (3 mL). The mixture was stirred at room temperature for 12 hours. At N ₂ Sodium triacetoxyborohydride (0.09 g,0.43 mmol) was added to the mixture in one portion. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated to afford 4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2, 3-b) as a yellow oil]Pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester (0.12 g). MS: m/z found 786[ M+H ]] ⁺ 。

(e) N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine

4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2, 3-b) amino) methyl]Pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester is subjected to a general Boc deprotection procedure to provide N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine (9% yield). LCMS: m/z found 686.3[ M+H ]] ⁺ Retention time = 2.93min (method a); ¹ h NMR (400 MHz, methanol-d) ₄ ):δ8.79-8.73(m,3H),8.35–8.25(m,1H),7.84–7.79(m,1H),7.74–7.72(m,1H),7.63(t,1H),7.58–7.34(m,5H),4.41–4.17(m,3H),3.96–3.85(m,8H),3.37(m,3H),3.32(m,6H),2.08–1.99(m,4H),1.66–1.52(m,4H).

Example 567:1,1'- ((((3, 3' -dichloro- [4,4 '-bipyridine ] -2,2' -diyl) bis (2-fluoro-6-methoxy-4, 1-phenylene)) bis (methylene)) bis (azanediyl)) bis (piperidin-4, 1-diyl)) bis (ethane-1-one) (313)

1,1' - ((((((3, 3' -dichloro- [4,4' -bipyridyl)) with 2-fluoro-6-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -benzaldehyde instead of 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -benzaldehyde in step (b) and 1- (4-aminopiperidin-1-yl) ethane-1-one instead of (S) -5- (aminomethyl) pyrrolidin-2-one in step (c) was prepared in a similar manner to that described with respect to example 132 ]-2,2' -diyl) Bis (2-fluoro-6-methoxy-4, 1-phenylene)) bis (methylene)) bis (azanediyl)) bis (piperidin-4, 1-diyl)) bis (ethan-1-one). The product was obtained as a tan solid (formate). LC/MS: m/z found 781,783[ M+H ]] ⁺ Retention time = 2.02min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.73(d,2H),8.43(s,2H),7.52(d,2H),7.26(s,2H),7.20(d,2H),4.63(d,2H),4.29(s,4H),4.00(s,8H),3.34(s,2H),3.19(t,2H),2.70(t,2H),2.21(t,4H),2.12(s,6H),1.67–1.39(m,4H).

Example 568:2,2'- ((3, 3' -dichloro- [4,4 '-bipyridine ] -2,2' -diyl) bis (2-fluoro-6-methoxy-4, 1-phenylene)) bis (methylene)) bis (2, 6-diazaspiro [3.4] octan-7-one) (323)

In a similar manner to that described with respect to example 132, 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -benzaldehyde was replaced with 2-fluoro-6-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -benzaldehyde in step (b) and 2, 6-diazaspiro [3.4] in step (c)]Preparation of 2,2' - (((3, 3' -dichloro- [4,4' -bipyridine) by substituting (S) -5- (aminomethyl) pyrrolidin-2-one with octan-7-one]-2,2' -diyl) bis (2-fluoro-6-methoxy-4, 1-phenylene)) bis (methylene)) bis (2, 6-diazaspiro [3.4]]Octane-7-one). The product was obtained as a tan solid (formate). LC/MS: m/z found 749,751[ M+H ]] ⁺ Retention time = 1.91min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.75–8.68(m,2H),8.38(s,2H),7.54–7.47(m,2H),7.23(s,2H),7.20–7.15(m,2H),4.17(s,4H),3.97(s,6H),3.85(s,8H),3.60(s,4H),2.62(s,4H).

Example 569: (5S, 5' S) -5,5' - ((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (8-methoxy-3, 4-dihydroisoquinoline-6, 2 (1H) -diyl)) bis (methylene)) bis (pyrrolidin-2-one) (266)

In the same manner as described in relation to example 132, in step (b) use is made of (5S) -5- [ [ 8-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydro-1H-isoquinolin-2-yl]-methyl group]Pyrrolidin-2-one was substituted for 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -benzaldehyde to prepare (5S, 5 'S) -5,5' - (((3, 3 '-dichloro- [4,4' -bipyridine)]-2,2' -diyl) bis (8-methoxy-3, 4-dihydroisoquinoline-6, 2 (1H) -diyl) bis (methylene)) bis (pyrrolidin-2-one). The product was obtained as a tan solid (formate). LC/MS: m/z found 741,743[ M+H ]] ⁺ Retention time = 1.98min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.65(d,2H),7.44(d,2H),7.05(d,4H),4.03(s,2H),3.87(s,8H),3.75(d,2H),3.62(d,2H),2.97(s,4H),2.92–2.57(m,8H),2.32(m,6H).

Example 570: ((3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) -5' -methoxy- [2,3' -bipyridin ] -6' -yl) methyl) -L-homoserine methyl ester (267)

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In a similar manner to that described for example 45, 3-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -Pi Kaolin aldehyde was used in place of 1-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyrrolo [3,2-b ] in step (d)]Pyridine-3-carbaldehyde and L-homoserine methyl ester is used to replace 1- (4-aminopiperidin-1-yl) ethane-1-one in step (e) to prepare ((3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxo-pyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) -5 '-methoxy- [2,3' -bipyridine ]-6' -yl) methyl) -L-homoserine methyl ester. The product was obtained as a white solid (formate). LC/MS: m/z found 709,711[ M+H ]] ⁺ Retention time = 2.05min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.69(d,1H),8.49(s,1H),8.43(s,1H),7.76(d,1H),7.71(d,2H),7.55(t,1H),7.48(d,1H),7.42(d,1H),7.27(d,1H),4.02(d,5H),3.96(s,3H),3.88(d,3H),3.79–3.55(m,5H),2.76(t,2H),2.32(s,3H),2.08–1.69(m,3H).

Example 571: (S) -5- (((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((((S) -2-oxotetrahydrofuran-3-yl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -amino) methyl) pyrrolidin-2-one (268)

In the same manner as described in relation to example 45, 3-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -Pi Kaolin aldehyde was used instead of 1-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyrrolo [3,2-b ] in step (d)]Pyridine-3-carboxaldehydes and substituting (S) -3-aminodihydrofuran-2 (3H) -one for 1- (4-aminopiperidin-1-yl) ethan-1-one in step (e) to prepare (S) -5- (((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - (((S) -2-oxotetrahydrofuran-3-yl) amino) methyl) - [2,3' -bipyridine)]-4-yl) phenyl) -2-methoxypyridin-3-yl-methyl) -amino) methyl) pyrrolidin-2-one. The product was obtained as a white solid (formate). LC/MS: m/z found 677,679[ M+H ]] ⁺ Retention time = 2.07min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.69(d,1H),8.46(s,1H),8.43(s,1H),7.79(d,1H),7.76–7.68(m,2H),7.56(t,1H),7.48(d,1H),7.43(d,1H),7.29(d,1H),4.42(t,1H),4.24(m,1H),4.13(s,2H),4.04(s,3H),3.97(s,5H),3.90(s,1H),3.76(t,1H),2.85(d,2H),2.64–2.50(m,1H),2.41–2.24(m,3H),2.22–2.08(m,1H),1.84(s,1H).

Example 572:1- (4- (((6- (3- (6 ' - (((1-acetylpiperidin-4-yl) amino) methyl) -3-chloro-5 ' -methoxy- [2,3' -bipyridin ] -4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (375)

(a) 3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) -5' -methoxy- [2,3' -bipyridine ] -6' -carbaldehyde

Tetrakis (triphenylphosphine) palladium (0) (41 mg,0.04 mmol), potassium carbonate (74 mg,0.53 mmol), 6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl]-2-methoxy-pyridine-3-carbaldehyde (70 mg,0.18 mmol), and 3-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine-2-carbaldehyde (70 mg,0.27 mmol) were suspended in 1, 4-dioxane/water (4:1, 3 ml), and the solution was then heated at 105 ℃ for 20 minutes. The reaction was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×5 mL). The combined organics were concentrated under reduced pressure and the crude sample was purified by silica gel chromatography (0-50% EtOAc/hexanes) to provide 3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) -5 '-methoxy- [2,3' -bipyridine as a pale yellow solid]-6' -Formaldehyde (24 mg,27% yield). MS: m/z found 494,496M+H] ⁺ .

(b) 1- (4- (((6- (3- (6 ' - ((1-acetylpiperidin-4-yl) amino) methyl) -3-chloro-5 ' -methoxy- [2,3' -bipyridin ] -4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

3-chloro-4- (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) -5 '-methoxy- [2,3' -bipyridine]-6' -Formaldehyde (12 mg,0.02 mmol), acetic acid (3 mg,0.05 mmol), and 1- (4-amino-1-piperidinyl) ethanone (14 mg,0.10 mmol) were dissolved in MeOH/THF (1:1, 1 mL) and the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (6 mg,0.10 mmol) was added and the resulting mixture was stirred at 25 ℃ for 1 hour. The reaction was then diluted with water (2 mL) and extracted with EtOAc (3×2 mL). The combined organics were further washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude sample was purified by reverse phase HPLC to afford 1- (4- (((6- (3- (6 ' - (((1-acetylpiperidin-4-yl) amino) methyl)) methyl) -3-chloro-5 ' -methoxy- [2,3' -bipyridine) as a white solid (formate salt)]-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl-methyl) amino) piperidin-1-yl) ethan-1-one(9 mg,50% yield). LC/MS: m/z found 746,748[ M+H ]] ⁺ Retention time = 2.07min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.72–8.68(m,1H),8.51(s,1H),8.49(d,1H),7.83(d,1H),7.79(s,1H),7.75–7.69(m,1H),7.57(t,1H),7.52–7.48(m,1H),7.43(d,1H),7.30(d,1H),4.59(t,2H),4.35(s,2H),4.07(s,2H),4.04(d,3H),4.00(t,5H),3.18(t,3H),2.70(t,2H),2.12(d,11H),1.50(m,4H).

Example 573:2- ((3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) pyridin-2-yl) phenyl) -5' -methoxy- [2,3' -bipyridin ] -6' -yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one (376)

In a similar manner to that described for example 572, 2, 6-diazaspiro [3.4 ] was used in step (b)]Preparation of 2- ((3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4 ]) by substituting 1- (4-amino-1-piperidinyl) -ethanone with octan-7-one]Octane-2-yl) methyl) pyridin-2-yl) phenyl) -5 '-methoxy- [2,3' -bipyridine]-6' -yl) methyl) -2, 6-diazaspiro [3.4]Octane-7-one. The product was obtained as a white solid (formate). LC/MS: m/z measured values 714,716[ M+H ]] ⁺ Retention time = 1.98min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.70(dd,1H),8.49(s,1H),8.39(s,2H),7.81–7.74(m,2H),7.74–7.68(m,1H),7.56(t,1H),7.52–7.47(m,1H),7.42(d,1H),7.28(d,1H),4.55(s,2H),4.21(s,4H),4.03–3.97(m,8H),3.76(s,4H),3.70(d,2H),3.62(d,2H),2.74(d,2H),2.63(d,2H).

Example 574:1- (6- ((6- (3- (6 ' - ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-chloro-5 ' -methoxy- [2,3' -bipyridin ] -4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one (428)

In a similar manner to that described for example 572, 1- (2, 6-diazaspiro [ 3.3) was used in step (b)]Preparation of 1- (6- ((6- (3- (6' - ((6-acetyl-2, 6-diazaspiro [3.3 ])) by substituting 1- (4-amino-1-piperidinyl) -ethanone for 1- (4-amino-1-piperidinyl) -ethanone]Heptane-2-yl) methyl) -3-chloro-5 '-methoxy- [2,3' -bipyridine]-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl-methyl) -2, 6-diazaspiro [3.3 ]Heptane-2-yl) ethan-1-one. The product was obtained as a white solid (formate). LC/MS: m/z found 742,744[ M+H ]] ⁺ Retention time = 2.09min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.70(d,1H),8.48(s,1H),7.79(s,1H),7.72(t,2H),7.56(t,1H),7.50(d,1H),7.42(d,1H),7.27(d,1H),4.46(s,2H),4.40(s,2H),4.32(s,2H),4.26(s,3H),4.16(s,2H),4.08(s,2H),4.01(d,3H),3.98(d,4H),3.90(s,2H),3.77(s,4H),1.85(d,6H).

Example 575: n- ((4- (3- (5- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloro-5 ' -methoxy- [2,3' -bipyridin ] -6' -yl) methyl) -2-oxaspiro [3.3] heptan-6-amine (429)

In a similar manner to that described with respect to example 572, 2-oxaspiro [3.3] was used in step (b)]Preparation of N- ((4- (3- (5- (((2-oxaspiro [3.3 ])) by substituting 1- (4-amino-1-piperidinyl) -ethanone) by heptane-6-amine]Heptane-6-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloro-5 '-methoxy- [2,3' -bipyridine]-6' -yl) methyl) -2-oxaspiro [3.3]Heptane-6-amine. The product was obtained as a white solid (formate). LC/MS: m/z found 688,690[ M+H ]] ⁺ Retention time = 2.10min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.71(d,1H),8.51(s,1H),8.46(s,1H),7.83(d,1H),7.80(s,1H),7.72(d,1H),7.57(t,1H),7.51(d,1H),7.44(d,1H),7.32(d,1H),4.73(d,4H),4.63(d,4H),4.26(s,2H),4.09–4.03(m,5H),3.99(d,3H),3.79–3.64(m,1H),3.58(q,1H),2.69(m,4H),2.41(t,2H),2.33(t,2H).

Example 576:2- ((3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6-oxo-2, 5-diazaspiro [3.4] octane-2-yl) methyl) pyridin-2-yl) phenyl) -5' -methoxy- [2,3' -bipyridin ] -6' -yl) methyl) -2, 5-diazaspiro [3.4] octane-6-one (430)

In a similar manner to that described for example 572, 2, 5-diazaspiro [3.4] was used in step (b) ]Preparation of 2- ((3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6-oxo-2, 5-diazaspiro [3.4 ]) by substituting 1- (4-amino-1-piperidinyl) -ethanone with octan-6-one]Octane-2-yl) methyl) pyridin-2-yl) phenyl) -5 '-methoxy- [2,3' -bipyridine]-6' -yl) methyl) -2, 5-diazaspiro [3.4]Octan-6-one. The product was obtained as a white solid (formate). LC/MS: m/z measured values 714,716[ M+H ]] ⁺ Retention time = 2.03min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.69(d,1H),8.47(s,1H),8.40(s,1H),7.78(s,1H),7.71(t,2H),7.55(t,1H),7.49(d,1H),7.41(d,1H),7.26(d,1H),4.34(s,2H),4.10(d,2H),4.03–3.96(m,6H),3.93(d,2H),3.83(s,2H),3.71–3.64(m,2H),3.51(d,2H),2.53–2.34(m,8H).

Example 577: n- ((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine (431)

In a similar manner to that described for example 572, N- ((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,3' -bipyridine) was prepared in step (b) using tetrahydropyran-4-amine instead of 1- (4-amino-1-piperidinyl) -ethanone]-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine. The product was obtained as a white solid (formate). LC/MS: m/z found 664,666[ M+H ]] ⁺ Retention time = 2.10min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.70(t,1H),8.51(s,2H),7.83(d,1H),7.79(s,1H),7.72(d,1H),7.57(t,1H),7.50(d,1H),7.43(d,1H),7.30(d,1H),4.34(d,2H),4.13–3.96(m,13H),3.44(t,4H),3.12(s,1H),2.11–2.00(m,4H),1.76–1.53(m,4H).

Example 578:2- ((6- (3- (6 ' - (((1-acetylpiperidin-4-yl) amino) methyl) -3-chloro-5 ' -methoxy- [2,3' -bipyridin ] -4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one (547)

(a) 3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) pyridin-2-yl) phenyl) -5' -methoxy- [2,3' -bipyridine ] -6' -carbaldehyde

Tetrakis (triphenylphosphine) palladium (0) (115 mg,0.10 mmol), potassium carbonate (205 mg,1.49 mmol), 2- [ [6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl]-2-methoxy-3-pyridinyl]Methyl group]-2, 7-diazaspiro [3.4]]Octane-6-one (250 mg,0.50 mmol), and 3-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine-2-carbaldehyde (170 mg,0.65 mmol) were suspended in 1, 4-dioxane/water (4:1, 8 ml), and the solution was then heated at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 15mL of water, and extracted with EtOAc (3×10 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (0-10% DCM/MeOH) to provide 3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [ 3.4) as a dark yellow foam]Octane-2-yl) methyl) pyridin-2-yl) phenyl) -5 '-methoxy- [2,3' -bipyridine]-6' -formaldehyde (79 mg,26% yield). MS: m/z found 604,606[ M+H ]] ⁺ .

(b) 2- ((6- (3- (6 ' - (((1-acetylpiperidin-4-yl) amino) methyl) -3-chloro-5 ' -methoxy- [2,3' -bipyridin ] -4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one

3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4 ])]Octane-2-yl) methyl) pyridin-2-yl) phenyl) -5 '-methoxy- [2,3' -bipyridine]-6' -Formaldehyde (19 mg,0.03 mmol), acetic acid (4 mg,0.06 mmol), and 1- (4-amino-1-piperidinyl) ethanone (13 mg,0.09 mmol) were dissolved in MeOH/THF (1:1, 1 mL) and the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (56 mg,0.09 mmol) was added and the resulting mixture was stirred at 25℃for 1 hour. The reaction was filtered through CELITE and the filtrate was concentrated under reduced pressure. The crude sample was purified by reverse phase HPLC to afford 2- ((6- (3- (6 ' - (((1-acetylpiperidin-4-yl) amino) methyl) -3-chloro-5 ' -methoxy- [2,3' -bipyridine) as a white solid (formate salt)]-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl-methyl) -2, 6-diazaspiro [3.4]Octan-7-one (12 mg,51% yield). LC/MS: m/z actual measurement 730,732[ M+H ]] ⁺ Retention time = 2.00min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.71(d,1H),8.53(s,1H),7.81(s,1H),7.73(dd,2H),7.56(t,1H),7.51(d,1H),7.42(d,1H),7.27(d,1H),4.66(d,1H),4.44(s,2H),4.07(d,1H),4.01(s,6H),3.90(s,2H),3.62(d,6H),3.45(s,1H),3.19(t,1H),2.69(t,1H),2.61(s,2H),2.24(t,2H),2.13(s,3H),1.60(dd,2H).

Example 579:2- ((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one (548)

In a similar manner to that described for example 578, 2- ((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,3' -bipyridine) was prepared in step (b) using tetrahydropyran-4-amine instead of 1- (4-amino-1-piperidinyl) ketene ]-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) -2, 6-diazaspiro [3.4]Octane-7-one. The product was obtained as a white solid (formate). LC/MS: m/z found 689,691[ M+H ]] ⁺ Retention time =2.03min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.72–8.68(m,1H),8.53(s,1H),8.50(s,1H),7.81(d,1H),7.71(d,2H),7.58–7.52(m,1H),7.51(d,1H),7.41(d,1H),7.25(d,1H),4.42(s,2H),4.05(d,2H),4.00(d,6H),3.78(s,2H),3.59(s,2H),3.48(d,6H),3.43(s,1H),2.59(s,2H),2.11(d,2H),1.82–1.66(m,2H).

Example 580:2- ((6- (2-chloro-3- (3-chloro-6 ' - ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -5' -methoxy- [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one (549)

In a similar manner to that described for example 578, 2- ((6- (2-chloro-3- (3-chloro-6 ' - ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -5' -methoxy- [2,3' -bipyridine) was prepared in step (b) using (1 r,4 r) -4-aminocyclohexane-1-ol instead of 1- (4-amino-1-piperidinyl) ketene]-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) -2, 6-diazaspiro [3.4]Octane-7-one. The product was obtained as a white solid (formate). LC/MS: m/z found 703,705[ M+H ]] ⁺ Retention time = 2.00min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.71(d,1H),8.53(s,1H),7.81(s,1H),7.75–7.67(m,2H),7.55(t,1H),7.52–7.49(m,1H),7.41(d,1H),7.25(d,1H),4.43(s,2H),4.00(d,6H),3.82(s,2H),3.57(d,7H),3.20(s,1H),2.60(d,2H),2.24(d,2H),2.07(d,2H),1.56(q,2H),1.38(t,2H).

Example 581: (S) -2- ((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one (550)

In a similar manner to that described with respect to example 578, 1- (4-amino-1-methylphenidate was replaced with (5S) -5- (aminomethyl) pyrrolidin-2-one in step (b)Preparation of (S) -2- ((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,3' -bipyridine) ketene]-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) -2, 6-diazaspiro [3.4]Octane-7-one. The product was obtained as a white solid (formate). LC/MS: m/z measured values 702,704[ M+H ]] ⁺ Retention time = 1.98min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.70(dd,1H),8.52(d,1H),8.41(s,1H),7.79(s,1H),7.76(d,1H),7.71(d,1H),7.56(t,1H),7.50(d,1H),7.45–7.39(m,1H),7.28(d,1H),4.33(d,2H),4.02(d,4H),3.99(d,3H),3.97(s,2H),3.72(s,4H),3.62(d,2H),3.12(q,2H),2.63(d,2H),2.46–2.29(m,3H),1.96–1.84(m,1H).

Example 582 1- (4- (((4- (4 '- (((1-acetylpiperidin-4-yl) amino) methyl) -2-chloro-3' -methoxy- [1,1 '-biphenyl ] -3-yl) -3-chloro-5' -methoxy- [2,3 '-bipyridin ] -6' -yl) methyl) amino) piperidin-1-yl) ethan-1-one (500)

(a) 4- (3-bromo-2-chlorophenyl) -3-chloro-5 ' -methoxy- [2,3' -bipyridine ] -6' -carbaldehyde

Tetrakis (triphenylphosphine) palladium (0) (103 mg,0.09 mmol), potassium carbonate (184 mg,1.33 mmol), 4- (3-bromo-2-chloro-phenyl) -2, 3-dichloro-pyridine (150 mg,0.44 mmol), and 3-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine-2-carbaldehyde (140 mg,0.53 mmol) were suspended in 1, 4-dioxane/water (4:1, 5 ml), and the solution was then heated at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×5 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (5-100% EtOAc/hexanes) to afford 4- (3-bromo-2-chlorophenyl) -3-chloro-5 '-methoxy- [2,3' -bipyridine as a yellow oil ]-6' -formaldehyde (62 mg,32% yield). MS: m/z found 438,440[ M+H ]] ⁺ .

(b) 3-chloro-4- (2-chloro-4 '-formyl-3' -methoxy- [1,1 '-biphenyl ] -3-yl) -5' -methoxy- [2,3 '-bipyridine ] -6' -carbaldehyde

Tetrakis (triphenylphosphine) palladium (0) (33 mg,0.03 mmol), potassium carbonate (59 mg,0.42 mmol), 4- (3-bromo-2-chlorophenyl) -3-chloro-5 '-methoxy- [2,3' -bipyridine]-6' -Formaldehyde (62 mg,0.14 mmol) and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (48 mg,0.18 mmol) were suspended in 1, 4-dioxane/water (4:1, 2 ml) and the solution was then heated at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×5 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (10-100% etoac/hexanes) to afford 3-chloro-4- (2-chloro-4 ' -formyl-3 ' -methoxy- [1,1' -biphenyl) as a yellow foam]-3-yl) -5 '-methoxy- [2,3' -bipyridine]-6' -formaldehyde (40 mg,57% yield). MS: m/z found 493,495M+H] ⁺ 。

(c) 1- (4- (((4- (4 '- (((1-acetylpiperidin-4-yl) amino) methyl) -2-chloro-3' -methoxy- [1,1 '-biphenyl ] -3-yl) -3-chloro-5' -methoxy- [2,3 '-bipyridin ] -6' -yl) methyl) amino) piperidin-1-yl) ethan-1-one

3-chloro-4- (2-chloro-4 ' -formyl-3 ' -methoxy- [1,1' -biphenyl)]-3-yl) -5 '-methoxy- [2,3' -bipyridine]-6' -Formaldehyde (20 mg,0.04 mmol), acetic acid (5 mg,0.08 mmol) and 1- (4-amino-1-piperidinyl) ethanone (17 mg,0.12 mmol) were dissolved in MeOH/THF (1:1, 1 mL) and the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (8 mg,0.12 mmol) was added and the resulting mixture was stirred at 25 ℃ for 1 hour. The reaction was filtered through CELITE and the filtrate was concentrated under reduced pressure. The crude sample was purified by reverse phase HPLC to afford 1- (4- (((4- (4 ' - ((1-acetylpiperidin-4-yl) amino) methyl) -2-chloro-3 ' -methoxy- [1,1' -bi-linkage) as a white solid (formate salt)Phenyl group]-3-yl) -3-chloro-5 '-methoxy- [2,3' -bipyridine]-6' -yl) methyl) amino) piperidin-1-yl) ethan-1-one (13 mg,43% yield). LC/MS: m/z found 745,747[ M+H ]] ⁺ Retention time = 2.09min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.69(d,1H),8.53(s,1H),8.47(d,1H),7.75(s,1H),7.53(d,2H),7.48(d,1H),7.45–7.38(m,2H),7.12(s,1H),7.07(d,1H),4.55(t,2H),4.17(s,2H),4.09(s,2H),3.98(t,5H),3.93(d,3H),3.21–2.99(m,4H),2.69(t,2H),2.11(d,10H),1.58–1.30(m,4H).

Example 583:2- ((3-chloro-4- (2-chloro-3 '-methoxy-4' - ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) - [1,1 '-biphenyl ] -3-yl) -5' -methoxy- [2,3 '-bipyridine ] -6' -yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one (501)

In a similar manner to that described for example 582, the intermediate 3-chloro-4- (2-chloro-4 ' -formyl-3 ' -methoxy- [1,1' -biphenyl) was utilized in step (c) ]-3-yl) -5 '-methoxy- [2,3' -bipyridine]-6' -Formaldehyde in combination with 2, 6-diazaspiro [3.4 ]]Preparation of 2- ((3-chloro-4- (2-chloro-3 '-methoxy-4' - ((7-oxo-2, 6-diazaspiro [3.4 ]) by substituting 1- (4-amino-1-piperidinyl) ethanone with octan-7-one]Octane-2-yl) methyl) - [1,1' -biphenyl]-3-yl) -5 '-methoxy- [2,3' -bipyridine]-6' -yl) methyl) -2, 6-diazaspiro [3.4]Octane-7-one. The product was obtained as a white solid (formate). LC/MS: m/z found 713,715[ M+H ]] ⁺ Retention time = 2.02min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.68(d,1H),8.52(s,1H),8.46–8.40(m,1H),7.73(s,1H),7.56–7.49(m,2H),7.47(dd,1H),7.40–7.33(m,2H),7.06(s,1H),7.03(d,1H),4.07(s,2H),3.95(d,3H),3.88(d,5H),3.68(s,4H),3.60(d,8H),2.63–2.57(m,4H).

Example 584:1- (4- (((5- (3- (6 ' - (((1-acetylpiperidin-4-yl) amino) methyl) -3-chloro-5 ' -methoxy- [2,3' -bipyridin ] -4-yl) -2-chlorophenyl) -3-methoxypyridin-2-yl) methyl) amino) piperidin-1-yl) ethan-1-one (567)

(a) 3-chloro-4- (2-chloro-3- (6-formyl-5-methoxypyridin-3-yl) phenyl) -5' -methoxy- [2,3' -bipyridine ] -6' -carbaldehyde

3-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine-2-carbaldehyde (156 mg,0.59 mmol), tetrakis (triphenylphosphine) palladium (0) (55 mg,0.05 mmol), potassium carbonate (98 mg,0.71 mmol), and 4- (3-bromo-2-chloro-phenyl) -2, 3-dichloro-pyridine (80 mg,0.24 mmol) were suspended in 1, 4-dioxane/water (4:1, 4 ml), and the solution was then heated at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×5 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (10-80% EtOAc/hexanes) to afford 3-chloro-4- (2-chloro-3- (6-formyl-5-methoxypyridin-3-yl) phenyl) -5 '-methoxy- [2,3' -bipyridine as a brown oil ]-6' -formaldehyde (96 mg,82% yield). MS: m/z found 494,496[ M+H ]] ⁺ .

(b) 1- (4- (((5- (3- (6 ' - ((1-acetylpiperidin-4-yl) amino) methyl) -3-chloro-5 ' -methoxy- [2,3' -bipyridin ] -4-yl) -2-chlorophenyl) -3-methoxypyridin-2-yl) methyl) amino) piperidin-1-yl) ethan-1-one

3-chloro-4- (2-chloro-3- (6-formyl-5-methoxypyridin-3-yl) phenyl) -5 '-methoxy- [2,3' -bipyridine]-6' -Formaldehyde (33 mg,0.07 mmol), acetic acid (8 mg,0.13 mmol), and 1- (4-amino-1-piperidinyl) ethanone (29 mg,0.20 mmol) were dissolved in MeOH/THF (1:1, 1 mL), and the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (13 mg,0.20 mmol) was added and the resulting mixture was stirred at 25℃for 1 hour. The reaction was filtered through CELITE and the filtrate was concentrated under reduced pressure. Purification of crude material by reverse phase HPLCThe sample was taken to provide 1- (4- (((5- (3- (6 ' - ((1-acetylpiperidin-4-yl) amino) methyl) -3-chloro-5 ' -methoxy- [2,3' -bipyridine) as a white solid (formate salt)]-4-yl) -2-chlorophenyl) -3-methoxypyridin-2-yl-methyl) amino) piperidin-1-yl-ethan-1-one (16 mg,32% yield). MS: m/z found 746,748[ M+H ]] ⁺ Retention time = 2.03min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.72(d,1H),8.53(s,1H),8.44(s,2H),8.29(s,1H),7.81(s,1H),7.61(d,3H),7.53–7.45(m,2H),4.65(d,2H),4.43(d,4H),4.07(d,2H),3.99(dd,6H),3.46(d,2H),3.20(t,2H),2.69(t,2H),2.23(t,4H),2.13(d,6H),1.73–1.45(m,4H).

Example 585:2- ((3-chloro-4- (2-chloro-3- (5-methoxy-6- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-3-yl) phenyl) -5' -methoxy- [2,3' -bipyridin ] -6' -yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one (569)

In a similar manner to that described for example 584, the intermediate 3-chloro-4- (2-chloro-3- (6-formyl-5-methoxypyridin-3-yl) phenyl) -5 '-methoxy- [2,3' -bipyridine was utilized in step (b)]-6' -Formaldehyde with 2, 6-diazaspiro [3.4 ]]Preparation of 2- ((3-chloro-4- (2-chloro-3- (5-methoxy-6- ((7-oxo-2, 6-diazaspiro [3.4 ]) by substituting 1- (4-amino-1-piperidinyl) ethanone with octan-7-one]Octane-2-yl) methyl) pyridin-3-yl) phenyl) -5 '-methoxy- [2,3' -bipyridine]-6' -yl) methyl) -2, 6-diazaspiro [3.4]Octane-7-one. The product was obtained as a white solid (formate). LC/MS: m/z measured values 714,716[ M+H ]] ⁺ Retention time = 1.94min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.71(d,1H),8.49(s,1H),8.40(s,2H),8.24(d,1H),7.79(s,1H),7.59(dd,3H),7.52–7.44(m,2H),4.53(d,4H),4.21(d,8H),3.97(dd,6H),3.70(s,4H),2.74(d,4H).

Example 586: n- ((5- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -3-methoxypyridin-2-yl) methyl) tetrahydro-2H-pyran-4-amine (570)

In a similar manner to that described for example 584, the intermediate 3-chloro-4- (2-chloro-3- (6-formyl-5-methoxypyridin-3-yl) phenyl) -5 '-methoxy- [2,3' -bipyridine was utilized in step (b)]-6 '-Formaldehyde and substitution of tetrahydropyran-4-amine for 1- (4-amino-1-piperidinyl) ketene to prepare N- ((5- (2-chloro-3- (3-chloro-5' -methoxy-6 '- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,3' -bipyridine) ]-4-yl) phenyl) -3-methoxypyridin-2-yl) methyl) tetrahydro-2H-pyran-4-amine. The product was obtained as a white solid (formate). LC/MS: m/z found 664,666[ M+H ]] ⁺ Retention time = 2.07min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.73–8.69(m,1H),8.53–8.49(m,2H),8.28(d,1H),7.80(s,1H),7.63–7.56(m,3H),7.49(m,2H),4.40–4.31(m,4H),4.07–4.01(m,4H),3.99(dd,6H),3.45(t,4H),3.34(s,2H),2.14–2.04(m,4H),1.79–1.63(m,4H).

Example 587:1- (4- (((6- (3- (5 ' - (((1-acetylpiperidin-4-yl) amino) methyl) -3-chloro-6 ' -methoxy- [2,2' -bipyridin ] -4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (627)

(a) 3' -chloro-4 ' - (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,2' -bipyridine ] -5-carbaldehyde

Tetrakis (triphenylphosphine) palladium (0) (117 mg,0.10 mmol), potassium carbonate (210 mg,1.52 mmol), 6- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl]-2-methoxy-pyridine-3-carbaldehyde (200 mg,0.51 mmol), and 2-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine-3-carbaldehyde (201 mg,0.76 mmol) were suspended in 1, 4-dioxane/water (4:1, 10 m)L), the solution was then heated at 105 ℃ for 20 minutes. The reaction was cooled to room temperature, diluted with 20mL of water, and extracted with EtOAc (3×10 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (0-50% EtOAc/hexanes) to provide 3' -chloro-4 ' - (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,2' -bipyridine as a yellow foam ]-5-Formaldehyde (170 mg,68% yield). MS: m/z found 494,496[ M+H ]] ⁺ .

(b) 1- (4- (((6- (3- (5 ' - ((1-acetylpiperidin-4-yl) amino) methyl) -3-chloro-6 ' -methoxy- [2,2' -bipyridin ] -4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

3' -chloro-4 ' - (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,2' -bipyridine]5-Formaldehyde (20 mg,0.04 mmol), acetic acid (5 mg,0.08 mmol), and 1- (4-amino-1-piperidinyl) ethanone (17 mg,0.12 mmol) were dissolved in MeOH/THF (1:1, 1 mL), and the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (8 mg,0.12 mmol) was added and the resulting mixture was stirred at 25 ℃ for 1 hour. The reaction was filtered through CELITE and the filtrate was concentrated under reduced pressure. The crude sample was purified by reverse phase HPLC to afford 1- (4- (((6- (3- (5 ' - (((1-acetylpiperidin-4-yl) amino) methyl)) methyl) -3-chloro-6 ' -methoxy- [2,2' -bipyridine) as a white solid (formate salt)]-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl-methyl) -amino) -piperidin-1-yl-ethane-1-one (21 mg,71% yield). LC/MS: m/z found 746,748[ M+H ]] ⁺ Retention time = 2.19min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.66(d,1H),8.46(s,2H),7.92(d,1H),7.86(d,1H),7.71(dd,1H),7.57(t,1H),7.50(d,1H),7.46–7.39(m,2H),7.33(d,1H),4.61(d,2H),4.18(d,4H),4.06(d,8H),3.19(t,4H),2.70(t,2H),2.20(d,4H),2.12(s,6H),1.64–1.38(m,4H).

Example 588:2- ((3 ' -chloro-4 ' - (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) pyridin-2-yl) phenyl) -6-methoxy- [2,2' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one (628)

In a similar manner to that described for example 587, the intermediate 3' -chloro-4 ' - (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,2' -bipyridine was utilized in step (b)]-5-Formaldehyde in combination with 2, 6-diazaspiro [3.4 ]]Preparation of 2- ((3 '-chloro-4' - (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4 ]) by substituting 1- (4-amino-1-piperidinyl) ethanone with octan-7-one]Octane-2-yl) methyl) pyridin-2-yl) phenyl) -6-methoxy- [2,2' -bipyridine]-5-yl) methyl) -2, 6-diazaspiro [3.4]Octane-7-one. The product was obtained as a white solid (formate). LC/MS: m/z measured values 714,716[ M+H ]] ⁺ Retention time = 2.02min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.66–8.62(m,1H),8.35(s,2H),7.86(d,1H),7.81–7.76(m,1H),7.70(d,1H),7.56(t,1H),7.49(d,1H),7.41(t,2H),7.33–7.28(m,1H),4.09(s,4H),4.03(s,6H),3.85(d,8H),3.63(d,4H),2.65(s,4H).

Example 589: n- ((6- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,2' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine (629)

In a similar manner to that described for example 587, the intermediate 3' -chloro-4 ' - (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,2' -bipyridine was utilized in step (b)]-5-Formaldehyde and substitution of tetrahydropyran-4-amine for 1- (4-amino-1-piperidinyl) ethanone to prepare N- ((6- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,2' -bipyridine) ]-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine. The product was obtained as a white solid (formate). LC/MS: m/z found 664,666[ M+H ]] ⁺ Retention time=217min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.66(dd,1H),8.50(s,1H),7.92(d,1H),7.86(d,1H),7.72(d,1H),7.57(t,1H),7.54–7.49(m,1H),7.48–7.41(m,2H),7.33(d,1H),4.22–4.13(m,4H),4.07(d,8H),4.02(s,2H),3.45(t,4H),2.07(d,4H),1.75–1.56(m,4H).

Example 590: (S) -5- (((6- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,2' -bipyridyl ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one (630)

In a similar manner to that described for example 587, the intermediate 3' -chloro-4 ' - (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,2' -bipyridine was utilized in step (b)]-5-Formaldehyde, (S) -5- ((((6- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,2' -bipyridine) was prepared by substituting (5S) -5- (aminomethyl) pyrrolidin-2-one for 1- (4-amino-1-piperidinyl) ethanone]-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one. LC/MS: m/z observed 690,692[ M+H ]] ⁺ Retention time = 2.07min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.65(d,1H),8.33(s,2H),7.89(d,1H),7.82(d,1H),7.71(d,1H),7.56(t,1H),7.50(d,1H),7.42(t,2H),7.31(d,1H),4.09(s,4H),4.07–4.04(m,6H),3.95(s,2H),2.97(q,4H),2.42–2.26(m,6H),1.93–1.78(m,2H).

Example 591:1- (4- (((6- (3- (5- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -4-chloropyridin-3-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (641)

(a) 6- (2-chloro-3- (4-chloro-5- (4-formyl-3-methoxyphenyl) pyridin-3-yl) phenyl) -2-methoxy nicotinaldehyde

Tetrakis (triphenylphosphine) palladium (0) (47 mg,0.04 mmol), potassium carbonate (85 mg,0.62 mmol), 6- [3- (5-bromo-4-chloro-3-pyridinyl) -2-chloro-phenyl]-2-methoxy-pyridine-3-carbaldehyde (90 mg,0.21 mmol) and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (81 mg,0.31 mmol) were suspended in 1, 4-dioxane/water (4:1, 3 ml) and the solution was then heated at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×5 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (0-50% EtOAc/hexanes) to afford 6- (2-chloro-3- (4-chloro-5- (4-formyl-3-methoxyphenyl) pyridin-3-yl) phenyl) -2-methoxy nicotinaldehyde (23 mg,23% yield) as a yellow foam. MS: m/z found 493,495[ M+H ]] ⁺ .

(b) 1- (4- (((6- (3- (5- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -4-chloropyridin-3-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

6- (2-chloro-3- (4-chloro-5- (4-formyl-3-methoxyphenyl) pyridin-3-yl) phenyl) -2-methoxynicotinaldehyde (11 mg,0.02 mmol), acetic acid (3 mg,0.04 mmol), and 1- (4-amino-1-piperidinyl) ethanone (10 mg,0.07 mmol) were dissolved in MeOH/THF (1:1, 1 mL) and the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (4 mg,0.07 mmol) was added and the resulting mixture was stirred at 25 ℃ for 1 hour. The reaction was filtered through CELITE and the filtrate was concentrated under reduced pressure. The crude sample was purified by reverse phase HPLC to provide 1- (4- (((6- (3- (5- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -4-chloropyridin-3-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (3 mg,17% yield) as a white solid (formate salt). LC/MS: m/z found 745,747[ [ M+H] ⁺ Retention time = 2.12min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.59(s,1H),8.51(d,1H),8.49(s,2H),7.84(d,1H),7.72(d,1H),7.60–7.51(m,2H),7.47(d,1H),7.32(d,1H),7.25(s,1H),7.18(d,1H),4.61(t,2H),4.26(s,2H),4.12(s,2H),4.06(d,4H),3.98(s,4H),3.19(t,4H),2.70(t,2H),2.28–2.06(m,10H),1.66–1.33(m,4H).

Example 592:2- (4- (4-chloro-5- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-3-yl) -2, 6-diazaspiro [3.4] octane-7-one (642)

In a similar manner to that described for example 591, the intermediate 6- (2-chloro-3- (4-chloro-5- (4-formyl-3-methoxyphenyl) pyridin-3-yl) phenyl) -2-methoxy nicotinaldehyde was used in step (b) and 2, 6-diazaspiro- [3.4]Preparation of 2- (4- (4-chloro-5- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4 ]) using octan-7-one instead of 1- (4-amino-1-piperidinyl) ketene]Octan-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-3-yl) -2-methoxybenzyl-2, 6-diazaspiro [3.4]Octane-7-one. The product was obtained as a white solid (formate). LC/MS: m/z found 713,715[ M+H ]] ⁺ Retention time = 2.00min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.58(s,1H),8.51(s,1H),8.38(s,2H),7.81–7.75(m,1H),7.71(d,1H),7.56(t,1H),7.51(d,1H),7.46(d,1H),7.30(d,1H),7.23(s,1H),7.17(d,1H),4.32(s,2H),4.08(s,3H),4.05(s,2H),4.03(d,3H),3.96(s,4H),3.82(s,4H),3.66(s,2H),3.63(s,2H),2.69(s,2H),2.65(s,2H).

Example 593:1- (4- (((6- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -4' -chloro-6-methoxy- [2,3' -bipyridin ] -5' -yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (639)

(a) 6- (3- (5-bromo-4-chloropyridin-3-yl) -2-chlorophenyl) -2-methoxy nicotinaldehyde

3, 5-dibromo-4-chloro-pyridine (203 mg,0.75 mmol), tetrakis (triphenylphosphine) palladium (0) (124 mg,0.11 mmol), potassium carbonate (222 mg,1.61 mmol), and 6- [ 2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl]-2-methoxy-pyridine-3-carbaldehyde (200 mg,0.54 mmol) was suspended in 1, 4-dioxane/water (4:1, 10 ml) and the solution was then heated at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×10 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (10-60% EtOAc/hexanes) to afford 6- (3- (5-bromo-4-chloropyridin-3-yl) -2-chlorophenyl) -2-methoxy nicotinaldehyde as a yellow foam (184 mg,79% yield). MS: m/z found 438,440[ M+H ]] ⁺ .

(b) 4' -chloro-5 ' - (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,3' -bipyridine ] -5-carbaldehyde

Tetrakis (triphenylphosphine) palladium (0) (47 mg,0.04 mmol), potassium carbonate (85 mg,0.62 mmol), 6- (3- (5-bromo-4-chloropyridin-3-yl) -2-chlorophenyl) -2-methoxynicotinaldehyde (90 mg,0.21 mmol), and 2-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine-3-carbaldehyde (81 mg,0.31 mmol) were suspended in 1, 4-dioxane/water (4:1, 4 ml), and the solution was heated at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×5 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (0-50% etoac/hexanes) to afford 4' -chloro-5 ' - (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,3' -bipyridine as a yellow solid ]-5-Formaldehyde (30 mg,29% yield). MS: m/z found 494,496M+H] ⁺ .

(c) 1- (4- (((6- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -4' -chloro-6-methoxy- [2,3' -bipyridin ] -5' -yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

4' -chloro-5 ' - (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,3' -bipyridine]5-Formaldehyde (15 mg,0.03 mmol), acetic acid (4 mg,0.06 mmol), and 1- (4-amino-1-piperidinyl) ethanone (13 mg,0.09 mmol) were dissolved in MeOH/THF (1:1, 1 mL), and the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (6 mg,0.09 mmol) was added and the resulting mixture was stirred at 25 ℃ for 1 hour. The reaction was filtered through CELITE and the filtrate was concentrated under reduced pressure. The crude sample was purified by reverse phase HPLC to afford 1- (4- (((6- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -4 '-chloro-6-methoxy- [2,3' -bipyridine) as a white solid (formate salt)]-5' -yl) -2-chlorophenyl) -2-methoxypyridin-3-yl-methyl) -amino) -piperidin-1-yl-ethane-1-one (7 mg,29% yield). LC/MS: m/z found 746,748[ M+H ]] ⁺ Retention time = 2.07min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.79(s,1H),8.52(s,1H),8.49(d,1H),7.86(dd,2H),7.72(d,1H),7.57(t,1H),7.48(d,1H),7.42(d,1H),7.32(d,1H),4.58(s,2H),4.11(s,2H),4.09–4.05(m,8H),4.01(d,2H),3.18(t,4H),2.70(t,2H),2.12(s,10H),1.46(m,4H).

Example 594:2- ((4 ' -chloro-5 ' - (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) -6-methoxy- [2,3' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one (640)

In a similar manner to that described for example 593, the intermediate 4 '-chloro-5' - (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) -6-methoxy was utilized in step (c)- [2,3' -bipyridyl]-5-Formaldehyde in combination with 2, 6-diazaspiro- [3.4]Preparation of 2- ((4 '-chloro-5' - (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4 ]) by substituting 1- (4-amino-1-piperidinyl) ketene with octan-7-one]Octane-2-yl) methyl) pyridin-2-yl) phenyl) -6-methoxy- [2,3' -bipyridine]-5-yl) methyl) -2, 6-diazaspiro [3.4]Octane-7-one. The product was obtained as a white solid (formate). LC/MS: m/z measured values 714,716[ M+H ]] ⁺ Retention time = 1.98min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.78(s,1H),8.51(s,1H),8.38(s,2H),7.81(dd,2H),7.72(d,1H),7.56(t,1H),7.47(d,1H),7.41(d,1H),7.31(d,1H),4.09(s,2H),4.06–4.00(m,8H),3.86(s,4H),3.77(s,4H),3.63(t,4H),2.65(d,4H).

Example 595:1- (4- (((6- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (572)

(a) 3' -chloro-2 ' - (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridine ] -5-carbaldehyde

6- (2, 3-dichloro-4-pyridinyl) -2-methoxy-pyridine-3-carbaldehyde (80 mg,0.28 mmol), tetrakis (triphenylphosphine) palladium (0) (65 mg,0.06 mmol), potassium carbonate (117 mg,0.85 mmol), and 6- [ 2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl ]-2-methoxy-pyridine-3-carbaldehyde (106 mg,0.28 mmol) was suspended in 1, 4-dioxane/water (4:1, 3 ml) and the solution was then heated at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×5 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (10-60% EtOAc/hexanes) to provide 3 '-chloro-2' - (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) -6-methoxy-[2,4' -bipyridine]-5-Formaldehyde (138 mg,99% yield). MS: m/z found 494,496[ M+H ]] ⁺ .

(b) 1- (4- (((6- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

3' -chloro-2 ' - (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridine]5-Formaldehyde (34 mg,0.07 mmol), acetic acid (8.26 mg,0.14 mmol), and 1- (4-amino-1-piperidinyl) ethanone (29 mg,0.21 mmol) were dissolved in MeOH/THF (1:1, 1 mL), and the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (13 mg,0.21 mmol) was added and the resulting mixture was stirred at 25℃for 1 hour. The reaction was filtered through CELITE and the filtrate was concentrated under reduced pressure. The crude sample was purified by reverse phase HPLC to afford 1- (4- (((6- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3 '-chloro-6-methoxy- [2,4' -bipyridine) as a white solid (formate salt) ]-2' -yl) -2-chlorophenyl) -2-methoxypyridin-3-yl-methyl) amino) piperidin-1-yl-ethan-1-one (23 mg,45% yield). LC/MS: m/z found 746,748[ M+H ]] ⁺ Retention time = 2.10min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.69–8.62(m,1H),8.41(s,2H),7.92(d,1H),7.87(d,1H),7.79–7.70(m,2H),7.58(t,1H),7.49(dd,2H),7.35(d,1H),4.63(t,2H),4.22(d,4H),4.08(dd,6H),3.37(s,2H),3.20(t,2H),2.70(t,2H),2.22(t,4H),2.12(d,6H),1.66–1.39(m,4H).

Example 596:2- ((3 ' -chloro-2 ' - (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one (573)

To be similar to that described with respect to instance 595In a similar manner, the intermediate 3' -chloro-2 ' - (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridine is utilized in step (b)]-5-Formaldehyde with 2, 6-diazaspiro [3.4]]Preparation of 2- ((3 '-chloro-2' - (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4 ]) by substituting 1- (4-amino-1-piperidinyl) ethanone with octan-7-one]Octane-2-yl) methyl) pyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridine]-5-yl) methyl) -2, 6-diazaspiro [3.4]Octane-7-one. The product was obtained as a white solid (formate). LC/MS: m/z measured values 714,716[ M+H ]] ⁺ Retention time = 1.97min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.68–8.58(m,1H),8.27(s,1H),7.89–7.81(m,2H),7.78–7.70(m,2H),7.57(dd,1H),7.52–7.44(m,2H),7.35(dd,1H),4.27(s,2H),4.16(d,2H),4.07(q,10H),3.93(s,4H),3.68–3.63(m,4H),2.71–2.66(m,4H).

Example 597: n- ((3 ' -chloro-2 ' - (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) tetrahydro-2H-pyran-4-amine (574)

In a similar manner to that described for example 595, the intermediate 3' -chloro-2 ' - (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridine was utilized in step (b)]-5-Formaldehyde and substitution of tetrahydropyran-4-amine for 1- (4-amino-1-piperidinyl) ethanone to prepare N- ((3 ' -chloro-2 ' - (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridine]-5-yl) methyl) tetrahydro-2H-pyran-4-amine. The product was obtained as a white solid (formate). LC/MS: m/z found 664,666[ M+H ]] ⁺ Retention time = 2.16min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.68–8.60(m,1H),8.48(d,2H),7.91(d,1H),7.86(d,1H),7.75(dd,2H),7.58(t,1H),7.49(dd,2H),7.35(d,1H),4.23–4.18(m,2H),4.16(d,2H),4.08(dd,6H),4.07–3.98(m,4H),3.45(t,4H),3.23(s,1H),2.05(q,4H),1.66(t,4H).

Example 598: (S) -5- ((((3 ' -chloro-2 ' - (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one (575)

In a similar manner to that described for example 595, the intermediate 3' -chloro-2 ' - (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridine was utilized in step (b)]-5-Formaldehyde and (5S) -5- (aminomethyl) pyrrolidin-2-one instead of 1- (4-amino-1-piperidinyl) ethanone to prepare (S) -5- (((3 ' -chloro-2 ' - (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridine ]-5-yl) methyl) amino) methyl) pyrrolidin-2-one. The product was obtained as a white solid (formate). LC/MS: m/z observed 690,692[ M+H ]] ⁺ Retention time = 2.00min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.67–8.62(m,1H),8.32(s,2H),7.87(d,1H),7.82(d,1H),7.77(dd,1H),7.73(d,1H),7.57(dd,1H),7.47(dd,2H),7.36–7.31(m,1H),4.11(d,2H),4.06(m,6H),4.04(s,2H),3.98–3.89(m,2H),2.96(m,4H),2.40–2.30(m,6H),1.87(d,2H).

Example 599:2- ((2 ' - (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one (680)

(a) 2- ((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one

The reaction mixture of 6- (2),3-dichloro-4-pyridinyl) -2-methoxy-pyridine-3-carbaldehyde (250 mg,0.88 mmol), acetic acid (53 mg,0.88 mmol), and 2, 6-diazaspiro [3.4]]Octan-7-one (145 mg,1.15 mmol) was dissolved in MeOH/THF (1:1, 5 mL) and the solution was stirred at 25℃for 2 h. Sodium cyanoborohydride (166 mg,2.65 mmol) was added in portions and the resulting mixture was stirred at 25 ℃ for 1 hour. The reaction was filtered through CELITE and the filtrate was concentrated under reduced pressure. The crude sample was purified by silica gel chromatography (0-10% DCM/MeOH) to provide 2- ((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridine) as a white foam]-5-yl) methyl) -2, 6-diazaspiro [3.4]Octan-7-one (200 mg,58% yield). MS: m/z found 393,395[ M+H ] ] ⁺ .

(b) 6- (2-chloro-3- (3 ' -chloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) - [2,4' -bipyridyl ] -2' -yl) phenyl) -2-methoxy nicotinaldehyde

2- ((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridine)]-5-yl) methyl) -2, 6-diazaspiro [3.4]Octan-7-one (200 mg,0.51 mmol), tetrakis (triphenylphosphine) palladium (0) (117 mg,0.10 mmol), potassium carbonate (211 mg,1.53 mmol), and 6- [ 2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl]-2-methoxy-pyridine-3-carbaldehyde (190 mg,0.51 mmol) was suspended in 1, 4-dioxane/water (4:1, 6 ml) and the solution was then heated at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 10mL of water, and extracted with DCM (3×10 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (0-10% MeOH/DCM) to provide 6- (2-chloro-3- (3' -chloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [ 3.4) as a yellow foam]Octane-2-yl) methyl) - [2,4' -bipyridine]-2' -yl) phenyl) -2-methoxy nicotinaldehyde (158 mg,51% yield). MS: m/z found 604,606[ M+H ]] ⁺ .

(c) 2- ((2 ' - (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one

6- (2-chloro-3- (3' -chloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [ 3.4)]Octane-2-yl) methyl) - [2,4' -bipyridine]-2' -yl) phenyl) -2-methoxynicotinaldehyde (20 mg,0.03 mmol), acetic acid (2 mg,0.03 mmol), and 1- (4-amino-1-piperidinyl) ethanone (7 mg,0.05 mmol) were dissolved in MeOH/THF (1:1, 1 mL), and the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (4 mg,0.07 mmol) was added and the resulting mixture was stirred at 25 ℃ for 1 hour. The reaction was filtered through CELITE and the filtrate was concentrated under reduced pressure. The crude sample was purified by reverse phase HPLC to provide 2- ((2 ' - (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3' -chloro-6-methoxy- [2,4' -bipyridine) as a white solid (formate salt)]-5-yl) methyl) -2, 6-diazaspiro [3.4]Octan-7-one (9 mg,39% yield). LC/MS: m/z actual measurement 730,732[ M+H ]] ⁺ Retention time = 1.99min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.66–8.61(m,1H),8.46(s,1H),7.86(d,1H),7.77(d,2H),7.73(d,1H),7.57(dd,1H),7.50(d,1H),7.42(d,1H),7.35(d,1H),4.63(d,1H),4.20(s,2H),4.07(d,3H),4.02(d,4H),3.81(s,2H),3.60(d,2H),3.53(s,4H),3.20(t,2H),2.70(t,1H),2.60(s,2H),2.19(t,2H),2.13(d,3H),1.64–1.41(m,2H).

Example 600:2- ((3 ' -chloro-2 ' - (2-chloro-3- (5- ((4-hydroxypiperidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one (681)

In a similar manner to that described with respect to example 599, intermediate 6- (2-chloro-3- (3' -chloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [ 3.4) was utilized in step (c) ]Octane-2-yl) methyl) - [2,4' -bipyridine]-2' -yl) phenyl) -2-methoxynicotinaldehyde and substituted 1- (4-amino-1-piperidinyl) ethanone with piperidin-4-ol to prepare 2- ((3 ' -chloro-2 ' - (2-chloro-3- (5- ((4-hydroxypiperidine)Pyridin-1-yl) methyl) -6-methoxypyridin-2-yl phenyl) -6-methoxy- [2,4' -bipyridin]-5-yl) methyl) -2, 6-diazaspiro [3.4]Octane-7-one. The product was obtained as a white solid (formate). LC/MS: m/z found 689,691[ M+H ]] ⁺ Retention time = 1.97min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.63(d,1H),8.48(s,1H),7.87(d,1H),7.81–7.71(m,3H),7.57(t,1H),7.50(d,1H),7.42(d,1H),7.37(d,1H),4.12(s,2H),4.04(d,6H),3.83(s,3H),3.57(d,6H),2.95(s,2H),2.60(s,2H),1.99(s,2H),1.77(s,2H).

Example 601:2- ((6- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridyl ] -2' -yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one (682)

(a) 1- (4- (((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) piperidin-1-yl) ethan-1-one

6- (2, 3-dichloro-4-pyridinyl) -2-methoxy-pyridine-3-carbaldehyde (177 mg,0.63 mmol), acetic acid (38 mg,0.63 mmol), and 1- (4-amino-1-piperidinyl) ethanone (125 mg,0.88 mmol) were dissolved in MeOH/THF (1:1, 5 mL), and the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (79 mg,1.25 mmol) was added portionwise and the resulting mixture was stirred at 25 ℃ for 1 hour. The reaction was filtered through CELITE and the filtrate was concentrated under reduced pressure. The oily residue was dissolved in 10mL of water and extracted with DCM (3×5 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 1- (4- (((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridine) as a yellow oil ]-5-yl-methyl) amino) piperidin-1-yl) ethan-1-one (255 mg, crude). MS: m/z found 409,411[ M+H ]] ⁺ . The material was used in the next step without further purification.

(b) (1-Acetylpiperidin-4-yl) ((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) carbamic acid tert-butyl ester

1- (4- (((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridine)]-5-yl) methyl) amino) piperidin-1-yl) ethan-1-one (255 mg,0.63mmol, crude), DMAP (15 mg,0.13 mmol), and N, N-diisopropylethylamine (161 mg,1.25 mmol) were dissolved in 8mL THF, then di-tert-butyl dicarbonate (191 mg,0.88 mmol) was added in portions. The resulting mixture was stirred at room temperature for 18 hours. The reaction was diluted with water (15 mL) and the solution extracted with EtOAc (3X 10 mL). Concentrating the combined organics under reduced pressure and passing through normal phase SiO ₂ Purification of the crude sample by chromatography (0-100% EtOAc/hexanes) provided (1-acetylpiperidin-4-yl) ((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridine) as a white foam]-5-yl) methyl-carbamic acid tert-butyl ester (198mg, 62% yield). MS: m/z found 509,511[ M+H ]] ⁺ .

(c) (1-Acetylpiperidin-4-yl) ((3 ' -chloro-2 ' - (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) carbamic acid tert-butyl ester

(1-Acetylpiperidin-4-yl) ((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridine)]-5-yl) methyl-carbamic acid tert-butyl ester (100 mg,0.20 mmol), tetrakis (triphenylphosphine) palladium (0) (45 mg,0.04 mmol), potassium carbonate (81 mg,0.59 mmol), and 6- [ 2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl ]]-2-methoxy-pyridine-3-carbaldehyde (73 mg,0.20 mmol) was suspended in 1, 4-dioxane/water (4:1, 3 ml) and the solution was then heated at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 5mL of water, and extracted with EtOAc (3×5 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (0-10% MeOH/DCM) to provide (1-acetylpiperidine) as a yellow foam-4-yl) ((3 ' -chloro-2 ' - (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridine)]-5-yl) methyl-carbamic acid tert-butyl ester (63 mg,45% yield). MS: m/z found 720,722[ M+H ]] ⁺ .

(d) (1-Acetylpiperidin-4-yl) ((3 ' -chloro-2 ' - (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) carbamic acid tert-butyl ester

(1-Acetylpiperidin-4-yl) ((3 ' -chloro-2 ' - (2-chloro-3- (5-formyl-6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridine) ]-5-yl) methyl-carbamic acid tert-butyl ester (20 mg,0.03 mmol), acetic acid (2 mg,0.03 mmol), and 2, 6-diazaspiro [3.4]]The octan-7-one (5 mg,0.04 mmol) was dissolved in MeOH/THF (1:1, 1 mL) and the solution was stirred at 25℃for 2 h. Sodium cyanoborohydride (4 mg,0.06 mmol) was added and the resulting mixture was stirred at 25 ℃ for 1 hour. The reaction was concentrated under reduced pressure and the residue was suspended in 5mL of water, then extracted with DCM (3×3 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide (1-acetylpiperidin-4-yl) as a clear oil (3 '-chloro-2' - (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4 ])]Octane-2-yl) methyl) pyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridine]-5-yl) methyl-carbamic acid tert-butyl ester (23 mg, crude). MS: m/z found 830,832[ M+H ]] ⁺ . The material was used in the next step without further purification.

(e) 2- ((6- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridyl ] -2' -yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one

Will (1-acetyl)Piperidin-4-yl) ((3 '-chloro-2' - (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4 ]) ]Octane-2-yl) methyl) pyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridine]Tert-butyl-5-yl) methyl carbamate (23 mg,0.03mmol, crude) was dissolved in 1mL DCM and 4M HCl solution in 1, 4-dioxane (28 μl,0.11 mmol) was added. The reaction was stirred at room temperature for 60 minutes and the solvent was removed under reduced pressure. The crude sample was purified by reverse phase HPLC to provide 2- ((6- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3 '-chloro-6-methoxy- [2,4' -bipyridine) as a white solid (formate salt)]-2' -yl) -2-chlorophenyl) -2-methoxypyridin-3-yl-methyl) -2, 6-diazaspiro [3.4]Octan-7-one (14 mg,67% yield). LC/MS: m/z actual measurement 730,732[ M+H ]] ⁺ Retention time = 2.0min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.65(d,1H),8.46(s,1H),7.90(d,1H),7.76(d,1H),7.72(d,2H),7.56(t,1H),7.49–7.45(m,2H),7.28(d,1H),4.59(d,1H),4.14(s,2H),4.08(d,3H),4.01(s,4H),3.87(s,2H),3.60(s,6H),3.20(d,2H),2.70(t,1H),2.61(s,2H),2.17(d,2H),2.12(s,3H),1.48(dd,2H).

Example 602:1- (4- (((6- (3- (4- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-2-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (621)

(a) 4- (2, 3-dichloropyridin-4-yl) -2-methoxybenzaldehyde

4-bromo-2-methoxy-benzaldehyde (1.10 g,5.11 mmol), tetrakis (triphenylphosphine) palladium (0) (0.30 g,0.26 mmol), potassium carbonate (1.06 g,7.67 mmol), and 2, 3-dichloro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine (0.70 g,2.56 mmol) were suspended in 1, 4-dioxane/water (4:1, 25 ml), and the solution was then heated at 105℃for 20 min. The reaction was cooled to room temperature, diluted with 40mL of water, and extracted with EtOAc (3X 30 mL) extraction. Concentrating the combined organics under reduced pressure and passing through normal phase SiO ₂ The crude sample was purified by chromatography (0-30% EtOAc/hexanes) to afford 4- (2, 3-dichloropyridin-4-yl) -2-methoxybenzaldehyde as a white solid (0.35 g,49% yield). MS: m/z found 282, 284[ M+H ]] ⁺ 。

(b) 6- (2-chloro-3- (3-chloro-4- (4-formyl-3-methoxyphenyl) pyridin-2-yl) phenyl) -2-methoxy nicotinaldehyde

4- (2, 3-dichloropyridin-4-yl) -2-methoxybenzaldehyde (150 mg,0.53 mmol), tetrakis (triphenylphosphine) palladium (0) (123 mg,0.11 mmol), potassium carbonate (220 mg,1.60 mmol), and 6- [ 2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl]-2-methoxy-pyridine-3-carbaldehyde (199mg, 0.53 mmol) was suspended in 1, 4-dioxane/water (4:1, 5 ml) and the solution was then heated at 105℃for 20 min. The reaction was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×5 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (10-60% EtOAc/hexanes) to afford 6- (2-chloro-3- (3-chloro-4- (4-formyl-3-methoxyphenyl) pyridin-2-yl) phenyl) -2-methoxy nicotinaldehyde as a yellow foam (262 mg,100% yield). MS: m/z found 493,495[ M+H ]] ⁺ .

(c) 1- (4- (((6- (3- (4- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-2-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

6- (2-chloro-3- (3-chloro-4- (4-formyl-3-methoxyphenyl) pyridin-2-yl) phenyl) -2-methoxynicotinaldehyde (20 mg,0.04 mmol), acetic acid (5 mg,0.08 mmol), and 1- (4-amino-1-piperidinyl) ethanone (17 mg,0.12 mmol) were dissolved in MeOH/THF (1:1, 1 mL) and the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (8 m)g,0.12 mmol) and the resulting mixture was stirred at 25℃for 1 hour. The reaction was filtered through CELITE and the filtrate was concentrated under reduced pressure. The crude sample was purified by reverse phase HPLC to provide 1- (4- (((6- (3- (4- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-2-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (19 mg,64% yield) as a white solid (formate salt). LC/MS: m/z found 745,747[ M+H ]] ⁺ Retention time = 2.15min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.62(d,1H),8.48(s,2H),7.86–7.79(m,1H),7.72(d,1H),7.60–7.51(m,3H),7.48(d,1H),7.32(d,1H),7.25(s,1H),7.19(d,1H),4.61(t,2H),4.24(s,2H),4.12(s,2H),4.05(d,5H),3.97(s,3H),3.19(t,4H),2.69(t,2H),2.20(t,4H),2.12(d,6H),1.69–1.30(m,4H).

Example 603:2- (4- (3-chloro-2- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-4-yl) -2, 6-diazaspiro [3.4] octane-7-one (622)

In a similar manner to that described for example 602, the intermediate 6- (2-chloro-3- (3-chloro-4- (4-formyl-3-methoxyphenyl) pyridin-2-yl) phenyl) -2-methoxy nicotinaldehyde was used in step (c) and 2, 6-diazaspiro [3.4] ]Preparation of 2- (4- (3-chloro-2- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4 ]) using octan-7-one instead of 1- (4-amino-1-piperidinyl) ethanone]Octan-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-4-yl) -2-methoxybenzyl-2, 6-diazaspiro [3.4]Octane-7-one. The product was obtained as a white solid (formate). LC/MS: m/z found 713,715[ M+H ]] ⁺ Retention time = 2.05min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.62–8.58(m,1H),8.46(s,1H),7.72(t,2H),7.55(dd,2H),7.46(d,2H),7.28(d,1H),7.20(s,1H),7.16(d,1H),4.11(s,2H),4.01(d,3H),3.93(s,3H),3.89(s,2H),3.84(s,4H),3.65–3.58(m,8H),2.64(s,2H),2.61(s,2H).

Example 604: n- (4- (3-chloro-2- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-4-yl) -2-methoxybenzyl) tetrahydro-2H-pyran-4-amine (623)

In a similar manner as described with respect to example 602, N- (4- (3-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) -2-methoxybenzyl) tetrahydro-2H-pyran-4-amine was prepared in step (c) using the intermediate 6- (2-chloro-3- (3-chloro-4- (4-formyl-3-methoxyphenyl) pyridin-2-yl) phenyl) -2-methoxy nicotinaldehyde and tetrahydropyran-4-amine instead of 1- (4-amino-1-piperidinyl) ethanone. The product was obtained as a white solid (formate). LC/MS: m/z found 663,665[ M+H ]] ⁺ Retention time = 2.2min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.61(d,1H),8.53(s,1H),7.79(d,1H),7.72(d,1H),7.56(dd,2H),7.49(dd,2H),7.29(d,1H),7.22(s,1H),7.17(d,1H),4.13(s,2H),4.03(d,3H),4.00(s,6H),3.96(d,3H),3.43(t,4H),3.16(s,1H),2.99(s,1H),2.01(t,4H),1.69–1.48(m,4H).

Example 605: (S) -5- (((4- (3-chloro-2- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) -amino) methyl) pyridin-2-yl) phenyl) pyridin-4-yl) -2-methoxybenzyl) -amino) methyl) pyrrolidin-2-one (624)

In a similar manner to that described for example 602, the intermediate 6- (2-chloro-3- (3-chloro-4- (4-formyl-3-methoxyphenyl) pyridin-2-yl) phenyl) -2-methoxynicotinaldehyde was used in step (c) and (5S) -5- (aminomethyl) -pyrrolidin-2-yl-substituted 1- (4-amino-1-piperidinyl) ethanone was used to prepare (S) -5- (((4- (3-chloro-2- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) -amino) methyl) pyridin-2-yl) phenyl) pyridin-4-yl) -2-methoxybenzyl) -amino) methyl) pyrrole in step (c)An alkan-2-one. The product was obtained as a white solid (formate). LC/MS: m/z found 689,691[ M+H ]] ⁺ Retention time = 2.07min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.62(d,1H),8.36(s,2H),7.81(d,1H),7.73(d,1H),7.60–7.46(m,4H),7.31(d,1H),7.24(s,1H),7.19(d,1H),4.27–4.14(m,2H),4.06(dd,5H),3.97(s,5H),3.06(t,2H),2.95(t,2H),2.44–2.28(m,6H),1.86(s,2H).

Example 606:1- (4- (((6- (3- (6- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -5-methylpyrimidin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (522)

(a) 4- (6-chloro-5-methylpyrimidin-4-yl) -2-methoxybenzaldehyde

By N ₂ A mixture of 4, 6-dichloro-5-methylpyrimidine (0.51 g,3.10 mmol), 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (example 77, step (a)) (0.81 g,3.10 mmol) and potassium carbonate (1.29 g,9.30 mmol) in 1, 4-dioxane (18 mL) and water (4.5 mL) was purged for 5 min. Tetrakis (triphenylphosphine) palladium (0) (110 mg,0.09 mmol) was then added and the mixture stirred in a sealed vial at 95 ℃ for 2 hours. The cooled reaction mixture was partitioned between ethyl acetate (75 mL) and water (75 mL). The organic phase was separated, washed with saturated brine (2×50 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a brown solid (1.13 g). By normal phase SiO ₂ The crude product was purified by chromatography (0 to 100% ethyl acetate in hexane) to afford 4- (6-chloro-5-methylpyrimidin-4-yl) -2-methoxybenzaldehyde (0.44 g,54.0% yield) as a pasty solid. MS: m/z found 263[ M+H ]] ⁺ Retention time = 0.87min (method B). ¹ H NMR (400 MHz, chloroform-d) δ10.53 (d, 1H), 8.90 (dd, 1H), 7.94 (dd, 1H), 7.19 (d, 1H), 7.16 (m, 1H), 4.00(s,3H),2.43(s,3H).

(b) 6- (2-chloro-3- (6- (4-formyl-3-methoxyphenyl) -5-methylpyrimidin-4-yl) phenyl) -2-methoxynicotinaldehyde

By N ₂ A mixture of 6- (2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -2-methoxynicotinaldehyde (181 mg,0.48 mmol), 4- (6-chloro-5-methylpyrimidin-4-yl) -2-methoxybenzaldehyde (127 mg,0.48 mmol) and potassium carbonate (201 mg,1.45 mmol) in 1, 4-dioxane (4 mL) and water (1 mL) was purged for 5 min. Tetrakis (triphenylphosphine) palladium (0) (17 mg,0.01 mmol) was added and the mixture stirred in a sealed vial at 95 ℃ for 2 hours. The cooled reaction mixture was then partitioned between ethyl acetate (40 mL) and water (40 mL). The organic phase was separated, washed with saturated brine (2×40 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford yellow syrup (0.371 g). By normal phase SiO ₂ The crude product was purified by chromatography (0 to 100% ethyl acetate in hexanes) to afford 6- (2-chloro-3- (6- (4-formyl-3-methoxyphenyl) -5-methylpyrimidin-4-yl) phenyl) -2-methoxynicotinaldehyde as a yellow foam (189.5 mg,82.5% yield). MS: m/z found 474[ M+H ]] ⁺ Retention time = 1.02min (method B). ¹ H NMR (400 MHz, chloroform-d) δ10.54 (d, 1H), 10.43 (d, 1H), 9.24 (d, 1H), 8.20 (dd, 1H), 7.95 (d, 1H), 7.75 (dd, 1H), 7.55 (dd, 1H), 7.45-7.42 (m, 1H), 7.40 (dd, 1H), 7.30 (d, 1H), 7.27-7.23 (m, 1H), 4.13 (s, 3H), 4.02 (s, 3H), 2.24 (s, 3H).

(c) 1- (4- (((6- (3- (6- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -5-methylpyrimidin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

At N ₂ 6- (2-chloro-3- (6- (4-formyl-3-methoxyphenyl) -5-methylpyrimidin-4-yl) phenyl) at room temperatureA mixture of 2-methoxynicotinaldehyde (50 mg,0.11 mmol), 1- (4-aminopiperidin-1-yl) ethan-1-one (45 mg,0.32 mmol) and acetic acid (13 mg,0.21 mmol) in dry tetrahydrofuran (1.5 mL) and dry methanol (1.5 mL) was stirred for 2h 20 min. Sodium cyanoborohydride (20 mg,0.32 mmol) was then added and the mixture was stirred for 2 hours. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution (5 mL) and the cloudy suspension was vigorously stirred for 15 minutes. The mixture was then partitioned between ethyl acetate (60 mL) and 1/2 saturated brine (30 mL), the organic phase was separated, washed with saturated brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a glass (glass) (62 mg). The crude product was purified by reverse phase HPLC to afford 1- (4- (((6- (3- (6- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -5-methylpyrimidin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (24.7 mg,32% yield) as a white solid (formate salt). MS: m/z found 726[ M+H ] ] ⁺ The retention time was 0.57min (method B). ¹ H NMR (400 MHz, methanol-d) ₄ )δ9.14(s,1H),7.83(d,1H),7.76(dd,1H),7.61(dd,1H),7.55(d,1H),7.50(dd,1H),7.36(d,1H),7.32(d,1H),7.28(dd,1H),4.68–4.52(m,2H),4.22(s,2H),4.07(s,2H),4.05(s,3H),4.04–4.01(m,2H),3.99(s,3H),3.29–3.04(m,4H),2.77–2.64(m,2H),2.23(s,3H),2.14–2.09(m,4H),2.13(s,3H),2.12(s,3H),1.65–1.34(m,4H).

Example 607: (S) -5- (((6- (2-chloro-3- (6- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -5-methylpyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (523)

(a) (S) -5- (((6- (2-chloro-3- (6- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -5-methylpyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

In a similar manner as described with respect to example 606, (S) -5- (((2-chloro-3- (6- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -5-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one was prepared in step (c) using (S) -5- (aminomethyl) pyrrolidin-2-one instead of 1- (4-aminopiperidin-1-yl) ethan-1-one. MS: m/z found 670[ M+H ]] ⁺ Retention time = 2.14min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ )δ9.13(q,1H),8.43(s,1H),7.81(d,1H),7.76(dd,1H),7.61(dd,1H),7.53(d,1H),7.50(dd,1H),7.35(d,1H),7.31(d,1H),7.28(dd,1.6Hz，1H),4.22–4.12(m,2H),4.04(s,3H),4.00(d,2H),3.99(s,3H),3.98–3.87(m,2H),3.07–2.94(m,2H),2.94–2.81(m,2H),2.47–2.26(m,6H),2.23(d,3H),1.93–1.79(m,2H).

Example 608:2- ((6- (2-chloro-3- (6- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) -5-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one (535)

(a) 2- ((6- (2-chloro-3- (6- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) -5-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one

In a similar manner to that described with respect to example 606, 2, 6-diazaspiro [3.4] was used in step (c)]Preparation of 2- ((6- (2-chloro-3- (6- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4 ]) by substituting 1- (4-aminopiperidin-1-yl) ethan-1-one with octan-7-one]Octane-2-yl) methyl) phenyl) -5-methylpyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) -2, 6-diAzaspiro [3.4]Octane-7-one. MS: m/z found 694[ M+H ]] ⁺ Retention time = 2.11min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ )δ9.13(s,1H),8.44(brs,1H),7.80–7.73(m,2H),7.60(dd,1H),7.54–7.46(m,2H),7.34(d,1H),7.30(d,1H),7.28(dd,1H),4.24(s,2H),4.02(s,3H),3.97(s,3H),3.97(s,6H),3.73(s,4H),3.65(s,2H),3.62(s,2H),2.68(s,2H),2.64(s,2H),2.22(s,3H).

Example 609:1- (6- ((6- (3- (6- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -5-methylpyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one (538)

(a) 1- (6- ((6- (3- (6- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -5-methylpyrimidin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one

At N ₂ 6- (2-chloro-3- (6- (4-formyl-3-methoxyphenyl) -5-methylpyrimidin-4-yl) phenyl) -2-methoxynicotinaldehyde (example 606, step (b)) (41 mg,0.09 mmol), 1- (2, 6-diazaspiro [ 3.3) at room temperature]A mixture of heptan-2-yl) ethan-1-one hydrochloride (46 mg,0.26 mmol) and diisopropylethylamine (37 mg,0.28 mmol) in methanol (1.5 mL) and tetrahydrofuran (1.5 mL) was stirred for 21 hours. Sodium cyanoborohydride (22 mg,0.35 mmol) was then added and the reaction mixture stirred at room temperature for 2 3/4 hours. The reaction was then quenched by the addition of saturated aqueous sodium bicarbonate (5 mL) and the resulting suspension was vigorously stirred for 15 minutes. The mixture was then partitioned between ethyl acetate (60 mL) and 1/2 saturated brine (30 mL), the organic phase was separated, washed with saturated brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to afford a colorless glass (50 mg). Benefit (benefit)The crude product was purified by reverse phase HPLC to afford 1- (6- ((6- (4- ((6-acetyl-2, 6-diazaspiro [3.3 ])) as a white solid (formate salt)]Heptane-2-yl) methyl) -3-methoxyphenyl) -5-methylpyrimidin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl methyl) -2, 6-diazaspiro [3.3]Heptane-2-yl) ethan-1-one (7.0 mg, 11.2%). MS: m/z found 722[ M+H ] ] ⁺ Retention time = 2.23min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ )δ9.13(d,1H),8.45(brs,1H),7.79–7.73(m,2H),7.61(dd,1H),7.53–7.47(m,2H),7.35(d,1H),7.31(d,1H),7.28(dd,1H),4.36(s,2H),4.34(s,2H),4.22(s,2H),4.12(s,2H),4.09(s,2H),4.08–4.05(m,4H),4.02(s,3H),3.98(s,3H),3.96(s,2H),3.88–3.80(m,4H),2.22(d,3H),1.85(s,6H).

Example 610:1- (4- (((6- (3- (6- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -5-chloropyrimidin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (540)

(a) 4- (5, 6-dichloropyrimidin-4-yl) -2-methoxybenzaldehyde

By N ₂ (4-formyl-3-methoxyphenyl) boronic acid (0.84 g,4.65 mmol), 4,5, 6-trichloropyrimidine (0.85 g,4.65 mmol) and potassium carbonate (1.93 g,13.95 mmol) in 1, 4-dioxane (16 mL) and H ₂ The mixture in O (4 mL) was purged for 5 minutes. Tetrakis (triphenylphosphine) palladium (0) (160 mg,0.14 mmol) was added and the mixture stirred in a sealed vial at 95 ℃ for 3 hours. The cooled reaction mixture was then partitioned between ethyl acetate (75 mL) and water (75 mL), the organic phase separated, washed with saturated brine (2×40 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a brown solid (1.28 g). By normal phase SiO ₂ Purification of the crude product by chromatography (0 to 100% ethyl acetate in hexanes) provided 4- (5, 6) as a white solidDichloropyrimidin-4-yl) -2-methoxybenzaldehyde (0.47 g,36% yield). ¹ H NMR (400 MHz, chloroform-d) δ10.54 (d, 1H), 8.94 (s, 1H), 7.95 (d, 1H), 7.46 (m, 1H), 7.39 (d, 1H), 4.01 (s, 3H).

(b) 6- (2-chloro-3- (5-chloro-6- (4-formyl-3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxy nicotinaldehyde

By N ₂ 4- (5, 6-dichloropyrimidin-4-yl) -2-methoxybenzaldehyde (0.44 g,1.55 mmol), 6- (2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -2-methoxynicotinaldehyde (0.58 g,1.55 mmol) and potassium carbonate (0.64 g,4.66 mmol) in 1, 4-dioxane (12 mL) and H ₂ The mixture in O (3 mL) was purged for 5 minutes. Tetrakis (triphenylphosphine) palladium (0) (54 mg,0.05 mmol) was then added and the mixture stirred in a sealed vial at 95 ℃ for 16 hours. The cooled reaction mixture was partitioned between ethyl acetate (75 mL) and H ₂ Between O (70 mL), the organic phase was separated, washed with saturated brine (2X 40 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford an orange syrup (1.08 g). By normal phase SiO ₂ The crude product was purified by chromatography (0-70% ethyl acetate in hexanes) to afford 6- (2-chloro-3- (5-chloro-6- (4-formyl-3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxy nicotinaldehyde (0.52 g, 67.7%) as an off-white solid. MS: m/z found 494[ M+H ]] ⁺ Retention time = 1.07min (method B). ¹ H NMR (400 MHz, chloroform-d) δ10.55 (s, 1H), 10.43 (s, 1H), 9.27 (s, 1H), 8.20 (d, 1H), 7.97 (d, 1H), 7.78 (dd, 1H), 7.60-7.52 (m, 2H), 7.51-7.45 (m, 2H), 7.45-7.39 (m, 1H), 4.13 (s, 3H), 4.03 (s, 3H).

(c) 1- (4- (((6- (3- (6- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -5-chloropyrimidin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

At N ₂ A mixture of 6- (2-chloro-3- (5-chloro-6- (4-formyl-3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxy nicotinaldehyde (50 mg,0.10 mmol), 1- (4-aminopiperidin-1-yl) ethan-1-one (43 mg,0.30 mmol) and acetic acid (12 mg,0.20 mmol) in dry tetrahydrofuran (1.5 mL) and dry methanol (1.5 mL) was stirred at room temperature for 14 h. Sodium cyanoborohydride (25 mg,0.40 mmol) was then added and the mixture was stirred for 2 hours. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution (5 mL) and the cloudy suspension was vigorously stirred for 15 minutes. The mixture was then partitioned between ethyl acetate (60 mL) and 1/2 saturated brine (30 mL), the organic phase was separated, washed with saturated brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford colorless syrup (83.5 mg). The crude product was purified by reverse phase HPLC to afford 1- (4- (((6- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -5-chloropyrimidin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (51 mg, 68%) as a white solid (formate salt). MS: m/z found 746[ M+H ] ] ⁺ Retention time = 2.57min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ )δ9.23(s,1H),8.56(brs),7.83(d,1H),7.78(dd,1H),7.61(dd,1H),7.58–7.50(m,4H),7.32(d,1H),4.67–4.51(m,2H),4.20(s,2H),4.07(s,2H),4.06(s,4H),4.04–4.01(m,2H),4.00(s,3H),3.29–3.04(m,4H),2.76–2.64(m,2H),2.24–2.07(m,4H),2.13(s,3H),2.12(s,3H),1.63–1.33(m,4H).

Example 611: (S) -5- (((6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (543)

(a) (S) -5- (((6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

In a similar manner as described with respect to example 610, (S) -5- (aminomethyl) pyrrolidin-2-one was used in place of 1- (4-aminopiperidin-1-yl) ethan-1-one in step (c) to prepare (S) -5- (((6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) pyrrolidin-2-one. MS: m/z found 690[ M+H ]] ⁺ Retention time = 2.38min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ )δ9.23(s,1H),8.39(brs),7.83(d,1H),7.78(dd,1H),7.61(dd,1H),7.58–7.51(m,4H),7.33(d,1H),4.27–4.18(m,2H),4.13–4.05(m,2H),4.06(s,3H),4.00(s,3H),4.00–3.91(m,2H),3.12–3.02(m,2H),3.02–2.91(m,2H),2.46–2.27(m,6H),1.95–1.80(m,2H).

Example 612:2- ((6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one (554)

(a) 2- ((6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one

In a similar manner to that described with respect to example 610, 2, 6-diazaspiro [3.4] was used in step (c)]Preparation of 2- ((6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4 ]) by substituting 1- (4-aminopiperidin-1-yl) ethan-1-one]Octan-2-yl) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methylRadical) -2, 6-diazaspiro [3.4]Octane-7-one. MS: m/z found 714[ M+H ]] ⁺ Retention time = 2.32min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ )δ9.22(s,1H),8.49(brs),7.80–7.73(m,2H),7.60(dd,1H),7.55–7.49(m,4H),7.30(d,1H),4.17(s,2H),4.02(s,3H),3.97(s,3H),3.94(s,2H),3.89(s,4H),3.68(s,4H),3.64(s,2H),3.62(s,2H),2.66(s,2H),2.63(s,2H).

Example 613:1- (4- ((6- (3- (6- (4- ((4-acetylpiperazin-1-yl) methyl) -3-methoxyphenyl) -5-chloropyrimidin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) piperazin-1-one (562)

(a) 1- (4- ((6- (3- (6- (4- ((4-acetylpiperazin-1-yl) methyl) -3-methoxyphenyl) -5-chloropyrimidin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) piperazin-1-one) ethane

1- (4- ((6- (4- ((4-acetylpiperazin-1-yl) methyl) -3-methoxyphenyl) -5-chloropyrimidin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) piperazin-1-yl) ethan-1-one was prepared in step (c) using 1- (piperazin-1-yl) ethan-1-one instead of 1- (4-aminopiperidin-1-yl) ethan-1-one in a similar manner as described for example 610. MS: m/z found 718[ M+H ] ] ⁺ Retention time = 2.41min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ )δ9.21(s,1H),7.82(d,1H),7.78(dd,1H),7.59(dd,1H),7.56–7.47(m,4H),7.29(d,1H),4.00(s,3H),3.93(s,3H),3.80(s,2H),3.67(s,2H),3.66–3.56(m,8H),2.72–2.53(m,8H),2.10(s,6H).

Example 614:2- ((6- (2-chloro-3- (5-chloro-6- (4- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2-azaspiro [3.3] heptan-6-ol (568)

At N ₂ 6- (2-chloro-3- (5-chloro-6- (4-formyl-3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxynicotinaldehyde (example 610, step (b)) (50 mg,0.10 mmol), 2-azaspiro [3.3] at room temperature]A mixture of heptane-6-ol hydrochloride (45 mg,0.30 mmol) and sodium acetate (25 mg,0.30 mmol) in dry methanol (1.5 mL) and dry THF (1.5 mL) was stirred for 19 h. Sodium cyanoborohydride (25 mg,0.40 mmol) was then added and stirring continued for 2 hours. The reaction was then quenched by the addition of saturated aqueous sodium bicarbonate solution (5 mL) and the resulting suspension was vigorously stirred for 15 minutes. The mixture was then partitioned between ethyl acetate (60 mL) and 1/2 saturated brine (30 mL) and the aqueous phase extracted with ethyl acetate (30 mL). The combined organic extracts were washed with saturated brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to provide a white foam (70 mg). The crude product was purified by reverse phase HPLC to afford 2- ((6- (2-chloro-3- (5-chloro-6- (4- ((6-hydroxy-2-azaspiro [ 3.3)) as a white solid (formate salt) ]Heptane-2-yl-methyl) -3-methoxyphenyl) pyrimidin-4-yl-phenyl) -2-methoxypyridin-3-yl-methyl) -2-azaspiro [3.3]Heptane-6-ol (38.1 mg, 55%). MS: m/z found 688[ M+H ]] ⁺ Retention time = 2.49min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ )δ9.24(s,1H),8.51(brs),7.84(d,1H),7.78(dd,1H),7.61(dd,1H),7.58–7.50(m,4H),7.35(d,1H),4.38(s,2H),4.27(s,2H),4.18–4.09(m,6H),4.07(s,2H),4.06(s,3H),4.04(s,2H),4.00(s,3H),2.68–2.56(m,4H),2.20–2.08(m,4H).

Example 615:2- (((6- (2-chloro-3- (5-chloro-6- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethan-1-ol

In a similar manner to that described for example 610, 2-aminoethan-1-ol was used in step (c) in place of 1- (4-aminopiperidin-1-yl)) Preparation of ethane-1-one 2- (((6- (2-chloro-3- (5-chloro-6- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethane-1-ol. MS: m/z found 584[ M+H ]] ⁺ Retention time = 2.31min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ )δ9.24(s,1H),8.48(brs),7.89(d,1H),7.79(dd,1H),7.62(dd,1H),7.60–7.52(m,4H),7.37(d,1H),4.34(s,2H),4.29(s,2H),4.09(s,3H),4.02(s,3H),3.87–3.81(m,4H),3.20–3.14(m,4H).

Example 616:1- (6- ((6- (3- (6- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -5-chloropyrimidin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one (589)

In a similar manner to that described with respect to example 614, 1- (2, 6-diazaspiro [ 3.3) was used in step (a) ]Heptan-2-yl) ethan-1-one hydrochloride instead of 2-azaspiro [3.3]Preparation of 1- (6- ((6- (3- (6- (4- ((6-acetyl-2, 6-diazaspiro [3.3 ])) by heptane-6-ol hydrochloride)]Heptane-2-yl) methyl) -3-methoxyphenyl) -5-chloropyrimidin-4-yl-2-chlorophenyl) -2-methoxypyridin-3-yl methyl) -2, 6-diazaspiro [3.3]Heptane-2-yl) ethan-1-one. MS: m/z found 742[ M+H ]] ⁺ Retention time = 2.43min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ )δ9.23(s,1H),8.42(brs),7.82–7.74(m,2H),7.61(dd,1H),7.57–7.50(m,4H),7.33(d,1H),4.37(s,2H),4.35(s,2H),4.30(s,2H),4.20–4.15(m,4H),4.15–4.07(m,7H),4.05(s,3H),4.02–3.95(m,8H),1.85(s,6H).

Example 617: (1 s,3 s) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 s,3 s) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol (592)

In a similar manner as described for example 610, (1 s,3 s) -3- (((6- (2-chloro-3- (5-chloro-6- (4- (((1 s,3 s) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol was prepared in step (c) using cis-3-aminocyclobutanol instead of 1- (4-aminopiperidin-1-yl) ethan-1-one. MS: m/z found 636[ M+H ]] ⁺ Retention time = 2.43min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ )δ9.24(s,1H),8.49(brs),7.86(d,1H),7.78(dd,1H),7.62(dd,1H),7.58–7.51(m,4H),7.35(d,1H),4.18(s,2H),4.11(s,2H),4.09(s,3H),4.10–4.04(m,2H),4.01(s,3H),3.38–3.27(m,2H),2.78–2.65(m,4H),2.13–1.96(m,4H).

Example 618: (1 r,3 r) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 r,3 r) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol (593)

In a similar manner as described for example 610, (1 r,3 r) -3- (((6- (2-chloro-3- (5-chloro-6- (4- (((1 r,3 r) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol was prepared in step (c) using trans-3-aminocyclobutanol instead of 1- (4-aminopiperidin-1-yl) ethan-1-one. MS: m/z found 636[ M+H ]] ⁺ Retention time = 2.38min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ )δ9.24(s,1H),8.50(brs,2H),7.86(d,1H),7.78(dd,1H),7.62(dd,1H),7.58–7.51(m,4H),7.35(d,1H),4.51–4.43(m,2H),4.17(s,2H),4.10(s,2H),4.08(s,3H),4.01(s,3H),3.98–3.82(m,2H),2.56–2.42(m,4H),2.38–2.26(m,4H).

Example 619: n- ((6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine (626)

In a similar manner to that described for example 610, N- ((6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine was prepared in step (c) using tetrahydro-2H-pyran-4-amine instead of 1- (4-aminopiperidin-1-yl) ethan-1-one. MS: m/z found 664[ M+H ]] ⁺ Retention time = 2.65min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ )d 9.23(s,1H),8.53(brs),7.84(d,1H),7.78(dd,1H),7.61(dd,1H),7.58–7.51(m,4H),7.33(d,1H),4.22(s,2H),4.10(s,2H),4.06(s,3H),4.06–4.01(m,4H),4.00(s,3H),3.51–3.40(m,4H),3.29–3.21(m,1H),3.19–3.08(m,1H),2.12–1.98(m,4H),1.75–1.54(m,4H).

Example 620:1- (6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- (((oxazol-5-ylmethyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N- (oxazol-5-ylmethyl) methylamine (643)

In a similar manner to that described with respect to example 614, oxazol-5-ylmethylamine hydrochloride was used in place of 2-azaspiro [3.3 ] in step (c)]Heptane-6-ol hydrochloride 1- (6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- (((oxazol-5-ylmethyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N- (oxazol-5-ylmethyl) methylamine is prepared. MS: m/z found 658[ M+H ]] ⁺ Retention time = 2.41min (method a).

¹ H NMR (400 MHz, methanol-d) ₄ )δ9.22(s,1H),8.35(brs),8.28(s,1H),8.24(s,1H),7.80–7.75(m,2H),7.60(dd,1H),7.56–7.49(m,4H),7.30(d,1H),7.25(s,1H),7.18(s,1H),4.26–4.20(m,2H),4.13(s,2H),4.12–4.10(m,2H),4.03(s,3H),3.99(s,2H),3.97(s,3H).

Example 621: n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) picolinamide (672)

(a) 2-chloro-3- (2, 3-dichloropyridin-4-yl) aniline

2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) aniline (1000 mg,3.94 mmol), 2, 3-dichloro-4-iodo-pyridine (1080 mg,3.94 mmol) and [1,1' -bis (biphenylphosphino) ferrocene were placed in a sealed tube]A complex of palladium (II) dichloride with dichloromethane (322 mg,0.39 mmol) and potassium carbonate (1633 mg,11.83 mmol) was suspended in 1, 4-dioxane/water (5:1). Nitrogen was bubbled through the reaction solution for 10 minutes, then the vessel was sealed and heated at 120 ℃ for 1 hour. The reaction was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organics were concentrated and passed through a silica gel column, eluting with a gradient of 0-40% EtOAc in hexanes to provide 2-chloro-3- (2, 3-dichloropyridin-4-yl) aniline (950 mg, 88%). LCMS: m/z found 273.0[ M+H ] ] ⁺ Retention time = 0.94min (method B).

(b) N- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -5- (dimethoxymethyl) picolinamide

To a solution of 5- (dimethoxymethyl) pyridine-2-carboxylic acid (1153 mg,5.85 mmol) and HATU (2224 mg,5.85 mmol) in DMF was added N, N-diisopropylethylamine (1.02 ml, 7516 mg,5.85 mmol). After stirring for 10 minutes, 2-chloro-3- (2, 3-dichloro-4-pyridinyl) aniline (400 mg,1.46 mmol) is added in portions and the reaction mixture is stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate, concentrated in vacuo, and purified by flash column chromatographyPurification by chromatography to afford N- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl]-5- (dimethoxymethyl) pyridine-2-carboxamide (650 mg, 98%). LCMS: m/z found 452.0[ M+H ]] ⁺ Retention time = 1.14min (method B).

(c) N- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -5-formylpyridinamide

N- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl group at room temperature]A mixture of 5- (dimethoxymethyl) pyridine-2-carboxamide (700 mg,1.55 mmol) and trifluoroacetic acid (5 mL) was stirred for 2 hours. Excess trifluoroacetic acid was evaporated. The resulting mixture was neutralized to ph=8 by saturated sodium bicarbonate solution and extracted three times with DCM. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford N- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl group ]-5-formyl-pyridine-2-carboxamide (620 mg, 99%). LCMS: m/z found 406.0[ M+H ]] ⁺ Retention time = 1.06min (method B).

(d) N- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -5-formylpyridinamide

To N- [ 2-chloro-3- (2, 3-dichloro-4-pyridinyl) phenyl]A mixture of 5-formyl-pyridine-2-carboxamide (500 mg,1.23 mmol), 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (322 mg,1.23 mmol) and potassium carbonate (510 mg,3.69 mmol) in degassed 1, 4-dioxane/water (6:1) was added tetrakis (triphenylphosphine) palladium (0) (142 mg,0.12 mmol) and the mixture stirred at 120℃for 2 hours. Water was added and the mixture was extracted three times into EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to provide N- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl]Phenyl group]-5-formyl-pyridine-2-carboxamide (350 mg, 56%). LCMS: m/z found 506.1[ M+H ]] ⁺ Retention time=1.03 min (method B).

(e) N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) picolinamide

Following reductive amination procedure a, starting from N- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl]Phenyl group]-5-formyl-pyridine-2-carboxamide (30 mg,0.06 mmol) and 2, 6-diazaspiro [3.4 ]]Octane-7-one (30 mg,0.24 mmol) prepared this compound as formate. 81% yield. LCMS: m/z found 726.2[ M+H ]] ⁺ Retention time = 2.46min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.70–8.60(m,3H),8.37(s,2H),8.24(d,1H),8.00(d,1H),7.58–7.49(m,2H),7.46(d,1H),7.39(s,1H),7.36(d,1H),7.24–7.15(m,1H),4.37(s,2H),4.13(s,4H),3.99(s,3H),3.83(s,2H),3.67(s,2H),3.58(s,2H),3.41(s,4H),2.71(s,2H),2.58(s,2H).

Example 622:5- (((1-Acetylpiperidin-4-yl) amino) methyl) -N- (3- (2- (4- (((1-Acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) picolinamide (673)

Following reductive amination procedure a, starting from N- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl]Phenyl group]-5-formyl-pyridine-2-carboxamide (30 mg,0.06 mmol) and 1- (4-amino-1-piperidinyl) ethanone (34 mg,0.24 mmol) 5- (((1-acetylpiperidin-4-yl) amino) methyl) -N- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) picolinamide was prepared as the formate salt. 82% yield. LCMS: m/z found 758.3[ M+H ]] ⁺ Retention time = 2.64min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.74(d,1H),8.71–8.59(m,2H),8.43(s,1H),8.28(d,1H),8.10(d,1H),7.54(dt,2H),7.47(d,1H),7.41(s,1H),7.39–7.34(m,1H),7.20(dd,1H),4.67(d,1H),4.50(d,1H),4.32(s,2H),4.08(s,3H),4.04–3.89(m,4H),3.45(t,1H),3.26–3.09(m,2H),3.01–2.87(m,1H),2.79–2.63(m,2H),2.24(t,2H),2.16–1.98(m,8H),1.77–1.21(m,4H).

Example 623: n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) picolinamide (674)

Following reductive amination procedure a, starting from N- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl]Phenyl group]-5-formyl-pyridine-2-carboxamide (30 mg,0.06 mmol) and tetrahydropyran-4-amine (24 mg,0.24 mmol) N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) picolinamide was prepared as formate salt. 87% yield. LCMS: m/z found 676.2[ M+H ]] ⁺ Retention time = 2.73min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.74(d,1H),8.71–8.62(m,2H),8.46(s,1H),8.28(d,1H),8.17–8.05(m,1H),7.59–7.50(m,2H),7.47(d,1H),7.41(s,1H),7.37(dd,1H),7.21(dd,1H),4.31(s,2H),4.10(s,2H),4.09–4.03(m,2H),4.03–3.93(m,5H),3.52–3.36(m,5H),3.04–2.90(m,1H),2.12(d,2H),1.98(d,2H),1.82–1.67(m,2H),1.62–1.43(m,2H).

Example 624: n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide (675)

Following reductive amination procedure a, starting from N- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl]Phenyl group]-5-formyl-pyridine-2-carboxamide (35 mg,0.07 mmol) and (5S) -5- (aminomethyl) pyrrolidin-2-one (32 mg,0.28 mmol) N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridine amide was prepared as formate. Yield 90%. LCMS: m/z found 702.2[ M+H ] ] ⁺ Retention time = 2.48min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.76–8.58(m,3H),8.40(s,2H),8.25(d,1H),8.12–8.01(m,1H),7.60–7.49(m,2H),7.47(d,1H),7.39(s,1H),7.36(d,1H),7.20(d,1H),4.24(d,2H),4.06–3.89(m,6H),3.84(q,1H),3.16–3.00(m,2H),2.84–2.62(m,2H),2.48–2.19(m,6H),1.98–1.73(m,2H).

Example 625: n- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide (676)

Following reductive amination procedure a, starting from N- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl]Phenyl group]-5-formyl-pyridine-2-carboxamide (40 mg,0.08 mmol) and 2-aminoethanol (19 mg,0.32 mmol) N- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide was prepared as formate. 91% yield. LCMS: m/z found 596.2[ M+H ]] ⁺ Retention time = 2.43min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.76(d,1H),8.71–8.61(m,2H),8.50(s,1H),8.30(d,1H),8.12(dd,1H),7.59–7.49(m,2H),7.47(d,1H),7.41(d,1H),7.36(dd,1H),7.21(dd,1H),4.32(s,2H),4.15(s,2H),4.00(s,3H),3.87–3.81(m,2H),3.76(t,2H),3.16(t,2H),2.96(t,2H).

Example 626:5- ((6-acetyl-2, 6-diazaspiro [3.3] heptane-2-yl) methyl) -N- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptane-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) pyridine amide (677)

Following reductive amination procedure a, starting from N- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl]Phenyl group]-5-formyl-pyridine-2-carboxamide (40 mg,0.08 mmol) and 1- (2, 6-diazaspiro [ 3.3) ]Heptan-2-yl) ethanone (44 mg,0.32 mmol) 5- ((6-acetyl-2, 6-diazaspiro [ 3.3)]Heptan-2-yl) methyl) -N- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [ 3.3)]Heptane-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) pyridine amide to form a formate salt. 34% yield. LCMS: m/z found 754.3[ M+H ]] ⁺ Retention time = 2.59min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.70–8.61(m,3H),8.40(s,2H),8.24(d,1H),7.99(d,1H),7.54(t,1H),7.51–7.43(m,2H),7.39(s,1H),7.36(d,1H),7.24–7.15(m,1H),4.37(s,2H),4.30(s,4H),4.23–4.09(m,6H),4.05(s,2H),3.98(s,3H),3.79(s,2H),3.56–3.42(m,4H),1.91–1.79(m,6H).

Example 627: n- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -5- (((((S) -2-hydroxypropyl) amino) methyl) picolinamide (678)

Following reductive amination procedure a, starting from N- [ 2-chloro-3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl]Phenyl group]-5-formyl-pyridine-2-carboxamide (40 mg,0.08 mmol) and (2S) -1-aminopropane-2-ol (24 mg,0.32 mmol) N- (2-chloro-3- (3-chloro-2- (4- ((((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -5- (((((S) -2-hydroxypropyl) amino) methyl) picolinamide was prepared as a formate salt. Yield 90%. LCMS: m/z found 624.2[ M+H ]] ⁺ Retention time = 2.62min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.73(s,1H),8.70–8.62(m,2H),8.52(s,1H),8.28(d,1H),8.10(dd,1H),7.59–7.49(m,2H),7.47(d,1H),7.40(d,1H),7.36(dd,1H),7.21(dd,1H),4.30(s,2H),4.13–4.02(m,3H),4.00(s,3H),3.98–3.87(m,1H),3.07(dd,1H),2.86(dd,1H),2.78(dd,1H),2.66(dd,1H),1.23(d,3H),1.19(d,3H).

Example 628: n- (3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) pyridine amide (590)

(a) 3- (2, 3-dichloropyridin-4-yl) -2-methylaniline

2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) aniline (500 mg,2.14 mmol), 2, 3-dichloro-4-iodo-pyridine (587 mg,2.14 mmol) and [1,1' -bis (biphenylphosphino) -ferrocene in a sealed tube]A complex of palladium (II) dichloride with dichloromethane (175 mg,0.21 mmol) and potassium carbonate (88 mg,6.43 mmol) was suspended in 1, 4-dioxane/water (5:1). Nitrogen was bubbled through the reaction solution for 10 minutes, then the vessel was sealed and heated at 120 ℃ for 90 minutes. The reaction was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organics were concentrated and passed through a silica gel column eluting with a gradient of 0-40% EtOAc in hexanes to provide 3- (2, 3-dichloro-4-pyridinyl) -2-methyl-aniline (500 mg, 92%). LCMS: m/z found 253.0[ M+H ]] ⁺ Retention time = 0.73min (method B).

(b) N- (3- (2, 3-dichloropyridin-4-yl) -2-methylphenyl) -5- (dimethoxymethyl) picolinamide

To a solution of 5- (dimethoxymethyl) pyridine-2-carboxylic acid (284 mg,2.96 mmol) and HATU (1127 mg,2.96 mmol) in DMF was added N, N-diisopropylethylamine (0.52 ml,383mg,2.96 mmol). After stirring for 10 min, 3- (2, 3-dichloro-4-pyridinyl) -2-methyl-aniline (250 mg,0.99 mmol) is added in portions and the reaction mixture is stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate, concentrated in vacuo, and purified by flash column chromatography to afford N- [3- (2, 3-dichloro-4-pyridinyl) -2-methyl-phenyl ]-5- (dimethoxymethyl) pyridine-2-carboxamide (406 mg, 95%). LCMS: m/z found 432.1[ M+H ]] ⁺ Retention time = 1.08min (method B).

(c) N- (3- (2, 3-dichloropyridin-4-yl) -2-methylphenyl) -5-formylpyridinamide

N- [3- (2, 3-dichloro-4-pyridinyl) -2-methyl-phenyl group at room temperature]A mixture of 5- (dimethoxymethyl) pyridine-2-carboxamide (420 mg,0.97 mmol) and trifluoroacetic acid (4 mL) was stirred for 2 hours. Excess trifluoroacetic acid was evaporated. The resulting mixture was neutralized to ph=8 by saturated sodium bicarbonate solution and extracted three times with DCM. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford N- [3- (2, 3-dichloro-4-pyridinyl) -2-methyl-phenyl]-5-formyl-pyridine-2-carboxamide (370 mg, 99%). LCMS: m/z found 386.0[ M+H ]] ⁺ Retention time = 0.99min (method B).

(d) N- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -5-formylpyridinamide

To N- [3- (2, 3-dichloro-4-pyridinyl) -2-methyl-phenyl]A mixture of 5-formyl-pyridine-2-carboxamide (300 mg,0.78 mmol), 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (204 mg,0.78 mmol) and potassium carbonate (322 mg,2.33 mmol) in degassed 1, 4-dioxane/water (6:1) was added tetrakis (triphenylphosphine) palladium (0) (90 mg,0.08 mmol) and the mixture stirred at 120℃for 4 hours. Water was added and the mixture was extracted three times into EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to provide N- [3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl]-2-methyl-phenyl]-5-formyl-pyridine-2-carboxamide (200 mg, 53%). LCMS: m/z found 486.1[ M+H ]] ⁺ Retention time = 0.98min (method B).

(e) N- (3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) picolinamide

Following reductive amination procedure a, starting from N- [3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl]-2-methyl-phenyl]-5-formyl-pyridine-2-carboxamide (30 mg,0.06 mmol) and 2, 6-diazaspiro [3.4]]Octan-7-one (31 mg,0.25 mmol) N- (3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4 ])]Octan-2-yl) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((7-oxo-2, 6-diazaspiro [3.4]Octane-2-yl) methyl) picolinamide to formate salt. 82% yield. LCMS: m/z found 706.3[ M+H ]] ⁺ Retention time = 2.27min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.69–8.58(m,2H),8.36(s,2H),8.20(d,1H),7.97(t,2H),7.51(d,1H),7.45–7.37(m,3H),7.35(d,1H),7.11(d,1H),4.37(s,2H),4.13(s,4H),3.98(s,3H),3.83(s,2H),3.67(s,2H),3.59(s,2H),3.45–3.36(m,4H),2.71(s,2H),2.58(s,2H),2.17(s,3H).

Example 629:5- (((1-Acetylpiperidin-4-yl) amino) methyl) -N- (3- (2- (4- (((1-Acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) picolinamide (645)

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According to reductive amination procedure A, starting from N- [3- [ 3-chloro-2- (4-formyl-3)-methoxy-phenyl) -4-pyridinyl]-2-methyl-phenyl]-5-formyl-pyridine-2-carboxamide (30 mg,0.06 mmol) and 1- (4-amino-1-piperidinyl) ethanone (35 mg,0.25 mmol) 5- (((1-acetylpiperidin-4-yl) amino) methyl) -N- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) picolinamide was prepared as the formate salt. Yield 50%. LCMS: m/z found 738.4[ M+H ]] ⁺ Retention time = 2.45min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.74(s,1H),8.64(d,1H),8.41(s,2H),8.24(d,1H),8.13–8.04(m,1H),7.96(d,1H),7.54(d,1H),7.47–7.31(m,4H),7.12(d,1H),4.67(d,1H),4.51(d,1H),4.32(s,2H),4.15–4.04(m,3H),4.03–3.90(m,4H),3.54–3.38(m,1H),3.26–3.10(m,2H),3.06–2.90(m,1H),2.71(q,2H),2.24(t,2H),2.17(s,3H),2.14(s,3H),2.12–2.02(m,5H),1.73–1.26(m,4H).

Example 630: n- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) picolinamide (646)

Following reductive amination procedure a, starting from N- [3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl]-2-methyl-phenyl]-5-formyl-pyridine-2-carboxamide (30 mg,0.06 mmol) and tetrahydropyran-4-amine (25 mg,0.25 mmol) N- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) picolinamide was prepared as a formate salt. 52% yield. LCMS: m/z found 656.3[ M+H ] ] ⁺ Retention time = 2.57min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.72(s,1H),8.64(d,1H),8.51(s,2H),8.22(d,1H),8.10–8.02(m,1H),7.97(d,1H),7.52(d,1H),7.46–7.37(m,3H),7.37–7.31(m,1H),7.12(d,1H),4.27(s,2H),4.10–4.02(m,2H),4.02–3.92(m,7H),3.54–3.35(m,5H),2.91–2.76(m,1H),2.17(s,3H),2.10(d,2H),1.94(d,2H),1.80–1.58(m,2H),1.58–1.41(m,2H).

Example 631: n- (3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide (647)

Following reductive amination procedure a, starting from N- [3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl]-2-methyl-phenyl]-5-formyl-pyridine-2-carboxamide (30 mg,0.06 mmol) and (5S) -5- (aminomethyl) pyrrolidin-2-one (28 mg,0.25 mmol) N- (3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridine amide was prepared as formate. Yield 66%. LCMS: m/z found 682.3[ M+H ]] ⁺ Retention time = 1.43min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.72(d,1H),8.64(d,1H),8.32(s,2H),8.22(d,1H),8.06(dd,1H),7.97(d,1H),7.53(d,1H),7.47–7.32(m,4H),7.12(d,1H),4.39–4.22(m,2H),4.09–3.94(m,6H),3.91–3.78(m,1H),3.24–3.08(m,2H),2.91–2.67(m,2H),2.48–2.21(m,6H),2.17(s,3H),1.98–1.75(m,2H).

Example 632: n- (3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide (648)

Following reductive amination procedure a, starting from N- [3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl]-2-methyl-phenyl ]-5-formyl-pyridine-2-carboxamide (30 mg,0.06 mmol) and 2-aminoethanol (15 mg,0.25 mmol) N- (3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide was prepared as formate. 65% yield. LCMS: m/z found 576.2[ M+H ]] ⁺ Protecting and protectingRetention time = 2.27min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.77(s,1H),8.64(dd,1H),8.46(s,2H),8.27(d,1H),8.15–8.08(m,1H),7.96(d,1H),7.52(d,1H),7.45–7.31(m,5H),7.13(d,1H),4.32(s,2H),4.20(s,2H),4.00(s,3H),3.84(t,2H),3.78(t,2H),3.16(t,2H),3.01(t,2H),2.17(s,3H).

Example 633:5- ((6-acetyl-2, 6-diazaspiro [3.3] heptane-2-yl) methyl) -N- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptane-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) pyridineamide (649)

Following reductive amination procedure a, starting from N- [3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl]-2-methyl-phenyl]-5-formyl-pyridine-2-carboxamide (30 mg,0.06 mmol) and 1- (2, 6-diazaspiro [ 3.3)]Heptan-2-yl) ethanone (35 mg,0.25 mmol) 5- ((6-acetyl-2, 6-diazaspiro [ 3.3)]Heptan-2-yl) methyl) -N- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [ 3.3)]Heptane-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) picolinamide to form the formate salt. 33% yield. LCMS: m/z found 734.3[ M+H ]] ⁺ Retention time = 2.42min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.74–8.52(m,2H),8.33(s,2H),8.21(d,1H),7.97(d,2H),7.50(d,1H),7.47–7.30(m,4H),7.12(d,1H),4.38(s,4H),4.31(s,2H),4.26(s,4H),4.14(s,2H),4.06(s,2H),3.99(s,3H),3.81(s,2H),3.56–3.50(m,4H),2.17(s,3H),1.85(s,6H).

Example 634: n- (3- (3-chloro-2- (4- ((((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- (((((S) -2-hydroxypropyl) amino) methyl) picolinamide (650)

Following reductive amination procedure a, starting from N- [3- [ 3-chloro-2- (4-formyl-3-methoxy-phenyl) -4-pyridinyl]-2-methyl group-phenyl group]-5-formyl-pyridine-2-carboxamide (30 mg,0.06 mmol) and (2S) -1-aminopropane-2-ol (19 mg,0.25 mmol) N- (3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- (((((S) -2-hydroxypropyl) amino) methyl) picolinamide) was prepared as a formate salt. 80% yield. LCMS: m/z found 604.3[ M+H ]] ⁺ Retention time = 1.51min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.77(s,1H),8.64(d,1H),8.47(s,2H),8.27(d,1H),8.12(dd,1H),7.96(d,1H),7.52(d,1H),7.47–7.38(m,3H),7.37–7.31(m,1H),7.13(d,1H),4.32(s,2H),4.21(s,2H),4.11–4.03(m,1H),4.03–3.92(m,4H),3.09(dd,1H),2.97–2.82(m,2H),2.77(dd,1H),2.17(s,3H),1.30–1.15(m,6H).

Example 635: (S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) pyrrolidin-2-one (223)

(a) (S) -3' -chloro-2 ' - (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine ] -5-carbaldehyde

Tetrakis (triphenylphosphine) palladium (0) (16 mg,0.01 mmol), potassium carbonate (29 mg,0.21 mmol), 2-methoxy-6- [ [ (1S) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) indan-1-yl]Amino group]-5- (trifluoromethyl) pyridine-3-carbaldehyde (32 mg,0.07 mmol) and 6- (2, 3-dichloro-4-pyridinyl) -2-methoxy-pyridine-3-carbaldehyde (29 mg,0.10 mmol) were suspended in 1, 4-dioxane/water (4:1, 2 ml) and the solution was then heated at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×5 mL). Concentrating the combined organics under reduced pressure and passing through normal phase SiO ₂ Chromatography (0-3% MeOH/DCM) purification of crude samples to afford (S) -3' -chloro-2 ' - (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine as a tan foam]-5-Formaldehyde (30 mg,74% yield). MS: m/z observed values 583,585[ M+H ]] ⁺ .

(b) (S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) pyrrolidin-2-one

(S) -3' -chloro-2 ' - (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine ]-5-Formaldehyde (10 mg,0.02 mmol), acetic acid (2 mg,0.03 mmol), and (5S) -5- (aminomethyl) pyrrolidin-2-one (8 mg,0.07 mmol) were dissolved in MeOH/THF (1:1, 1 mL) and the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (2 mg,0.03 mmol) was added and the resulting mixture was stirred at 25 ℃ for 1 hour. The reaction was then diluted with water (2 mL) and extracted with EtOAc (3×2 mL). The combined organics were further washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude sample was purified by reverse phase HPLC to provide (S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridine) as a white solid (formate salt)]-5-yl) methyl) amino) methyl) pyrrolidin-2-one (9 mg,65% yield). LC/MS: m/z found 779,781[ M+H ]] ⁺ Retention time = 2.22min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.66–8.57(m,1H),8.39(s,2H),7.86(d,1H),7.81(s,1H),7.69(d,1H),7.43(d,1H),7.33(s,3H),6.30(d,1H),5.89(t,1H),4.06(d,5H),3.99(d,3H),3.94(s,4H),3.06(s,2H),2.87(d,4H),2.62(s,1H),2.35(d,6H),2.17–2.02(m,1H),1.86(s,2H).

Example 636: (S) -N- (4- (3 ' -chloro-6-methoxy-5- ((methylamino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine (224)

In the same manner as described for example 635, intermediate (S) -3' -chloro-2 ' - (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine is utilized in step (b)]Preparation of (S) -N- (4- (3 '-chloro-6-methoxy-5- ((methylamino) methyl) - [2,4' -bipyridine) with (5S) -5- (aminomethyl) -pyrrolidin-2-one substituted with methylamine]-2' -yl) -2, 3-dihydro-1H-inden-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine. The product was obtained as a white solid (formate). MS: m/z found 613,615[ M+H ]] ⁺ Retention time = 2.27min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.68–8.59(m,1H),8.51(s,2H),7.92(d,1H),7.81(s,1H),7.72–7.63(m,1H),7.48(dd,1H),7.33(d,3H),6.35(d,1H),5.92(q,1H),4.23(s,2H),4.10(t,3H),4.06(s,2H),3.94(d,3H),2.85(t,2H),2.74(d,3H),2.70–2.67(m,3H),2.67–2.57(m,1H),2.12(q,1H).

Example 637: (1S, 3 r) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1 r, 3S) -3-hydroxy-3-methylcyclobutyl) -amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutane-1-ol (225)

In the same manner as described for example 635, intermediate (S) -3' -chloro-2 ' - (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) -pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine is utilized in step (b) ]-5-Formaldehyde and substitution with 3-amino-1-methyl-cyclobutanol (5S)-5- (aminomethyl) -pyrrolidin-2-one to prepare (1S, 3 r) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1 r, 3S) -3-hydroxy-3-methylcyclobutyl) -amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine]-5-yl) methyl) amino) -1-methylcyclobutan-1-ol. The product was obtained as a white solid (formate). LC/MS: m/z found 753,755[ M+H ]] ⁺ Retention time = 2.25min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.62(d,1H),8.51(s,2H),7.85(d,1H),7.78(d,1H),7.69(s,1H),7.43(d,1H),7.32(s,3H),6.31(d,1H),5.90(d,1H),4.07(d,3H),3.94(s,7H),3.83(t,1H),3.71(s,1H),2.85(s,2H),2.63(s,1H),2.34(d,4H),2.13(t,3H),2.07–1.99(m,2H),1.39–1.34(m,6H).

Example 638: (S) -2- ((3 ' -chloro-6-methoxy-2 ' - (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one (304)

(a) (S) -3' -chloro-2 ' - (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine ] -5-carbaldehyde

A mixture of (S) -3-methoxy-5- ((4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2, 3-dihydro-1H-inden-1-yl) amino) -6- (trifluoromethyl) pyrazine-2-carbaldehyde (example 644, step (a)) (0.5 g,1.08 mmol), 6- (2, 3-dichloro-4-pyridinyl) -2-methoxy-pyridine-3-carbaldehyde (183mg, 648. Mu. Mol), potassium carbonate (298 mg,2.16 mmol), and tetrakis (triphenylphosphine) palladium (125 mg, 108. Mu. Mol) in dioxane/water (10:1, 11 mL) was stirred at 110℃for 2 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (2×20 mL), without Dried over sodium sulfate, filtered and concentrated. By normal phase SiO ₂ Chromatography (10-50% ethyl acetate/petroleum ether) purification of the residue to afford (S) -3' -chloro-2 ' - (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine as a yellow oil]-5-Formaldehyde (0.4 g). MS: m/z found 584.1[ M+H ]] ⁺ .

(b) (S) -2- ((3 ' -chloro-6-methoxy-2 ' - (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one

To (S) -3' -chloro-2 ' - (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine]-5-Formaldehyde (150 mg, 257. Mu. Mol) and 2, 6-diazaspiro [3.4]]A solution of octan-7-one hydrochloride (84 mg, 514. Mu. Mol) in methanol (5 mL) was added sodium acetate (84 mg,1 mmol). The solution was stirred at room temperature for 12 hours. Sodium cyanoborohydride (65 mg,1 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was purified by reverse phase HPLC to afford (S) -2- ((3 '-chloro-6-methoxy-2' - (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [ 3.4) ]Octane-2-yl) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridine]-5-yl) methyl) -2, 6-diazaspiro [3.4]Octane-7-one (35 mg). MS: m/z found 804.3[ M+H ]] ⁺ Retention time = 2.78min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ＝8.62(d,1H),8.37(br s,1H),7.80(d,1H),7.69(d,1H),7.42(d,1H),7.34 -7.33(m,3H),5.84(t,1H),4.19 -4.15(m,2H),4.04–4.01(m,7H),3.94 -3.90(m,5H),3.65 -3.62(m,8H),288-2.84(m,2H),2.68(s,2H),2.62(s,3H),2.19 -2.09(m,1H).

Example 639: (S) -1- (6- ((5- ((4- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxy-6- (trifluoromethyl) pyrazin-2-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one (305)

To (S) -3' -chloro-2 ' - (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine]-5-Formaldehyde (example 638, step (a)) (150 mg, 257. Mu. Mol) and 1- (2, 6-diazaspiro [ 3.3) as formate salt]A solution of heptan-2-yl) ethanone (131 mg, 514. Mu. Mol) in methanol (1.5 mL) was added sodium acetate (84 mg,1 mmol). The solution was stirred at room temperature for 12 hours. Sodium cyanoborohydride (65 mg,1 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was purified by reverse phase HPLC to afford (S) -1- (6- ((5- ((4- (5- ((6-acetyl-2, 6-diazaspiro [3.3 ]) ]Heptane-2-yl) methyl) -3 '-chloro-6-methoxy- [2,4' -bipyridine]-2' -yl) -2, 3-dihydro-1H-inden-1-yl-amino) -3-methoxy-6- (trifluoromethyl) pyrazin-2-yl-methyl) -2, 6-diazaspiro [3.3]Heptane-2-yl) ethan-1-one (41 mg). MS: m/z found 832.3[ M+H ]] ⁺ Retention time = 2.89min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.62(d,1H),8.37(s,1H),7.79(d,1H),7.69(d,1H),7.42(d,1H),7.37 -7.33(m,3H),5.84(t,1H),4.35(d,4H),4.19-4.09(m,10H),4.04(s,3H),3.94(s,3H),3.89(s,2H),3.75(s,4H),2.88-2.84(m,2H),2.65-2.59(m,1H),2.19 -2.09(m,1H),1.85(s,6H).

Example 640: (S) -5- ((((6- (((S) -4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (486)

(a) 2',3' -dichloro-6-methoxy- [2,4' -bipyridine ] -5-carbaldehyde

A mixture of 2, 3-dichloro-4- (4, 5-tetramethyl-1, 2-oxaborane-2-yl) pyridine (22.75 g,83 mmol), 6-chloro-2-methoxy-pyridine-3-carbaldehyde (15 g,87 mmol), tetrakis (triphenylphosphine) palladium (0) (5.05 g,4.37 mmol), and potassium carbonate (36.25 g,262 mmol) in 1, 4-dioxane (375 mL) and water (20 mL) was degassed and used with N ₂ And (5) purging. The mixture was stirred at 95℃for 4 hours. The mixture was concentrated, after which water (300 mL) was added. The aqueous layer was extracted with EtOAc (2×400 mL), dried over sodium sulfate, filtered and concentrated. The solid was washed with EtOAc (200 mL) and dried to afford 2',3' -dichloro-6-methoxy- [2,4' -bipyridine ]-5-Formaldehyde (10 g,40% yield).

(b) 1- (4- (((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) piperidin-1-yl) ethan-1-one

To 2',3' -dichloro-6-methoxy- [2,4' -bipyridine]A mixture of 5-formaldehyde (1.5 g,5.3 mmol) and 1- (4-amino-1-piperidinyl) ethanone (1.13 g,7.95 mmol) in a THF/MeOH mixture (1:1, 30 mL) was added sodium acetate (0.87 g,10.6 mmol). The mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (1 g,15.9 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was used in the next step without post-treatment (out work-up). 1- (4- (((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridine)]-5-yl) methyl) amino) piperidin-1-yl) ethan-1-one. MS: m/z found 409[ M+Na ]] ⁺ .

(c) (1-Acetylpiperidin-4-yl) ((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) carbamic acid tert-butyl ester

To 1- (4- (((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridine)]-5-yl) methyl) amino) piperazineA solution of pyridin-1-yl) ethan-1-one in THF/MeOH was added di-tert-butyl dicarbonate (3 ml,13 mmol) and triethylamine (0.74 ml,5.3 mmol). The mixture was stirred at room temperature for 5 hours. The mixture was concentrated, and the residue was diluted with water (20 mL) and brine (30 mL). The mixture was extracted with ethyl acetate/THF mixture (3:1, 50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ Chromatography (0-15% ethyl acetate/petroleum ether) of the residue to afford (1-acetylpiperidin-4-yl) ((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridine)]-5-yl) methyl) carbamic acid tert-butyl ester (2.3 g, 68%). MS: m/z found 531[ M+Na ]] ⁺ .

(d) (S) -6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxynicotinonitrile

At N ₂ N, N-diisopropylethylamine (9.3 mL,53.4 mmol) was added in one portion under an atmosphere to a mixture of 6-chloro-2-methoxynicotinic carbonitrile (4.5 g,26.7 mmol) and (S) -4-bromo-2, 3-dihydro-1H-inden-1-amine (7.3 g,29.4 mmol) as the hydrochloride salt in NMP (80 mL). The mixture was stirred at 100℃for 6 hours. To the mixture was added water (50 mL) and brine (50 mL). The mixture was extracted with ethyl acetate (40 mL). The combined organic phases were washed with brine (2×100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-15% ethyl acetate/petroleum ether) to afford (S) -6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxynicotinonitrile (3 g,32% yield) as a brown solid. ¹ H NMR (400 MHz, chloroform-d): delta 7.46 (d, 1H), 7.37 (d, 1H), 7.18 (d, 1H), 7.03 (t, 1H), 5.96 (d, 1H), 5.50 (br s, 1H), 5.04 (d, 1H), 3.87 (s, 3H), 3.01-2.97 (m, 1H), 2.87-2.83 (m, 1H), 2.61-2.58 (m, 1H), 1.91-1.85 (m, 1H).

(e) (S) -6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -5-iodo-2-methoxynicotinic carbonitrile

To a mixture of (S) -6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxynicotinic carbonitrile (3 g,8.72 mmol) in acetic acid (50 mL) was added N-iodosuccinimide (2.16 g,9.59 mmol) and sodium acetate (8.55 g,87.2 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was neutralized with saturated aqueous NaOH solution (800 mL). The mixture was extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with brine (2×100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Directly through normal phase SiO ₂ Chromatography (0-7% ethyl acetate/petroleum ether) purified the residue to afford (S) -6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -5-iodo-2-methoxynicotinic carbonitrile (3.2 g,78% yield). ¹ H NMR (400 MHz, chloroform-d): delta 7.81 (s, 1H), 7.38 (d, 1H), 7.16 (d, 1H), 7.05 (t, 1H), 5.67 (q, 1H), 5.54 (d, 1H), 3.89 (s, 3H), 3.03-3.00 (m, 1H), 2.88-2.84 (m, 1H), 2.66-2.64 (m, 1H), 1.95-1.88 (m, 1H).

(f) (S) -6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) nicotinic carbonitrile

To a mixture of (S) -6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -5-iodo-2-methoxynicotinic carbonitrile (3.2 g,6.8 mmol) and methyl 2, 2-difluoro-2- (fluorosulfonyl) acetate (1.73 mL,13.6 mmol) in DMF (30 mL) was added cuprous iodide (1.94 g,10.2 mmol). The mixture was stirred at 110℃for 2 hours. The mixture was filtered, and then water (100 mL) and brine (100 mL) were added to the filtrate. The mixture was extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with brine (2×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Directly through normal phase SiO ₂ The residue was purified by chromatography (0-10% ethyl acetate/petroleum ether) to provide (S) -6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) nicotinic carbonitrile (2.7 g, 96%). ¹ H NMR (400 MHz, chloroform-d) delta 7.77 (s, 1H), 7.39 (d, 1H), 7.14 (d, 1H), 7.06 (t, 1H), 5.78 (q, 1H), 5.50 (d, 1H), 3.93 (s, 3H), 3.03-3.00 (m, 1H), 2.89-2.84 (m, 1H), 2.68-2.65 (m, 1H), 1.93-1.88 (m, 1H).

(g) (S) -6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde

At N ₂ To a mixture of (S) -6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) nicotinic carbonitrile (2.4 g,5.82 mmol) in dichloromethane (80 mL) was added zirconium oxychloride hydrate (metalloyl) (2.64 g,9.9 mmol) at 0deg.C under an atmosphere. The mixture was stirred at 0℃for 20 min. By normal phase SiO ₂ The mixture was purified by chromatography (0-10% ethyl acetate/petroleum ether) to afford (S) -6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde (1.2 g, 49%). ¹ H NMR (400 MHz, chloroform-d): delta 10.03 (s, 1H), 8.14 (s, 1H), 7.39 (d, 1H), 7.16 (d, 1H), 7.06 (t, 1H), 5.87-5.79 (m, 1H), 5.58 (d, 1H), 3.96 (s, 3H), 3.05-3.01 (m, 1H), 2.89-2.85 (m, 1H), 2.70-2.68 (m, 1H), 1.95-1.52 (m, 1H).

(h) (S) -2-methoxy-6- ((4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2, 3-dihydro-1H-inden-1-yl) amino) -5- (trifluoromethyl) nicotinaldehyde

To a mixture of (S) -6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde (0.3 g,0.72 mmol) and bis (pinacolato) diborane (0.55 g,2.17 mmol) in 1, 4-dioxane (5 mL) was added potassium acetate (0.21 g,2.17 mmol) and [1,1' -bis (biphenylphosphino) ferrocene]Palladium (II) dichloride complex with dichloromethane (0.03 g,0.04 mmol). The mixture was stirred at 120 ° for 24 hours. The mixture was concentrated and passed through normal phase SiO ₂ The residue was purified by chromatography (0-15% ethyl acetate/petroleum ether) to provide (S) -2-methoxy-6- ((4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2, 3-dihydro-1H-inden-1-yl) amino) -5- (trifluoromethyl) nicotinaldehyde (0.54 g, crude. ¹ H NMR (400 MHz, chloroform-d) δ10.03 (s, 1H), 8.13 (s, 1H), 7.69 (d, 1H),7.31(d,1H),7.19-7.18(m,2H),5.75(q,1H),5.57-5.56(m,1H),3.97(s,3H),3.29-3.27(m,1H),3.03-2.99(m,1H),2.67-2.63(m,1H),1.88-1.83(m,1H),1.28(s,12H).

(i) (S) - (1-Acetylpiperidin-4-yl) ((3 ' -chloro-2 ' - (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) carbamic acid tert-butyl ester

At N ₂ Palladium diacetate (10 mg,0.04 mmol) and triphenylphosphine-3, 3' -trisulphonic acid trisodium salt (0.1 g,0.17 mmol) were combined at MeCN/H ₂ The mixture in the O mixture (1:2, 2.7 mL) was kept under an ultrasonic cleaner for 5 minutes. To the above mixture was added MeCN/H at once ₂ (S) -2-methoxy-6- ((4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2, 3-dihydro-1H-inden-1-yl) amino) -5- (trifluoromethyl) nicotinaldehyde (0.1 g,0.22 mmol), (1-acetylpiperidin-4-yl) ((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridine) in an O mixture (1:2, 6 mL)]-5-yl) methyl-carbamic acid tert-butyl ester (0.1 g,0.19 mmol) and sodium sulfate (0.07 g,0.65 mmol). At N ₂ The mixture was stirred at 100℃for 1 hour. The mixture was combined with another batch at 30mg scale. To the mixture was added water (5 mL) and brine (10 mL). The mixture was extracted with ethyl acetate/THF mixture (1:1, 20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (silica gel, petroleum ether: ethyl acetate=0:1 to afford (S) - (1-acetylpiperidin-4-yl) ((3 ' -chloro-2 ' - (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine)]-5-yl) methyl) carbamic acid tert-butyl ester (0.1 g, 50%). MS: m/z found 809[ M+H ]] ⁺ .

(j) (1-Acetylpiperidin-4-yl) ((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) carbamic acid tert-butyl ester

To (S) - (1-acetylpiperidin-4-yl) ((3 ' -chloro-2 ' - (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine)]A mixture of tert-butyl (5-yl) methyl) carbamate (95 mg,0.12 mmol) and (S) -5- (aminomethyl) -2-pyrrolidone hydrochloride (26 mg,0.18 mmol) in methanol (4 mL) was added sodium acetate (29 mg,0.35 mmol). The mixture was stirred at room temperature for 12 hours. Sodium triacetoxyborohydride (74 mg,0.35 mmol) was added and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated to provide crude (1-acetylpiperidin-4-yl) ((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridine]-5-yl) methyl-carbamic acid tert-butyl ester (0.16 g, crude). MS: m/z found 907[ M+H ]] ⁺ .

(k) (S) -5- ((((6- (((S) -4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

To (1-acetylpiperidin-4-yl) ((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridine ]A mixture of tert-butyl-5-yl-methyl-carbamate (0.15 g,0.16 mmol) in acetonitrile (0.2 mL) was added trifluoroacetic acid (3 mL,41 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide (S) -5- (((6- (((S) -4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3 '-chloro-6-methoxy- [2,4' -bipyridine)]-2' -yl) -2, 3-dihydrogen-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) pyrrolidin-2-one (3.5 mg, 2%). MS: m/z found 807[ M+H ]] ⁺ Retention time = 3.26min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.61(d,1H),7.81(d,1H),7.69(d,1H),7.66(s,1H),7.40(d,1H),7.36-7.30(m,3H),5.89-5.80(m,2H),4.49-4.44(m,1H),4.04(s,3H),3.94-3.87(m,6H),3.83-3.79(m,1H),3.70-3.66(m,2H),3.17-3.13(m,1H),2.85-2.63(m,7H),2.34-2.27(m,3H),2.10-2.02(m,6H),1.83-1.73(m,1H),1.40-1.27(m,2H).

Example 641: (S) -5- ((((2 ' - ((S) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one (633)

(a) (S) - ((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To 2',3' -dichloro-6-methoxy- [2,4' -bipyridine]A mixture of 5-formaldehyde (example 640, step (a)) (5.0 g,5.3 mmol) and (5S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride (1.6 g,10.6 mmol) in dichloromethane (15 mL) was added sodium acetate (1.74 g,21.2 mmol). At N ₂ The mixture was stirred at room temperature for 1.5 hours. Sodium cyanoborohydride (0.67 g,10.6 mmol) was added and the mixture was taken up in N ₂ The mixture was stirred at room temperature for 1.5 hours. To the mixture were added di-tert-butyl dicarbonate (3.66 g,16.8 mmol) and triethylamine (1.33 g,13.11 mmol). At N ₂ The mixture was stirred at room temperature for 1 hour. The mixture was concentrated and passed through normal phase SiO ₂ Chromatography (0-100% EtOAc/petroleum ether) followed by reverse phase HPLC was used to purify the residue to provide (S) - ((2 ',3' -dichloro-6-methoxy- [2,4' -bipyramid)Pyridine and pyridine]-5-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (500 mg,62% yield). ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.54(d,1H),7.83(s,1H),7.75(d,1H),7.62-7.47(m,2H),4.54-4.41(m,2H),4.00(s,3H),3.83-3.82(m,1H),3.36-3.33(m,2H),2.24-2.12(m,3H),1.79-1.78(m,1H),1.49-1.36(m,9H).

(b) ((3 ' -chloro-2 ' - ((S) -1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) carbamic acid tert-butyl ester

To (S) -2-methoxy-6- ((4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2, 3-dihydro-1H-inden-1-yl) amino) -5- (trifluoromethyl) nicotinaldehyde (example 640, step (H)) (0.49 g,1.06 mmol) and (S) - ((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridine)]A mixture of tert-butyl (5-oxopyrrolidin-2-yl) methyl) carbamate (0.3 g,0.62 mmol) in THF/water (20:3, 23 mL) was added potassium phosphate (0.4 g,1.87 mmol) and chloro [ (di (1-adamantyl) -N-butylphosphine) -2- (2-aminobiphenyl) ]Palladium (II) (0.04 g,0.06 mmol). The mixture was stirred at 80℃for 5 hours. The mixture was concentrated and the residue was diluted with water (50 mL) and brine (50 mL). The mixture was extracted with ethyl acetate/THF mixture (1:1, 100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ Chromatography (0-100% ethyl acetate/petroleum ether) purification of the residue to afford ((3 ' -chloro-2 ' - ((S) -1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine) as a yellow solid]-5-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (0.8 g, 40%). MS: m/z actual measurement 781[ M+H ]] ⁺ .

(c) ((2 ' - ((S) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To ((3 ' -chloro-2 ' - ((S) -1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine]A mixture of tert-butyl (S) -5-oxopyrrolidin-2-yl) methyl) carbamate (0.38 g,0.49 mmol) and 1- (4-aminopiperidin-1-yl) ethanone (0.08 g,0.54 mmol) in methanol (6 mL) was added sodium acetate (0.12 g,1.46 mmo). The mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (0.09 g,1.46 mmol) was added and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated and the residue was passed through normal phase SiO ₂ Chromatography (50-100% ethyl acetate/petroleum ether to 20% MeOH/ethyl acetate) and further purification by preparative TLC (silica gel, ethyl acetate: methanol=1:1.5) afforded ((2 ' - ((S) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridine) amino)]-5-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (75 mg, 13%). MS: m/z found 907[ M+H ]] ⁺ .

(d) (S) -5- ((((2 ' - ((S) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one

To ((2 ' - ((S) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridine)]A mixture of tert-butyl-5-yl) methyl (((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (0.07 g,0.08 mmol) in dichloromethane (3 mL) was added 2, 6-lutidine (0.04 g, 0.3)9 mmol) and trimethylsilyl triflate (0.07 ml,0.39 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide (S) -5- (((2 ' - ((S) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridine ]-5-yl-methyl) amino) methyl) pyrrolidin-2-one (2.7 mg, 2%). MS: m/z found 807[ M+H ]] ⁺ Retention time = 3.11min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.51(d,1H),7.71(d,1H),7.62-7.59(m,2H),7.30(d,1H),7.25-7.20(m,3H),5.81-5.75(m,1H),4.44-4.41(m,1H),3.94(s,3H),3.85-3.78(m,4H),3.76-3.68(m,5H),3.06-3.05(m,1H),2.86-2.79(m,1H),2.76-2.73(m,2H),2.62-2.52(m,4H),2.25-2.18(m,3H),2.01-1.92(m,6H),1.74-1.66(m,1H),1.33-1.21(m,2H).

Example 642: (S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one (634)

(a) (3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) carbamic acid tert-butyl ester(((S) -5-oxopyrrolidin-2-yl) methyl)

To ((3 ' -chloro-2 ' - ((S) -1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine]-5-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (example 641, step (b)) (0.38 g,0.49 mmol) and tetrahydro-2H-pyran-4-amine (0.06 g,0.58 mmol) in methanol (6)mL) was added sodium acetate (0.12 g,1.46 mmo). The mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (0.09 g,1.46 mmol) was added and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated and the residue was passed through normal phase SiO ₂ Chromatography (50-100% ethyl acetate/petroleum ether to 20% methanol/ethyl acetate) and further purification by preparative TLC (silica gel, ethyl acetate: meoh=1:1) provided ((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridine)]-5-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (0.1 g, 20%). MS: m/z found 866[ M+H ]] ⁺ .

(b) (S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) pyrrolidin-2-one

To ((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridine)]A mixture of tert-butyl 5-yl) methyl (((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (0.1 g,0.11 mmol) in dichloromethane (3 mL) was added 2, 6-lutidine (0.06 g,0.58 mmol) and trimethylsilyl triflate (0.1 mL,0.58 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide (S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridine) as a white solid ]-5-yl-methyl) amino) methyl) pyrrolidin-2-one (6.7 mg, 2%). MS: m/z found 766[ M+H ]] ⁺ Retention time = 3.24min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.51(d,1H),7.71(d,1H),7.62-7.59(m,2H),7.30(d,1H),7.25-7.20(m,3H),5.81-5.75(m,1H),3.94(s,3H),3.90-3.86(m,2H),3.82(s,3H),3.76-3.70(m,5H),3.35-3.30(m,2H),2.76-2.73(m,3H),2.62-2.52(m,3H),2.25-2.22(m,3H),1.98-1.92(m,1H),1.85-1.83(m,2H),1.75-1.70(m,1H),1.42-1.39(m,2H).

Example 643: (S) -5- ((((6- (((S) -4- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one (666)

(a) (S) - ((3 ' -chloro-2 ' - (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester

At N ₂ Downward (S) -2-methoxy-6- ((4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2, 3-dihydro-1H-inden-1-yl) amino) -5- (trifluoromethyl) nicotinaldehyde (example 640, step (H)) (0.18 g,0.38 mmol) and ((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridine)]A mixture of tert-butyl-5-yl-methyl) (tetrahydro-2H-pyran-4-yl) carbamate (0.1 g,0.21 mmol) in a THF/water mixture (20:1, 20.4 mL) was added potassium phosphate (0.14 g,0.64 mmol) and chloro [ (di (1-adamantyl) -N-butylphosphine) -2- (2-aminobiphenyl) at one time]Palladium (II) (0.02 g,0.02 mmol). The mixture was stirred at 85℃for 5 hours. To the mixture was added water (5 mL). The mixture was extracted with ethyl acetate (2×5 mL). The combined organic phases were washed with brine (2×5 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue passes through normal phase SiO ₂ Chromatography (0-90% MeOH in ethyl acetate) and purification by reverse phase HPLC afforded (S) - ((3 '-chloro-2' - (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2,3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine]-5-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester (13 mg, 4%). MS: m/z found 768[ M+H ]] ⁺ .

(b) (3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester

To (S) - ((3 ' -chloro-2 ' - (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine)]A mixture of tert-butyl (5-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamate (8 mg, 10.4. Mu. Mol) and (S) -5- (aminomethyl) -2-pyrrolidone hydrochloride (2 mg, 12.5. Mu. Mol) in methanol (1.5 mL) was added sodium acetate (1.7 mg, 20.8. Mu. Mol). The mixture was stirred at room temperature for 1.5 hours. Sodium cyanoborohydride (2 mg, 31.2. Mu. Mol) was added and the mixture was stirred at room temperature for 0.5 h. The mixture was concentrated to provide ((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridine) as a white solid ]-5-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester (15 mg, crude). MS: m/z found 866[ M+H ]] ⁺ .

(c) (S) -5- ((((6- (((S) -4- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one

At N ₂ Downward ((3 '-chloro-6-methoxy-2' - ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl))) Methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridine]A mixture of tert-butyl-5-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamate (23 mg,0.03 mmol) in 1, 4-dioxane (1.5 mL) was added in one portion to the aqueous HCl solution (12M, 0.4 mL). The mixture was stirred at room temperature for 1 hour. The mixture was purified by reverse phase HPLC to afford (S) -5- (((6- (((S) -4- (3 '-chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridine) as a white solid (formate salt)]-2' -yl) -2, 3-dihydro-1H-inden-1-yl-amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl-methyl) amino) methyl) pyrrolidin-2-one (1.1 mg, 4%). MS: m/z found m/z 766[ M+H ] ] ⁺ 。 ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),7.94-7.90(m,1H),7.76(s,1H),7.71(d,1H),7.50-7.48(m,1H),7.37-7.32(m,3H),5.93-5.88(m,1H),4.20(s,2H),4.11(s,3H),4.08-4.04(m,3H),3.98(s,3H),3.95-3.88(m,3H),3.46-3.44(m,2H),2.92-2.85(m,4H),2.68-2.65(m,1H),2.40-2.33(m,3H),2.13-2.09(m,3H),1.87-1.81(m,1H),1.69-1.61(m,2H).

Example 644: (S) -5- ((((6- (3-chloro-2- ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (532)

(a) (S) -3-methoxy-5- ((4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2, 3-dihydro-1H-inden-1-yl) amino) -6- (trifluoromethyl) pyrazine-2-carbaldehyde

To (S) -5- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxy-6- (trifluoromethyl) pyrazine-2-carbaldehyde (example 646, step (e)) (2.25 g,5.41 mmol), bis (pinacolato) diborane (2.06 g,8.11 mmol) in 1, 4-dioxane (4)0 mL) was added potassium acetate (1.59 g,16.2 mmol) and [1,1' -bis (biphenylphosphino) ferrocene]Palladium (II) dichloride complex with dichloromethane (441 mg,0.540 mmol). At N ₂ The mixture was stirred at 110℃for 5 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc (2×15 mL). The combined organic phases were dried over anhydrous sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (8-15% EtOAc/petroleum ether) to give (S) -3-methoxy-5- ((4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2, 3-dihydro-1H-inden-1-yl) amino) -6- (trifluoromethyl) pyrazine-2-carbaldehyde (2 g,79% yield) as a yellow oil. ¹ H NMR(400MHz,DMSO-d ₆ ):δ9.85(s,1H),8.23(d,1H),7.61(d,1H),7.38-7.37(m，1H),7.26-7.26(m，1H),5.96-5.90(m,1H),3.99(s，3H),3.57-3.48(m，1H),3.03-2.73(m，1H),2.57-2.56(m，1H),2.52-2.27(m，1H),1.39(s,12H).

(b) 6-chloro-1-methyl-1H-pyrrolo [2,3-b ] pyridine-3-carbaldehyde

At N ₂ 6-chloro-1H-pyrrolo [2,3-b ] at room temperature]A mixture of pyridine-3-carbaldehyde (10 g,55.4 mmol), sodium hydroxide (4.43 g,111 mmol) and methyl iodide (15.7 g,111 mmol) in DMF (150 mL) was stirred for 12 hours. To the mixture was added water (500 mL) and extracted with ethyl acetate (3×500 mL). The combined organic phases were dried over anhydrous sulfate, filtered and concentrated. By normal phase SiO ₂ Chromatography (0-35% EtOAc/petroleum ether) purified the residue to afford 6-chloro-1-methyl-1H-pyrrolo [2,3-b ] as a white solid]Pyridine-3-carbaldehyde (8.1 g,75% yield). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ9.92(s,1H),8.52(s,1H),8.42(d,1H),7.39(d,1H),3.88(s,3H).

(c) 1-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrrolo [2,3-b ] pyridine-3-carbaldehyde

To 6-chloro-1-methyl-1H-pyrrolo [2,3-b]A mixture of pyridine-3-carbaldehyde (2.8 g,14.4 mmol) and bis (pinacolato) diborane (11 g,43.2 mmol) in 1, 4-dioxane (60 mL) was added potassium acetate (4.24 g,43.2 mmol) and [1,1' -bis (biphenylphosphino) ferrocene]Complexes of palladium (II) dichloride with dichloromethane (1.17 g,1.44 mmol). At N ₂ The mixture was stirred at 85℃for 2 hours. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x100 mL). The combined organic phases were dried over anhydrous sulfate, filtered and concentrated. By normal phase SiO ₂ Chromatography (0-40% EtOAc/petroleum ether) of the residue afforded 1-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrrolo [2,3-b ] as a brown solid]Pyridine-3-carbaldehyde (850 mg, 20%). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ9.92(s,1H),8.60(s,1H),8.40(d,1H),7.71(d,1H),3.95(s,3H),1.34(s,12H).

(d) 6- (2, 3-dichloropyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridine-3-carbaldehyde

To 1-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrrolo [2,3-b]A mixture of pyridine-3-carbaldehyde (1 g,3.49 mmol) and 2, 3-dichloro-4-iodopyridine (0.96 g,3.49 mmol) in dioxane/water (5:1, 24 mL) was added [1,1' -bis (di-tert-butylphosphino) -ferrocene]Palladium (II) dichloride (0.23 g,0.35 mmol) and potassium phosphate (2.23 g,10.5 mmol). At N ₂ The mixture was stirred at 95℃for 2 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×30 mL). The combined organic phases were dried over anhydrous sulphate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ Chromatography (0-40% EtOAc/petroleum ether) of the residue afforded 6- (2, 3-dichloropyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] as a brown solid]Pyridine-3-carbaldehyde (480 mg,44% yield). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ10.03(s,1H),8.70(s,1H),8.63(d,1H),8.57(d,1H),7.78-7.76(m,2H),4.00(s,3H).

(e) (S) -6- (3-chloro-2- (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridine-3-carbaldehyde

To (S) -3-methoxy-5- ((4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2, 3-dihydro-1H-inden-1-yl) amino) -6- (trifluoromethyl) pyrazine-2-carbaldehyde (150 mg, 489. Mu. Mol) and 6- (2, 3-dichloropyridin-4-yl) -1-methyl-1H-pyrrolo [2, 3-b)]A mixture of pyridine-3-carbaldehyde (340 mg, 734. Mu. Mol) in 1, 4-dioxane/water (4:1, 5 mL) was added potassium carbonate (203 mg,1.47 mmol) and [1,1' -bis (biphenylphosphino) ferrocene]Palladium (II) dichloride complex with dichloromethane (40 mg,49 μmol). At N ₂ The mixture was stirred at 95℃for 1 hour. Evaporating the solvent and passing through normal phase SiO ₂ Chromatography (20-28% ethyl acetate/petroleum ether) purification of the residue to afford (S) -6- (3-chloro-2- (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] as a yellow solid]Pyridine-3-carbaldehyde (270 mg, 52%). MS: m/z found 607[ M+H ]] ⁺ .

(f) (S) -5- ((((6- (3-chloro-2- ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

To (S) -6- (3-chloro-2- (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b]A mixture of pyridine-3-carbaldehyde (260 mg,0.43 mmol), ((S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride (146 mg,0.96 mmol) in methanol (4 mL) was added sodium acetate (105 mg,1.29 mmol). Under N ₂ The mixture was stirred at room temperature for 1 hourWhen (1). Sodium triacetoxyborohydride (272 mg,1.29 mmol) was added and the mixture was taken up in N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was filtered and the filtrate was concentrated and the residue was purified by reverse phase HPLC to provide (S) -5- ((((6- (3-chloro-2- ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2, 3-b) as a white solid (formate salt)]Pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (51 mg, 13%). MS: m/z found 803[ M+H ]] ⁺ Retention time = 2.89min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.66(d,1H),8.29(d,1H),7.72(d,1H),7.65(s,1H),7.58(d,1H),7.37(s，3H),5.88-5.84(m,1H),4.60(s,1H),4.31-4.30(m,2H),4.05-4.01(m,2H),3.96-3.91(m,8H),3.04-3.01(m，2H),2.93-2.89(m,4H),2.66-2.63(m,1H),2.38-2.33(m,6H),1.91-1.86(m,2H).

Example 645: (S) -5- ((((6- (3-chloro-2- ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (545)

(a) 2-chloro-6-methoxy-3- (trifluoromethyl) pyridine

To a solution of 2, 6-dichloro-3- (trifluoromethyl) pyridine (10 g,46 mmol) in methanol (80 mL) was added sodium methoxide (9.2 g,51mmol, 30%). The mixture was stirred at room temperature for 1h and at 60℃for 1 h. The reaction was diluted with water (100 mL) and filtered to provide a filter cake. The filter cake was then dried to provide 2-chloro-6-methoxy-3- (trifluoromethyl) pyridine (7 g,71% yield) as a white solid. The product was used in the next step without further purification. ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.17(d,1H),7.02(d,1H),3.95(s,3H).

(b) 6-chloro-2-methoxy-5- (trifluoromethyl) nicotinaldehyde

To a solution of 2-chloro-6-methoxy-3- (trifluoromethyl) pyridine (4 g,19 mmol) in THF (30 mL) at-78deg.C was added tert-butyllithium (26.2 mL,1.3 mol/L). At N ₂ The mixture was stirred at-78℃for 1 hour, after which time ethyl formate (4.2 g,57 mmol) was added. At N ₂ The mixture was stirred for 0.5 hours. The reaction was quenched with HCl and diluted with water (50 mL). The aqueous layer was extracted with EtOAc (2X 200 mL). The combined organic phases were dried over anhydrous sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-10% EtOAc/petroleum ether) to afford 6-chloro-2-methoxy-5- (trifluoromethyl) nicotinaldehyde as a yellow oil (2.4 g,53% yield). ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.23(s,1H),8.32(s,1H),4.10(s,3H).

(c) 2-chloro-5- (1, 3-dioxolan-2-yl) -6-methoxy-3- (trifluoromethyl) pyridine

To a mixture of 6-chloro-2-methoxy-5- (trifluoromethyl) nicotinaldehyde (2.5 g,10.4 mmol) and ethylene glycol (2.59 g,41.74 mmol) in toluene (25 mL) was added 4-methylbenzenesulfonic acid hydrate (397 mg,2.09 mmol). At N ₂ The mixture was stirred at 130℃for 5 hours. The reaction was quenched with saturated sodium bicarbonate (30 mL) solution and extracted with EtOAc (2X 100 mL). The combined organic phases were dried over anhydrous sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-15% EtOAc/petroleum ether) to afford 2-chloro-5- (1, 3-dioxolan-2-yl) -6-methoxy-3- (trifluoromethyl) pyridine (1.9 g,64% yield) as a colorless oil. ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.03(s,1H),5.87(s,1H),4.02-3.86(m,7H).

(d) (S) -2- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) oxy) -5- (1, 3-dioxolan-2-yl) -6-methoxy-3- (trifluoromethyl) pyridine

To a solution of (S) -4-bromo-2, 3-dihydro-1H-inden-1-ol (1.89 g,8.9 mmol) in DMF (35 mL) at 0deg.C was added sodium hydride (385 mg,9.7mmol, 60%). At N ₂ The mixture was stirred at 0℃for 1 hour. 2-chloro-5- (1, 3-dioxolan-2-yl) -6-methoxy-3- (trifluoromethyl) pyridine (2.1 g,7.4 mmol) was added and the mixture was taken up in N ₂ The mixture was stirred at room temperature for 0.5 hours. A saturated sodium bicarbonate (200 mL) solution was added and the mixture extracted with EtOAc (2X 100 mL). The combined organic phases were dried over anhydrous sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-15% EtOAc/petroleum ether) to afford (S) -2- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) oxy) -5- (1, 3-dioxolan-2-yl) -6-methoxy-3- (trifluoromethyl) pyridine (2 g,59% yield) as a yellow oil. ¹ H NMR(400MHz,DMSO-d ₆ ):δ7.95(s,1H),7.56(d,1H),7.42(d,1H),7.25-7.21(m,1H),6.69-6.64(m,1H),5.90(s,1H),4.09-3.94(m,7H),3.04-3.01(m,1H),2.93-2.91(m,1H),2.77-2.75(m,1H),2.17-2.14(m,1H).

(e) (S) -6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde

To a solution of (S) -2- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) oxy) -5- (1, 3-dioxolan-2-yl) -6-methoxy-3- (trifluoromethyl) pyridine (1.7 g,3.69 mmol) in THF (45 mL) was added HCl (9 mL,6 mol/L). At N ₂ The mixture was stirred at room temperature for 2 hours. The mixture was diluted with saturated sodium bicarbonate solution and extracted with EtOAc (2×100 mL). The combined organic phases were dried over anhydrous sulfate, filtered and concentrated. By normal phase SiO ₂ Chromatography (0-15% EtOAc/petroleum ether) purityThe residue was esterified to provide (S) -6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde (1.4 g,77% yield) as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.17(s,1H),8.33(s,1H),7.63(d,1H),7.50(d,1H),7.29(t,1H),6.82-6.79(m,1H),4.02(s,3H),3.10-3.07(m,1H),3.00-2.98(m,1H),2.85-2.83(m,1H),2.26-2.22(m,1H).

(f) (S) -2-methoxy-6- ((4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -5- (trifluoromethyl) nicotinaldehyde

To a mixture of (S) -6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde (150 mg,0.36 mmol) and bis (pinacolato) diborane (275 mg,1.08 mmol) in 1, 4-dioxane (5 mL) was added [1,1' -bis (biphenylphosphino) ferrocene ]Complexes of palladium (II) dichloride with dichloromethane (29 mg,0.04 mmol) and potassium acetate (106 mg,1.08 mmol). At N ₂ The mixture was stirred at 110℃for 5 hours. The mixture was filtered, the filtrate concentrated and passed through normal phase SiO ₂ The residue was purified by chromatography (0-20% EtOAc/petroleum ether) to afford (S) -2-methoxy-6- ((4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -5- (trifluoromethyl) nicotinaldehyde as a white solid (150 mg,89% yield). ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.12(s,1H),8.29(s,1H),7.68(d,1H),7.57(d,1H),7.31-7.26(m,1H),6.71-6.8(m,1H),4.17(s,3H),3.24-3.20(m,1H),3.12-3.10(m,1H),2.72-2.69(m,1H),2.17-2.14(m,1H),1.32(s,12H).

(g) (S) -6- (3-chloro-2- (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridine-3-carbaldehyde

To 6- (2, 3-dichloropyrazine)Pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b]Pyridine-3-carbaldehyde (example 644, step (d)) (150 mg,0.49 mmol) and a mixture of (S) -2-methoxy-6- ((4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -5- (trifluoromethyl) nicotinaldehyde (454 mg,0.98 mmol) in THF/water (5:1, 6 mL) potassium acetate (312 mg,1.47 mmol) and [1,1' -bis (di-tert-butylphosphino) -ferrocene were added]Palladium (II) dichloride (32 mg,0.05 mmol). At N ₂ The mixture was stirred at 80℃for 3 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The combined organic phases were dried over anhydrous sulfate, filtered and concentrated. By normal phase SiO ₂ Chromatography (0-100% EtOAc/petroleum ether) purification of the residue to afford (S) -6- (3-chloro-2- (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] as a yellow solid]Pyridine-3-carbaldehyde (110 mg, 37%). MS: m/z found 607[ M+H ]] ⁺ .

(h) (S) -5- ((((6- (3-chloro-2- ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

To (S) -6- (3-chloro-2- (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b]Sodium acetate (68 mg, 824. Mu. Mol) was added to a mixture of pyridine-3-carbaldehyde (100 mg, 165. Mu. Mol) and (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride (99 mg, 659. Mu. Mol) in methanol (5 mL). At N ₂ The mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (41 mg, 659. Mu. Mol) was added and the mixture was stirred under N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide (S) -5- (((6- (3-chloro-2- ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (tris) as a white solid Fluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl-pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b]Pyridin-3-yl) methyl) amino) pyrrolidin-2-one (28.5 mg,20% yield). MS: m/z found 803[ M+H ]] ⁺ Retention time = 3.19min (method a). ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.71(d,1H),8.22(d,1H),7.98(s,1H),7.69-7.67(m,3H),7.55(s,1H),7.52-7.41(m,4H),6.64(t,1H),4.04(s,3H),3.90(s,2H),3.83(s,3H),3.65-3.61(m,4H),3.02-2.94(m,1H),2.87-2.73(m,2H),2.11-2.08(m,9H),1.73-1.66(m,2H),1.64-1.54(m,1H),1.29-1.24(m,1H),1.04-1.02(m,1H),0.87-0.82(m,1H).

Example 646: (S) -2- (4- (3-chloro-4- (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one (366)

(a) (S) -5- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -3-chloropyrazine-2-carbonitrile

A solution of (S) -4-bromo-2, 3-dihydro-1H-inden-1-amine hydrochloride (3 g,12.1 mmol) in DMF (30 mL) and N, N-diisopropylethylamine (4.6 mL,26.5 mmol) was stirred at 0deg.C for 10 min. To the mixture was added 3, 5-dichloropyrazine-2-carbonitrile (2.2 g,12.7 mmol). The resulting mixture was stirred at room temperature for 20 minutes. The reaction was combined with another batch on a 2g scale. The reaction mixture was poured into water (50 mL). The combined organic layers were washed with ethyl acetate (3×40 mL). The combined organic layers were washed with brine (2×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (5-50% ethyl acetate/petroleum ether) to afford (S) -5- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -3-chloropyrazine-2-carbonitrile (5.2 g) as a pale yellow solid. ¹ H NMR (400 MHz, methanol-d) ₄ ):δ＝7.85(s,1H),7.44(d,1H),7.28(d,1H),7.15 -7.12(m,1H),5.68(t,1H),3.35 -3.05(m,1H),2.97 -2.92(m,1H),2.90-2.63(m,1H),2.01 -1.97(m,1H).

(b) (S) -5- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxypyrazine-2-carbonitrile

To a solution of (S) -5- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -3-chloropyrazine-2-carbonitrile (5.1 g,14.6 mmol) in methanol (50 mL) was added sodium methoxide (5.25 g,29mmol,30% in MeOH). The mixture was stirred at 40℃for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was triturated with methanol (50 mL) at room temperature for 10min to give (S) -5- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxypyrazine-2-carbonitrile (4.3 g) as a white solid. ¹ H NMR (400 MHz, methanol-d) ₄ )δ＝7.53(s,1H),7.42(d,1H),7.27(d,1H),7.14 -7.10(m,1H),5.71(br s,1H),3.98(d,3H),3.31–3.07(m,1H),2.94 -2.90(m,1H),2.66 -2.64(m,1H),2.04-1.99(m,1H).

(c) (S) -5- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -6-iodo-3-methoxypyrazine-2-carbonitrile

To a solution of S) -5- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxypyrazine-2-carbonitrile (4.3 g,12.5 mmol) in acetic acid (60 mL) was added potassium acetate (3.07 g,31.3 mmol). The suspension was stirred at room temperature for 20 minutes. N-iodosuccinimide (3.03 g,13.4 mmol) was added and the resulting mixture stirred at 50℃for 3 hours. The reaction mixture was diluted with water (40 mL). The solid formed was filtered and the filter cake was washed with water (100 mL). The solid was dried to provide (S) -5- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -6-iodo-3-methoxypyrazine-2-carbonitrile (5.5 g, crude) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ＝7.93(d,1H),7.46(d,1H),7.21 -7.19(m,1H),7.15 -7.12(m,1H),5.57-5.54(m,1H),3.79(s,3H),3.05 -2.98(m,1H),2.90-2.50(m,1H),2.50-2.48(m，1H),2.28 -2.25(m,1H).

(d) (S) -5- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxy-6- (trifluoromethyl) pyrazine-2-carbonitrile

At N ₂ A mixture of (S) -5- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -6-iodo-3-methoxypyrazine-2-carbonitrile (3 g,6.4 mmol), cuprous iodide (I) (1.46 g,7.6 mmol) and methyl 2, 2-difluoro-2-fluorosulfonyl-acetate (6.12 g,4.05 mL) in DMF (40 mL) was stirred under an atmosphere at 120℃for 3 hours. The reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine (2×25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ Chromatography (0-25% ethyl acetate/petroleum ether) purified the residue to afford (S) -5- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxy-6- (trifluoromethyl) pyrazine-2-carbonitrile (1.82 g,3 steps 31%/yield) as a yellow solid. ¹ H NMR (400 MHz, chloroform-d) delta=7.46 (d, 1H), 7.19-7.11 (m, 2H), 5.80-5.76 (m, 2H), 4.04 (s, 3H), 3.11-3.08 (m, 1H), 2.98-2.92 (m, 1H), 2.74-2.72 (m, 1H), 2.01-1.96 (m, 1H)

(e) (S) -5- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxy-6- (trifluoromethyl) pyrazine-2-carbaldehyde

To a solution of (S) -5- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxy-6- (trifluoromethyl) pyrazine-2-carbonitrile (0.55 g,1.33 mmol) in dichloromethane (20 mL) was added bis (cyclopentadienyl) zirconium (IV) chloride (bis (cyclopentadienyl) zirconium (IV) chloride hydride) (0.62 g,2.33 mmol) at 0deg.C. At N ₂ The solution was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×20mL x 3). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous sodium sulfate, filtered andconcentrating under reduced pressure. By normal phase SiO ₂ The residue was purified by chromatography (5-20% ethyl acetate/petroleum ether) to give (S) -5- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxy-6- (trifluoromethyl) pyrazine-2-carbaldehyde (0.15 g,27% yield). ¹ H NMR(400MHz,DMSO-d ₆ ):δ＝9.79(s,1H),8.31(d,1H),7.48 -7.42(m,1H),7.21 -7.19(m,1H),7.16 -7.12(m,1H),5.97(q,1H),3.85(s,3H),3.01 -2.99(m,1H),2.92-2.90(m,1H),2.88-2.86(m,1H),2.31 -2.26(m,1H).

(f) (S) -5- ((4- (2, 3-dichloropyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxy-6- (trifluoromethyl) pyrazine-2-carbaldehyde

(S) -5- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxy-6- (trifluoromethyl) pyrazine-2-carbaldehyde (1 g,2.40 mmol), 2, 3-dichloro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine (1.32 g,4.81 mmol), potassium phosphate (1.53 g,7.21 mmol) and [1,1' -bis (di-tert-butylphosphino) ferrocene]A mixture of palladium (II) dichloride (156 mg, 240. Mu. Mol) in 1, 4-dioxane/water (10:1, 33 mL) was degassed and N ₂ And (5) purging. At N ₂ The mixture was stirred for 3 hours at 100 ℃ under an atmosphere. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (2×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ The residue was purified by chromatography (10-50% ethyl acetate/petroleum ether) to give (S) -5- ((4- (2, 3-dichloropyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxy-6- (trifluoromethyl) pyrazine-2-carbaldehyde (1.1 g,63% yield) as a yellow oil. ¹ H NMR (400 MHz, chloroform-d) delta=9.98 (s, 1H), 8.36 (d, 1H), 7.40-7.39 (m, 2H), 7.27-7.22 (m, 1H), 7.18 (d, 1H), 5.89 (br s, 2H), 4.11 (s, 3H), 2.80 (br s, 2H), 2.06-2.0 (m, 2H).

(g) (S) -5- ((4- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxy-6- (trifluoromethyl) pyrazine-2-carbaldehyde

(S) -5- ((4- (2, 3-dichloropyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxy-6- (trifluoromethyl) pyrazine-2-carbaldehyde (0.6 g,1.24 mmol), 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (651 mg,2.48 mmol), potassium phosphate (791 mg,3.7 mmol) and [1,1' -bis (di-tert-butylphosphino) ferrocene]A mixture of palladium (II) dichloride (405 mg, 620. Mu. Mol) in 1, 4-dioxane/water (10:1, 2.2 mL) was degassed and N ₂ And (5) purging. The mixture was stirred at 95℃for 3 hours. The reaction mixture was quenched by the addition of brine (25 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (2×15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ The residue was purified by chromatography (10-50% ethyl acetate/petroleum ether) to afford (S) -5- ((4- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxy-6- (trifluoromethyl) pyrazine-2-carbaldehyde (0.32 g, 44%) as a yellow solid. MS: m/z found 583.2[ M+H ]] ⁺ .

(h) (S) -2- (4- (3-chloro-4- (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one

To (S) -5- ((4- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxy-6- (trifluoromethyl) pyrazine-2-carbaldehyde (150 mg, 257. Mu. Mol) and 2, 6-diazaspiro [3.4] as the hydrochloride salt]A solution of octan-7-one (126 mg, 772. Mu. Mol) in methanol (1 mL) was added sodium acetate (84 mg,1 mmol). The solution was stirred at room temperature for 12 hours. Sodium triacetoxyborohydride (109 mg, 515. Mu. Mol) was added and the solution was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure and purified by reverse phase HPLCThe residue was taken up to give (S) -2- (4- (3-chloro-4- (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4 ]) as a white solid ]Octane-2-yl) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl-pyridin-2-yl) -2, 6-diazaspiro [3.4]Octane-7-one (29.4 mg, 13%). MS: M/z found 803.3[ (M+H)] ⁺ Retention time = 2.88min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ＝8.59(d,1H),8.49(br s,1H),7.45(br d，1H),7.39-7.29(m,6H),7.22(br d，1H),5.82(br t，1H),4.10 -4.08(m,2H),3.94(s,4H),3.90(s,5H),3.79(br s,4H),3.68(s,4H),3.62(s,2H),3.60(s,2H),2.86-2.84(m,2H),2.64(s,2H),2.61(s,2H),2.17 -2.12(m,1H).

Example 647: (S) -1- (6- ((5- ((4- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxy-6- (trifluoromethyl) pyrazin-2-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one (367)

To (S) -5- ((4- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxy-6- (trifluoromethyl) pyrazine-2-carbaldehyde (example 646, step (g)) (150 mg, 257. Mu. Mol) and 1- (2, 6-diazaspiro [ 3.3)]A solution of heptan-2-yl) ethanone trifluoroacetate (131 mg, 515. Mu. Mol) in methanol (1 mL) was added sodium acetate (84 mg,1 mmol). The solution was stirred at room temperature for 12 hours. Sodium triacetoxyborohydride (109 mg, 515. Mu. Mol) was added thereto and the resulting solution was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure and the residue was purified by reverse phase HPLC to afford (S) -1- (6- ((5- ((4- (2- (4- ((6-acetyl-2, 6-diazaspiro [ 3.3)) as a white solid ]Heptane-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl amino) -3-methoxy-6- (trifluoromethyl) pyrazin-2-yl methyl) -2, 6-diazaspiro [3.3]Heptane-2-yl) ethan-1-one (49 mg, 22%). MS m/z found 831.3[ M+H ]] ⁺ Retention time = 3.06min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ＝8.60(d,1H),8.48(br s,1H),7.45(d,1H),7.39-7.38(m,1H),7.35 -7.30(m,4H),7.22(d,1H),5.83(t,1H),4.34(d,4H),4.14(s,2H),4.09(d,4H),3.99 -3.86(m,17H),2.86-2.83(m,2H),2.66 -2.59(m,1H),2.20 -2.10(m,1H),1.85(s,6H).

Example 648: (S) -5- ((((6- (((S) -4- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one (269)

(a) (S) -6- ((4- (2, 3-dichloropyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde

(S) -6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde (25 mg,0.06 mmol), 2, 3-dichloro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine (17 mg,0.06 mmol), [1,1' -bis (biphenylphosphino) ferrocene]The complex of palladium (II) dichloride with dichloromethane (5 mg,0.01 mmol), and potassium carbonate (21 mg,0.15 mmol) were suspended in 1, 4-dioxane/water (4:1, 2 mL) and the solution was then heated at 100deg.C for 6 hours. The reaction was cooled to room temperature, diluted with 5mL of water, and extracted with EtOAc (3×3 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (0-20% EtOAc/hexanes) to afford (S) -6- ((4- (2, 3-dichloropyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde as a yellow oil (8 mg,27% yield). MS: m/z found 483,485[ M+H ] ] ⁺ .

(b) (S) -6- ((4- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde

Tetrakis (triphenylphosphine) palladium (0) (4 mg,0.05 mmol), potassium carbonate (7 mg,0.05 mmol), (S) -6- ((4- (2, 3-dichloropyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde (8 mg,0.02 mmol), and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (6 mg,0.02 mmol) were suspended in 1, 4-dioxane/water (4:1, 1 ml), and the solution was heated at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 3mL of water, and extracted with EtOAc (3×2 mL). Concentrating the combined organics under reduced pressure and passing through normal phase SiO ₂ The crude sample was purified by chromatography (0-50% EtOAc/hexanes) to afford (S) -6- ((4- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde as a white solid (7 mg,72% yield). MS: m/z found 583[ M+H ]] ⁺ .

(c) (S) -5- ((((6- (((S) -4- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) -amino) methyl) phenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one

(S) -6- ((4- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde (7 mg,0.01 mmol), acetic acid (2 mg,0.02 mmol), and (5S) -5- (aminomethyl) pyrrolidin-2-one (5 mg,0.05 mmol) were dissolved in MeOH/THF (1:1, 1 mL) and the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (2 mg,0.02 mmol) was added and the resulting mixture was stirred at 25 ℃ for 1 hour. The reaction was then diluted with water (2 mL) and extracted with EtOAc (3×2 mL). The combined organics were further washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the crude sample by reverse phase HPLC to afford (S) as a white solid (formate salt)-5- (((6- (((S) -4- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) -amino) methyl) phenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (8 mg,84% yield). LC/MS: m/z found 779,781[ M+H ]] ⁺ Retention time = 2.31min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.61(d,1H),7.94(s,1H),7.54(d,1H),7.49(d,1H),7.44(s,1H),7.37(d,2H),7.31(dd,2H),6.67(s,1H),4.20(s,2H),4.12(d,3H),3.98(d,4H),3.89(s,3H),3.04(s,3H),2.81(s,4H),2.48–2.15(m,7H),1.85(s,2H).

Example 649: (S) -1- (((6- (((S) -4- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) propan-2-ol (270)

In the same manner as described for example 648, (S) -1- (((6- (((S) -4- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde was prepared in step (c) using the intermediate (S) -6- ((4- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) propan-2-ol and replacing (5S) -5- (aminomethyl) -pyrrolidin-2-one with (2S) -1-aminopropane-2-ol. The product was obtained as a white solid (formate). LC/MS: m/z found 701,703[ M+H ]] ⁺ Retention time = 2.38min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.61(d,1H),8.53(s,2H),7.96(s,1H),7.54(d,1H),7.49(d,1H),7.44(s,1H),7.40(d,1H),7.37(s,1H),7.31(dd,2H),6.68(s,1H),4.22(s,2H),4.13(s,3H),3.96(d,7H),2.99(d,2H),2.88–2.61(m,5H),2.22(s,1H),1.21(t,6H).

Example 650: (S) -2- (4- (3-chloro-4- (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one (292)

(a) (S) -6- ((4- (2, 3-dichloropyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde

At N ₂ (S) -6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde (500 mg,1.20 mmol), 2, 3-dichloro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine (362 mg,1.32 mmol), potassium carbonate (498 mg,3.60 mmol) and [1,1' -bis (biphenylphosphino) ferrocene at 95℃C ]A mixture of palladium (II) dichloride complex with dichloromethane (98.1 mg,0.12 mmol) in 1, 4-dioxane/water (5:1, 18 mL) was stirred for 1.5 hours. The mixture was combined with another batch on a 200mg scale. The mixture was diluted with water (30 mL) and extracted with EtOAc (2×30 mL). The combined organic phases were dried over anhydrous sulphate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ Chromatography (0-20% EtOAc/petroleum ether) purified the residue to afford (S) -6- ((4- (2, 3-dichloropyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde (280 mg). ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.13(s,1H),8.48(d,1H),8.30(s,1H),7.58-7.57(m,2H),7.46-7.44(m,1H),7.38-7.36(m,1H),6.79(m,1H),4.18(s,3H),2.90-2.75(m,3H),2.16-2.12(m,1H).

(b) (S) -6- ((4- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde

To (S) -6- ((4 ]A mixture of (2, 3-dichloropyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde (180 mg,0.37 mmol) and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzaldehyde (195 mg,0.74 mmol) in THF/water (5:1, 6 mL) was added potassium phosphate (237 mg,1.12 mmol) and [1,1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) dichloride (24 mg,0.04 mmol). At N ₂ The mixture was stirred at 80℃for 1 hour. The mixture was diluted with water (30 mL) and extracted with EtOAc (2×10 mL). The combined organic phases were dried over anhydrous sulphate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ Chromatography (0-40% EtOAc/petroleum ether) purified the residue to afford (S) -6- ((4- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde (130 mg, crude). MS: m/z found 583[ M+H ]] ⁺ .

(c) (S) -2- (4- (3-chloro-4- (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one

At N ₂ (S) -6- ((4- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde (120 mg,0.21 mmol), 2, 6-diazaspiro [ 3.4)]A mixture of octan-7-one (104 mg,0.82 mmol) and sodium acetate (101 mg,1.24 mmol) in methanol (5 mL) was stirred for 0.5 h. Sodium cyanoborohydride (78 mg,1.24 mmol) was added and the mixture was taken up in N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford (S) -2- (4- (3-chloro-4- (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4 ])]Octane-2-yl) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy-2, 3-dihydro-1H-inden-4-yl-pyridin-2-yl) -2, 6-diazaspiro [3.4 ]Octane-7-one (40.6 mg, 23%). MS: m/z found 803[ M+H ]] ⁺ Retention time =3.28min (method A). ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.64(d,1H),7.79(s,1H),7.54(s,1H),7.47(d,1H),7.40(t,1H),7.34-7.31(m,2H),7.24-7.22(m,2H),6.61-6.58(m,1H),3.99(s,3H),3.86(s,3H),3.57(s,2H),3.47(s,2H),3.38-3.35(m,4H),3.21-3.14(m,8H),3.86-3.76(m,3H),2.33(s,2H),2.31(s,2H),2.09-2.05(m,1H).

Example 651: (S) -2- (4- (3-chloro-4- (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-2-yl) -2-fluoro-6-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one (306)

(a) (S) -6- ((4- (3-chloro-2- (3-fluoro-4-formyl-5-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde

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To a mixture of (S) -6- ((4- (2, 3-dichloropyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde (example 650, step (a)) (100 mg,0.21 mmol) and 2-fluoro-6-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (116 mg,0.41 mmol) in THF/water (5:1, 6 mL) was added potassium phosphate (132 mg,0.62 mol) and [1,1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) dichloride (14 mg,0.02 mmol). At N ₂ The mixture was stirred at 80℃for 1 hour. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2×20 mL). The combined organic phases were dried over anhydrous sulfate, filtered and concentrated. By normal phase SiO ₂ Chromatography (0-30% EtOAc/petroleum ether) purified the residue to afford (S) -6- ((4- (3-chloro-2- (3-fluoro-4-formyl-5-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde (95 mg, crude). MS: m/z found 601[ M+H ]] ⁺ .

(b) (S) -2- (4- (3-chloro-4- (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-2-yl) -2-fluoro-6-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one

At N ₂ (S) -6- ((4- (3-chloro-2- (3-fluoro-4-formyl-5-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde (76 mg, 599. Mu. Mol), 2, 6-diazaspiro [ 3.4)]A mixture of octan-7-one and sodium acetate (73.71 mg, 899. Mu. Mol) in methanol (8 mL) was stirred for 1.5 hours. Sodium cyanoborohydride (57 mg, 899. Mu. Mol) was added and the mixture was stirred under N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford (S) -2- (4- (3-chloro-4- (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4 ])]Octane-2-yl) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy-2, 3-dihydro-1H-inden-4-yl-pyridin-2-yl) -2-fluoro-6-methoxybenzyl-2, 6-diazaspiro [3.4 ]Octane-7-one (27.9 mg, 22%). MS: m/z found 821[ M+H ]] ⁺ Retention time = 3.32min (method a). ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.69(d,1H),7.82(s,1H),7.57-7.50(m,4H),7.43(t,1H),7.36-7.34(m,1H),7.16-7.14(m,2H),6.64-6.63(m,1H),4.02(s,3H),3.87(s,3H),3.60(s,2H),3.50(s,2H),3.38(s,2H),3.31(s,2H),3.19(s,8H),3.89-3.87(m,3H),2.36(s,2H),2.31(s,2H),2.11-2.06(m,1H).

Example 652: (S) -2- ((2 ' - (1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one (551)

(a) 2- ((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one

6- (2, 3-dichloro-4-pyridinyl) -2-methoxy-pyridine-3-carbaldehyde (200 mg,0.71 mmol), 2, 6-diazaspiro [3.4]]Octan-7-one (125 mg,0.99 mmol), and acetic acid (21 mg,0.35 mmol) were dissolved in MeOH/THF (1:1, 4 mL) and the solution was stirred at 25℃for 2 h. The reaction was cooled to 0deg.C and sodium cyanoborohydride (89 mg,1.41 mmol) was added in portions over 3 minutes. The resulting mixture was warmed to 25 ℃ and stirred for an additional 1 hour. The reaction was concentrated under reduced pressure and the residue was dissolved in 15mL DCM. The organic solution was washed with water (2×15 mL) and brine solution, then dried over sodium sulfate. The solution was concentrated under reduced pressure and the crude sample was purified by silica gel chromatography (0-10% meoh/DCM) to provide 2- ((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridine) as a clear oil ]-5-yl) methyl) -2, 6-diazaspiro [3.4]Octan-7-one (203 mg,73% yield). MS: m/z found 393,395[ M+H ]] ⁺ .

(b) (S) -6- ((4- (3 ' -chloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) - [2,4' -bipyridyl ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde

Tetrakis (triphenylphosphine) palladium (0) (19 mg,0.02 mmol), potassium carbonate (35 mg,0.25 mmol), and (S) -2-methoxy-6- ((4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -5- (trifluoromethyl) nicotinaldehyde (example 645, step (f)) (39 mg,0.08 mmol), and 2- ((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridine]-5-yl) methyl) -2, 6-diazaspiro [3.4]Octan-7-one (46 mg,0.12 mmol) was suspended in 1, 4-dioxane/water (4:1, 3 ml) and the solution was then heated at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×10 mL). Concentrating the combined organics under reduced pressure and introducingPassing normal phase SiO ₂ The crude sample was purified by chromatography (0-100% EtOAc/hexanes) to afford (S) -6- ((4- (3' -chloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [ 3.4) as a yellow solid]Octane-2-yl) methyl) - [2,4' -bipyridine]-2' -yl) -2, 3-dihydro-1H-inden-1-yl-oxy) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde (16 mg,28% yield). MS: m/z found 694,696[ M+H ] ] ⁺ 。

(c) (S) -2- ((2 ' - (1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one

(S) -6- ((4- (3' -chloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4 ])]Octane-2-yl) methyl) - [2,4' -bipyridine]-2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde (16 mg,0.02 mmol), acetic acid (3 mg,0.05 mmol), and 1- (4-amino-1-piperidinyl) ethanone (7 mg,0.05 mmol) were dissolved in MeOH/THF (1:1, 1 mL), and the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (4 mg,0.07 mmol) was added and the resulting mixture was stirred at 25 ℃ for 1 hour. The reaction was filtered through CELITE and the filtrate was concentrated under reduced pressure. The crude sample was purified by reverse phase HPLC to provide (S) -2- ((2 ' - (1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridine) as a white solid (formate salt)]-5-yl) methyl) -2, 6-diazaspiro [3.4]Octan-7-one (4 mg,19% yield). LC/MS: m/z found 820,822[ M+H ] ] ⁺ Retention time = 2.28min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.60(d,1H),8.50(s,1H),7.98(s,1H),7.76(d,1H),7.70(d,1H),7.55(s,1H),7.41(d,3H),6.69(d,1H),4.57(d,1H),4.14(d,3H),4.02(d,6H),3.76(s,2H),3.59(s,2H),3.46(s,4H),3.25–2.96(m,3H),2.89–2.64(m,3H),2.59(s,2H),2.12(s,6H),1.39(s,2H).

Example 653: (S) -2- ((3 ' -chloro-6-methoxy-2 ' - (1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one (552)

In a similar manner to that described with respect to example 652, intermediate (S) -6- ((4- (3' -chloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [ 3.4) was utilized in step (c)]Octane-2-yl) methyl) - [2,4' -bipyridine]-2 '-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde and replacement of 1- (4-amino-1-piperidinyl) ethanone with tetrahydropyran-4-amine to prepare (S) -2- ((3' -chloro-6-methoxy-2 '- (1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridine]-5-yl) methyl) -2, 6-diazaspiro [3.4]Octane-7-one. The product was obtained as a white solid (formate). LC/MS: m/z found 779,781[ M+H ]] ⁺ Retention time = 2.35min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.60(d,1H),8.53(s,1H),7.97(s,1H),7.75(d,1H),7.70(d,1H),7.55(d,1H),7.44–7.36(m,3H),6.69(t,1H),4.13(s,3H),4.04–3.95(m,7H),3.73(s,2H),3.58(s,2H),3.42(d,6H),3.10–2.96(m,2H),2.88–2.70(m,2H),2.58(s,2H),2.27–2.14(m,1H),2.00(d,2H),1.63–1.48(m,2H).

Example 654:2- ((3 ' -chloro-2 ' - ((S) -1- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one (553)

In a similar manner to that described with respect to example 652, intermediate (S) -6- ((4- (3' -chloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [ 3.4) was utilized in step (c)]Octane-2-yl) methyl) - [2,4' -bipyridine]-2 '-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde and (2S) -1-aminopropane-2-ol was used instead of 1- (4-amino-1-piperidinyl) ethanone to prepare 2- ((3' -chloro-2 '- ((S) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine]-5-yl) methyl) -2, 6-diazaspiro [3.4]Octane-7-one. The product was obtained as a white solid (formate). LC/MS: m/z found 753,755[ M+H ]] ⁺ Retention time = 2.31min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.60(d,1H),8.52(s,1H),7.99(s,1H),7.75(d,1H),7.70(d,1H),7.56(s,1H),7.43–7.37(m,3H),6.69(s,1H),4.15(s,3H),4.07(s,2H),4.01(s,4H),3.73(s,2H),3.58(s,2H),3.44(s,4H),2.92(s,2H),2.76(s,3H),2.58(s,2H),2.21(s,1H),1.21(d,3H).

Example 655: (S) -5- ((((2 ' - ((S) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one (527)

(a) (S) - ((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

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To 2',3' -dichloro-6-methoxy- [2,4' -bipyridine]A mixture of (5-Formaldehyde (example 640, step (a)) (5.0 g,5.3 mmol), (5S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride (1.6 g,10.6 mmol) in DCM (15 mL) was added sodium acetate (1.74 g,21.2 mmol) followed by N ₂ The mixture was stirred at room temperature for 1.5 hours. Sodium cyanoborohydride (0.67 g,10.6 mmol) was then added and the mixture was taken up in N ₂ The mixture was stirred at room temperature for 1.5 hours to afford (S) -5- ((((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridine)]-5-yl) Methyl) amino) methyl) pyrrolidin-2-one (MS: m/z found 381[ M+H ]] ⁺ ). Di-tert-butyl dicarbonate (3.66 g,16.8 mmol) and triethylamine (1.33 g,13.11mmol,1.83ml,2.5 eq) were then added and the mixture was taken up in N ₂ The mixture was stirred at room temperature for 1 hour. Concentrating the mixture and passing through normal phase SiO ₂ The residue was purified by chromatography (0-100% EtOAc/petroleum ether) to afford the crude product (1.9 g). 800mg of the crude product was purified by reverse phase HPLC to afford (S) - ((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridine)]-5-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (500 mg,62% yield). ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.54(d,1H),7.83(s,1H),7.75(d,1H),7.62-7.47(m,2H),4.54-4.41(m,2H),4.00(s,3H),3.83-3.82(m,1H),3.36-3.33(m,2H),2.24-2.12(m,3H),1.79-1.78(m,1H),1.49-1.36(m,9H).

(b) ((3 ' -chloro-2 ' - ((S) -1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) carbamic acid tert-butyl ester

To (S) - ((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridine)]-5-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (300 mg,0.62 mmol) and a mixture of (S) -2-methoxy-6- ((4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -5- (trifluoromethyl) nicotinaldehyde (example 645, step (f)) (577 mg,1.25 mmol) in THF/water (5:1, 12 mL) was added potassium phosphate (397 mg,1.87 mmol) and [2- (amino-. Kappa.N) [1, 1-biphenyl)]-2-yl- κC]Chloro [ dicyclohexyl [2,4, 6-tris (1-methylethyl) [1, 1-biphenyl ]]-2-yl]Phosphine (P)]Palladium (49 mg,0.06 mmol). At N ₂ The mixture was stirred at 80℃for 6 hours. The mixture was diluted with water (10 mL) and extracted with EtOAc (2×25 mL). The combined organic phases were dried over anhydrous sulphate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ The residue was purified by chromatography (0-100% EtOAc/petroleum ether) as ((3 '-chloro-2' - ((S) -1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridine)Pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl-6-methoxy- [2,4' -bipyridine]-5-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (190 mg, 38%). MS: m/z actual measurement 782[ M+H ]] ⁺ .

(c) ((2 ' - ((S) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) carbamic acid tert-butyl ester(((S) -5-oxopyrrolidin-2-yl) methyl)

At N ₂ ((3 ' -chloro-2 ' - ((S) -1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine) is reacted at room temperature]A mixture of tert-butyl 5-yl) methyl (((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (180 mg, 230. Mu. Mol), 1- (4-aminopiperidin-1-yl) ethanone (65.4 mg, 460. Mu. Mol) and sodium acetate (57 mg, 690. Mu. Mol) in methanol (10 mL) was stirred for 1 hour. Sodium triacetoxyborohydride (146 mg, 690. Mu. Mol) was added and the mixture was stirred under N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and the residue was purified by preparative TLC (SiO 2, etOAc: meoh=3:1) to afford ((2 ' - ((S) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridine)]-5-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (145 mg, 69%). MS: m/z found 908[ M+H ]] ⁺ .

(d) (S) -5- ((((2 ' - ((S) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one

At N ₂ ((2 ' - ((S) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridine) is reacted at room temperature]-5-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (140 mg,154 μmol) and a mixture of HCl/dioxane (2 mol/L,12 mL) in DCM/MeOH (3:1, 8 mL) was stirred for 5 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide (S) -5- (((2 ' - ((S) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridine]-5-yl-methyl) amino) methyl) pyrrolidin-2-one (14.1 mg, 10%). MS: m/z found 808[ M+H ]] ⁺ Retention time = 3.14min (method a). ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.70(d,1H),7.99(s,1H),7.89(d,1H),7.71-7.69(m,2H),7.50(d,1H),7.45-7.38(m,3H),6.63(t,1H),4.16-4.13(m,1H),4.04(s,3H),3.95(s,3H),3.74-3.63(m,6H),3.09-3.06(m,1H),2.93-2.81(m,1H),2.75-2.67(m,6H),2.34-2.09(m,6H),1.98(s,3H),1.83-1.70(m,3H),1.25-1.10(m,2H).

Example 656: (S) -5- ((((6- (((S) -4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (544)

(a) (S) - (1-Acetylpiperidin-4-yl) ((3 ' -chloro-2 ' - (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) carbamic acid tert-butyl ester

To (1-acetylpiperidin-4-yl) ((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridine)]-5-yl) methyl) amino groupA mixture of tert-butyl formate (example 640, step (c)) (300 mg,0.59 mmol) and (S) -2-methoxy-6- ((4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -5- (trifluoromethyl) nicotinaldehyde (example 645, step (f)) (406 mg,1.18 mmol) in THF/water (5:1, 6 mL) was added potassium phosphate (375 mg,1.77 mmol) and [2- (amino-. Kappa.N) [1, 1-biphenyl ]]-2-yl- κC]Chloro [ dicyclohexyl [2,4, 6-tris (1-methylethyl) [1, 1-biphenyl ]]-2-yl]Phosphine (P)]Palladium (46.3 mg,0.065 mmol). At N ₂ The mixture was stirred at 80℃for 4 hours. The mixture was concentrated and purified by preparative TLC (SiO ₂ The residue was purified with EtOAc: meoh=9:1) as a yellow oil of (S) - (1-acetylpiperidin-4-yl) ((3 ' -chloro-2 ' - (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine]-5-yl) methyl-carbamic acid tert-butyl ester (150 mg, 31%). MS: m/z found 810[ M+H ]] ⁺ .

(b) (1-Acetylpiperidin-4-yl) ((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) carbamic acid tert-butyl ester

At N ₂ (S) - (1-Acetylpiperidin-4-yl) ((3 ' -chloro-2 ' - (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine) at room temperature]A mixture of tert-butyl (140 mg, 173. Mu. Mol), (5S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride (52 mg, 346. Mu. Mol) and sodium acetate (43 mg, 518. Mu. Mol) in methanol (5 mL) was stirred for 5 hours. Sodium triacetoxyborohydride (110 mg, 518. Mu. Mol) was added and the mixture was stirred under N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and purified by preparative TLC (SiO ₂ The residue was purified with EtOAc in meoh=3:1 to afford (1-acetylpiperidin-4-yl) as a yellow oil (3 '-chloro-6-methoxy-2' - ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidine) S-j-1)2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridine]-5-yl) methyl) carbamic acid tert-butyl ester (60 mg, 38%). MS: m/z found 908[ M+H ]] ⁺ .

(c) (S) -5- ((((6- (((S) -4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one

At N ₂ (1-Acetylpiperidin-4-yl) ((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridine) at room temperature]A mixture of tert-butyl 5-yl methyl carbamate (60 mg, 66. Mu. Mol) and HCl/dioxane (2 mol/L,6 mL) in DCM/MeOH (4:1, 5 mL) was stirred for 5 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide (S) -5- (((6- (((S) -4- (5- (((1-acetylpiperidin-4-yl) amino) methyl)) methyl) -3 '-chloro-6-methoxy- [2,4' -bipyridine) as a white solid]-2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl-methyl) amino) pyrrolidin-2-one (11.9 mg, 21%). MS: m/z found 808[ M+H ]] ⁺ Retention time = 3.21min (method a). ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.70(d,1H),7.98(s,1H),7.91(d,1H),7.70(d,2H),7.50(d,1H),7.44-7.38(m,3H),6.63(t,1H),4.17-4.14(m,1H),4.04(s,3H),3.95(s,3H),3.76-3.73(m,3H),3.65-3.60(m,3H),3.10-3.07(m,1H),3.00-2.90(m,1H),2.82-2.67(m,4H),2.13-2.09(m,6H),1.99(s,3H),1.87-1.81(m,2H),1.69-1.64(m,1H),1.31-1.13(m,2H).

Example 657: (S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one (608)

(a) (3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) carbamic acid tert-butyl ester((S) -5-oxopyrrolidin-2-yl) methyl)

At N ₂ ((3 ' -chloro-2 ' - ((S) -1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine) is reacted at room temperature]A mixture of tert-butyl 5-yl) methyl (((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (example 655, step (b)) (190 mg, 243. Mu. Mol), tetrahydro-2H-pyran-4-amine (49.1 mg, 486. Mu. Mol) and sodium acetate (60 mg, 729. Mu. Mol) in methanol (5 mL) was stirred for 3 hours. Sodium triacetoxyborohydride (154 mg, 729. Mu. Mol) was added and the mixture was stirred under N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and purified by preparative TLC (SiO ₂ EtOAc: meoh=3:1) the residue was purified to provide ((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridine) as a white solid]-5-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (45 mg, 21%). MS: m/z found 867[ M+H ]] ⁺ .

(b) (S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one

At N ₂ ((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridine) is reacted at room temperature]-5-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (80 mg, 92. Mu. Mol) and a mixture of HCl/dioxane (2 mol/L,10 mL) in DCM/MeOH (3:1, 8 mL) was stirred for 5 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide (S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridine) as a white solid]-5-yl-methyl) amino) methyl) pyrrolidin-2-one (3.6 mg, 9%). MS: m/z found 767[ M+H ]] ⁺ Retention time = 3.28min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.62(d,1H),7.93(s,1H),7.83(d,1H),7.73(d,1H),7.59-7.57(m,1H),7.44-7.41(m,3H),6.69(t,1H),4.13(s,3H),4.06(s,3H),4.00-3.97(m,2H),3.87-3.81(m,5H),3.51-3.44(m,2H),3.07-2.99(m,1H),2.77-2.70(m,5H),2.38-2.26(m,4H),1.95-1.83(m,3H),1.53-1.31(m,2H).

Example 658: (S) -1- (6- ((6- ((4- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one (248)

(a) (S) -3' -chloro-2 ' - (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine ] -5-carbaldehyde

Tetrakis (triphenylphosphine) palladium (0) (51 mg,0.04 mmol), potassium carbonate (91 mg,0.66 mmol), (S) -2-methoxy-6- ((4- (4, 5-tetramethyl-1),3, 2-Dioxaborane-2-yl) -2, 3-dihydro-1H-inden-1-yl-oxy) -5- (trifluoromethyl) nicotinaldehyde (example 645, step (f)) (102 mg,0.22 mmol), and 2',3' -dichloro-6-methoxy- [2,4' -bipyridine]5-Formaldehyde (example 640, step (a)) (94 mg,0.33 mmol) was suspended in 1, 4-dioxane/water (4:1, 3 mL) and the solution was then heated at 105℃for 20 min. The reaction was cooled to room temperature, diluted with 10mL of water, and extracted with EtOAc (3×5 mL). Concentrating the combined organics under reduced pressure and passing through normal phase SiO ₂ The crude sample was purified by chromatography (0-100% etoac/hexanes) to afford (S) -3' -chloro-2 ' - (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine as a yellow solid]-5-Formaldehyde (67 mg,52% yield). MS: m/z found 584[ M+H ]] ⁺ .

(b) (S) -1- (6- ((6- ((4- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one

(S) -3' -chloro-2 ' - (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine]-5-Formaldehyde (16 mg,0.03 mmol), 1- (2, 6-diazaspiro [ 3.3)]Heptan-2-yl) ketene (5 mg,0.03 mmol), and acetic acid (3 mg,0.05 mmol) were dissolved in MeOH/THF (1:1, 1 mL) and the solution was stirred at 25℃for 4 h. Sodium cyanoborohydride (3 mg,0.05 mmol) was then added and the resulting mixture was stirred at 25 ℃ for 2 hours. The reaction was diluted with water (2 mL) and extracted with EtOAc (3×2 mL). The combined organics were further washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude sample was purified by reverse phase HPLC to provide (S) -1- (6- ((6- ((4- (5- ((6-acetyl-2, 6-diazaspiro [ 3.3)) as a white solid (formate))]Heptane-2-yl) methyl) -3 '-chloro-6-methoxy- [2,4' -bipyridine]-2' -yl) -2, 3-dihydro-1H-inden-1-yl-oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) Methyl) -2, 6-diazaspiro [3.3]Heptane-2-yl) ethan-1-one (2 mg,7% yield). LC/MS: m/z found 832,834[ M+H ]] ⁺ Retention time = 2.34min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.61(d,1H),8.45(s,2H),7.93–7.84(m,1H),7.78(d,1H),7.70(d,1H),7.54(s,1H),7.46–7.33(m,3H),6.67(s,1H),4.32(s,4H),4.11(t,3H),4.07(s,4H),4.03(t,3H),3.85(d,3H),3.74(d,7H),2.98(s,1H),2.87–2.69(m,2H),1.84(s,6H).

Example 659: (S) -1- (((3 ' -chloro-2 ' - ((S) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) propan-2-ol (253)

In the same manner as described for example 658, intermediate (S) -3' -chloro-2 ' - (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine is utilized in step (b)]-5-Formaldehyde and (S) -1-aminopropane-2-ol instead of 1- (2, 6-diazaspiro [3.3 ]]Heptane-2-yl) ketene to prepare (S) -1- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine]-5-yl) methyl) amino) propan-2-ol. The product was obtained as a white solid (formate). LC/MS: m/z measured values 702,704[ M+H ]] ⁺ Retention time = 2.27min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.62(m,1H),8.52(s,1H),8.01(s,1H),7.89(d,1H),7.71(m,1H),7.56(d,1H),7.50–7.43(m,1H),7.43–7.36(m,2H),6.70(t,1H),4.18–4.12(m,5H),4.11(s,2H),4.09–4.06(m,3H),4.02(d,2H),3.07–2.91(m,3H),2.90–2.66(m,4H),2.27–2.16(m,1H),1.25–1.15(m,6H).

Example 660: (S) -1- (4- (((6- ((4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (254)

In the same manner as described for example 658, intermediate (S) -3' -chloro-2 ' - (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) -pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine is utilized in step (b) ]-5-Formaldehyde and substitution of 1- (2, 6-diazaspiro- [3.3 ] with 1- (4-amino-1-piperidinyl) -ethanone]Heptane-2-yl) ketene to prepare (S) -1- (4- (((6- ((4- (5- (((1-acetylpiperidin-4-yl) amino) methyl)) 3 '-chloro-6-methoxy- [2,4' -bipyridine)]-2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) piperidin-1-yl) ethan-1-one. The product was obtained as a white solid (formate). LC/MS: m/z found 836,838[ M+H ]] ⁺ Retention time = 2.31min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.66–8.58(m,1H),8.51(s,1H),8.00(s,1H),7.88(d,1H),7.71(m,1H),7.56(s,1H),7.48–7.42(m,1H),7.39(m,2H),6.70(d,1H),4.55(d,2H),4.16–4.11(m,3H),4.09–4.05(m,5H),4.01(d,4H),3.23–2.95(m,5H),2.90–2.62(m,4H),2.11(d,11H),1.43(m,4H).

Example 661: (S) -2- ((3 ' -chloro-6-methoxy-2 ' - (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one (336)

(a) (S) -2- ((3 ' -chloro-6-methoxy-2 ' - (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one

At N ₂ (S) -3' -chloro-2 ' - (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine) at room temperature ]-5-Formaldehyde (17 mg, 29.1. Mu. Mol), 2, 6-diazaspiro [3.4 ]]A mixture of octane-7-one (15 mg, 116. Mu. Mol) and sodium acetate (14.3 mg, 175. Mu. Mol) in methanol (3 mL) was stirred for 1.5 hours. Sodium cyanoborohydride (11.0 mg, 175. Mu. Mol) was added to the solution, and the mixture was stirred at room temperature for 0.5 hr. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide (S) -2- ((3 '-chloro-6-methoxy-2' - (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [ 3.4) as a white solid]Octane-2-yl) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridine]-5-yl) methyl) -2, 6-diazaspiro [3.4]Octane-7-one (3.8 mg, 15%). MS: m/z found 804[ M+H ]] ⁺ Retention time = 3.02min (method a). ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.69(d,1H),7.82-7.78(m,2H),7.68(d,1H),7.56(d,2H),7.50(d,1H),7.45-7.40(m,3H),6.64-6.61(m,1H),4.03(s,3H),3.93(s,3H),3.58(s,2H),3.50(s,2H),3.43-3.40(m,4H),3.28-3.19(m,8H),2.97-2.96(m,1H),2.82-2.76(m,1H),2.38(s,2H),2.36(s,2H),2.10-2.09(m,1H).

Example 662: n- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (656)

(a) 2-chloro-3- (2, 3-dichloropyridin-4-yl) aniline

3-bromo-2-chloro-aniline (428 mg,2.04 mmol), 2, 3-dichloro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine (400 mg, 1) were placed in a sealed tube.46 mmol), [1,1' -bis (biphenylphosphino) ferrocene]Palladium (II) dichloride complex with dichloromethane (119 mg,0.15 mmol), and potassium carbonate (564 mg,4.09 mmol) were suspended in 15ml1, 4-dioxane. Nitrogen was bubbled through the reaction solution for 2 minutes, then the vessel was sealed and heated at 75 ℃ for 18 hours. The reaction was filtered through CELITE and the filtrate was concentrated under reduced pressure. The crude sample was purified by silica gel chromatography (0-30% EtOAc/hexanes) to afford 2-chloro-3- (2, 3-dichloropyridin-4-yl) aniline as a white solid (206 mg,52% yield). MS: m/z found 273,275[ M+H ] ] ⁺ .

(b) 4- (4- (3-amino-2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzaldehyde

Tetrakis (triphenylphosphine) palladium (0) (174 mg,0.15 mmol), potassium carbonate (312 mg,2.26 mmol), 2-chloro-3- (2, 3-dichloropyridin-4-yl) aniline (206 mg,0.75 mmol), and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (257 mg,0.98 mmol) were suspended in 1, 4-dioxane/water (4:1, 15 ml), and the solution was then heated at 105 ℃ for 20 min. The reaction was cooled to room temperature, diluted with 20mL of water, and extracted with EtOAc (3×10 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (10-50% EtOAc/hexanes) to afford 4- (4- (3-amino-2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzaldehyde as a yellow oil (168 mg,60% yield). MS: m/z found 373,375[ M+H ]] ⁺ .

(c) N- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide

1- [ bis (dimethylamino) methylene]-1H-1,2, 3-triazolo [4,5-b]Pyridinium 3-oxide Hexafluorophosphate (HATU) (257 mg,0.68 mmol), 1, 3-dimethyl-2, 4-dioxo-pyrimidine-5-carboxylic acid (91 mg,0.50 mmol),And 2 equivalents of N, N-diisopropylethylamine were dissolved in 5mL of DMF, and the mixture was stirred at room temperature for 20 minutes. This solution was added dropwise at room temperature to a solution of 4- (4- (3-amino-2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzaldehyde (168 mg,0.45 mmol) and 2 equivalents of N, N-diisopropylethylamine in 5mL DMF. The resulting mixture was stirred at 70 ℃ for 18 hours. The reaction was diluted with water (30 mL) and extracted with EtOAc (3X 10 mL). The combined organics were concentrated under reduced pressure and the crude sample purified by silica gel chromatography (5-80% EtOAc/hexanes) to afford N- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (44 mg,18% yield) as a yellow solid. MS: m/z found 539,541[ M+H ] ] ⁺ .

(d) N- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide

N- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (14 mg,0.03 mmol), acetic acid (3 mg,0.05 mmol), and 1- (4-amino-1-piperidinyl) ethanone (11 mg,0.08 mmol) were dissolved in MeOH/THF (1:1, 1 mL), and the solution was stirred at 25℃for 2 hours. Sodium cyanoborohydride (5 mg,0.08 mmol) was added and the resulting mixture was stirred at 25 ℃ for 1 hour. The reaction was filtered through CELITE and the filtrate was concentrated under reduced pressure. The crude sample was purified by reverse phase HPLC to provide N- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (8 mg,48% yield) as a white solid (formate). LC/MS: m/z found 665,667[ M+H ]] ⁺ Retention time = 2.37min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.67(s,1H),8.65(d,1H),8.61(d,1H),8.52(s,1H),7.52–7.42(m,3H),7.37(s,1H),7.33(d,1H),7.13(d,1H),4.62(d,1H),4.21(s,2H),4.04(d,1H),3.98(s,3H),3.56(s,3H),3.39(s,3H),3.27–3.11(m,2H),2.69(t,1H),2.12(s,5H),1.67–1.35(m,2H).

Example 663: (S) -N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (657)

In a similar manner to that described for example 662, (S) -N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((5-oxo-pyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide was prepared in step (d) using the intermediate N- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) and (5S) -5- (aminomethyl) pyrrolidin-2-one instead of 1- (4-amino-1-piperidinyl) ethanone. The product was obtained as a white solid (formate). LC/MS: m/z found 637,639[ M+H ]] ⁺ Retention time = 2.33min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.67(s,1H),8.63(dd,2H),8.46(s,1H),7.46(t,2H),7.42(d,1H),7.36(s,1H),7.32(d,1H),7.13(d,1H),4.14(s,2H),3.97(s,4H),3.56(s,3H),3.39(d,3H),2.98(s,2H),2.37(d,3H),1.85(s,1H).

Example 664: n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (658)

In a similar manner to that described for example 662, the intermediate N- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine is utilized in step (d)-5-carboxamide and 2, 6-diazaspiro [3.4] ]Preparation of N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4 ]) using octan-7-one instead of 1- (4-amino-1-piperidinyl) ethanone]Octane-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide. The product was obtained as a white solid (formate). LC/MS: m/z found 649,651[ M+H ]] ⁺ Retention time = 2.34min (method C). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.67(d,1H),8.63(dd,2H),8.46(s,1H),7.50–7.39(m,3H),7.36–7.28(m,2H),7.13(d,1H),4.18(s,2H),3.95(s,3H),3.91(s,4H),3.63(s,2H),3.56(d,3H),3.39(s,3H),2.66(s,2H).

Example 665:1- (2- ((6- (2-chloro-3- (3-chloro-2- (4- ((4-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octane-6-yl) ethan-1-one (692)

(a) 2- ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octane-6-carboxylic acid tert-butyl ester

To 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (0.10 g,0.25 mmol), 2, 6-diazaspiro [3.4]]A mixture of tert-butyl octane-6-carboxylate (0.11 g,0.51 mmol), and 4A molecular sieve (1 g) in 1:1THF/MeOH (8 mL) was added acetic acid (0.03 g,0.51 mmol) and the mixture stirred at room temperature for 3 hours. Sodium cyanoborohydride (0.04 g,0.64 mmol) was then added and the mixture was stirred at room temperature for 30 minutes. The reaction was quenched by the addition of 1mL of water, then diluted with 50mL of ethyl acetate and washed with saturated aqueous brine solution (1×30 mL). The aqueous layer was extracted with ethyl acetate (3×30 mL), then the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. By positive rapid SiO ₂ Chromatography, collectionThe residue was purified with a linear gradient (0-5% methanol/dichloromethane) to provide 2- ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4]Tert-butyl octane-6-carboxylate (0.14 g,93% yield). MS: m/z found 589[ M+H ]] ⁺ .

(b) 1- (2- ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octane-6-yl) ethan-1-one

2- ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] was accommodated using dichloromethane (3 ml) and trifluoroacetic acid (1 ml) pair]Tert-butyl octane-6-carboxylate (0.05 g,0.08 mmol) was fed into the flask. The reaction was stirred for 10 min, then evaporated, and the crude product was used as TFA salt (0.06 g,10% yield). MS: m/z found 489[ M+H ]] ⁺ . To the material were added potassium carbonate (0.06 g,0.41 mmol), acetonitrile (5 ml), and acetyl chloride (0.02 g,0.25 mmol). The reaction was stirred at 90 ℃ for 2 hours, then evaporated, diluted with 50mL ethyl acetate and then washed with saturated aqueous brine solution (1 x30 mL). The aqueous layer was extracted with ethyl acetate (3×30 mL), then the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. By positive rapid SiO ₂ Chromatography, purification of the residue using a linear gradient (0-10% methanol/dichloromethane) provided 1- (2- ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [ 3.4)]Octane-6-yl) ethan-1-one (0.094 g,22% yield). MS: m/z found 531[ M+H ]] ⁺ .

(c) 4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzaldehyde:

with 2-methoxy-4- (4, 5-tris)Methyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (0.06 g,0.24 mmol), 1- (2- ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4]To the flask was fed octane-6-yl) ethan-1-one (0.10 g,0.19 mmol), potassium carbonate (0.08 g,0.56 mmol), and tetrakis (triphenylphosphine) palladium (0) (0.04 g,0.04 mmol). The flask was purged with nitrogen, then 1, 4-dioxane (16 mL) was added, and the reaction was bubbled with nitrogen, then 4mL of water was added. The mixture was stirred thermally at 110℃for 30 minutes. The mixture was diluted with 50mL of ethyl acetate, then washed with saturated aqueous brine solution (1×30 mL), then the aqueous layer was extracted with ethyl acetate (3×30 mL), and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. By positive rapid SiO ₂ Chromatography, purification of the residue using a gradient (0-5% MeOH/dichloromethane) provided 4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [ 3.4))]Octane-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl-2-methoxybenzaldehyde (0.085 g,71% yield). MS: m/z found 631[ M+H ]] ⁺ .

(d) 1- (2- ((6- (2-chloro-3- (3-chloro-2- (4- ((4-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-6-yl) ethan-1-one

To 4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.4 ])]A mixture of octane-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl-2-methoxybenzaldehyde (0.09 g,0.14 mmol), piperidin-4-ol (0.03 g,0.29 mmol), and 4A molecular sieve (1 g) in 1:1THF/MeOH (20 mL) was added to acetic acid (0.02 g,0.29 mmol) and the mixture stirred at room temperature for 3 hours. Sodium cyanoborohydride (0.02 g,0.36 mmol) was then added and the mixture stirred at room temperature for 30 minutes. The reaction was quenched by the addition of 1mL of water, then diluted with 50mL of ethyl acetate and washed with saturated aqueous brine solution (1×30 mL). The aqueous layer was extracted with ethyl acetate (3×30 mL) and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. By preparative HPLC (containing 0.05% formic acid modifier) to provide 1- (2- ((6- (2-chloro-3- (3-chloro-2- (4- ((4-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4]Octane-6-yl) ethan-1-one (0.038 g,40% yield). MS: m/z found 716[ M+H ]] ⁺ Retention time = 1.63min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.65(d,1H),8.34(s,1H),7.80(t,1H),7.70(dd,1H),7.55(t,2H),7.49–7.33(m,4H),7.30(dd,1H),4.36(s,2H),4.17(s,1H),4.11(s,1H),4.03(d,3H),3.98(s,3H),3.90–3.75(m,4H),3.72(s,1H),3.65–3.60(m,1H),3.55(t,1H),3.43(t,3H),3.27-3.15(m,4H),2.27(t,1H),2.17(t,1H),2.03(d,4H),1.83(s,2H).

Example 666:1- (2- (4- (3-chloro-4- (2-chloro-3- (5- ((4-hydroxypiperidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octane-6-yl) ethan-1-one (693)

In a similar manner to example 665, 2, 6-diazaspiro [3.4] is replaced with piperidin-4-ol in step (a)]Octane-6-carboxylic acid tert-butyl ester and 2, 6-diazaspiro [3.4] used in step (d)]Preparation of 1- (2- (4- (3-chloro-4- (2-chloro-3- (5- ((4-hydroxypiperidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] by substituting piperidin-4-ol with octan-7-one]Octan-6-yl) ethan-1-one. MS: m/z found 716[ M+H ]] ⁺ The method comprises the steps of carrying out a first treatment on the surface of the Retention time = 1.62min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.63(d,1H),8.46(s,1H),7.85(d,1H),7.72(dd,1H),7.55(t,1H),7.51–7.38(m,3H),7.37–7.26(m,3H),4.28(s,1H),4.22(s,1H),4.03(d,5H),3.99–3.83(m,7H),3.82(s,1H),3.72(s,1H),3.63(s,1H),3.55(t,1H),3.43(t,1H),3.22(s,2H),2.86(s,2H),2.28(t,1H),2.17(t,1H),2.06–1.92(m,5H),1.77–1.69(m,2H).

Example 667:1- ((3 ' -chloro-2 ' - (2-chloro-3- (5- ((4-hydroxypiperidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) piperidin-4-ol (759)

In a similar manner to example 595, 1- ((3 ' -chloro-2 ' - (2-chloro-3- (5- ((4-hydroxypiperidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin was prepared in step (b) using piperidin-4-ol instead of 1- (4-amino-1-piperidinyl) ethanone]-5-yl) methyl) piperidin-4-ol. The formate obtained is converted into the free base. MS: m/z found 664[ M+H ]] ⁺ The method comprises the steps of carrying out a first treatment on the surface of the Retention time = 1.59min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.60(d,1H),7.81(d,1H),7.79–7.68(m,3H),7.53(t,1H),7.48–7.38(m,2H),7.25(d,1H),3.98(d,6H),3.67–3.55(m,6H),2.84(d,4H),2.27(t,4H),1.85(dd,4H),1.58(q,4H).

Example 668:1- (2- ((6- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octane-6-yl) ethan-1-one (760)

In a similar manner to example 595, 1- (2, 6-diazaspiro [ 3.4) was used in step (b)]Preparation of 1- (2- ((6- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.4 ])) by substituting 1- (4-amino-1-piperidinyl) ethan-1-one for 1- (6-acetyl-2, 6-diazaspiro [ 3.4))]Octane-2-yl) methyl) -3 '-chloro-6-methoxy- [2,4' -bipyridine]-2' -yl) -2-chlorophenyl) -2-methoxypyridin-3-yl-methyl) -2, 6-diazaspiro [3.4]Octan-6-yl) ethan-1-one. The formate obtained is converted into the free base. MS m/z found 770[ M+H ] ] ⁺ Retention time = 1.65min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.60(d,1H),7.77–7.64(m,4H),7.53(t,1H),7.48–7.36(m,2H),7.24(dd,1H),3.99(dd,6H),3.73(t,4H),3.65(s,2H),3.56–3.48(m,4H),3.42–3.34(m,10H),2.19(t,2H),2.14–1.97(m,8H).

Example 669:1- (4- (((6- (2-chloro-3- (3 ' -chloro-5- ((4-hydroxypiperidin-1-yl) methyl) -6-methoxy- [2,4' -bipyridin ] -2' -yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (761)

(a) 1- ((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) piperidin-4-ol

To 2',3' -dichloro-6-methoxy- [2,4' -bipyridine]A mixture of 5-formaldehyde (example 640, step (a)) (0.10 g,0.35 mmol), piperidin-4-ol (0.07 g,0.71 mmol) and 4A molecular sieve (1 g) in 1:1THF/MeOH (20 mL) was added acetic acid (0.04 g,0.71 mmol) and the mixture stirred at room temperature for 3 hours. Sodium cyanoborohydride (0.06 g,0.88 mmol) was then added and the mixture stirred at room temperature for 30 minutes. The reaction was quenched by the addition of 1mL of water. The reaction was then diluted with 50mL of ethyl acetate, washed with saturated aqueous brine solution (1×30 mL), and then the aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. By positive rapid SiO ₂ Chromatography, purification of the residue using a linear gradient (0-10% MeOH/dichloromethane) provided 1- ((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridine)]-5-yl) methyl) piperidin-4-ol (0.1 g,77% yield). MS: m/z found 368[ M+H ] ] ⁺ .

(b) 1- (4- (((6- (2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

To 6- (2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -2-methoxynicotinaldehyde (0.50 g,1.34 mmol), 1- (4-aminopiperidin-1-yl) ethan-1-one (0.21 g,1.47 mmol), and 4A moleculesA mixture of sieve (1 g) in 1:1THF/MeOH (20 mL) was added acetic acid (0.1 g,1.61 mmol) and the mixture stirred at room temperature for 3 hours. Sodium cyanoborohydride (0.1 g,1.61 mmol) was then added and the mixture stirred at room temperature for 30 minutes. The reaction was quenched by the addition of 1mL of water. The mixture was diluted with 50mL of ethyl acetate, then washed with saturated aqueous brine solution (1×30 mL), and then the aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. By positive rapid SiO ₂ Chromatography, purification of the residue using a linear gradient (0-10% MeOH in dichloromethane) provided 1- (4- (((6- (2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (0.46 g,69% yield). MS: m/z found 500[ M+H ] ] ⁺ .

(c) 1- (4- (((6- (2-chloro-3- (3 ' -chloro-5- ((4-hydroxypiperidin-1-yl) methyl) -6-methoxy- [2,4' -bipyridin ] -2' -yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

With 1- (4- (((6- (2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (0.07 g,0.14 mmol), 1- ((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridine)]5-yl) methyl piperidin-4-ol (0.05 g,0.14 mmol), potassium carbonate (0.06 g,0.41 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.03 g,0.03 mmol) were fed to the flask. The flask was purged with nitrogen, then 1, 4-dioxane (16 mL) was added and the reaction was bubbled with nitrogen, then 4mL of water was added. The mixture was stirred at 110℃for 30 minutes. The mixture was diluted with 50mL of ethyl acetate, then washed with saturated aqueous brine solution (1×30 mL), then the aqueous layer was extracted with ethyl acetate (3×30 mL), then the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (containing 0.05% formic acid modifier). Acetonitrile was evaporated and the aqueous layer was then basified with 5% sodium carbonate and extracted with ethyl acetate (5×10 ml). The combined organic layers were evaporated and then added 2mL of water was added and the aqueous portion was lyophilized to provide 1- (4- (((6- (2-chloro-3- (3 '-chloro-5- ((4-hydroxypiperidin-1-yl) methyl)) 6-methoxy- [2,4' -bipyridine)]-2' -yl) phenyl) -2-methoxypyridin-3-yl methyl) amino) piperidin-1-yl-ethan-1-one (0.014 g,15% yield). MS: m/z found 705[ M+H ]] ⁺ Retention time = 1.57min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.60(d,1H),7.84–7.67(m,4H),7.53(t,1H),7.48–7.37(m,2H),7.25(d,1H),4.45(d,1H),3.99(d,6H),3.91(d,1H),3.84(s,2H),3.65–3.56(m,3H),3.12(t,1H),2.88–2.72(m,3H),2.76–2.63(m,1H),2.26(t,2H),2.10–1.93(m,6H),1.86–1.80(m,1H),1.65–1.51(m,2H),1.43–1.24(m,2H).

Example 670: (R) -1- ((3 ' -chloro-2 ' - (2-chloro-3- (5- (((R) -3-hydroxypyrrolidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) pyrrolidin-3-ol (772)

In a similar manner to example 595, (R) -1- ((3 ' -chloro-2 ' - (2-chloro-3- (5- (((R) -3-hydroxypyrrolidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin-e was prepared in step (b) using (R) -pyrrolidin-3-ol instead of 1- (4-amino-1-piperidinyl) ethanone]-5-yl) methyl) pyrrolidin-3-ol. The formate obtained is converted into the free base. MS: m/z found 636[ M+H ]] ⁺ Retention time = 1.66min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.59(d,1H),7.82(d,1H),7.78–7.66(m,3H),7.52(t,1H),7.47–7.36(m,2H),7.24(d,1H),4.38–4.28(m,2H),3.98(d,6H),3.76–3.62(m,4H),2.89–2.73(m,4H),2.64–2.50(m,4H),2.21–2.07(m,2H),1.77–1.64(m,2H).

Example 671: (S) -1- ((3 ' -chloro-2 ' - (2-chloro-3- (5- (((S) -3-hydroxypyrrolidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) pyrrolidin-3-ol (773)

In a similar manner to example 595, (S) -1- ((3 ' -chloro-2 ' - (2-chloro-3- (5- (((S) -3-hydroxypyrrolidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin-e was prepared in step (b) using (S) -pyrrolidin-3-ol instead of 1- (4-amino-1-piperidinyl) ethanone]-5-yl) methyl) pyrrolidin-3-ol. The formate obtained is converted into the free base. MS: m/z found 636[ M+H ]] ⁺ Retention time = 1.66min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.59(d,1H),7.82(d,1H),7.78–7.66(m,3H),7.52(t,1H),7.47–7.36(m,2H),7.24(d,1H),4.38–4.28(m,2H),3.98(d,6H),3.77–3.63(m,4H),2.90–2.75(m,4H),2.65–2.51(m,4H),2.21–2.07(m,2H),1.77–1.66(m,2H).

Example 672:1- (4- (((3 ' -chloro-2 ' - (2-chloro-3- (5- ((4-hydroxypiperidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) piperidin-1-yl) ethan-1-one (774)

This compound is made in a similar manner to example 669 by substituting 1- (4-aminopiperidin-1-yl) ethan-1-one for piperidin-4-ol in step (a) and substituting piperidin-4-ol for 1- (4-aminopiperidin-1-yl) ethan-1-one in step (b). MS: m/z found 705[ M+H ]] ⁺ ； ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.58(dd,1H),7.77(d,1H),7.76–7.65(m,3H),7.51(t,1H),7.46–7.35(m,2H),7.23(dd,1H),4.42(d,1H),4.02–3.92(m,6H),3.82(s,2H),3.55(s,2H),3.09(t,1H),2.87–2.63(m,4H),2.24(t,3H),2.08–1.91(m,5H),1.81(d,2H),1.59–1.52(m,2H),1.37–1.22(m,3H).

Example 673: n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((methylamino) methyl) pyridine amide (694)

Formate salt was prepared from N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) phenyl) -5-formylpyridinamide (40 mg,0.08 mmol) and methylamine solution (33% wt in ethanol, 0.32 mmol) N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((methylamino) methyl) picolinamide by reductive amination procedure A. 87% yield. LCMS: m/z found 536.2[ M+H ] ] ⁺ Retention time = 2.55min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.73(d,1H),8.72–8.60(m,2H),8.53(s,2H),8.30(d,1H),8.09(dd,1H),7.55(t,1H),7.51(d,1H),7.47(d,1H),7.41(d,1H),7.36(dd,1H),7.21(dd,1H),4.26(s,2H),4.07(s,2H),4.00(s,3H),2.74(s,3H),2.58(s,3H).

Example 674: n- (3- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((methylamino) methyl) picolinamide (696)

N- (3- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((methylamino) methyl) picolinamide was prepared from N- (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5-formylpyridinamide (50 mg,0.10 mmol) and a solution of methylamine (33% wt in ethanol, 0.41 mmol) by reductive amination procedure A. 92% yield. LCMS: m/z found 516.2[ M+H ]] ⁺ Retention time = 1.46min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.72–8.65(m,1H),8.60(d,1H),8.21(d,1H),8.05–7.91(m,2H),7.46–7.35(m,3H),7.31–7.22(m,2H),7.11(dd,1H),3.93(s,3H),3.85(s,2H),3.82(s,2H),2.45–2.36(m,6H),2.18(s,3H).

Example 675: n- (3- (3-chloro-2- (3- (difluoromethoxy) -4- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide (725)

(a) N- (3- (3-chloro-2- (3- (difluoromethoxy) -4-formylphenyl) pyridin-4-yl) -2-methylphenyl) -5-formylpyridinamide

To a mixture of N- (3- (2, 3-dichloropyridin-4-yl) -2-methylphenyl) -5-formylpyridinamide (example 628, step (c)) (50 mg,0.13 mmol), (3- (difluoromethoxy) -4-formyl-phenyl) boronic acid (28 mg,0.13 mmol) and potassium phosphate (82 mg,0.39 mmol) in degassed 1, 4-dioxane/water (6:1) was added [1,1' -bis (di-tert-butylphosphino) ferrocene ]Palladium (II) dichloride (8 mg,0.01 mmol) and the mixture was stirred at 90℃for 2 hours. Water was added and the mixture was extracted three times into EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to afford N- (3- (3-chloro-2- (3- (difluoromethoxy) -4-formylphenyl) pyridin-4-yl) -2-methylphenyl) -5-formylpyridinamide (60 mg, 89%). LCMS m/z found 522.1[ M+H ]] ⁺ .

(b) N- (3- (3-chloro-2- (3- (difluoromethoxy) -4- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide

A mixture of N- (3- (3-chloro-2- (3- (difluoromethoxy) -4-formylphenyl) pyridin-4-yl) -2-methylphenyl) -5-formylpyridinamide (30 mg,0.06 mmol), (S) -5- (aminomethyl) pyrrolidin-2-one (26 mg,0.23 mmol) and acetic acid (3 uL,3mg,0.06 mmol) in MeOH/THF (1:1) was stirred at room temperature for 1 hour before sodium cyanoborohydride (14 mg,0.23 mmol) was added. The mixture was stirred for an additional 30 minutes, quenched with water, and purified directly by reverse phase chromatography to provide the product as formate. The collected fractions were pooled and in trueAcetonitrile was removed under air. The concentrated aqueous solution was neutralized with aqueous sodium carbonate and the product was extracted into dichloromethane three times. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to provide N- (3- (3-chloro-2- (3- (difluoromethoxy) -4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide (25 mg, 54%) as the free base. LCMS: m/z found 718.3[ M+H ] ] ⁺ Retention time = 1.54min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.70(d,1H),8.63(d,1H),8.21(d,1H),8.03(dd,1H),7.99(d,1H),7.63–7.56(m,2H),7.51(s,1H),7.44–7.35(m,2H),7.12(d,1H),6.96(t,1H),3.99–3.89(m,4H),3.87–3.77(m,2H),2.77–2.62(m,4H),2.38–2.22(m,6H),2.17(s,3H),1.88–1.76(m,2H).

Example 676: n- (3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide (726)

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(a) N- (3- (3-chloro-2- (3-fluoro-4-formyl-5-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5-formylpyridinamide

To a mixture of N- (3- (2, 3-dichloropyridin-4-yl) -2-methylphenyl) -5-formylpyridinamide (example 628, step (c)) (30 mg,0.08 mmol), (3-fluoro-4-formyl-5-methoxy-phenyl) boronic acid (15 mg,0.08 mmol) and potassium phosphate (49 mg,0.23 mmol) in degassed 1, 4-dioxane/water (6:1) was added [1,1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) dichloride (5 mg,0.01 mmol) and the mixture was stirred overnight at 90 ℃. Water was added and the mixture was extracted three times into EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to provide N- (3- (3-chloro) s-2- (3-fluoro-4-formyl-5-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5-formylpyridinamide (13 mg, 33%). LCMS m/z found 504.1[ M+H ]] ⁺ .

(b) N- (3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide

A mixture of N- (3- (3-chloro-2- (3-fluoro-4-formyl-5-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5-formylpyridinamide (10 mg,0.02 mmol), (S) -5- (aminomethyl) pyrrolidin-2-one (9 mg,0.08 mmol) and acetic acid (1 uL,1mg,0.02 mmol) in MeOH/THF (1:1) was stirred at room temperature for 1 hour before sodium cyanoborohydride (5 mg,0.08 mmol) was added. The mixture was stirred for an additional 30 minutes, quenched with water, and purified directly by reverse phase chromatography to provide the product as formate. The collected fractions were combined and acetonitrile was removed under vacuum. The concentrated aqueous solution was neutralized with aqueous sodium carbonate and the product was extracted into dichloromethane three times. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to afford N- (3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide (6 mg, 43%) as the free base. LCMS: m/z found 700.3[ M+H ]] ⁺ Retention time = 1.49min (method D).

Example 677: (S) -N- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) -5- (((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide (747)

(a) (S) -N- (3- (2, 3-dichloropyridin-4-yl) -2-methylphenyl) -5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide

A mixture of N- (3- (2, 3-dichloropyridin-4-yl) -2-methylphenyl) -5-formylpyridinamide (example 628, step (c)) (300 mg,0.78 mmol), (S) -5- (aminomethyl) pyrrolidin-2-one (177 mg,1.55 mmol) and acetic acid (44 uL,47mg,0.78 mmol) in MeOH/THF (1:1) was stirred at room temperature for 1 hour. Sodium cyanoborohydride (98 mg,1.55 mmol) was added and the mixture was stirred for an additional 2 hours and quenched with water. After concentration, the crude material was extracted three times into dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under vacuum to afford (S) -N- (3- (2, 3-dichloropyridin-4-yl) -2-methylphenyl) -5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide which was used directly in the next step without further purification. LCMS: m/z found 484.1[ M+H ]] ⁺ Retention time = 0.74min (method B).

(b) (S) - ((6- ((3- (2, 3-dichloropyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To a solution of (S) -N- (3- (2, 3-dichloropyridin-4-yl) -2-methylphenyl) -5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide (300 mg,0.62 mmol) in dichloromethane was added di-tert-butyl dicarbonate (149 mg,0.68 mmol) and a catalytic amount of DMAP (8 mg,0.06 mmol). The mixture was stirred for 2 hours, concentrated in vacuo, and purified on a silica gel column with MeOH in dichloromethane (0 to 10% gradient) as eluent to afford tert-butyl (S) - ((6- ((3- (2, 3-dichloropyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate. LCMS: m/z found 584.2[ M+H ] ] ⁺ Retention time = 1.02min (method B).

(c) (S) - ((6- ((3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) carbamic acid tert-butyl ester

To a solution of tert-butyl (S) - ((6- ((3- (2, 3-dichloropyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (280 mg,0.48 mmol), 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (126 mg,0.48 mmol) and potassium carbonate (199mg, 1.44 mmol) in degassed 1, 4-dioxane/water (6:1) was added [1,1' -bis (biphenylphosphino) ferrocene]Palladium (II) dichloride complex with dichloromethane (39 mg,0.05 mmol) and the mixture was stirred at 130 ℃ for 2 hours. Water was added and the mixture was extracted three times into EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to afford tert-butyl (S) - ((6- ((3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (280 mg, 85%). LCMS: m/z found 684.3[ M+H ]] ⁺ Retention time = 1.00min (method B).

(d) (S) - ((6- ((3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

A mixture of (S) - ((6- ((3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (30 mg,0.04 mmol), 1- (4-aminopiperidin-1-yl) ethan-1-one (12 mg,0.09 mmol) and acetic acid (3 uL,3mg,0.04 mmol) in MeOH/THF (1:1) was stirred at room temperature for 1 hour. Adding cyanoboronSodium hydride (6 mg,0.09 mmol), the mixture was stirred for an additional 30 min, quenched with water and purified directly by reverse phase chromatography to afford tert-butyl (S) - ((6- ((3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (32 mg,90% yield). LCMS: m/z found 810.4[ M+H ]] ⁺ Retention time = 2.31min (method D).

(e) (S) -N- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) -5- (((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide

A mixture of (S) - ((6- ((3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (30 mg,0.04 mmol) and dichloromethane/trifluoroacetic acid (1:1) was stirred for 30 minutes, concentrated and purified directly by reverse phase chromatography. The collected fractions were combined and acetonitrile was removed under vacuum. The concentrated aqueous solution was neutralized with aqueous sodium carbonate and the product was extracted into dichloromethane three times. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to afford (S) -N- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) -5- (((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide (19 mg,73% yield) as the free base. LCMS: m/z found 710.3[ M+H ]] ⁺ Retention time = 1.58min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.70(s,1H),8.60(d,1H),8.20(d,1H),8.08–8.01(m,1H),7.99(d,1H),7.46–7.33(m,3H),7.32–7.22(m,2H),7.11(d,1H),4.47(d,1H),3.96–3.86(m,8H),3.86–3.77(m,1H),3.17–3.10(m,1H),2.80–2.62(m,4H),2.37–2.30(m,2H),2.30–2.22(m,1H),2.18(s,3H),2.10(s,3H),2.06–1.93(m,2H),1.87–1.77(m,1H),1.43–1.30(m,2H).

Example 678: (S) -N- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide (748)

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(a) (S) - ((6- ((3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

A mixture of (S) - ((6- ((3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (example 677, step (c)) (30 mg,0.04 mmol), tetrahydro-2H-pyran-4-amine (9 mg,0.09 mmol) and acetic acid (3 uL,3mg,0.04 mmol) in MeOH/THF (1:1) was stirred at room temperature for 1 hour. Sodium cyanoborohydride (6 mg,0.09 mmol) was added and the mixture was stirred for an additional 30 min, quenched with water and purified directly by reverse phase chromatography to afford tert-butyl (S) - ((6- ((3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (27 mg, 80%). LCMS: m/z found 769.3[ M+H ]] ⁺ Retention time = 2.38min (method D).

(b) (S) -N- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide

Will be%A mixture of S) - ((6- ((3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (30 mg,0.04 mmol) and dichloromethane/trifluoroacetic acid (1:1) was stirred for 30 minutes, concentrated and purified directly by reverse phase chromatography. The collected fractions were combined and acetonitrile was removed under vacuum. The concentrated aqueous solution was neutralized with aqueous sodium carbonate and the product was extracted into dichloromethane three times. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to afford (S) -N- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide (18 mg, 69%) as the free base. LCMS: m/z found 669.3[ M+H ] ] ⁺ Retention time = 1.61min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.70(s,1H),8.60(d,1H),8.20(d,1H),8.03(dd,1H),8.01–7.95(m,1H),7.40(dd,3H),7.30–7.22(m,2H),7.11(d,1H),3.99–3.95(m,1H),3.95–3.91(m,6H),3.90–3.87(m,2H),3.85–3.78(m,1H),3.43–3.35(m,2H),2.77–2.60(m,3H),2.37–2.30(m,2H),2.29–2.22(m,1H),2.18(s,3H),1.95–1.86(m,2H),1.86–1.77(m,1H),1.53–1.39(m,2H).

Example 679: (S) -N- (3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide (749)

(a) (S) - ((6- ((3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) carbamic acid tert-butyl ester

(S) - ((6-)) at room temperatureA mixture of tert-butyl (3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (example 677, step (c)) (30 mg,0.04 mmol), 3-fluoropropane-1-amine (7 mg,0.09 mmol) and acetic acid (3 uL,3mg,0.04 mmol) in MeOH/THF (1:1) was stirred for 1 hour. Sodium cyanoborohydride (6 mg,0.09 mmol) was added and the mixture was stirred for an additional 30 min, quenched with water and purified directly by reverse phase chromatography to afford tert-butyl (S) - ((6- ((3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (27 mg, 82%). LCMS: m/z found 745.3[ M+H ] ] ⁺ Retention time = 2.43min (method D).

(b) (S) -N- (3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide

A mixture of (S) - ((6- ((3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) tert-butyl (5-oxopyrrolidin-2-yl) methyl) carbamate (20 mg,0.03 mmol) and dichloromethane/trifluoroacetic acid (1:1) was stirred for 30 minutes, concentrated and purified directly by reverse phase chromatography. The collected fractions were combined and acetonitrile was removed under vacuum. The concentrated aqueous solution was neutralized with aqueous sodium carbonate and the product was extracted into dichloromethane three times. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to provide tert-butyl (S) - ((6- ((3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (12 mg, 68%) as the free base. LCMS: m/z found 645.3[ M+H ]] ⁺ Retention time = 1.65min (method D). ¹ H NMR (400 MHz, acetonitrile-d) ₃ ):δ10.14(s,1H),8.73–8.47(m,2H),8.31–8.09(m,2H),7.97(dd,1H),7.39(dt,2H),7.33–7.19(m,3H),7.06(dd,1H),6.15(s,1H),4.59(t,1H),4.47(t,1H),3.97–3.81(m,5H),3.78(s,2H),3.71–3.63(m,1H),2.73–2.62(m,3H),2.55(dd,1H),2.24–2.07(m,6H),1.92–1.67(m,3H).

Example 680: (S) -N- (3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide (750)

(a) (S) - ((6- ((3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) carbamic acid tert-butyl ester

A mixture of (S) - ((6- ((3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (example 677, step (c)) (30 mg,0.04 mmol), 2-aminoethanol (5 mg,0.09 mmol) and acetic acid (3 uL,3mg,0.04 mmol) in MeOH/THF (1:1) was stirred at room temperature for 1 hour. Sodium cyanoborohydride (6 mg,0.09 mmol) was added and the mixture was stirred for an additional 30 min, quenched with water and purified directly by reverse phase chromatography to afford tert-butyl (S) - ((6- ((3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (20 mg, 62%). LCMS: m/z found 729.3[ M+H ]] ⁺ Retention time = 2.27min (method D).

(b) (S) -N- (3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide

A mixture of (S) - ((6- ((3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) tert-butyl (5-oxopyrrolidin-2-yl) methyl) carbamate (20 mg,0.03 mmol) and dichloromethane/trifluoroacetic acid (1:1) was stirred for 30 minutes, concentrated and purified directly by reverse phase chromatography. The collected fractions were combined and acetonitrile was removed under vacuum. The concentrated aqueous solution was neutralized with aqueous sodium carbonate and the product was extracted into dichloromethane three times. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to afford (S) -N- (3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide (10 mg, 57%) as the free base. LCMS: m/z found 629.3[ M+H ]] ⁺ Retention time = 1.53min (method D).

Example 681:2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6- (2-methoxyacetyl) -2, 6-diazaspiro [3.3] heptan-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one (687)

(a) 2-methoxy-1- (2, 6-diazaspiro [3.3] heptane-2-yl) ethane-1-one trifluoroacetate salt

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To 2, 6-diazaspiro [3.3]]A mixture of tert-butyl heptane-2-carboxylate half-oxalate (0.75 g,1.54 mmol) in 40mL of dichloromethane was added triethylamine (1.89 mL,13.56 mmol). The mixture was cooled in an ice bath. A solution of 2-methoxyacetyl chloride (0.42 mL,4.62 mmol) in 10mL of dichloromethane was slowly added. After 3 hours, the mixture was treated with saturated aqueous sodium bicarbonate (20 mL), aqueous HCl (0.2M, 20 mL), and saturated aqueous sodium bicarbonate (20 mL). The organics were dried over sodium sulfate, evaporated, and purified by normal phase SiO ₂ Chromatography (15% to 100% EtOAc/hexanes) purification provided 6- (2-methoxyacetyl) -2, 6-diazaspiro [3.3]Heptane-2-carboxylic acid tert-butyl ester (0.59 g, 71%).

To 0 ℃ 6- (2-methoxyacetyl) -2, 6-diazaspiro [3.3]]A solution of tert-butyl heptane-2-carboxylate (0.20 g,0.74 mmol) in 7mL of dichloromethane was added to a solution of trifluoroacetic acid (1.85 mL,7.40 mmol) in 3mL of dichloromethane. After 10min, the ice bath was removed. After 30min, volatiles were removed in vacuo. The resulting clear oil was azeotroped twice with toluene (5 mL) to afford crude 2-methoxy-1- (2, 6-diazaspiro [ 3.3)]Heptane-2-yl) ethan-1-one trifluoroacetate (0.27 g). ¹ H NMR (400 MHz, methanol-d) ₄ )δ4.47(s,2H),4.23(d,6H),3.97(s,2H),3.37(d,3H).

(b) 1- (6- ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -2-methoxyethan-1-one

2-methoxy-1- (2, 6-diazaspiro [3.3] at room temperature]A mixture of heptan-2-yl) ethan-1-one trifluoroacetate (86 mg,0.30 mmol) and sodium acetate (71 mg,0.86 mmol) in 0.45mL of dichloromethane was stirred for 10 min. After addition of 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (85 mg,0.22 mmol), the mixture was stirred for 5 min. Sodium triacetoxyborohydride (92 mg,0.43 mmol) was added. After stirring overnight, the reaction mixture was diluted with EtOAc (20 mL) and washed with saturated aqueous sodium bicarbonate (20 mL). The aqueous layer was extracted with EtOAc (10 mL). The combined organics were washed with brine (10 mL), dried over sodium sulfate, and concentrated. By normal phase SiO ₂ Chromatography (1% to 10% methanol/dichloromethane) of the crude product afforded 1- (6- ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3]Heptane-2-yl) -2-methoxyethane-1-one (61 mg, 51%). MS: m/z actual measurement 547.2 and 549.2[ M+H ]] ⁺ .

(c) 4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6- (2-methoxyacetyl) -2, 6-diazaspiro [3.3] heptan-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzaldehyde

Tetrakis (triphenylphosphine) palladium (0) (10 mg,0.01 mmol), potassium carbonate (45 mg,0.33 mmol), 1- (6- ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3 ]Heptan-2-yl) -2-methoxyethan-1-one (60 mg,0.11 mmol), and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (32 mg,0.12 mmol) were suspended in 1, 4-dioxane/water (4:1, 2 mL) and the reaction mixture was heated at 100deg.C for 30 min. After cooling, the reaction mixture was diluted with 10mL of water and extracted with EtOAc (3×10 mL). The combined organics were dried over sodium sulfate and then concentrated under reduced pressure. By normal phase SiO ₂ The crude sample was purified by chromatography (20-100% etoac/hexanes) to afford 4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6- (2-methoxyacetyl) -2, 6-diazaspiro [ 3.3) as a white foam]Heptane-2-yl) methyl pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzaldehyde (55 mg, 78%). MS: m/z found 647.3 and 649.3[ M+H ]] ⁺ .

(d) 2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6- (2-methoxyacetyl) -2, 6-diazaspiro [3.3] heptan-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one

To 2, 6-diazaspiro [3.4]]Octan-7-one (12 mg,0.09 mmol) and 4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6- (2-methoxyacetyl) -2, 6-diazaspiro [ 3.3)]Heptan-2-yl-methyl) pyridin-2-yl-phenyl) pyridin-2-methoxybenzaldehyde (33 mg,0.05 mmol) was added as a solution in 0.12mL THF and 0.12mL MeOH Acetic acid (3. Mu.L, 0.05 mmol). After 2 hours, sodium cyanoborohydride (8 mg,0.13 mmol) was added. After stirring overnight at room temperature, the mixture was concentrated. The resulting residue was purified by reverse phase HPLC to provide 2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6- (2-methoxyacetyl) -2, 6-diazaspiro [ 3.3) as formate salt]Heptane-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl-2-methoxybenzyl) -2, 6-diazaspiro [3.4]Octan-7-one (18 mg, 46%). LCMS: m/z found 757.4[ M+H ]] ⁺ Retention time = 2.58min (method a); ¹ h NMR (400 MHz, methanol-d) ₄ )δ8.65(dd,1H),8.47(s,1H),7.77–7.67(m,2H),7.56(td,1H),7.48–7.40(m,3H),7.37–7.27(m,3H),4.40(s,2H),4.23(s,2H),4.14(s,2H),4.02(d,3H),4.00–3.93(m,9H),3.90(s,2H),3.78(s,4H),3.65(m,2H),3.36(m,3H),2.68(s,2H).

Example 682:1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -2-methoxyethane-1-one (691)

To sodium acetate (8 mg,0.10 mmol), 1- (2, 6-diazaspiro [ 3.3)]Heptan-2-yl) ethan-1-one HCl (17 mg,0.10 mmol) and 4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6- (2-methoxyacetyl) -2, 6-diazaspiro [ 3.3)]Heptan-2-yl) methyl pyridin-2-yl) phenyl pyridin-2-yl) -2-methoxybenzaldehyde (34 mg,0.05 mmol) in a mixture of 0.12mL THF and 0.12mL MeOH was added acetic acid (3 μl,0.05 mmol). After 2 hours, sodium cyanoborohydride (8 mg,0.13 mmol) was added. After stirring overnight at room temperature, the mixture was concentrated. The resulting residue was purified by reverse phase HPLC to afford 1- (6- ((6- (3- (4- ((6-acetyl-2, 6-diazaspiro [ 3.3)) as a white solid (formate)) ]Heptane-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl-2-chlorophenyl) -2-methoxypyridin-3-yl methyl) -2, 6-diazaspiro [3.3]Heptane-2-yl) -2-methoxyethane-1-one (8 mg, 18%). LCMS: m/z found 771.4[ M+H ]]Retention time = 2.64min, (method a); ¹ h NMR (400 MHz, methanol-d) ₄ )δ8.64(d,1H),8.49(s,1H),7.74–7.67(m,2H),7.55(t,1H),7.49–7.38(m,3H),7.37–7.29(m,2H),7.26(d,1H),4.37(d,4H),4.12(d,7H),4.01(s,3H),3.98(s,4H),3.96(d,6H),3.82(s,2H),3.68(s,4H),3.36(s,3H),1.85(s,3H).

Example 683: (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -4-methoxypyrrolo [2,1-f ] [1,2,4] triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (697)

(a) (S) - ((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -4-methoxypyrrolo [2,1-f ] [1,2,4] triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To (S) - ((6- (2-chloro-3- (3-chloro-2- (2- (hydroxymethyl) -4-methoxypyrrolo [2, 1-f))][1,2,4]A solution of tert-butyl triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (20 mg,0.03 mmol) in dichloromethane (0.5 mL) was added triethylamine (8 uL,6mg,0.05 mmol) and methanesulfonyl chloride (4 uL,6mg,0.05 mmol). The reaction was stirred at room temperature for 1 hour. LCMS indicated the formation of the desired mesylate. The solvent was evaporated and the residue was suspended in THF (0.4 mL), followed by the addition of potassium carbonate (7 mg,0.05 mmol) and 3-methylazetidin-3-ol hydrochloride (7 mg,0.05 mmol). The mixture was stirred at room temperature for 12 hours. The solvent was evaporated and the residue was suspended in water. The precipitate formed was collected to provide (S) - ((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -4-methoxypyrrolo [2, 1-f) ][1,2,4]Triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-Oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (12 mg, 91%). LCMS: m/z found 803.6[ M+H ]] ⁺ .

(b) (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -4-methoxypyrrolo [2,1-f ] [1,2,4] triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

To (S) - ((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -4-methoxypyrrolo [2, 1-f)][1,2,4]A solution of t-butyl triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl (-5-oxopyrrolidin-2-yl) methyl) carbamate (12 mg,0.01 mmol) in dichloromethane (0.3 mL) was added trifluoroacetic acid (0.06 mL,0.09g,0.75 mmol) and the reaction stirred at room temperature for 1 hour. The solvent was evaporated and the residue was purified by reverse phase HPLC to afford (S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl)) methyl) -4-methoxypyrrolo [2, 1-f) as a white solid][1,2,4]Triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one (5 mg, 47%). LCMS: m/z found 703.4[ M+H ] ] ⁺ Retention time = 0.65min (method B). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.63(d,1H),8.50(d,1H),7.82(d,1H),7.71(dd,1H),7.61–7.53(m,2H),7.40(dd,1H),7.35–7.27(m,2H),4.37(s,2H),4.20(s,3H),4.14(d,2H),4.08(d,2H),4.06(s,2H),3.97(d,3H),2.97(t,2H),2.43–2.29(m,3H),1.86(dd,1H),1.56(s,3H).

Example 684:1- (4- (((6- (3- (2- (2- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (698)

(a) ((6- (3- (2- (2- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) (1-acetylpiperidin-4-yl) carbamic acid tert-butyl ester

(1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxy- [1,2, 4))]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamic acid tert-butyl ester (20 mg,0.03 mmol), acetic acid (3 uL,3mg,0.05 mmol) and 2-oxa-6-azaspiro [3.3]]Heptane (5 mg,0.05 mmol) was dissolved in 1mL of 1:1thf/MeOH and the reaction stirred at room temperature for 10 min. Sodium cyanoborohydride (3 mg,0.05 mmol) was added in one portion and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was suspended in 2mL of water. The precipitate formed was collected by filtration and dried to provide ((6- (3- (2- (2- ((2-oxa-6-azaspiro [3.3 ])) as a white solid ]Heptane-6-yl) methyl) -8-methoxy- [1,2,4]Triazolo [1,5-a ]]Pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl methyl) (1-acetylpiperidin-4-yl) carbamic acid tert-butyl ester (15 mg, 68%). LCMS: m/z found 843.5[ M+H ]] ⁺ .

(b) 1- (4- (((6- (3- (2- (2- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

To ((6- (3- (2- (2- ((2-oxa-6-azaspiro [ 3.3))]Heptane-6-yl) methyl) -8-methoxy- [1,2,4]Triazolo [1,5-a ]]Pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl methyl) (1-acetylpiperidin-4-yl) carbamic acid tert-butyl ester (15 mg,0.02 mmol) in dichloromethane (0)Trifluoroacetic acid (0.07 mL,0.10g,0.89 mmol) was added to the solution in 3mL and the reaction was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was purified by reverse phase HPLC to afford 1- (4- (((6- (3- (2- (2- ((2-oxa-6-azaspiro [ 3.3))]Heptane-6-yl) methyl) -8-methoxy- [1,2,4]Triazolo [1,5-a ]]Pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl-methyl) amino) piperidin-1-yl) ethan-1-one (2.4 mg, 18%). LCMS: m/z found 743.5[ M+H ] ] ⁺ Retention time = 0.52min (method B). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ9.20(d,1H),8.79(d,1H),8.15(d,1H),7.88(d,1H),7.74(dd,1H),7.60(d,2H),7.47(dd,1H),7.34(d,1H),5.00(s,2H),4.63(d,1H),4.57(s,2H),4.25(s,3H),4.22(s,2H),4.07(s,7H),3.74(s,2H),3.34(d,2H),3.20(t,1H),2.68(d,1H),2.21(t,2H),2.13(s,3H),1.48(d,1H).

Example 685:1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1-hydroxycyclopropyl) methyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (699)

(a) (1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- ((((1-hydroxycyclopropyl) methyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

(1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxy- [1,2, 4))]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamic acid tert-butyl ester (20 mg,0.03 mmol), acetic acid (3 uL,3mg,0.05 mmol) and 1- (aminomethyl) cyclopropan-1-ol (5 mg,0.05 mmol) were dissolved in 1:1THF/MeOH (1 mL) and reacted at room temperature with stirring for 10 min. Adding cyano boron at one timeSodium hydride (3 mg,0.05 mmol) and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was suspended in 2mL of water. The precipitate formed was collected by filtration and dried to provide (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- (((1-hydroxycyclopropyl) methyl) amino) methyl) -8-methoxy- [1,2, 4) as a white solid ]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamic acid tert-butyl ester (17 mg, 78%). LCMS: m/z found 831.6[ M+H ]] ⁺ .

(b) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((1-hydroxycyclopropyl) methyl) amino) methyl) 8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

To (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- (((1-hydroxycyclopropyl) methyl) amino) methyl) -8-methoxy- [1,2, 4)]Triazolo [1,5-a ]]A solution of tert-butyl pyridin-6-yl) pyridin-4-yl-phenyl) -2-methoxypyridin-3-yl methyl) carbamate (17 mg,0.02 mmol) in dichloromethane (0.3 mL) was added trifluoroacetic acid (0.08 mL,0.12g,1.02 mmol) and the reaction stirred at room temperature for 1 hour. The solvent was evaporated and the residue was purified by preparative HPLC to afford 1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((1-hydroxycyclopropyl) methyl) amino) methyl) -8-methoxy- [1,2, 4) methyl) as a white solid]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) amino) piperidin-1-yl) ethan-1-one (6 mg, 40%). LCMS: m/z found 731.5[ M+H ]] ⁺ Retention time = 0.61min (method B). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.81(d,1H),8.72(d,1H),7.86(d,1H),7.73(dd,1H),7.58(t,1H),7.52(d,1H),7.48–7.43(m,2H),7.33(d,1H),4.60(d,1H),4.43(s,2H),4.16(d,2H),4.12(s,3H),4.06(s,3H),4.01(s,1H),3.28–3.15(m,2H),3.14(s,2H),2.70(t,1H),2.19(d,2H),2.12(s,3H),1.63–1.37(m,2H),0.87–0.80(m,2H),0.71–0.65(m,2H).

Example 686:1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((3-fluoropropyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (713)

(a) (1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- (((3-fluoropropyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

(1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxy- [1,2, 4))]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamic acid tert-butyl ester (20 mg,0.03 mmol), acetic acid (3 uL,3mg,0.05 mmol) and 3-fluoropropane-1-amine (4 mg,0.05 mmol) were dissolved in 1:1THF/MeOH (1 mL) and reacted at room temperature with stirring for 10 min. Sodium cyanoborohydride (3 mg,0.05 mmol) was added in one portion and the resulting mixture was stirred at room temperature for 1 hour. The reaction was concentrated and the residue was dissolved in 2mL of water. The precipitate formed was collected by filtration and dried to afford (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- (((3-fluoropropyl) amino) methyl)) methyl) -8-methoxy- [1,2, 4) as a white solid ]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamic acid tert-butyl ester (15 mg, 69%). LCMS: m/z found 821.4[ M+H ]] ⁺ .

(b) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((3-fluoropropyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

To (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- (((3-fluoropropyl) amino) methyl)) methyl) -8-methoxy- [1,2, 4)]Triazolo [1,5-a ]]A solution of tert-butyl pyridin-6-yl) pyridin-4-yl-phenyl) -2-methoxypyridin-3-yl methyl) carbamate (15 mg,0.02 mmol) in dichloromethane (0.3 mL) was added trifluoroacetic acid (0.07 mL,0.10g,0.89 mmol) and the reaction stirred at room temperature for 1 hour. The solvent was evaporated and the residue was purified by reverse phase HPLC to afford 1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((3-fluoropropyl) amino) methyl)) methyl) -8-methoxy- [1,2, 4) as a white solid]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) amino) piperidin-1-yl) ethan-1-one (4 mg, 32%). LCMS: m/z found 721.3[ M+H ]] ⁺ Retention time = 1.61min (method D). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.81(d,1H),8.74–8.70(m,1H),7.86(d,1H),7.73(dd,1H),7.58(t,1H),7.52(d,1H),7.48–7.44(m,2H),7.33(d,1H),4.66–4.58(m,2H),4.50(t,1H),4.29(s,1H),4.17(d,3H),4.11(d,4H),4.06(s,4H),4.02(s,1H),3.19(t,2H),3.08(t,2H),2.70(t,1H),2.20(d,2H),2.12(s,4H),2.09–1.99(m,1H).

Example 687:1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxy-2-methylpropyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (714)

(a) (1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxy-2-methylpropyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

(1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2-formyl)-8-methoxy- [1,2,4]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamic acid tert-butyl ester (26 mg,0.03 mmol), acetic acid (4 uL,4mg,0.07 mmol) and 1-amino-2-methyl-propan-2-ol (6 mg,0.07 mmol) were dissolved in 1:1THF/MeOH (1 mL) and reacted at room temperature with stirring for 60 min. Sodium cyanoborohydride (4 mg,0.07 mmol) was added in one portion and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was suspended in 2mL of water. The precipitate formed was collected by filtration and dried to provide (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxy-2-methylpropyl) amino) methyl)) 8-methoxy- [1,2, 4) methyl) as a white solid ]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamic acid tert-butyl ester (17 mg, 60%). LCMS: m/z found 833.5[ M+H ]] ⁺ .

(b) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxy-2-methylpropyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

To (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxy-2-methylpropyl) amino) methyl)) 8-methoxy- [1,2, 4)]Triazolo [1,5-a ]]A solution of tert-butyl pyridin-6-yl) pyridin-4-yl-phenyl) -2-methoxypyridin-3-yl methyl) carbamate (17 mg,0.02 mmol) in dichloromethane (0.3 mL) was added trifluoroacetic acid (0.08 mL,0.12g,1.02 mmol) and the reaction stirred at room temperature for 1 hour. The solvent was evaporated and the residue was purified by reverse phase HPLC to afford 1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((2-hydroxy-2-methylpropyl) amino) methyl)) m-ethyl) -8-methoxy- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) amino) piperidin-1-yl) ethan-1-one (6 mg, 41%). LCMS: m/z found 733.4[ M+H ]] ⁺ Retention time = 0.61min (method B). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.85(d,1H),8.73(dd,1H),7.91(d,1H),7.73(dd,1H),7.59(t,1H),7.53(dd,1H),7.50–7.45(m,2H),7.37(d,1H),4.68(d,1H),4.56(s,2H),4.33(s,2H),4.13(d,3H),4.09(s,4H),3.56–3.46(m,1H),3.33(d,1H),3.22(s,3H),2.70(t,1H),2.26(t,2H),2.13(s,3H),1.75–1.45(m,1H),1.33(s,6H).

Example 688:1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxyethyl) (methyl) amino) methyl) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one (715)

(a) (1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxyethyl) (methyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

(1-Acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxy- [1,2, 4))]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamic acid tert-butyl ester (26 mg,0.03 mmol), acetic acid (4 uL,4mg,0.07 mmol) and 2- (methylamino) ethanol (5 mg,0.07 mmol) were dissolved in 1:1THF/MeOH (1 mL) and reacted at room temperature with stirring for 60 min. Sodium cyanoborohydride (4 mg,0.07 mmol) was added in one portion and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was suspended in 2mL of water. The precipitate formed was collected by filtration and dried to provide (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxyethyl) (methyl) amino) methyl)) methyl) -8-methoxy- [1,2, 4) as a white solid ]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) carbamic acid tert-butyl ester (18 mg, 64%). LCMS: m/z found 819.4[ M+H ]] ⁺ .

(b) 1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxyethyl) (methyl) amino) methyl) 8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one

To (1-acetylpiperidin-4-yl) ((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxyethyl) (methyl) amino) methyl)) methyl) -8-methoxy- [1,2, 4)]Triazolo [1,5-a ]]A solution of tert-butyl pyridin-6-yl) pyridin-4-yl-phenyl) -2-methoxypyridin-3-yl methyl) carbamate (18 mg,0.02 mmol) in dichloromethane (0.3 mL) was added trifluoroacetic acid (0.08 mL,0.13g,1.10 mmol) and the reaction stirred at room temperature for 1 hour. The solvent was evaporated and the residue was purified by reverse phase HPLC to afford 1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((2-hydroxyethyl) (methyl)) amino) methyl) -8-methoxy- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) amino) piperidin-1-yl) ethan-1-one (6 mg, 38%). LCMS: m/z found 719.4[ M+H ]] ⁺ Retention time = 0.59min (method B). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.83(d,1H),8.73(d,1H),7.91(d,1H),7.73(dd,1H),7.59(t,1H),7.52(d,1H),7.47(td,2H),7.36(d,1H),4.67(d,1H),4.42(s,2H),4.31(s,2H),4.12(s,3H),4.08(s,4H),3.91–3.81(m,2H),3.54–3.42(m,1H),3.23(d,1H),3.20–3.13(m,2H),2.81(s,3H),2.70(t,1H),2.25(t,2H),2.13(s,3H),1.74–1.46(m,1H).

Example 689:2- ((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one (685)

(a) 2- ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one

To 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (600 mg,1.52 mmol) and 2, 6-diazaspiro [3.4]]A mixture of octan-7-one trifluoroacetate (1.46 g,6.10 mmol) in methanol (10 mL) was added sodium acetate (1.25 g,15.2 mmol) and under N ₂ The mixture was stirred at room temperature for 3 hours. Sodium triacetoxyborohydride (1.62 g,7.62 mmol) was then added and added under N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was then filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-45% EtOAc/petroleum ether) to afford the compound 2- ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] as a white solid]Octan-7-one (480 mg,56% yield). MS: m/z found 503[ M+H ]] ⁺ .

(b) 2- (difluoromethoxy) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde

To a mixture of 4-bromo-2- (difluoromethoxy) benzaldehyde (300 mg,1.20 mmol) and bis (pinacolato) diboron (390 mg,1.55 mmol) in 1, 4-dioxane (3 mL) was added potassium acetate (234 mg,2.39 mmol) and [1,1' -bis (biphenylphosphino) ferrocene]Complex of palladium (II) dichloride with dichloromethane (97.6 mg,0.119 mmol) and under N ₂ The mixture was stirred at 100℃for 1 hour. Water (10 mL) was then added and the mixture extracted with EtOAc (2X 10 mL). The combined organic phases were dried over anhydrous sulphate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ The residue was purified by chromatography (0-15% EtOAc/petroleum ether) to afford 2- (difluoromethoxy) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (230 mg, crude) as a yellow oil. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.37(s,1H),7.92(d,1H),7.75-7.35(m,1H),7.68-7.32(m,2H),1.34(s,12H).

(c) 4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (difluoromethoxy) benzaldehyde

To 2- ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4]A mixture of octan-7-one (200 mg,0.397 mmol) and 2- (difluoromethoxy) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (177 mg,0.59 mmol) in THF/water (5:1, 6 mL) was added potassium phosphate (252 mg,1.19 mmol) and [1,1' -bis (di-tert-butylphosphino) ferrocene ]Palladium (II) dichloride (25.8 mg,0.04 mmol) and under N ₂ The mixture was stirred at 80℃for 2 hours. Water (10 mL) was then added and the mixture extracted with EtOAc (2X 10 mL). The combined organic phases were dried over anhydrous sulphate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ Chromatography (0-60% EtOAc/petroleum ether) of the residue afforded 4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [ 3.4) as a white solid]Octan-2-yl) methyl pyridin-2-yl) phenyl pyridin-2-yl) -2- (difluoromethoxy) benzaldehyde (130 mg,24% yield). MS: m/z found 639[ M+H ]] ⁺ .

(d) 2- ((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one

To 4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4 ])]A mixture of octan-2-yl-methyl) pyridin-2-yl-phenyl) pyridin-2-yl-2- (difluoromethoxy) benzaldehyde (120 mg,187 mol) and tetrahydro-2H-pyran-4-amine (28.4 mg, 281mol) in dichloromethane (3 mL) was added sodium acetate (46.2 mg,56 umol) and concentrated under N ₂ The mixture was stirred at room temperature for 1h. Sodium triacetoxyborohydride (119 mg, 262. Mu. Mol) was then added and added to the mixture at N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide 2- ((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] as a white solid]Octan-7-one (26 mg,18% yield). MS: m/z found 724[ M+H ]] ⁺ Retention time = 2.94min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),7.73-7.68(m,2H),7.60-7.50(m,4H),7.47(d,1H),7.45-7.43(m,1H),7.24(d,1H),6.97(t,1H),4.05-3.97(m,7H),3.82(s,2H),3.60(s,2H),3.43-3.41(m,6H),2.82-2.79(m,1H),2.59(s,2H),1.96-1.93(m,2H),1.56-1.50(m,2H).

Example 690:2- (4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (difluoromethoxy) benzyl) -2, 6-diazaspiro [3.4] octan-7-one (688)

(a) 1- (6- ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one

To 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (0.60 g,1.52 mmol) and 1- (2, 6-diazaspiro [ 3.3)]A mixture of heptan-2-yl) ethan-1-one formate (1.16 g,4.57 mmol) in dichloromethane (10 mL) was added triethylamine (0.62 g,6.10 mmol) and under N ₂ The mixture was stirred at room temperature for 2.5 hours. Sodium triacetoxyborohydride (0.97 g,4.57 mmol) was then added and added under N ₂ The mixture was stirred at room temperature for 0.5 hours. Water (20 mL) was added and the mixture extracted with EtOAc (2X 30 mL). The combined organic phases were dried over anhydrous sulphate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ Chromatography (0-The residue was purified with 40% MeOH/EtOAc) to afford 1- (6- ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] as a white solid]Heptane-2-yl) ethan-1-one (600 mg,76% yield). ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.51(d,1H),7.84-7.82(m,1H),7.75(dd,1H),7.63-7.57(m,2H),7.51(dd,1H),7.34(d,1H),4.23(s,2H),3.95(s,3H),3.62-3.59(m,4H),1.78-1.75(m,4H),1.73(s,3H).

(b) 4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptane-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (difluoromethoxy) benzaldehyde

To 1- (6- ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3]A mixture of heptan-2-yl) ethan-1-one (500 mg,0.97 mmol) and 2- (difluoromethoxy) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (example 689, step (b)) (432 mg,1.45 mmol) in THF/water (5:1, 18 mL) was added potassium phosphate (616 mg,2.90 mmol) and [1,1' -bis (di-t-butylphosphino) ferrocene]Palladium (II) dichloride (62.9 mg,0.09 mmol) and under N ₂ The mixture was stirred at 80℃for 3 hours. Water (20 mL) was added and the mixture extracted with EtOAc (2X 30 mL). The combined organic phases were dried over anhydrous sulphate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ Chromatography (0-30% EtOAc/MeOH) purified the residue to afford 4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [ 3.3)) as a white solid]Heptane-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl-2- (difluoromethoxy) benzaldehyde (444 mg,70% yield). ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.30(s,H),8.75(d,1H),7.95(d,1H),7.68-7.66(m,4H),7.59(d,2H),7.45(d,1H),7.22(m,2H),4.14(s,2H),3.86(s,5H),3.50(s,2H),3.32-3.31(m,4H),1.68(s,3H).

(c) 2- (4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (difluoromethoxy) benzyl) -2, 6-diazaspiro [3.4] octan-7-one

To 4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3 ])]Heptane-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl-2- (difluoromethoxy) benzaldehyde (150 mg,0.23 mmol) and 2, 6-diazaspiro [3.4]]A mixture of octane-7-ketoformate (276 mg,1.15 mmol) in dichloromethane (5 mL) was added sodium acetate (151 mg,1.84 mmol) and the mixture was stirred at room temperature for 2.5 hours. Sodium cyanoborohydride (57.7 mg,0.92 mmol) was then added and the mixture was taken up in N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 2- (4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3 ]) as a white solid (formate))]Heptane-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl-2- (difluoromethoxy) benzyl) -2, 6-diazaspiro [3.4 ]Octan-7-one (35.3 mg,19% yield). MS: m/z found 763[ M+H ]] ⁺ Retention time = 2.63min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.67(d,1H),7.77-7.71(m,2H),7.61-7.54(m,4H),7.48-7.43(m,2H),7.31(d,1H),6.97(t,1H),4.60(s,2H),4.35(s,2H),4.11(s,2H),4.05(s,3H),3.96(s,2H),3.92(s,2H),3.84(s,3H),3.62(s,2H),3.55(s,3H),2.62(s,2H),1.87(s,3H).

Example 691:1- (6- ((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one (689)

In a similar manner to example 690, tetrahydro-2H-pyran-4-amine is used in step (c) in place of 2, 6-diazaspiro [3.4 ]]Preparation of 1- (6- ((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((tetrahydro-2H-pyran-4-yl) amino)) methyl) by octane-7-one formatePhenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) -2, 6-diazaspiro [3.3]Heptane-2-yl) ethan-1-one. White solid (formate), MS: m/z found 738[ M+H ]] ⁺ Retention time = 2.74min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.68(d,1H),7.73-7.66(m,4H),7.59-7.55(m,2H),7.49(d,1H),7.44-7.42(m,1H),7.26(d,1H),7.04(t,1H),4.33(s,2H),4.17(s,2H),4.08-4.02(m,7H),3.76(s,2H),3.60(s,3H),3.50-3.42(m,3H),3.15-3.12(m,1H),2.06-2.03(m,2H),1.86(s,3H),1.65-1.55(m,2H).

Example 692:1- (4- ((4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (difluoromethoxy) benzyl) amino) piperidin-1-yl) ethan-1-one (690)

In a similar manner to example 690, 1- (4-aminopiperidin-1-yl) ethan-1-one hydrochloride was used in step (c) to replace 2, 6-diazaspiro [3.4 ] ]Preparation of 1- (4- ((4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3 ])) by substituting sodium triacetoxyborohydride for sodium cyanoborohydride]Heptane-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (difluoromethoxy) benzyl amino) piperidin-1-yl-ethan-1-one. White solid (formate), MS: m/z found 779[ M+H ]] ⁺ Retention time = 2.85min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.65(d,1H),7.74-7.64(m,4H),7.57(s,1H),7.54(t,1H),7.45(d,1H),7.40(dd,1H),7.26(d,1H),7.03(t,1H),4.60-4.56(m,1H),4.31(s,2H),4.23(s,2H),4.07(s,2H),4.03-4.00(m,4H),3.94-3.92(m,2H),3.82-3.79(m,4H),3.21-3.17(m,1H),2.73-2.66(m,1H),2.20-2.12(m,3H),2.10(s,3H),1.82(s,3H),1.55-1.42(m,2H).

Example 693:1- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid (705)

(a) (S) -6- ((5-bromo-1, 2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxynicotinonitrile

At N ₂ Sodium tert-butoxide (6.77 g,70.5 mmol) and 1,1 '-bis (biphenylphosphino) ferrocene (0.89 g,1.6 mmol) and [1,1' -bis (biphenylphosphino) ferrocene were added at one time to a mixture of 6-chloro-2-methoxynicotinic carbonitrile (5.4 g,32 mmol) and (S) -5-bromo-1, 2,3, 4-tetrahydronaphthalen-1-amine (7.57 g,28.8 mmol) as hydrochloride in 1, 4-dioxane (120 mL)]Palladium (II) dichloride complex with dichloromethane (0.52 g,0.64 mmol). The mixture was stirred at 110℃for 3 hours. The mixture was concentrated, and then water (500 mL) and saturated aqueous brine solution (100 mL) were added to the residue. The mixture was extracted with ethyl acetate/THF mixture (1:1,500 ml), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-10% ethyl acetate/petroleum ether) to afford (S) -6- ((5-bromo-1, 2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxynicotinonitrile (16.8 g,60% yield) as a yellow solid. ¹ H NMR (400 MHz, chloroform-d): delta 7.46-7.42 (m, 2H), 7.22-7.19 (m, 1H), 6.98 (t, 1H), 5.92 (d, 1H), 5.11-5.01 (m, 2H), 3.88 (s, 3H), 2.82-2.68 (m, 2H), 1.92-1.85 (m, 4H).

(b) (S) -6- ((5-bromo-1, 2,3, 4-tetrahydronaphthalen-1-yl) amino) -5-iodo-2-methoxynicotinic carbonitrile

At N ₂ N-iodosuccinimide (3.87 g, 17.2) was added in one portion to a mixture of (S) -6- ((5-bromo-1, 2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxynicotinic carbonitrile (5.6 g,15.6 mmol) in glacial acetic acid (55 mL) and potassium acetate (15.3 g,156 mmol)mmol) and the mixture was stirred at room temperature for 3 hours. The mixture was neutralized with saturated aqueous sodium bicarbonate solution, then water (500 mL) and saturated aqueous brine solution (100 mL) were added. The mixture was extracted with ethyl acetate/THF mixture (1:1,500 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. Directly through normal phase SiO ₂ The residue was purified by chromatography (0-7% ethyl acetate/petroleum ether) to afford (S) -6- ((5-bromo-1, 2,3, 4-tetrahydronaphthalen-1-yl) amino) -5-iodo-2-methoxynicotinonitrile (18 g,63% yield) as a white solid. ¹ H NMR (400 MHz, chloroform-d): delta 7.81 (s, 1H), 7.44 (d, 1H), 7.19-7.18 (m, 2H), 7.00 (t, 1H), 5.51-5.49 (m, 1H), 5.33-5.28 (m, 1H), 3.90 (s, 3H), 2.84-2.72 (m, 2H), 1.91-1.84 (m, 4H).

(c) (S) -6- ((5-bromo-1, 2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) nicotinic carbonitrile

At N ₂ To a mixture of (S) -6- ((5-bromo-1, 2,3, 4-tetrahydronaphthalen-1-yl) amino) -5-iodo-2-methoxynicotinic carbonitrile (6 g,12.4 mmol) and methyl 2, 2-difluoro-2- (fluorosulfonyl) acetate (6.3 mL,49.6 mmol) in DMF (70 mL) was added copper (I) iodide (3.5 g,18.6 mmol) at one time and the mixture stirred at 110℃for 3 hours. The mixture was combined with another batch on a 7g scale. The mixture was filtered and the filtrate was concentrated. To the residue was added water (500 mL) and a saturated aqueous brine solution (100 mL) and the mixture was extracted with an ethyl acetate/THF mixture (1:1,500 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. Directly through normal phase SiO ₂ The residue was purified by chromatography (0-10% ethyl acetate/petroleum ether) to provide (S) -6- ((5-bromo-1, 2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) nicotinic carbonitrile (20 g,79% purity) as a yellow oil. ¹ H NMR (400 MHz, chloroform-d): delta 7.75 (s, 1H), 7.44 (dd, 1H), 7.19-7.16 (m, 1H), 7.00 (t, 1H), 5.43-5.41 (m, 2H), 3.95 (s, 3H), 2.79-2.72 (m, 2H), 2.02-1.90 (m, 1H), 1.88-1.53 (m, 3H).

(d) (S) -6- ((5-bromo-1, 2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde

At N ₂ To a mixture of (S) -6- ((5-bromo-1, 2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) nicotinic carbonitrile (5 g,11.7 mmol) in dichloromethane (50 mL) was added dropwise diisobutylaluminum hydride (1M, 16 mL) at-60 ℃. The mixture was stirred at-60℃for 1 hour. Water (0.1 mL) and 2N aqueous NaOH solution (0.1 mL) were added to the mixture at-20deg.C to quench the diisobutylaluminum hydride. Then ethyl acetate/THF mixture (1:1, 100 ml) was added and the mixture was dried over anhydrous sodium sulfate, filtered and concentrated. Directly through normal phase SiO ₂ The residue was purified by chromatography (1-10% ethyl acetate/petroleum ether) to afford (S) -6- ((5-bromo-1, 2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde as a yellow solid (8 g,69% yield). ¹ H NMR (400 MHz, chloroform-d): delta 10.03 (s, 1H), 8.13 (s, 1H), 7.45 (dd, 1H), 7.20-7.18 (m, 1H), 7.00 (t, 1H), 5.53-5.47 (m, 2H), 3.97 (s, 3H), 2.80-2.74 (m, 2H), 2.05-1.89 (m, 1H), 1.88-1.51 (m, 3H).

(e) (S) -6- ((5- (2, 3-dichloropyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde

At N ₂ To a mixture of (S) -6- ((5-bromo-1, 2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde (0.5 g,1.16 mmol) and 2, 3-dichloro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine (0.7 g,2.56 mmol) in a 1, 4-dioxane/water mixture (5:1, 18 mL) was added at one time [1,1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) dichloride (0.08 g,0.12 mmol) and potassium carbonate (0.74 g,3.49 mmol) and the mixture was stirred at 120℃for 12 hours. To the mixture was added 2, 3-dichloro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine (0.32 g,1.16 mmol) and the mixture was stirred at 120℃for a further 12 hours. The mixture was concentrated, water (50 mL) and saturated aqueous brine solution (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate/THF mixture (1:1, 100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-6% ethyl acetate/petroleum ether) to provide (S) -6- ((5- (2, 3-dichloropyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde (0.23 g,28% yield) as a yellow gum. MS: m/z found 496[ M+H ]] ⁺ .

(f) 4- (3-chloro-4- ((S) -5- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

At N ₂ To a mixture of (S) -6- ((5- (2, 3-dichloropyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde (0.14 g,0.28 mmol) and tert-butyl (S) -2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl ((5-oxopyrrolidin-2-yl) methyl) carbamate (0.39 g,0.85 mmol) in THF/water mixture (10:1, 5.5 mL) was added potassium phosphate (0.18 g,0.85 mmol) and chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) at one time]Palladium (II) (0.02 g,0.03 mmol) and the mixture was stirred at 85℃for 3 hours. The mixture was concentrated, water (5 mL) and saturated aqueous brine solution (5 mL) were added to the residue, and the mixture was extracted with ethyl acetate/THF mixture (1:1, 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (15-70% (10% THF in ethyl acetate)/petroleum ether) to provide tert-butyl 4- (3-chloro-4- ((S) -5- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl (((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (0.2 g,67% yield) as a yellow gum. MS: m/z found 794[ M+H ] ] ⁺ .

(g) 1- (((6- (((S) -5- (2- (4- (((tert-butoxycarbonyl) (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropanecarboxylic acid

At N ₂ To a mixture of tert-butyl 4- (3-chloro-4- ((S) -5- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl (((S) -5-oxopyrrolidin-2-yl) methyl) carbamate (0.19 g,0.24 mmol) and 1-aminocyclopropane carboxylic acid (24 mg,0.24 mmol) in dichloromethane/methanol mixture (3:2, 5 ml) was added sodium acetate (0.04 g,0.48 mmol) at one time and the mixture was stirred at room temperature for 5 hours. Sodium cyanoborohydride (0.05 g,0.72 mmol) was added to the mixture and the mixture was stirred at room temperature for 1 hour. Concentrating the mixture and passing through normal phase SiO ₂ The residue was purified by chromatography (10-100% (10% meoh in ethyl acetate)/petroleum ether) to afford 1- (((6- (((S) -5- (2- (4- (((tert-butoxycarbonyl) (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropanecarboxylic acid as a white solid (110 mg,44% yield). MS: m/z found 879[ M+H ] ] ⁺ .

(h) 1- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropanecarboxylic acid

To 1- (((6- (((S) -5- (2- (4- (((tert-butoxycarbonyl) ((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridine)A mixture of pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl-amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino cyclopropanecarboxylic acid (0.11 g,0.12 mmol) in 1, 4-dioxane (2 mL) was added in one portion to a concentrated HCl solution (0.3 mL) and the mixture stirred at room temperature for 4 hours. The mixture was neutralized with aqueous ammonia and purified directly by reverse phase HPLC to afford 1- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropanecarboxylic acid (34.1 mg,35% yield) as a white solid. MS: m/z found 779[ M+H ]] ⁺ Retention time = 3.47min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.61-8.59(m,1H),7.84(s,1H),7.45-7.39(m,2H),7.34-7.27(m,4H),7.08(d,1H),6.22-6.13(m,1H),5.64-5.54(m,1H),4.24(s,2H),4.01-3.96(m,8H),3.91-3.87(m,1H),2.80-2.75(m,2H),2.65-2.45(m,2H),2.38-2.32(m,3H),2.14-2.12(m,2H),1.96-1.82(m,3H),1.40-1.37(m,2H),1.19-1.16(m,2H).

Example 694: (S) -5- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one (710)

(S) -5- ((((6- (((S) -5- (3-chloro-2- (3-methoxy-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one was prepared in step (g) using (R) -5- (aminomethyl) pyrrolidin-2-one hydrochloride instead of 1-aminocyclopropane carboxylic acid in analogy to example 693. White solid, MS: m/z found 792[ M+H ]] ⁺ Retention time = 3.34min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.60(d,1H),7.68(s,1H),7.45-7.41(m,2H),7.35-7.23(m,4H),7.08(d,1H),5.87-5.78(m,1H),5.59-5.53(m,1H),4.00-3.82(m,10H),3.72-3.68(m,2H),2.71-2.24(m,12H),2.12-1.73(m,6H).

Example 695:2- ((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one (724)

In a similar manner to example 693, 2, 6-diazaspiro [3.4] was used in step (g)]Preparation of 2- ((6- (((S) -5- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [ 3.4) by substituting 1-aminocyclopropane carboxylic acid with sodium triacetoxyborohydride and sodium cyanoborohydride ]Octane-7-one. White solid, MS: m/z found 804[ M+H ]] ⁺ Retention time = 3.28min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.59(d,1H),7.62(s,1H),7.44-7.41(m,2H),7.34-7.26(m,4H),7.08(d,1H),5.84-5.76(m,1H),5.57-5.54(m,1H),3.95-3.85(m,9H),3.58-3.56(m,4H),3.36-3.35(m,4H),2.70-2.28(m,9H),2.13-1.82(m,5H).

Example 696: (S) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one (736)

In a manner analogous to example 693, (S) -5- (((4- (3-chloro-4- ((S) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methyl) was prepared in step (g) using (S) -1-aminopropane-2-ol instead of 1-aminocyclopropanecarboxylic acidOxy benzyl) amino) methyl) pyrrolidin-2-one. White solid, MS: m/z found 753[ M+H ]] ⁺ Retention time = 3.65min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.60(d,1H),7.69(s,1H),7.44-7.41(m,2H),7.35-7.26(m,4H),7.08(d,1H),5.94-5.85(m,1H),5.62-5.51(m,1H),3.95-3.94(m,6H),3.90-3.72(m,6H),2.71-2.46(m,6H),2.38-2.26(m,3H),2.12-2.04(m,2H),1.96-1.76(m,3H),1.19(d,3H).

Example 697: (S) -N- (5- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine (741)

(a) (S) -6- ((5- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde

To a solution of (S) -6- ((5- (2, 3-dichloropyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde (0.32 g,0.64 mmol) (example 693, step (e)) and 2-methoxy-4- (4, 5-tetramethyl-1, 2-dioxaborane-2-yl) benzaldehyde (0.24 g,0.9 mmol) in THF/water mixture (6:1, 7.2 mL) was added chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl)]Palladium (II) (0.05 g,0.06 mmol) and potassium phosphate (0.41 g,1.93 mmol) and the mixture was stirred at 80℃for 1 hour. Water (10 mL) was then added and the mixture extracted with ethyl acetate (2X 10 mL). The combined organic phases were washed with saturated aqueous brine solution (2×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ Chromatography (10-50% ethyl acetate/petroleum ether) purification of the residue to afford (S) -6- ((5- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methyl as a white solidOxy-5- (trifluoromethyl) nicotinaldehyde (230 mg,46% yield). MS: m/z found 596[ M+H ]] ⁺ .

(b) (S) -N- (5- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine

At N ₂ To a mixture of (S) -6- ((5- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde (0.1 g,0.17 mmol) and methylamine hydrochloride (0.03 g,0.5 mmol) in THF/methanol (3:2, 5 mL) was added triethylamine (0.05 g,0.5 mmol) in one portion and the mixture stirred at room temperature for 1 h. Sodium cyanoborohydride (0.03 g,0.5 mmol) was added to the mixture and the mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide (S) -N- (5- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine (20 mg) as the hydrochloride salt. 20mg of (S) -N- (5- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine hydrochloride was neutralized with saturated aqueous sodium bicarbonate solution and the mixture was extracted with dichloromethane (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and freeze dried to afford (S) -N- (5- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine (8.2 mg,7% yield) as a white solid. MS: m/z found 626[ M+H ] ] ⁺ Retention time = 3.48min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):8.48(d,1H),7.54(s,1H),7.33-7.27(m,2H),7.21(dd,1H),7.20-7.14(m,3H),6.96(d,1H),5.46-5.41(m,1H),3.83-3.79(m,6H),3.74(s,2H),3.56-3.50(m,2H),2.54-2.39(m,2H),2.33(s,3H),2.28(s,3H),2.03-1.91(m,2H),1.87-1.71(m,2H).

Example 698:1- (((6- (((S) -5- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropanecarboxylic acid (704)

(a) (S) -2-methoxy-6- ((5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -5- (trifluoromethyl) nicotinaldehyde

At N ₂ To a mixture of (S) -6- ((5-bromo-1, 2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) nicotinaldehyde (example 693, step (d)) (3 g,6.99 mmol) and bis (pinacolato) diboron (4.44 g,17.5 mmol) in 1, 4-dioxane (100 mL) was added potassium acetate (2.06 g,21 mmol) and [1,1' -bis (biphenylphosphino) ferrocene at one time]Palladium (II) dichloride complex with dichloromethane (0.29 g,0.35 mmol) and the mixture was stirred at 120 ° for 12 hours. Concentrating the mixture and passing through normal phase SiO ₂ The residue was purified by chromatography (0-10% ethyl acetate/petroleum ether) to afford 5.5g of product. Purification of 0.5g of the product by reverse phase HPLC provided (S) -2-methoxy-6- ((5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -5- (trifluoromethyl) nicotinaldehyde as a yellow gum (0.2 g,36% yield). ¹ H NMR (400 MHz, chloroform-d): delta 10.03 (s, 1H), 8.12 (s, 1H), 7.67 (d, 1H), 7.28 (d, 1H), 7.12 (t, 1H), 5.55-5.53 (m, 1H), 5.48-5.43 (m, 1H), 3.98 (s, 3H), 3.17-3.11 (m, 1H), 3.00-2.98 (m, 1H), 1.97-1.77 (m, 4H), 1.28 (s, 12H).

(b) ((3 ' -chloro-2 ' - ((S) -5- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) carbamic acid tert-butyl ester((S) -5-oxopyrrolidin-2-yl) methyl)

At N ₂ Downward (S) -2-methoxy-6- ((5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -5- (trifluoromethyl) nicotinaldehyde (0.15 g,0.31 mmol) and (S) - ((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridine)]-5-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (0.08 g,0.16 mmol) in THF/water mixture (10:1, 5.5 mL) potassium phosphate (0.1 g,0.47 mmol) and chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (mixture of 2 '-amino-1, 1' -biphenyl) were added in one portion]Palladium (II) (12 mg,16 umol) and the mixture was stirred at 80℃for 3 hours. The mixture was concentrated and water (5 mL) and saturated aqueous brine solution (5 mL) were added to the residue. The mixture was extracted with ethyl acetate/THF mixture (1:1, 10 ml) and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (15-60% (10% THF in ethyl acetate)/petroleum ether) to afford ((3 ' -chloro-2 ' - ((S) -5- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridine) as a yellow gum]-5-yl) methyl) (((S) -5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (0.11 g,59% yield). MS: m/z found 795[ M+H ]] ⁺ .

(c) 1- (((6- (((S) -5- (5- (((tert-butoxycarbonyl) (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropanecarboxylic acid

At N ₂ Downward ((3 ' -chloro-2 ' - ((S) -5- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridine)]-5-yl) methyl (((S) -5-oxopyrrolidin-2-yl) methyl)A mixture of tert-butyl carbamate (0.11 g,0.14 mmol) and 1-aminocyclopropane carboxylic acid (14 mg,0.14 mmol) in a dichloromethane/methanol mixture (3:2, 5 mL) was added sodium acetate (23 mg,0.28 mmol) in one portion and the mixture stirred at room temperature for 12 hours. Sodium cyanoborohydride (26 mg,0.41 mmol) was then added and the mixture was stirred at room temperature for 1 hour. The mixture was purified directly by preparative TLC (silica gel, ethyl acetate: meoh=2:1) to afford 1- (((6- (((S) -5- (5- (((tert-butoxycarbonyl) (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3 '-chloro-6-methoxy- [2,4' -bipyridine) as a white solid ]-2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl-amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl-methyl) amino) cyclopropanecarboxylic acid (70 mg,47% yield). MS: m/z found 902[ M+Na ]] ⁺ .

(d) 1- (((6- (((S) -5- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropanecarboxylic acid

To 1- (((6- (((S) -5- (5- (((tert-butoxycarbonyl) ((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3 '-chloro-6-methoxy- [2,4' -bipyridine)]A mixture of (2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino cyclopropanecarboxylic acid (0.14 g,0.15 mmol) in 1, 4-dioxane (2 mL) was added in one portion to concentrated HCl solution (0.3 mL) and the mixture stirred at room temperature for 4 hours. The mixture was then neutralized with aqueous ammonia and the mixture was purified directly by reverse phase HPLC to afford 1- (((6- (((S) -5- (3 '-chloro-6-methoxy-5- (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridine) as a white solid]-2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl-amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl-methyl) amino) cyclopropanecarboxylic acid (19.2 mg,15% yield). MS: m/z found 780[ M+H ] ] ⁺ Retention time = 3.30min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.51(t,1H),7.74-7.73(m,2H),7.61(d,1H),7.34-7.28(m,2H),7.20-7.15(m,1H),7.07-7.05(m,1H),6.14-5.91(m,1H),5.53-5.42(m,1H),4.17(d,2H),4.00-3.78(m,9H),2.72-2.66(m,2H),2.51-2.21(m,5H),2.02-1.98(m,2H),1.76-1.71(m,3H),1.31-1.27(m,2H),1.11-1.07(m,2H).

Example 699: (S) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one (707)

In a similar manner to example 698, (S) -5- (((3 ' -chloro-2 ' - ((S) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridine) was prepared in step (c) using (S) -1-aminopropane-2-ol instead of 1-aminocyclopropane carboxylic acid]-5-yl) methyl) amino) methyl) pyrrolidin-2-one. White solid, MS: m/z found 754[ M+H ]] ⁺ Retention time = 3.11min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.63-8.61(m,1H),7.83(d,1H),7.73(d,1H),7.68(s,1H),7.46-7.42(m,2H),7.34-7.29(m,1H),7.18(d,1H),5.85-5.61(m,1H),5.60-5.54(m,1H),4.06(s,3H),3.99-3.85(m,7H),3.77-3.67(m,2H),2.73-2.34(m,9H),2.18-1.83(m,5H),1.19(d,3H).

Example 700: (S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) pyrrolidin-2-one (709)

In a similar manner to example 698, (S) -5- ((((3 '-chloro-6-methoxy-2' - ((S) -5- (-) -a) amino cyclopropanecarboxylic acid) was prepared in step (c) using (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride instead of 1-aminocyclopropane carboxylic acid 6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridine]-5-yl) methyl) amino) methyl) pyrrolidin-2-one. White solid, MS: m/z found 793[ M+H ]] ⁺ Retention time = 3.21min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.63-8.61(m,1H),7.83(d,1H),7.73(d,1H),7.69(s,1H),7.46-7.42(m,2H),7.34-7.29(m,1H),7.18(d,1H),5.84-5.62(m,1H),5.60-5.54(m,1H),4.06(s,3H),3.99-3.83(m,7H),3.71-3.67(m,2H),2.74-2.23(m,12H),2.21-1.74(m,6H).

Example 701:2- ((6- (((S) -5- (3 ' -chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one (720)

In a similar manner to example 698, 2, 6-diazaspiro [3.4] was used in step (c)]Preparation of 2- ((6- (((S) -5- (3 '-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridine) using octane-7-one trifluoroacetate instead of 1-aminocyclopropane carboxylic acid and triethylamine instead of sodium acetate]-2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl-amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl-methyl) -2, 6-diazaspiro [3.4]Octane-7-one. White solid, MS: m/z found 805[ M+H ]] ⁺ Retention time = 3.06min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.51-8.49(m,1H),7.71(d,1H),7.61(d,1H),7.51(s,1H),7.33-7.30(m,2H),7.21-7.17(m,1H),7.06(d,1H),5.72-5.50(m,1H),5.48-5.40(m,1H),3.94(s,3H),3.89-3.85(m,3H),3.79-3.66(m,3H),3.46-3.45(m,4H),3.25-3.24(m,4H),2.60-2.17(m,9H),2.05-1.92(m,2H),1.85-1.62(m,3H).

Example 702: (S) -N- (5- (3 ' -chloro-6-methoxy-5- ((methylamino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine (732)

(a) (S) -3' -chloro-2 ' - (5- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridine ] -5-carbaldehyde

At N ₂ Downward (S) -2-methoxy-6- ((5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -5- (trifluoromethyl) nicotinaldehyde (0.21 g,0.45 mmol) (example 698, step (a)) and 2',3' -dichloro-6-methoxy- [2,4' -bipyridine]A mixture of 5-carbaldehyde (0.07 g,0.25 mmol) in THF/water mixture (10:1, 4.4 mL) was added at once to chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl)]Palladium (II) (0.02 g,0.02 mmol) and potassium phosphate (0.16 g,0.74 mmol) and the mixture was stirred at 80℃for 4 hours. The mixture was combined with another batch on the same scale and the mixture was concentrated. To the residue was added water (20 mL) and saturated aqueous brine solution (20 mL) and the mixture was extracted with ethyl acetate/THF mixture (1:1, 50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ Chromatography (0-15% ethyl acetate/petroleum ether) of the residue to afford (S) -3' -chloro-2 ' - (5- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridine as a yellow gum]5-Formaldehyde (0.12 g,40% yield). MS: m/z found 597[ M+H ]] ⁺ .

(b) ((S) -N- (5- (3 ' -chloro-6-methoxy-5- ((methylamino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine

At N ₂ Downward (S) -3' -chloro-2 ' - (5- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridine]A mixture of 5-formaldehyde (0.11 g,0.18 mmol) and methylamine hydrochloride (0.04 g,0.52 mmol) in a THF/methanol mixture (3:2, 5 mL) was added triethylamine (0.04 g,0.53 mmol) in one portion and the mixture stirred at room temperature for 1 hour. Sodium cyanoborohydride (0.06 g,0.88 mmol)) was added to the mixture. The mixture was stirred at room temperature for 0.5 hours, then water (1 mL) was added and the mixture was concentrated. The residue was purified by reverse phase HPLC to provide (S) -N- (5- (3 '-chloro-6-methoxy-5- ((methylamino) methyl) - [2,4' -bipyridine) as a yellow solid ]-2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine hydrochloride (20 mg,16% yield). The product was neutralized with saturated aqueous sodium bicarbonate solution and the mixture was extracted with dichloromethane (2×10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was freeze-dried to provide (S) -N- (5- (3 '-chloro-6-methoxy-5- ((methylamino) methyl) - [2,4' -bipyridine) as a white solid]-2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine (17.2 mg,58% yield). MS: m/z found 741[ M+TFA ]] ⁺ Retention time = 3.36min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.51-8.49(m,1H),7.66(d,1H),7.61(d,1H),7.54(s,1H),7.34-7.29(m,2H),7.22-7.17(m,1H),7.06(d,1H),5.49-5.39(m,1H),3.94(s,3H),3.87-3.81(m,3H),3.67(s,2H),3.52(s,2H),2.54-2.80(m,8H),2.02-1.97(m,2H),1.97-1.73(m,2H).

Example 703:5- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -N- (3- (2- (4- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) picolinamide (695)

(a) 2-chloro-3- (2, 3-dichloropyridin-4-yl) aniline

At N ₂ Potassium carbonate (5.3 g,38.3 mmol) and [1,1' -bis (biphenylphosphino) ferrocene were added in one portion to a mixture of 2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) aniline (3.8 g,15 mmol) and 2, 3-dichloro-4-iodopyridine (3.5 g,12.8 mmol) in a 1, 4-dioxane/water mixture (70:15, 85 mL) was added dropwise ]Palladium (II) dichloride complex with dichloromethane (0.21 g,0.26 mmo). The mixture was stirred at 110℃for 3 hours. The mixture was concentrated. To the residue was added water (30 mL) and saturated aqueous brine solution (100 mL) and the mixture was extracted with ethyl acetate/THF mixture (1:1, 200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-15% ethyl acetate/petroleum ether) to afford 2-chloro-3- (2, 3-dichloropyridin-4-yl) aniline (2.7 g,77% yield) as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.26(d,1H),7.19-7.07(m,2H),6.79(dd,1H),6.52(dd,1H).

(b) 6- ((2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) carbamoyl) nicotinic acid methyl ester

At N ₂ A mixture of 5- (methoxycarbonyl) pyridine carboxylic acid (0.5 g,2.76 mmol) in thionyl chloride (4 mL) was stirred at 80deg.C for 3 hours. The mixture was concentrated to give crude methyl 6- (chlorocarbonyl) nicotinate (0.55 g, crude) as a white solid. At N ₂ To a mixture of methyl 6- (chlorocarbonyl) nicotinate (0.55 g,2.76 mmol) and 2-chloro-3- (2, 3-dichloropyridin-4-yl) aniline (0.64 g,2.34 mmol) in dichloromethane (3 mL) was added triethylamine (1.2 mL,8.27 mmol) in one portion and the mixture was stirred at room temperature for 12 hours. Water (50 mL) was added to the reaction solution and the mixture was filtered. The filter cake was dried to provide methyl 6- ((2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) carbamoyl) nicotinate (0.65 g,54% yield) as a white solid. MS: m/z found 436 and 438[ M+H ] ] ⁺ .

(c) N- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -5- (hydroxymethyl) picolinamide

At N ₂ To a mixture of methyl 6- ((2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) carbamoyl) nicotinic acid (0.65 g,1.49 mmol) in a MeOH/THF mixture (2:5, 70 mL) was added sodium borohydride (0.56 mg,14.9 mmol) in portions at 0deg.C. The mixture was stirred at room temperature for 12 hours. Water (20 mL) was added to the mixture to quench the sodium borohydride and the mixture was concentrated. To the residue was added water (20 mL) and saturated aqueous brine solution (5 mL) and the mixture was extracted with ethyl acetate/THF mixture (1:1, 50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-50% (30% THF in ethyl acetate)/petroleum ether) to afford N- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -5- (hydroxymethyl) picolinamide (0.4 g,65% yield) as a pale yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.73(s,1H),8.71(d,1H),8.59(d,1H),8.31(d,1H),8.23(d,1H),7.88(dd,1H),7.38(t,1H),7.13(d,1H),6.93(dd,1H),4.80(s,2H).

(d) N- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -5- (hydroxymethyl) picolinamide

At N ₂ To a mixture of N- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -5- (hydroxymethyl) pyridine amide (0.2 g,0.49 mmol) and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (0.17 g,0.64 mmol) (example 714, step (f)) in a 1, 4-dioxane/water mixture (6:1, 7 mL) was added at one time chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ]Palladium (II) (0.04 g,0.05 mmol) and potassium phosphate (0.31 g,1.47 mmol). The mixture was stirred at 80℃for 12 hours. To the mixtureWater (10 mL) was added and the mixture extracted with ethyl acetate (2X 50 mL). The combined organic phases were washed with saturated aqueous brine solution (2×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-30% (30% THF in ethyl acetate)/petroleum ether) to afford N- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -5- (hydroxymethyl) pyridineamide (90 mg,32% yield) as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.80(s,1H),10.48(s,1H),8.83(d,1H),8.74(d,1H),8.59-8.57(m,1H),8.26(d,1H),8.10(dd,1H),7.88(d,1H),7.67-7.62(m,2H),7.57(d,1H),7.46(d,1H),7.34(dd,1H),5.60(t,1H),4.73(d,2H),4.05(s,3H).

(e) N- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -5-formylpyridinamide

At N ₂ To a mixture of N- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -5- (hydroxymethyl) pyridine amide (0.08 g,0.16 mmol) in dichloromethane (4 mL) was added once dess-martin periodate (0.09 g,0.2 mmol) and the mixture stirred at room temperature for 1 hour. Directly through normal phase SiO without post-treatment ₂ The mixture was purified by chromatography (0-30% (30% THF in ethyl acetate)/petroleum ether) to afford N- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -5-formylpyridinamide (70 mg,62% yield) as a pale yellow solid. MS: m/z found 506[ M+H ] ] ⁺ .

(f) 5- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -N- (3- (2- (4- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) picolinamide

At N ₂ Downward N- (2-chloro-)3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -5-formylpyridinamide (0.06 g,0.12 mmol) and 2-oxaspiro [3.3]]Sodium acetate (0.06 g,0.71 mmol) was added in one portion as a mixture of heptane-6-amine hydrochloride (0.04 g,0.3 mmol) in a dichloromethane/methanol mixture (1:1, 4 mL). The mixture was stirred at room temperature for 2 hours, then sodium cyanoborohydride (0.03 g,0.47 mmol) was added. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated and the residue purified by reverse phase HPLC to afford 5- (((2-oxaspiro [ 3.3) as a white solid (formate salt)]Heptane-6-yl) amino methyl) -N- (3- (2- (4- (((2-oxaspiro [3.3 ]) -2)]Heptane-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) picolinamide (17.6 mg,19% yield). MS: m/z found 700[ M+H ]] ⁺ Retention time = 0.70min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.63(s,1H),8.60(d,1H),8.57(dd,1H),8.39(br s,1H),8.19(d,1H),7.99(d,1H),7.47(t,1H),7.43(d,1H),7.39(d,1H),7.32(d,1H),7.28(dd,1H),7.13(dd,1H),4.67(s,2H),4.64(s,2H),4.57(s,2H),4.54(s,2H),4.08(s,2H),3.93(s,3H),3.88(s,2H),3.64-3.57(m,1H),3.29-3.27(m,1H),2.65-2.61(m,2H),2.53-2.52(m,2H),2.35-2.32(m,2H),2.08-2.07(m,2H).

Example 704:5- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -N- (3- (2- (4- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) pyridineamide (701)

(a) 5- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -N- (3- (2- (4- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) picolinamide

At N ₂ Downward N- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -5-formylPyridinylamide (0.1 g,0.20 mmol) (example 703, step (e)) and 2-oxa-6-azaspiro [3.3]]A mixture of heptane (0.05 g,0.49 mmol) in a methanol/dichloromethane mixture (1:1, 4 mL) was added sodium acetate (0.1 g,1.18 mmol) in one portion and the mixture stirred at room temperature for 11 hours. Sodium cyanoborohydride (0.05 g,0.79 mmol) was then added and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated and the residue purified by preparative HPLC to provide 5- ((2-oxa-6-azaspiro [3.3] as a white solid (formate salt)]Heptan-6-yl) methyl) -N- (3- (2- (4- ((2-oxa-6-azaspiro [ 3.3)]Heptane-6-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl-2-chlorophenyl) pyridine amide (11.7 mg,8% yield). MS: m/z found 672[ M+H ]] ⁺ Retention time = 2.75min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.69-8.68(m,2H),8.66-8.65(m,1H),8.45(br s,1H),8.25(d,1H),7.99(d,1H),7.56(t,1H),7.51-7.47(m,2H),7.41(s,1H),7.38(d,1H),7.22(dd,1H),4.81(s,4H),4.77(s,4H),4.31(s,2H),4.25(s,4H),4.00(s,3H),3.80(s,2H),3.56(s,4H).

Example 705: n- (2-chloro-3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -5- (((3-fluoropropyl) amino) methyl) picolinamide (702)

(a) N- (2-chloro-3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -5- (((3-fluoropropyl) amino) methyl) picolinamide

At N ₂ To a mixture of N- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -5-formylpyridinamide (0.1 g,0.2 mmol) (example 703, step (e)) and 3-fluoropropane-1-amine hydrochloride (0.06 g,0.5 mmol) in a dichloromethane/methanol mixture (1:1, 1 mL) was added sodium acetate (0.1 g,1.18 mmol) at one time and the mixture stirred at room temperature for 12 hours.Sodium cyanoborohydride (0.05 g,0.79 mmol) was then added and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide N- (2-chloro-3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -5- (((3-fluoropropyl) amino) methyl) picolinamide (14.4 mg,10% yield) as a white solid (formate). MS: m/z found 628[ M+H ]] ⁺ Retention time = 2.97min (method a). 1H NMR (400 MHz, methanol-d) ₄ ):δ8.75(s,1H),8.70-8.66(m,2H),8.51(s,1H),8.30(d,1H),8.10(d,1H),7.58-7.54(m,2H),7.49(d,1H),7.43(s,1H),7.38(d,1H),7.22(dd,1H),4.67(t,1H),4.62(t,1H),4.55(t,1H),4.50(t,1H),4.32(s,2H),4.08(s,2H),4.02(s,3H),3.24(t,2H),2.93(t,2H),2.20-1.96(m,4H).

Example 706:5- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -N- (3- (2- (4- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) picoline amide (706)

(a) 5- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -N- (3- (2- (4- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) picolinamide

At N ₂ N- (2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) -5-formylpyridinamide (0.13 g,0.26 mmol) (example 703, step (e)) and 1- (6-amino-2-azaspiro [3.3] at room temperature]A mixture of heptan-2-yl) ethanone (0.1 g,0.65 mmol) (example 375, step (d)) in a methanol/dichloromethane mixture (1:1, 4 mL) was added sodium acetate (0.1 g,1.31 mmol) in one portion and the mixture stirred at room temperature for 11 hours. Sodium cyanoborohydride (0.07 g,1.05 mmol) was then added and the mixture was stirred at room temperature 1Hours. The mixture was concentrated and the residue purified by preparative HPLC to afford 5- (((2-acetyl-2-azaspiro [ 3.3) as a white solid]Heptane-6-yl) amino methyl) -N- (3- (2- (4- (((2-acetyl-2-azaspiro [3.3 ])]Heptane-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) picolinamide (8.7 mg 4% yield). MS: m/z actual measurement 782[ M+H ]] ⁺ Retention time = 2.73min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.60-8.58(m,3H),8.17(d,1H),7.96(dd,1H),7.48(t,1H),7.38(d,1H),7.36(d,1H),7.25-7.22(m,2H),7.13(dd,1H),4.15(d,2H),4.05(d,2H),3.92-3.89(m,5H),3.82-3.81(m,4H),3.75(s,2H),3.35-3.32(m,1H),3.19-3.13(m,1H),2.46-2.40(m,4H),2.08-2.07(m,2H),1.99-1.94(m,2H),1.78-1.77(m,6H).

Example 707: n- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide (733)

(a) N- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -5-formylpyridinamide

At N ₂ To a mixture of N- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -5- (hydroxymethyl) pyridine amide (example 703, step (c)) (1 g,2.45 mmol) in dichloromethane (10 mL) was added sodium bicarbonate (0.41 g,4.89 mmol) and dess-martin periodate (1.14 g,2.69 mmol) at one time and the mixture was stirred at room temperature for 1 hour. Directly through normal phase SiO without post-treatment ₂ The mixture was purified by chromatography (0-15% (10% THF in ethyl acetate)/petroleum ether) to afford N- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -5-formylpyridinamide as a white solid (0.37 g,22% yield). ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.78(s,1H),10.24(s,1H),9.24(s,1H),8.54-8.53(m,2H),8.46-8.40(m,2H),7.56(m,2H),7.30(d,1H).

(b) ((6- ((2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester

At N ₂ Sodium acetate was added to a mixture of N- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -5-formylpyridinamide (0.47 g,1.16 mmol) and 2-aminoethanol (0.08 g,1.27 mmol) in a dichloromethane/methanol mixture (2:1, 30 mL) and the mixture was stirred at room temperature for 12 hours. Sodium cyanoborohydride (0.22 g,3.47 mmol) was then added and the mixture was stirred at room temperature for 1 hour. Then at N ₂ Di-tert-butyl dicarbonate (0.31 ml,1.35 mmol) and triethylamine (0.14 ml,1.04 mmol) were added in one portion and the mixture was stirred at room temperature for 1 hour. Water (10 mL) was added and the mixture extracted with ethyl acetate (2X 10 mL). The combined organic phases were washed with saturated aqueous brine solution (2×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (15-50% ethyl acetate/petroleum ether) to give tert-butyl ((6- ((2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamate (0.47 g,52% yield) as a yellow oil. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.75(s,1H),10.76(s,1H),8.59-8.56(m,2H),8.26(d,1H),8.02(d,1H),7.66-7.61(m,2H),7.32(dd,1H),4.79(t,1H),4.64-4.61(m,2H),3.57-3.54(m,2H),3.33-3.32(m,2H),1.49-1.36(m,9H).

(c) ((6- ((2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester

At N ₂ Downward ((6- ((2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl)A mixture of tert-butyl carbamate (0.12 g,0.22 mmol) and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (example 714, step (f)) (0.07 g,0.28 mmol) in a 1, 4-dioxane/water mixture (4:1, 5 mL) was added to tetrakis (triphenylphosphine) palladium (0) (0.02 g,0.02 mmol) and potassium carbonate (0.09 g,0.65 mmol) in one portion. The mixture was stirred at 110 ℃ for 3 hours, then the mixture was combined with additional batches on a scale of 30mg and 130 mg. The combined reaction mixtures were concentrated, water (20 mL) and ethyl acetate (20 mL) were added to the residue and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with saturated aqueous brine solution (2×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-25% ethyl acetate/petroleum ether) to give tert-butyl ((6- ((2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamate (0.24 g,72% yield) as a white solid. MS: m/z found 651[ M+H ]] ⁺ .

(d) ((6- ((3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester

At N ₂ To a mixture of tert-butyl ((6- ((2-chloro-3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) phenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamate (0.2 g,0.3 mmol) and 1- (4-aminopiperidin-1-yl) ethanone hydrochloride (0.08 g,0.46 mmol) in a methanol/THF mixture (1:1, 5 ml) was added sodium acetate (0.07 g,0.9 mmol) at one time and the mixture stirred at room temperature for 12 hours. Sodium cyanoborohydride (0.06 g,0.92 mmol) was then added and the mixture was stirred at room temperature for 1 hour. Concentrating the mixture and passing through normal phase SiO ₂ The residue was purified by chromatography (0-50% methanol/ethyl acetate) to afford ((6- ((3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3) as a white solid -chloropyridin-4-yl) -2-chlorophenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester (0.18 g,62% yield). MS: m/z found 777[ M+H ]] ⁺ .

(e) N- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide

At N ₂ To a mixture of tert-butyl ((6- ((3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamate (0.17 g,0.22 mmol) in 1, 4-dioxane (1 mL) was added concentrated HCl solution (3 mL) at once and the mixture stirred at room temperature for 3 hours. The mixture was neutralized with aqueous ammonia and concentrated. The residue was purified by reverse phase HPLC to provide N- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide (9.3 mg,5% yield) as a white solid. MS: m/z found 677[ M+H ]] ⁺ Retention time = 2.65min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.72(d,1H),8.69-8.65(m,2H),8.26(d,1H),8.07(dd,1H),7.55(t,1H),7.45-7.44(m,2H),7.32-7.30(m,2H),7.21(dd,1H),4.52-4.47(m,1H),3.98-3.92(m,8H),3.71(t,2H),3.15-3.12(m,1H),2.84-2.68(m,4H),2.12(s,3H),2.09-2.03(m,2H),1.43-1.32(m,2H).

Example 708: n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -5- (((2-hydroxyethyl) amino) methyl) pyridine amide (754)

In a similar manner to example 707, 2, 6-diazaspiro [3.4 ] was used in step (d)]Octane-7-ketone substituted 1- (4-amino)Preparation of N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4 ]) by piperidin-1-yl) ethanone hydrochloride]Octan-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide. MS: m/z found 661[ M+H ]] ⁺ Retention time = 2.56min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.72-8.65(m,3H),8.26(d,1H),8.07(dd,1H),7.55(t,1H),7.45-7.39(m,2H),7.30-7.28(m,2H),7.21(dd,1H),3.98(s,2H),3.93(s,3H),3.79(s,2H),3.71(t,2H),3.59(s,2H),3.44(s,4H),2.78(t,2H),2.58(s,2H).

Example 709: (S) -N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide (755)

(S) -N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide was prepared in step (d) using (S) -5- (aminomethyl) pyrrolidin-2-one as the hydrochloride salt instead of 1- (4-aminopiperidin-1-yl) ethanone hydrochloride in analogy to example 707. MS: m/z found 649[ M+H ]] ⁺ Retention time = 2.56min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.72-8.65(m,3H),8.26(d,1H),8.07(dd,1H),7.55(t,1H),7.45-7.42(m,2H),7.31-7.29(m,2H),7.21(dd,1H),3.97(s,2H),3.95(s,3H),3.90-3.89(m,2H)3.87-3.82(m,1H),3.71(t,2H),2.78(t,2H),2.72 -2.69(m,2H),2.37-2.26(m,3H),1.84-1.77(m,1H).

Example 710: n- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptane-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -5- (((2-hydroxyethyl) amino) methyl) pyridine amide (757)

To be similar toExample 707 by using 1- (2, 6-diazaspiro [3.3 ] in step (d)]Preparation of N- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3 ]) by substituting 1- (4-aminopiperidin-1-yl) ethan-1-one trifluoroacetate for 1- (4-aminopiperidin-1-yl) ethan-one hydrochloride]Heptane-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide. MS: m/z found 675[ M+H ]] ⁺ Retention time = 2.61min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.72-8.65(m,3H),8.26(d,1H),8.07(dd,1H),7.55(t,1H),7.44(d,1H),7.38(d,1H),7.29-7.27(m,2H),7.21(dd,1H),4.30(s,2H),4.05(s,2H),3.97(s,2H),3.92(s,3H),3.74(s,2H),3.71(t,2H),3.51(q,4H),2.77(t,2H),1.86(s,3H).

Example 711: n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide (768)

N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide was prepared in analogy to example 707 substituting tetrahydro-2H-pyran-4-amine for 1- (4-aminopiperidin-1-yl) ethanone hydrochloride in step (d). MS: m/z found 636[ M+H ]] ⁺ Retention time = 2.74min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.72-8.65(m,3H),8.26(d,1H),8.07(dd,1H),7.55(t,1H),7.45-7.42(m,2H),7.31-7.28(m,2H),7.21(dd,1H),3.99-3.95(m,7H),3.92(s,2H),3.71(t,2H),3.45-3.38(m,2H),2.77(t,3H),1.92(dd,2H),1.54-1.44(m,2H).

Example 712: (S) -N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((methylamino) methyl) picolinamide (751)

(a) (S) - (4- (3-chloro-4- (2-chloro-3- (5- (hydroxymethyl) pyridinylamino) phenyl) pyridin-2-yl) -2-methoxybenzyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

At N ₂ To a mixture of N- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -5- (hydroxymethyl) pyridine amide (example 703, step (c)) (0.35 g,0.86 mmol) and tert-butyl (5-oxopyrrolidin-2-yl) methyl) carbamate (example 542, step (p)) (0.55 g,1.2 mmol) of (S) - (2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) ((5-oxopyrrolidin-2-yl) methyl) ferrocene in a 1, 4-dioxane/water mixture (10:1, 8.8 mL) was added at one time [1,1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) dichloride (0.03 g,0.04 mmol) and potassium phosphate (0.55 g,2.57 mmol) and the mixture was stirred at 100℃for 12 hours. The mixture was combined with another batch at 50mg scale. Concentrating the mixture and passing through normal phase SiO ₂ The residue was purified by chromatography (0-15% (30% THF in ethyl acetate)/petroleum ether) to afford tert-butyl (S) - (4- (3-chloro-4- (2-chloro-3- (5- (hydroxymethyl) pyridinamido) phenyl) pyridin-2-yl) -2-methoxybenzyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (0.35 g,50% yield) as a yellow solid. ¹ H NMR (400 MHz, methanol-d) ₄ )δ8.70-8.65(m,3H),8.27(d,1H),8.04(dd,1H),7.55(t,1H),7.44(d,1H),7.31-7.25(m,3H),7.21(dd,1H),4.78(s,2H),3.95-3.92(m,4H),3.42-3.37(m,2H),2.32-2.26(m,3H),1.86-1.81(m,1H),1.53-1.44(m,9H).

(b) (S) - (4- (3-chloro-4- (2-chloro-3- (5-formylpyridinium amido) phenyl) pyridin-2-yl) -2-methoxybenzyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

At N ₂ Downward (S) - (4- (3-chloro-4- (2-chloro-3- (5- (hydroxymethyl) pyridinylamino) phenyl) pyridin-2-yl) -2-methoxybenzylA mixture of tert-butyl (5-oxopyrrolidin-2-yl) methyl) carbamate (0.34 g,0.48 mmol) in dichloromethane (10 mL) was added once to dess-martin periodate (0.26 g,0.63 mmol) and the mixture stirred at room temperature for 0.5 hours. Directly through normal phase SiO ₂ The mixture was purified by chromatography (30% thf/petroleum ether in 30-100% ethyl acetate) to afford tert-butyl (S) - (4- (3-chloro-4- (2-chloro-3- (5-formylpyridinium amido) phenyl) pyridin-2-yl) -2-methoxybenzyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (MS: m/z found 704[ m+h)] ⁺ ) With (S) -6- ((3- (2- (4- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) carbamoyl) nicotinic acid (MS: m/z found 720[ M+H)] ⁺ ) (0.34 g) as a yellow solid.

(c) (S) - (4- (3-chloro-4- (2-chloro-3- (5- ((methylamino) methyl) pyridinoylamino) phenyl) pyridin-2-yl) -2-methoxybenzyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

At N ₂ To a mixture of tert-butyl (S) - (4- (3-chloro-4- (2-chloro-3- (5-formylpyridinium amido) phenyl) pyridin-2-yl) -2-methoxybenzyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate and (S) -6- ((3- (2- (4- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) carbamoyl) nicotinic acid (0.34 g,0.48 mmol) and methylamine hydrochloride (0.16 g,2.41 mmol) in a THF/MeOH mixture (5:1, 6 mL) was added triethylamine (0.33 ml,2.41 mmol) at one time and the mixture was stirred at room temperature for 0.5 hours. Sodium cyanoborohydride (0.09 g,1.45 mmol) was then added and the mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated, water (5 mL) and saturated aqueous brine solution (5 mL) were added to the residue and the mixture was extracted with ethyl acetate/THF mixture (1:1, 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by reverse phase HPLC and neutralized with saturated aqueous sodium bicarbonate solution to yieldThe material was extracted with dichloromethane (2×20 mL) to afford tert-butyl (S) - (4- (3-chloro-4- (2-chloro-3- (5- ((methylamino) methyl) pyridinoylamino) phenyl) pyridin-2-yl) -2-methoxybenzyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (70 mg,15% yield) as a yellow solid (MS: m/z found 719[ m+h ] ] ⁺ ) And (S) -6- ((3- (2- (4- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) carbamoyl) nicotinic acid (70 mg,18% yield) as a yellow solid. MS: m/z found 720[ M+H ]] ⁺ ).

(d) (S) -N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((methylamino) methyl) picolinamide

To a mixture of tert-butyl (S) - (4- (3-chloro-4- (2-chloro-3- (5- ((methylamino) methyl) pyridinoylamino) phenyl) pyridin-2-yl) -2-methoxybenzyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (65 mg,0.09 mmol) in 1, 4-dioxane (1.5 mL) was added concentrated HCl solution (0.4 mL) at once and the mixture stirred at room temperature for 0.5 hours. The mixture was combined with another batch at 5mg scale. The mixture was neutralized with saturated aqueous sodium carbonate solution, the mixture was concentrated and the residue was purified by reverse phase HPLC to afford (S) -N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((methylamino) methyl) picolinamide (14 mg,20% yield) as a white solid. MS: m/z found 599[ M+H ] ] ⁺ Retention time = 2.35min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.70-8.64(m,3H),8.24(d,1H),8.04(dd,1H),7.55(t,1H),7.45-7.41(m,2H),7.30-7.28(m,2H),7.21(dd,1H),3.95(s,3H),3.91-3.83(m,5H),2.73-2.67(m,2H),2.43(s,3H),2.37-2.28(m,3H),1.83-1.80(m,1H).

Example 713: (S) -6- ((2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) carbamoyl) nicotinic acid (752)

(a) (S) -6- ((2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) carbamoyl) nicotinic acid

To a mixture of (S) -6- ((3- (2- (4- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) carbamoyl) nicotinic acid (example 712, step (c)) (65 mg,0.09 mmol) in 1, 4-dioxane (1 mL) was added concentrated HCl solution (0.3 mL) at one time and the mixture stirred at room temperature for 0.5 hours. The mixture was combined with another batch at 5mg scale. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide (S) -6- ((2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) carbamoyl) nicotinic acid (26.2 mg,35% yield) as a white solid. MS: m/z found 620[ M+H ]] ⁺ Retention time = 3.51min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ9.17(d,1H),8.69-8.66(m,2H),8.50(dd,1H),8.29(d,1H),7.57-7.52(m,2H),7.48(d,1H),7.41(s,1H),7.37(d,1H),7.20(dd,1H),4.33-4.25(m,2H),4.07-3.96(m,4H),3.16-3.14(m,2H),2.47-2.36(m,3H),1.94-1.86(m,1H).

Example 714: n- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide (700)

(a) 6- ((3-bromo-2-methylphenyl) carbamoyl) nicotinic acid methyl ester

To a mixture of 5- (methoxycarbonyl) pyridine carboxylic acid (3 g,16.6 mmol) in DMF (2 mL) was added HATU (9.45 g,24.84 mmol) and N, N-diisopropylethylamine (7.21 mL,41.40 mmol). After 0.2 h, 3-bromo-2-methylaniline (2.24 ml,18.2 mmol) was added and the reaction stirred at room temperature for 12 h. Water (60 mL) was added to the reaction and the mixture was stirred for 1 hour. The mixture was then filtered and the filter cake was washed with water (100 mL) to provide an off-white solid. The solid was dried under reduced pressure to provide methyl 6- ((3-bromo-2-methylphenyl) carbamoyl) nicotinate (4.71 g,81% yield) as an off-white solid, which was used in the next step without further purification. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.64(s,1H),9.15(s,1H),8.51(dd,1H),8.24(d,1H),7.54(d,1H),7.49(d,1H),7.16(t,1H),3.91(s,3H),2.29(s,3H).

(b) N- (3-bromo-2-methylphenyl) -5- (hydroxymethyl) pyridine amide

At N ₂ To a mixture of methyl 6- ((3-bromo-2-methylphenyl) carbamoyl) nicotinate (4.1 g,11.7 mmol) in MeOH/THF (1/1, 300 mL) was added sodium borohydride (1.78 g,47.0 mmol) at 0deg.C and the mixture was stirred at room temperature for 12 hours. Water (20 mL) was then added and the mixture was concentrated. The residue was partitioned between ethyl acetate (200 mL) and water (200 mL) and the aqueous phase extracted with ethyl acetate (200 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-100% ethyl acetate/petroleum ether) to afford N- (3-bromo-2-methylphenyl) -5- (hydroxymethyl) pyridine amide (2.66 g,70% yield) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.50(s,1H),8.69(s,1H),8.14(d,1H),8.00(dd,1H),7.69(d,1H),7.51(d,1H),7.21(t,1H),5.54(t,1H),4.68(d,2H),2.36(s,3H).

(c) N- (3-bromo-2-methylphenyl) -5-formylpyridinamide

To a solution of N- (3-bromo-2-methylphenyl) -5- (hydroxymethyl) pyridine amide (2.6 g,8.10 mmol) in dichloromethane (40 mL) was added dess-martin periodate (8.58 g,20.2 mmol) and the mixture stirred at room temperature for 2 hours. The mixture is then concentrated and passed through normal phase SiO ₂ The residue was purified by chromatography (20-30% EtOAc/petroleum ether) to afford N- (3-bromo-2-methylphenyl) -5-formylpyridinamide (2 g,77% yield) as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.73(s,1H),10.30(s,1H),9.28(s,1H),8.58-8.55(m,1H),8.39(d 1H),7.66(d,1H),7.69(d,1H),7.27(t,1H),2.40(s,3H).

(d) ((6- ((3-bromo-2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester

To a mixture of N- (3-bromo-2-methylphenyl) -5-formylpyridinamide (1 g,3.13 mmol) and 2-aminoethanol (383 mg,6.27 mmol) in methanol (80 mL) was added sodium acetate (771 mg,9.40 mmol) and the mixture was stirred for 12 hours. Sodium cyanoborohydride (591 mg,9.40 mmol) was then added and the mixture was stirred at room temperature for an additional 2 hours. Additional sodium cyanoborohydride (4 eq) was added and stirring continued for a further 6 hours. Di-tert-butyl dicarbonate (1.71 g,7.82 mmol) and triethylamine (1.31 ml,9.39 mmol) were then added and the mixture was stirred at room temperature for 2 hours. To the mixture was added a saturated aqueous brine solution (30 mL) and the mixture was extracted with dichloromethane (40 mL x 3). The combined organic layers were concentrated under reduced pressure. By normal phase SiO ₂ The residue was purified by chromatography (0-100% EtOAc/petroleum ether) to afford tert-butyl ((6- ((3-bromo-2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamate (1.2 g,71% yield) as a yellow oil. MS: m/z observed values 464 and 466[ M+H ]] ⁺ .

(e) ((6- ((3- (2, 3-dichloropyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester

At N ₂ To a mixture of tert-butyl ((6- ((3-bromo-2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamate (400 mg,0.86mmol,3 batches) and 2, 3-dichloro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine (719 mg,1.90 mmol) in 1, 4-dioxane/water (5/1, 24 mL) was added potassium phosphate (549 mg,2.58 mmol) and [1,1' -bis (di-tert-butylphosphino) ferrocene at one time]Palladium (II) dichloride (56 mg,0.09 mmol) and the mixture was stirred at 85℃for 6 hours. Water (20 mL) was added and the mixture extracted with ethyl acetate (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-100% EtOAc/petroleum ether) to afford tert-butyl ((6- ((3- (2, 3-dichloropyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamate (340 mg,16% yield) as a red oil. MS: m/z found 531[ M+H ] ] ⁺ .

(f) 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde

To a solution of 4-bromo-2-methoxybenzaldehyde (10 g,46.5 mmol) and bis (pinacolato) diborane (23.6 g,93.0 mmol) in 1, 4-dioxane (100 mL) was added potassium acetate (13.7 g,139 mmol) and [1,1' -bis (biphenylphosphino) ferrocene]Palladium (II) dichloride complex with dichloromethane (1.90 g,2.33 mmol) and the mixture was stirred at 95 ℃ for 12 hours. The cooled reaction mixture was then filtered, and the filtrate was concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-100% EtOAc/petroleum ether) to afford a yellow solid. Then recrystallized twice from petroleum ether/EtOAc (6/1, 50 mL) at-30deg.CThe solid product was further purified to provide 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (12 g,98% yield) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.40(s,1H),7.70(d,1H),7.37(d,2H),3.95(s,3H),1.32(s,12H).

(g) ((6- ((3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester

At N ₂ To a mixture of tert-butyl ((6- ((3- (2, 3-dichloropyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamate (200 mg,0.38 mmol) and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (109 mg,0.41 mmol) in 1, 4-dioxane/water (10/1, 9.9 ml) was added potassium carbonate (156 mg,1.13 mmol) and tetrakis (triphenylphosphine) palladium (0) (43.5 mg,0.04 mmol) at one time and the mixture was stirred at 110℃for 12 hours. A saturated aqueous brine solution (10 mL) was then added and the mixture extracted with EtOAc (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. By normal phase SiO ₂ The residue was purified by chromatography (0-25% EtOAc/petroleum ether) to afford tert-butyl ((6- ((3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamate (230 mg,35% yield) as a yellow oil. MS: m/z found 631[ M+H ]] ⁺ .

(h) ((6- ((3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester

To ((6- ((3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridine-4))Tert-butyl (100 mg,0.16 mmol) of methyl) (2-hydroxyethyl) carbamate and 1- (4-aminopiperidin-1-yl) ethanone hydrochloride (42.5 mg,0.24 mmol) in methanol (3 mL) was added sodium acetate (39 mg,0.48 mmol) and the mixture was stirred for 2 hours. Sodium cyanoborohydride (29.9 mg,0.48 mmol) was added and the mixture was stirred at room temperature for another 4 hours. The mixture is then concentrated and passed through normal phase SiO ₂ Chromatography (20% MeOH/CH) ₂ Cl ₂ ) The residue was purified to provide tert-butyl ((6- ((3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamate (85 mg,60% yield) as a white solid. MS: m/z found 757[ M+H ] ] ⁺ .

(i) N- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide

To a mixture of tert-butyl ((6- ((3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamate (80 mg,0.11 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL,13.5 mmol) and the reaction stirred at room temperature for 0.5 hours. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC to afford N- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide (36.5 mg,48% yield) as a white solid (formate salt). MS: m/z found 657[ M+H ]] ⁺ Retention time = 1.49min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.80(s,1H),8.66(d,1H),8.47(br s,2H),8.29(d,1H),8.14(dd,1H),7.97(d,1H),7.55(d,1H),7.45-7.41(m,3H),7.37(dd,1H),7.14(d,1H),4.68(d,1H),4.32(s,2H),4.25(s,2H),4.09(d,1H),4.02(s,3H),3.81(t,2H),3.44(t,1H),3.23(t,1H),3.05(t,2H),2.72(t,1H),2.29-2.22(m,2H),2.19(s,3H),2.15(s,3H),1.68-1.63(m,1H),1.57-1.53(m,1H).

Example 715: n- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide (703)

(a) ((6- ((3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester

To a mixture of ((6- ((3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester (110 mg,0.17 mmol) (example 714, step (g)) and tetrahydro-2H-pyran-4-amine (26.4 mg,0.26 mmol) in methanol (2 mL) was added sodium acetate (42.9 mg,0.52 mmol) and the mixture was stirred for 2 hours. Sodium cyanoborohydride (32.9 mg,0.52 mmol) was then added and the mixture was stirred at room temperature for an additional 10 hours. The reaction mixture was purified by preparative TLC (20% methanol/dichloromethane) to afford tert-butyl ((6- ((3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamate (85 mg,68% yield) as a white solid.

(b) N- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide

To a mixture of tert-butyl ((6- ((3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamate (80 mg,0.11 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL,13.51 mmol) and the mixture was stirred at room temperature for 20 min. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC to provide N- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide (27.3 mg,39% yield) as a white solid. MS: m/z found 616[ M+H ] ] ⁺ Retention time = 2.54min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.72(d,1H),8.64(d,1H),8.23(d,1H),8.06(dd,1H),8.00(d,1H),7.49(d,1H),7.44-7.40(m,2H),7.36(s,1H),7.33(d,1H),7.13(dd,1H),4.60(s,1H),4.12(s,2H),4.03(dd,2H),3.98(s,4H),3.72(t,2H),3.48-3.42(m,2H),3.15-3.10(m,1H),2.80(t,2H),2.19(s,3H),2.03(dd,2H),1.67-1.58(m,2H).

Example 716: (S) -N- (3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide (735)

(a) (S) - ((6- ((3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester

To ((6- ((3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester (135 mg,0.21 mmol) (example 714, step (g)) and (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride (64.4 mg, 0).43 mmol) in methanol (2 mL) sodium acetate (52.6 mg,0.64 mmol) was added and the mixture stirred for 11 h. Sodium cyanoborohydride (40.3 mg,0.64 mmol) was added and the mixture was stirred at room temperature for an additional 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (20% methanol/dichloromethane) to provide tert-butyl (S) - ((6- ((3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamate as a white solid (130 mg,75% yield). MS: m/z found 729[ M+H ] ] ⁺ .

(b) (S) -N- (3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide

To a solution of tert-butyl (S) - ((6- ((3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamate (120 mg,0.16 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2.40 mL,32 mmol) and the mixture stirred at room temperature for 0.5 hours. The reaction was concentrated under reduced pressure and the residue was purified by reverse phase HPLC to afford (S) -N- (3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide (30.1 mg,28% yield) as a white solid. MS: m/z found 629[ M+H ]] ⁺ Retention time = 2.37min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.72(d,1H),8.62(d,1H),8.23(d,1H),8.05(dd,1H),8.01(d,1H),7.44-7.40(m,3H),7.30-7.21(m,2H),7.13(d,1H),3.96(d,5H),3.90-3.84(m,3H),3.71(t,2H),2.78(t,2H),2.71-2.69(m,2H),2.37-2.28(m,3H),2.20(s,3H),1.85-1.77(m,1H).

Example 717: n- (3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) pyridine amide (744)

(a) ((6- ((3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester

To tert-butyl ((6- ((3- (3-chloro-2- (4-formyl-3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamate (100 mg,0.16 mmol) (example 714, step (g)) and 2, 6-diazaspiro [3.4]]A mixture of octane-7-one trifluoroacetate (114 mg,0.48 mmol) in methanol/dichloromethane (1/1, 2.4 mL) was added sodium acetate (114 mg,1.39 mmol) and the mixture was stirred for 0.5 h. Sodium cyanoborohydride (29.9 mg,0.48 mmol) was added and the mixture was stirred at room temperature for an additional 11.5 hours. The reaction mixture was concentrated under reduced pressure and passed through normal phase SiO ₂ Chromatography (0-10% methanol/ethyl acetate) purified the residue to afford ((6- ((3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [ 3.4)) as a white solid]Octan-2-yl) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester (140 mg,59% yield).

(b) N- (3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide

To ((6- ((3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [ 3.4)) ]Octane-2-yl) methyl) phenyl) pyridineA mixture of tert-butyl 4-yl) -2-methylphenyl-carbamoyl) pyridin-3-yl methyl) (2-hydroxyethyl) carbamate (130 mg,0.18 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL,13.5 mmol) and the mixture stirred at room temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure and the residue was purified by reverse phase HPLC to afford N- (3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [ 3.4) as a yellow solid]Octan-2-yl) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide (21.6 mg,18.7% yield). MS: m/z found 641[ M+H ]] ⁺ Retention time 2.32min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.80(s,1H),8.66(d,1H),8.29(d,1H),8.14(dd,1H),7.97(d,1H),7.55(d,1H),7.45-7.41(m,2H),7.38-7.34(m,2H),7.14(d,1H),4.25(s,4H),3.98(s,7H),3.81(m,2H),3.66(s,2H),3.06(m,2H),2.69(s,2H),2.19(s,3H).

Example 718: (S) -N- (3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((methylamino) methyl) picolinamide (756)

(a) ((6- ((3-bromo-2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (methyl) carbamic acid tert-butyl ester

To a mixture of N- (3-bromo-2-methylphenyl) -5-formylpyridinamide (example 714, step (c)) (1 g,3.13 mmol) and methylamine hydrochloride (317 mg,4.70 mmol) in MeOH/dichloromethane (1/1, 30 mL) was added sodium acetate (771 mg,9.40 mmol) and stirred for 12 hours. Sodium cyanoborohydride (591 mg,9.40 mmol) was then added and the mixture was stirred at room temperature for an additional 1 hour. Triethylamine (1.31 ml,9.43 mmol) and di-tert-butyl dicarbonate (1.37 g,6.28 mmol) were then added and the reaction stirred at room temperature for 12 hours. Saturated aqueous brine solution (15 mL) was added and extracted with ethyl acetate (40 mL) Taking the mixture. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. By normal phase SiO ₂ The residue was purified by chromatography (0-50% ethyl acetate/petroleum ether) to afford tert-butyl ((6- ((3-bromo-2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (methyl) carbamate (1 g,73% yield) as a white solid. ₁ H NMR (400 MHz, chloroform-d): delta 10.07 (s, 1H), 8.50 (s, 1H), 8.25 (d, 1H), 8.15 (d, 1H), 7.70 (br s, 1H), 7.38 (d, 1H), 7.11 (t, 1H), 4.51 (s, 2H), 2.90-2.85 (m, 3H), 2.49 (s, 3H), 1.48 (s, 9H).

(b) ((6- ((3- (2, 3-dichloropyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (methyl) carbamic acid tert-butyl ester

At N ₂ To a mixture of tert-butyl ((6- ((3-bromo-2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (methyl) carbamate (200 mg,0.46 mmol) and 2, 3-dichloro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine (290 mg,1.06 mmol) in 1, 4-dioxane/water (5/1, 12 mL) was added at once potassium phosphate (293 mg,1.38 mmol) and [1,1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) dichloride (30.0 mg,0.05 mmol) and the mixture was stirred at 85℃for 6 hours. Additional 2, 3-dichloro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine (150 mg) was added and the mixture was stirred at 85℃for an additional 12 hours. The mixture was combined with another batch at 20mg scale, water (50 mL) was added and the mixture was extracted with ethyl acetate (200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. By normal phase SiO ₂ The residue was purified by chromatography (0-100% ethyl acetate/petroleum ether) to afford tert-butyl ((6- ((3- (2, 3-dichloropyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (methyl) carbamate (250 mg,79% yield) as a yellow oil. MS: m/z found 501[ M+H ]] ⁺ .

(c) (S) - ((6- ((3- (2- (4- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (methyl) carbamic acid tert-butyl ester

At N ₂ To a mixture of tert-butyl ((6- ((3- (2, 3-dichloropyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (methyl) carbamate (100 mg,0.20 mmol) and tert-butyl (5-oxopyrrolidin-2-yl) methyl) carbamate (example 542, step (p)) (119 mg,0.26 mmol) in 1, 4-dioxane/water (5/1, 6 ml) was added potassium carbonate (82.7 mg,0.60 mmol) and tetrakis (triphenylphosphine) palladium (0) (23.0 mg,0.02 mmol) at one time and the mixture was stirred at 95℃for 3 hours. Water (30 mL) was added and the mixture extracted with ethyl acetate (200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. By normal phase SiO ₂ The residue was purified by chromatography (0-100% ethyl acetate/petroleum ether) to provide tert-butyl (S) - ((6- ((3- (2- (4- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (methyl) carbamate as a yellow solid (150 mg,34% yield). MS: m/z found 799[ M+H ]] ⁺ .

(d) (S) -N- (3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((methylamino) methyl) picolinamide

To a mixture of tert-butyl (S) - ((6- ((3- (2- (4- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (methyl) carbamate (145 mg,0.18 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL,13.5 mmol) and the reaction stirred at room temperature for 0.5 hours. Under reduced pressureThe mixture was concentrated and the residue was purified twice by reverse phase HPLC to provide (S) -N- (3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((methylamino) methyl) picolinamide (20.6 mg,18% yield) as a white solid. MS: m/z found 599[ M+H ] ] ⁺ Retention time 2.35min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.72(s,1H),8.63(d,1H),8.25(d,1H),8.05(d,1H),8.00(d,1H),7.44-7.40(m,3H),7.31-7.28(m,2H),7.14(d,1H),3.97-3.92(m,7H),3.88-3.84(m,1H),2.77-2.72(m,2H),2.52(s,3H),2.37-2.27(m,3H),2.20(s,3H),1.85-1.79(m,1H).

Example 719: n- (3- (3-chloro-2- (3-fluoro-4- (((2-hydroxyethyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide (762)

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(a) 2-fluoro-6-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde

To a solution of 4-bromo-2-fluoro-6-methoxybenzaldehyde (980 mg,4.21 mmol) and bis (pinacolato) diboron (2.14 g,8.41 mmol) in 1, 4-dioxane (20 mL) was added potassium acetate (823mg, 8.41 mmol) and [1,1' -bis (biphenylphosphino) ferrocene]Palladium (II) dichloride complex with dichloromethane (343mg, 0.42 mmol) and stirring the mixture at 85 ℃ for 6 hours. The mixture was filtered and the filtrate was concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-10% ethyl acetate/petroleum ether) to give 2-fluoro-6-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (1.3 g,99% yield) as a yellow solid. MS: m/z found 199[ M-82 ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.32(s,1H),7.17(s,1H),7.02(d,1H),3.95(s,3H),1.32(s,12H).

(b) ((6- ((3- (3-chloro-2- (3-fluoro-4-formyl-5-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester

At N ₂ To a mixture of tert-butyl ((6- ((3- (2, 3-dichloropyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamate (50 mg,0.09 mmol) (example 714, step (e)) and 2-fluoro-6-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (36.9 mg,0.13 mmol) in 1, 4-dioxane/water (10/1, 3.3 ml) was added potassium carbonate (39.0 mg,0.28 mmol) and tetrakis (triphenylphosphine) palladium (0) (10.9 mg,9.41 umol) at one time and the mixture was stirred at 110℃for 12 hours. Saturated aqueous brine solution (20 mL) was added and the mixture was extracted with ethyl acetate (80 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-80% ethyl acetate/petroleum ether) to give tert-butyl ((6- ((3- (3-chloro-2- (3-fluoro-4-formyl-5-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamate (83 mg,39% yield) as a yellow oil. MS: m/z found 649[ M+H ]] ⁺ .

(c) ((6- ((3- (3-chloro-2- (3-fluoro-4- (((2-hydroxyethyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester

To a mixture of ((6- ((3- (3-chloro-2- (3-fluoro-4-formyl-5-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester (78 mg,0.12 mmol) and 2-aminoethanol (22.02 mg,0.36 mmol) in MeOH/dichloromethane (1/1, 2 mL) was added sodium acetate (29.6 mg,0.36 umol) and the mixture was stirred for 12 hours. Sodium cyanoborohydride (22.7 mg, 0) was added.36 umol) and the mixture was stirred at room temperature for a further 1 hour. The reaction mixture was concentrated under reduced pressure and passed through normal phase SiO ₂ The residue was purified by chromatography (0-20% methanol/dichloromethane) to provide tert-butyl ((6- ((3- (3-chloro-2- (3-fluoro-4- (((2-hydroxyethyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamate (73 mg,77.0% yield) as an off-white solid. MS: m/z found 694[ M+H ] ] ⁺ .

(d) N- (3- (3-chloro-2- (3-fluoro-4- (((2-hydroxyethyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide

To a mixture of tert-butyl ((6- ((3- (3-chloro-2- (3-fluoro-4- (((2-hydroxyethyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamate (68 mg,98 umol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.5 mL,6.75 mmol) and the mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC to provide N- (3- (3-chloro-2- (3-fluoro-4- (((2-hydroxyethyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide (21.7 mg,37% yield) as a white solid. MS: m/z found 594[ M+H ]] ⁺ Retention time 2.43min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.68(d,1H),8.60(d,1H),8.19(d,1H),8.01(dd,1H),7.97(d,1H),7.40-7.36(m,2H),7.15(s,1H),7.10(s,1H),7.08(d,1H),3.93(d,7H),3.66(dd,4H),2.74(t,4H),2.15(s,3H).

Example 720: n- (3- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide (766)

(a) (2-hydroxyethyl) ((6- ((2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) carbamoyl) pyridin-3-yl) methyl) carbamic acid tert-butyl ester

To a mixture of tert-butyl ((6- ((3-bromo-2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamate (example 714, step (d)) (1 g,2.15 mmol) and bis (pinacolato) diboron (1.64 g,6.46 mmol) in 1, 4-dioxane (8 mL) was added potassium acetate (634 mg,6.46 mmol) and [1,1' -bis (biphenylphosphino) ferrocene]Complex of palladium (II) dichloride with dichloromethane (176 mg,0.22 mmol) and under N ₂ The mixture was stirred at 110℃for 3 hours. Concentrating the mixture and passing through normal phase SiO ₂ The residue was purified by chromatography (10-50% ethyl acetate/petroleum ether) to give tert-butyl (2-hydroxyethyl) ((6- ((2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) carbamoyl) pyridin-3-yl) methyl) carbamate (800 mg,79% yield) as a white solid. MS: m/z found 512[ M+H ]] ⁺ .

(b) ((6- ((3- (3 ' -chloro-5-formyl-6-methoxy- [2,4' -bipyridyl ] -2' -yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester

To tert-butyl (2-hydroxyethyl) ((6- ((2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) carbamoyl) pyridin-3-yl) methyl) carbamate (271mg, 0.53 mmol) and 2',3' -dichloro-6-methoxy- [2,4' -bipyridine ]A mixture of 5-carbaldehyde (example 640, step (a)) (100 mg,0.35 mmol) in THF/water (10:1, 5.5 mL) was added chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl)]Palladium (II) (27.8 mg,0.04 umol) and potassium phosphate (225 mg,1.06 mmol) and under N ₂ Is arranged underThe mixture was stirred at 80℃for 1 hour. Water (5 mL) was added and the mixture extracted with ethyl acetate (2X 10 mL). The combined organic phases were dried over anhydrous sulphate, filtered and concentrated under reduced pressure. By preparative TLC (SiO) ₂ Ethyl acetate: petroleum ether = 1:0) the residue was purified to provide ((6- ((3- (3 '-chloro-5-formyl-6-methoxy- [2,4' -bipyridine) as a yellow oil]-2' -yl) -2-methylphenyl) carbamoyl) pyridin-3-yl methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester (70 mg,31% yield). MS: m/z found 632[ M+H ]] ⁺ .

(c) ((6- ((3- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester

To ((6- ((3- (3 '-chloro-5-formyl-6-methoxy- [2,4' -bipyridine)]A mixture of tert-butyl (2' -yl) -2-methylphenyl) carbamoyl) pyridin-3-yl methyl) (2-hydroxyethyl) carbamate (60 mg,94.9 umol) and tetrahydro-2H-pyran-4-amine (19.2 mg,190 umol) in dichloromethane/MeOH (1:1, 6 mL) was added sodium acetate (23.4 mg, 284 umol) and under N ₂ The mixture was stirred at room temperature for 1.5 hours. Sodium cyanoborohydride (17.9 mg, 284 umol) was then added and the mixture was stirred under N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and purified by preparative TLC (SiO ₂ Ethyl acetate meoh=1:2) to afford ((6- ((3- (3 '-chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridine) methyl) as a white solid]-2' -yl) -2-methylphenyl) carbamoyl) pyridin-3-yl methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester (45 mg,66% yield). MS: m/z found 717[ M+H ]] ⁺ .

(d) N- (3- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide

To ((6- ((3- (3 '-chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridine)]A solution of tert-butyl (2' -yl) -2-methylphenyl) carbamoyl) pyridin-3-yl methyl) (2-hydroxyethyl) carbamate (40 mg,0.06 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL,13.5 mmol) and taken up in N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide N- (3- (3 '-chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridine) as a white solid ]-2' -yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide (12.3 mg,34% yield). MS: m/z found 617[ M+H ]] ⁺ Retention time 2.32min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.72(d,1H),8.64(d,1H),8.23(d,1H),8.08-8.04(m,2H),7.84(d,1H),7.76(d,1H),7.45-7.41(m,2H),7.21(d,1H),4.06(s,3H),4.00-3.97(m,4H),3.91(s,2H),3.71(t,2H),3.47-3.44(m,2H),2.83-2.77(m,3H),2.19(s,3H),1.96-1.93(m,2H),1.54-1.49(m,2H).

Example 721: n- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridyl ] -2' -yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide (769)

N- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3 '-chloro-6-methoxy- [2,4' -bipyridine) was prepared in a similar manner to example 720 substituting 1- (4-aminopiperidin-1-yl) ethan-1-one hydrochloride for tetrahydro-2H-pyran-4-amine in step (c)]-2' -yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide. MS: m/z found 658[ M+H ]] ⁺ Retention time = 2.32min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.59(d,1H),8.52(d,1H),8.11(d,1H),7.96-7.92(m,2H),7.72(d,1H),7.64(d,1H),7.33-7.29(m,2H),7.09(d,1H),4.38-4.35(m,1H),3.94(s,3H),3.85(s,2H),3.81-3.80(m,1H),3.78(s,2H),3.59(t,2H),3.11-3.05(m,1H),2.70-2.62(m,4H),2.11(s,3H),2.07(s,3H),1.95-1.88(m,2H),1.32-1.17(m,2H).

Example 722: (S) -N- (3- (3 ' -chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide (771)

(a) (S) - ((6- ((3- (5- (((tert-Butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester

At N ₂ Downward (S) - ((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridine)]-5-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (0.2 g,0.42 mmol) (example 655, step (a)) and (2-hydroxyethyl) ((6- ((2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) carbamoyl) pyridin-3-yl) methyl) carbamic acid tert-butyl ester (example 720, step (a)) (0.32 g,0.62 mmol) in 1, 4-dioxane/water mixture (5:1, 6 mL) potassium phosphate (0.26 g,1.25 mmol) and chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) were added in one portion]Palladium (II) (0.03 g,0.04 mmol) and the mixture was stirred at 100℃for 4 hours. The mixture was combined with another batch at 85mg scale. Water (15 mL) was added and the mixture extracted with ethyl acetate (2X 15 mL). The combined organic phases were washed with saturated aqueous brine solution (2×15 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by reverse phase HPLC to provide (S) - ((6- ((3- (5- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3 '-chloro-6-methoxy- [2,4' -bipyridine) as a colorless solid]-2' -yl) -2-methylphenyl) carbamoyl) pyridin-3-yl ) Methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester (0.12 g,24% yield). MS: m/z found 830[ M+H ]] ⁺ .

(b) (S) -N- (3- (3 ' -chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide

At N ₂ Downward (S) - ((6- ((3- (5- (((tert-butoxycarbonyl) ((5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3 '-chloro-6-methoxy- [2,4' -bipyridine)]A mixture of tert-butyl (2' -yl) -2-methylphenyl) carbamoyl) pyridin-3-yl methyl) (2-hydroxyethyl) carbamate (0.11 g,0.13 mmol) in 1, 4-dioxane (1 mL) was added in one portion to concentrated HCl solution (0.13 mL) and the mixture stirred at room temperature for 2 hours. The mixture was combined with another batch on a 10mg scale. The mixture was neutralized with saturated aqueous sodium bicarbonate solution. The mixture was purified by reverse phase HPLC to afford (S) -N- (3- (3 '-chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridine) as a white solid]-2' -yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide (25.2 mg,28% yield). MS: m/z found 630[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.68(d,1H),8.60(d,1H),8.19(d,1H),8.04-8.01(m,2H),7.79(d,1H),7.72(d,1H),7.41-7.37(m,2H),7.17(d,1H),4.02(s,3H),3.94(s,2H),3.83-3.79(m,3H),3.67(t,2H),2.75(t,2H),2.70-2.63(m,2H),2.34-2.22(m,3H),2.15(s,3H),1.83-1.76(m,1H).

Example 723: (S) -N- (3- (3-chloro-2- (3- (difluoromethoxy) -4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide (770)

(a) ((6- ((3- (3-chloro-2- (3- (difluoromethoxy) -4-formylphenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester

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To a mixture of ((6- ((3- (2, 3-dichloropyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester (example 714, step (e)) (266 mg,0.89 mmol) and 2- (difluoromethoxy) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (example 529, step (b)) (190 mg,0.38 mmol) in 1, 4-dioxane/water (5:1, 12 mL) was added tetrakis (triphenylphosphine) palladium (0) (41.3 mg,0.05 mmol) and potassium carbonate (148 mg,1.07 mmol) and in N ₂ The mixture was stirred at 110℃for 12 hours. Concentrating the mixture and passing through normal phase SiO ₂ The residue was purified by chromatography (10-50% ethyl acetate/petroleum ether) to give tert-butyl ((6- ((3- (3-chloro-2- (3- (difluoromethoxy) -4-formylphenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamate (150 mg,62% yield) as a white solid. MS: m/z found 667[ M+H ]] ⁺ .

(b) (S) - ((6- ((3- (3-chloro-2- (3- (difluoromethoxy) -4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester

To a mixture of ((6- ((3- (3-chloro-2- (3- (difluoromethoxy) -4-formylphenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester (140 mg,0.21 mmol) and (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride (94.8 mg,0.63 mmol) in dichloromethane/MeOH (1:1, 3 mL) was added sodium acetate (51.6 mg,0.63 mmol) and N ₂ The mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (65.9 mg,1.05 mmol) was then added and the mixture was taken up in N ₂ At room temperatureThe mixture was stirred for 0.5 hours. The mixture was concentrated and purified by normal phase prep TLC (SiO ₂ Ethyl acetate methanol = 1:1) the residue was purified to provide tert-butyl (S) - ((6- ((3- (3-chloro-2- (3- (difluoromethoxy) -4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamate as a white solid (80 mg,77% yield). MS: m/z found 765[ M+H ]] ⁺ .

(c) (S) -N- (3- (3-chloro-2- (3- (difluoromethoxy) -4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide

To a mixture of tert-butyl (S) - ((6- ((3- (3-chloro-2- (3- (difluoromethoxy) -4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) carbamoyl) pyridin-3-yl) methyl) (2-hydroxyethyl) carbamate (70 mg,0.09 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.70 mL,9.45 mmol) and in N ₂ The mixture was stirred at room temperature for 1 hour. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide (S) -N- (3- (3-chloro-2- (3- (difluoromethoxy) -4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide (20.5 mg,32% yield) as a white solid. MS: m/z found 665[ M+H ]] ⁺ Retention time = 2.68min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.72(d,1H),8.64(d,1H),8.23(d,1H),8.05(dd,1H),8.01(d,1H),7.64-7.60(m,2H),7.53(s,1H),7.44-7.40(m,2H),7.15-6.79(m,2H),3.99-3.95(m,4H),3.87-3.84(m,1H),3.71(t,2H),2.80-2.71(m,4H),2.38-2.27(m,3H),2.19(s,3H),1.86-1.82(m,1H).

Example 724: (S) -5- ((((6- (((S) -4- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (686)

(a) ((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridyl ] -5-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester

To a solution of 2',3' -dichloro-6-methoxy- [2,4' -bipyridine ] -5-carbaldehyde (1.4 g,4.95 mmol) (example 640, step (a)) and tetrahydro-2H-pyran-4-amine (750 mg,7.42 mmol) in dichloromethane (30 mL) was added sodium acetate (1.62 g,19.8 mmol) and the solution stirred at room temperature for 12 hours. Sodium cyanoborohydride (932 mg,14.8 mmol) was then added and the mixture was stirred at room temperature for 2 hours. Triethylamine (1.36 ml,9.78 mmol) and di-tert-butyl dicarbonate (2.13 g,9.78 mmol) were then added and the mixture was stirred at room temperature for 4 hours. The reaction was concentrated under reduced pressure and the residue was purified by reverse phase HPLC to give tert-butyl ((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamate (1.3 g,56% yield) as a white solid.

(b) (S) - ((3 ' -chloro-2 ' - (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester

At N ₂ Downward (S) -2-methoxy-6- ((4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -5- (trifluoromethyl) nicotinaldehyde (example 645, step (f)) (640 mg,1.38 mmol) and ((2 ',3' -dichloro-6-methoxy- [2,4' -bipyridine)]A mixture of tert-butyl-5-yl-methyl) (tetrahydro-2H-pyran-4-yl) carbamate (220 mg,0.47 mmol) in THF/water (4/1, 7.5 mL) was taken oncePotassium phosphate (299 mg,1.41 mmol) and chloro [ (di (1-adamantyl) -N-butylphosphine) -2- (2-aminobiphenyl) were added]Palladium (II) (31.4 mg,0.05 mmol) and the mixture was stirred at 80℃for 1 hour. Water (20 mL) was added and the mixture extracted with ethyl acetate (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. By normal phase SiO ₂ Chromatography (10-30% ethyl acetate/petroleum ether) purification of the residue to afford (S) - ((3 ' -chloro-2 ' - (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine) as a yellow oil ]-5-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester (145 mg,40% yield).

(c) ((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester

To (S) - ((3 ' -chloro-2 ' - (1- ((5-formyl-6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridine)]A mixture of tert-butyl (5-yl) methyl) (tetrahydro-2H-pyran-4-yl) carbamate (60 mg,0.08 mmol) in dichloromethane (1 mL) was added (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride (17.6 mg,0.11 mmol) and sodium acetate (19.2 mg,0.23 mmol) and the mixture stirred at room temperature for 2 hours. Sodium cyanoborohydride (14.7 mg,0.23 mmol) was then added and the mixture was stirred for an additional 10 hours. Water (5 mL) was added and the mixture extracted with dichloromethane (30 mL). The organic layer was concentrated under vacuum and the residue passed through normal phase SiO ₂ Chromatography (0-100% ethyl acetate/petroleum ether to 0-50% MeOH/ethyl acetate) followed by preparative TLC (20% MeOH/ethyl acetate) purification afforded ((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridine) as a white solid ]-5-yl) methyl esterRadical) (tetrahydro-2H-pyran-4-yl) carbamic acid tert-butyl ester (85 mg,24% yield). MS: m/z found 867[ M+H ]] ⁺ .

(d) (S) -5- ((((6- (((S) -4- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one

To ((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridine)]A mixture of tert-butyl-5-yl-methyl) (tetrahydro-2H-pyran-4-yl) carbamate (74 mg,85.3 umol) in dichloromethane/MeOH (3/1, 3.2 mL) was added to 2M HCl (2.5 ml,5 mmol) in dioxane and the reaction stirred at room temperature for 12H. To the mixture was added 2M HCl in dioxane (1 mL) and the mixture was stirred for an additional 12 hours. Saturated aqueous ammonia (0.5 mL) was then added and the mixture concentrated under reduced pressure. The residue was purified by reverse phase HPLC twice to afford (S) -5- (((6- (((S) -4- (3 '-chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino)) methyl) - [2,4' -bipyridine) as a white solid (formate salt) ]-2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl-methyl) amino) pyrrolidin-2-one (2.3 mg,3.4% yield). MS: m/z found 767[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.64(d,1H),8.53(br s,1H),7.91(d,2H),7.73(d,1H),7.59-7.56(m,1H),7.48(d,1H),7.41(d,2H),6.69(t,1H),4.13-4.10(m,7H),4.04(dd,2H),3.87-3.84(m,1H),3.80(d,2H),3.50-3.41(m,3H),3.21-3.15(m,1H),3.06-3.00(m,1H),2.87-2.69(m,4H),2.38-2.23(m,4H),2.07-2.03(m,2H),1.86-1.81(m,1H),1.65-1.61(m,2H).

Example 725:2- (4- (5-chloro-6- (2-chloro-3- (5- (((2-hydroxyethyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octane-7-one (711)

(a) 6- (2-chloro-3- (5, 6-dichloropyrimidin-4-yl) phenyl) -2-methoxy nicotinaldehyde

At N ₂ Potassium carbonate (1.11 g,8.03 mmol) and [1,1' -bis (biphenylphosphino) ferrocene were added in one portion to a mixture of 6- (2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -2-methoxynicotinaldehyde (1 g,2.68 mmol) and 4,5, 6-trichloropyrimidine (0.98 g,5.35 mmol) in a 1, 4-dioxane/water mixture (10:1, 20 mL)]Palladium (II) dichloride complex with dichloromethane (0.11 g,0.13 mmol) and the mixture was stirred at 100 ℃ for 3 hours. The mixture was concentrated, water (200 mL) and saturated aqueous brine solution (20 mL) were added to the residue, and the mixture was extracted with ethyl acetate/THF mixture (1:1, 200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-15% ethyl acetate/petroleum ether) to afford 6- (2-chloro-3- (5, 6-dichloropyrimidin-4-yl) phenyl) -2-methoxynicotinaldehyde as a white solid (0.6 g,51% yield). ¹ H NMR (400 MHz, chloroform-d) δ10.36 (s, 1H), 8.91 (s, 1H), 8.13 (d, 1H), 7.71 (dd, 1H), 7.47 (t, 1H), 7.34-7.31 (m, 2H), 4.06 (s, 3H).

(b) ((6- (2-chloro-3- (5, 6-dichloropyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester

To a solution of 6- (2-chloro-3- (5, 6-dichloropyrimidin-4-yl) phenyl) -2-methoxynicotinaldehyde (0.6 g,1.5 mmol) and 2-aminoethanol (0.1 g,2 mmol) in a dichloromethane/methanol mixture (1:1, 10 ml) was added glacial acetic acid (0.2 ml,3 mmol) and the mixture was stirred at room temperature for 0.5 h. Sodium triacetoxyborohydride (0.3 g,4.6 mmo) was then addedl) and the mixture was stirred at room temperature for 0.5 h. Triethylamine (0.2 ml,1.5 mmol) and di-tert-butyl dicarbonate (1 ml,3 mmol) were then added and the mixture was stirred at room temperature for 1 hour. Water (20 mL) was added and the mixture extracted with ethyl acetate (2X 20 mL). The combined organic phases were washed with saturated aqueous brine solution (2×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (10-100% ethyl acetate/petroleum ether) to give tert-butyl ((6- (2-chloro-3- (5, 6-dichloropyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (2-hydroxyethyl) carbamate (570 mg,70% yield) as a yellow solid. MS: m/z found 539 and 541[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ ):δ9.16(s,1H),7.80(dd,1H),7.67-7.65(m,1H),7.63-7.60(m,2H),7.31(d,1H),4.42(s,2H),3.95(s,3H),3.54-3.53(m,2H),3.33-3.32(m,2H),1.45-1.35(m,9H).

(c) ((6- (2-chloro-3- (5-chloro-6- (4-formyl-3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester

To a solution of ((6- (2-chloro-3- (5, 6-dichloropyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester (0.3 g,0.6 mmol) and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzaldehyde (example 714, step (f)) (0.15 g,0.6 mmol) in 1, 4-dioxane/water mixture (5:1, 6 mL) was added potassium phosphate (0.35 g,2 mmol) and [1,1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) dichloride (18 mg,0.03 mmol) and the mixture was stirred at 80℃for 1 hour. Water (20 mL) was added and the mixture extracted with ethyl acetate (2X 20 mL). The combined organic phases were washed with saturated aqueous brine solution (2×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-50% ethyl acetate/petroleum ether) to give tert-butyl ((6- (2-chloro-3- (5-chloro-6- (4-formyl-3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (2-hydroxyethyl) carbamate (250 mg) as a yellow solid70% yield). MS: m/z found 639[ M+H ]] ⁺ .

(d) ((6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester

To ((6- (2-chloro-3- (5-chloro-6- (4-formyl-3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester (0.23 g,0.36 mmol) and 2, 6-diazaspiro [3.4]]A solution of octan-7-one trifluoroacetate (0.78 g,3.24 mmol) in a dichloromethane/methanol mixture (10:3, 13 mL) was added sodium acetate (0.35 g,4.32 mmol) and the mixture stirred at room temperature for 12 hours. Sodium cyanoborohydride (0.07 g,1.08 mmol) was then added and the mixture was stirred at room temperature for 1 hour. Concentrating the mixture and passing through normal phase SiO ₂ Chromatography (20-100% ethyl acetate/petroleum ether) purified the residue to afford ((6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [ 3.4)) as a white solid]Octan-2-yl) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester (0.55 g, crude. MS: m/z found 749[ M+H ]] ⁺ .

(e) 2- (4- (5-chloro-6- (2-chloro-3- (5- (((2-hydroxyethyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one

To ((6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4 ])]An aqueous solution of tert-butyl (2-hydroxyethyl) carbamate (0.5 g,0.7 mmol) in 1, 4-dioxane (3 mL) was added to a concentrated HCl solution (0.4 mL) and the mixture stirred at room temperature for 1 hour. Mixing the reaction The residue was concentrated and purified by reverse phase HPLC to provide 2- (4- (5-chloro-6- (2-chloro-3- (5- (((2-hydroxyethyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] as a white solid]Octan-7-one (29.6 mg,6% yield). MS: m/z found 649[ M+H ]] ⁺ Retention time = 2.23min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ9.21(s,1H),7.80-7.75(m,2H),7.60(t,1H),7.54-7.48(m,3H),7.45-7.43(m,1H),7.29(d,1H),4.05(s,3H),3.94(s,3H),3.88(s,2H),3.78(s,2H),3.72(t,2H),3.59(s,2H),3.45-3.41(m,4H),2.79(t,2H),2.58(s,2H).

Example 726: (S) -2- (4- (5-chloro-6- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one (742)

(a) (S) - ((6- (2-chloro-3- (5, 6-dichloropyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To a solution of 6- (2-chloro-3- (5, 6-dichloropyrimidin-4-yl) phenyl) -2-methoxynicotinaldehyde (0.6 g,1.52 mmol) (example 725, step (a)) and (S) -5- (aminomethyl) -2-pyrrolidone hydrochloride (0.25 g,1.67 mmol) in a THF/MeOH mixture (1:1, 6 ml) was added sodium acetate (0.37 g,4.56 mmol) and the mixture stirred at room temperature for 1 hour. Sodium cyanoborohydride (0.29 g,4.56 mmol) was then added and the mixture was stirred at room temperature for 1 hour. Di-tert-butyl dicarbonate (0.66 g,3 mmol) and triethylamine (0.2 ml,1.5 mmol) were then added and the mixture was stirred at room temperature for 1 hour. Water (20 mL) was then added and the mixture extracted with ethyl acetate (2X 10 mL). The combined organic phases were washed with saturated aqueous brine solution (2×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-100% ethyl acetate/petroleum ether) to give tert-butyl (S) - ((6- (2-chloro-3- (5, 6-dichloropyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (640 mg,72% yield) as a white solid. MS: m/z observed values 592 and 594[ M+H ]] ⁺ .

(b) (S) - ((6- (2-chloro-3- (5-chloro-6- (4-formyl-3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) carbamic acid tert-butyl ester

To a solution of (S) - ((6- (2-chloro-3- (5, 6-dichloropyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (0.1 g,0.17 mmol) and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (example 714, step (f)) (0.07 g,0.25 mmol) in 1, 4-dioxane/water mixture (10:1, 3 mL) was added potassium phosphate (0.11 g,0.5 mmol) and [1,1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) dichloride (6 mg,8 umol) and the mixture was stirred at 95℃for 2 hours. Water (20 mL) was then added and the mixture extracted with ethyl acetate (2X 20 mL). The combined organic phases were washed with saturated aqueous brine solution (2×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-50% ethyl acetate/petroleum ether) to give tert-butyl (S) - ((6- (2-chloro-3- (5-chloro-6- (4-formyl-3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (450 mg,50% yield) as a white solid. MS: m/z found 692[ M+H ]] ⁺ .

(c) (S) - ((6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester

To tert-butyl (S) - ((6- (2-chloro-3- (5-chloro-6- (4-formyl-3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate (0.42 g,0.61 mmol) and 2, 6-diazaspiro [ 3.4)]A solution of octan-7-one trifluoroacetate (0.66 g,2.73 mmol) in a dichloromethane/methanol mixture (1:1, 40 mL) was added sodium acetate (0.6 g,7.28 mmol) and the mixture stirred at room temperature for 1 hour. Sodium cyanoborohydride (0.11 g,1.82 mmol) was then added and the mixture was stirred at room temperature for 1 hour. The mixture was purified by reverse phase HPLC to afford (S) - ((6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [ 3.4)) as a white solid ]Octan-2-yl) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamic acid tert-butyl ester (70 mg,14% yield). MS: m/z found 802[ M+H ]] ⁺ .

(d) (S) -2- (4- (5-chloro-6- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one

To (S) - ((6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4 ])]A solution of tert-butyl (5-oxopyrrolidin-2-yl) methyl) carbamate (65 mg,0.081 mmol) in 1, 4-dioxane (2 mL) was added to concentrated HCl (0.4 mL) and the mixture stirred at room temperature for 1 hour. The mixture was purified by reverse phase HPLC to afford (S) -2- (4- (5-chloro-6- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] as a white solid]Octan-7-one (27.4 mg,48% yield). MS: m/z found 702[ M+H ]] ⁺ Retention time = 2.36min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ9.21(s,1H),7.79-7.76(m,2H),7.60(t,1H),7.52-7.46(m,3H),7.44-7.42(m,1H),7.28(d,1H),4.04(s,3H),3.94(s,3H),3.89-3.82(m,3H),3.78(s,2H),3.59(s,2H),3.45-3.40(m,4H),2.73-2.69(m,2H),2.58(s,2H),2.37-2.30(m,3H),1.88-1.79(m,1H).

Example 727:2- (4- (5-chloro-6- (2-chloro-3- (5- ((((1 s,3 s) -3-hydroxycyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one (737)

In a similar manner to example 726, 2- (4- (5-chloro-6- (2-chloro-3- (5- ((((1S, 3S) -3-hydroxycyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] hydrochloride was prepared in step (a) by substituting (1S, 3S) -3-aminocyclobutane-1-ol hydrochloride for (S) -5- (aminomethyl) -2-pyrrolidone hydrochloride]Octane-7-one. MS: m/z found 675[ M+H ]] ⁺ Retention time = 2.44min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ9.21(s,1H),7.78(dd,1H),7.73(d,1H),7.60(t,1H),7.54-7.48(m,3H),7.43(d,1H),7.27(d,1H),4.05(s,3H),3.99-3.89(m,4H),3.78(s,2H),3.75(s,2H),3.59(s,2H),3.45-3.40(m,4H),2.89-2.81(m,1H),2.62-2.56(m,4H),1.73-1.66(m,2H).

Example 728:2- (4- (5-chloro-6- (2-chloro-3- (5- ((((1 r,3 r) -3-hydroxycyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one (740)

In a similar manner to example 726, 2- (4- (5-chloro-6- (2-chloro-3- (5- ((((1 r,3 r) -3-hydroxycyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro-ne hydrochloride was prepared in step (a) by substituting (1 r,3 r) -3-aminocyclobutane-1-ol hydrochloride for (S) -5- (aminomethyl) -2-pyrrolidone hydrochloride[3.4]Octane-7-one. MS: m/z found 675[ M+H ]] ⁺ Retention time = 2.41min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ9.21(s,1H),7.78(dd,1H),7.73(d,1H),7.60(t,1H),7.53-7.48(m,3H),7.43(d,1H),7.27(d,1H),4.45-4.40(m,1H),4.04(s,3H),3.94(s,3H),3.78(s,2H),3.73(s,2H),3.59(s,2H),3.51-3.44(m,1H),3.42-3.33(m,4H),2.58(s,2H),2.22-2.12(m,4H).

Example 729: (S) -5- (((6- (2-chloro-3- (5-methoxy-6- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (716)

(a) 6- (2-chloro-3- (6-chloro-5-methoxypyrimidin-4-yl) phenyl) -2-methoxypolynicotinaldehyde

At N ₂ To a mixture of 6- (2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -2-methoxynicotinaldehyde (2 g,5.35 mmol) and 4, 6-dichloro-5-methoxypyrimidine (1.44 g,8.03 mmol) in 1, 4-dioxane/water (5/1, 120 mL) was added potassium carbonate (2.22 g,16.1 mmol) and tetrakis (triphenylphosphine) palladium (0) (309 mg,0.27 mmol) at once and the mixture was stirred at 95℃for 5 hours. Saturated aqueous brine solution (30 mL) was added and the mixture was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-30% ethyl acetate/petroleum ether) to afford 6- (2-chloro-3- (6-chloro-5-methoxypyrimidin-4-yl) phenyl) -2-methoxynicotinaldehyde as a yellow oil (0.8 g,32% yield). ¹ H NMR (400 MHz, chloroform-d): δ10.41 (s, 1H), 8.82 (s, 1H), 8.18 (d, 1H), 7.75 (dd, 1H), 7.51 (t, 1H), 7.44 (dd, 1H), 7.39 (d, 1H), 4.11 (s, 3H), 3.73 (s, 3H).

(b) 6- (2-chloro-3- (6- (4-formyl-3-methoxyphenyl) -5-methoxypyrimidin-4-yl) phenyl) -2-methoxypolynicotinaldehyde

To a solution of 6- (2-chloro-3- (6-chloro-5-methoxypyrimidin-4-yl) phenyl) -2-methoxyplanal (800 mg,2.05 mmol) and 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzaldehyde (example 714, step (f)) (591 mg,2.26 mmol) in 1, 4-dioxane/water (10/1, 44 mL) was added tetrakis (triphenylphosphine) palladium (0) (237 mg,0.21 mmol) and potassium carbonate (850 mg,6.15 mmol) and the mixture was stirred at 110℃for 12 hours. The mixture was combined with another batch on a 200mg scale. Water (20 mL) was added and the mixture extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (0-100% ethyl acetate/petroleum ether) to afford 6- (2-chloro-3- (6- (4-formyl-3-methoxyphenyl) -5-methoxypyrimidin-4-yl) phenyl) -2-methoxypolynicotinaldehyde (430 mg,40% yield) as a white solid. MS: m/z found 490 and 492[ M+H ]] ⁺ . ¹ H NMR (400 MHz, chloroform-d): delta 10.56 (s, 1H), 10.44 (s, 1H), 9.16 (s, 1H), 8.21 (d, 1H), 7.97 (d, 1H), 7.84-7.77 (m, 3H), 7.55 (d, 2H), 7.45 (d, 1H), 4.14 (s, 3H), 4.06 (s, 3H), 3.47 (s, 3H).

(c) (S) -5- (((6- (2-chloro-3- (5-methoxy-6- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one

A mixture of 6- (2-chloro-3- (6- (4-formyl-3-methoxyphenyl) -5-methoxypyrimidin-4-yl) phenyl) -2-methoxypolynicotinaldehyde (80 mg,0.16 mmol), (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride (98.4 mg,0.65 mmol) and sodium acetate (67 mg,0.82 mmol) in methanol (5 mL) was stirred for 12 hours. Sodium cyanoborohydride (51.3 mg,0.82 mmol) was then added and the mixture was stirred at 15 ℃ for an additional 1 hour. The reaction mixture was concentrated under reduced pressure and passed throughThe residue was purified by reverse phase HPLC to provide (S) -5- (((6- (2-chloro-3- (5-methoxy-6- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one (48.1 mg,42% yield) as a white solid. MS: m/z found 686[ M+H ] ] ⁺ Retention time = 2.13min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ9.04(s,1H),7.79-7.76(m,4H),7.60-7.59(m,2H),7.48(d,1H),7.30(d,1H),4.05(s,3H),3.98(s,3H),3.91-3.85(m,6H),3.46(s,3H),2.75-2.69(m,4H),2.38-2.28(m,6H),1.86-1.81(m,2H).

Example 730:2- ((6- (2-chloro-3- (5-methoxy-6- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one (727)

In a similar manner to example 729, 2, 6-diazaspiro [3.4] was used in step (c)]Preparation of 2- ((6- (2-chloro-3- (5-methoxy-6- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4 ]) by substituting (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride with octan-7-one trifluoroacetate]Octane-2-yl-methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl-methyl) -2, 6-diazaspiro [3.4]Octane-7-one. MS: m/z found 710[ M+H ]] ⁺ Retention time = 2.25min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ9.04(s,1H),7.78-7.75(m,3H),7.72(d,1H),7.59-7.58(m,2H),7.44(d,1H),7.29(d,1H),4.02(s,3H),3.96(s,3H),3.79(s,2H),3.73(s,2H),3.60(d,4H),3.45-3.42(m,11H),2.59(d,4H).

Example 731:2- ((4- (6- (2-chloro-3- (5- (((2-hydroxyethyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) -5-methoxypyrimidin-4-yl) -2-methoxyphenylmethyl) amino) ethan-1-ol (728)

2- ((4- (6- (2-chloro-3- (5- (((2-hydroxyethyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) -5-methoxypyrimidin-4-yl) -2-methoxyphenylmethyl) amino) ethan-1-ol is prepared in a similar manner to example 729 by substituting 2-aminoethanol for (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride in step (c). MS: m/z found 580[ M+H ] ] ⁺ Retention time = 2.22min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ9.05(s,1H),7.79-7.75(m,4H),7.60-7.59(m,2H),7.47(d,1H),7.30(d,1H),4.05(s,3H),3.99(s,3H),3.95(s,2H),3.88(s,2H),3.73-3.71(m,4H),3.46(s,3H),2.82-2.78(m,4H).

Example 732: n- ((6- (2-chloro-3- (5-methoxy-6- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine (734)

In analogy to example 729, N- ((6- (2-chloro-3- (5-methoxy-6- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine was prepared in step (c) using tetrahydro-2H-pyran-4-amine instead of (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride. MS: m/z found 660[ M+H ]] ⁺ Retention time = 2.68min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ9.04(s,1H),7.79-7.76(m,4H),7.62-7.58(m,2H),7.48(d,1H),7.30(d,1H),4.05(s,3H),3.99-3.97(m,7H),3.93(s,2H),3.88(s,2H),3.46-3.39(m,7H),2.80-2.74(m,2H),1.95-1.92(m,4H),1.54-1.44(m,4H).

Example 733:2- ((6- (2-chloro-3- (5-methoxy-6- (3-methoxy-4- ((6-oxo-2, 5-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 5-diazaspiro [3.4] octan-6-one (743)

In a similar manner to example 729, 2, 5-diazaspiro [3.4] was used in step (c)]Preparation of 2- ((6- (2-chloro-3- (5-methoxy-6- (3-methoxy-4- ((6-oxo-2, 5-diazaspiro [3.4 ]) by substituting (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride with octan-6-one trifluoroacetate ]Octane-2-yl-methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl-methyl) -2, 5-diazaspiro [3.4]Octan-6-one. MS: m/z found 710[ M+H ]] ⁺ Retention time = 2.28min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ9.04(s,1H),7.78-7.76(m,3H),7.73(d,1H),7.62-7.57(m,2H),7.44(d,1H),7.30(d,1H),4.02(s,3H),3.96(s,3H),3.80(s,2H),3.74(s,2H),3.60-3.56(m,4H),3.45(s,3H),3.40(d,4H),2.45-2.35(m,8H).

Example 734:1- (4- (((6- (3- (6- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -5-methoxypyrimidin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one (717)

In a similar manner to example 729, 1- (4-aminopiperidin-1-yl) ethan-1-one was substituted for (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride in step (c) to prepare 1- (4- (((6- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -5-methoxypyrimidin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one. MS: m/z found 742[ M+H ]] ⁺ Retention time = 2.33min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ9.04(s,1H),7.79-7.76(m,4H),7.60-7.58(m,2H),7.49(d,1H),7.30(d,1H),4.49(d,2H),4.05(s,3H),3.99-3.94(m,7H),3.89(s,2H),3.46(s,3H),3.20-3.12(m,2H),2.84-2.71(m,4H),2.12(d,6H),2.07-2.00(m,4H),1.43-1.29(m,4H).

Example 735: (S) -N- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,2' -bipyridyl ] -4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (738)

(a) 1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carbonyl chloride

At N ₂ To a mixture of 1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxylic acid (1 g,5.43 mmol) in dichloromethane (15 mL) was added oxalyl chloride (0.82 g,6.52 mmol) and DMF (0.039 g,0.54 mmol) in one portion and the mixture was stirred at room temperature for 0.5 h. The mixture was concentrated to afford 1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carbonyl chloride (1.2 g, crude) as a white solid.

(b) N- (2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide

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At N ₂ To a mixture of 1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carbonyl chloride (1.2 g,5.92 mmol) and 2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) aniline (1.65 g,6.52 mmol) in dichloromethane (20 mL) was added triethylamine (2.47 mL,17.7 mmol) at room temperature in one portion and the mixture stirred at room temperature for 12 h. The mixture was concentrated, water (5 mL) was added to the residue and the mixture was filtered. The filter cake was dried under vacuum to obtain a crude product. The crude product was washed with petroleum ether (5 mL) and dried under vacuum to afford N- (2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (2.8 g,73% yield) as a white solid. MS: m/z found 420[ M+H ] ] ⁺ .

(c) N- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide

At N ₂ To a mixture of N- (2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (0.6 g,1.43 mmol) and 2, 3-dichloro-4-iodopyridine (0.39 g,1.43 mmol) in a 1, 4-dioxane/water mixture (6:1, 12.5 mL) was added [1,1' -bis (biphenylphosphino) ferrocene in one portion]Palladium (II) dichloride complex with dichloromethane (0.12 g,0.14 mol) and potassium carbonate (0.6 g,4.29 mmol) and the mixture was stirred at 85 ℃ for 3 hours. The mixture was concentrated and the residue purified directly by column chromatography to afford N- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (0.6 g,66% yield) as a yellow solid. MS: m/z found 439 and 441[ M+H ]] ⁺ .

(d) N- (2-chloro-3- (3-chloro-5 ' -formyl-6 ' -methoxy- [2,2' -bipyridyl ] -4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide

At N ₂ To a mixture of N- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (0.28 g,0.64 mmol) and 2-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) nicotinaldehyde (example 376, step (a)) (0.57 g,2.17 mmol) in THF/water (5:1, 17 mL) was added chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) at one time ]Palladium (II) (0.03 g,0.03 mmol) and potassium phosphate (0.41 g,1.91 mmol) and the mixture was stirred at 85℃for 3 hours. The mixture was concentrated and the residue purified directly by column chromatography to afford N- (2-chloro-3- (3-chloro-5 ' -formyl-6 ' -methoxy- [2,2' -bipyridine) as a white solid]-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine5-carboxamide (0.22 g,25% yield). ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.68(s,1H),10.33(s,1H),8.83(s,1H),8.79(d,1H),8.64(d,1H),8.30(d,1H),7.66-7.63(m,2H),7.56(t,1H),7.24(d,1H),4.07(s,3H),3.53(s,3H),3.29(s,3H).

(e) (S) -N- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,2' -bipyridyl ] -4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide

At N ₂ Downward N- (2-chloro-3- (3-chloro-5 ' -formyl-6 ' -methoxy- [2,2' -bipyridine)]-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (0.1 g,0.19 mmol) and (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride (0.03 g,0.2 mmol) in THF/MeOH (1:1, 3 mL) sodium acetate (0.05 g,0.6 mmol) was added in one portion and the mixture stirred at room temperature for 1 hour. Sodium cyanoborohydride (0.03 g,0.6 mmol) was then added and the mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide (S) -N- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,2' -bipyridine) as a white solid ]-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (17.3 mg,14% yield). MS: m/z found 638[ M+H ]] ⁺ Retention time = 3.13min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.70(s,1H),8.67-8.62(m,2H),7.84(d,1H),7.51-7.47(m,2H),7.38(d,1H),7.16(d,1H),4.05(s,3H),3.88-3.83(m,3H),3.58(s,3H),3.41(s,3H),2.75-2.70(m,2H),2.38-2.29(m,3H),1.90-1.77(m,1H).

Example 736: (S) -N- (2-chloro-3- (3-chloro-5 ' - (((2-hydroxypropyl) amino) methyl) -6' -methoxy- [2,2' -bipyridyl ] -4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (739)

In a similar manner to example 735, (S) -N- (2-chloro-3- (3-chloro-5 ' - (((2-hydroxypropyl) amino) methyl) -6' -methoxy- [2,2' -bipyridine) was prepared in step (e) using (S) -1-aminopropane-2-ol instead of (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride]-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide. MS: m/z found 599[ M+H ]] ⁺ The method comprises the steps of carrying out a first treatment on the surface of the Retention time = 3.24min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.69(s,1H),8.65(d,1H),8.62(dd,1H),7.83(d,1H),7.50-7.46(m,2H),7.39(d,1H),7.16(dd,1H),4.05(s,3H),3.94-3.82(m,3H),3.58(s,3H),3.41(s,3H),2.68-2.58(m,2H),1.19(d,3H).

Example 737: (S) -N- (2-chloro-3- (4 ' -chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,3' -bipyridyl ] -5' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (712)

(a) 5' -bromo-4 ' -chloro-6-methoxy- [2,3' -bipyridine ] -5-carbaldehyde

To a mixture of 2-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) nicotinaldehyde (example 376, step (a)) (1 g,3.80 mmol) and 3, 5-dibromo-4-chloropyridine (2.58 g,9.50 mmol) in 1, 4-dioxane/water (5:1, 12 mL) was added potassium carbonate (1.58 g,11.4 mmol) and [1,1' -bis (biphenylphosphino) ferrocene ]Complex of palladium (II) dichloride with dichloromethane (0.31 g,0.38 mmol) and under N ₂ The mixture was stirred at 100℃for 2 hours. The mixture was concentrated, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic phases were dried over anhydrous sulphate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ Chromatography (0-25% ethyl acetate/petroleum ether) of the residue to afford 5' -bromo as a white solid-4 '-chloro-6-methoxy- [2,3' -bipyridine]-5-Formaldehyde (0.5 g,41% yield). ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.31(s,1H),8.98(s,1H),8.79(s,1H),8.26(d,1H),7.57(d,1H),4.06(s,3H).

(b) N- (2-chloro-3- (4 ' -chloro-5-formyl-6-methoxy- [2,3' -bipyridyl ] -5' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide

To 5' -bromo-4 ' -chloro-6-methoxy- [2,3' -bipyridine]A mixture of 5-formaldehyde (120 mg,0.37 mmol) and N- (2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (example 735, step (b)) (200 mg,0.48 mmol) in 1, 4-dioxane/water (5:1, 6 mL) was added potassium phosphate (233 mg,1.10 mmol) and [1,1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) dichloride (23.9 mg,0.04 mmol) and under N ₂ The mixture was stirred at 130℃for 3 hours. The mixture was combined with another batch on a 0.3g scale. The mixture was concentrated, water (10 mL) was added to the residue and the mixture was extracted with ethyl acetate (2×30 mL). The combined organic phases were dried over anhydrous sulphate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ Chromatography (0-25% ethyl acetate/petroleum ether) of the residue to afford N- (2-chloro-3- (4 '-chloro-5-formyl-6-methoxy- [2,3' -bipyridine) as a yellow solid]-5' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (500 mg, crude). ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.66(s,1H),10.32(s,1H),8.94(s,1H),8.81(s,1H),8.66-8.63(m,2H),8.27(d,1H),7.62(d,1H),7.54(t,1H),7.27(d,1H),4.10(s,3H),3.51(s,3H),3.28(s,3H).

(c) (S) -N- (2-chloro-3- (4 ' -chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,3' -bipyridyl ] -5' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide

To N- (2-chloro-3- (4 '-chloro-5-formyl-6-methoxy- [2,3' -bipyridine)]A mixture of (E) -5' -yl) phenyl-1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (200 mg,0.4 mmol), (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride (167 mg,1.11 mmol) in dichloromethane/MeOH (1:1, 10 mL) was added sodium acetate (152 mg,1.85 mmol) and N ₂ The mixture was stirred at room temperature for 1.5 hours. Sodium cyanoborohydride (69.8 mg,1.11 mmol) was then added and the mixture was taken up in N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was filtered and concentrated and the residue was purified by reverse phase HPLC to provide (S) -N- (2-chloro-3- (4 '-chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,3' -bipyridine) as a white solid ]-5' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (61.5 mg,25% yield). MS: m/z found 638[ M+H ]] ⁺ The method comprises the steps of carrying out a first treatment on the surface of the Retention time = 2.95min (method a). ¹ H NMR (400 MHz, methanol-d) ₆ ):δ8.81(s,1H),8.69(s,1H),8.64(dd,1H),8.49(s,1H),7.82(d,1H),7.49(t,1H),7.39(d,1H),7.20(dd,1H),4.06(s,3H),3.91-3.83(m,3H),3.58(s,3H),3.41(s,3H),2.77-2.67(m,2H),2.38-2.29(m,3H),1.87-1.82(m,1H).

Example 738: n- (2-chloro-3- (4 ' -chloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) - [2,3' -bipyridine ] -5' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (722)

In a similar manner to example 737, 2, 6-diazaspiro [3.4] was used in step (c)]Preparation of N- (2-chloro-3- (4' -chloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [ 3.4) by substituting (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride with octan-7-one]Octane-2-yl) methyl) - [2,3' -bipyridine]-5' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide. MS: m/z found 650[ M+H ]] ⁺ The method comprises the steps of carrying out a first treatment on the surface of the Retention time = 2.95min (method a). ¹ H NMR (400 MHz, methanol)-d ₄ ):δ8.81(s,1H),8.69(s,1H),8.64(dd,1H),8.49(s,1H),7.77(d,1H),7.49(t,1H),7.39(d,1H),7.20(dd,1H),4.04(s,3H),3.74(s,2H),3.61(s,2H),3.58(s,3H),3.44-3.43(m,4H),3.41(s,3H),2.60(s,2H).

Example 739: n- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -4' -chloro-6-methoxy- [2,3' -bipyridyl ] -5' -yl) -2-chlorophenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (723)

In a similar manner to example 737, N- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -4 '-chloro-6-methoxy- [2,3' -bipyridine) was prepared in step (c) using 1- (4-aminopiperidin-1-yl) ethan-1-one instead of (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride ]-5' -yl) -2-chlorophenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide. MS: m/z found 666[ M+H ]] ⁺ The method comprises the steps of carrying out a first treatment on the surface of the Retention time = 3.11min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.82(s,1H),8.69(s,1H),8.65-8.63(m,1H),8.49(s,1H),7.83(d,1H),7.49(t,1H),7.39(d,1H),7.20(dd,1H),4.50-4.47(m,1H),4.07(s,3H),3.97-3.90(m,3H),3.58(s,3H),3.41(s,3H),3.20-3.13(m,1H),2.82-2.72(m,2H),2.12(s,3H),2.08-2.00(m,2H),1.46-1.26(m,2H).

Example 740: (S) -N- (2-chloro-3- (4 ' -chloro-5- (((2-hydroxypropyl) amino) methyl) -6-methoxy- [2,3' -bipyridyl ] -5' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (729)

In a similar manner to example 737, (S) -N- (2-chloro-3- (4 '-chloro-5- (((2-hydroxypropyl) amino) methyl) -6-methoxy- [2,3' -bipyridine) was prepared in step (c) using (S) -1-aminopropane-2-ol instead of (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride]-5' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide. MS: m/z realMeasured value 599[ M+H ]] ⁺ The method comprises the steps of carrying out a first treatment on the surface of the Retention time = 3.17min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.83(s,1H),8.69(s,1H),8.63(d,1H),8.49(s,1H),7.80(d,1H),7.49(t,1H),7.39(d,1H),7.20(d,1H),4.07(s,3H),3.94-3.81(m,2H),3.58(s,3H),3.41(s,3H),2.67-2.57(m,2H),1.33-1.26(m,1H),1.19(d,3H).

Example 741: n- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptane-2-yl) methyl) -4' -chloro-6-methoxy- [2,3' -bipyridyl ] -5' -yl) -2-chlorophenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (730)

In a similar manner to example 737, 1- (2, 6-diazaspiro [3.3] was used in step (c)]Preparation of N- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3 ]) by substituting heptan-2-yl) ethan-1-one trifluoroacetate salt for (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride ]Heptane-2-yl) methyl) -4 '-chloro-6-methoxy- [2,3' -bipyridine]-5' -yl) -2-chlorophenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide. MS: m/z found 664[ M+H ]] ⁺ The method comprises the steps of carrying out a first treatment on the surface of the Retention time = 3.13min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.80(s,1H),8.69(s,1H),8.64(d,1H),8.49(s,1H),7.75(d,1H),7.49(t,1H),7.38(d,1H),7.20(d,1H),4.32(s,2H),4.07(s,2H),4.04(s,3H),3.71(s,2H),3.58(s,3H),3.56-3.51(m,4H),3.41(s,3H),1.86(s,3H).

Example 742: (S) -N- (2-chloro-3- (3 ' -chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (718)

(a) N- (2-chloro-3- (3 ' -chloro-5-formyl-6-methoxy- [2,4' -bipyridyl ] -2' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide

To 2',3' -dichloro-6-methoxy- [2,4' -bipyridine]A mixture of (1 g,3.53 mmol) of (example 640, step (a)) and N- (2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (example 735, step (b)) (1.93 g,4.59 mmol) in 1, 4-dioxane/water (5:1, 36 mL) was added potassium phosphate (2.25 g,10.6 mmol) and [1,1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) dichloride (230 mg,0.35 mmol) and under N ₂ The mixture was stirred at 130℃for 2 hours. The mixture was concentrated, water (20 mL) was added to the residue and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic phases were dried over anhydrous sulphate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ Chromatography (0-70% ethyl acetate/petroleum ether) of the residue to afford N- (2-chloro-3- (3 '-chloro-5-formyl-6-methoxy- [2,4' -bipyridine) as a yellow solid]-2' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (700 mg,37% yield). ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.64(s,1H),10.31(s,1H),8.81-8.79(m,2H),8.62(dd,1H),8.28(d,1H),7.82(d,1H),7.61(d,1H),7.53(t,1H),7.25(dd,1H),4.09(s,3H),3.52(s,3H),3.28(s,3H).

(b) (S) -N- (2-chloro-3- (3 ' -chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide

To N- (2-chloro-3- (3 '-chloro-5-formyl-6-methoxy- [2,4' -bipyridine)]A mixture of (2' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (100 mg,185 umol) and (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride (83.6 mg,555 umol) in dichloromethane/MeOH (1:1, 10 mL) was added sodium acetate (75.9 mg,925 umol) and N ₂ At room temperatureThe mixture was stirred for 1.5 hours. Sodium cyanoborohydride (34.9 mg,555 umol) was added and the mixture was stirred under N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide (S) -N- (2-chloro-3- (3 '-chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridine) as a white solid ]-2' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (27.9 mg,23% yield). MS: m/z found 638[ M+H ]] ⁺ The method comprises the steps of carrying out a first treatment on the surface of the Retention time = 2.89min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.68(s,1H),8.66-8.64(m,2H),7.83(d,1H),7.79(d,1H),7.49(t,1H),7.44(d,1H),7.22(dd,1H),4.06(s,3H),3.87-3.83(m,3H),3.58(s,3H),3.41(s,3H),2.75-2.68(m,2H),2.38-2.27(m,3H),1.86-1.83(m,1H).

Example 743: n- (2-chloro-3- (3 ' -chloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) - [2,4' -bipyridine ] -2' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (719)

In a similar manner to example 742, 2, 6-diazaspiro [3.4] was used in step (b)]Preparation of N- (2-chloro-3- (3' -chloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4 ]) using octane-7-one trifluoroacetate salt instead of (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride]Octane-2-yl) methyl) - [2,4' -bipyridine]-2' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide. MS: m/z found 650[ M+H ]] ⁺ The method comprises the steps of carrying out a first treatment on the surface of the Retention time = 2.88min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.69(s,1H),8.66-8.63(m,2H),7.79-7.76(m,2H),7.49(t,1H),7.23(d,1H),7.22(dd,1H),4.04(s,3H),3.73(s,2H),3.60(s,2H),3.58(s,3H),3.45-3.41(m,7H),2.60(s,2H).

Example 744: n- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridyl ] -2' -yl) -2-chlorophenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (721)

In a similar manner to example 742, N- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3 '-chloro-6-methoxy- [2,4' -bipyridine) was prepared in step (b) using 1- (4-aminopiperidin-1-yl) ethan-1-one hydrochloride instead of (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride ]-2' -yl) -2-chlorophenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide. MS: m/z found 666[ M+H ]] ⁺ The method comprises the steps of carrying out a first treatment on the surface of the Retention time = 3.03min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.69(s,1H),8.66-8.63(m,2H),7.84(d,1H),7.79(d,1H),7.49(t,1H),7.45(d,1H),7.22(dd,1H),4.50-4.46(m,1H),4.07(s,3H),3.94-3.93(m,1H),3.90(s,2H),3.58(s,3H),3.41(s,3H),3.20-3.13(m,1H),2.82-2.71(m，2H),2.12(s,3H),2.07-2.00(m,2H),1.44-1.29(m,2H).

Example 745: n- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptane-2-yl) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridyl ] -2' -yl) -2-chlorophenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (731)

In a similar manner to example 742, 1- (2, 6-diazaspiro [3.3] used as trifluoroacetate salt in step (b)]Preparation of N- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3 ]) by substituting (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride with heptan-2-yl) ethan-1-one]Heptane-2-yl) methyl) -3 '-chloro-6-methoxy- [2,4' -bipyridine]-2' -yl) -2-chlorophenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide. MS: m/z found 664[ M+H ]] ⁺ The method comprises the steps of carrying out a first treatment on the surface of the Retention time = 3.07min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.69-8.64(m,3H),7.79-7.75(m,2H),7.49(t,1H),7.43(d,1H),7.22(d,1H),4.32(s,2H),4.11(s,2H),4.04(s,3H),3.68(s,2H),3.58-3.50(m,7H),3.41(s,3H),1.86(s,3H).

Example 746: (S) -N- (2-chloro-3- (3 ' -chloro-5- (((2-hydroxypropyl) amino) methyl) -6-methoxy- [2,4' -bipyridyl ] -2' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (745)

Preparation of (S) -N- (2-chloro-3- (3 '-chloro-5- (((2-hydroxypropyl) amino) methyl) -6-methoxy- [2,4' -bipyridine) in step (b) using (S) -1-aminopropane-2-ol instead of (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride in analogy to example 742 ]-2' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide. MS: m/z found 599[ M+H ]] ⁺ The method comprises the steps of carrying out a first treatment on the surface of the Retention time = 3.01min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.54(s,1H),8.51-8.49(m,2H),7.67-7.65(m,2H),7.35(t,1H),7.30(d,1H),7.07(dd,1H),3.92(s,3H),3.79-3.65(m,3H),3.44(s,3H),3.27(s,3H),2.51-2.41(m,2H),1.04(d,3H).

Example 747: (S) -N- (2-chloro-3- (5-chloro-6- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (708)

(a) 4- (5, 6-dichloropyrimidin-4-yl) -2-methoxybenzaldehyde

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At N ₂ To a mixture of 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (example 714, step (f)) (3 g,11.5 mmol) and 4,5, 6-trichloropyrimidine (4.2 g,22.9 mmol) in a 1, 4-dioxane/water mixture (10:1, 77 mL) was added in one portion [1,1' -bis (biphenylphosphino) ferrocene]Palladium (II) dichloride complex with dichloromethane (0.19 g,0.23 mmol) and potassium carbonate (3.95 g,28.6 mmol) and the mixture was stirred at 100 ℃ for 2 hours. Adding water(100 mL) and the mixture was filtered. The filter cake was washed with petroleum ether (5 mL) and dried under vacuum to afford crude 4- (5, 6-dichloropyrimidin-4-yl) -2-methoxybenzaldehyde (3.8 g,92% yield) as a yellow solid. ¹ H NMR (400 MHz, chloroform-d): delta 10.47 (s, 1H), 8.87 (s, 1H), 7.88 (d, 1H), 7.39 (d, 1H), 7.33 (s, 1H), 3.94 (s, 3H).

(b) N- (2-chloro-3- (5-chloro-6- (4-formyl-3-methoxyphenyl) pyrimidin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide

At N ₂ To a mixture of N- (2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (0.41 g,0.97 mmol) (example 735, step (b)) and 4- (5, 6-dichloropyrimidin-4-yl) -2-methoxybenzaldehyde (0.25 g,0.88 mmol) in a 1, 4-dioxane/water mixture (5:1, 6 mL) was added potassium phosphate (0.56 g,2.65 mmol) and [1,1' -bis (di-tert-butylphosphino) ferrocene at one time]Palladium (II) dichloride (0.06 g,0.09 mmol) and the mixture was stirred at 90℃for 2 hours. The mixture was concentrated and water (50 mL) and saturated aqueous brine solution (10 mL) were added to the residue. The mixture was extracted with ethyl acetate/THF mixture (1:1, 50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. By normal phase SiO ₂ The residue was purified by chromatography (30-100% ethyl acetate/petroleum ether) to give N- (2-chloro-3- (5-chloro-6- (4-formyl-3-methoxyphenyl) pyrimidin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (0.1 g,15% yield) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.74(s,1H),10.50(s,1H),9.44(s,1H),8.87(s,1H),8.72(d,1H),7.93(d,1H),7.70(s,1H),7.64(t,1H),7.58(d,1H),7.38(dd,1H),4.07(s,3H),3.58(s,3H),3.34(s,3H).

(c) (S) -N- (2-chloro-3- (5-chloro-6- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide

At N ₂ To a mixture of N- (2-chloro-3- (5-chloro-6- (4-formyl-3-methoxyphenyl) pyrimidin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (0.08 g,0.16 mmol) and (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride (0.03 g,0.19 mmol) in dichloromethane/MeOH (2:1, 3 ml) was added sodium acetate (0.04 g,0.47 mmol) at one time and the mixture stirred at room temperature for 11 hours. Sodium cyanoborohydride (0.03 g,0.47 mmol) was then added and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford (S) -N- (2-chloro-3- (5-chloro-6- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide as a white solid (20.7 mg,16% yield). MS: m/z found 638[ M+H ]] ⁺ The method comprises the steps of carrying out a first treatment on the surface of the Retention time = 2.89min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ9.22(s,1H),8.70-8.69(m,2H),7.55-7.48(m,4H),7.26(d,1H),3.98(s,3H),3.95-3.87(m,3H),3.58(m,3H),3.42(s,3H),2.79-2.70(m,2H),2.38-2.28(m,3H),1.87-1.78(m,1H).

Example 748: (S) -N- (2-chloro-3- (5-chloro-6- (4- (((2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide (746)

(S) -N- (2-chloro-3- (5-chloro-6- (4- (((2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide was prepared in analogy to example 747 substituting (S) -1-aminopropane-2-ol for (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride in step (c). MS: m/z found 599[ M+H ]] ⁺ The method comprises the steps of carrying out a first treatment on the surface of the Retention time = 3.11min (method a).

Example 749: n- ((6- (2-chloro-3- (3-chloro-2- (2- ((isopropylamino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) propan-2-amine (763)

(a) 1-amino-5-bromo-3-methoxypyridine-2 (1H) -imine 2, 4-dinitrophenol salt

At N ₂ A mixture of O- (2, 4-dinitrophenyl) hydroxylamine (3.0 g,15.1 mmol) and 5-bromo-3-methoxypyridin-2-amine (3.1 g,15.1 mmol) in acetonitrile (20 mL) was stirred at 45℃for 12 hours. The mixture was filtered to provide 1-amino-5-bromo-3-methoxypyridine-2 (1H) -imine 2, 4-dinitrophenol salt (205 mg,53% yield) as a yellow solid. ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.77(d,1H),8.03-8.00(m,1H),7.84(d,1H),7.47(d,1H),6.67(d,1H),4.04(s,3H).

(b) (6-bromo-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methanol

To a mixture of 1-amino-5-bromo-3-methoxypyridine-2 (1H) -imine ion 2, 4-dinitrophenol salt (11.5 g,28.6 mmol) in ethanol (60 mL) was added sodium hydroxide (1.49 g,37.2 mmol), then under N ₂ The mixture was stirred at 60℃for 1 hour. Then methyl 2-glycolate (2.42 ml,31.5 mmol) was added and added under N ₂ The mixture was stirred at 80℃for 4 hours. Concentrating the mixture and passing through normal phase SiO ₂ Chromatography (0-11% ethyl acetate/petroleum ether) of the residue to afford (6-bromo-8-methoxy- [1,2, 4) as a yellow solid]Triazolo [1,5-a ]]Pyridin-2-yl) methanol (4.8 g,88% yield). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.49(d,1H),7.11(d,1H),4.68(s,2H),3.96(s,3H).

(c) (2- (hydroxymethyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) boronic acid

To (6-bromo-8-methoxy- [1,2, 4)]Triazolo [1,5-a ]]Potassium acetate (2.19 g,22.3 mmol) and [1,1' -bis (biphenylphosphino) ferrocene were added as a mixture of pyridin-2-yl) methanol (1.92 g,7.44 mmol) and bis (pinacolato) diboron (4.72 g,18.6 mmol) in 1, 4-dioxane (25 mL)]Complex of palladium (II) dichloride with dichloromethane (607.56 mg,0.744 mmol) and under N ₂ The mixture was stirred at 110℃for 2 hours. Concentrating the mixture and passing through normal phase SiO ₂ The residue was purified by chromatography (100% MeOH in ethyl acetate) to afford (2- (hydroxymethyl) -8-methoxy- [1,2, 4) as a yellow solid]Triazolo [1,5-a ]]Pyridin-6-yl) boronic acid (2.1 g, 91%). ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.16(s,1H),7.21(s,1H),4.78(s,2H),4.03(s,3H),1.91(s,2H).

(d) ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (isopropyl) carbamic acid tert-butyl ester

To a mixture of 6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxynicotinaldehyde (example 10, step (a)) (2 g,5.10 mmol) and propane-2-amine (450 mg,7.62 mmol) in methanol (30 mL) was added sodium acetate (1.25 g,15.2 mmol) and N ₂ The mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (3.19 g,50.2 mmol) was then added and the mixture was taken up in N ₂ The mixture was stirred at room temperature for 0.5h to provide N- ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) propan-2-amine (MS: m/z found 436[ M+H)] ⁺ ). Di-tert-butyl dicarbonate (3.70 ml,16.0 mmol) and triethylamine (2.55 ml,18.3 mmol) were then added and taken up in N ₂ The mixture was stirred at room temperature for 2 hours. Water (20 mL) was added andthe mixture was extracted with ethyl acetate (2×20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. By normal phase SiO ₂ The residue was purified by chromatography (0-16% ethyl acetate/petroleum ether) to give tert-butyl ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (isopropyl) carbamate (2.1 g,85% yield) as a white solid. MS: m/z found 536[ M+H ]] ⁺ .

(e) ((6- (2-chloro-3- (3-chloro-2- (2- (hydroxymethyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (isopropyl) carbamic acid tert-butyl ester

To ((6- (2-chloro-3- (2, 3-dichloropyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (isopropyl) carbamic acid tert-butyl ester (1 g,1.86 mmol) and (2- (hydroxymethyl) -8-methoxy- [1,2, 4)]Triazolo [1,5-a ]]A mixture of pyridin-6-yl) boronic acid (1.66 g,7.45 mmol) in 1, 4-dioxane/water (5:1, 18 mL) was added to [1,1' -bis (biphenylphosphino) ferrocene]Complex of palladium (II) dichloride with dichloromethane (121 mg,0.19 umol) and potassium phosphate (1.20 g,5.60 mmol) and under N ₂ The mixture was stirred at 110℃for 3 hours. Concentrating the mixture and passing through normal phase SiO ₂ Chromatography (100% methanol/ethyl acetate) purified the residue to afford ((6- (2-chloro-3- (3-chloro-2- (2- (hydroxymethyl) -8-methoxy- [1,2, 4)) as a white solid]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) (isopropyl) carbamic acid tert-butyl ester (900 mg,70% yield). MS: m/z found 679[ M+H ]] ⁺ .

(f) ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (isopropyl) carbamic acid tert-butyl ester

To ((6- (2-chloro-3- (3-chloro-2- (2- (hydroxymethyl) -8-methoxy) 1,2, 4)]Triazolo [1,5-a ]]A mixture of tert-butyl pyridin-6-yl) pyridin-4-yl phenyl) -2-methoxypyridin-3-yl methyl) (isopropyl) carbamate (900 mg,1.32 mmol) in dichloromethane (5 mL) was added to dess-Martin periodate (1.00 g,2.36 mmol) and taken up in N ₂ The mixture was stirred at room temperature for 3 hours. Concentrating the mixture and passing through normal phase SiO ₂ Chromatography (50-65% ethyl acetate/petroleum ether) purified the residue to afford ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxy- [1,2, 4)) as a yellow solid]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) (isopropyl) carbamic acid tert-butyl ester (700 mg,70% yield). ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.12(s,1H),9.10(s,1H),8.81(d,1H),8.67(dd,1H),7.75(dd,1H),7.65-7.61(m,2H),7.33-7.30(m,2H),7.21(d,1H),4.27(s,2H),4.06-4.01(m,4H),3.95(s,3H),1.55-1.24(m,9H),1.11(d,6H).

(g) ((6- (2-chloro-3- (3-chloro-2- (2- ((isopropylamino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (isopropyl) carbamic acid tert-butyl ester

To ((6- (2-chloro-3- (3-chloro-2- (2-formyl-8-methoxy- [1,2, 4))]Triazolo [1,5-a ]]Sodium acetate (43.6 mg,531 mol) was added to a mixture of tert-butyl pyridin-6-yl) pyridin-4-yl phenyl) -2-methoxypyridin-3-yl methyl) (isopropyl) carbamate (120 mg,177 mol) and propane-2-amine hydrochloride (33.8 mg,354 mol) in dichloromethane/methanol (1:1, 4 mL) and was concentrated in N ₂ The mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (33.4 mg,531 umol) was then added and the mixture was stirred under N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated to afford ((6- (2-chloro-3- (3-chloro-2- (2- ((isopropylamino) methyl) -8-methoxy- [1,2, 4) as a white solid ]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) (isopropyl) carbamic acid tert-butyl ester (250 mg,65% yield).MS: m/z found 720[ M+H ]] ⁺ .

(h) N- ((6- (2-chloro-3- (3-chloro-2- (2- ((isopropylamino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) propan-2-amine

To ((6- (2-chloro-3- (3-chloro-2- (2- ((isopropylamino) methyl) -8-methoxy- [1,2, 4)]Triazolo [1,5-a ]]A mixture of tert-butyl pyridin-6-yl) pyridin-4-yl phenyl) -2-methoxypyridin-3-yl methyl) (isopropyl) carbamate (200 mg,0.28 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1.88 mL,25.4 mmol) and taken up in N ₂ The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to provide N- ((6- (2-chloro-3- (3-chloro-2- (2- ((isopropylamino) methyl) -8-methoxy- [1,2, 4) as a white solid]Triazolo [1,5-a ]]Pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl methyl) propan-2-amine (1.8 mg,1% yield). MS: m/z found 620[ M+H ]] ⁺ . ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.80(d,1H),8.73(d,1H),7.77-7.73(m,2H),7.60-7.56(m,1H),7.54-7.53(m,1H),7.46-7.44(m,2H),7.27(d,1H),4.14(s,3H),4.09(s,2H),4.05(s,3H),3.85(s,2H),2.95-2.90(m,2H),1.18-1.16(m,12H).

Example 750:2- ((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) -2-azaspiro [3.3] heptan-6-ol (753)

In a similar manner to example 749, 2-azaspiro [3.3 ] was used in step (g)]Heptane-6-ol hydrochloride in place of propane-2-amine hydrochloride to prepare 2- ((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4]Triazolo [1,5-a ]]Pyridin-2-yl) methyl) -2-azaspiro [3.3]Heptane-6-ol. MS: m/z found 674[ M+H ]] ⁺ The method comprises the steps of carrying out a first treatment on the surface of the Retention time = 2.79min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.80(d,1H),8.73(d,1H),7.78-7.73(m,2H),7.60-7.56(m,1H),7.52(d,1H),7.46-7.43(m,2H),7.27(d,1H),4.18-4.08(m,4H),4.05(s,3H),3.90(s,2H),3.87(s,2H),3.49(s,2H),3.45(s,2H),2.96-2.89(m,1H),2.52-2.47(m,2H),2.06-2.01(m,2H),1.18(d,6H).

Example 751: (1 r,4 r) -4- (((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) cyclohexanol (758)

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In a similar manner to example 749, (1 r,4 r) -4- (((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2, 4) was prepared in step (g) using (1 r,4 r) -4-aminocyclohexane-1-ol instead of propane-2-amine hydrochloride]Triazolo [1,5-a ]]Pyridin-2-yl) methyl) amino) cyclohexanol. MS: m/z found 676[ M+H ]] ⁺ The method comprises the steps of carrying out a first treatment on the surface of the Retention time = 2.76min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.80(d,1H),8.73(d,1H),7.82(d,1H),7.74(dd,1H),7.59(t,1H),7.53(d,1H),7.48-7.45(m,2H),7.32(d,1H),4.14(s,3H),4.11(s,2H),4.07(s,3H),4.02(s,2H),3.56-3.54(m,1H),3.16-3.15(m,1H),2.60-2.56(m,1H),2.07-1.96(m,4H),1.34-1.24(m,10H).

Example 752: (S) -5- ((((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) methyl) pyrrolidin-2-one (764)

In a similar manner to example 749, in step (g) use is made of (S) -5- (aminomethyl) pyrrolidin-2-one saltPreparation of (S) -5- ((((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2, 4) by substituting the acid salt for propane-2-amine hydrochloride]Triazolo [1,5-a ]]Pyridin-2-yl) methyl) amino) methyl) pyrrolidin-2-one. MS: m/z found 675[ M+H ]] ⁺ The method comprises the steps of carrying out a first treatment on the surface of the Retention time = 2.71min (method a). 1H NMR (400 MHz, methanol-d) ₄ ):δ8.68(d,1H),8.62(d,1H),7.78(d,1H),7.63(dd,1H),7.49(t,1H),7.41(d,1H),7.37(dd,1H),7.33(d,1H),7.26(d,1H),4.12(s,2H),4.02(s,3H),3.99-3.94(m,5H),3.75-3.72(m,1H),3.38-3.31(m,1H),2.73-2.62(m,2H),2.26-2.09(m,3H),1.75-1.72(m,1H),1.29(d,6H).

Example 753:1- (4- (((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) piperidin-1-yl) ethan-1-one (765)

In a similar manner to example 749, 1- (4-aminopiperidin-1-yl) ethan-1-one hydrochloride was used in step (g) to prepare 1- (4- (((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2, 4) in place of propane-2-amine hydrochloride]Triazolo [1,5-a ]]Pyridin-2-yl) methyl) amino) piperidin-1-yl) ethan-1-one. MS: m/z found 703[ M+H ]] ⁺ The method comprises the steps of carrying out a first treatment on the surface of the Retention time = 2.78min (method a). ¹ NMR (400 MHz, methanol-d) ₄ ):δ8.80(d,1H),8.73(d,1H),7.83-7.73(m,2H),7.57(t,1H),7.53(d,1H),7.47-7.45(m,2H),7.28(d,1H),4.47-4.44(m,1H),4.14-4.12(m,5H),4.05(s,3H),3.95-3.87(m,3H),3.16-3.15(m,1H),2.90-2.88(m,2H),2.78-2.75(m,1H),2.11(s,3H),2.08-1.99(m,2H),1.42-1.30(m,2H),1.18(d,6H).

Example 754:1- (6- ((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one (767)

In a similar manner to example 749, 1- (2, 6-diazaspiro [3.3 ] was used in step (g)]Heptane-2-yl) ethane-1-one trifluoroacetate salt instead of propane-2-amine hydrochloride to prepare 1- (6- ((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4]Triazolo [1,5-a ]]Pyridin-2-yl) methyl) -2, 6-diazaspiro [3.3]Heptane-2-yl) ethan-1-one. MS: m/z found 701[ M+H ]] ⁺ The method comprises the steps of carrying out a first treatment on the surface of the Retention time = 2.75min (method a). ¹ H NMR (400 MHz, methanol-d) ₄ ):δ8.75(d,1H),8.69(d,1H),7.73(d,1H),7.70(dd,1H),7.54(t,1H),7.49(d,1H),7.43-7.40(m,2H),7.24(d,1H),4.28(s,2H),4.09(s,3H),4.03(s,2H),4.01(s,3H),3.88(s,2H),3.85(s,2H),3.61-3.56(m,4H),2.95-2.90(m,1H),1.82(s,3H),1.17(d,6H).

Compounds 196-205 may be prepared according to synthetic pathways described elsewhere herein and/or according to methods known to those skilled in the art in view of the teachings provided elsewhere herein.

Example 755: HTRF assay

PD-L1 His protein was prepared and added to a white opaque 384 well plate (Corning, catalog #3824 BC) at a final concentration of 6 nM. The PD-L1 small molecule inhibitor was diluted 3-fold starting at 1 μm and the final concentration was 0.00001 μm and added to the wells. PD-1Fc protein was added at a final concentration of 6 nm. PD-L1 His protein, PD-L1 small molecule inhibitor, and PD 1Fc protein were added to the wells in this order, 5. Mu.l volumes each, and incubated at room temperature for 15 minutes. PAb anti-human IgG-XL665 (Cisbio, catalog #61 HFCXLA) and Mab anti-6 HIS terbium cryptate Gold (Cisbio, catalog #61HI2 TLA) were mixed at 6.7nM and 0.35nM, respectively, and the total volume of the mixture was added to the wells and incubated overnight at room temperature. Plates were read using a PerkinElmer Envision plate reader and data analyzed using Prism 6 software. The results are shown in Table 1.

Table 1.

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Example 756: t cell activation luciferase reports in vitro activity in cell culture systems (T cell activation assay)

In one aspect, this assay measures the ability of a test compound to bind to and inhibit PD-L1 activity. PD-1/PD-L1 binding has a net effect of inhibiting T cell receptor signaling. Test compounds capable of binding and inhibiting PD-L1 will disrupt PD-1/PD-L1 binding, thus resulting in increased T cell receptor signaling.

As previously described, compounds were evaluated for their ability to mediate T cell activation in a T cell activating luciferase reporter cell culture system (Park et al Nature Communications,2021; 12:1222). According to the manufacturer's instructions (Promega), CHO-K1 cells stably expressing human PD-L1 and cell surface proteins designed to activate the cognate T cell receptor in an antigen-independent manner (PD-L1 aAPC/CHO-K1, promega) were cultured with PD-1 effector Jurkat T cells stably expressing human PD-1 and NFAT transcription factor-induced luciferases in the absence or presence of small molecules or anti-PD-L1 blocking antibodies in the indicated concentration ranges. Bio-GloTM reagent was added and luminescence was quantified as a signal of Jurkat T cell activation. In the absence of PD-L1 inhibition, PD-1/PD-L1 interactions in this co-culture system result in inhibition of T cell receptor signaling and NFAT-mediated inhibition of luciferase activity. Disruption of the interaction of PD-1/PD-L1 with a compound or antibody treatment results in luciferase activity.

TABLE 2T cell activation EC in luciferase reporter assay ₅₀ Value of

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Example 757: in vitro assay for HBV-specific T cell recovery (reinvigoration) using Peripheral Blood Mononuclear Cells (PBMC) from chronic hepatitis B patients

In one aspect, the assay measures the ability of PD-L1 inhibitors to increase HBV-specific T cell activity in an infected subject as measured by an increase in the expression of these T cell interferon gamma. In certain embodiments, the ability of a test compound to increase expression of interferon gamma in HBV-specific T cells indicates that the compound is useful in treating, ameliorating, and/or preventing HBV infection in a subject.

PD-L1 checkpoint inhibition showed that HBV-specific T cell activity was restored and enhanced when Peripheral Blood Mononuclear Cells (PBMC) isolated from chronic hepatitis B patients were treated in vitro with PD-L1-targeting monoclonal antibodies (Fischer et al, gastroenterology,2010; 138:682-693). As described, PD-L1 inhibitor compounds were evaluated for their ability to restore HBV-specific T cell activity. As previously described, 9 chronic forms B were obtained by Ficoll separation of fresh whole bloodPBMC from hepatitis patients were frozen in liquid nitrogen (Park et al Nature Communications,2021; 12:1222). Thawing frozen PBMC and thawing at 2X10 ⁶ Individual cells/ml will be seeded into 12-well plates. PBMCs were allowed to stand overnight at 37 ℃ and then stimulated with HBV specific peptide pools and allowed to proliferate for 5 days. The expanded PBMCs were then re-stimulated with HBV specific peptide pools alone or with HBV specific peptide pools and incubated with compounds 89, 90 and 139, negative controls, or anti-PD-L1 antibodies as reference. After 24 hours, the supernatant was obtained and IFN-. Gamma.was measured using the Luminex platform. The fold increase in IFN-gamma expression mediated by compound treatment was determined relative to HBV specific peptide treatment alone (Table 3).

TABLE 3 fold-change in IFN-gamma expression in HBV-specific T cells treated with the compounds

Example 758: in vivo anti-tumor efficacy in MC38 tumor mouse models expressing humanized PD-L1 and PD-1

In one aspect, this assay measures the ability of a PD-L1 inhibitor to reduce the tumor size of mouse MC38 (murine colon cancer cell line) as an indication of the ability of the PD-L1 inhibitor to help treat, ameliorate, and/or prevent cancer in a subject.

The in vivo antitumor efficacy of the compounds was evaluated in mice expressing humanized PD-1 and PD-L1, wherein the extracellular domains of murine PD-1 and PD-L1 were replaced with human extracellular domain counterpart genes (Huang et al Scientific Reports,2017; 7:42687). Humanized PD-1/PD-L1 (hPD-1/hPD-L1) mice were subcutaneously implanted with colorectal cancer cell line MC38 expressing human PD-L1 and reached about 100mm in tumor volume ³ Compound treatment was started at this time. The compound was administered by oral gavage once daily at a dose of 30mg/kg during study days 1 to 7; or 10mg/kg for 28 days. The anti-PD-L1 monoclonal antibody, alemtuzumab (atezolizumab), was included as a positive control and was administered intraperitoneally at 0.3mg/kg three times per week during study days 1 through 15. Measuring tumor length and width with digital calipersDegree, and tumor volume was calculated by the following formula: volume=1/2 (length×width) ² 。

TABLE 4 tumor volumes (group mean, mm) of MC38 tumor-bearing hPD-1/hPD-L1 mice treated with compounds of the present disclosure ³ )

Examples are given

The following enumerated examples are provided, the numbering of which should not be construed as indicating a level of importance.

Example 1 provides a compound of formula (I), or a salt, solvate, geometric isomer, stereoisomer, or tautomer thereof:

wherein:

a is

Y is NR ^3b Or O;

l is selected from the group consisting of-C (R ^3g )(R ^3h )-、-(C(R ^3g )(R ^3h ))-(C(R ³ⁱ )(R ^3j ) -and a bond;

X ¹ selected from CR' ¹ And N;

X ² selected from CR' ² And N;

X ³ selected from CR' ³ And N;

X ⁴ selected from CR' ¹ And N;

X ⁵ selected from CR' ² And N;

X ⁶ selected from CR' ³ And N;

wherein X is ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ And X ⁶ One to four of (a) are N;

R' ¹ 、R' ² 、R' ³ 、R” ¹ 、R” ² and R'. ³ Each independently selected from H, halogen, C ₁ -C ₃ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₃ Alkoxy, cyano, C ₁ -C ₃ Haloalkyl, and C ₁ -C ₃ Haloalkoxy groups;

R ^1a and R is ^1b Each independently selected from H, halogen, C ₁ -C ₃ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₃ Alkoxy, cyano, C ₁ -C ₃ Haloalkyl, and C ₁ -C ₃ Haloalkoxy groups;

R ^1c and R is ^1d Each independently selected from the group consisting of:

wherein Z is ¹ Each occurrence of (2) is CR ^V10 Or N;

R ^2a selected from-C (=O) NR ⁶ R ⁶ 、C(＝O)OR ^I Optionally substituted heterocyclyl, - (CH) ₂ ) _1-3 (optionally substituted heterocyclyl), optionally substituted C ₁ -C ₆ Alkoxy, optionally substituted C ₁ -C ₆ Aminoalkyl, and optionally substituted C ₁ -C ₆ A group consisting of a hydroxyalkyl group, and a hydroxyl group,

wherein R is ^2a Each of which is optionalThe substituents are independently selected from optionally substituted heterocyclyl, optionally substituted C ₁ -C ₆ Alkyl, optionally substituted C ₁ -C ₆ Hydroxyalkyl, optionally substituted cycloalkyl, C (=o) (optionally substituted C) ₁ -C ₆ Alkyl), and optionally substituted- (CH) ₂ ) _1-2 (heterocyclyl) a group consisting of,

wherein R is ^2a Two optional substituents of (a) may be combined with the atom to which they are bound to form an optionally substituted C ₂ -C ₈ Heterocyclyl or optionally substituted C ₃ -C ₈ A cycloalkyl group,

wherein R is ^I Each occurrence of (a) is independently H, C ₁ -C ₆ Alkyl, or C ₃ -C ₈ Cycloalkyl, wherein alkyl or cycloalkyl is independently optionally substituted with halogen, -OH, C ₁ -C ₆ Alkoxy, -NH ₂ 、-NH(C ₁ -C ₆ Alkyl), and-N (C) ₁ -C ₆ Alkyl) (C) ₁ -C ₆ Alkyl) at least one of which is substituted,

wherein R is ⁶ Each occurrence of (a) is independently H, C ₁ -C ₆ Alkyl, or C ₃ -C ₈ Cycloalkyl, wherein alkyl or cycloalkyl is independently optionally substituted with halogen, -OH, C ₁ -C ₆ Alkoxy, -NH ₂ 、-NH(C ₁ -C ₆ Alkyl), and-N (C) ₁ -C ₆ Alkyl) (C) ₁ -C ₆ Alkyl) at least one of which is substituted,

R ^2b selected from H, - (CH) ₂ ) _1-3 C(＝O)OR ^I 、-(CH ₂ ) _1-3 C(＝O)NR ^I R ^I Optionally substituted heterocyclyl, - (CH) ₂ ) _1-2 (optionally substituted heterocyclyl), optionally substituted C ₁ -C ₆ Alkyl, optionally substituted C ₁ -C ₆ Haloalkyl, optionally substituted C ₁ -C ₆ Alkoxy, optionally substituted C ₁ -C ₆ Aminoalkyl, and optionally substituted C ₁ -C ₆ A group consisting of a hydroxyalkyl group, and a hydroxyl group,

wherein R is ^2b Independently selected from the group consisting of optionally substituted C ₁ -C ₆ Alkyl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, and optionally substituted- (CH) ₂ ) _1-3 (heterocyclyl) groups;

R ^3a 、R ^3b 、R ^3c 、R ^3d 、R ^3e 、R ^3f 、R ^3g 、R ^3h 、R ³ⁱ and R ^3j Each independently selected from H, halogen, C ₁ -C ₃ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Haloalkyl, and C ₁ -C ₃ Haloalkoxy groups;

R ⁵ selected from the group consisting of H, C ₁ -C ₃ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Haloalkyl, and C ₁ -C ₃ A group consisting of haloalkoxy groups,

wherein R is ⁵ And R is ^2b Can be combined with the nitrogen atom to which they are bound to form C ₃ -C ₁₂ A heterocyclic group;

R ^4a and R is ^4b Each occurrence of (a) is independently selected from the group consisting of H, C ₁ -C ₃ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Haloalkyl, and C ₁ -C ₃ A group consisting of haloalkoxy groups,

wherein R is ^4a And R is ^4b Can combine with the carbon atoms to which they are bound to form a carbonyl group (c=o);

R ^V1 、R ^V2 、R ^V3 、R ^V4 、R ^V5 、R ^V6 、R ^V7 、R ^V8 、R ^V9 and R ^V10 Each occurrence of (a) is independently selected from the group consisting of H, C ₁ -C ₃ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₃ Alkoxy, cyano, halogen, C ₁ -C ₃ Haloalkyl group,C ₁ -C ₃ Haloalkoxy, and C (=o) OR ^I A group of groups;

R ^V11 selected from the group consisting of H, C ₁ -C ₃ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Haloalkyl, and C ₁ -C ₃ Haloalkoxy groups;

wherein if R is ^1c And R is ^1d The same applies, then at least one of the following:

if X ¹ Is N, then R ^1c Z in (a) ¹ If present, CR ^V10 And;

if X ⁶ Is N, then R ^1d Z in (a) ¹ If present, CR ^V10 。

Example 2 provides the compound of example 1 selected from the group consisting of:

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embodiment 3 provides the compound of any one of embodiments 1-2, wherein at least one of the following applies: (a) R's' ² 、R' ³ 、R” ¹ 、R” ² And R'. ³ Each of is H, and X ¹ Is N;

(b)R' ¹ 、R' ³ 、R” ¹ 、R” ² and R'. ³ Each of is H, and X ² Is N;

(c)R' ¹ 、R' ² 、R” ¹ 、R” ² and R'. ³ Each of is H, and X ³ Is N;

(d)R' ¹ 、R' ² 、R' ³ 、R” ² and R'. ³ Each of is H, and X ⁴ Is N;

(e)R' ¹ 、R' ² 、R' ³ 、R” ¹ and R'. ³ Each of is H, and X ⁵ Is N;

(f)R' ¹ 、R' ² 、R' ³ 、R” ¹ and R'. ² Is each H, and X ⁶ Is N;

(g)R' ² 、R' ³ 、R” ² and R'. ³ Each of is H, and X ¹ And X ⁴ Is N;

(h)R' ² 、R' ³ 、R” ¹ and R'. ³ Each of is H, and X ¹ And X ⁵ Is N;

(i)R' ² 、R' ³ 、R” ¹ and R'. ² Each of is H, and X ¹ And X ⁶ Is N;

(j)R' ¹ 、R' ³ 、R” ² and R'. ³ Each of is H, and X ² And X ⁴ Is N;

(k)R' ¹ 、R' ³ 、R” ¹ and R'. ³ Each of is H, and X ² And X ⁵ Is N;

(l)R' ¹ 、R' ³ 、R” ¹ and R'. ² Each of is H, and X ² And X ⁶ Is N;

(m)R' ¹ 、R' ² 、R” ¹ and R'. ³ Each of is H, and X ³ And X ⁵ Is N;

(n)R' ¹ 、R' ² 、R” ¹ and R'. ² Each of is H, and X ³ And X ⁶ Is N;

(o)R' ² 、R” ¹ 、R” ² and R'. ³ Each of is H, and X ¹ And X ³ Is N; and

(p)R' ¹ 、R' ² 、R' ³ and R'. ² Each of is H, and X ⁴ And X ⁶ Is N.

Embodiment 4 provides the compound of any one of embodiments 1-3, wherein at least one of the following applies:

(a) L is a bond and R ^3a 、R ^3c 、R ^3d 、R ^3e And R ^3f Each of which is H;

(b) L is a bond, Y is NR ^3b And R is ^3a 、R ^3b 、R ^3c 、R ^3d 、R ^3e And R ^3f Each of which is H;

(c) L is-C (R) ^3g )(R ^3h ) -and R ^3a 、R ^3c 、R ^3d 、R ^3e 、R ^3f 、R ^3g And R ^3h Each of which is H;

(d) L is-C (R) ^3g )(R ^3h ) Y is NR ^3b And R is ^3a 、R ^3b 、R ^3c 、R ^3d 、R ^3e 、R ^3f 、R ^3g And R ^3h Each of which is H;

(e) L is- (C (R) ^3g )(R ^3h ))(C(R ³ⁱ )(R ^3j ) -and R ^3a 、R ^3c 、R ^3d 、R ^3e 、R ^3f 、R ^3g 、R ^3h 、R ³ⁱ And R ^3j Each of which is H; and

(f) L is-C (R) ^3g )(R ^3h ) Y is NR ^3b And R is ^3a 、R ^3b 、R ^3c 、R ^3d 、R ^3e 、R ^3f 、R ^3g 、R ^3h 、R ³ⁱ And R ^3j Is H.

Example 5 provides a compound of any one of examples 1-4, wherein R ^1a And R is ^1b Each of (a) is independent ofThe standing is selected from H, F, cl, me, CF ₃ And CN.

Example 6 provides a compound of any one of examples 1-5, wherein R ^1a And R is ^1b The same applies.

Example 7 provides a compound of any one of examples 1-6, wherein R ^2a Selected from the group consisting of: - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted 5-oxopyrrolidin-2-yl), - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted 5-oxopyrrolidin-2-yl), - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl group ₂ 、-(CH ₂ ) _0-2 NH(CH ₂ ) _0-2 (C ₁ -C ₆ Haloalkyl) - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (C) ₁ -C ₆ Haloalkyl) - (CH) ₂ ) _{0- 2} NH(CH ₂ ) _0-2 (C ₁ -C ₆ Hydroxyalkyl) - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (C ₁ -C ₆ Hydroxyalkyl) - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 C(＝O)O(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 C(＝O)O(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _{0- 2} NH(CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) C (=O) (C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 NHC(＝O)(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) C (=O) (C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 NHC(＝O)(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted oxetanyl), - (CH) ₂ ) _{0- 2} N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted oxetanyl), - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted oxacyclopentylalkyl), - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted oxacyclopentylalkyl), - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted oxazolidinyl), - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted oxazolidinyl), - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted cyclobutyl), - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted cyclobutyl), - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted cyclohexyl), - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted cyclohexyl), - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted C) ₅ -C ₆ Cycloalkyl sulfonyl) - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted C) ₅ -C ₆ Cycloalkyl sulfonyl) - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted azetidinyl), - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted azetidinyl), - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted pyrrolidinyl), - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted pyrrolidinyl), - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted piperidinyl), - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted piperidinyl), - (CH) ₂ ) _0-2 (optionally substituted guanidino), - (CH) ₂ ) _0-2 NH(C(CH ₂ ) _2-5 )C(＝O)O(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (C (CH) ₂ ) _2-5 )C(＝O)O(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 NH(CH(C ₁ -C ₃ Alkyl)) C (=o) O (C) ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH (C) ₁ -C ₃ Alkyl)) C (=o) O (C) ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-1 (C ₅ -C ₉ Bridged cycloalkyl) (CH ₂ ) _0-1 C(＝O)O(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-1 (C ₅ -C ₉ Bridged cycloalkyl) (CH ₂ ) _0-1 C(＝O)O(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-1 (CHOH)(CH ₂ ) _0-1 C(＝O)O(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-1 (CHO(C ₁ -C ₆ Alkyl)) (CH ₂ ) _0-1 C(＝O)O(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-1 (CHOH)(CH ₂ ) _0-1 C(＝O)O(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-1 (CHO(C ₁ -C ₆ Alkyl)) (CH ₂ ) _0-1 C(＝O)O(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 (C ₄ -C ₁₀ Bridged heterocycloalkyl) - (CH) ₂ ) _0-2 (optionally substituted azetidinyl), - (CH) ₂ ) _0-2 (optionally substituted pyrrolidinyl), - (CH) ₂ ) _0-2 (optionally substituted piperidinyl), - (CH) ₂ ) _0-2 (optionally substituted morpholinyl), - (CH) ₂ ) _0-2 (optionally substituted piperazinyl), - (CH) ₂ ) _0-2 (optionally substituted piperazin-2-one) C (CH) ₃ )N(C ₁ -C ₆ Alkyl group ₂ 、-(CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (CHF ₂ )、-(CH ₂ ) _0-2 NH(CH ₂ ) _0-2 (CHF ₂ )、-(CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-4 (CH ₂ F)、-(CH ₂ ) _0-2 NH(CH ₂ ) _0-4 (CH ₂ F)、-(CH ₂ ) _{0- 2} NH(CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) C (=o) CH ₃ 、-(CH ₂ ) _0-2 NH(CH ₂ ) _0-2 NHC(＝O)CH ₃ 、-(CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) C (=o) CH ₃ 、-(CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 NHC(＝O)CH ₃ 、-(CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) C ((C (=O) OC) ₁ -C ₆ Alkyl) ((CH) ₂ ) _0-2 O(C ₁ -C ₆ Alkyl)), - (CH) ₂ ) _0-2 NHC((C(＝O)OC ₁ -C ₆ Alkyl) ((CH) ₂ ) _0-2 O(C ₁ -C ₆ Alkyl)), - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) C ((C (=o) OH ((CH) ₂ ) _0-2 O(C ₁ -C ₆ Alkyl)), - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) C ((C (=O) OC) ₁ -C ₆ Alkyl) ((CH) ₂ ) _0-2 OH))、-(CH ₂ ) _0-2 NHC((C(＝O)OH)((CH ₂ ) _0-2 O(C ₁ -C ₆ Alkyl)), - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) C ((C (=o) OH ((CH) ₂ ) _0-2 OH))、-(CH ₂ ) _0-2 NHC((C(＝O)OC ₁ -C ₆ Alkyl) ((CH) ₂ ) _0-2 OH))、-(CH ₂ ) _0-2 NHC((C(＝O)OH((CH ₂ ) _0-2 OH))、-(CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _1-4 N(C ₁ -C ₆ Alkyl) C (=o) Me, - (CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _1-4 NHC(＝O)Me、-(CH ₂ ) _0-2 NH(CH ₂ ) _1-4 N(C ₁ -C ₆ Alkyl) C (=o) Me, - (CH ₂ ) _0-2 NH(CH ₂ ) _1-4 NHC(＝O)Me、-(CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _1-5 C(＝O)N(C ₁ -C ₆ Alkyl) (C) ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 NH(CH ₂ ) _1-5 C(＝O)N(C ₁ -C ₆ Alkyl) (C) ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _1-5 C(＝O)NH(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _1-5 C(＝O)NH ₂ 、-(CH ₂ ) _0-2 NH(CH ₂ ) _1-5 C(＝O)NH(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 NH(CH ₂ ) _1-5 C(＝O)NH ₂ 、-(CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted cyclopropyl), - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted cyclopropyl), - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted butyrolactone-2-yl), - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted butyrolactone-2-yl), - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl group)CH ₂ ) _0-2 (optionally substituted tetrahydro-4-thiopyranyl), - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted oxazolyl), - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted tetrahydro-4-thiopyranyl), -CH (CH) ₃ )NH(CH ₂ ) _0-2 (optionally substituted piperidinyl), -CH (CH) ₃ )N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted piperidinyl), - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted piperazinyl), and- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted piperazinyl).

Example 8 provides a compound of any one of examples 1-7, wherein R ^2b Selected from the group consisting of: - (CH) ₂ ) _0-2 (optionally substituted 5-oxopyrrolidin-2-yl), - (CH) ₂ ) _0-2 (optionally substituted piperidinyl), - (CH) ₂ ) _0-2 (optionally substituted azetidinyl), - (CH) ₂ ) _0-2 (C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 (C ₁ -C ₆ Haloalkyl) - (CH) ₂ ) _0-2 (C ₁ -C ₆ Hydroxyalkyl) - (CH) ₂ ) _0-2 (optionally substituted cyclopropyl), - (CH) ₂ ) _0-2 (optionally substituted cyclobutyl), - (CH) ₂ ) _0-2 C(＝O)OH、-(CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) CH ₃ ；-(CH ₂ ) _0-2 NHCH ₃ 、-(CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 C(＝O)O(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 C(＝O)O(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 C(＝O)OH、-(CH ₂ ) _0-2 NH(CH ₂ ) _0-2 C(＝O)OH、-(CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted 5-oxopyrrolidin-2-yl), - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted 5-oxopyrrolidin-2-yl), - (CH) ₂ ) _0-2 C(＝O)N(C ₁ -C ₆ Alkyl) (C) ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 C(＝O)NH(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 C(＝O)NH ₂ 、-(CH ₂ ) _0-2 CH(OC ₁ -C ₆ Alkyl) CH ₂ F、-(CH ₂ ) _0-2 CH(OH)CH ₂ F, and- (CH) ₂ ) _0-2 C(＝O)O(C ₁ -C ₆ Alkyl).

Example 9 provides a compound of any one of examples 1-8, wherein R ^2a Selected from the group consisting of: OR (OR) ^c 、/>

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Wherein R is ^a 、R ^b 、R ^c 、R ^d 、R ^e And R ^f Each of which is independently selected from H, C ₁ -C ₃ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Haloalkoxy, and-C (=o) C ₁ -C ₃ Alkyl groups; and is also provided with

R ^g Selected from optionally substituted C ₂ -C ₆ Heteroaryl and optionally substituted phenyl.

Embodiment 10 provides a compound of any one of embodiments 1-9, wherein R ^a 、R ^b 、R ^c 、R ^d 、R ^e And R ^f At least one of them is selected from methyl, isopropyl, and-C (=o) CH ₃ A group of groups.

Example 11 provides a compound of any one of examples 1-10, wherein R ^a 、R ^b 、R ^c 、R ^d 、R ^e And R ^f At least one of which, if present, is H.

Example 12 provides a compound of any one of examples 1-11, wherein R ^2b Selected from the group consisting of:

wherein R is ⁱ 、R ⁱⁱ And R ⁱⁱⁱ Each of which is independently selected from H, C ₁ -C ₃ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Haloalkoxy, and-C (=o) C ₁ -C ₃ Alkyl groups.

Example 13 provides a compound of any one of examples 1-12, wherein R ^1c And R is ^1d Independently selected from the group consisting of:

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wherein:

R ^a1 、R ^a2 、R ^a3 、R ^a4 、R ^a5 、R ^a6 and R ^a7 Each of which is independently selected from H, C ₁ -C ₆ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Haloalkyl, and C ₁ -C ₆ Haloalkoxy groups;

R ^b1 and R is ^b2 Each of which is independently selected from H, C ₁ -C ₃ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₃ Alkoxy, cyano, halogen, C ₁ -C ₃ Haloalkyl, and C ₁ -C ₃ Haloalkoxy groups; and is also provided with

R ^1c Selected from the group consisting of H, C ₁ -C ₃ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Haloalkoxy, and C (=o) OH.

Examples14 provides a compound of any one of embodiments 1-13, wherein R ^1c And R is ^1d Independently selected from the group consisting of:

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embodiment 15 provides the compound of any one of embodiments 1-14, selected from the group consisting of: 8- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -3- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4H-pyrido [1,2-a ] pyrimidin-4-one;

8- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -3- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4H-pyrido [1,2-a ] pyrimidin-4-one;

8- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -3- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4H-pyrido [1,2-a ] pyrimidin-4-one;

8- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -3- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4H-pyrido [1,2-a ] pyrimidin-4-one;

8- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4H-pyrido [1,2-a ] pyrimidin-4-one;

8- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4H-pyrido [1,2-a ] pyrimidin-4-one;

8- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4H-pyrido [1,2-a ] pyrimidin-4-one;

8- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4H-pyrido [1,2-a ] pyrimidin-4-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5 s, 5's) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (2-methoxy-4, 1-phenylene)) bis (methylene)) bis (azanediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 s,5' r) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (2-methoxy-4, 1-phenylene)) bis (methylene)) bis (azanediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 r, 5's) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (2-methoxy-4, 1-phenylene)) bis (methylene)) bis (azanediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 r,5' r) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (2-methoxy-4, 1-phenylene)) bis (methylene)) bis (azanediyl)) bis (methylene)) bis (pyrrolidin-2-one);

n- (1- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-yl) acetamide;

(S) -N- (1- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-yl) acetamide;

(R) -N- (1- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-yl) acetamide;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (((R) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (((R) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5 s, 5's) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (2-fluoro-6-methoxy-4, 1-phenylene)) bis (methylene)) bis (azanediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 s,5' r) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (2-fluoro-6-methoxy-4, 1-phenylene)) bis (methylene)) bis (azanediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 r, 5's) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (2-fluoro-6-methoxy-4, 1-phenylene)) bis (methylene)) bis (azanediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 r,5' r) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (2-fluoro-6-methoxy-4, 1-phenylene)) bis (methylene)) bis (azanediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((4- (3, 3' -dichloro-2 ' - (1-methyl-3- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indol-6-yl) - [4,4' -bipyridin ] -2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3, 3' -dichloro-2 ' - (1-methyl-3- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indol-6-yl) - [4,4' -bipyridin ] -2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3, 3' -dichloro-2 ' - (1-methyl-3- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indol-6-yl) - [4,4' -bipyridin ] -2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3, 3' -dichloro-2 ' - (1-methyl-3- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indol-6-yl) - [4,4' -bipyridin ] -2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(5 s, 5's) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (1-methyl-1H-indol-6, 3-diyl)) bis (methylene)) bis (azetidinediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 s,5' r) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (1-methyl-1H-indol-6, 3-diyl)) bis (methylene)) bis (azetidinediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 r, 5's) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (1-methyl-1H-indol-6, 3-diyl)) bis (methylene)) bis (azetidinediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 r,5' r) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (1-methyl-1H-indol-6, 3-diyl)) bis (methylene)) bis (azetidinediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(S) -5- (((4- (3, 3' -dichloro-2 ' - (1-methyl-3- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) - [4,4' -bipyridin ] -2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3, 3' -dichloro-2 ' - (1-methyl-3- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) - [4,4' -bipyridin ] -2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3, 3' -dichloro-2 ' - (1-methyl-3- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) - [4,4' -bipyridin ] -2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3, 3' -dichloro-2 ' - (1-methyl-3- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) - [4,4' -bipyridin ] -2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one;

(S) -5- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one;

(R) -5- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one;

(R) -5- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-4- (((S) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-4- (((R) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-4- (((S) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-4- (((R) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((5- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -3-methoxypyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((5- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -3-methoxypyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((5- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -3-methoxypyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((5- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -3-methoxypyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -oxetan-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((R) -oxetan-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -oxetan-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((R) -oxetan-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,3' -bipyridyl ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((S) -2-hydroxypropyl) -1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((R) -2-hydroxypropyl) -1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((S) -2-hydroxypropyl) -1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((R) -2-hydroxypropyl) -1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- ((S) -2-hydroxypropyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- ((R) -2-hydroxypropyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((S) -2-hydroxypropyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((R) -2-hydroxypropyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-indol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-indol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-hydroxyethyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-hydroxyethyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-methoxyethyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-methoxyethyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((methylamino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((methylamino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- ((ethylamino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- ((ethylamino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- ((dimethylamino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- ((dimethylamino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -oxetan-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((R) -oxetan-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -oxetan-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((R) -oxetan-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (((S) -2-hydroxypropyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3- ((((R) -2-hydroxypropyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (((S) -2-hydroxypropyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (((R) -2-hydroxypropyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-hydroxy-2-methylpropyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-hydroxy-2-methylpropyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one;

(S) -5- ((6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one;

(R) -5- ((6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one;

(R) -5- ((6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- ((isobutylamino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- ((isobutylamino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-hydroxyethyl) (methyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-hydroxyethyl) (methyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (((S) -2-methoxypropyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3- ((((R) -2-methoxypropyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (((S) -2-methoxypropyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3- ((((R) -2-methoxypropyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((((R) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((R) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -5-methoxy-1, 2,3, 4-tetrahydroisoquinolin-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -5-methoxy-1, 2,3, 4-tetrahydroisoquinolin-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -5-methoxy-1, 2,3, 4-tetrahydroisoquinolin-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -5-methoxy-1, 2,3, 4-tetrahydroisoquinolin-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxy-2-methylpropyl) -5-methoxy-1, 2,3, 4-tetrahydroisoquinolin-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxy-2-methylpropyl) -5-methoxy-1, 2,3, 4-tetrahydroisoquinolin-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (2-hydroxy-2-methylpropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (2-hydroxy-2-methylpropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (5-fluoro-2- (2-hydroxy-2-methylpropyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (5-fluoro-2- (2-hydroxy-2-methylpropyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(R) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (3-hydroxy-3-methylbutyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (3-hydroxy-3-methylbutyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (2- (1-hydroxycyclobutyl) ethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (2- (1-hydroxycyclobutyl) ethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (7- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) quinolin-3-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (7- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) quinolin-3-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (7- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) quinolin-3-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (7- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) quinolin-3-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxy-3-methylbutyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxy-3-methylbutyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (3- (((1-acetylazetidin-3-yl) amino) methyl) -1-methyl-1H-indol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (3- (((1-acetylazetidin-3-yl) amino) methyl) -1-methyl-1H-indol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-indol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-indol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (4- (3- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (4- (3- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((((S) -oxetan-2-yl) methyl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((((R) -oxetan-2-yl) methyl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((((S) -oxetan-2-yl) methyl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((((R) -oxetan-2-yl) methyl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (((R) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (((R) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (3- (2- (2- ((1-acetylpiperidin-4-yl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (2- ((1-acetylpiperidin-4-yl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (2- (piperidin-4-yl) ethyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (2- (piperidin-4-yl) ethyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (3-fluoropropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (3-fluoropropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

5- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (((R) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (((R) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -L-proline isopropyl ester;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -D-proline isopropyl ester;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -L-proline isopropyl ester;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -D-proline isopropyl ester;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- ((S) -2-hydroxypropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- ((R) -2-hydroxypropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- ((S) -2-hydroxypropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- ((R) -2-hydroxypropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4-chloro-6- (2-chloro-3- (3-chloro-2- (4- ((((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4-chloro-6- (2-chloro-3- (3-chloro-2- (4- ((((R) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4-chloro-6- (2-chloro-3- (3-chloro-2- (4- ((((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4-chloro-6- (2-chloro-3- (3-chloro-2- (4- ((((R) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (3-fluoropropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (3-fluoropropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (((4, 4-difluorocyclohexyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((4, 4-difluorocyclohexyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (2- (1-hydroxycyclopropyl) ethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (2- (1-hydroxycyclopropyl) ethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((R) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((R) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid isopropyl ester;

(S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid isopropyl ester;

(R) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid isopropyl ester;

(R) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid isopropyl ester;

(S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid;

(S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid;

(R) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid;

(R) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -L-proline;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -D-proline;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -L-proline;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -D-proline;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((1R, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((1R, 3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((1 s, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((1S, 3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((1 r, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((1S, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((S) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((S) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((R) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((R) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((isopropylamino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((isopropylamino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((isobutylamino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((isobutylamino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

2- (((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethan-1-ol;

2- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (2- (piperidin-4-yl) ethyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethan-1-ol;

(S) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((1R, 3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((1 s, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((1S, 3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((1 r, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((1R, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((1S, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(S) -2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] oct-7-one;

1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((S) -2-hydroxypropyl) amino) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (((((R) -2-hydroxypropyl) amino) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((S) -2-hydroxypropyl) amino) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (((((R) -2-hydroxypropyl) amino) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(S) -5- (((4- (4- (3- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (4- (3- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((((S) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((((R) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((((S) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((((R) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- ((methylamino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- ((methylamino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (4- (3- (3- (((1-acetylazetidin-3-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (4- (3- (3- (((1-acetylazetidin-3-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((4, 4-difluorocyclohexyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((4, 4-difluorocyclohexyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((2-hydroxyethyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((2-hydroxyethyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (3- ((((S) -2-hydroxypropyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (3- ((((R) -2-hydroxypropyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (3- ((((S) -2-hydroxypropyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (3- ((((R) -2-hydroxypropyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((2-hydroxy-2-methylpropyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((2-hydroxy-2-methylpropyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((2-methoxyethyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((2-methoxyethyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((2-hydroxyethyl) (methyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((2-hydroxyethyl) (methyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (((3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(R) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (((3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3-methyl-2- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3-methyl-2- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3-methyl-2- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3-methyl-2- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(S) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) - (4- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) glycine;

(R) - (4- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) glycine;

3-chloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) -2- (4, 5-dihydro-1H-imidazol-2-yl) -3-methoxyphenyl) pyridine;

(S) - (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) glycine;

(R) - (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) glycine;

(S) - (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) glycine isopropyl ester;

(R) - (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) glycine isopropyl ester;

(S) -5- ((((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(R) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((isopropylamino) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(R) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((isopropylamino) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(5S) -5- (((6- (2-chloro-3- (3-chloro-2- (5- (((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5S) -5- (((6- (2-chloro-3- (3-chloro-2- (5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5R) -5- (((6- (2-chloro-3- (3-chloro-2- (5- (((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5R) -5- (((6- (2-chloro-3- (3-chloro-2- (5- (((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5S) -5- ((((6- (2-chloro-3- (3-chloro-2- (5- (((S) -2-hydroxypropyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5S) -5- (((6- (2-chloro-3- (3-chloro-2- (5- (((R) -2-hydroxypropyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5R) -5- (((6- (2-chloro-3- (3-chloro-2- (5- (((S) -2-hydroxypropyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5R) -5- (((6- (2-chloro-3- (3-chloro-2- (5- (((R) -2-hydroxypropyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxy-5-methylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((R) -2-hydroxypropyl) amino) methyl) -3-methoxy-5-methylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxy-5-methylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((R) -2-hydroxypropyl) amino) methyl) -3-methoxy-5-methylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5-methyl-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5-methyl-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5-methyl-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5-methyl-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5-methyl-4- ((methyl (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5-methyl-4- ((methyl (((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5-methyl-4- ((methyl (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5-methyl-4- ((methyl (((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxy-5-methylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((R) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxy-5-methylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxy-5-methylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((R) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxy-5-methylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (1- (azetidin-3-yl) -1H-pyrazol-4-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (1- (azetidin-3-yl) -1H-pyrazol-4-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (1- (azetidin-3-ylmethyl) -1H-pyrazol-4-yl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (1- (azetidin-3-ylmethyl) -1H-pyrazol-4-yl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -1- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid;

(R) -1- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((S) -oxetan-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -oxetan-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -oxetan-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -oxetan-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) - (4- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) glycine isopropyl ester;

(R) - (4- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) glycine isopropyl ester;

(S) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -L-alanine isopropyl ester;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -D-alanine isopropyl ester;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -L-alanine isopropyl ester;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -D-alanine isopropyl ester;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -L-alanine;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -D-alanine;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -L-alanine;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -D-alanine;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (((1 r,3 r) -3-hydroxycyclobutyl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (((1S, 3S) -3-hydroxycyclobutyl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (((1S, 3 r) -3-hydroxycyclobutyl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (((1 s,3 s) -3-hydroxycyclobutyl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (((1 r,3 r) -3-hydroxycyclobutyl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (((1 s, 3R) -3-hydroxycyclobutyl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (((1R, 3 s) -3-hydroxycyclobutyl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (((1R, 3R) -3-hydroxycyclobutyl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -1- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid isopropyl ester;

(R) -1- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid isopropyl ester;

1- (6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine;

1- (6- (2-chloro-3- (3-chloro-2- (4- ((dimethylamino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N, N-dimethylamine;

2- (((6- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxyethyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) ethan-1-ol;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indol-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indol-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

5- (3-chloro-4- (2-chloro-3- (5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3- (5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3- (5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3- (5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

(S) -5- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (2- (((5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

(R) -5- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (2- (((5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

(S) -5- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (2- (((5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

(R) -5- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (2- (((5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

(S) -2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-fluoro-6-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-fluoro-6-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- (((3-fluoropropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- (((3-fluoropropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

methyl (S) -2- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) acetate;

methyl (R) -2- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) acetate;

(S) -2- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) acetic acid;

(R) -2- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) acetic acid;

(S) -5- (((6- (3- (2- (2- ((1R, 3S, 4S) -2-azabicyclo [2.2.1] heptan-3-yl) -1H-benzo [ d ] imidazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (3- (2- (2- ((1R, 3S, 4S) -2-azabicyclo [2.2.1] heptan-3-yl) -1H-benzo [ d ] imidazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (3- (2- (2- ((1R, 3R, 4S) -2-azabicyclo [2.2.1] heptan-3-yl) -1H-benzo [ d ] imidazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (3- (2- (2- ((1R, 3R, 4S) -2-azabicyclo [2.2.1] heptan-3-yl) -1H-benzo [ d ] imidazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (3- (2- (2- ((1S, 3S,4 r) -2-azabicyclo [2.2.1] heptan-3-yl) -1H-benzo [ d ] imidazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (3- (2- (2- ((1 s,3s, 4R) -2-azabicyclo [2.2.1] heptan-3-yl) -1H-benzo [ d ] imidazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (3- (2- (2- ((1S, 3r,4 r) -2-azabicyclo [2.2.1] heptan-3-yl) -1H-benzo [ d ] imidazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (3- (2- (2- ((1 s,3R, 4R) -2-azabicyclo [2.2.1] heptan-3-yl) -1H-benzo [ d ] imidazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- (((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -5-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (6- (2-chloro-3- (3-chloro-2- (3-methoxy-5- ((methylamino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine;

chloro-3- (3-chloro-2- (3- (((2-hydroxyethyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethan-1-ol;

(S) -1- (((6- (2-chloro-3- (3-chloro-2- (3- (((S) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(S) -1- (((6- (2-chloro-3- (3-chloro-2- (3- ((((R) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (2-chloro-3- (3-chloro-2- (3- ((((S) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (2-chloro-3- (3-chloro-2- (3- ((((R) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(S) -5- ((((3 ' -chloro-2 ' - ((S) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((S) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((R) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((S) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((R) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((S) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((R) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((R) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (((6- (((S) -4- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((S) -4- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -4- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -4- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

methyl 1- (((6- (((S) -4- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylate;

methyl 1- (((6- (((S) -4- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylate;

methyl 1- (((6- (((R) -4- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylate;

methyl 1- (((6- (((R) -4- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylate;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indol-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indol-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine;

2- (((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethan-1-ol;

(S) -1- (((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) piperidin-1-yl) ethan-1-one;

1- (((6- (((S) -4- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((S) -4- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -4- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -4- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

(S) -5- ((((3 ' -chloro-2 ' - ((S) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((S) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((R) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((R) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((R) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((S) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((S) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((R) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -4- ((3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) amino) -3-hydroxybutyric acid;

(R) -4- ((3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) amino) -3-hydroxybutyric acid;

3- ((3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) amino) propanoic acid;

(S) -1- (3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) pyrrolidine-3-carboxylic acid;

(R) -1- (3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) pyrrolidine-3-carboxylic acid;

2- (1- (3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) azetidin-3-yl) acetic acid;

2- (3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) -2-azaspiro [3.3] heptane-6-carboxylic acid;

3- ((3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) amino) bicyclo [1.1.1] pentane-1-carboxylic acid;

3- (((3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) amino) methyl) bicyclo [1.1.1] pentane-1-carboxylic acid;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] sulfan-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] sulfan-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

5- (3-chloro-4- (2-chloro-3- (4-fluoro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3- (4-fluoro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3- (4-fluoro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3- (4-fluoro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4, 5-dihydro-1H-imidazol-2-yl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (4, 5-dihydro-1H-imidazol-2-yl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -4- ((4- (3-chloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) amino) -3-hydroxybutyric acid;

(R) -4- ((4- (3-chloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) amino) -3-hydroxybutyric acid;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((S) -oxetan-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((R) -oxetan-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((S) -oxetan-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((S) -oxetan-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2,1-f ] [1,2,4] triazin-2-yl) methyl) azetidine-3-carboxylic acid methyl ester;

(R) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2,1-f ] [1,2,4] triazin-2-yl) methyl) azetidine-3-carboxylic acid methyl ester;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- ((S) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- ((S) -5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- ((S) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (((6- (((S) -5- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((S) -5- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

(S) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

2- ((6- (((S) -5- (3 ' -chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((S) -5- (3 ' -chloro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3 ' -chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3 ' -chloro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -N- (5- (3 ' -chloro-6-methoxy-5- ((methylamino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine;

(R) -N- (5- (3 ' -chloro-6-methoxy-5- ((methylamino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine;

1- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

(S) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -5- (3-chloro-2- (3-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -5- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

2- ((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -N- (5- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine;

(R) -N- (5- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine;

1- (((6- (((S) -5- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((S) -5- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

(S) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

2- ((6- (((S) -5- (3 ' -chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((S) -5- (3 ' -chloro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((S) -5- (3 ' -chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3 ' -chloro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -1- (3 ' -chloro-6-methoxy-2 ' - (5- ((6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) -N-methyl methylamine;

(R) -1- (3 ' -chloro-6-methoxy-2 ' - (5- ((6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) -N-methyl methylamine;

1- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

(S) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -5- (3-chloro-2- (3-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -5- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

2- ((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -1- (6- ((5- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) -N-methyl methylamine;

(R) -1- (6- ((5- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) -N-methyl methylamine;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (8-chloro-6- ((((S) -2-hydroxypropyl) amino) methyl) -5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (8-chloro-6- ((((R) -2-hydroxypropyl) amino) methyl) -5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (8-chloro-6- ((((S) -2-hydroxypropyl) amino) methyl) -5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (8-chloro-6- ((((R) -2-hydroxypropyl) amino) methyl) -5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((8-chloro-2- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5-methoxyquinolin-6-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((8-chloro-2- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5-methoxyquinolin-6-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((8-chloro-2- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5-methoxyquinolin-6-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((8-chloro-2- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5-methoxyquinolin-6-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (3-hydroxy-3-methylbutyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (3-hydroxy-3-methylbutyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -4- ((4- (3-chloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) amino) -3-hydroxybutyric acid isopropyl ester;

(R) -4- ((4- (3-chloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) amino) -3-hydroxybutyric acid isopropyl ester;

(S) -5- (((6- (3- (2- (4- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (4- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

n- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) propan-2-amine;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -1- (((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(S) -1- (((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(1 r,3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3R) -3- (((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r, 3S) -3- (((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1S, 3S) -3- (((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 s) -3- (((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s, 3R) -3- (((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1S, 3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3 s) -3- (((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(S) -1- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol;

(S) -1- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol;

(R) -1- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol;

(R) -1- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol;

(S) -1- ((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -3-methylazetidin-3-ol;

(R) -1- ((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -3-methylazetidin-3-ol;

(S) - ((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) glycine methyl ester;

(R) - ((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) glycine methyl ester;

(S) -2- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) -3-hydroxybutyric acid;

(R) -4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) -3-hydroxybutyric acid;

3- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) propanoic acid;

6- (3-chloro-4- (2-chloro-3- (5- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -N- (4- (3 ' -chloro-6-methoxy-5- ((methylamino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine;

(R) -N- (4- (3 ' -chloro-6-methoxy-5- ((methylamino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine;

(1S, 3 r) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1 r, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3R) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1R, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3R) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1R, 3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3R) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1 s, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3R) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 r) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 r) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1 r, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 r) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1S, 3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 r) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1S, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3 s) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1R, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3 s) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1R, 3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3 s) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1 s, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3 s) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3R) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1R, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r, 3S) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1 r, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r, 3S) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1S, 3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r, 3S) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1S, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s, 3R) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1R, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s, 3R) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1R, 3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s, 3R) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1 s, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s, 3R) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1S, 3 r) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1S, 3 r) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1S, 3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1S, 3 r) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1S, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 s) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1R, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 s) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1R, 3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 s) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1 s, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 s) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s, 3R) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1R, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1S, 3S) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1 r, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1S, 3S) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1S, 3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1S, 3S) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1S, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid;

(R) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -2-azaspiro [3.3] heptane-6-carboxylic acid;

3- (((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) bicyclo [1.1.1] pentane-1-carboxylic acid;

(S) - ((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) glycine;

(R) - ((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) glycine;

2- ((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

6- (3-chloro-4- (2-chloro-3- (5- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (5- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (5- ((((1 r,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (5- ((((1 s,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (5- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (5- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (5- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (5- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (5- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -oxetan-2-yl) methyl) amino) methyl) -1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((((R) -oxetan-2-yl) methyl) amino) methyl) -1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -oxetan-2-yl) methyl) amino) methyl) -1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((R) -oxetan-2-yl) methyl) amino) methyl) -1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((8-chloro-2- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5-methoxyquinolin-6-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((8-chloro-2- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5-methoxyquinolin-6-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((8-chloro-2- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5-methoxyquinolin-6-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((8-chloro-2- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5-methoxyquinolin-6-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (3- (2- (4- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (4- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (8-chloro-6- (((2-hydroxyethyl) amino) methyl) -5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (8-chloro-6- (((2-hydroxyethyl) amino) methyl) -5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -1- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) pyrrolidine-3-carboxylic acid;

(R) -1- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) pyrrolidine-3-carboxylic acid;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -5- (((4- (4- (3- (6- (((1-acetylpiperidin-4-yl) amino) methyl) -8-chloro-5-methoxyquinolin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (4- (3- (6- (((1-acetylpiperidin-4-yl) amino) methyl) -8-chloro-5-methoxyquinolin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

5- (3-chloro-4- (2-chloro-3 '-fluoro-5' -methoxy-4 '- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,1' -biphenyl ] -3-yl) pyridin-2-yl) -2- (2- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3 '-fluoro-5' -methoxy-4 '- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,1' -biphenyl ] -3-yl) pyridin-2-yl) -2- (2- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3 '-fluoro-5' -methoxy-4 '- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,1' -biphenyl ] -3-yl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3 '-fluoro-5' -methoxy-4 '- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,1' -biphenyl ] -3-yl) pyridin-2-yl) -2- (2- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

2- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2-azaspiro [3.3] heptane-6-carboxylic acid;

2- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -1- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) pyrrolidine-3-carboxylic acid isopropyl ester;

(R) -1- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) pyrrolidine-3-carboxylic acid isopropyl ester;

1- (4- ((4- (4- (3- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-hydroxyethyl) (methyl) amino) methyl) -1-methyl-1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-hydroxyethyl) (methyl) amino) methyl) -1-methyl-1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -1- (6- ((6- ((4- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

(R) -1- (6- ((6- ((4- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

1- (6- ((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

2- ((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

n- ((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2-oxaspiro [3.3] heptane-6-amine;

(1- ((((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) cyclopropyl) methanol;

(S) -1- (((3 ' -chloro-2 ' - ((S) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) propan-2-ol;

(S) -1- (((3 ' -chloro-2 ' - ((R) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) propan-2-ol;

(S) -1- (((3 ' -chloro-2 ' - ((R) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) propan-2-ol;

(S) -1- (((3 ' -chloro-2 ' - ((S) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) propan-2-ol;

(R) -1- (((3 ' -chloro-2 ' - ((R) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) propan-2-ol;

(R) -1- (((3 ' -chloro-2 ' - ((R) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) propan-2-ol;

(R) -1- (((3 ' -chloro-2 ' - ((S) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) propan-2-ol;

(R) -1- (((3 ' -chloro-2 ' - ((S) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) propan-2-ol;

(S) -1- (4- (((6- ((4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(R) -1- (4- (((6- ((4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- ((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- ((S) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- ((S) -5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -5- ((((R) -6- (3-chloro-4- (2-chloro-3- (5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((R) -6- (3-chloro-4- (2-chloro-3- (5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((S) -6- (3-chloro-4- (2-chloro-3- (5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((S) -6- (3-chloro-4- (2-chloro-3- (5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((R) -6- (3-chloro-4- (2-chloro-3- (5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((R) -6- (3-chloro-4- (2-chloro-3- (5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((S) -6- (3-chloro-4- (2-chloro-3- (5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((S) -6- (3-chloro-4- (2-chloro-3- (5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((R) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((R) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((R) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((R) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((R) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((R) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((((1S, 4S) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((((1S, 4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r, 4S) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((((1R, 4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s, 4R) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((((1R, 4R) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) azetidine-3-carboxylic acid;

(R) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) azetidine-3-carboxylic acid;

(S) -1- (2- (((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) ethyl) cyclopropane-1-carboxylic acid;

(R) -1- (2- (((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) ethyl) cyclopropane-1-carboxylic acid;

1- (4- (((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- ((4- (4- (3- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -L-homoserine;

((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -L-homoserine;

((6- (2-chloro-3- (3-chloro-2- ((S) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -L-homoserine;

((6- (2-chloro-3- (3-chloro-2- ((S) -5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -L-homoserine;

((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -D-homoserine;

((6- (2-chloro-3- (3-chloro-2- ((S) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -D-homoserine;

((6- (2-chloro-3- (3-chloro-2- ((S) -5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -D-homoserine;

((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -D-homoserine;

(5 s, 5's) -5,5' - ((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (8-methoxy-3, 4-dihydroisoquinoline-6, 2 (1H) -diyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 s,5' r) -5,5' - ((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (8-methoxy-3, 4-dihydroisoquinoline-6, 2 (1H) -diyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 r, 5's) -5,5' - ((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (8-methoxy-3, 4-dihydroisoquinoline-6, 2 (1H) -diyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 r,5' r) -5,5' - ((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (8-methoxy-3, 4-dihydroisoquinoline-6, 2 (1H) -diyl)) bis (methylene)) bis (pyrrolidin-2-one);

((3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) -5' -methoxy- [2,3' -bipyridin ] -6' -yl) methyl) -L-homoserine methyl ester;

((3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) -5' -methoxy- [2,3' -bipyridin ] -6' -yl) methyl) -L-homoserine methyl ester;

((3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) -5' -methoxy- [2,3' -bipyridin ] -6' -yl) methyl) -D-homoserine methyl ester;

((3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) -5' -methoxy- [2,3' -bipyridin ] -6' -yl) methyl) -D-homoserine methyl ester;

(S) -5- (((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((((S) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((((R) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((((S) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((((R) -2-oxotetrahydrofuran-3-yl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (((S) -4- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (((S) -4- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (((R) -4- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (((S) -4- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -4- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -4- (3-chloro-2- (3-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((R) -4- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -4- (3-chloro-2- (3-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -1- (((6- (((S) -4- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) propan-2-ol;

(S) -1- (((6- (((S) -4- (3-chloro-2- (4- (((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) propan-2-ol;

(S) -1- (((6- (((R) -4- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) propan-2-ol;

(S) -1- (((6- (((R) -4- (3-chloro-2- (4- (((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (((S) -4- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (((S) -4- (3-chloro-2- (4- (((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (((R) -4- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (((R) -4- (3-chloro-2- (4- (((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) propan-2-ol;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -3- (6- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propionic acid methyl ester;

(R) -methyl 3- (6- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propanoate;

methyl 3- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propanoate;

(S) -1- (((6- (2-chloro-3- (2- (4- ((((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(S) -1- (((6- (2-chloro-3- (2- (4- ((((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (2-chloro-3- (2- (4- ((((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (2-chloro-3- (2- (4- ((((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(S) -2- (6- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) acetamide;

(R) -2- (6- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) acetamide;

1- (6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((methylamino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine;

1- (4- (((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-indol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid isopropyl ester;

(R) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid isopropyl ester;

Isopropyl 3- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) propionate;

(S) -4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) -3-hydroxybutyric acid isopropyl ester;

(R) -4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) -3-hydroxybutyric acid isopropyl ester;

isopropyl 2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -2-azaspiro [3.3] heptane-6-carboxylate;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-fluorophenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((methylamino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine;

2- ((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methylamine;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-fluoro-6-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one;

(S) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-indazol-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-indazol-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -5- (((6- (3- (2- (2- ((1-acetylpiperidin-4-yl) methyl) -8-chloro-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (2- ((1-acetylpiperidin-4-yl) methyl) -8-chloro-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) -1, 2-dihydro-3H-pyrrolo [3,4-c ] pyridin-3-one;

6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2- (2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) -1, 2-dihydro-3H-pyrrolo [3,4-c ] pyridin-3-one;

6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) -1, 2-dihydro-3H-pyrrolo [3,4-c ] pyridin-3-one;

6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2- (2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) -1, 2-dihydro-3H-pyrrolo [3,4-c ] pyridin-3-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) imidazo [1,2-a ] pyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) imidazo [1,2-a ] pyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) imidazo [1,2-a ] pyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) imidazo [1,2-a ] pyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -2- (4- (3-chloro-4- (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one;

(R) -2- (4- (3-chloro-4- (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one;

(S) -3- (6- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propionic acid;

(R) -3- (6- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propionic acid;

3- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propionic acid;

1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) cyclopropane-1-carboxylic acid methyl ester;

2- ((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoro-2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -2- ((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoro-2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- ((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoro-2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) cyclopropane-1-carboxylic acid;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

1, 1-dioxo 4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) tetrahydro-2H-thiopyran;

1- (3- (((6- (3- (2- (4- (((1-acetylazetidin-3-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) azetidin-1-one;

(S) -1- (((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(S) -1- (((6- (2-chloro-3- (3-chloro-2- (4- (((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (2-chloro-3- (3-chloro-2- (4- (((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

2- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((5-oxo-6-azaspiro [3.4] oct-2-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) -6-azaspiro [3.4] octan-5-one;

1- (2- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((2- (2-oxopyrrolidin-1-yl) ethyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethyl) pyrrolidin-2-one;

(S) -2- ((3 ' -chloro-6-methoxy-2 ' - (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one;

(R) -2- ((3 ' -chloro-6-methoxy-2 ' - (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one;

(S) -1- (6- ((5- ((4- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxy-6- (trifluoromethyl) pyrazin-2-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

(R) -1- (6- ((5- ((4- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxy-6- (trifluoromethyl) pyrazin-2-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

(S) -2- (4- (3-chloro-4- (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-2-yl) -2-fluoro-6-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one;

(R) -2- (4- (3-chloro-4- (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-2-yl) -2-fluoro-6-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (oxetan-3-ylmethyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (oxetan-3-ylmethyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (3- (2- (3- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (3- (2- (3- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-indazol-3-yl) methyl) pyrrolidine-3-carboxylic acid;

(S) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-indazol-3-yl) methyl) pyrrolidine-3-carboxylic acid;

(R) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-indazol-3-yl) methyl) pyrrolidine-3-carboxylic acid;

(R) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-indazol-3-yl) methyl) pyrrolidine-3-carboxylic acid;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) imidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) imidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) imidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) imidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

1- (4- (((5- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -3-methoxypyrazin-2-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1S, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1S, 3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1R, 3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1R, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1,1'- ((((3, 3' -dichloro- [4,4 '-bipyridine ] -2,2' -diyl) bis (2-fluoro-6-methoxy-4, 1-phenylene)) bis (methylene)) bis (azanediyl)) bis (piperidin-4, 1-diyl)) bis (ethane-1-one);

(S) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (cyclopropanecarbonyl) piperidin-4-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (cyclopropyl) methanone;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (2- (((1-acetylpiperidin-4-yl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (2- (((1-acetylpiperidin-4-yl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (3- (2- (2- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (2- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) -2, 5-diazaspiro [3.4] octan-6-one;

(R) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) -2, 5-diazaspiro [3.4] octan-6-one;

(S) -5- ((((6- (3- (2- (2- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (2- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

n- (1- ((6- (3- (2- (4- ((4-acetamidopiperidin-1-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

2,2'- ((3, 3' -dichloro- [4,4 '-bipyridine ] -2,2' -diyl) bis (2-fluoro-6-methoxy-4, 1-phenylene)) bis (methylene)) bis (2, 6-diazaspiro [3.4] octan-7-one);

2- (4- (4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) -3-fluoropyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

n- (1- (4- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) piperidin-4-yl) acetamide;

n- ((6- (2-chloro-3- (3-chloro-2- (4- (((1-isopropylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1-isopropylpiperidin-4-amine;

n- ((6- (2-chloro-3- (3-chloro-2- (4- (((4, 4-difluorocyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4, 4-difluorocyclohexane-1-amine;

2- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (2-hydroxyethyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-ol;

n- (2- (((6- (3- (2- (4- (((2-acetamidoethyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) ethyl) acetamide;

1- (6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((tetrahydro-2H-pyran-4-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N- ((tetrahydro-2H-pyran-4-yl) methyl) methylamine;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((1-propionylpiperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

2- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (4- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) piperidin-1-yl) ethan-1-one;

1- (6- (2-chloro-3- (2- (3-methoxy-4- ((methylamino) methyl) phenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methylamine;

(S) -5- ((((6- (3- (2- (4- ((S) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (4- ((S) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (4- ((R) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (4- ((R) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -2- ((3 ' -chloro-6-methoxy-2 ' - (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one;

(R) -2- ((3 ' -chloro-6-methoxy-2 ' - (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-fluoropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -4- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) dihydrofuran-2 (3H) -one;

(R) -4- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) dihydrofuran-2 (3H) -one;

(S) -3- ((methyl 4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) -4-hydroxybutyrate;

(R) -3- ((methyl 4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) -4-hydroxybutyrate;

(S) -3- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) dihydrofuran-2 (3H) -one;

(R) -3- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) dihydrofuran-2 (3H) -one;

n- (1- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

(S) -3- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) -4-hydroxybutyric acid;

(R) -3- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) -4-hydroxybutyric acid;

(4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -L-homoserine;

(4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -D-homoserine;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1-propionylpiperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) propan-1-one;

(4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (cyclopropanecarbonyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (cyclopropyl) methanone;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1-isobutyrylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methylpropan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- (((1-isobutyrylpiperidin-4-yl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methylpropan-1-one;

n- ((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

1, 1-dioxo 4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) tetrahydro-2H-thiopyran;

(S) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) azetidine-3-carboxylic acid;

(R) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) azetidine-3-carboxylic acid;

(S) -1- (2- (((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) amino) ethyl) cyclopropane-1-carboxylic acid;

(R) -1- (2- (((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) amino) ethyl) cyclopropane-1-carboxylic acid;

(4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (cyclobutanecarbonyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (cyclobutyl) methanone;

7- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((2-oxo-1, 7-diazaspiro [3.5] nonan-7-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -1, 7-diazaspiro [3.5] nonan-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

n- (1- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

(R) -N- (1- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

(S) -N- (1- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

(S) -N- (1- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

(R) -N- (1- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

n- (3- (((6- (3- (2- (4- (((3-acetamidopropyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) propyl) acetamide;

4- (((6- (2-chloro-3- (3-chloro-2- (4- (((2, 6-dioxopiperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidine-2, 6-dione;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (2-methoxy-4- (4- (3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) -2-methylphenyl) -3-methylpyridin-2-yl) phenyl) -N-methylamine;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

n- (4- (4- (3- (5- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2-oxaspiro [3.3] heptan-6-amine;

(S) -2- (4- (3-chloro-4- (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one;

(R) -2- (4- (3-chloro-4- (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one;

(S) -1- (6- ((5- ((4- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxy-6- (trifluoromethyl) pyrazin-2-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

(R) -1- (6- ((5- ((4- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxy-6- (trifluoromethyl) pyrazin-2-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

2- (4- (4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) -3-methylpyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1R, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1R, 3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1S, 3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1S, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

1- (4- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) piperidin-1-yl) -2-methylpropan-1-one;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (methylsulfonyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (methylsulfonyl) piperidin-4-amine;

5- (((6- (3- (2- (4- (((5-amino-5-oxopentyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) pentanoylalkane;

1- ((R) -3- (((6- (3- (2- (4- ((((R) -1-acetylpyrrolidin-3-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-1-yl) ethan-1-one;

1- ((S) -3- (((6- (3- (2- (4- ((((R) -1-acetylpyrrolidin-3-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-1-yl) ethan-1-one;

1- ((R) -3- (((6- (3- (2- (4- ((((S) -1-acetylpyrrolidin-3-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-1-yl) ethan-1-one;

1- ((S) -3- (((6- (3- (2- (4- ((((S) -1-acetylpyrrolidin-3-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-1-yl) ethan-1-one;

1- (4- (((6- (3- (6 ' - ((1-acetylpiperidin-4-yl) amino) methyl) -3-chloro-5 ' -methoxy- [2,3' -bipyridin ] -4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- ((3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) -5' -methoxy- [2,3' -bipyridin ] -6' -yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -N- (1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-3-yl) methyl) piperidin-4-yl) acetamide;

(R) -N- (1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-3-yl) methyl) piperidin-4-yl) acetamide;

(S) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (4- (((6- (3- (2- (4- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (3- (2- (4- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((3, 3-dimethylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methylpropan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (methylsulfonyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1R, 4R) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1R, 4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s, 4R) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r, 4S) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1S, 4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1S, 4S) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(1 r,3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 s) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 s) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 s) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 s) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 s) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 s) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 s) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 s) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2-azaspiro [3.3] heptan-6-ol;

6- (4- (4- (3- (5- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2-oxa-6-azaspiro [3.3] heptane;

(S) -1- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) pyrrolidine-3-carboxylic acid;

(R) -1- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) pyrrolidine-3-carboxylic acid;

3- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) propanoic acid;

3- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) propanoic acid;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -1- (6- (3- (2- (4- ((S) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethan-1-amine;

(R) -1- (6- (3- (2- (4- ((S) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethan-1-amine;

(S) -1- (6- (3- (2- (4- ((R) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethan-1-amine;

(R) -1- (6- (3- (2- (4- ((R) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethan-1-amine;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3- (difluoromethoxy) phenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (6- (3- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine;

1- ((6- (2-chloro-3- (3-chloro-2- (4- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -3-methylazetidin-3-ol;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (2-methoxyacetyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methoxyethan-1-one;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6-oxo-2, 5-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2, 5-diazaspiro [3.4] oct-6-one;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

N- (1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) piperidin-4-yl) acetamide;

n- (1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6-oxo-2, 5-diazaspiro [3.4] octane-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) piperidin-4-yl) acetamide;

n- (1- (4- (4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) piperidin-4-yl) acetamide;

(S) -N- (1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) piperidin-4-yl) acetamide;

(R) -N- (1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) piperidin-4-yl) acetamide;

2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) nicotinonitrile;

(S) -4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-3-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-3-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-3-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-3-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- (((6- (3- (2- (4- ((4-amino-4-methylpiperidin-1-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -4- (((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) methyl) pyrrolidin-2-one;

(R) -4- (((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) methyl) pyrrolidin-2-one;

2- (4- (3-chloro-4- (3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) -2-methylphenyl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

4- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (morpholinomethyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) morpholine;

1- ((6- (2-chloro-3- (3-chloro-2- (4- ((4-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-ol;

1- (4- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) piperidin-1-yl) -2-methoxyethan-1-one;

(S) -5- (((6- (2-chloro-3- (2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (2- (3-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

2- (2-methoxy-4- (4- (3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) -2-methylphenyl) -3-methylpyridin-2-yl) benzyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((piperidin-4-ylamino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1-methyl-2-oxopiperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylpiperidin-2-one;

4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (dimethylcarbamoyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -N, N-dimethylpiperidine-1-carboxamide;

N- ((6- (2-chloro-3- (3-chloro-2- (4- (((1- (2, 2-difluoroethyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (2, 2-difluoroethyl) piperidin-4-amine;

(4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (furan-2-carbonyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (furan-2-yl) methanone;

(4- (((6- (3- (2- (4- (((1-benzoylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (phenyl) methanone;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1-phenylpiperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1-phenylpiperidin-4-amine;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (pyridin-4-yl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (pyridin-4-yl) piperidin-4-amine;

n- (2-methoxy-4- (4- (3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) -2-methylphenyl) -3-methylpyridin-2-yl) benzyl) tetrahydro-2H-pyran-4-amine;

N- ((6- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (6- ((6- (3- (6 ' - ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-chloro-5 ' -methoxy- [2,3' -bipyridin ] -4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

n- ((4- (3- (5- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloro-5 ' -methoxy- [2,3' -bipyridin ] -6' -yl) methyl) -2-oxaspiro [3.3] heptan-6-amine;

2- ((3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6-oxo-2, 5-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) -5' -methoxy- [2,3' -bipyridin ] -6' -yl) methyl) -2, 5-diazaspiro [3.4] octan-6-one;

n- ((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

N- (1- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) -2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) nicotinonitrile;

4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) -2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) nicotinonitrile;

(S) -1- ((6- (2-chloro-3- (3-chloro-2- (4- (((S) -3-hydroxypyrrolidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) pyrrolidin-3-ol;

(S) -1- ((6- (2-chloro-3- (3-chloro-2- (4- (((R) -3-hydroxypyrrolidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) pyrrolidin-3-ol;

(R) -1- ((6- (2-chloro-3- (3-chloro-2- (4- (((S) -3-hydroxypyrrolidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) pyrrolidin-3-ol;

(R) -1- ((6- (2-chloro-3- (3-chloro-2- (4- (((R) -3-hydroxypyrrolidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) pyrrolidin-3-ol;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methyl (tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (2, 2-trifluoroethyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (2, 2-trifluoroethyl) piperidin-4-amine;

2- (4- (3-chloro-4- (2-fluoro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] oct-7-one;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-fluorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

n- ((6- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-fluorophenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

n- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -N-methyltetrahydro-2H-pyran-4-amine;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) (methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (2-hydroxyacetyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-hydroxyethan-1-one;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (pyridin-2-yl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (pyridin-2-yl) piperidin-4-amine;

n- ((6- (2-chloro-3- (3-chloro-2- (4- (((1- (3-chloropyridin-2-yl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (3-chloropyridin-2-yl) piperidin-4-amine;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((2-methoxyethyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2-methoxyethane-1-amine;

3-chloro-4- (2-chloro-3- (6-methoxy-5- ((4-methoxypiperidin-1-yl) methyl) pyridin-2-yl) phenyl) -2- (3-methoxy-4- ((4-methoxypiperidin-1-yl) methyl) phenyl) pyridine;

(1 s,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-fluoropyridin-4-yl) -2-fluorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(1 r,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

2- (4- (3-fluoro-4- (2-fluoro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] oct-7-one;

n- ((6- (2-fluoro-3- (3-fluoro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6-oxo-2, 5-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) -2, 5-diazaspiro [3.4] octan-6-one;

1- ((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -3-methylazetidin-3-ol;

(4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (cyclohexanecarbonyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (cyclohexyl) methanone;

4- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((3-oxopiperazin-1-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperazin-2-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (morpholinomethyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((4-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) - (2- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxy-4-oxopyrrolo [2,1-f ] [1,2,4] triazin-3 (4H) -yl) ethyl) glycine;

(R) - (2- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxy-4-oxopyrrolo [2,1-f ] [1,2,4] triazin-3 (4H) -yl) ethyl) glycine;

n- (1- ((6- (3- (2- (4- ((4-acetamidopiperidin-1-yl) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

N- ((6- (2-chloro-3- (2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

(1 r,4 r) -4- (((6- (2-chloro-3- (2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

6- (4- (4- (3- (5- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-methylpyridin-2-yl) -2-methoxyphenylmethyl) -2-oxa-6-azaspiro [3.3] heptane;

4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (methoxycarbonyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidine-1-carboxylic acid methyl ester;

n- (1- ((6- (3- (2- (4- ((4-acetamidopiperidin-1-yl) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

n- (1- ((6- (3- (2- (4- ((4-acetamidopiperidin-1-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -N-methyltetrahydro-2H-pyran-4-amine;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) piperidin-1-yl) ethan-1-one;

2- (4- (4- (3- (5- ((7-oxa-2-azaspiro [3.5] nonan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -7-oxa-2-azaspiro [3.5] nonane;

2- (1- ((6- (2-chloro-3- (3-chloro-2- (4- ((3- (2-hydroxypropane-2-yl) azetidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) azetidin-2-ol;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) pyrrolidin-2-one;

(R) -4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (((R) -5-oxopyrrolidin-3-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) pyrrolidin-2-one;

(S) -4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (((R) -5-oxopyrrolidin-3-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) pyrrolidin-2-one;

(R) -4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (((S) -5-oxopyrrolidin-3-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) pyrrolidin-2-one;

(S) -4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (((S) -5-oxopyrrolidin-3-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) pyrrolidin-2-one;

2- ((6- (3-chloro-4- (2-chloro-3- (5- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) -2-azaspiro [3.3] heptan-6-ol;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (morpholinomethyl) imidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((3, 3-difluoropyrrolidin-1-yl) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- ((6- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) -3-methylazetidine-3-carbonitrile;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2, 2-difluoroethyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

4- (2- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) ethyl) piperazin-2-one;

2- (3- (6- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) -2-oxopyrrolidin-1-yl) acetic acid;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methoxyethan-1-one;

1- (4- (((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- ((4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) piperidin-1-yl) ethan-1-one;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-thiopyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-thiopyran-4-amine;

1- (2- ((6- (3- (2- (4- ((7-acetyl-2, 7-diazaspiro [3.5] nonan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 7-diazaspiro [3.5] nonan-7-yl) ethan-1-one;

(S) -5- ((((6- (((S) -4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- ((((6- (((R) -4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((R) -4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (5- ((4-hydroxypiperidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((1 s,4 r) -4-methoxycyclohexyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((1 r,4 s) -4-methoxycyclohexyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((1 s,4 s) -4-methoxycyclohexyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

(R) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((3-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((3-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((1- (2-methoxyacetyl) piperidin-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (4- (((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methoxyethan-1-one;

1- (6- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

2- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (3- (2- (4- ((2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (4- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (4- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (3- ((((6- (3- (2- (4- (((1-acetylazetidin-3-yl) methyl) (methyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) azetidin-1-one;

1- (4- (((4- (4 '- ((1-acetylpiperidin-4-yl) amino) methyl) -2-chloro-3' -methoxy- [1,1 '-biphenyl ] -3-yl) -3-chloro-5' -methoxy- [2,3 '-bipyridin ] -6' -yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- ((2 '-chloro-3' - (3-chloro-5 '-methoxy-6' - ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) - [2,3 '-bipyridin ] -4-yl) -3-methoxy- [1,1' -biphenyl ] -4-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1-hydroxycyclopropyl) methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) cyclopropan-1-ol;

n- ((6- (2-chloro-3- (3-chloro-2- (4- (((2, 2-difluoroethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 2-difluoroethane-1-amine;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((3-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(R) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((3-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((4- (hydroxymethyl) piperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((4- (methoxymethyl) piperidin-1-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((4-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methoxyethan-1-one;

1- (6- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1-hydroxycyclopropyl) methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((2, 2-difluoroethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

n- ((6- (2-chloro-3- (3-chloro-2- (4- ((isopropylamino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) propan-2-amine;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 s,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 r,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (4- (3- (5- ((2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (4- (((6- (3- (6- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -5-methylpyrimidin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -5- (((6- (2-chloro-3- (6- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -5-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (6- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -5-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (6- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -5-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (6- (3-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -5-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

n- ((6- (2-chloro-3- (3-chloro-2- (4- ((cyclohexylamino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) cyclohexylamine;

2- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-5-one;

2- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) -2,5, 7-triazaspiro [3.4] octan-6-one;

(S) -5- ((((2 ' - ((S) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((2 ' - ((R) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((2 ' - ((S) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((2 ' - ((R) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

n- ((6- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

n- ((6- (3- (2- (4- ((7-oxa-2-azaspiro [3.5] nonan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

n- (4- (4- (3- (5- ((7-oxa-2-azaspiro [3.5] nonan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) tetrahydro-2H-pyran-4-amine;

(S) -5- ((((6- (3-chloro-2- ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3-chloro-2- ((R) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3-chloro-2- ((R) -1- ((6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3-chloro-2- ((S) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3-chloro-2- ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3-chloro-2- ((R) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3-chloro-2- ((R) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3-chloro-2- ((S) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-hydroxyethan-1-one;

n- ((6- (2-chloro-3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -3-fluoropropane-1-amine;

2- (4- (6- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) -5-methylpyrimidin-4-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (1- ((6- (3- (2- (4- ((4-acetylpiperidin-1-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (6- ((6- (3- (6- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -5-methylpyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-hydroxyethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-hydroxyethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-hydroxyethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-hydroxyethan-1-one;

1- (4- (((6- (3- (6- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -5-chloropyrimidin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(R) -5- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-2-one;

(S) -5- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-2-one;

(S) -5- (((6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (((S) -4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- ((((6- (((R) -4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((R) -4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- ((((6- (3-chloro-2- ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3-chloro-2- ((R) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3-chloro-2- ((R) -1- ((6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3-chloro-2- ((S) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3-chloro-2- ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3-chloro-2- ((R) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3-chloro-2- ((R) -1- ((6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3-chloro-2- ((S) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (3-methoxypropionyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -3-methoxypropane-1-one;

2- ((6- (3- (6 ' - (((1-acetylpiperidin-4-yl) amino) methyl) -3-chloro-5 ' -methoxy- [2,3' -bipyridin ] -4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-6 ' - ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -5' -methoxy- [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-6 ' - ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -5' -methoxy- [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-6 ' - ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -5' -methoxy- [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-6 ' - ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -5' -methoxy- [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -2- ((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- ((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -2- ((2 ' - (1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- ((2 ' - (1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -2- ((3 ' -chloro-6-methoxy-2 ' - (1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- ((3 ' -chloro-6-methoxy-2 ' - (1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((3 ' -chloro-2 ' - ((S) -1- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((3 ' -chloro-2 ' - ((S) -1- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((3 ' -chloro-2 ' - ((R) -1- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((3 ' -chloro-2 ' - ((R) -1- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (5-chloro-6- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyrimidin-4-yl) -2, 6-diazaspiro [3.4] oct-7-one;

(S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxy-3- (2- (methylamino) ethyl) pyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(R) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxy-3- (2- (methylamino) ethyl) pyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- ((((tetrahydro-2H-pyran-4-yl) methyl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (3- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (3- (((2-hydroxyethyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4-methyl-1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (4-methyl-1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- ((6- (3- (6- (4- ((4-acetylpiperazin-1-yl) methyl) -3-methoxyphenyl) -5-chloropyrimidin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) piperazin-1-one;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

1- (4- (((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((5- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -3-methoxypyridin-2-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- (4- (3-chloro-4- (2-chloro-3- (5-methoxy-6- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-3-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] oct-7-one;

1- (4- (((5- (3- (6 ' - ((1-acetylpiperidin-4-yl) amino) methyl) -3-chloro-5 ' -methoxy- [2,3' -bipyridin ] -4-yl) -2-chlorophenyl) -3-methoxypyridin-2-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- (4- (5-chloro-6- (2-chloro-3- (5- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxyphenylmethyl) -2-azaspiro [3.3] heptan-6-ol;

2- ((5- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -3-methoxypyridin-2-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one;

n- ((5- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -3-methoxypyridin-2-yl) methyl) tetrahydro-2H-pyran-4-amine;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6-methyl-7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -6-methyl-2, 6-diazaspiro [3.4] octan-7-one;

1- (4- (((6- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- ((6- (2-chloro-3- (3 ' -chloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) - [2,4' -bipyridin ] -2' -yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

n- ((3 ' -chloro-2 ' - (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) tetrahydro-2H-pyran-4-amine;

(S) -5- ((((3 ' -chloro-2 ' - (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

2- (4- (3-chloro-4- (3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) -2- (trifluoromethyl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

6- (4- (4- (3- (5- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -6-methoxypyridin-2-yl) -2- (trifluoromethyl) phenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2-oxa-6-azaspiro [3.3] heptane;

2- (4- (4- (3- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -1- (((6- (3- (3-chloro-2- (4- ((((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(S) -1- (((6- (3- (3-chloro-2- (4- ((((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (3- (3-chloro-2- (4- ((((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (3- (3-chloro-2- (4- ((((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

2- (((6- (2-chloro-3- (5-chloro-6- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethan-1-ol;

5- (((6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-4- (((S) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

5- (((6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-4- (((R) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-4- (((S) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] sulfan-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-4- (((R) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] sulfan-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-4- (((S) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] sulfan-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-4- (((R) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] sulfan-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((((1 s,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((((1 r,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-ethoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- ((6- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-ethoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

n- ((6- (3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) -3-fluoropropane-1-amine;

(1 r,4 r) -4- (((6- (3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

1- (6- ((6- (3- (6- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -5-chloropyrimidin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

n- (3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) picolinamide;

(3- (((6- (2-chloro-3- (3-chloro-2- (4- (((3- (hydroxymethyl) bicyclo [1.1.1] pentan-1-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) bicyclo [1.1.1] pentan-1-yl) methanol;

(1 s,3 s) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 s,3 s) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 r,3 r) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 r,3 r) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 r,3 r) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 r,3 s) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 r,3 r) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 s,3 r) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 r,3 r) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 s,3 s) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 r,3 s) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 r,3 r) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 r,3 s) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 r,3 s) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 r,3 s) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 s,3 r) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 r,3 s) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 s,3 s) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 s,3 r) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 r,3 r) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 s,3 r) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 r,3 s) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 s,3 r) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 s,3 r) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 s,3 r) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 s,3 s) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 s,3 s) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 r,3 r) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 s,3 s) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 r,3 s) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 s,3 s) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 s,3 r) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

1- (6- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((6- (2-methoxyacetyl) -2, 6-diazaspiro [3.3] heptan-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -2-methoxyethane-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

2- ((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3- (difluoromethoxy) phenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

1- (4- (((S) -1- (6- (3- (2- (4- ((S) -1- ((1-acetylpiperidin-4-yl) amino) ethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((S) -1- (6- (3- (2- (4- ((R) -1- ((1-acetylpiperidin-4-yl) amino) ethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((R) -1- (6- (3- (2- (4- ((S) -1- ((1-acetylpiperidin-4-yl) amino) ethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((R) -1- (6- (3- (2- (4- ((R) -1- ((1-acetylpiperidin-4-yl) amino) ethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) (methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) (methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (3- (3-chloro-2- (3-methoxy-4- (((1- (2-methoxyacetyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methoxyethan-1-one;

2- (4- (4- (3- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

n- (4- (4- (3- (5- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -6-methoxypyridin-2-yl) -2- (trifluoromethyl) phenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2-oxaspiro [3.3] heptan-6-amine;

2- (4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) ethan-1-ol;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -3-methoxypropane-1-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (6- (4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

(S) -5- (((6- (3- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((S) -2-hydroxypropyl) -1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((R) -2-hydroxypropyl) -1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((S) -2-hydroxypropyl) -1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((R) -2-hydroxypropyl) -1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

2- (((6- (3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethan-1-ol;

1- (6- (3- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine;

n- ((6- (3- (3-chloro-2- (3-methoxy-4- (((2-methoxyethyl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) -2-methoxyethane-1-amine;

2- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -6- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) benzonitrile;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((4-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -3-methoxypropane-1-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

n- ((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

4- (((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((1-methyl-2-oxopiperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylpiperidin-2-one;

2- (4- (((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((1- (2-hydroxyethyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-ol;

1- (4- (((6- (3- (4- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-2-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- (4- (3-chloro-2- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-4-yl) -2, 6-diazaspiro [3.4] oct-7-one;

n- (4- (3-chloro-2- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-4-yl) -2-methoxybenzyl) tetrahydro-2H-pyran-4-amine;

(S) -5- (((4- (3-chloro-2- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-4-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-2- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-4-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-2- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-4-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-2- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-4-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((1- (3-methoxypropionyl) piperidin-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

n- ((6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

1- (4- (((6- (3- (5 ' - ((1-acetylpiperidin-4-yl) amino) methyl) -3-chloro-6 ' -methoxy- [2,2' -bipyridin ] -4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- ((6- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) - [2,2' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one;

n- ((6- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,2' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

(S) -5- (((6- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,2' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,2' -bipyridyl ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,2' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,2' -bipyridyl ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- (((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -3-methoxypropane-1-one;

(S) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -3-methoxypropane-1-one;

(R) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -3-methoxypropane-1-one;

(S) -5- ((((2 ' - ((S) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((2 ' - ((R) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((2 ' - ((S) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((2 ' - ((R) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) -N-methyltetrahydro-2H-pyran-4-amine;

2- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -6- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) benzonitrile;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

(R) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxypropyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxypropyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -4' -chloro-6-methoxy- [2,3' -bipyridin ] -5' -yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- ((6- (2-chloro-3- (4 ' -chloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) - [2,3' -bipyridin ] -5' -yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (4- (((6- (3- (5- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -4-chloropyridin-3-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- (4- (4-chloro-5- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-3-yl) -2, 6-diazaspiro [3.4] oct-7-one;

1- (6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- (((oxazol-5-ylmethyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N- (oxazol-5-ylmethyl) methylamine;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((isopropylamino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

5- (((1-acetylpiperidin-4-yl) amino) methyl) -N- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) picolinamide;

n- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

N- (3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -N- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) pyridine amide;

n- (3- (3-chloro-2- (4- ((((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((S) -2-hydroxypropyl) amino) methyl) picolinamide;

N- (3- (3-chloro-2- (4- ((((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((R) -2-hydroxypropyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (4- ((((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((S) -2-hydroxypropyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (4- ((((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((R) -2-hydroxypropyl) amino) methyl) picolinamide;

1- (6- (((6- (3- (2- (4- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -2-azaspiro [3.3] heptan-2-yl) ethan-1-one;

2- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -6- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) benzonitrile;

2- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) -6- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) benzonitrile;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxyethyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- ((6- (3- (2- (4- ((4-acetylpiperazin-1-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) piperazin-1-one;

n- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(S) -N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(R) -N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

2- ((6- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxyethyl) amino) methyl) -4-methoxypyrrolo [2,1-f ] [1,2,4] triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3- (difluoromethoxy) phenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (6- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (difluoromethoxy) benzyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

1- (4- (((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3- (difluoromethoxy) phenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3- (difluoromethoxy) phenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -5- ((((6- (((S) -4- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- ((((6- (((R) -4- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -4- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((R) -4- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

1- (6- ((6- (2-chloro-3- (3-chloro-2- (4- ((6- (2-hydroxyacetyl) -2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -2-hydroxyethan-1-one;

1- (4- ((4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3',3 "-dichloro-6-methoxy- [2,4':2',4" -terpyridin ] -2 "-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

2- (4- (3 ',3 "-dichloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) - [2,4':2',4" -terpyridin ] -2 "-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one;

2- (2- ((6- (2-chloro-3- (3-chloro-2- (4- ((6- (2-hydroxyethyl) -2, 6-diazaspiro [3.4] oct-2-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] oct-6-yl) ethan-1-ol;

1- (2- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.4] oct-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] oct-6-yl) ethan-1-one;

n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) picolinamide;

5- (((1-acetylpiperidin-4-yl) amino) methyl) -N- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) picolinamide;

n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) picolinamide;

n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

N- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -N- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) pyridine amide;

n- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -5- ((((S) -2-hydroxypropyl) amino) methyl) picolinamide;

n- (2-chloro-3- (3-chloro-2- (4- ((((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -5- ((((R) -2-hydroxypropyl) amino) methyl) picolinamide;

n- (2-chloro-3- (3-chloro-2- (4- ((((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -5- ((((S) -2-hydroxypropyl) amino) methyl) picolinamide;

n- (2-chloro-3- (3-chloro-2- (4- (((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -5- ((((R) -2-hydroxypropyl) amino) methyl) picolinamide;

1- (6- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((6- (3-methoxypropionyl) -2, 6-diazaspiro [3.3] heptan-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -3-methoxypropane-1-one;

2- ((2 ' - (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((3 ' -chloro-2 ' - (2-chloro-3- (5- ((4-hydroxypiperidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridyl ] -2' -yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (difluoromethoxy) benzyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (difluoromethoxy) benzyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -5- ((((6- (((S) -4- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -4- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (((R) -4- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (((R) -4- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6- (2-methoxyacetyl) -2, 6-diazaspiro [3.3] heptan-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (difluoromethoxy) benzyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (6- ((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

1- (4- ((4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (difluoromethoxy) benzyl) amino) piperidin-1-yl) ethan-1-one;

1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -2-methoxyethane-1-one;

1- (2- ((6- (2-chloro-3- (3-chloro-2- (4- ((4-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-6-yl) ethan-1-one;

1- (2- (4- (3-chloro-4- (2-chloro-3- (5- ((4-hydroxypiperidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-6-yl) ethan-1-one;

N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((methylamino) methyl) pyridine amide;

5- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -N- (3- (2- (4- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) picolinamide;

n- (3- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((methylamino) methyl) picolinamide;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -4-methoxypyrrolo [2,1-f ] [1,2,4] triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -4-methoxypyrrolo [2,1-f ] [1,2,4] triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- (((6- (3- (2- (2- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1-hydroxycyclopropyl) methyl) amino) methyl) 8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

n- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

5- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -N- (3- (2- (4- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) picolinamide;

n- (2-chloro-3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -5- (((3-fluoropropyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

1- (((6- (((S) -5- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((S) -5- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

5- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -N- (3- (2- (4- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) picolinamide;

(S) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -N- (2-chloro-3- (5-chloro-6- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(R) -N- (2-chloro-3- (5-chloro-6- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -5- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -5- (3-chloro-2- (3-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

2- (4- (5-chloro-6- (2-chloro-3- (5- (((2-hydroxyethyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -N- (2-chloro-3- (4 ' -chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,3' -bipyridyl ] -5' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(R) -N- (2-chloro-3- (4 ' -chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,3' -bipyridyl ] -5' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((3-fluoropropyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxy-2-methylpropyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxyethyl) (methyl) amino) methyl) 8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -5- (((6- (2-chloro-3- (5-methoxy-6- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (5-methoxy-6- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (5-methoxy-6- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (5-methoxy-6- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- (((6- (3- (6- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -5-methoxypyrimidin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -N- (2-chloro-3- (3 ' -chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(R) -N- (2-chloro-3- (3 ' -chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

N- (2-chloro-3- (3 ' -chloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) - [2,4' -bipyridyl ] -2' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

2- ((6- (((S) -5- (3 ' -chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3 ' -chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((S) -5- (3 ' -chloro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3 ' -chloro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

N- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridyl ] -2' -yl) -2-chlorophenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

n- (2-chloro-3- (4 ' -chloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) - [2,3' -bipyridyl ] -5' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

n- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -4' -chloro-6-methoxy- [2,3' -bipyridyl ] -5' -yl) -2-chlorophenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

2- ((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

n- (3- (3-chloro-2- (3- (difluoromethoxy) -4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (3- (difluoromethoxy) -4- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (3- (difluoromethoxy) -4- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (3- (difluoromethoxy) -4- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

N- (3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

2- (4- (6- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) -5-methoxypyrimidin-4-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((4- (6- (2-chloro-3- (5- (((2-hydroxyethyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) -5-methoxypyrimidin-4-yl) -2-methoxyphenylmethyl) amino) ethan-1-ol;

(S) -N- (2-chloro-3- (4 ' -chloro-5- (((2-hydroxypropyl) amino) methyl) -6-methoxy- [2,3' -bipyridyl ] -5' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(R) -N- (2-chloro-3- (4 ' -chloro-5- (((2-hydroxypropyl) amino) methyl) -6-methoxy- [2,3' -bipyridyl ] -5' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

n- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -4' -chloro-6-methoxy- [2,3' -bipyridyl ] -5' -yl) -2-chlorophenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

n- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridyl ] -2' -yl) -2-chlorophenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(S) -N- (5- (3 ' -chloro-6-methoxy-5- ((methylamino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine;

(R) -N- (5- (3 ' -chloro-6-methoxy-5- ((methylamino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine;

n- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

n- ((6- (2-chloro-3- (5-methoxy-6- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

(S) -N- (3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(R) -N- (3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(S) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

2- (4- (5-chloro-6- (2-chloro-3- (5- ((((1 s,3 s) -3-hydroxycyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (5-chloro-6- (2-chloro-3- (5- ((((1 s,3 r) -3-hydroxycyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (5-chloro-6- (2-chloro-3- (5- ((((1 r,3 s) -3-hydroxycyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (5-chloro-6- (2-chloro-3- (5- ((((1 r,3 r) -3-hydroxycyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -N- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - (((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,2' -bipyridyl ] -4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(R) -N- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - (((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,2' -bipyridyl ] -4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(S) -N- (2-chloro-3- (3-chloro-5 ' - (((2-hydroxypropyl) amino) methyl) -6' -methoxy- [2,2' -bipyridyl ] -4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(R) -N- (2-chloro-3- (3-chloro-5 ' - (((2-hydroxypropyl) amino) methyl) -6' -methoxy- [2,2' -bipyridyl ] -4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(S) -N- (5- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine;

(R) -N- (5- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine;

(S) -2- (4- (5-chloro-6- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- (4- (5-chloro-6- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (6- (2-chloro-3- (6-methoxy-5- ((6-oxo-2, 5-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) -5-methoxypyrimidin-4-yl) -2-methoxyphenylmethyl) -2, 5-diazaspiro [3.4] octan-6-one;

n- (3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(S) -N- (2-chloro-3- (3 ' -chloro-5- (((2-hydroxypropyl) amino) methyl) -6-methoxy- [2,4' -bipyridyl ] -2' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(R) -N- (2-chloro-3- (3 ' -chloro-5- (((2-hydroxypropyl) amino) methyl) -6-methoxy- [2,4' -bipyridyl ] -2' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(S) -N- (2-chloro-3- (5-chloro-6- (4- (((2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(R) -N- (2-chloro-3- (5-chloro-6- (4- (((2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(S) -N- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) -5- (((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

(R) -N- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) -5- (((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

(S) -N- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

(R) -N- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

(S) -N- (3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

(R) -N- (3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

(S) -N- (3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

(R) -N- (3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

(S) -N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((methylamino) methyl) picolinamide;

(R) -N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((methylamino) methyl) picolinamide;

(S) -6- ((2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) carbamoyl) nicotinic acid;

(R) -6- ((2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) carbamoyl) nicotinic acid;

2- ((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) -2-azaspiro [3.3] heptan-6-ol;

n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(S) -N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(R) -N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(S) -N- (3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((methylamino) methyl) picolinamide;

(R) -N- (3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((methylamino) methyl) picolinamide;

n- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(1 r,4 r) -4- (((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) cyclohexan-1-ol;

1- ((3 ' -chloro-2 ' - (2-chloro-3- (5- ((4-hydroxypiperidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) piperidin-4-ol;

1- (2- ((6- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octane-6-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3 ' -chloro-5- ((4-hydroxypiperidin-1-yl) methyl) -6-methoxy- [2,4' -bipyridin ] -2' -yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

n- (3- (3-chloro-2- (3-fluoro-4- (((2-hydroxyethyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

n- ((6- (2-chloro-3- (3-chloro-2- (2- ((isopropylamino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) propan-2-amine;

(S) -5- ((((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- (((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

n- (3- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

1- (6- ((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

n- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridyl ] -2' -yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(S) -N- (3- (3-chloro-2- (3- (difluoromethoxy) -4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(R) -N- (3- (3-chloro-2- (3- (difluoromethoxy) -4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(S) -N- (3- (3 ' -chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(R) -N- (3- (3 ' -chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(R) -1- ((3 ' -chloro-2 ' - (2-chloro-3- (5- (((R) -3-hydroxypyrrolidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) pyrrolidin-3-ol;

(R) -1- ((3 ' -chloro-2 ' - (2-chloro-3- (5- (((S) -3-hydroxypyrrolidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) pyrrolidin-3-ol;

(S) -1- ((3 ' -chloro-2 ' - (2-chloro-3- (5- (((R) -3-hydroxypyrrolidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) pyrrolidin-3-ol;

(S) -1- ((3 ' -chloro-2 ' - (2-chloro-3- (5- (((S) -3-hydroxypyrrolidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) pyrrolidin-3-ol; and

1- (4- (((3 ' -chloro-2 ' - (2-chloro-3- (5- ((4-hydroxypiperidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) piperidin-1-yl) ethan-1-one.

Embodiment 16 provides a pharmaceutical composition comprising at least one compound of any of embodiments 1-15 and at least one pharmaceutically acceptable carrier.

Embodiment 17 provides the pharmaceutical composition of embodiment 16, further comprising at least one additional agent that treats, ameliorates, and/or prevents a hepatitis virus infection.

Embodiment 18 provides the pharmaceutical composition of embodiment 17, wherein the at least one additional agent comprises at least one selected from the group consisting of: reverse transcriptase inhibitors; a capsid inhibitor; cccDNA formation inhibitors; an RNA destabilizer; an oligonucleotide targeting the HBV genome; an immunostimulant; galNAc-siRNA conjugates targeting HBV gene transcripts; and therapeutic vaccines.

Embodiment 19 provides the pharmaceutical composition of embodiment 18, wherein the immunostimulant is a checkpoint inhibitor.

Embodiment 20 provides the pharmaceutical composition of embodiment 19, wherein the checkpoint inhibitor is a PD-L1 inhibitor.

Embodiment 21 provides the pharmaceutical composition of any one of embodiments 16-20, wherein the hepatitis virus is at least one selected from the group consisting of Hepatitis B Virus (HBV) and Hepatitis Delta Virus (HDV).

Embodiment 22 provides a method of treating, ameliorating, and/or preventing a hepatitis virus infection in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments 1-15 and/or a pharmaceutical composition of any one of embodiments 16-21, or a salt, solvate, prodrug, stereoisomer, tautomer, or any mixture thereof.

Embodiment 23 provides the method of embodiment 22, wherein the subject is infected with Hepatitis B Virus (HBV).

Embodiment 24 provides the method of any one of embodiments 22-23, wherein the subject is further infected with Hepatitis Delta Virus (HDV).

Embodiment 25 provides the method of any one of embodiments 22-24, wherein the subject is infected with HBV and HDV.

Embodiment 26 provides the method of any one of embodiments 22-25, wherein the subject is further administered at least one additional agent for treating a hepatitis virus infection.

Embodiment 27 provides the method of embodiment 26, wherein the at least one other agent comprises at least one selected from the group consisting of: reverse transcriptase inhibitors; a capsid inhibitor; cccDNA formation inhibitors; an RNA destabilizer; an oligonucleotide targeting the HBV genome; an immunostimulant; galNAc-siRNA conjugates targeting HBV gene transcripts; and therapeutic vaccines.

Embodiment 28 provides the method of embodiment 27, wherein the immunostimulant is a checkpoint inhibitor.

Embodiment 29 provides the method of embodiment 28, wherein the checkpoint inhibitor is a PD-L1 inhibitor.

Embodiment 30 provides the method of any one of embodiments 26-29, wherein the subject is co-administered the at least one compound and the at least one other agent.

Embodiment 31 provides the method of any one of embodiments 26-30, wherein the at least one compound is co-formulated with the at least one other agent.

Embodiment 32 provides the method of any one of embodiments 22-31, wherein the subject is a mammal.

Embodiment 33 provides the method of embodiment 32, wherein the mammal is a human.

Embodiment 34 provides a method of treating, ameliorating, and/or preventing cancer in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of embodiments 1-15 and/or a pharmaceutical composition of any of embodiments 16-21, or a salt, solvate, prodrug, stereoisomer, tautomer, or any mixture thereof.

Embodiment 35 provides the method of embodiment 34, wherein the compound or composition is the only anti-cancer agent administered to the subject.

Embodiment 36 provides the method of any one of embodiments 34-35, wherein the compound is administered to the subject in a pharmaceutically acceptable composition.

Embodiment 37 provides the method of embodiment 34 or 36, wherein the subject is further administered at least one additional agent or therapy for treating, ameliorating and/or preventing cancer.

Embodiment 38 provides the method of embodiment 37, wherein the additional anti-cancer agent or therapy comprises nivolumab, pembrolizumab, alemtuzumab, ipilimab, chemotherapy, radiation therapy, and/or ablation therapy.

Embodiment 39 provides the method of embodiment 37, wherein the additional anti-cancer agent or therapy comprises rituximab, doxorubicin, gemcitabine, nivolumab, pembrolizumab, and/or ipilimumab.

Embodiment 40 provides the method of any one of embodiments 34 and 36-39, wherein the compound or composition is co-formulated and/or co-administered with the at least one other agent.

Embodiment 41 provides the method of any one of embodiments 34-40, wherein the cancer is amenable to treatment by inhibition of PD-1, PD-L1, or PD-1/PD-L1 interactions.

Embodiment 42 provides the method of any one of embodiments 34-41, wherein the cancer is at least one of: pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain cancer, bone cancer, soft tissue sarcoma, non-small cell lung cancer, or colon cancer.

Embodiment 43 provides the method of any one of embodiments 34-41, wherein the cancer is at least one of: acute Lymphoblastic Leukemia (ALL), acute Myelogenous Leukemia (AML), chronic Lymphocytic Leukemia (CLL), small Lymphocytic Lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic Myelogenous Leukemia (CML), multiple Myeloma (MM), non-hodgkin's lymphoma (NHL), mantle Cell Lymphoma (MCL), follicular lymphoma, macroglobulinemia (WM), T cell lymphoma, B cell lymphoma, and Diffuse Large B Cell Lymphoma (DLBCL).

Embodiment 44 provides the method of any one of embodiments 34-43, wherein the subject is a mammal.

Embodiment 45 provides the method of embodiment 44, wherein the mammal is a human.

The disclosures of each patent, patent application, and publication cited herein are hereby incorporated by reference in their entirety. Although the present disclosure has been disclosed with reference to specific embodiments, it will be apparent to those skilled in the art that other embodiments and variations of the present disclosure can be devised without departing from the true spirit and scope of the disclosure. It is intended that the following claims be interpreted to embrace all such embodiments and equivalent variations.

Claims (45)

1. A compound of formula (I), or a salt, solvate, geometric isomer, stereoisomer or tautomer thereof:

wherein:

a is

Y is NR ^3b Or O;

l is selected from the group consisting of-C (R ^3g )(R ^3h )-、-(C(R ^3g )(R ^3h ))-(C(R ³ⁱ )(R ^3j ) -and a bond;

X ¹ selected from CR' ¹ And N;

X ² selected from CR' ² And N;

X ³ selected from CR' ³ And N;

X ⁴ selected from CR' ¹ And N;

X ⁵ selected from CR' ² And N;

X ⁶ selected from CR' ³ And N;

wherein X is ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ And X ⁶ One to four of (a) are N;

R' ¹ 、R' ² 、R' ³ 、R" ¹ 、R" ² and R'. ³ Each independently selected from H, halogen, C ₁ -C ₃ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₃ Alkoxy, cyano, C ₁ -C ₃ Haloalkyl, and C ₁ -C ₃ Haloalkoxy groups;

R ^1a and R is ^1b Each independently selected from H, halogen, C ₁ -C ₃ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₃ Alkoxy, cyano, C ₁ -C ₃ Haloalkyl, and C ₁ -C ₃ Haloalkoxy groups;

R ^1c and R is ^1d Each independently selected from the group consisting of:

wherein Z is ¹ Each occurrence of (2) is CR ^V10 Or N;

R ^2a selected from-C (=O) NR ⁶ R ⁶ 、C(＝O)OR ^I Optionally substituted heterocyclyl, - (CH) ₂ ) _1-3 (optionally substituted heterocyclyl), optionally substituted C ₁ -C ₆ Alkoxy, optionally substituted C ₁ -C ₆ Aminoalkyl, and optionally substituted C ₁ -C ₆ A group consisting of a hydroxyalkyl group, and a hydroxyl group,

wherein R is ^2a Independently selected from the group consisting of optionally substituted heterocyclyl, optionally substituted C ₁ -C ₆ Alkyl, optionally substituted C ₁ -C ₆ Hydroxyalkyl, optionally substituted cycloalkyl, C (=o) (optionally substituted C) ₁ -C ₆ Alkyl), and optionally substituted- (CH) ₂ ) _1-2 (heterocyclyl) a group consisting of,

wherein R is ^2a Two optional substituents of (a) may be combined with the atom to which they are bound to form an optionally substituted C ₂ -C ₈ Heterocyclyl or optionally substituted C ₃ -C ₈ A cycloalkyl group,

wherein R is ^I Each occurrence of (a) is independently H, C ₁ -C ₆ Alkyl, or C ₃ -C ₈ Cycloalkyl, wherein alkyl or cycloalkyl is independently optionally substituted with halogen, -OH, C ₁ -C ₆ Alkoxy, -NH ₂ 、-NH(C ₁ -C ₆ Alkyl), and-N (C) ₁ -C ₆ Alkyl) (C) ₁ -C ₆ Alkyl) at least one of which is substituted,

wherein R is ⁶ Each occurrence of (a) is independently H, C ₁ -C ₆ Alkyl, or C ₃ -C ₈ Cycloalkyl, wherein the alkyl or cycloalkyl is independently optionally substituted with halogen, -OH, C ₁ -C ₆ Alkoxy, -NH ₂ 、-NH(C ₁ -C ₆ Alkyl), and-N (C) ₁ -C ₆ Alkyl) (C) ₁ -C ₆ Alkyl) at least one of which is substituted,

R ^2b selected from H, - (CH) ₂ ) _1-3 C(＝O)OR ^I 、-(CH ₂ ) _1-3 C(＝O)NR ^I R ^I Optionally substituted heterocyclyl, - (CH) ₂ ) _1-2 (optionally substituted heterocyclyl), optionally substituted C ₁ -C ₆ Alkyl, optionally substituted C ₁ -C ₆ Haloalkyl, optionally substituted C ₁ -C ₆ Alkoxy, optionally substituted C ₁ -C ₆ Aminoalkyl, and optionally substituted C ₁ -C ₆ A group consisting of a hydroxyalkyl group, and a hydroxyl group,

wherein R is ^2b Independently selected from the group consisting of optionally substituted C ₁ -C ₆ Alkyl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, and optionally substituted- (CH) ₂ ) _1-3 (heterocyclyl) groups;

R ^3a 、R ^3b 、R ^3c 、R ^3d 、R ^3e 、R ^3f 、R ^3g 、R ^3h 、R ³ⁱ and R ^3j Each independently selected from H, halogen, C ₁ -C ₃ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Haloalkyl, and C ₁ -C ₃ Haloalkoxy groups；

R ⁵ Selected from the group consisting of H, C ₁ -C ₃ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Haloalkyl, and C ₁ -C ₃ A group consisting of haloalkoxy groups,

wherein R is ⁵ And R is ^2b Can be combined with the nitrogen atom to which they are bound to form C ₃ -C ₁₂ A heterocyclic group;

R ^4a and R is ^4b Each occurrence of (a) is independently selected from the group consisting of H, C ₁ -C ₃ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Haloalkyl, and C ₁ -C ₃ A group consisting of haloalkoxy groups,

wherein R is ^4a And R is ^4b Can combine with the carbon atoms to which they are bound to form a carbonyl group (c=o);

R ^V1 、R ^V2 、R ^V3 、R ^V4 、R ^V5 、R ^V6 、R ^V7 、R ^V8 、R ^V9 and R ^V10 Each occurrence of (a) is independently selected from the group consisting of H, C ₁ -C ₃ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₃ Alkoxy, cyano, halogen, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Haloalkoxy, and C (=o) OR ^I A group of groups;

R ^V11 selected from the group consisting of H, C ₁ -C ₃ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Haloalkyl, and C ₁ -C ₃ Haloalkoxy groups;

wherein if R is ^1c And R is ^1d The same applies, then at least one of the following:

(a) If X ¹ Is N, then R ^1c Z in (a) ¹ If present, CR ^V10 And;

(b) If X ⁶ Is N, then R ^1d Z in (a) ¹ If present, CR ^V10 。

2. The compound of claim 1, selected from the group consisting of:

3. the compound of any one of claims 1 to 2, wherein at least one of the following applies:

(a)R' ² 、R' ³ 、R" ¹ 、R" ² and R'. ³ Each of is H, and X ¹ Is N;

(b)R' ¹ 、R' ³ 、R" ¹ 、R" ² and R'. ³ Each of is H, and X ² Is N;

(c)R' ¹ 、R' ² 、R" ¹ 、R" ² and R'. ³ Each of is H, and X ³ Is N;

(d)R' ¹ 、R' ² 、R' ³ 、R" ² and R'. ³ Each of is H, and X ⁴ Is N;

(e)R' ¹ 、R' ² 、R' ³ 、R" ¹ and R'. ³ Each of is H, and X ⁵ Is N;

(f)R' ¹ 、R' ² 、R' ³ 、R" ¹ and R'. ² Each of is H, and X ⁶ Is N;

(g)R' ² 、R' ³ 、R" ² and R'. ³ Each of is H, and X ¹ And X ⁴ Is N;

(h)R' ² 、R' ³ 、R" ¹ and R'. ³ Each of is H, and X ¹ And X ⁵ Is N;

(i)R' ² 、R' ³ 、R" ¹ and R'. ² Each of is H, and X ¹ And X ⁶ Is N;

(j)R' ¹ 、R' ³ 、R" ² and R'. ³ Each of is H, and X ² And X ⁴ Is N;

(k)R' ¹ 、R' ³ 、R" ¹ and R'. ³ Each of is H, and X ² And X ⁵ Is N;

(l)R' ¹ 、R' ³ 、R" ¹ and R'. ² Each of is H, and X ² And X ⁶ Is N;

(m)R' ¹ 、R' ² 、R" ¹ and R'. ³ Each of is H, and X ³ And X ⁵ Is N;

(n)R' ¹ 、R' ² 、R" ¹ and R'. ² Is each H, and X ³ And X ⁶ Is N;

(o)R' ² 、R" ¹ 、R" ² and R'. ³ Each of is H, and X ¹ And X ³ Is N; and

(p)R' ¹ 、R' ² 、R' ³ and R'. ² Each of is H, and X ⁴ And X ⁶ Is N.

4. A compound according to any one of claims 1 to 3, wherein at least one of the following applies:

(a) L is a bond and R ^3a 、R ^3c 、R ^3d 、R ^3e And R ^3f Each of (a)Each is H;

(b) L is a bond, Y is NR ^3b And R is ^3a 、R ^3b 、R ^3c 、R ^3d 、R ^3e And R ^3f Each of which is H;

(c) L is-C (R) ^3g )(R ^3h ) -and R ^3a 、R ^3c 、R ^3d 、R ^3e 、R ^3f 、R ^3g And R ^3h Each of which is H;

(d) L is-C (R) ^3g )(R ^3h ) Y is NR ^3b And R is ^3a 、R ^3b 、R ^3c 、R ^3d 、R ^3e 、R ^3f 、R ^3g And R ^3h Each of which is H;

(e) L is- (C (R) ^3g )(R ^3h ))(C(R ³ⁱ )(R ^3j ) -and R ^3a 、R ^3c 、R ^3d 、R ^3e 、R ^3f 、R ^3g 、R ^3h 、R ³ⁱ And R ^3j Each of which is H; and

(f) L is-C (R) ^3g )(R ^3h ) Y is NR ^3b And R is ^3a 、R ^3b 、R ^3c 、R ^3d 、R ^3e 、R ^3f 、R ^3g 、R ^3h 、R ³ⁱ And R ^3j Is H.

5. The compound of any one of claims 1 to 4, wherein R ^1a And R is ^1b Each of which is independently selected from H, F, cl, me, CF ₃ And CN.

6. The compound of any one of claims 1 to 5, wherein R ^1a And R is ^1b The same applies.

7. The compound of any one of claims 1 to 6, wherein R ^2a Selected from the group consisting of: - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optional)Substituted 5-oxopyrrolidin-2-yl), - (CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted 5-oxopyrrolidin-2-yl), - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl group ₂ 、-(CH ₂ ) _0-2 NH(CH ₂ ) _0-2 (C ₁ -C ₆ Haloalkyl) - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (C) ₁ -C ₆ Haloalkyl) - (CH) ₂ ) _{0- 2} NH(CH ₂ ) _0-2 (C ₁ -C ₆ Hydroxyalkyl) - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (C ₁ -C ₆ Hydroxyalkyl) - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 C(＝O)O(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 C(＝O)O(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _{0- 2} NH(CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl group ₎ C(＝O)(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 NHC(＝O)(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) C (=O) (C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 NHC(＝O)(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted oxetanyl), - (CH) ₂ ) _{0- 2} N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted oxetanyl), - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted oxacyclopentylalkyl), - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted oxacyclopentylalkyl), - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted oxazolidinyl), - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted oxazolidinyl), - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted cyclobutyl), - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted cyclobutyl), - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted cyclohexyl), - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted cyclohexyl), - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted C) ₅ -C ₆ Cycloalkyl sulfonyl) - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted C) ₅ -C ₆ Cycloalkyl sulfonyl) - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted azetidinyl), - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted azetidinyl), - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted pyrrolidinyl), - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted pyrrolidinyl), - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted piperidinyl), - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted piperidinyl), - (CH) ₂ ) _0-2 (optionally substituted guanidino), - (CH) ₂ ) _0-2 NH(C(CH ₂ ) _2-5 )C(＝O)O(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (C (CH) ₂ ) _2-5 )C(＝O)O(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 NH(CH(C ₁ -C ₃ Alkyl)) C (=o) O (C) ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH (C) ₁ -C ₃ Alkyl)) C (=o) O (C) ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-1 (C ₅ -C ₉ Bridged cycloalkyl) (CH ₂ ) _0-1 C(＝O)O(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-1 (C ₅ -C ₉ Bridged cycloalkyl) (CH ₂ ) _0-1 C(＝O)O(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-1 (CHOH)(CH ₂ ) _0-1 C(＝O)O(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-1 (CHO(C ₁ -C ₆ Alkyl)) (CH ₂ ) _0-1 C(＝O)O(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-1 (CHOH)(CH ₂ ) _0-1 C(＝O)O(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-1 (CHO(C ₁ -C ₆ Alkyl)) (CH ₂ ) _0-1 C(＝O)O(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 (C ₄ -C ₁₀ Bridged heterocycloalkyl) - (CH) ₂ ) _0-2 (optionally substituted azetidinyl), - (CH) ₂ ) _0-2 (optionally substituted pyrrolidinyl), - (CH) ₂ ) _0-2 (optionally substituted piperidinyl), - (CH) ₂ ) _0-2 (optionally substituted morpholinyl), - (CH) ₂ ) _0-2 (optionally substituted piperazinyl), - (CH) ₂ ) _0-2 (optionally substituted piperazin-2-one) C (CH) ₃ )N(C ₁ -C ₆ Alkyl group ₂ 、-(CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (CHF ₂ )、-(CH ₂ ) _0-2 NH(CH ₂ ) _0-2 (CHF ₂ )、-(CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-4 (CH ₂ F)、-(CH ₂ ) _0-2 NH(CH ₂ ) _0-4 (CH ₂ F)、-(CH ₂ ) _{0- 2} NH(CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) C (=o) CH ₃ 、-(CH ₂ ) _0-2 NH(CH ₂ ) _0-2 NHC(＝O)CH ₃ 、-(CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) C (=o) CH ₃ 、-(CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 NHC(＝O)CH ₃ 、-(CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) C ((C (=O) OC) ₁ -C ₆ Alkyl) ((CH) ₂ ) _0-2 O(C ₁ -C ₆ Alkyl)), - (CH) ₂ ) _0-2 NHC((C(＝O)OC ₁ -C ₆ Alkyl) ((CH) ₂ ) _0-2 O(C ₁ -C ₆ Alkyl)), - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) C ((C (=o) OH ((CH) ₂ ) _0-2 O(C ₁ -C ₆ Alkyl)), - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) C ((C (=O) OC) ₁ -C ₆ Alkyl) ((CH) ₂ ) _0-2 OH))、-(CH ₂ ) _0-2 NHC((C(＝O)OH)((CH ₂ ) _0-2 O(C ₁ -C ₆ Alkyl)), - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) C ((C (=o) OH ((CH) ₂ ) _0-2 OH))、-(CH ₂ ) _0-2 NHC((C(＝O)OC ₁ -C ₆ Alkyl) ((CH) ₂ ) _0-2 OH))、-(CH ₂ ) _0-2 NHC((C(＝O)OH((CH ₂ ) _0-2 OH))、-(CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _1-4 N(C ₁ -C ₆ Alkyl group)C(＝O)Me、-(CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _1-4 NHC(＝O)Me、-(CH ₂ ) _0-2 NH(CH ₂ ) _1-4 N(C ₁ -C ₆ Alkyl) C (=o) Me, - (CH ₂ ) _0-2 NH(CH ₂ ) _1-4 NHC(＝O)Me、-(CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _1-5 C(＝O)N(C ₁ -C ₆ Alkyl) (C) ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 NH(CH ₂ ) _1-5 C(＝O)N(C ₁ -C ₆ Alkyl) (C) ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _1-5 C(＝O)NH(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _1-5 C(＝O)NH ₂ 、-(CH ₂ ) _0-2 NH(CH ₂ ) _1-5 C(＝O)NH(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 NH(CH ₂ ) _1-5 C(＝O)NH ₂ 、-(CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted cyclopropyl), - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted cyclopropyl), - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted butyrolactone-2-yl), - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted butyrolactone-2-yl), - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted tetrahydro-4-thiopyranyl), - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted oxazolyl), - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted tetrahydro-4-thiopyranyl), -CH (CH) ₃ )NH(CH ₂ ) _0-2 (optionally substituted piperidinyl), -CH (CH) ₃ )N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted piperidinyl), - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted piperazinyl), and- (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted piperazinyl).

8. The compound of any one of claims 1 to 7, wherein R ^2b Selected from- (CH) ₂ ) _0-2 (optionally substituted 5-oxopyrrolidin-2-yl), - (CH) ₂ ) _0-2 (optionally substituted piperidinyl), - (CH) ₂ ) _0-2 (optionally substituted azetidinyl), - (CH) ₂ ) _0-2 (C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 (C ₁ -C ₆ Haloalkyl) - (CH) ₂ ) _0-2 (C ₁ -C ₆ Hydroxyalkyl) - (CH) ₂ ) _0-2 (optionally substituted cyclopropyl), - (CH) ₂ ) _0-2 (optionally substituted cyclobutyl), - (CH) ₂ ) _0-2 C(＝O)OH、-(CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) CH ₃ ；-(CH ₂ ) _0-2 NHCH ₃ 、-(CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 C(＝O)O(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 C(＝O)O(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 C(＝O)OH、-(CH ₂ ) _0-2 NH(CH ₂ ) _0-2 C(＝O)OH、-(CH ₂ ) _0-2 N(C ₁ -C ₆ Alkyl) (CH ₂ ) _0-2 (optionally substituted 5-oxopyrrolidin-2-yl), - (CH) ₂ ) _0-2 NH(CH ₂ ) _0-2 (optionally substituted 5-oxopyrrolidin-2-yl), - (CH) ₂ ) _0-2 C(＝O)N(C ₁ -C ₆ Alkyl) (C) ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 C(＝O)NH(C ₁ -C ₆ Alkyl) - (CH) ₂ ) _0-2 C(＝O)NH ₂ 、-(CH ₂ ) _0-2 CH(OC ₁ -C ₆ Alkyl) CH ₂ F、-(CH ₂ ) _0-2 CH(OH)CH ₂ F. And- (CH) ₂ ) _0-2 C(＝O)O(C ₁ -C ₆ Alkyl).

9. The compound of any one of claims 1 to 8, wherein R ^2a Selected from the group consisting of:

OR ^c 、

/>

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wherein R is ^a 、R ^b 、R ^c 、R ^d 、R ^e And R ^f Each of which is independently selected from H, C ₁ -C ₃ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Haloalkoxy, and-C (=o) C ₁ -C ₃ Alkyl groups; and is also provided with

R ^g Selected from optionally substituted C ₂ -C ₆ Heteroaryl and optionally substituted phenyl.

10. The compound according to any one of claims 1 to 9, wherein R ^a 、R ^b 、R ^c 、R ^d 、R ^e And R is ^f At least one of them is selected from methyl, isopropyl, and-C (=o) CH ₃ A group of groups.

11. The compound according to any one of claims 1 to 10, wherein R ^a 、R ^b 、R ^c 、R ^d 、R ^e And R ^f At least one of which, if present, is H.

12. The compound according to any one of claims 1 to 11, wherein R ^2b Selected from the group consisting of:

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wherein R is ⁱ 、R ⁱⁱ And R ⁱⁱⁱ Each of which is independently selected from H, C ₁ -C ₃ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Haloalkoxy, and-C (=o) C ₁ -C ₃ Alkyl groups.

13. The compound of any one of claims 1 to 12, wherein R ^1c And R is ^1d Independently selected from the group consisting of:

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wherein:

R ^a1 、R ^a2 、R ^a3 、R ^a4 、R ^a5 、R ^a6 and R ^a7 Each of which is independently selected from H, C ₁ -C ₆ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Haloalkyl, and C ₁ -C ₆ Haloalkoxy groups;

R ^b1 and R is ^b2 Each of which is independently selected from H, C ₁ -C ₃ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₃ Alkoxy, cyano, halogen, C ₁ -C ₃ Haloalkyl, and C ₁ -C ₃ Haloalkoxy groups; and is also provided with

R ^1c Selected from the group consisting of H, C ₁ -C ₃ Alkyl, C ₃ -C ₈ Cycloalkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Haloalkoxy, and C (=o) OH.

14. The compound of any one of claims 1 to 13, wherein R ^1c And R is ^1d Independently selected from the group consisting of:

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15. the compound of any one of claims 1 to 14, selected from the group consisting of:

8- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -3- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4H-pyrido [1,2-a ] pyrimidin-4-one;

8- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -3- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4H-pyrido [1,2-a ] pyrimidin-4-one;

8- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -3- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4H-pyrido [1,2-a ] pyrimidin-4-one;

8- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -3- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4H-pyrido [1,2-a ] pyrimidin-4-one;

8- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4H-pyrido [1,2-a ] pyrimidin-4-one;

8- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4H-pyrido [1,2-a ] pyrimidin-4-one;

8- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4H-pyrido [1,2-a ] pyrimidin-4-one;

8- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -4H-pyrido [1,2-a ] pyrimidin-4-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5 s, 5's) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (2-methoxy-4, 1-phenylene)) bis (methylene)) bis (azanediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 s,5' r) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (2-methoxy-4, 1-phenylene)) bis (methylene)) bis (azanediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 r, 5's) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (2-methoxy-4, 1-phenylene)) bis (methylene)) bis (azanediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 r,5' r) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (2-methoxy-4, 1-phenylene)) bis (methylene)) bis (azanediyl)) bis (methylene)) bis (pyrrolidin-2-one);

n- (1- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-yl) acetamide;

(S) -N- (1- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-yl) acetamide;

(R) -N- (1- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-yl) acetamide;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (((R) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (((R) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5 s, 5's) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (2-fluoro-6-methoxy-4, 1-phenylene)) bis (methylene)) bis (azanediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 s,5' r) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (2-fluoro-6-methoxy-4, 1-phenylene)) bis (methylene)) bis (azanediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 r, 5's) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (2-fluoro-6-methoxy-4, 1-phenylene)) bis (methylene)) bis (azanediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 r,5' r) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (2-fluoro-6-methoxy-4, 1-phenylene)) bis (methylene)) bis (azanediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((4- (3, 3' -dichloro-2 ' - (1-methyl-3- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indol-6-yl) - [4,4' -bipyridin ] -2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3, 3' -dichloro-2 ' - (1-methyl-3- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indol-6-yl) - [4,4' -bipyridin ] -2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3, 3' -dichloro-2 ' - (1-methyl-3- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indol-6-yl) - [4,4' -bipyridin ] -2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3, 3' -dichloro-2 ' - (1-methyl-3- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indol-6-yl) - [4,4' -bipyridin ] -2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(5 s, 5's) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (1-methyl-1H-indol-6, 3-diyl)) bis (methylene)) bis (azetidinediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 s,5' r) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (1-methyl-1H-indol-6, 3-diyl)) bis (methylene)) bis (azetidinediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 r, 5's) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (1-methyl-1H-indol-6, 3-diyl)) bis (methylene)) bis (azetidinediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 r,5' r) -5,5' - ((((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (1-methyl-1H-indol-6, 3-diyl)) bis (methylene)) bis (azetidinediyl)) bis (methylene)) bis (pyrrolidin-2-one);

(S) -5- (((4- (3, 3' -dichloro-2 ' - (1-methyl-3- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) - [4,4' -bipyridin ] -2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3, 3' -dichloro-2 ' - (1-methyl-3- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) - [4,4' -bipyridin ] -2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3, 3' -dichloro-2 ' - (1-methyl-3- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) - [4,4' -bipyridin ] -2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3, 3' -dichloro-2 ' - (1-methyl-3- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) - [4,4' -bipyridin ] -2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one;

(S) -5- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one;

(R) -5- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one;

(R) -5- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-4- (((S) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-4- (((R) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-4- (((S) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-4- (((R) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((5- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -3-methoxypyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((5- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -3-methoxypyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((5- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -3-methoxypyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((5- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -3-methoxypyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -oxetan-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((R) -oxetan-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -oxetan-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((R) -oxetan-2-yl) methyl) amino) methyl) -1H-pyrrolo [3,2-b ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,3' -bipyridyl ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((S) -2-hydroxypropyl) -1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((R) -2-hydroxypropyl) -1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((S) -2-hydroxypropyl) -1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((R) -2-hydroxypropyl) -1-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ e ] [1,4] diazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- ((S) -2-hydroxypropyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- ((R) -2-hydroxypropyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((S) -2-hydroxypropyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((R) -2-hydroxypropyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-indol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-indol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-hydroxyethyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-hydroxyethyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-methoxyethyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-methoxyethyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((methylamino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((methylamino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- ((ethylamino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- ((ethylamino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- ((dimethylamino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- ((dimethylamino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -oxetan-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((R) -oxetan-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -oxetan-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((R) -oxetan-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (((S) -2-hydroxypropyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3- ((((R) -2-hydroxypropyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (((S) -2-hydroxypropyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (((R) -2-hydroxypropyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-hydroxy-2-methylpropyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-hydroxy-2-methylpropyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one;

(S) -5- ((6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one;

(R) -5- ((6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one;

(R) -5- ((6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- ((isobutylamino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- ((isobutylamino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-hydroxyethyl) (methyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-hydroxyethyl) (methyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (((S) -2-methoxypropyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3- ((((R) -2-methoxypropyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (((S) -2-methoxypropyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3- ((((R) -2-methoxypropyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((((R) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((R) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -5-methoxy-1, 2,3, 4-tetrahydroisoquinolin-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -5-methoxy-1, 2,3, 4-tetrahydroisoquinolin-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -5-methoxy-1, 2,3, 4-tetrahydroisoquinolin-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -5-methoxy-1, 2,3, 4-tetrahydroisoquinolin-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxy-2-methylpropyl) -5-methoxy-1, 2,3, 4-tetrahydroisoquinolin-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxy-2-methylpropyl) -5-methoxy-1, 2,3, 4-tetrahydroisoquinolin-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (2-hydroxy-2-methylpropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (2-hydroxy-2-methylpropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (5-fluoro-2- (2-hydroxy-2-methylpropyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (5-fluoro-2- (2-hydroxy-2-methylpropyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(R) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (3-hydroxy-3-methylbutyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (3-hydroxy-3-methylbutyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (2- (1-hydroxycyclobutyl) ethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (2- (1-hydroxycyclobutyl) ethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (7- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) quinolin-3-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (7- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) quinolin-3-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (7- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) quinolin-3-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (7- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) quinolin-3-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxy-3-methylbutyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxy-3-methylbutyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (3- (((1-acetylazetidin-3-yl) amino) methyl) -1-methyl-1H-indol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (3- (((1-acetylazetidin-3-yl) amino) methyl) -1-methyl-1H-indol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-indol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-indol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (4- (3- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (4- (3- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((((S) -oxetan-2-yl) methyl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((((R) -oxetan-2-yl) methyl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((((S) -oxetan-2-yl) methyl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((((R) -oxetan-2-yl) methyl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (((R) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (((R) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (3- (2- (2- ((1-acetylpiperidin-4-yl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (2- ((1-acetylpiperidin-4-yl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (2- (piperidin-4-yl) ethyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (2- (piperidin-4-yl) ethyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (3-fluoropropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-fluoro-2- (3-fluoropropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

5- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (((R) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (((S) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (((R) -5-oxopyrrolidin-2-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -L-proline isopropyl ester;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -D-proline isopropyl ester;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -L-proline isopropyl ester;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -D-proline isopropyl ester;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- ((S) -2-hydroxypropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- ((R) -2-hydroxypropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- ((S) -2-hydroxypropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- ((R) -2-hydroxypropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4-chloro-6- (2-chloro-3- (3-chloro-2- (4- ((((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4-chloro-6- (2-chloro-3- (3-chloro-2- (4- ((((R) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4-chloro-6- (2-chloro-3- (3-chloro-2- (4- ((((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4-chloro-6- (2-chloro-3- (3-chloro-2- (4- ((((R) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (3-fluoropropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (3-fluoropropyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (((4, 4-difluorocyclohexyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((4, 4-difluorocyclohexyl) amino) methyl) -1-methyl-1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (2- (1-hydroxycyclopropyl) ethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (2- (1-hydroxycyclopropyl) ethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((R) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((R) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid isopropyl ester;

(S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid isopropyl ester;

(R) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid isopropyl ester;

(R) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid isopropyl ester;

(S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid;

(S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid;

(R) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid;

(R) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -L-proline;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -D-proline;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -L-proline;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -D-proline;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((1R, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((1R, 3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((1 s, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((1S, 3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((1 r, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((1S, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((S) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((S) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((R) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((((R) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((isopropylamino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((isopropylamino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((isobutylamino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((isobutylamino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

2- (((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethan-1-ol;

2- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (2- (piperidin-4-yl) ethyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethan-1-ol;

(S) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((1R, 3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((1 s, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((1S, 3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((1 r, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((1R, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((1S, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(S) -2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] oct-7-one;

1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((S) -2-hydroxypropyl) amino) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (((((R) -2-hydroxypropyl) amino) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((((S) -2-hydroxypropyl) amino) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (((((R) -2-hydroxypropyl) amino) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(S) -5- (((4- (4- (3- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (4- (3- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((((S) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((((R) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((((S) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((((R) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- ((methylamino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- ((methylamino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (4- (3- (3- (((1-acetylazetidin-3-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (4- (3- (3- (((1-acetylazetidin-3-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((4, 4-difluorocyclohexyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((4, 4-difluorocyclohexyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((2-hydroxyethyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((2-hydroxyethyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (3- ((((S) -2-hydroxypropyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (3- ((((R) -2-hydroxypropyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (3- ((((S) -2-hydroxypropyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (3- ((((R) -2-hydroxypropyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((2-hydroxy-2-methylpropyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((2-hydroxy-2-methylpropyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((2-methoxyethyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((2-methoxyethyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((2-hydroxyethyl) (methyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (3- (((2-hydroxyethyl) (methyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (((3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(R) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (((3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3-methyl-2- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3-methyl-2- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3-methyl-2- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3-methyl-2- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(S) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) - (4- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) glycine;

(R) - (4- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) glycine;

3-chloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) -2- (4, 5-dihydro-1H-imidazol-2-yl) -3-methoxyphenyl) pyridine;

(S) - (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) glycine;

(R) - (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) glycine;

(S) - (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) glycine isopropyl ester;

(R) - (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) glycine isopropyl ester;

(S) -5- ((((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(R) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((isopropylamino) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(R) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- ((isopropylamino) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(5S) -5- (((6- (2-chloro-3- (3-chloro-2- (5- (((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5S) -5- (((6- (2-chloro-3- (3-chloro-2- (5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5R) -5- (((6- (2-chloro-3- (3-chloro-2- (5- (((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5R) -5- (((6- (2-chloro-3- (3-chloro-2- (5- (((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5S) -5- ((((6- (2-chloro-3- (3-chloro-2- (5- (((S) -2-hydroxypropyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5S) -5- (((6- (2-chloro-3- (3-chloro-2- (5- (((R) -2-hydroxypropyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5R) -5- (((6- (2-chloro-3- (3-chloro-2- (5- (((S) -2-hydroxypropyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(5R) -5- (((6- (2-chloro-3- (3-chloro-2- (5- (((R) -2-hydroxypropyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxy-5-methylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((R) -2-hydroxypropyl) amino) methyl) -3-methoxy-5-methylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxy-5-methylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((R) -2-hydroxypropyl) amino) methyl) -3-methoxy-5-methylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5-methyl-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5-methyl-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5-methyl-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5-methyl-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5-methyl-4- ((methyl (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5-methyl-4- ((methyl (((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5-methyl-4- ((methyl (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5-methyl-4- ((methyl (((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxy-5-methylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((R) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxy-5-methylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxy-5-methylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((R) -2-hydroxypropyl) (methyl) amino) methyl) -3-methoxy-5-methylphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (1- (azetidin-3-yl) -1H-pyrazol-4-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (1- (azetidin-3-yl) -1H-pyrazol-4-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (1- (azetidin-3-ylmethyl) -1H-pyrazol-4-yl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (1- (azetidin-3-ylmethyl) -1H-pyrazol-4-yl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -1- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid;

(R) -1- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((S) -oxetan-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -oxetan-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -oxetan-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -oxetan-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) - (4- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) glycine isopropyl ester;

(R) - (4- (3-chloro-4- (2-chloro-3- (4-chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) glycine isopropyl ester;

(S) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((4-chloro-6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -L-alanine isopropyl ester;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -D-alanine isopropyl ester;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -L-alanine isopropyl ester;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -D-alanine isopropyl ester;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (4- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -L-alanine;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -D-alanine;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -L-alanine;

(4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -D-alanine;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (((1 r,3 r) -3-hydroxycyclobutyl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (((1S, 3S) -3-hydroxycyclobutyl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (((1S, 3 r) -3-hydroxycyclobutyl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (((1 s,3 s) -3-hydroxycyclobutyl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (((1 r,3 r) -3-hydroxycyclobutyl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (((1 s, 3R) -3-hydroxycyclobutyl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (((1R, 3 s) -3-hydroxycyclobutyl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (((1R, 3R) -3-hydroxycyclobutyl) methyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -1- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid isopropyl ester;

(R) -1- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid isopropyl ester;

1- (6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine;

1- (6- (2-chloro-3- (3-chloro-2- (4- ((dimethylamino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N, N-dimethylamine;

2- (((6- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxyethyl) (methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) ethan-1-ol;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indol-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indol-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

5- (3-chloro-4- (2-chloro-3- (5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3- (5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3- (5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3- (5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

(S) -5- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (2- (((5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

(R) -5- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (2- (((5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

(S) -5- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (2- (((5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

(R) -5- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (2- (((5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

(S) -2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-fluoro-6-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-fluoro-6-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- (((3-fluoropropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- (((3-fluoropropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

methyl (S) -2- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) acetate;

methyl (R) -2- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) acetate;

(S) -2- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) acetic acid;

(R) -2- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) acetic acid;

(S) -5- (((6- (3- (2- (2- ((1R, 3S, 4S) -2-azabicyclo [2.2.1] heptan-3-yl) -1H-benzo [ d ] imidazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (3- (2- (2- ((1R, 3S, 4S) -2-azabicyclo [2.2.1] heptan-3-yl) -1H-benzo [ d ] imidazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (3- (2- (2- ((1R, 3R, 4S) -2-azabicyclo [2.2.1] heptan-3-yl) -1H-benzo [ d ] imidazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (3- (2- (2- ((1R, 3R, 4S) -2-azabicyclo [2.2.1] heptan-3-yl) -1H-benzo [ d ] imidazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (3- (2- (2- ((1S, 3S,4 r) -2-azabicyclo [2.2.1] heptan-3-yl) -1H-benzo [ d ] imidazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (3- (2- (2- ((1 s,3s, 4R) -2-azabicyclo [2.2.1] heptan-3-yl) -1H-benzo [ d ] imidazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (3- (2- (2- ((1S, 3r,4 r) -2-azabicyclo [2.2.1] heptan-3-yl) -1H-benzo [ d ] imidazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (3- (2- (2- ((1 s,3R, 4R) -2-azabicyclo [2.2.1] heptan-3-yl) -1H-benzo [ d ] imidazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- (((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -5-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (6- (2-chloro-3- (3-chloro-2- (3-methoxy-5- ((methylamino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine;

chloro-3- (3-chloro-2- (3- (((2-hydroxyethyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethan-1-ol;

(S) -1- (((6- (2-chloro-3- (3-chloro-2- (3- (((S) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(S) -1- (((6- (2-chloro-3- (3-chloro-2- (3- ((((R) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (2-chloro-3- (3-chloro-2- (3- ((((S) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (2-chloro-3- (3-chloro-2- (3- ((((R) -2-hydroxypropyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(S) -5- ((((3 ' -chloro-2 ' - ((S) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((S) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((R) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((S) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((R) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((S) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((R) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((R) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (((6- (((S) -4- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((S) -4- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -4- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -4- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

methyl 1- (((6- (((S) -4- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylate;

methyl 1- (((6- (((S) -4- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylate;

methyl 1- (((6- (((R) -4- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylate;

methyl 1- (((6- (((R) -4- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylate;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indol-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxyethyl) -5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indol-7-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine;

2- (((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethan-1-ol;

(S) -1- (((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) piperidin-1-yl) ethan-1-one;

1- (((6- (((S) -4- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((S) -4- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -4- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -4- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

(S) -5- ((((3 ' -chloro-2 ' - ((S) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((S) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((R) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((R) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((R) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((S) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((S) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((R) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -4- ((3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) amino) -3-hydroxybutyric acid;

(R) -4- ((3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) amino) -3-hydroxybutyric acid;

3- ((3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) amino) propanoic acid;

(S) -1- (3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) pyrrolidine-3-carboxylic acid;

(R) -1- (3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) pyrrolidine-3-carboxylic acid;

2- (1- (3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) azetidin-3-yl) acetic acid;

2- (3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) -2-azaspiro [3.3] heptane-6-carboxylic acid;

3- ((3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) amino) bicyclo [1.1.1] pentane-1-carboxylic acid;

3- (((3- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -5-methoxybenzyl) amino) methyl) bicyclo [1.1.1] pentane-1-carboxylic acid;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -4-fluoro-2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] sulfan-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] sulfan-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

5- (3-chloro-4- (2-chloro-3- (4-fluoro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3- (4-fluoro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3- (4-fluoro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3- (4-fluoro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4, 5-dihydro-1H-imidazol-2-yl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (4, 5-dihydro-1H-imidazol-2-yl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -4- ((4- (3-chloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) amino) -3-hydroxybutyric acid;

(R) -4- ((4- (3-chloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) amino) -3-hydroxybutyric acid;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((S) -oxetan-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((R) -oxetan-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((S) -oxetan-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((S) -oxetan-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2,1-f ] [1,2,4] triazin-2-yl) methyl) azetidine-3-carboxylic acid methyl ester;

(R) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -3-methyl-4-oxo-3, 4-dihydropyrrolo [2,1-f ] [1,2,4] triazin-2-yl) methyl) azetidine-3-carboxylic acid methyl ester;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- ((S) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- ((S) -5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- ((S) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (((6- (((S) -5- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((S) -5- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

(S) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

2- ((6- (((S) -5- (3 ' -chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((S) -5- (3 ' -chloro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3 ' -chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3 ' -chloro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -N- (5- (3 ' -chloro-6-methoxy-5- ((methylamino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine;

(R) -N- (5- (3 ' -chloro-6-methoxy-5- ((methylamino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine;

1- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

(S) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -5- (3-chloro-2- (3-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -5- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

2- ((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -N- (5- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine;

(R) -N- (5- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine;

1- (((6- (((S) -5- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((S) -5- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

(S) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

2- ((6- (((S) -5- (3 ' -chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((S) -5- (3 ' -chloro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((S) -5- (3 ' -chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3 ' -chloro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -1- (3 ' -chloro-6-methoxy-2 ' - (5- ((6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) -N-methyl methylamine;

(R) -1- (3 ' -chloro-6-methoxy-2 ' - (5- ((6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) -N-methyl methylamine;

1- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

(S) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -5- (3-chloro-2- (3-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -5- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

2- ((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -1- (6- ((5- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) -N-methyl methylamine;

(R) -1- (6- ((5- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) -N-methyl methylamine;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (8-chloro-6- ((((S) -2-hydroxypropyl) amino) methyl) -5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (8-chloro-6- ((((R) -2-hydroxypropyl) amino) methyl) -5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (8-chloro-6- ((((S) -2-hydroxypropyl) amino) methyl) -5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (8-chloro-6- ((((R) -2-hydroxypropyl) amino) methyl) -5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((8-chloro-2- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5-methoxyquinolin-6-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((8-chloro-2- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5-methoxyquinolin-6-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((8-chloro-2- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5-methoxyquinolin-6-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((8-chloro-2- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5-methoxyquinolin-6-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (3-hydroxy-3-methylbutyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (3-hydroxy-3-methylbutyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -4- ((4- (3-chloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) amino) -3-hydroxybutyric acid isopropyl ester;

(R) -4- ((4- (3-chloro-4- (2-chloro-3- (5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) amino) -3-hydroxybutyric acid isopropyl ester;

(S) -5- (((6- (3- (2- (4- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (4- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

n- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) propan-2-amine;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -1- (((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(S) -1- (((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(1 r,3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3R) -3- (((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r, 3S) -3- (((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1S, 3S) -3- (((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 s) -3- (((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s, 3R) -3- (((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1S, 3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (2- ((S) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3 s) -3- (((6- (2-chloro-3- (3-chloro-2- (2- ((R) -2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(S) -1- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol;

(S) -1- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol;

(R) -1- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol;

(R) -1- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -tetrahydrofuranyl-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol;

(S) -1- ((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -3-methylazetidin-3-ol;

(R) -1- ((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -3-methylazetidin-3-ol;

(S) - ((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) glycine methyl ester;

(R) - ((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) glycine methyl ester;

(S) -2- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) -3-hydroxybutyric acid;

(R) -4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) -3-hydroxybutyric acid;

3- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) propanoic acid;

6- (3-chloro-4- (2-chloro-3- (5- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -N- (4- (3 ' -chloro-6-methoxy-5- ((methylamino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine;

(R) -N- (4- (3 ' -chloro-6-methoxy-5- ((methylamino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine;

(1S, 3 r) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1 r, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3R) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1R, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3R) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1R, 3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3R) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1 s, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3R) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 r) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 r) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1 r, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 r) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1S, 3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 r) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1S, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3 s) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1R, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3 s) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1R, 3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3 s) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1 s, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3 s) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1R, 3R) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1R, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r, 3S) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1 r, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r, 3S) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1S, 3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r, 3S) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1S, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s, 3R) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1R, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s, 3R) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1R, 3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s, 3R) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1 s, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s, 3R) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1S, 3 r) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1S, 3 r) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1S, 3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1S, 3 r) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1S, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 s) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1R, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 s) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1R, 3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 s) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1 s, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 s) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s, 3R) -3- (((3 ' -chloro-2 ' - ((R) -1- ((5- ((((1R, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1S, 3S) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1 r, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1S, 3S) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1S, 3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1S, 3S) -3- (((3 ' -chloro-2 ' - ((S) -1- ((5- ((((1S, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid;

(R) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -2-azaspiro [3.3] heptane-6-carboxylic acid;

3- (((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) bicyclo [1.1.1] pentane-1-carboxylic acid;

(S) - ((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) glycine;

(R) - ((6- (2-chloro-3- (3-chloro-2- (2- (2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) glycine;

2- ((6- (2-chloro-3- (3-chloro-2- (isoindolin-5-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

6- (3-chloro-4- (2-chloro-3- (5- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (5- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (5- ((((1 r,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (5- ((((1 s,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (5- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (5- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (5- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (5- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

6- (3-chloro-4- (2-chloro-3- (5- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methylpyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -oxetan-2-yl) methyl) amino) methyl) -1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- (((((R) -oxetan-2-yl) methyl) amino) methyl) -1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((S) -oxetan-2-yl) methyl) amino) methyl) -1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((((R) -oxetan-2-yl) methyl) amino) methyl) -1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((8-chloro-2- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5-methoxyquinolin-6-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((8-chloro-2- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5-methoxyquinolin-6-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((8-chloro-2- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5-methoxyquinolin-6-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((8-chloro-2- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5-methoxyquinolin-6-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (3- (2- (4- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (4- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- (2-chloro-3- (8-chloro-6- (((2-hydroxyethyl) amino) methyl) -5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- (2-chloro-3- (8-chloro-6- (((2-hydroxyethyl) amino) methyl) -5-methoxyquinolin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -1- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) pyrrolidine-3-carboxylic acid;

(R) -1- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) pyrrolidine-3-carboxylic acid;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -5- (((4- (4- (3- (6- (((1-acetylpiperidin-4-yl) amino) methyl) -8-chloro-5-methoxyquinolin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (4- (3- (6- (((1-acetylpiperidin-4-yl) amino) methyl) -8-chloro-5-methoxyquinolin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

5- (3-chloro-4- (2-chloro-3 '-fluoro-5' -methoxy-4 '- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,1' -biphenyl ] -3-yl) pyridin-2-yl) -2- (2- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3 '-fluoro-5' -methoxy-4 '- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,1' -biphenyl ] -3-yl) pyridin-2-yl) -2- (2- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3 '-fluoro-5' -methoxy-4 '- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,1' -biphenyl ] -3-yl) pyridin-2-yl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

5- (3-chloro-4- (2-chloro-3 '-fluoro-5' -methoxy-4 '- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,1' -biphenyl ] -3-yl) pyridin-2-yl) -2- (2- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) isoindolin-1-one;

2- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2-azaspiro [3.3] heptane-6-carboxylic acid;

2- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -1- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) pyrrolidine-3-carboxylic acid isopropyl ester;

(R) -1- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) pyrrolidine-3-carboxylic acid isopropyl ester;

1- (4- ((4- (4- (3- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-hydroxyethyl) (methyl) amino) methyl) -1-methyl-1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (3- (((2-hydroxyethyl) (methyl) amino) methyl) -1-methyl-1H-indazol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -1- (6- ((6- ((4- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

(R) -1- (6- ((6- ((4- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

1- (6- ((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

2- ((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

n- ((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2-oxaspiro [3.3] heptane-6-amine;

(1- ((((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoropropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) cyclopropyl) methanol;

(S) -1- (((3 ' -chloro-2 ' - ((S) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) propan-2-ol;

(S) -1- (((3 ' -chloro-2 ' - ((R) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) propan-2-ol;

(S) -1- (((3 ' -chloro-2 ' - ((R) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) propan-2-ol;

(S) -1- (((3 ' -chloro-2 ' - ((S) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) propan-2-ol;

(R) -1- (((3 ' -chloro-2 ' - ((R) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) propan-2-ol;

(R) -1- (((3 ' -chloro-2 ' - ((R) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) propan-2-ol;

(R) -1- (((3 ' -chloro-2 ' - ((S) -1- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) propan-2-ol;

(R) -1- (((3 ' -chloro-2 ' - ((S) -1- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) propan-2-ol;

(S) -1- (4- (((6- ((4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(R) -1- (4- (((6- ((4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- ((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- ((S) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- ((S) -5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -5- ((((R) -6- (3-chloro-4- (2-chloro-3- (5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((R) -6- (3-chloro-4- (2-chloro-3- (5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((S) -6- (3-chloro-4- (2-chloro-3- (5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((S) -6- (3-chloro-4- (2-chloro-3- (5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((R) -6- (3-chloro-4- (2-chloro-3- (5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((R) -6- (3-chloro-4- (2-chloro-3- (5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((S) -6- (3-chloro-4- (2-chloro-3- (5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((S) -6- (3-chloro-4- (2-chloro-3- (5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((R) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((R) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((R) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((R) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((R) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((R) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((S) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((((1S, 4S) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((((1S, 4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r, 4S) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((((1R, 4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s, 4R) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((((1R, 4R) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) azetidine-3-carboxylic acid;

(R) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) azetidine-3-carboxylic acid;

(S) -1- (2- (((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) ethyl) cyclopropane-1-carboxylic acid;

(R) -1- (2- (((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) ethyl) cyclopropane-1-carboxylic acid;

1- (4- (((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- ((4- (4- (3- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -L-homoserine;

((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -L-homoserine;

((6- (2-chloro-3- (3-chloro-2- ((S) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -L-homoserine;

((6- (2-chloro-3- (3-chloro-2- ((S) -5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -L-homoserine;

((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -D-homoserine;

((6- (2-chloro-3- (3-chloro-2- ((S) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -D-homoserine;

((6- (2-chloro-3- (3-chloro-2- ((S) -5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -D-homoserine;

((6- (2-chloro-3- (3-chloro-2- ((R) -5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -D-homoserine;

(5 s, 5's) -5,5' - ((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (8-methoxy-3, 4-dihydroisoquinoline-6, 2 (1H) -diyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 s,5' r) -5,5' - ((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (8-methoxy-3, 4-dihydroisoquinoline-6, 2 (1H) -diyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 r, 5's) -5,5' - ((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (8-methoxy-3, 4-dihydroisoquinoline-6, 2 (1H) -diyl)) bis (methylene)) bis (pyrrolidin-2-one);

(5 r,5' r) -5,5' - ((3, 3' -dichloro- [4,4' -bipyridine ] -2,2' -diyl) bis (8-methoxy-3, 4-dihydroisoquinoline-6, 2 (1H) -diyl)) bis (methylene)) bis (pyrrolidin-2-one);

((3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) -5' -methoxy- [2,3' -bipyridin ] -6' -yl) methyl) -L-homoserine methyl ester;

((3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) -5' -methoxy- [2,3' -bipyridin ] -6' -yl) methyl) -L-homoserine methyl ester;

((3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) -5' -methoxy- [2,3' -bipyridin ] -6' -yl) methyl) -D-homoserine methyl ester;

((3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) -5' -methoxy- [2,3' -bipyridin ] -6' -yl) methyl) -D-homoserine methyl ester;

(S) -5- (((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((((S) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((((R) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((((S) -2-oxotetrahydrofuranyl-3-yl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((((R) -2-oxotetrahydrofuran-3-yl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (((S) -4- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (((S) -4- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (((R) -4- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (((S) -4- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -4- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -4- (3-chloro-2- (3-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((R) -4- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -4- (3-chloro-2- (3-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -1- (((6- (((S) -4- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) propan-2-ol;

(S) -1- (((6- (((S) -4- (3-chloro-2- (4- (((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) propan-2-ol;

(S) -1- (((6- (((R) -4- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) propan-2-ol;

(S) -1- (((6- (((R) -4- (3-chloro-2- (4- (((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (((S) -4- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (((S) -4- (3-chloro-2- (4- (((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (((R) -4- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (((R) -4- (3-chloro-2- (4- (((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) propan-2-ol;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -3- (6- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propionic acid methyl ester;

(R) -methyl 3- (6- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propanoate;

methyl 3- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propanoate;

(S) -1- (((6- (2-chloro-3- (2- (4- ((((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(S) -1- (((6- (2-chloro-3- (2- (4- ((((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (2-chloro-3- (2- (4- ((((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (2-chloro-3- (2- (4- ((((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(S) -2- (6- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) acetamide;

(R) -2- (6- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) acetamide;

1- (6- (2-chloro-3- (3-chloro-2- (1-methyl-3- ((methylamino) methyl) -1H-indol-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine;

1- (4- (((6- (3- (2- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-indol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid isopropyl ester;

(R) -1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid isopropyl ester;

Isopropyl 3- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) propionate;

(S) -4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) -3-hydroxybutyric acid isopropyl ester;

(R) -4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) -3-hydroxybutyric acid isopropyl ester;

isopropyl 2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -2-azaspiro [3.3] heptane-6-carboxylate;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-fluorophenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((methylamino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine;

2- ((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methylamine;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-fluoro-6-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one;

(S) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-indazol-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-indazol-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -5- (((6- (3- (2- (2- ((1-acetylpiperidin-4-yl) methyl) -8-chloro-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (2- ((1-acetylpiperidin-4-yl) methyl) -8-chloro-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) -1, 2-dihydro-3H-pyrrolo [3,4-c ] pyridin-3-one;

6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2- (2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) -1, 2-dihydro-3H-pyrrolo [3,4-c ] pyridin-3-one;

6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2- (2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) -1, 2-dihydro-3H-pyrrolo [3,4-c ] pyridin-3-one;

6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2- (2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) ethyl) -1, 2-dihydro-3H-pyrrolo [3,4-c ] pyridin-3-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) imidazo [1,2-a ] pyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) imidazo [1,2-a ] pyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) imidazo [1,2-a ] pyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) imidazo [1,2-a ] pyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -2- (4- (3-chloro-4- (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one;

(R) -2- (4- (3-chloro-4- (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one;

(S) -3- (6- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propionic acid;

(R) -3- (6- (3-chloro-4- (2-chloro-3- (5- (((2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propionic acid;

3- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) propionic acid;

1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) cyclopropane-1-carboxylic acid methyl ester;

2- ((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoro-2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -2- ((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoro-2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- ((6- (2-chloro-3- (3-chloro-2- (2- (3-fluoro-2-hydroxypropyl) -8-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) cyclopropane-1-carboxylic acid;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

1, 1-dioxo 4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) tetrahydro-2H-thiopyran;

1- (3- (((6- (3- (2- (4- (((1-acetylazetidin-3-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) azetidin-1-one;

(S) -1- (((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(S) -1- (((6- (2-chloro-3- (3-chloro-2- (4- (((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (2-chloro-3- (3-chloro-2- (4- (((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

2- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((5-oxo-6-azaspiro [3.4] oct-2-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) -6-azaspiro [3.4] octan-5-one;

1- (2- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((2- (2-oxopyrrolidin-1-yl) ethyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethyl) pyrrolidin-2-one;

(S) -2- ((3 ' -chloro-6-methoxy-2 ' - (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one;

(R) -2- ((3 ' -chloro-6-methoxy-2 ' - (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one;

(S) -1- (6- ((5- ((4- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxy-6- (trifluoromethyl) pyrazin-2-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

(R) -1- (6- ((5- ((4- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxy-6- (trifluoromethyl) pyrazin-2-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

(S) -2- (4- (3-chloro-4- (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-2-yl) -2-fluoro-6-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one;

(R) -2- (4- (3-chloro-4- (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-2-yl) -2-fluoro-6-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (oxetan-3-ylmethyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (8-chloro-2- (oxetan-3-ylmethyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (3- (2- (3- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (3- (2- (3- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -1-methyl-1H-indazol-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-indazol-3-yl) methyl) pyrrolidine-3-carboxylic acid;

(S) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-indazol-3-yl) methyl) pyrrolidine-3-carboxylic acid;

(R) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-indazol-3-yl) methyl) pyrrolidine-3-carboxylic acid;

(R) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-indazol-3-yl) methyl) pyrrolidine-3-carboxylic acid;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) imidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) imidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) imidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) imidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

1- (4- (((5- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -3-methoxypyrazin-2-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1S, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1S, 3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1R, 3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1R, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1,1'- ((((3, 3' -dichloro- [4,4 '-bipyridine ] -2,2' -diyl) bis (2-fluoro-6-methoxy-4, 1-phenylene)) bis (methylene)) bis (azanediyl)) bis (piperidin-4, 1-diyl)) bis (ethane-1-one);

(S) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (cyclopropanecarbonyl) piperidin-4-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (cyclopropyl) methanone;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (2- (((1-acetylpiperidin-4-yl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (2- (((1-acetylpiperidin-4-yl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (3- (2- (2- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (2- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) -2, 5-diazaspiro [3.4] octan-6-one;

(R) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) -2, 5-diazaspiro [3.4] octan-6-one;

(S) -5- ((((6- (3- (2- (2- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (2- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

n- (1- ((6- (3- (2- (4- ((4-acetamidopiperidin-1-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

2,2'- ((3, 3' -dichloro- [4,4 '-bipyridine ] -2,2' -diyl) bis (2-fluoro-6-methoxy-4, 1-phenylene)) bis (methylene)) bis (2, 6-diazaspiro [3.4] octan-7-one);

2- (4- (4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) -3-fluoropyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

n- (1- (4- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) piperidin-4-yl) acetamide;

n- ((6- (2-chloro-3- (3-chloro-2- (4- (((1-isopropylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1-isopropylpiperidin-4-amine;

n- ((6- (2-chloro-3- (3-chloro-2- (4- (((4, 4-difluorocyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4, 4-difluorocyclohexane-1-amine;

2- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (2-hydroxyethyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-ol;

n- (2- (((6- (3- (2- (4- (((2-acetamidoethyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) ethyl) acetamide;

1- (6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((tetrahydro-2H-pyran-4-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N- ((tetrahydro-2H-pyran-4-yl) methyl) methylamine;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((1-propionylpiperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

2- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (4- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) piperidin-1-yl) ethan-1-one;

1- (6- (2-chloro-3- (2- (3-methoxy-4- ((methylamino) methyl) phenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N-methylamine;

(S) -5- ((((6- (3- (2- (4- ((S) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (4- ((S) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3- (2- (4- ((R) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3- (2- (4- ((R) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -2- ((3 ' -chloro-6-methoxy-2 ' - (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one;

(R) -2- ((3 ' -chloro-6-methoxy-2 ' - (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-fluoropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -4- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) dihydrofuran-2 (3H) -one;

(R) -4- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) dihydrofuran-2 (3H) -one;

(S) -3- ((methyl 4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) -4-hydroxybutyrate;

(R) -3- ((methyl 4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) -4-hydroxybutyrate;

(S) -3- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) dihydrofuran-2 (3H) -one;

(R) -3- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) dihydrofuran-2 (3H) -one;

n- (1- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

(S) -3- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) -4-hydroxybutyric acid;

(R) -3- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) -4-hydroxybutyric acid;

(4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -L-homoserine;

(4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -D-homoserine;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1-propionylpiperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) propan-1-one;

(4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (cyclopropanecarbonyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (cyclopropyl) methanone;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1-isobutyrylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methylpropan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-fluoro-4- (((1-isobutyrylpiperidin-4-yl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methylpropan-1-one;

n- ((6- (2-chloro-3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

1, 1-dioxo 4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -3-fluoro-5-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) tetrahydro-2H-thiopyran;

(S) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) azetidine-3-carboxylic acid;

(R) -1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) azetidine-3-carboxylic acid;

(S) -1- (2- (((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) amino) ethyl) cyclopropane-1-carboxylic acid;

(R) -1- (2- (((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) amino) ethyl) cyclopropane-1-carboxylic acid;

(4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (cyclobutanecarbonyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (cyclobutyl) methanone;

7- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((2-oxo-1, 7-diazaspiro [3.5] nonan-7-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -1, 7-diazaspiro [3.5] nonan-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

n- (1- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

(R) -N- (1- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

(S) -N- (1- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

(S) -N- (1- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

(R) -N- (1- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

n- (3- (((6- (3- (2- (4- (((3-acetamidopropyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) propyl) acetamide;

4- (((6- (2-chloro-3- (3-chloro-2- (4- (((2, 6-dioxopiperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidine-2, 6-dione;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (2-methoxy-4- (4- (3- (6-methoxy-5- ((methylamino) methyl) pyridin-2-yl) -2-methylphenyl) -3-methylpyridin-2-yl) phenyl) -N-methylamine;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

n- (4- (4- (3- (5- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2-oxaspiro [3.3] heptan-6-amine;

(S) -2- (4- (3-chloro-4- (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one;

(R) -2- (4- (3-chloro-4- (1- ((6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one;

(S) -1- (6- ((5- ((4- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxy-6- (trifluoromethyl) pyrazin-2-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

(R) -1- (6- ((5- ((4- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2, 3-dihydro-1H-inden-1-yl) amino) -3-methoxy-6- (trifluoromethyl) pyrazin-2-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

2- (4- (4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) -3-methylpyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1R, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1R, 3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s, 3R) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1S, 3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1S, 3S) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

1- (4- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) piperidin-1-yl) -2-methylpropan-1-one;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (methylsulfonyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (methylsulfonyl) piperidin-4-amine;

5- (((6- (3- (2- (4- (((5-amino-5-oxopentyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) pentanoylalkane;

1- ((R) -3- (((6- (3- (2- (4- ((((R) -1-acetylpyrrolidin-3-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-1-yl) ethan-1-one;

1- ((S) -3- (((6- (3- (2- (4- ((((R) -1-acetylpyrrolidin-3-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-1-yl) ethan-1-one;

1- ((R) -3- (((6- (3- (2- (4- ((((S) -1-acetylpyrrolidin-3-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-1-yl) ethan-1-one;

1- ((S) -3- (((6- (3- (2- (4- ((((S) -1-acetylpyrrolidin-3-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-1-yl) ethan-1-one;

1- (4- (((6- (3- (6 ' - ((1-acetylpiperidin-4-yl) amino) methyl) -3-chloro-5 ' -methoxy- [2,3' -bipyridin ] -4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- ((3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) -5' -methoxy- [2,3' -bipyridin ] -6' -yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -N- (1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-3-yl) methyl) piperidin-4-yl) acetamide;

(R) -N- (1- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-3-yl) methyl) piperidin-4-yl) acetamide;

(S) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (4- (((6- (3- (2- (4- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (3- (2- (4- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((3, 3-dimethylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methylpropan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (methylsulfonyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1R, 4R) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1R, 4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s, 4R) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r, 4S) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1S, 4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1S, 4S) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(1 r,3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 s) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 s) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 s) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 r,3 s) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 r) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 s) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 s) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 s) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

(1 s,3 s) -3- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylcyclobutan-1-ol;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2-azaspiro [3.3] heptan-6-ol;

6- (4- (4- (3- (5- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2-oxa-6-azaspiro [3.3] heptane;

(S) -1- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) pyrrolidine-3-carboxylic acid;

(R) -1- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) pyrrolidine-3-carboxylic acid;

3- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) propanoic acid;

3- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) propanoic acid;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -1- (6- (3- (2- (4- ((S) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethan-1-amine;

(R) -1- (6- (3- (2- (4- ((S) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethan-1-amine;

(S) -1- (6- (3- (2- (4- ((R) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethan-1-amine;

(R) -1- (6- (3- (2- (4- ((R) -1-aminoethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethan-1-amine;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3- (difluoromethoxy) phenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (6- (3- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine;

1- ((6- (2-chloro-3- (3-chloro-2- (4- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -3-methylazetidin-3-ol;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (2-methoxyacetyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methoxyethan-1-one;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6-oxo-2, 5-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2, 5-diazaspiro [3.4] oct-6-one;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

N- (1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) piperidin-4-yl) acetamide;

n- (1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6-oxo-2, 5-diazaspiro [3.4] octane-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) piperidin-4-yl) acetamide;

n- (1- (4- (4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) piperidin-4-yl) acetamide;

(S) -N- (1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) piperidin-4-yl) acetamide;

(R) -N- (1- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) piperidin-4-yl) acetamide;

2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) nicotinonitrile;

(S) -4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-3-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-3-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-3-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-3-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- (((6- (3- (2- (4- ((4-amino-4-methylpiperidin-1-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -4- (((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) methyl) pyrrolidin-2-one;

(R) -4- (((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) methyl) pyrrolidin-2-one;

2- (4- (3-chloro-4- (3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) -2-methylphenyl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

4- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (morpholinomethyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) morpholine;

1- ((6- (2-chloro-3- (3-chloro-2- (4- ((4-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-ol;

1- (4- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) piperidin-1-yl) -2-methoxyethan-1-one;

(S) -5- (((6- (2-chloro-3- (2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (2- (3-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

2- (2-methoxy-4- (4- (3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) -2-methylphenyl) -3-methylpyridin-2-yl) benzyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((piperidin-4-ylamino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1-methyl-2-oxopiperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylpiperidin-2-one;

4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (dimethylcarbamoyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -N, N-dimethylpiperidine-1-carboxamide;

N- ((6- (2-chloro-3- (3-chloro-2- (4- (((1- (2, 2-difluoroethyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (2, 2-difluoroethyl) piperidin-4-amine;

(4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (furan-2-carbonyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (furan-2-yl) methanone;

(4- (((6- (3- (2- (4- (((1-benzoylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (phenyl) methanone;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1-phenylpiperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1-phenylpiperidin-4-amine;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (pyridin-4-yl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (pyridin-4-yl) piperidin-4-amine;

n- (2-methoxy-4- (4- (3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) -2-methylphenyl) -3-methylpyridin-2-yl) benzyl) tetrahydro-2H-pyran-4-amine;

N- ((6- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (6- ((6- (3- (6 ' - ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-chloro-5 ' -methoxy- [2,3' -bipyridin ] -4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

n- ((4- (3- (5- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloro-5 ' -methoxy- [2,3' -bipyridin ] -6' -yl) methyl) -2-oxaspiro [3.3] heptan-6-amine;

2- ((3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6-oxo-2, 5-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) -5' -methoxy- [2,3' -bipyridin ] -6' -yl) methyl) -2, 5-diazaspiro [3.4] octan-6-one;

n- ((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

N- (1- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

4- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) -2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) nicotinonitrile;

4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) -2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) nicotinonitrile;

(S) -1- ((6- (2-chloro-3- (3-chloro-2- (4- (((S) -3-hydroxypyrrolidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) pyrrolidin-3-ol;

(S) -1- ((6- (2-chloro-3- (3-chloro-2- (4- (((R) -3-hydroxypyrrolidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) pyrrolidin-3-ol;

(R) -1- ((6- (2-chloro-3- (3-chloro-2- (4- (((S) -3-hydroxypyrrolidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) pyrrolidin-3-ol;

(R) -1- ((6- (2-chloro-3- (3-chloro-2- (4- (((R) -3-hydroxypyrrolidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) pyrrolidin-3-ol;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((methyl (tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (2, 2-trifluoroethyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (2, 2-trifluoroethyl) piperidin-4-amine;

2- (4- (3-chloro-4- (2-fluoro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] oct-7-one;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-fluorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

n- ((6- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-fluorophenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

n- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -N-methyltetrahydro-2H-pyran-4-amine;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) (methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (2-hydroxyacetyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-hydroxyethan-1-one;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (pyridin-2-yl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (pyridin-2-yl) piperidin-4-amine;

n- ((6- (2-chloro-3- (3-chloro-2- (4- (((1- (3-chloropyridin-2-yl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -1- (3-chloropyridin-2-yl) piperidin-4-amine;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((2-methoxyethyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2-methoxyethane-1-amine;

3-chloro-4- (2-chloro-3- (6-methoxy-5- ((4-methoxypiperidin-1-yl) methyl) pyridin-2-yl) phenyl) -2- (3-methoxy-4- ((4-methoxypiperidin-1-yl) methyl) phenyl) pyridine;

(1 s,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-fluoropyridin-4-yl) -2-fluorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(1 r,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 r,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 r) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 r,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 r) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

(1 s,4 s) -N- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((1 s,4 s) -4-methoxycyclohexyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -4-methoxycyclohexane-1-amine;

2- (4- (3-fluoro-4- (2-fluoro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] oct-7-one;

n- ((6- (2-fluoro-3- (3-fluoro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

2- ((6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6-oxo-2, 5-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) -2, 5-diazaspiro [3.4] octan-6-one;

1- ((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -3-methylazetidin-3-ol;

(4- (((6- (2-chloro-3- (3-chloro-2- (4- (((1- (cyclohexanecarbonyl) piperidin-4-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) (cyclohexyl) methanone;

4- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((3-oxopiperazin-1-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) piperazin-2-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (morpholinomethyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((4-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) - (2- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxy-4-oxopyrrolo [2,1-f ] [1,2,4] triazin-3 (4H) -yl) ethyl) glycine;

(R) - (2- (6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxy-4-oxopyrrolo [2,1-f ] [1,2,4] triazin-3 (4H) -yl) ethyl) glycine;

n- (1- ((6- (3- (2- (4- ((4-acetamidopiperidin-1-yl) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

N- ((6- (2-chloro-3- (2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

(1 r,4 r) -4- (((6- (2-chloro-3- (2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (2-chloro-3- (2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (2-chloro-3- (2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (2-chloro-3- (2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (2-chloro-3- (2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

6- (4- (4- (3- (5- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-methylpyridin-2-yl) -2-methoxyphenylmethyl) -2-oxa-6-azaspiro [3.3] heptane;

4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (methoxycarbonyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidine-1-carboxylic acid methyl ester;

n- (1- ((6- (3- (2- (4- ((4-acetamidopiperidin-1-yl) methyl) -3-methoxyphenyl) -3-methylpyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

n- (1- ((6- (3- (2- (4- ((4-acetamidopiperidin-1-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) acetamide;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -N-methyltetrahydro-2H-pyran-4-amine;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) piperidin-1-yl) ethan-1-one;

2- (4- (4- (3- (5- ((7-oxa-2-azaspiro [3.5] nonan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -7-oxa-2-azaspiro [3.5] nonane;

2- (1- ((6- (2-chloro-3- (3-chloro-2- (4- ((3- (2-hydroxypropane-2-yl) azetidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) azetidin-2-ol;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) pyrrolidin-2-one;

(R) -4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (((R) -5-oxopyrrolidin-3-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) pyrrolidin-2-one;

(S) -4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (((R) -5-oxopyrrolidin-3-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) pyrrolidin-2-one;

(R) -4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (((S) -5-oxopyrrolidin-3-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) pyrrolidin-2-one;

(S) -4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methyl (((S) -5-oxopyrrolidin-3-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) pyrrolidin-2-one;

2- ((6- (3-chloro-4- (2-chloro-3- (5- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) -2-azaspiro [3.3] heptan-6-ol;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-methoxy-2- (morpholinomethyl) imidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((3, 3-difluoropyrrolidin-1-yl) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- ((6- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-methoxyimidazo [1,2-a ] pyridin-2-yl) methyl) -3-methylazetidine-3-carbonitrile;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2, 2-difluoroethyl) amino) methyl) -8-methoxyimidazo [1,2-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

4- (2- ((4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) ethyl) piperazin-2-one;

2- (3- (6- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) -2-oxopyrrolidin-1-yl) acetic acid;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methoxyethan-1-one;

1- (4- (((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- ((4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) amino) piperidin-1-yl) ethan-1-one;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-thiopyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-thiopyran-4-amine;

1- (2- ((6- (3- (2- (4- ((7-acetyl-2, 7-diazaspiro [3.5] nonan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 7-diazaspiro [3.5] nonan-7-yl) ethan-1-one;

(S) -5- ((((6- (((S) -4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- ((((6- (((R) -4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((R) -4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (5- ((4-hydroxypiperidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((1 r,4 r) -4-methoxycyclohexyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((1 s,4 r) -4-methoxycyclohexyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((1 r,4 s) -4-methoxycyclohexyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((1 s,4 s) -4-methoxycyclohexyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

(R) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((3-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((3-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((1- (2-methoxyacetyl) piperidin-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (4- (((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methoxyethan-1-one;

1- (6- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

2- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (3- (2- (4- ((2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (4- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (4- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (3- ((((6- (3- (2- (4- (((1-acetylazetidin-3-yl) methyl) (methyl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) (methyl) amino) methyl) azetidin-1-one;

1- (4- (((4- (4 '- ((1-acetylpiperidin-4-yl) amino) methyl) -2-chloro-3' -methoxy- [1,1 '-biphenyl ] -3-yl) -3-chloro-5' -methoxy- [2,3 '-bipyridin ] -6' -yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- ((2 '-chloro-3' - (3-chloro-5 '-methoxy-6' - ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) - [2,3 '-bipyridin ] -4-yl) -3-methoxy- [1,1' -biphenyl ] -4-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1-hydroxycyclopropyl) methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) cyclopropan-1-ol;

n- ((6- (2-chloro-3- (3-chloro-2- (4- (((2, 2-difluoroethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 2-difluoroethane-1-amine;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((3-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(R) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((3-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((4- (hydroxymethyl) piperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((4- (methoxymethyl) piperidin-1-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((4-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methoxyethan-1-one;

1- (6- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1-hydroxycyclopropyl) methyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((2, 2-difluoroethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

n- ((6- (2-chloro-3- (3-chloro-2- (4- ((isopropylamino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) propan-2-amine;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 s,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 r,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (4- (3- (5- ((2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (5- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (4- (((6- (3- (6- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -5-methylpyrimidin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -5- (((6- (2-chloro-3- (6- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -5-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (6- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -5-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (6- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -5-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (6- (3-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -5-methylpyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

n- ((6- (2-chloro-3- (3-chloro-2- (4- ((cyclohexylamino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) cyclohexylamine;

2- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-5-one;

2- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) -2,5, 7-triazaspiro [3.4] octan-6-one;

(S) -5- ((((2 ' - ((S) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((2 ' - ((R) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((2 ' - ((S) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((2 ' - ((R) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

n- ((6- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

n- ((6- (3- (2- (4- ((7-oxa-2-azaspiro [3.5] nonan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

n- (4- (4- (3- (5- ((7-oxa-2-azaspiro [3.5] nonan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) tetrahydro-2H-pyran-4-amine;

(S) -5- ((((6- (3-chloro-2- ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3-chloro-2- ((R) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3-chloro-2- ((R) -1- ((6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3-chloro-2- ((S) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3-chloro-2- ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3-chloro-2- ((R) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3-chloro-2- ((R) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3-chloro-2- ((S) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyrazin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-hydroxyethan-1-one;

n- ((6- (2-chloro-3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -3-fluoropropane-1-amine;

2- (4- (6- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) -5-methylpyrimidin-4-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (1- ((6- (3- (2- (4- ((4-acetylpiperidin-1-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) piperidin-4-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (6- ((6- (3- (6- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -5-methylpyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-hydroxyethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-hydroxyethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-hydroxyethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-hydroxyethan-1-one;

1- (4- (((6- (3- (6- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -5-chloropyrimidin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(R) -5- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-2-one;

(S) -5- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-2-one;

(S) -5- (((6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (((S) -4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- ((((6- (((R) -4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((R) -4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- ((((6- (3-chloro-2- ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3-chloro-2- ((R) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3-chloro-2- ((R) -1- ((6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3-chloro-2- ((S) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3-chloro-2- ((S) -1- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3-chloro-2- ((R) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3-chloro-2- ((R) -1- ((6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (3-chloro-2- ((S) -1- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) pyridin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((1- (3-methoxypropionyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -3-methoxypropane-1-one;

2- ((6- (3- (6 ' - (((1-acetylpiperidin-4-yl) amino) methyl) -3-chloro-5 ' -methoxy- [2,3' -bipyridin ] -4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-6 ' - ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -5' -methoxy- [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-6 ' - ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -5' -methoxy- [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-6 ' - ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -5' -methoxy- [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-6 ' - ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -5' -methoxy- [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -2- ((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- ((6- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -2- ((2 ' - (1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- ((2 ' - (1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -2- ((3 ' -chloro-6-methoxy-2 ' - (1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- ((3 ' -chloro-6-methoxy-2 ' - (1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((3 ' -chloro-2 ' - ((S) -1- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((3 ' -chloro-2 ' - ((S) -1- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((3 ' -chloro-2 ' - ((R) -1- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((3 ' -chloro-2 ' - ((R) -1- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (5-chloro-6- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyrimidin-4-yl) -2, 6-diazaspiro [3.4] oct-7-one;

(S) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxy-3- (2- (methylamino) ethyl) pyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

(R) -6- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxy-3- (2- (methylamino) ethyl) pyrrolo [2,1-f ] [1,2,4] triazin-4 (3H) -one;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- ((((tetrahydro-2H-pyran-4-yl) methyl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (3- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- ((4- (3-chloro-4- (2-chloro-3- (3- (((2-hydroxyethyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4-methyl-1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (4-methyl-1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- ((6- (3- (6- (4- ((4-acetylpiperazin-1-yl) methyl) -3-methoxyphenyl) -5-chloropyrimidin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) piperazin-1-one;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

1- (4- (((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((5- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -3-methoxypyridin-2-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- (4- (3-chloro-4- (2-chloro-3- (5-methoxy-6- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-3-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] oct-7-one;

1- (4- (((5- (3- (6 ' - ((1-acetylpiperidin-4-yl) amino) methyl) -3-chloro-5 ' -methoxy- [2,3' -bipyridin ] -4-yl) -2-chlorophenyl) -3-methoxypyridin-2-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- (4- (5-chloro-6- (2-chloro-3- (5- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxyphenylmethyl) -2-azaspiro [3.3] heptan-6-ol;

2- ((5- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -3-methoxypyridin-2-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one;

n- ((5- (2-chloro-3- (3-chloro-5 ' -methoxy-6 ' - (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,3' -bipyridin ] -4-yl) phenyl) -3-methoxypyridin-2-yl) methyl) tetrahydro-2H-pyran-4-amine;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6-methyl-7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) -6-methyl-2, 6-diazaspiro [3.4] octan-7-one;

1- (4- (((6- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- ((6- (2-chloro-3- (3 ' -chloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) - [2,4' -bipyridin ] -2' -yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

n- ((3 ' -chloro-2 ' - (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) tetrahydro-2H-pyran-4-amine;

(S) -5- ((((3 ' -chloro-2 ' - (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

2- (4- (3-chloro-4- (3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) -2- (trifluoromethyl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

6- (4- (4- (3- (5- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -6-methoxypyridin-2-yl) -2- (trifluoromethyl) phenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2-oxa-6-azaspiro [3.3] heptane;

2- (4- (4- (3- (3- (((1-acetylpiperidin-4-yl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -1- (((6- (3- (3-chloro-2- (4- ((((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(S) -1- (((6- (3- (3-chloro-2- (4- ((((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (3- (3-chloro-2- (4- ((((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

(R) -1- (((6- (3- (3-chloro-2- (4- ((((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) propan-2-ol;

2- (((6- (2-chloro-3- (5-chloro-6- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethan-1-ol;

5- (((6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-4- (((S) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

5- (((6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-4- (((R) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-4- (((S) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] sulfan-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-4- (((R) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] sulfan-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-4- (((S) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] sulfan-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (1, 1-dioxo-4- (((R) -5-oxopyrrolidin-2-yl) methyl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] sulfan-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((((1 s,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((((1 r,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (8-ethoxy-2- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-ethoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- ((6- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-ethoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

n- ((6- (3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) -3-fluoropropane-1-amine;

(1 r,4 r) -4- (((6- (3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 r) -4- (((6- (3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (3- (3-chloro-2- (4- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (3- (3-chloro-2- (4- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (3- (3-chloro-2- (4- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (3- (3-chloro-2- (4- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclohexan-1-ol;

1- (6- ((6- (3- (6- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -5-chloropyrimidin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

n- (3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) picolinamide;

(3- (((6- (2-chloro-3- (3-chloro-2- (4- (((3- (hydroxymethyl) bicyclo [1.1.1] pentan-1-yl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) bicyclo [1.1.1] pentan-1-yl) methanol;

(1 s,3 s) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 s,3 s) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 r,3 r) -3- (((6- (2-chloro-3- (5-chloro-6- (4- (((1 r,3 r) -3-hydroxycyclobutyl) amino) methyl) -3) -methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 r,3 r) -3- (((6- (2-chloro-3- (5-chloro-6- (4- (((1 r,3 s) -3-hydroxycyclobutyl) amino) methyl) -3) -methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 r,3 r) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 s,3 r) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 r,3 r) -3- (((6- (2-chloro-3- (5-chloro-6- (4)) (((1 s,3 s) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 r,3 s) -3- (((6- (2-chloro-3- (5-chloro-6- (4- (((1 r,3 r) -3-hydroxycyclobutyl) amino) methyl) -3) -methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 r,3 s) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 r,3 s) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 r,3 s) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 s,3 r) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 r,3 s) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 s,3 s) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 s,3 r) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 r,3 r) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 s,3 r) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 r,3 s) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 s,3 r) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 s,3 r) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 s,3 r) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 s,3 s) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 s,3 s) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 r,3 r) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 s,3 s) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 r,3 s) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

(1 s,3 s) -3- (((6- (2-chloro-3- (5-chloro-6- (4- ((((1 s,3 r) -3-hydroxycyclobutyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) cyclobutan-1-ol;

1- (6- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((6- (2-methoxyacetyl) -2, 6-diazaspiro [3.3] heptan-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -2-methoxyethane-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 r) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,4 s) -4-hydroxycyclohexyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,3 r) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 r,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

2- ((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3- (difluoromethoxy) phenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

1- (4- (((S) -1- (6- (3- (2- (4- ((S) -1- ((1-acetylpiperidin-4-yl) amino) ethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((S) -1- (6- (3- (2- (4- ((R) -1- ((1-acetylpiperidin-4-yl) amino) ethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((R) -1- (6- (3- (2- (4- ((S) -1- ((1-acetylpiperidin-4-yl) amino) ethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((R) -1- (6- (3- (2- (4- ((R) -1- ((1-acetylpiperidin-4-yl) amino) ethyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) ethyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) (methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) (methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (3- (3-chloro-2- (3-methoxy-4- (((1- (2-methoxyacetyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -2-methoxyethan-1-one;

2- (4- (4- (3- (3- (((1-acetylpiperidin-4-yl) (methyl) amino) methyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

n- (4- (4- (3- (5- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -6-methoxypyridin-2-yl) -2- (trifluoromethyl) phenyl) -3-chloropyridin-2-yl) -2-methoxyphenylmethyl) -2-oxaspiro [3.3] heptan-6-amine;

2- (4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2-methoxybenzyl) amino) ethan-1-ol;

1- (4- (((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -3-methoxypropane-1-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (6- (4- (3-chloro-4- (2-chloro-3- (1-methyl-3- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

(S) -5- (((6- (3- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((S) -2-hydroxypropyl) -1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((R) -2-hydroxypropyl) -1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((S) -2-hydroxypropyl) -1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (4- ((R) -2-hydroxypropyl) -1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] thiazepin-8-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

2- (((6- (3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) ethan-1-ol;

1- (6- (3- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) -N-methyl methylamine;

n- ((6- (3- (3-chloro-2- (3-methoxy-4- (((2-methoxyethyl) amino) methyl) phenyl) pyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) -2-methoxyethane-1-amine;

2- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -6- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) benzonitrile;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- ((4-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -3-methoxypropane-1-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

n- ((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

4- (((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((1-methyl-2-oxopiperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -1-methylpiperidin-2-one;

2- (4- (((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((1- (2-hydroxyethyl) piperidin-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-ol;

1- (4- (((6- (3- (4- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-2-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- (4- (3-chloro-2- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-4-yl) -2, 6-diazaspiro [3.4] oct-7-one;

n- (4- (3-chloro-2- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-4-yl) -2-methoxybenzyl) tetrahydro-2H-pyran-4-amine;

(S) -5- (((4- (3-chloro-2- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-4-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-2- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-4-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-2- (2-chloro-3- (6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-4-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-2- (2-chloro-3- (6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyridin-4-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((1- (3-methoxypropionyl) piperidin-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

n- ((6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

1- (4- (((6- (3- (5 ' - ((1-acetylpiperidin-4-yl) amino) methyl) -3-chloro-6 ' -methoxy- [2,2' -bipyridin ] -4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- ((6- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) - [2,2' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octane-7-one;

n- ((6- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,2' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

(S) -5- (((6- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,2' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,2' -bipyridyl ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,2' -bipyridin ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,2' -bipyridyl ] -4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- (((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -3-methoxypropane-1-one;

(S) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -3-methoxypropane-1-one;

(R) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) -3-methoxypropane-1-one;

(S) -5- ((((2 ' - ((S) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((2 ' - ((R) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((2 ' - ((S) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((2 ' - ((R) -1- ((5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -1- ((6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

n- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) -N-methyltetrahydro-2H-pyran-4-amine;

2- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -6- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) benzonitrile;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

(R) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxypropyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxypropyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -4' -chloro-6-methoxy- [2,3' -bipyridin ] -5' -yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- ((6- (2-chloro-3- (4 ' -chloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) - [2,3' -bipyridin ] -5' -yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (4- (((6- (3- (5- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -4-chloropyridin-3-yl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- (4- (4-chloro-5- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-3-yl) -2, 6-diazaspiro [3.4] oct-7-one;

1- (6- (2-chloro-3- (5-chloro-6- (3-methoxy-4- (((oxazol-5-ylmethyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) -N- (oxazol-5-ylmethyl) methylamine;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((isopropylamino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

5- (((1-acetylpiperidin-4-yl) amino) methyl) -N- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) picolinamide;

n- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

N- (3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -N- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) pyridine amide;

n- (3- (3-chloro-2- (4- ((((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((S) -2-hydroxypropyl) amino) methyl) picolinamide;

N- (3- (3-chloro-2- (4- ((((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((R) -2-hydroxypropyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (4- ((((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((S) -2-hydroxypropyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (4- ((((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((R) -2-hydroxypropyl) amino) methyl) picolinamide;

1- (6- (((6- (3- (2- (4- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2- (trifluoromethyl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) -2-azaspiro [3.3] heptan-2-yl) ethan-1-one;

2- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -6- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) benzonitrile;

2- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) -6- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) benzonitrile;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxyethyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- ((6- (3- (2- (4- ((4-acetylpiperazin-1-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) piperazin-1-one;

n- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(S) -N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(R) -N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

2- ((6- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((6-hydroxy-2-azaspiro [3.3] heptan-2-yl) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxyethyl) amino) methyl) -4-methoxypyrrolo [2,1-f ] [1,2,4] triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3- (difluoromethoxy) phenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (6- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (difluoromethoxy) benzyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

1- (4- (((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3- (difluoromethoxy) phenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

2- ((6- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3- (difluoromethoxy) phenyl) -3-chloropyridin-4-yl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -5- ((((6- (((S) -4- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- ((((6- (((R) -4- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -4- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((R) -4- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

1- (6- ((6- (2-chloro-3- (3-chloro-2- (4- ((6- (2-hydroxyacetyl) -2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -2-hydroxyethan-1-one;

1- (4- ((4- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3',3 "-dichloro-6-methoxy- [2,4':2',4" -terpyridin ] -2 "-yl) -2-methoxybenzyl) amino) piperidin-1-yl) ethan-1-one;

2- (4- (3 ',3 "-dichloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) - [2,4':2',4" -terpyridin ] -2 "-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octane-7-one;

2- (2- ((6- (2-chloro-3- (3-chloro-2- (4- ((6- (2-hydroxyethyl) -2, 6-diazaspiro [3.4] oct-2-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] oct-6-yl) ethan-1-ol;

1- (2- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.4] oct-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] oct-6-yl) ethan-1-one;

n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) picolinamide;

5- (((1-acetylpiperidin-4-yl) amino) methyl) -N- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) picolinamide;

n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) picolinamide;

n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

N- (2-chloro-3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -N- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) pyridine amide;

n- (2-chloro-3- (3-chloro-2- (4- (((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -5- ((((S) -2-hydroxypropyl) amino) methyl) picolinamide;

n- (2-chloro-3- (3-chloro-2- (4- ((((S) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -5- ((((R) -2-hydroxypropyl) amino) methyl) picolinamide;

n- (2-chloro-3- (3-chloro-2- (4- ((((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -5- ((((S) -2-hydroxypropyl) amino) methyl) picolinamide;

n- (2-chloro-3- (3-chloro-2- (4- (((R) -2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -5- ((((R) -2-hydroxypropyl) amino) methyl) picolinamide;

1- (6- ((6- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((6- (3-methoxypropionyl) -2, 6-diazaspiro [3.3] heptan-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -3-methoxypropane-1-one;

2- ((2 ' - (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((3 ' -chloro-2 ' - (2-chloro-3- (5- ((4-hydroxypiperidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridyl ] -2' -yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2- (difluoromethoxy) benzyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (4- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (difluoromethoxy) benzyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -5- ((((6- (((S) -4- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -4- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((6- (((R) -4- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (((R) -4- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

2- (4- (3-chloro-4- (2-chloro-3- (6-methoxy-5- ((6- (2-methoxyacetyl) -2, 6-diazaspiro [3.3] heptan-2-yl) methyl) pyridin-2-yl) phenyl) pyridin-2-yl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (difluoromethoxy) benzyl) -2, 6-diazaspiro [3.4] octan-7-one;

1- (6- ((6- (2-chloro-3- (3-chloro-2- (3- (difluoromethoxy) -4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

1- (4- ((4- (4- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chlorophenyl) -3-chloropyridin-2-yl) -2- (difluoromethoxy) benzyl) amino) piperidin-1-yl) ethan-1-one;

1- (6- ((6- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -2-methoxyethane-1-one;

1- (2- ((6- (2-chloro-3- (3-chloro-2- (4- ((4-hydroxypiperidin-1-yl) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-6-yl) ethan-1-one;

1- (2- (4- (3-chloro-4- (2-chloro-3- (5- ((4-hydroxypiperidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-6-yl) ethan-1-one;

N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((methylamino) methyl) pyridine amide;

5- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -N- (3- (2- (4- (((2-oxaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) picolinamide;

n- (3- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((methylamino) methyl) picolinamide;

(S) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -4-methoxypyrrolo [2,1-f ] [1,2,4] triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (2-chloro-3- (3-chloro-2- (2- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -4-methoxypyrrolo [2,1-f ] [1,2,4] triazin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- (((6- (3- (2- (2- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-chloropyridin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- ((((1-hydroxycyclopropyl) methyl) amino) methyl) 8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

n- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

5- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -N- (3- (2- (4- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) picolinamide;

n- (2-chloro-3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) phenyl) -5- (((3-fluoropropyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

1- (((6- (((S) -5- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3 ' -chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((S) -5- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3 ' -chloro-6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

1- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) cyclopropane-1-carboxylic acid;

5- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -N- (3- (2- (4- (((2-acetyl-2-azaspiro [3.3] heptan-6-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) picolinamide;

(S) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((S) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-2 ' - ((R) -5- ((5- (((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -N- (2-chloro-3- (5-chloro-6- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(R) -N- (2-chloro-3- (5-chloro-6- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((S) -5- ((6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((3 ' -chloro-6-methoxy-2 ' - ((R) -5- ((6-methoxy-5- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) - [2,4' -bipyridin ] -5-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(S) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -5- (3-chloro-2- (3-methoxy-4- ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- ((((6- (((S) -5- (3-chloro-2- (3-methoxy-4- ((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

(R) -5- (((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidin-2-one;

2- (4- (5-chloro-6- (2-chloro-3- (5- (((2-hydroxyethyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -N- (2-chloro-3- (4 ' -chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,3' -bipyridyl ] -5' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(R) -N- (2-chloro-3- (4 ' -chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,3' -bipyridyl ] -5' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((3-fluoropropyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxy-2-methylpropyl) amino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3-chloro-2- (2- (((2-hydroxyethyl) (methyl) amino) methyl) 8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -5- (((6- (2-chloro-3- (5-methoxy-6- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((6- (2-chloro-3- (5-methoxy-6- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (5-methoxy-6- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((6- (2-chloro-3- (5-methoxy-6- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- (((6- (3- (6- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -5-methoxypyrimidin-4-yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

(S) -N- (2-chloro-3- (3 ' -chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(R) -N- (2-chloro-3- (3 ' -chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

N- (2-chloro-3- (3 ' -chloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) - [2,4' -bipyridyl ] -2' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

2- ((6- (((S) -5- (3 ' -chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3 ' -chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((S) -5- (3 ' -chloro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3 ' -chloro-6-methoxy-5- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

N- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridyl ] -2' -yl) -2-chlorophenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

n- (2-chloro-3- (4 ' -chloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) - [2,3' -bipyridyl ] -5' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

n- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -4' -chloro-6-methoxy- [2,3' -bipyridyl ] -5' -yl) -2-chlorophenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

2- ((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((S) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((6- (((R) -5- (3-chloro-2- (3-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) amino) -2-methoxy-5- (trifluoromethyl) pyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octan-7-one;

n- (3- (3-chloro-2- (3- (difluoromethoxy) -4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (3- (difluoromethoxy) -4- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (3- (difluoromethoxy) -4- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (3- (difluoromethoxy) -4- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

N- (3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

n- (3- (3-chloro-2- (3-fluoro-5-methoxy-4- (((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((((R) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

2- (4- (6- (2-chloro-3- (6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) -5-methoxypyrimidin-4-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- ((4- (6- (2-chloro-3- (5- (((2-hydroxyethyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) -5-methoxypyrimidin-4-yl) -2-methoxyphenylmethyl) amino) ethan-1-ol;

(S) -N- (2-chloro-3- (4 ' -chloro-5- (((2-hydroxypropyl) amino) methyl) -6-methoxy- [2,3' -bipyridyl ] -5' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(R) -N- (2-chloro-3- (4 ' -chloro-5- (((2-hydroxypropyl) amino) methyl) -6-methoxy- [2,3' -bipyridyl ] -5' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

n- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -4' -chloro-6-methoxy- [2,3' -bipyridyl ] -5' -yl) -2-chlorophenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

n- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridyl ] -2' -yl) -2-chlorophenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(S) -N- (5- (3 ' -chloro-6-methoxy-5- ((methylamino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine;

(R) -N- (5- (3 ' -chloro-6-methoxy-5- ((methylamino) methyl) - [2,4' -bipyridin ] -2' -yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine;

n- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

n- ((6- (2-chloro-3- (5-methoxy-6- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyrimidin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) tetrahydro-2H-pyran-4-amine;

(S) -N- (3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(R) -N- (3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(S) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(S) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((S) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((S) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

(R) -5- (((4- (3-chloro-4- ((R) -5- ((5- ((((R) -2-hydroxypropyl) amino) methyl) -6-methoxy-3- (trifluoromethyl) pyridin-2-yl) amino) -5,6,7, 8-tetrahydronaphthalen-1-yl) pyridin-2-yl) -2-methoxybenzyl) amino) methyl) pyrrolidin-2-one;

2- (4- (5-chloro-6- (2-chloro-3- (5- ((((1 s,3 s) -3-hydroxycyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (5-chloro-6- (2-chloro-3- (5- ((((1 s,3 r) -3-hydroxycyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (5-chloro-6- (2-chloro-3- (5- ((((1 r,3 s) -3-hydroxycyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (5-chloro-6- (2-chloro-3- (5- ((((1 r,3 r) -3-hydroxycyclobutyl) amino) methyl) -6-methoxypyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxyphenylmethyl) -2, 6-diazaspiro [3.4] octan-7-one;

(S) -N- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - (((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,2' -bipyridyl ] -4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(R) -N- (2-chloro-3- (3-chloro-6 ' -methoxy-5 ' - (((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,2' -bipyridyl ] -4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(S) -N- (2-chloro-3- (3-chloro-5 ' - (((2-hydroxypropyl) amino) methyl) -6' -methoxy- [2,2' -bipyridyl ] -4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(R) -N- (2-chloro-3- (3-chloro-5 ' - (((2-hydroxypropyl) amino) methyl) -6' -methoxy- [2,2' -bipyridyl ] -4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(S) -N- (5- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine;

(R) -N- (5- (3-chloro-2- (3-methoxy-4- ((methylamino) methyl) phenyl) pyridin-4-yl) -1,2,3, 4-tetrahydronaphthalen-1-yl) -6-methoxy-5- ((methylamino) methyl) -3- (trifluoromethyl) pyridin-2-amine;

(S) -2- (4- (5-chloro-6- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

(R) -2- (4- (5-chloro-6- (2-chloro-3- (6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) phenyl) pyrimidin-4-yl) -2-methoxybenzyl) -2, 6-diazaspiro [3.4] octan-7-one;

2- (4- (6- (2-chloro-3- (6-methoxy-5- ((6-oxo-2, 5-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) phenyl) -5-methoxypyrimidin-4-yl) -2-methoxyphenylmethyl) -2, 5-diazaspiro [3.4] octan-6-one;

n- (3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] octane-2-yl) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(S) -N- (2-chloro-3- (3 ' -chloro-5- (((2-hydroxypropyl) amino) methyl) -6-methoxy- [2,4' -bipyridyl ] -2' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(R) -N- (2-chloro-3- (3 ' -chloro-5- (((2-hydroxypropyl) amino) methyl) -6-methoxy- [2,4' -bipyridyl ] -2' -yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(S) -N- (2-chloro-3- (5-chloro-6- (4- (((2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(R) -N- (2-chloro-3- (5-chloro-6- (4- (((2-hydroxypropyl) amino) methyl) -3-methoxyphenyl) pyrimidin-4-yl) phenyl) -1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide;

(S) -N- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) -5- (((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

(R) -N- (3- (2- (4- (((1-acetylpiperidin-4-yl) amino) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-methylphenyl) -5- (((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

(S) -N- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

(R) -N- (3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

(S) -N- (3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

(R) -N- (3- (3-chloro-2- (4- (((3-fluoropropyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

(S) -N- (3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

(R) -N- (3- (3-chloro-2- (4- (((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) picolinamide;

(S) -N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((methylamino) methyl) picolinamide;

(R) -N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- ((methylamino) methyl) picolinamide;

(S) -6- ((2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) carbamoyl) nicotinic acid;

(R) -6- ((2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) carbamoyl) nicotinic acid;

2- ((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) -2-azaspiro [3.3] heptan-6-ol;

n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) phenyl) pyridin-4-yl) phenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(S) -N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(R) -N- (2-chloro-3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(S) -N- (3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((methylamino) methyl) picolinamide;

(R) -N- (3- (3-chloro-2- (3-methoxy-4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- ((methylamino) methyl) picolinamide;

n- (3- (2- (4- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -3-methoxyphenyl) -3-chloropyridin-4-yl) -2-chlorophenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(1 r,4 r) -4- (((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 r) -4- (((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) cyclohexan-1-ol;

(1 r,4 s) -4- (((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) cyclohexan-1-ol;

(1 s,4 s) -4- (((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) cyclohexan-1-ol;

1- ((3 ' -chloro-2 ' - (2-chloro-3- (5- ((4-hydroxypiperidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) piperidin-4-ol;

1- (2- ((6- (3- (5- ((6-acetyl-2, 6-diazaspiro [3.4] octane-2-yl) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridin ] -2' -yl) -2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.4] octane-6-yl) ethan-1-one;

1- (4- (((6- (2-chloro-3- (3 ' -chloro-5- ((4-hydroxypiperidin-1-yl) methyl) -6-methoxy- [2,4' -bipyridin ] -2' -yl) phenyl) -2-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

n- (3- (3-chloro-2- (3-fluoro-4- (((2-hydroxyethyl) amino) methyl) -5-methoxyphenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

n- ((6- (2-chloro-3- (3-chloro-2- (2- ((isopropylamino) methyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) pyridin-4-yl) phenyl) -2-methoxypyridin-3-yl) methyl) propan-2-amine;

(S) -5- ((((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) methyl) pyrrolidin-2-one;

(R) -5- ((((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) methyl) pyrrolidin-2-one;

1- (4- (((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) amino) piperidin-1-yl) ethan-1-one;

n- (3- (3 ' -chloro-6-methoxy-5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

1- (6- ((6- (3-chloro-4- (2-chloro-3- (5- ((isopropylamino) methyl) -6-methoxypyridin-2-yl) phenyl) pyridin-2-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one;

n- (2-chloro-3- (3-chloro-2- (3-methoxy-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) pyridin-4-yl) phenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

n- (3- (5- (((1-acetylpiperidin-4-yl) amino) methyl) -3' -chloro-6-methoxy- [2,4' -bipyridyl ] -2' -yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(S) -N- (3- (3-chloro-2- (3- (difluoromethoxy) -4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(R) -N- (3- (3-chloro-2- (3- (difluoromethoxy) -4- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) pyridin-4-yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(S) -N- (3- (3 ' -chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(R) -N- (3- (3 ' -chloro-6-methoxy-5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) - [2,4' -bipyridyl ] -2' -yl) -2-methylphenyl) -5- (((2-hydroxyethyl) amino) methyl) picolinamide;

(R) -1- ((3 ' -chloro-2 ' - (2-chloro-3- (5- (((R) -3-hydroxypyrrolidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) pyrrolidin-3-ol;

(R) -1- ((3 ' -chloro-2 ' - (2-chloro-3- (5- (((S) -3-hydroxypyrrolidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) pyrrolidin-3-ol;

(S) -1- ((3 ' -chloro-2 ' - (2-chloro-3- (5- (((R) -3-hydroxypyrrolidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) pyrrolidin-3-ol;

(S) -1- ((3 ' -chloro-2 ' - (2-chloro-3- (5- (((S) -3-hydroxypyrrolidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) pyrrolidin-3-ol; and

1- (4- (((3 ' -chloro-2 ' - (2-chloro-3- (5- ((4-hydroxypiperidin-1-yl) methyl) -6-methoxypyridin-2-yl) phenyl) -6-methoxy- [2,4' -bipyridin ] -5-yl) methyl) amino) piperidin-1-yl) ethan-1-one.

16. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 15 and at least one pharmaceutically acceptable carrier.

17. The pharmaceutical composition of claim 16, further comprising at least one additional agent that treats, ameliorates, and/or prevents a hepatitis virus infection.

18. The pharmaceutical composition of claim 17, wherein the at least one other agent comprises at least one selected from the group consisting of: reverse transcriptase inhibitors; a capsid inhibitor; cccDNA formation inhibitors; an RNA destabilizer; an oligonucleotide targeting the HBV genome; an immunostimulant; galNAc-siRNA conjugates targeting HBV gene transcripts; and therapeutic vaccines.

19. The pharmaceutical composition of claim 18, wherein the immunostimulant is a checkpoint inhibitor.

20. The pharmaceutical composition of claim 19, wherein the checkpoint inhibitor is a PD-L1 inhibitor.

21. The pharmaceutical composition according to any one of claims 16 to 20, wherein the hepatitis virus is at least one selected from the group consisting of hepatitis b virus (hepatitis B virus, HBV) and hepatitis delta virus (hepatitis D virus, HDV).

22. A method of treating, ameliorating and/or preventing a hepatitis virus infection in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 15 and/or a pharmaceutical composition according to any one of claims 16 to 21, or a salt, solvate, prodrug, stereoisomer, tautomer, or any mixture thereof.

23. The method of claim 22, wherein the subject is infected with Hepatitis B Virus (HBV).

24. The method of any one of claims 22-23, wherein the subject is further infected with Hepatitis Delta Virus (HDV).

25. The method of any one of claims 22-24, wherein the subject is infected with HBV and HDV.

26. The method of any one of claims 22-25, wherein the subject is further administered at least one additional agent for treating the hepatitis virus infection.

27. The method of claim 26, wherein the at least one other agent comprises at least one selected from the group consisting of: reverse transcriptase inhibitors; a capsid inhibitor; cccDNA formation inhibitors; an RNA destabilizer; an oligonucleotide targeting the HBV genome; an immunostimulant; galNAc-siRNA conjugates targeting HBV gene transcripts; and therapeutic vaccines.

28. The method of claim 27, wherein the immunostimulant is a checkpoint inhibitor.

29. The method of claim 28, wherein the checkpoint inhibitor is a PD-L1 inhibitor.

30. The method of any one of claims 26-29, wherein the subject is co-administered the at least one compound and the at least one other agent.

31. The method of any one of claims 26-30, wherein the at least one compound is co-formulated with the at least one other agent.

32. The method of any one of claims 22-31, wherein the subject is a mammal.

33. The method of claim 32, wherein the mammal is a human.

34. A method of treating, ameliorating and/or preventing cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 15 and/or a pharmaceutical composition according to any one of claims 16 to 21, or a salt, solvate, prodrug, stereoisomer, tautomer or any mixture thereof.

35. The method of claim 34, wherein the compound or composition is the only anti-cancer agent administered to the subject.

36. The method of any one of claims 34-35, wherein the compound is administered to the subject in a pharmaceutically acceptable composition.

37. The method of claim 34 or 36, wherein the subject is further administered at least one other agent or therapy for treating, ameliorating and/or preventing the cancer.

38. The method of claim 37, wherein the other anti-cancer agent or therapy comprises nivolumab, pembrolizumab, alemtuzumab, ipilimab, chemotherapy, radiation therapy, and/or ablation therapy.

39. The method of claim 37, wherein the other anti-cancer agent or therapy comprises rituximab, doxorubicin, gemcitabine, nivolumab, pembrolizumab, and/or ipilimumab.

40. The method of any one of claims 34 and 36-39, wherein the compound or composition is co-formulated and/or co-administered with the at least one other agent.

41. The method of any one of claims 34-40, wherein the cancer is amenable to treatment by inhibition of PD-1, PD-L1, or PD-1/PD-L1 interactions.

42. The method of any one of claims 34 to 41, wherein the cancer is at least one of: pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain cancer, bone cancer, soft tissue sarcoma, non-small cell lung cancer, or colon cancer.

43. The method of any one of claims 34 to 41, wherein the cancer is at least one of: acute Lymphoblastic Leukemia (ALL), acute Myelogenous Leukemia (AML), chronic Lymphocytic Leukemia (CLL), small Lymphocytic Lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic Myelogenous Leukemia (CML), multiple Myeloma (MM), non-hodgkin's lymphoma (NHL), mantle Cell Lymphoma (MCL), follicular lymphoma, macroglobulinemia (WM), T cell lymphoma, B cell lymphoma, and Diffuse Large B Cell Lymphoma (DLBCL).

44. The method of any one of claims 34 to 43, wherein the subject is a mammal.

45. The method of claim 44, wherein the mammal is a human.