WO2024083246A1

WO2024083246A1 - Kras inhibitors

Info

Publication number: WO2024083246A1
Application number: PCT/CN2023/125769
Authority: WO
Inventors: Chao Li; Jianyong Chen; Gaojie YE; Liugen LI; Wenliang HU; Chengzhe Wu
Original assignee: Ascentage Pharma (Suzhou) Co., Ltd.; Ascentage Pharma Group Corp Limited
Priority date: 2022-10-21
Filing date: 2023-10-20
Publication date: 2024-04-25

Abstract

The present disclosure relates to compounds that inhibit KRAS. In particular, the present disclosure relates to compounds that inhibit the activity of KRAS G12D or KRAS G12V, pharmaceutical compositions comprising the compounds and methods of use therefor.

Description

KRAS INHIBITORS

Technical Field

Background of the Invention

RAS represents a group of monomeric globular proteins of 189 amino acids (21 kDa molecular mass) that are associated with the plasma membrane and that bind either GDP or GTP. RAS acts as a molecular switch. When RAS contains bound GDP, it is in the resting or off position and is "inactive" . In response to exposure of the cell to certain growth promoting stimuli, RAS is induced to exchange its bound GDP for a GTP. With GTP bound, RAS is "switched on" and is able to interact with and activate other proteins (its "downstream targets" ) . The RAS protein itself has a very low intrinsic ability to hydrolyze GTP back to GDP, thus turning itself into the off state. Switching RAS off requires extrinsic proteins termed GTPase-activating proteins (GAPs) that interact with RAS and greatly accelerate the conversion of GTP to GDP. Any mutation in RAS that affects its ability to interact with GAP or to convert GTP back to GDP will result in a prolonged activation of the protein and consequently a prolonged signal to the cell telling it to continue to grow and divide. Because these signals result in cell growth and division, overactive RAS signaling may ultimately lead to cancer. The most notable members of the RAS are HRAS, KRAS, and NRAS.

Structurally, RAS proteins contain a G domain that is responsible for the enzymatic activity of RAS, i.e., the guanine nucleotide binding and the hydrolysis (GTPase reaction) . It also contains a C-terminal extension, known as the CAAX box, which may be post-translationally modified, and is responsible for targeting the protein to the membrane. The G domain is approximately 21-25 kDa in size and it contains a phosphate binding loop (P-loop) . The P-loop represents the pocket where the nucleotides are bound in the protein, and this is the rigid part of the domain with conserved amino acid residues that are essential for nucleotide binding and hydrolysis (Glycine 12, Threonine 26 and Lysine 16) . The G domain also contains the Switch I (residues 30-40) and Switch II (residues 60-76) regions, both of which are the dynamic parts of the protein which are often represented as the "spring-loaded" mechanism because of their ability to switch between the resting and loaded state. The key interaction is the hydrogen bonds formed by Threonine-35 and glycine-60 with the gamma-phosphate of GTP that maintain the Switch 1 and Switch 2 regions, respectively, in their active conformation. After hydrolysis of GTP and release of phosphate, these two relax into the inactive GDP conformation.

Mutations in the KRAS gene are common events in human tumorigenesis. Indeed, mutations in KRAS are prevalent in the some of the most deadly cancer types: pancreatic (95%) , colorectal (45%) , and lung (35%) . The most common KRAS mutations are found at residue G12 and G13 in the P-loop and at residue Q61.

Single nucleotide substitutions that result in missense mutations at codons 12 and 13 of the KRAS primary amino acid sequence comprise approximately 40%of these KRAS driver mutations in lung adenocarcinoma. KRAS G12D mutation is present in 25.0%of all pancreatic ductal adenocarcinoma patients, 13.3%of all colorectal carcinoma patients, 10.1%of all rectal carcinoma patients, 4.1%of all non-small cell lung carcinoma patients and 1.7%of all small cell lung carcinoma patients (e.g., see The AACR Project GENIE Consortium, (2017) Cancer Discovery; 7 (8) : 818-831. Dataset Version 4) .

Compounds that inhibit KRAS activity are still highly desirable and under investigation, including those that disrupt effectors such as guanine nucleotide exchange factors (e.g., see Sun et al., (2012) Agnew Chem Int Ed Engl. 51 (25) : 6140-6143 doi: 10.1002/anie201201358) as well recent advances in the covalent targeting of an allosteric pocket of KRAS G12C (e.g., see Ostrem et al., (2013) Nature 503: 548-551 and Fell et al., (2018) ACS Med. Chem. Lett. 9: 1230-1234) . Clearly there remains a continued interest and effort to develop inhibitors of KRAS, particularly inhibitors of activating KRAS mutants, especially KRAS G12D.

Thus, there is a need to develop new KRAS (especially KRAS G12D) inhibitors that demonstrate sufficient efficacy for treating KRAS G12D-mediated cancer.

Summary of the Invention

In one aspect, the present disclosure provides compounds represented by any one of Formula I, II, and III below, and the pharmaceutically acceptable salts and solvates, e.g., hydrates, thereof, collectively referred to as "compounds of the disclosure. " Compounds of the disclosure are KRAS (especially KRAS G12D) inhibitors and are thus useful in treating or preventing diseases or conditions such as KRAS G12D-associated cancer wherein the inhibition of KRAS G12D provides a benefit.

In another aspect, the present disclosure provides pharmaceutical compositions comprising the compound of the disclosure, and a pharmaceutically acceptable carrier.

In another aspect, the present disclosure provides methods for inhibiting KRAS G12D or KRAS G12V activity in a cell, comprising contacting the cell in which inhibition of KRAS G12D or KRAS G12V activity is desired with an effective amount of a compound of the disclosure; or a pharmaceutical composition of the disclosure.

In another aspect, the present disclosure provides methods for treating a KRAS G12D or G12V-associated cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the disclosure; or a pharmaceutical composition of the disclosure. Preferably, the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.

In another aspect, the present disclosure provides a method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with a KRAS G12D or KRAS G12V mutation (e.g., a KRAS G12D or G12V-associated cancer) ; and (b) administering to the patient a therapeutically effective amount of a compound of the disclosure; or a pharmaceutical composition of the disclosure.

In another aspect, the present disclosure provides compounds of the disclosure for use in inhibiting KRAS G12D or KRAS G12V activity in a cell.

In another aspect, the present disclosure provides compounds of the disclosure for use in treating a KRAS G12D or G12V-associated cancer.

In another aspect, the present disclosure provides the use of compounds of the disclosure in the manufacture of a medicament for inhibiting KRAS G12D or KRAS G12V activity in a cell.

In another aspect, the present disclosure provides the use of compounds of the disclosure in the manufacture of a medicament for treating a KRAS G12D or G12V -associated cancer.

In another aspect, the present disclosure provides kits comprising compounds of the disclosure, and instructions for administering the compounds of the disclosure to a subject (e.g., a patient) having cancer (e.g., KRAS G12D or G12V-associated cancer) .

Additional embodiments and advantages of the disclosure will be set forth, in part, in the description that follows, and will flow from the description, or can be learned by practice of the disclosure. The embodiments and advantages of the disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.

It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only, and are not restrictive of the invention as claimed.

Detailed Description of the Invention

Unless otherwise defined below, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques that are generally understood in the art, including those obvious changes or equivalent replacements of the techniques for those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the disclosure.

I. Definitions

As used herein, the terms "including" , "comprising" , "having" , "containing" or "comprising" , and other variants thereof, are inclusive or open, and do not exclude other unlisted elements or method steps.

The use of the terms "a" , "an" , "the" , and similar referents in the context of describing the disclsoure (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated. Recitation of ranges of values herein merely are intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The use of any and all examples, or exemplary language (e.g., "such as" ) provided herein, is intended to better illustrate the disclosure and is not a limitation on the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure.

The term "KRAS" as used herein refers collectively to the wild-type KRAS gene and protein, and mutant forms thereof. The mutations found most frequently in the KRAS gene are primarily at codons 12, 13, or 61. KRAS mutations also occur in codons 63, 117, 119, and 146. Liu et al., Acta Pharmaceutica Sinica B 9: 871–879 (2019) .

The term "KRAS inhibitor" as used herein refers a compound that inhibits wild-type KRAS and/or mutant KRAS, and includes electrophilic compounds that form irreversible covalent bonds with the KRAS protein.

As used herein, “KRAS G12D” refers to a mutant form of a mammalian KRAS protein that contains an amino acid substitution of an aspartic acid for a glycine at amino acid position 12. The assignment of amino acid codon and residue positions for human KRAS is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: Variantp. Gly12Asp.

As used herein, a “KRAS G12D inhibitor” refers to compounds of the present disclosure that are represented by Formulae as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRAS G12D.

A "KRAS G12D-associated disease or disorder" as used herein refers to diseases or disorders associated with or mediated by or having a KRAS G12D mutation. A non-limiting example of a KRAS G12D-associated disease or disorder is a KRAS G12D-associated cancer.

As used herein, the term “subject, ” "individual, " or "patient, " used interchangeably, refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer having a KRAS G12D mutation. In some embodiments, the subject has a tumor that is positive for a KRAS G12D mutation. The subject can be a subject with a tumor (s) that is positive for a KRAS G12D mutation. The subject can be a subject whose tumors have a KRAS G12D mutation. In some embodiments, the subject is suspected of having a KRAS G12D gene-associated cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a KRAS G12D mutation.

As used herein, the terms "treat, " "treating, " "treatment, " and the like refer to eliminating, reducing, or ameliorating a disease or condition, and/or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated. The term "treat" and synonyms contemplate administering a therapeutically effective amount of a compound of the disclosure to a subject in need of such treatment. The treatment can be orientated symptomatically, for example, to suppress symptoms. It can be effected over a short period, be oriented over a medium term, or can be a long-term treatment, for example within the context of a maintenance therapy.

As used herein, the terms "prevent, " "preventing, " and "prevention" refer to a method of preventing the onset of a disease or condition and/or its attendant symptoms or barring a subject from acquiring a disease. As used herein, "prevent, " "preventing, " and "prevention" also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring a disease. The terms "prevent, " "preventing" and "prevention" may include "prophylactic treatment, " which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition.

The term "therapeutically effective amount" or "effective dose" as used herein refers to an amount of the active ingredient (s) that is (are) sufficient, when administered by a method of the disclosure, to efficaciously deliver the active ingredient (s) for the treatment of condition or disease of interest to a subject in need thereof. In the case of a cancer or other proliferation disorder, the therapeutically effective amount of the agent may reduce (i.e., retard to some extent or stop) unwanted cellular proliferation; reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., retard to some extent or stop) cancer cell infiltration into peripheral organs; inhibit (i.e., retard to some extent or stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve, to some extent, one or more of the symptoms associated with the cancer. To the extent the administered compound or composition prevents growth and/or kills existing cancer cells, it may be cytostatic and/or cytotoxic.

The term "halo" or “halogen” as used herein by itself or as part of another group refers to -Cl, -F, -Br, or -I.

The term "cyano" as used herein by itself or as part of another group refers to -CN.

The term "hydroxy" as herein used by itself or as part of another group refers to -OH.

The term "alkyl" as used herein by itself or as part of another group refers to a straight-or branched-chain aliphatic hydrocarbon containing one to twelve carbon atoms, i.e., a C₁-C₁₂ alkyl, or the number of carbon atoms designated, e.g., a C₁ alkyl such as methyl, a C₂ alkyl such as ethyl, etc. In one embodiment, the alkyl is a C₁-C₁₀ alkyl. In another embodiment, the alkyl is a C₁-C₆ alkyl. In another embodiment, the alkyl is a C₁-C₄ alkyl. In another embodiment, the alkyl is a C₁-C₃ alkyl, i.e., methyl, ethyl, propyl, or isopropyl. Non-limiting exemplary C₁-C₁₂ alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl. In another embodiment, one or more of the hydrogen atoms of the alkyl group are replaced by deuterium atoms, i.e., the alkyl group is isotopically-labeled with deuterium. A non-limiting exemplarly deteuterated alkyl group is -CD₃. In another embodiment, none of the hydrogen atoms of the alkyl group are replaced by deuterium atoms, i.e., the alkyl group is isotopically-labeled with deuterium.

The term “alkylene” means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. For example, methylene (i.e., -CH₂-) , ethylene (i.e., -CH₂-CH₂-or -CH (CH₃) -) and propylene (i.e., -CH₂-CH₂-CH₂-, -CH (-CH₂-CH₃) -or -CH₂-CH (CH₃) -) .

The term "haloalkyl" as used herein by itself or as part of another group refers to an alkyl group substituted by one or more fluorine, chlorine, bromine, and/or iodine atoms. In one embodiment, the alkyl is substituted by one, two, or three fluorine and/or chlorine atoms. In another embodiment, the alkyl is substituted by one, two, or three fluorine atoms. In another embodiment, the alkyl is a C₁-C₆ alkyl. In another embodiment, the alkyl is a C₁-C₄ alkyl. In another embodiment, the alkyl group is a C₁ or C₂ or C₃ alkyl. Non-limiting exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1, 1-difluoroethyl, 2, 2-difluoroethyl, 2, 2, 2-trifluoroethyl, 3, 3, 3-trifluoropropyl, 4, 4, 4-trifluorobutyl, and trichloromethyl groups.

The terms "hydroxyalkyl" or " (hydroxy) alkyl" as used herein by themselves or as part of another group refer to an alkyl group substituted with one, two, or three hydroxy groups. In one embodiment, the alkyl is a C₁-C₆ alkyl. In another embodiment, the alkyl is a C₁-C₄ alkyl. In another embodiment, the alkyl is a C₁ or C₂ alkyl. In another embodiment, the hydroxyalkyl is a monohydroxyalkyl group, i.e., substituted with one hydroxy group. In another embodiment, the hydroxyalkyl group is a dihydroxyalkyl group, i.e., substituted with two hydroxy groups. Non-limiting exemplary (hydroxy) alkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups, such as 1-hydroxyethyl, 2-hydroxyethyl, 1, 2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl, and 1, 3-dihydroxyprop-2-yl.

The term "alkoxy" as used herein by itself or as part of another group refers to an alkyl group attached to a terminal oxygen atom. In one embodiment, the alkyl is a C₁-C₆ alkyl and resulting alkoxy is thus referred to as a "C₁-C₆ alkoxy. " In another embodiment, the alkyl is a C₁-C₄ alkyl group and resulting alkoxy is thus referred to as a C₁-C₄ alkoxy. Non-limiting exemplary alkoxy groups include methoxy, ethoxy, and tert-butoxy.

The term "carbocyclic" as used herein by itself or as part of another group refers to saturated and partially unsaturated, e.g., containing one or two double bonds, monocyclic, bicyclic, or tricyclic aliphatic hydrocarbons containing three to twelve carbon atoms, i.e., a C_3-12 carbocyclic. For example, a C₅ carbocyclic or a C₆ carbocyclic. When the aliphatic hydrocarbons are saturated, carbocyclic may also be called as cycloalkyl, e.g., a C₃ cycloalkyl such a cyclopropyl, a C₄ cycloalkyl such as cyclobutyl, etc. In one embodiment, the carbocyclic is cycloalkyl. In one embodiment, the cycloalkyl is bicyclic, i.e., it has two rings. In another embodiment, the cycloalkyl is monocyclic, i.e., it has one ring. In another embodiment, the cycloalkyl is a C_3-8 cycloalkyl. In another embodiment, the cycloalkyl is a C_3-6 cycloalkyl, i.e., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In another embodiment, the cycloalkyl is a C₅ cycloalkyl, i.e., cyclopentyl. In another embodiment, the cycloalkyl is a C₆ cycloalkyl, i.e., cyclohexyl. Non-limiting exemplary C_3-12 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, and spiro [3.3] heptane.

The term "heterocyclo" as used herein by itself or as part of another group refers to saturated and partially unsaturated, e.g., containing one or two double bonds, monocyclic, bicyclic, or tricyclic groups containing three to fourteen ring members, i.e., a 3-to 14-membered heterocyclo, comprising one, two, three, or four heteroatoms, for example 5-membered, 6-membered, 7-menbered, 8-membered, 9-membered, 10-membered heterocyclo. Each heteroatom is independently oxygen, sulfur, or nitrogen. Each sulfur atom is independently oxidized to give a sulfoxide, i.e., S (=O) , or sulfone, i.e., S (=O) ₂.

The term heterocyclo includes groups wherein one or more -CH₂-groups is replaced with one or more -C (=O) -groups, including cyclic ureido groups such as imidazolidinyl-2-one, cyclic amide groups such as pyrrolidin-2-one or piperidin-2-one, and cyclic carbamate groups such as oxazolidinyl-2-one.

The term heterocyclo also includes groups having fused optionally substituted aryl or optionally substituted heteroaryl groups such as indoline, indolin-2-one, 2, 3-dihydro-1H-pyrrolo [2, 3-c] pyridine, 2, 3, 4, 5-tetrahydro-1H-benzo [d] azepine, or 1, 3, 4, 5-tetrahydro-2H-benzo [d] azepin-2-one.

In one embodiment, the heterocyclo group is a 4-to 8-membered cyclic group containing one ring and one or two oxygen atoms, e.g., tetrahydrofuran or tetrahydropyran, or one or two nitrogen atoms, e.g., pyrrolidine, piperidine, or piperazine, or one oxygen and one nitrogen atom, e.g., morpholine, and, optionally, one -CH₂-group is replaced with one -C (=O) -group, e.g., pyrrolidin-2-one or piperazin-2-one. In another embodiment, the heterocyclo group is a 5-to 8-membered cyclic group containing one ring and one or two nitrogen atoms and, optionally, one -CH₂-group is replaced with one -C (=O) -group. In another embodiment, the heterocyclo group is a 5-or 6-membered cyclic group containing one ring and one or two nitrogen atoms and, optionally, one -CH₂-group is replaced with one -C (=O) -group. In another embodiment, the heterocyclo group is a 8-to 12-membered cyclic group containing two rings and one or two nitrogen atoms. The heterocyclo can be linked to the rest of the molecule through any available carbon or nitrogen atom. Non-limiting exemplary heterocyclo groups include:

The term "aryl" as used herein by itself or as part of another group refers to an aromatic ring system having six to fourteen carbon atoms, i.e., C₆-C₁₄ aryl, C₉-C₁₀ aryl. Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph" ) , naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. In one embodiment, the aryl group is phenyl or naphthyl. In another embodiment, the aryl group is phenyl.

The term "heteroaryl" as used herein by itself or as part of another group refers to monocyclic and bicyclic aromatic ring systems having five to 14 fourteen ring members, i.e., a 5-to 14-membered heteroaryl, a 5-to 6-membered-heteroaryl, a 9-to 10-membered comprising one, two, three, or four heteroatoms. Each heteroatom is independently oxygen, sulfur, or nitrogen. In one embodiment, the heteroaryl has three heteroatoms. In another embodiment, the heteroaryl has two heteroatoms. In another embodiment, the heteroaryl has one heteroatom. In another embodiment, the heteroaryl is a 5-to 10-membered heteroaryl. In another embodiment, the heteroaryl has 5 ring atoms, e.g., thienyl, a 5-membered heteroaryl having four carbon atoms and one sulfur atom. In another embodiment, the heteroaryl has 6 ring atoms, e.g., pyridyl, a 6-membered heteroaryl having five carbon atoms and one nitrogen atom. Non-limiting exemplary heteroaryl groups include thienyl, benzo [b] thienyl, naphtho [2, 3-b] thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, and phenoxazinyl. In one embodiment, the heteroaryl is chosen from thienyl (e.g., thien-2-yl and thien-3-yl) , furyl (e.g., 2-furyl and 3-furyl) , pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl) , imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl) , pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl) , pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl) , pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin-5-yl) , thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl) , isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl) , oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl) and isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl) . The term heteroaryl also includes N-oxides. A non-limiting exemplary N-oxide is pyridyl N-oxide.

The term " (cycloalkyl) alkyl" as used herein by itself or as part of another group refers to an alkyl substituted with one or two optionally substituted cycloalkyl groups. In one embodiment, the cycloalkyl group (s) is an optionally substituted C₃-C₆ cycloalkyl. In another embodiment, the alkyl is a C₁-C₆ alkyl. In another embodiment, the alkyl is a C₁-C₄ alkyl. In another embodiment, the alkyl is a C₁ or C₂ alkyl. In another embodiment, the alkyl is substituted with one optionally substituted cycloalkyl group. In another embodiment, the alkyl is substituted with two optionally substituted cycloalkyl groups. Non-limiting exemplary (cycloalkyl) alkyl groups include:

The term "carboxy" as used by itself or as part of another group refers to a radical of the formula -C (=O) OH.

The term " (heterocyclo) alkyl" as used herein by itself or as part of another group refers to an alkyl substituted with one, two, or three optionally substituted heterocyclo groups. In one embodiment, the alkyl is substituted with one optionally substituted 5-to 8-membered heterocyclo group. In another embodiment, alkyl is a C₁-C₆ alkyl. In another embodiment, alkyl is a C₁-C₄ alkyl. The heterocyclo group can be linked to the alkyl group through a carbon or nitrogen atom. Non-limiting exemplary (heterocyclo) alkyl groups include:

The term " (heteroaryl) alkyl" as used herein by itself or as part of another group refers to an alkyl substituted with one or two optionally substituted heteroaryl groups. In one embodiment, the alkyl group is substituted with one optionally substituted 5-to 14-membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5-to 14-membered heteroaryl groups. In another embodiment, the alkyl group is substituted with one optionally substituted 5-to 9-membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5-to 9-membered heteroaryl groups. In another embodiment, the alkyl group is substituted with one optionally substituted 5-or 6-membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5-or 6-membered heteroaryl groups. In one embodiment, the alkyl group is a C₁-C₆ alkyl. In another embodiment, the alkyl group is a C₁-C₄ alkyl. In another embodiment, the alkyl group is a C₁ or C₂ alkyl. Non-limiting exemplary (heteroaryl) alkyl groups include:

The terms "aralkyl" or " (aryl) alkyl" as used herein by themselves or as part of another group refers to an alkyl substituted with one, two, or three optionally substituted aryl groups. In one embodiment, the alkyl is substituted with one optionally substituted aryl group. In another embodiment, the alkyl is substituted with two optionally substituted aryl groups. In one embodiment, the aryl is an optionally substituted phenyl or optionally substituted naphthyl. In another embodiment, the aryl is an optionally substituted phenyl. In one embodiment, the alkyl is a C₁-C₆ alkyl. In another embodiment, the alkyl is a C₁-C₄ alkyl. In another embodiment, the alkyl is a C₁ or C₂ alkyl. Non-limiting exemplary (aryl) alkyl groups include benzyl, phenethyl, -CHPh₂, and -CH (4-F-Ph) ₂.

The term "amino" as used by itself or as part of another group refers to a radical of the formula -NR^55aR^55b, wherein R^55a and R^55b are independently hydrogen, optionally substituted alkyl, haloalkyl, (hydroxy) alkyl, (alkoxy) alkyl, (amino) alkyl, heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, optionally substituted heteroaryl, (aryl) alkyl, (cycloalkyl) alkyl, (heterocyclo) alkyl, or (heteroaryl) alkyl.

In one embodiment, the amino is -NH₂.

The present disclosure encompasses any of the Compounds of the Disclosure being isotopically-labelled (i.e., radiolabeled) by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ²H (or deuterium (D) ) , ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively, e.g., ³H, ¹¹C, and ¹⁴C. In one embodiment, provided is a compound wherein substantially all of the atoms at a position within the Compound of the Disclosure are replaced by an atom having a different atomic mass or mass number. In another embodiment, provided is a compound wherein substantially all of the atoms at a position within the Compound of the Disclosure are replaced by deuterium atoms, e.g., all of the hydrogen atoms of a -CH₃ group are replaced by deuterium atoms to give a -CD₃ group. In another embodiment, provided is a compound wherein a portion of the atoms at a position within the Compound of the disclosure are replaced, i.e., the Compound of the Disclosure is enriched at a position with an atom having a different atomic mass or mass number. In another embodiment, provided is a compound wherein none of the atoms of the Compound of the Disclosure are replaced by an atom having a different atomic mass or mass number. Isotopically-labelled Compounds of the Disclosure can be prepared by methods known in the art.

Compounds of the Disclosure contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present disclosure encompasses the use of all such possible forms, as well as their racemic and resolved forms and mixtures thereof. The individual enantiomers can be separated according to methods known in the art in view of the present disclosure. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that they include both E and Z geometric isomers. All tautomers are also encompassed by the present disclosure.

As used herein, the term "stereoisomers" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers) .

The term "chiral center" or "asymmetric carbon atom" refers to a carbon atom to which four different groups are attached.

The terms "enantiomer" and "enantiomeric" refer to a molecule that cannot be superimposed on its mirror image and hence is optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction.

The term "racemic" refers to a mixture of equal parts of enantiomers and which mixture is optically inactive. In one embodiment, Compounds of the Disclosure are racemic.

The term "absolute configuration" refers to the spatial arrangement of the atoms of a chiral molecular entity (or group) and its stereochemical description, e.g., R or S.

The stereochemical terms and conventions used in the specification are meant to be consistent with those described in Pure &Appl. Chem 68: 2193 (1996) , unless otherwise indicated.

The term "enantiomeric excess" or "ee" refers to a measure for how much of one enantiomer is present compared to the other. For a mixture of R and S enantiomers, the percent enantiomeric excess is defined as │R -S│*100, where R and S are the respective mole or weight fractions of enantiomers in a mixture such that R + S = 1. With knowledge of the optical rotation of a chiral substance, the percent enantiomeric excess is defined as ( [α] _obs/ [α] _max) *100, where [α] _obs is the optical rotation of the mixture of enantiomers and [α] _max is the optical rotation of the pure enantiomer. Determination of enantiomeric excess is possible using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography or optical polarimetry.

The term "about, " as used herein, includes the recited number ± 10%. Thus, "about 10" means 9 to 11.

II. Compounds

In one aspect, the present disclosure provides a compound of Formula I:

or a pharmaceutically acceptable salt or solvate thereof,

wherein:

R₁ represents C₃-C₆ cycloalkyl or 5-6-membered heterocyclyl or heteroaryl containg 1, 2 or 3 N atoms, and R₂ represents H, C₁-C₆ alkyl or deuterated C₁-C₆ alkyl, wherein the C₃-C₆ cycloalkyl or 5-6-membered heterocyclyl or heteroaryl is optionally substituted with one or more of C₁-C₄ alkyl, amino, halogen, or OH; or

R₁ and R₂ taken together with the nitrogen atom to which they are attached form a N-containing heterocyclic, wherein the N-containing heterocyclic is optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, amino, OH, CN, halogen, or -C₁-C₆ alkyl-CN;

L is selected from the group consisting of -O-, -S-, and -N (R₆) -; or L is a bond;

R₆ is selected from the group consisting of hydrogen, C₁-C₆ alkyl and C₁-C₆ haloalkyl;

A and Q are independently selected from the group consisting of =C (R₇) -and =N-;

R₇ is selected from the group consisting of hydrogen, CN, C₁-C₆ alkyl, C₁-C₆ haloalkyl and C₃-C₆ cycloalkyl;

R₃ is - (CH₂) _n-heterocycle, wherein the heterocycle is a optionally substituted 7-12 membered heterocycle comprising at least two rings bridged to each other; and n is 0, 1, 2 or 3;

R₄ is selected from the group consisting of C₆-C₁₀ aryl, C₆-C₁₀ heteraryl, C₆-C₁₀ heterocyclic, and C₃-C₆ cycloalkyl, wherein the aryl, heteraryl, heterocyclic, and cycloalkyl is optionally substituted with one or more R₈;

wherein each R₈ may be the same or different, and is independent selected from the group consisting of C₁-C₆ alkyl, -S-C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, C₂-C₆ alkenyl; C₂-C₆ alkynyl, -C₁-C₆ alkyl- (CO) -N (C₁-C₆ alkyl) ₂, C₂-C₄hydroxyalkynyl, and -N (C₁-C₆ alkyl) ₂,

R₅ is selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, and halogen.

In one aspect, the present disclosure provides a compound of Formula I:

or a pharmaceutically acceptable salt or solvate thereof,

wherein:

R₁ and R₂ taken together with the nitrogen atom to which they are attached form a N-containing heterocyclic, wherein the N-containing heterocyclic is optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, amino, OH, CN, halogen, or -C₁-C₆ alkylene-CN;

wherein each R₈ may be the same or different, and is independent selected from the group consisting of C₁-C₆ alkyl, -S-C₁-C₆ alkyl, O-C₁-C₆ alky, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, C₂-C₆ alkenyl; C₂-C₆ alkynyl, -C₁-C₆ alkyl- (CO) -N (C₁-C₆ alkyl) ₂, C₂-C₄hydroxyalkynyl, and -N (C₁-C₆ alkyl) ₂,

In some embodiments, R₁ and R₂ taken together with the nitrogen atom to which they are attached form a 5-8 membered N-containing heterocyclic.

In some embodiments, R₁ is cyclopropyl optionally substituted with one or more of C₁-C₄ alkyl, amino, halogen, or OH.

In some embodiments, R₁ and R₂ taken together with the nitrogen atom to which they are attached form a N-containing heterocycle optionally substituted with one or more Rb groups as follow:

whereinrepresents a single bond or a double bond; when is a single bond, then U represents O, NH or CH₂; and when is a double bond, then U represents N or CH;

t is 0, 1, 2, or 3;

each Rb may be the same or different, and is independently selected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, -C₁-C₆ alkyl-CN, amino, OH, CN, halogen;

or two R_b on the same carbon atom together with the carbon atom to which they are attached form C=CH₂, C=CH-C₁-C₆ alkyl, C=O, C₃-C₆ haloalkyl, or C₃-C₆ heterocycle; wherein the C₃-C₆ haloalkyl, or C₃-C₆ heterocycle is optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, amino, OH, CN, and halogen;

or two R_b on the different carbon atoms are linked together to form a - (CH₂) _s- (CH=CH) _p-linker, wherein s is 0, 1, 2 or 3; and p is 0, 1, 2 or 3.

wherein U represents O, NH or CH₂;

t is 0, 1, 2, or 3;

In some embodiments, the N-containing heterocyclic is

wherein, R^2a, R^2b, R^2c and R^2d independently represent H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, -C₁-C₆ alkylene-CN, amino, OH, CN, halogen; or any one of R^2a, R^2b, R^2c and R^2d are linked together to form a - (CH₂) _s- (CH=CH) _p-linker, wherein s is 0, 1, 2 or 3; and p is 0, 1, 2 or 3.

In some embodiments, the N-containing heterocyclyl is selected from:

represents a single or double bond,

wherein the N-containing heterocyclyl is optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy_, amino, OH, CN, halogen, or -C₁-C₆ alkylene-CN.

In some embodiments, the N-containing heterocyclyl is selected from:

represents a single or double bond,

In some embodiments, the N-containing heterocyclyl is selected from:

represents a single or double bond,

In some embodiments, the N-containing heterocyclyl is selected from:

represents a single or double bond.

wherein the heterocyclyl is optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy_, amino, OH, CN, halogen, or -C₁-C₆ alkylene-CN.

In some embodiments, the N-containing heterocyclyl is selected from:

represents a single or double bond.

wherein the heterocyclyl is optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl , C₁-C₆ alkoxy_, amino, OH, CN, halogen, or -C₁-C₆ alkylene-CN.

In some embodiments, R₃ is selected from:

wherein the R₃ is optionally substituted with one or more R_a, each R_a may be the same or different, and is independent selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, -C₁-C₆ alkyl- (CO) -N (C₁-C₆ alkyl) ₂, C₂-C₄hydroxyalkynyl, -N (C₁-C₆ alkyl) ₂, -CH₂O-CO-N (C₁-C₆ alkyl) ₂, and -CH₂NH-CO-N (C₁-C₆ alkyl) ₂; or two R_a on the same carbon atom form C=CH₂, C=CH-C₁-C₆ alkyl, or C=O.

In some embodiments, R₃ is selected from:

wherein each Ra may be the same or different, and is independent represents C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, -C₁-C₆ alkyl- (CO) -N (C₁-C₆ alkyl) ₂, C₂-C₄hydroxyalkynyl, -N (C₁-C₆ alkyl) ₂, -CH₂O-CO-N (C₁-C₆ alkyl) ₂, and -CH₂NH-CO-N (C₁-C₆ alkyl) ₂; or two R_a on the same carbon atom form C=CH₂, C=CHF, C=CF₂, C=CH-C₁-C₆ alkyl, C=O, cyclopropyl or cyclobutyl; or two R_a on the adjacent carbon atoms together with the carbon atoms to which they are attached form a cyclopropyl or cyclobutyl optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, amino, OH, CN, halogen; and n is 0, 1, 2 or 3.

In some embodiments, R₃ is selected from:

In some embodiments, R₅ is F.

In some embodiments, A and Q are both =N-.

In some embodiments, the N-containing heterocyclic is

In some embodiments, the N-containing heterocyclyl is selected from:

represents a single or double bond,

In some embodiments, the N-containing heterocyclyl is selected from:

represents a single or double bond.

In some embodiments, R₃ is selected from:

wherein each Ra may be the same or different, and is independent represents C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, -C₁-C₆ alkyl- (CO) -N (C₁-C₆ alkyl) ₂, C₂-C₄hydroxyalkynyl, -N (C₁-C₆ alkyl) ₂, -CH₂O-CO-N (C₁-C₆ alkyl) ₂, and -CH₂NH-CO-N (C₁-C₆ alkyl) ₂; or two R_a on the same carbon atom form C=CH₂, C=CH-C₁-C₆ alkyl, C=O, cyclopropyl or cyclobutyl; or two R_a on the adjacent carbon atoms together with the carbon atoms to which they are attached form a cyclopropyl or cyclobutyl optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, amino, OH, CN, halogen; and n is 0, 1, 2 or 3.

In some embodiments, R₃ is selected from:

wherein the R₃ is optionally substituted with one or more R_a, each R_a may be the same or different, and is independent selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, -C₁-C₆ alkyl- (CO) -N (C₁-C₆ alkyl) ₂, C₂-C₄hydroxyalkynyl, -N (C₁-C₆ alkyl) ₂, -CH₂O-CO-N (C₁-C₆ alkyl) ₂, and -CH₂NH-CO-N (C₁-C₆ alkyl) ₂; or two R_a on the same carbon atom form C=CH₂, C=CH-C₁-C₆ alkyl, C=O, cyclopropyl or cyclobutyl.

In some embodiments, R₄ is selected from:

wherein M is selected from the group consisting of =C (R₇) -and =N-; and R₇ is selected from the group consisting of hydrogen, CN, C₁-C₆ alkyl, C₁-C₆ haloalkyl and C₃-C₆ cycloalkyl;

each R₈ may be the same or different, and is independent selected from the group consisting of C₁-C₆ alkyl, -S-C₁-C₆ alkyl, O-C₁-C₆ alky, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, C₂-C₆ alkenyl; C₂-C₆ alkynyl, -C₁-C₆ alkyl- (CO) -N (C₁-C₆ alkyl) ₂, C₂-C₄hydroxyalkynyl, and -N (C₁-C₆ alkyl) ₂; or two R₈ on the adjacent carbon atoms together with the carbon atoms to which they are attached form a fused phenyl optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, amino, OH, CN, halogen, C₂-C₆ alkenyl and C₂-C₆ alkynyl.

In another aspect, the present disclosure provides a compound of Formula II:

or a pharmaceutically acceptable salt or solvate thereof,

wherein:

A, Q and M are independently selected from the group consisting of =C (R₇) -and =N-;

n is 0, 1, 2 or 3; represents a single or double bond,

each R_a may be the same or different, and independent represents C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, -C₁-C₆ alkyl- (CO) -N (C₁-C₆ alkyl) ₂, C₂-C₄hydroxyalkynyl, -N (C₁-C₆ alkyl) ₂, -CH₂O-CO-N (C₁-C₆ alkyl) ₂, and -CH₂NH-CO-N (C₁-C₆ alkyl) ₂; or two R_a on the same carbon atom form C=CH₂, C=CH-C₁-C₆ alkyl, C=O, cyclopropyl or cyclobutyl; or two R_a on the adjacent carbon atoms together with the carbon atoms to which they are attached form a cyclopropyl or cyclobutyl optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, amino, OH, CN, halogen;

R₅ is selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, and halogen;

each R₈ may be the same or different, and is independent selected from the group consisting of C₁-C₆ alkyl, -S-C₁-C₆ alkyl, O-C₁-C₆ alky, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, C₂-C₆ alkenyl; C₂-C₆ alkynyl, - (CO) -, -C₁-C₆ alkyl- (CO) -N (C₁-C₆ alkyl) ₂, C₂-C₄hydroxyalkynyl, and -N (C₁-C₆ alkyl) ₂; or two R₈ on the adjacent carbon atoms together with the carbon atoms to which they are attached form a fused phenyl optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, amino, OH, CN, halogen, C₂-C₆ alkenyl and C₂-C₆ alkynyl.

In another aspect, the present disclosure provides a compound of Formula III:

wherein each R₉ may be the same or different, and is independent selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, C₂-C₆ alkenyl; and C₂-C₆ alkynyl; and other substituents and parameters are as defined above.

In another aspect, the N-containing heterocyclyl is selected from:

In another aspect, the present disclosure provides a compound of Formula IV:

or a pharmaceutically acceptable salt or solvate thereof,

wherein:

each n is independent 0, 1, 2 or 3;

R₈ is independent selected from the group consisting of C₁-C₆ alkyl, -S-C₁-C₆ alkyl, O-C₁-C₆ alky, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, C₂-C₆ alkenyl; C₂-C₆ alkynyl, - (CO) -, -C₁-C₆ alkyl- (CO) -N (C₁-C₆ alkyl) ₂, C₂-C₄hydroxyalkynyl, and -N (C₁-C₆ alkyl) ₂; or two R₈ on the adjacent carbon atoms together with the carbon atoms to which they are attached form a fused phenyl optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, amino, OH, CN, halogen, C₂-C₆ alkenyl and C₂-C₆ alkynyl;

each R₉ may be the same or different, and is independent selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, C₂-C₆ alkenyl; and C₂-C₆ alkynyl;

each R₁₀ may be the same or different, and may be on the same carbon atom or different carbon atoms, and is independent selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy_, amino, OH, CN, halogen, and -C₁-C₆ alkylene-CN.

In some embodiments, the above piperidine ring is

In another aspect, the present disclosure provides a compound of Formula V:

or a pharmaceutically acceptable salt or solvate thereof,

wherein:

each n is independent 0, 1, 2 or 3;

each R_a may be the same or different, and independent represents C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, -C₁-C₆ alkyl- (CO) -N (C₁-C₆ alkyl) ₂, C₂-C₄hydroxyalkynyl, -N (C₁-C₆ alkyl) ₂, -CH₂O-CO-N (C₁-C₆ alkyl) ₂, and -CH₂NH-CO-N (C₁-C₆ alkyl) ₂; or two R_a on the same carbon atom form C=CH₂, C=CHF, C=CF₂, C=CH-C₁-C₆ alkyl, C=O, cyclopropyl or cyclobutyl; or two R_a on the adjacent carbon atoms together with the carbon atoms to which they are attached form a cyclopropyl or cyclobutyl optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, amino, OH, CN, halogen;

U represents O, NH or CH₂;

t is 0, 1, 2, or 3;

In another aspect, the present disclosure provides a compound of Formula VI:

or a pharmaceutically acceptable salt or solvate thereof,

wherein:

R₂ represents H, C₁-C₆ alkyl or deuterated C₁-C₆ alkyl;

each n is independent 0, 1, 2 or 3;

j is 1, 2, 3 or 4;

R₁₁ represents hydrogen, C₁-C₄ alkyl, amino, halogen, or OH.

In some embodiments, the compound of present disclosure is selected from the group consisting of:

wherein A is selected from the group consisting of =C (R₇) -and =N-;

R₁ is selected from the group consisting of hydrogen, C₁-C₆ alkyl, -S-C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, C₂-C₆ alkenyl; C₂-C₆ alkynyl, -C₁-C₆ alkyl- (CO) -N (C₁-C₆ alkyl) ₂, C₂-C₄hydroxyalkynyl, and -N (C₁-C₆ alkyl) ₂; and

X is selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, C₂-C₆ alkenyl; and C₂-C₆ alkynyl,

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the compound of present disclosure is selected from Table 1 to Table 9.

Table 1 Compounds

Table 2 Compounds

Table 3 Compounds

Table 4 Compounds

Table 5 Compounds

Table 6 Compounds

Table 7 Compounds

Table 8 Compounds

Table 9 Compounds

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the compound is selected from:

or a pharmaceutically acceptable salt or solvate thereof.

The present disclosure encompasses the preparation and use of salts of Compounds of the Disclosure. As used herein, the term "pharmaceutically acceptable salt" refers to salts or zwitterionic forms of Compounds of the Disclosure that are suitable for administration to a subject, e.g., a human. Salts of Compounds of the Disclosure can be prepared during the final isolation and purification of the compounds or separately by reacting the compound with a suitable acid. The pharmaceutically acceptable salts of Compounds of the Disclosure can be acid addition salts formed with pharmaceutically acceptable acids. Examples of acids which can be employed to form pharmaceutically acceptable salts include inorganic acids such as nitric, boric, hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Non-limiting examples of salts of Compounds of the Disclosure include, but are not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethansulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerolphsphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, paratoluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, ethanedisulfonate, benzene sulfonate, and p-toluenesulfonate salts. In addition, available amino groups present in the compounds of the disclosure can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. In light of the foregoing, any reference Compounds of the Disclosure appearing herein is intended to include compounds of Compounds of the Disclosure as well as pharmaceutically acceptable salts, hydrates, or solvates thereof.

The present disclosure encompasses the preparation and use of solvates of Compounds of the Disclosure. Solvates typically do not significantly alter the physiological activity or toxicity of the compounds, and as such may function as pharmacological equivalents. The term "solvate" as used herein is a combination, physical association and/or solvation of a compound of the present disclosure with a solvent molecule such as, e.g. a disolvate, monosolvate or hemisolvate, where the ratio of solvent molecule to compound of the present disclosure is about 2: 1, about 1: 1 or about 1: 2, respectively. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, "solvate" encompasses both solution-phase and isolatable solvates. Compounds of the Disclosure can be present as solvated forms with a pharmaceutically acceptable solvent, such as water, methanol, and ethanol, and it is intended that the disclosure includes both solvated and unsolvated forms of Compounds of the Disclosure. One type of solvate is a hydrate. A "hydrate" relates to a particular subgroup of solvates where the solvent molecule is water. Solvates typically can function as pharmacological equivalents. Preparation of solvates is known in the art. See, for example, M. Caira et al, J. Pharmaceut. Sci., 93 (3) : 601-611 (2004) , which describes the preparation of solvates of fluconazole with ethyl acetate and with water. Similar preparation of solvates, hemisolvates, hydrates, and the like are described by E.C. van Tonder et al., AAPS Pharm. Sci. Tech., 5 (1) : Article 12 (2004) , and A.L. Bingham et al., Chem. Commun. 603-604 (2001) . A typical, non-limiting, process of preparing a solvate would involve dissolving a Compound of the Disclosure in a desired solvent (organic, water, or a mixture thereof) at temperatures above 20℃ to about 25℃, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, e.g., filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvate in a crystal of the solvate.

III. Compositions

In one aspect, the present disclosure provides compositions comprising the compound of the disclsoure, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier .

Pharmaceutical compositions for use in accordance with the present disclosure are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of Compound of the Disclosure.

These pharmaceutical compositions can be manufactured, for example, by conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, entrapping, or lyophilizing processes. Proper formulation is dependent upon the route of administration chosen. When a therapeutically effective amount of the Compound of the Disclosure is administered orally, the composition typically is in the form of a tablet, capsule, powder, solution, or elixir. When administered in tablet form, the composition additionally can contain a solid carrier, such as a gelatin or an adjuvant. The tablet, capsule, and powder contain about 0.01%to about 95%, and preferably from about 1%to about 50%, of a Compound of the Disclosure. When administered in liquid form, a liquid carrier, such as water, petroleum, or oils of animal or plant origin, can be added. The liquid form of the composition can further contain physiological saline solution, dextrose or other saccharide solutions, or glycols. When administered in liquid form, the composition contains about 0.1%to about 90%, and preferably about 1%to about 50%, by weight, of a Compound of the Disclosure.

When a therapeutically effective amount of a Compound of the Disclosure is administered by intravenous, cutaneous, or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions, having due regard to pH, isotonicity, stability, and the like, is within the skill in the art. A preferred composition for intravenous, cutaneous, or subcutaneous injection typically contains, an isotonic vehicle.

Compounds of the Disclosure can be readily combined with pharmaceutically acceptable carriers well-known in the art. Standard pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995. Such carriers enable the active agents to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained by adding the Compound of the Disclosure to a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. If desired, disintegrating agents can be added.

Compound of the Disclosure can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampules or in multidose containers, with an added preservative. The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and/or dispersing agents.

Pharmaceutical compositions for parenteral administration include aqueous solutions of the active agent in water-soluble form. Additionally, suspensions of a Compound of the Disclosure can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension. Optionally, the suspension also can contain suitable stabilizers or agents that increase the solubility of the compounds and allow for the preparation of highly concentrated solutions. Alternatively, a present composition can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

Compounds of the Disclosure also can be formulated in rectal compositions, such as suppositories or retention enemas, e.g., containing conventional suppository bases. In addition to the formulations described previously, the Compound of the Disclosure also can be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the Compound of the Disclosure can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins.

In particular, the Compounds of the Disclosure can be administered orally, buccally, or sublingually in the form of tablets containing excipients, such as starch or lactose, or in capsules or ovules, either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. Such liquid preparations can be prepared with pharmaceutically acceptable additives, such as suspending agents. Compound of the Disclosure also can be injected parenterally, for example, intravenously, intramuscularly, subcutaneously, or intracoronarily. For parenteral administration, the Compound of the Disclosure are typically used in the form of a sterile aqueous solution which can contain other substances, for example, salts or monosaccharides, such as mannitol or glucose, to make the solution isotonic with blood.

IV. Methods and uses

In one aspect, the present disclosure provides a method for inhibiting KRAS G12D activity in a cell, comprising contacting the cell in which inhibition of KRAS G12D activity is desired with an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof; or a pharmaceutical composition of the disclosure.

In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo.

As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a KRAS G12D with a compound provided herein includes the administration of a compound provided herein to an individual or patient, such as a human, having KRAS G12D, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the KRAS G12D.

By negatively modulating the activity of KRAS G12D, the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRAS G12D activity within the cell. The cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of KRAS G12D. The ability of compounds to bind KRAS G12D may be monitored in vitro using well known methods. In addition, the inhibitory activity of exemplary compounds in cells may be monitored, for example, by measuring the inhibition of KRAS G12D activity of the amount of phosphorylated ERK.

In another aspect, the present disclosure provides a method for treating a KRAS G12D-associated cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof; or a pharmaceutical composition of the disclosure.

In another aspect, the present disclosure provides a method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with a KRAS G12D mutation (e.g., a KRAS G12D-associated cancer) ; and (b) administering to the patient a therapeutically effective amount of a compound of he disclosure, or a pharmaceutically acceptable salt or solvate thereof; or a pharmaceutical composition of the disclosure.

The compounds and compositions provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compounds and compositions of the disclosure include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas. More specifically, these compounds can be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma) , myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma) , alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma) , stomach (carcinoma, lymphoma, leiomyosarcoma) , pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma) , small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma) , large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma) ; Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma) , lymphoma, leukemia) , bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma) , prostate (adenocarcinoma, sarcoma) , testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma) ; Liver: hepatoma (hepatocellular carcinoma) , cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma) , fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma) , multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses) , benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans) , meninges (meningioma, meningiosarcoma, gliomatosis) , brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma) , glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors) , spinal cord neurofibroma, meningioma, glioma, sarcoma) ; Gynecological: uterus (endometrial carcinoma) , cervix (cervical carcinoma, pre-tumor cervical dysplasia) , ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma) , granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma) , vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma) , vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma) , fallopian tubes (carcinoma) ; Hematologic: blood (myeloid leukemia (acute and chronic) , acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome) , Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma) ; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.

In certain embodiments, the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer. In certain embodiments, the cancer is non-small cell lung cancer.

A therapeutically effective amount of a Compound of the Disclosure required for use in therapy varies with the nature of the condition being treated, the length of time that activity is desired, and the age and the condition of the subject, and ultimately is determined by the attendant physician. Dosage amounts and intervals can be adjusted individually to provide plasma levels of the Compound of the Disclosure that are sufficient to maintain the desired therapeutic effects. The desired dose can be administered in a single dose, or as multiple doses administered at appropriate intervals, for example as one, two, three, four or more subdoses per day. Multiple doses often are desired, or required. For example, a Compound of the Disclosure can be administered at a frequency of: four doses delivered as one dose per day at four-day intervals (q4d x 4) ; four doses delivered as one dose per day at three-day intervals (q3d x 4) ; one dose delivered per day at five-day intervals (qd x 5) ; one dose per week for three weeks (qwk3) ; five daily doses, with two days rest, and another five daily doses (5/2/5) ; or, any dose regimen determined to be appropriate for the circumstance.

A Compound of the Disclosure used in a method of the present disclosure can be administered in an amount of about 0.005 to about 500 milligrams per dose, about 0.05 to about 250 milligrams per dose, or about 0.5 to about 100 milligrams per dose. For example, a Compound of the Disclosure can be administered, per dose, in an amount of about 0.005, about 0.05, about 0.5, about 5, about 10, about 20, about 30, about 40, about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500 milligrams, including all doses between 0.005 and 500 milligrams.

The dosage of a composition containing a Compound of the Disclosure, or a composition containing the same, can be from about 1 ng/kg to about 200 mg/kg, about 1 μg/kg to about 100 mg/kg, or about 1 mg/kg to about 50 mg/kg. The dosage of a composition can be at any dosage including, but not limited to, about 1 μg/kg. The dosage of a composition may be at any dosage including, but not limited to, about 1 μg/kg, about 10 μg/kg, about 25 μg/kg, about 50 μg/kg, about 75 μg/kg, about 100 μg/kg, about 125 μg/kg, about 150 μg/kg, about 175 μg/kg, about 200 μg/kg, about 225 μg/kg, about 250 μg/kg, about 275 μg/kg, about 300 μg/kg, about 325 μg/kg, about 350 μg/kg, about 375 μg/kg, about 400 μg/kg, about 425 μg/kg, about 450 μg/kg, about 475 μg/kg, about 500 μg/kg, about 525 μg/kg, about 550 μg/kg, about 575 μg/kg, about 600 μg/kg, about 625 μg/kg, about 650 μg/kg, about 675 μg/kg, about 700 μg/kg, about 725 μg/kg, about 750 μg/kg, about 775 μg/kg, about 800 μg/kg, about 825 μg/kg, about 850 μg/kg, about 875 μg/kg, about 900 μg/kg, about 925 μg/kg, about 950 μg/kg, about 975 μg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 60 mg/kg, about 70 mg/kg, about 80 mg/kg, about 90 mg/kg, about 100 mg/kg, about 125 mg/kg, about 150 mg/kg, about 175 mg/kg, about 200 mg/kg, or more. The above dosages are exemplary of the average case, but there can be individual instances in which higher or lower dosages are merited, and such are within the scope of this disclosure. In practice, the physician determines the actual dosing regimen that is most suitable for an individual subject, which can vary with the age, weight, and response of the particular subject.

In certain embodiments, the therapeutically effective amount of the compound is between about 0.01 to 100 mg/kg per day.

In another aspect, the present disclosure provides compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, for use in inhibiting KRAS G12D activity in a cell.

In another aspect, the present disclosure provides compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, for use in treating a KRAS G12D-associated cancer.

In another aspect, the present disclosure provides the use of the compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of the disclosure, in the manufacture of a medicament for inhibiting KRAS G12D activity in a cell.

In another aspect, the present disclosure provides the use of the compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of the disclosure, in the manufacture of a medicament for treating a KRAS G12D-associated cancer.

V. Kits

In another embodiment, the present disclosure provides kits which comprise a Compound of the Disclosure (or a composition comprising a Compound of the Disclosure) packaged in a manner that facilitates their use to practice methods of the present disclosure. In one embodiment, the kit comprises Compound of the Disclosure (or a composition comprising a Compound of the Disclosure) , and instructions for administering the compound, or a pharmaceutically acceptable salt or solvate thereof, to a subject having cancer. In one embodiment, the compound or composition is packaged in a unit dosage form. The kit further can include a device suitable for administering the composition according to the intended route of administration.

Examples

In order to make the objects and technical solutions of the present disclosure clearer, the present disclosure will be further described below in conjunction with specific example. It should be understood that the examples are not intended to limit the scope of the invention. Further, specific experimental methods not mentioned in the following examples were carried out in accordance with a conventional experimental method.

Example 1

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1aR, 5aR, 6aR) -hexahy drocyclopropa [b] pyrrolizin-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Cpd. NO. 1)

Step 1: 2- (tert-butyl) 3-methyl (1R, 3S, 5R) -2-azabicyclo [3.1.0] hexane-2, 3-dicarboxylate

Under Ar, to a solution of (1R, 3S, 5R) -2- (tert-butoxycarbonyl) -2-azabicyclo [3.1.0] hexane-3-carboxylic acid (1 g, 4.40 mmol) in DMF (10mL) was added K₂CO₃ (1.216 g, 8.80 mmol) and MeI (1.874 g, 13.20 mmol) at 0 ℃. And then, the mixture was stirred at room temperature for 2 hours. The filtrate was concentrated under reduced pressure to give a residual, which was purified by silica gel column and eluted with Eaand PE from 0 to 30%to afford the title compound (1.03 g, 97 %) as a cololess oil. ¹H NMR (400 MHz, CDCl₃) : 4.07-3.95 (m, 1H) , 3.73 (s, 3H) , 3.54-3.43 (m, 1H) , 2.37-2.18 (m, 2H) , 1.60-1.55 (m, 1H) , 1.43 (s, 9H) , 0.83-0.77 (m, 1H) , 0.48-0.44 (m, 1H) .

Step 2: 2- (tert-butyl) 3-methyl (1R, 3R, 5R) -3- (3-chloropropyl) -2-azabicyclo [3.1.0] hexane-2, 3-dicarboxylate

Under Ar, to a solution of 2- (tert-butyl) 3-methyl (1R, 3S, 5R) -3- (3-chloropropyl) -2-azabicyclo [3.1.0] hexane-2, 3-dicarboxylate (410 mg, 2.487 mmol) in THF (10 mL) was added lithium bis (trimethylsilyl) amide (4.97 mmol) dropwise at -70 ℃, after the addition, the mixture was keeped at -70 ℃ for 1 hour. Then 1-chloro-3-iodopropane (559 mg, 2.74 mmol) was added at -70 ℃. At last, the temperature was rised to room temperature slowly within one hour. Quenched with saturated NH₄Cl solution (20 mL) and extracted with ethyl acetate (20 mL x 3) . The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated in vacuo to a residual, which was purified by silica gel column and eluted with EA/PE from 0 to 20%to afford the title compound (410 mg, 51.9 %) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) : 3.74-3.29 (m, 6H) , 2.34-2.15 (m, 3H) , 2.04-1.83 (m, 3H) , 1.49-1.40 (m, 10H) , 0.98-0.94 (m, 1H) , 0.81-0.67 (m, 1H) .

Step 3: methyl (1aR, 5aR, 6aR) -hexahydrocyclopropa [b] pyrrolizine-5a (3H) -carboxylate

Under Ar, the mixture of 2- (tert-butyl) 3-methyl (1R, 3R, 5R) -3- (3-chloropropyl) -2-azabicyclo [3.1.0] hexane-2, 3-dicarboxylate (410mg, 1.290 mmol) in DCM (3 mL) and HCl/dioxane (3.00 mL, 4N) was stirred at rt for 1h. The LC-MS showed reaction was complete, the volatiles was removed under reduced pressure to give a residual, which was dissolved in ACN (5 mL) , and then, K₂CO₃ (891 mg, 6.45 mmol) was added to the above mixture. The resulting mixture was stirred at rt for 1h. The filtrate was concentrated in vacuo to give a residual, which was purified by silica gel column and eluted with MeOH/DCM from 0 to 5%to afford the title compound (172 mg, 73.6 %) as a colorless oil. MS: 182.3 (M+H⁺) .

Step 4: ( (1aR, 5aR, 6aR) -hexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methanol

Under Ar, The mixture of methyl (1aR, 5aR, 6aR) -hexahydrocyclopropa [b] pyrrolizine-5a (3H) -carboxylate (165 mg, 0.910 mmol) inTHF was added LiAlH₄ (69.1 mg, 1.821 mmol) at 0 ℃, then the mixture was stirrd at rt for 1h. Quenched with Sodium sulfafe decahydrate, diluted with EA, the mixture was filtered, the filtrate was concentrated in vacuo to give a residue, which was purified by silica gel column and eluted with MeOH/DCM from 0 to 10%to afford the title compound (101 mg, 72.4 %) as a colorless oil. MS: 154.25 (M+H⁺) .

Step 5: tert-butyl (1R, 5S) -3- (7-chloro-8-fluoro-2- ( ( (1aR, 5aR, 6aR) -hexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

Under Ar, to a solution of ( (1aR, 5aR, 6aR) -hexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methanol (28.3 mg, 0.185 mmol) was added sodium hydride (123 mg, 3.08 mmol) at RT, then the mixture was stirred at RT for 0.5h. Tert-butyl (1R, 5S) -3- (2, 7-dichloro -8-fluoropyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (75 mg, 0.154 mmol) was added to the above mixture, and the mixture was stirred at RT for 2h. Quenched with NH₄Cl solution, extracted with EA for three times, the combined organic layer was washed with brine, dried over Na₂SO₄, filterd, the filtrate was concentrated in vacuo to give a reside, which was purified by silica gel column and eluted with MeOH/DCM from 0 to 5%to afford the title compound (75 mg, 89 %) as a light brown solid. MS: 372.4 (M+H⁺) .

Step 6: tert-butyl (1R, 5S) -3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( ( (1aR, 5aR, 6aR) -hexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

Under Ar, the mixture of tripotassium phosphate (88 mg, 0.413 mmol) , tert-butyl (1R, 5S) -3- (7-chloro-8-fluoro-2- ( ( (1aR, 5aR, 6aR) -hexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carb oxylate (75mg, 0.138 mmol) , ( (2-fluoro-6- (methoxymethoxy) -8- (4, 4, 5, 5-tetramethyl -1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (70.5 mg, 0.138 mmol) , Ruphos-Pd-G3 (115 mg, 0.138 mmol) in Water (1.5 mL) and THF (3 mL) was stirred at 60 ℃ for 1h. After cooling down to RT, EA was added and the resulting mixture was washed with water, brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to give a residual, which was purified by silica gel column and eluted with MeOH/DCM from 0 to 2%to afford the title compound (100 mg, 64.9 %) as a brown solid. LCMS: 896.7 (M+H⁺) .

Step 7:

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1aR, 5aR, 6aR) -hexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol

Under Ar, to a solution of tert-butyl (1R, 5S) -3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( ( (1aR, 5aR, 6aR) -hexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (100 mg, 0.112 mmol) in DMF (5 mL) was added CsF (85 mg, 0.559 mmol) , then the mixture was stirred at rt for 1h. After the LCMS showed the started material was disappeared. The solvent was removed under reduced pressure to give a residual, which was dissolved in HCl/DCM (10 mL, 2N) and resulting mixture was stirred at rt for 1h. The volatiles were removed under reduced pressure to give a residual, which was purified by Pre-HPLC to afford the title compound (4.2mg, 6.32 %) as a light-yellow solid.

HNMR (DMSO-d6, 400M) : 9.02 (s, 1H) , 7.97 (dd, J=9.1 , 5.9Hz, 1H) , 7.46 (t, J=9.0Hz, 1H) , 7.38 (d, J=2.4Hz, 1H) , 7.17 (d, J=2.1Hz, 1H) , 4.47 (d, J=12.2Hz, 1H) , 4.30 (d, J=12.3Hz, 1H) , 4.10-3.83 (m, 3H) , 3.69-3.49 (m, 4H) , 3.11-2.94 (m, 1H) , 2.84-2.70 (m, 1H) , 2.67-2.53 (m, 1H) , 2.00-1.72 (m, 10H) , 1.50-1.44 (m, 1H) , 0.54-0.48 (m, 1H) , 0.31-0.20 (m, 1H) . MS: 595.5 (M+H⁺)

Exampel 2:

3- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1aR, 5aR, 6aR) -hexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol (Cpd. NO. 2)

Step 1: tert-butyl (1R, 5S) -3- (7- (3-chloro-5- (methoxymethoxy) -2- (trifluoromethyl) phenyl) -8-fluoro-2- ( ( (1aR, 5aR, 6aR) -hexahydrocyclopropa [b] pyrroliz in-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

Under Ar, the mixture of 2- (3-chloro-5- (methoxymethoxy) -2- (trifluoromethyl) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (105 mg, 0.286 mmol) , tert-butyl (1R, 5S) -3- (7-chloro-8-fluoro-2- ( ( (1aR, 5aR6aR) -hexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carbo xylate (120 mg, 0.22 mmol) , Pd (dppf) Cl₂ (16 mg, 0.022 mmol) and Cs₂CO₃ (359 mg, 1.1 mmol) in dioxane (4 mL) and water (1 mL) was stirred at 100℃ for 8h. After cooling down to RT, water was added, extracted with EA for 3 times. The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated in vacuo to gvie a residue, which was purified by silica gel column and eluted with MeOH/DCM from 0 to 5%to afford the title compound (40 mg, 24.3 %) as brown oil. MS: 749.6 (M+H⁺)

Step 2: 3- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1aR, 5aR, 6aR) -hexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol

Under Ar, the mixture of tert-butyl (1R, 5S) -3- (7- (3-chloro-5- (methoxymethoxy) -2- (trifluoromethyl) phenyl) -8-fluoro-2- ( ( (1aR, 5aR, 6aR) -hexahydrocyclopropa [b] pyrroliz in-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (40 mg, 0.053 mmol) in ACN (4 mL) and 4M HCl/Dioxane (2 mL) was stirred at rt for 3h. Quenched with NaHCO₃ aq, extracted with EA for 3 times. The combined EA layers were dried over anhydrous Na₂SO₄ and concentrated in vacuo to give a residual, which was purified by Pre-HPLC to afford the title compound (5.5 mg, 17.0 %) as a white solid.

¹H NMR (400 MHz, DMSO) δ 9.06 (s, 1H) , 7.19 (d, J = 2.1 Hz, 1H) , 6.79 (d, J = 2.2 Hz, 1H) , 4.46-4.40 (m, 2H) , 4.30-3.95 (m, 2H) , 3.80-3.60 (m, 5H) , 3.10-3.05 (m, 1H) , 2.90-2.80 (m, 1H) , 2.68-2.60 (m, 1H) , 2.05-1.89 (m, 3H) , 1.85-1.60 (m, 7H) , 1.55-1.45 (m, 1H) , 0.60-0.45 (m, 1H) , 0.38-0.28 (m, 1H) . MS: 605.3 (M+H⁺) .

Example 3

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1aR, 5aS, 6aR) -hexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Cpd. NO. 3)

The title compound was prepared essentially the same protocol described in example1 with (1R, 3R, 5R) -2- (tert-butoxycarbonyl) -2-azabicyclo [3.1.0] hexane-3-carboxylicacid in place of (1R, 3S, 5R) -2- (tert-butoxycarbonyl) -2-azabicyclo [3.1.0] hexane-3-carboxylic acid to afford (8.8 mg) as a white solid.

HNMR (400 MHz, DMSO) : 10.1 (s, 1H) , 9.03 (s, 1H) , 8.05-7.90 (m, 1H) , 7.44 (t, J=8.8Hz, 1H) , 7.39 (s, 1H) , 7.17 (s, 1H) , 4.48 (d, J = 11.4 Hz, 1H) , 4.31 (d, J = 11.2 Hz, 1H) , 4.15 –3.84 (m, 3H) , 3.74 –3.50 (m, 4H) , 3.07-3.02 (m, 1H) , 2.80-2.76 (m, 1H) , 2.67-2.57 (m, 2H) , 1.99-1.62 (m, 10H) , 1.47-1.42 (m, 1H) , 0.52-0.47 (m, 1H) , 0.28-0.24 (m, 1H) . MS: 595.5 (M+H⁺) .

Example 4

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1aS, 5aR, 6aS) -hexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Cpd. NO. 4)

The title compound was prepared essentially the same protocol described in example 1 with (1S, 3S, 5S) -2- (tert-butoxycarbonyl) -2-azabicyclo [3.1.0] hexane-3-carboxylic acid in place of (1R, 3S, 5R) -2- (tert-butoxycarbonyl) -2-azabicyclo [3.1.0] hexane-3-carboxylic acid to afford (7.1 mg) as a white solid.

HNMR (400 MHz, DMSO) : 10.1 (s, 1H) , 9.03 (s, 1H) , 7.97 (dd, J = 9.1, 6.0 Hz, 1H) , 7.44 (t, J=9.0 Hz, 1H) , 7.39 (s, 1H) , 7.17 (s, 1H) , 4.48 (d, J = 12.2 Hz, 1H) , 4.31 (d, J =12.2 Hz, 1H) , 4.15 –3.84 (m, 3H) , 3.74 –3.50 (m, 4H) , 3.07-3.02 (m, 1H) , 2.80-2.76 (m, 1H) , 2.67-2.54 (m, 2H) , 1.99-1.62 (m, 10H) , 1.47-1.42 (m, 1H) , 0.54-0.44 (m, 1H) , 0.29-0.24 (m, 1H) . MS: 595.5 (M+H⁺) .

Example 5

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1aS, 5aS, 6aS) -hexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Cpd. NO. 5)

The title compound was prepared essentially the same protocol described in example1 with (1S, 3R, 5S) -2- (tert-butoxycarbonyl) -2-azabicyclo [3.1.0] hexane-3-carboxylic acid acid in place of (1R, 3S, 5R) -2- (tert-butoxycarbonyl) -2-azabicyclo [3.1.0] hexane-3-carboxylic acid to afford (7.1 mg) as a white solid. HNMR (400 MHz, DMSO) : 10.1 (s, 1H) , 9.03 (s, 1H) , 7.97 (dd, J = 9.1, 6.0 Hz, 1H) , 7.44 (t, J=9.0 Hz, 1H) , 7.39 (s, 1H) , 7.17 (s, 1H) , 4.48 (d, J = 12.2 Hz, 1H) , 4.31 (d, J = 12.2 Hz, 1H) , 4.15 –3.84 (m, 3H) , 3.74 –3.50 (m, 4H) , 3.07-3.02 (m, 1H) , 2.80-2.76 (m, 1H) , 2.67-2.54 (m, 2H) , 1.99-1.62 (m, 10H) , 1.47-1.42 (m, 1H) , 0.54-0.44 (m, 1H) , 0.29-0.24 (m, 1H) . MS: 595.5 (M+H⁺) .

Example 6

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Cpd. NO. 6)

Step 1: 3- (tert-butyl) 2-methyl (1R, 2R, 5S) -3-azabicyclo [3.1.0] hexane-2, 3-dicarboxylate

Under Ar, to a solution of (1R, 2R, 5S) -3- (tert-butoxycarbonyl) -3-azabicyclo [3.1.0] hexane-2-carboxylic acid (1.026g, 4.51 mmol) in DMF (20 mL) was added potassium carbonate (1.248 g, 9.03 mmol) and MeI (1.922 g, 13.54 mmol) at 0 ℃. And the resulting mixture was stirred at room temperature for 2 hours. The filtrate was concentrated under reduced pressure to give a residual, which was purified by silica gel column and eluted with EA/PE from 0 to 30%to afford the title compound (1.05 g, 96 %) as a colorless oil.

Step 2: 3- (tert-butyl) 2-methyl (1R, 2S, 5S) -2- (3-chloropropyl) -3-azabicyclo [3.1.0] hexane-2, 3-dicarboxylate

Under Ar, To the solution of 3- (tert-butyl) 2-methyl (1R, 2R, 5S) -3-azabicyclo [3.1.0] hexane-2, 3-dicarboxylate (500 mg, 2.072 mmol) in of THF (5 mL) was added LiHMDS (520 mg, 3.11 mmol) dropwise at 70 ℃, and the resulting mixture was keeped at -70 ℃ for 1h. Then 1-chloro-3-iodopropane (635 mg, 3.11 mmol) in THF was added at -70 ℃. At last, the temperature was rised to room temperature slowly within one hour. Quenched with saturated NH₄Cl solution (50 mL) and extracted with ethyl acetate (50 mL x 3) . The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated in vacuo to a residual, which was purified by silica gel column and eluted with EA/PE from 0 to 20%to afford the title compound (370 mg, 56.2 %) as a colorless oil.

Step 3: methyl (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizine-6a (4H) -carboxylate

Under Ar, the mixture of 3- (tert-butyl) 2-methyl (1R, 2S, 5S) -2- (3-chloropropyl) -3-azabicyclo [3.1.0] hexane-2, 3-dicarboxylate (370 mg, 1.164 mmol) in DCM (3 mL) and HCl/dioxane (3.00 mL, 4N) was stirred at rt for 1h. The volatiles were removed under reduced pressure to give a residual, which was dissolve in CAN (5mL) , and then K₂CO₃ (805 mg, 5.82 mmol) was added to the above mixture. The resulting mixture was stirred at rt overnight. The mixture was filtered, filtrate was concentrated in vacuo to give residue, which was purified by silica gel column and eluted with MeOH/DCM from 0 to 5%to afford the title compound (160 mg, 76 %) as a brown oil. MS: 182.2 (M+H⁺)

Step 4 : ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methanol

Under Ar, to a solution of methyl (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizine-6a (4H) -carboxylate (160 mg, 0.883 mmol) in THF (5 mL) was added LiAlH₄ (67.0 mg, 1.766 mmol) at 0 ℃, then the mixture was stirred at rt for 1h. Quenched with Na₂SO₄.10H₂O. The mixture was filtered, the filtrate was concentrated in vacuo to afford the title compound (129 mg, 95 %) as a colorless oil which was used for next step directly. MS: 154.3 (M+H⁺) .

Step 5 : tert-butyl (1R, 5S) -3- (7-chloro-8-fluoro-2- ( ( (1aS, 6aS, 6bR) -hexahydrocyclo propa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

Under Ar, to the mixture of ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methanol (60.8 mg, 0.397 mmol) in THF (5 mL) was added sodium hydride (47.6 mg, 1.191 mmol) at RT, then the mixture was stirred at RT for 0.5h. Tert-butyl (1R, 5S) -3- (2, 7-dichloro-8-fluoropyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (170mg, 0.397 mmol) was added to the above mixture, and then the mixture was stirred at RT for 2h. Quenched with NH₄Cl solution, the resulting mixture was extracted with EA three times. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, the filtrate was concentrated in vacuo to give a residual, which was purified by silica gel column and eluted with MeOH/DCM from 0 to 5%to afford the title compound (101 mg, 46.7 %) as a yellow solid. MS: 545.4 (M+H⁺) .

Step 6: tert-butyl (1R, 5S) -3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

Under Ar, The mixture of tripotassium phosphate (118 mg, 0.556 mmol) , tert-butyl (1R, 5S) -3- (7-chloro-8-fluoro-2- ( ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carb oxylate (101 mg, 0.185 mmol) , ( (2-fluoro-6- (methoxymethoxy) -8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (123 mg, 0.241 mmol) , Ruphos-Pd-G3 (23.27 mg, 0.028 mmol) in Water (1.5mL) and THF (3 mL) was stirred at 70 ℃ for 2h. After cooling down to RT, extracted with EA for three times, the combined organic layers were washed with water, brine, dried over Na₂SO₄, filtered, concentrated in vacuo to give a residue, which was purified by silica gel column and eluted with MeOH /DCM from 0 to 2%to afford the title compound (130 mg, 78 %) as a brown solid. MS: 895.7 (M+H⁺)

Step 7: 4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol

Under Ar, to a solution oftert-butyl (1R, 5S) -3- (8-fluoro-7- (7-fluoro -3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( ( (1aS, 6aS, 6b R) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (130 mg, 0.145 mmol) in DMF (5 mL) was added CsF (221 mg, 1.452 mmol) , then the mixture was stirred at rt for 1h. After the LCMS showed the started material was disappeared. The solvent was removed under reduced pressure to give a residual, which was dissolved in HCl/DCM (10 mL, 2N) and resulting mixture was stirred at rt for 1h. The volatiles were removed under reduced pressure to give a residual, which was purified by Pre-HPLC to afford the title compound (43.3 mg, 50.1 %) as a light yellow solid.

H NMR (400 MHz, DMSO) 10.16 (s, 1H) , 9.04 (s, 1H) , 7.97 (dd, J=9.2 , 6.0Hz, 1H) , 7.46 (t, J=9.2Hz, 1H) , 7.39 (d, J=2.4Hz, 1H) , 7.17 (d, J=2.4Hz, 1H) , 4.49 (d, J = 11.1 Hz, 1H) , 4.40 –4.26 (m, 1H) , 4.15 (d, J = 10.2 Hz, 1H) , 4.03 (d, J = 10.3 Hz, 1H) , 3.93 (d, J = 5.5 Hz, 1H) , 3.66-3.56 (m, 4H) , 3.26-2.51 (m, 5H) , 1.99-1.62 (m, 9H) , 1.56-1.47 (m, 1H) , 0.63-0.55 (m, 1H) , 0.05-0.11 (m, 1H) . MS: 595.5 (M+H⁺) .

Example 7

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1aR, 6aR, 6bS) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Cpd. NO. 7)

The title compound was prepared essentially the same protocol described in example 6 with (1S, 2S, 5R) -3- (tert-butoxycarbonyl) -3-azabicyclo [3.1.0] hexane-2-carboxylic acid in place of (1R, 2R, 5S) -3- (tert-butoxycarbonyl) -3-azabicyclo [3.1.0] hexane-2-carboxylic acid to afford (4.5 mg) as a white solid.

Example 8

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1aS, 6aR, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Cpd. NO. 8A) and

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1aR, 6aS, 6bS) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Cpd. NO. 8B)

The mixtured title compound was prepared essentially the same protocol described in example 6 with rel- (1R, 2S, 5S) -3-tert-butoxycarbonyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid in place of (1R, 2R, 5S) -3- (tert-butoxycarbonyl) -3-azabicyclo [3.1.0] hexane-2-carboxylic acid to afford (10.6 mg) as a white solid.

Example 9

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1aR, 5aS, 6aR) -4-methylenehexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Cpd. NO. 9)

Step 1: 2- (tert-butyl) 3-methyl (1R, 3S, 5R) -3- (2- (chloromethyl) allyl) -2-azabicyclo [3.1.0] hexane-2, 3-dicarboxylate

Under Ar, to the solution of 2- (tert-butyl) 3-methyl (1R, 3S, 5R) -2-azabicyclo [3.1.0] hexane-2, 3-dicarboxylate (1.0 g, 4.14 mmol) in THF (10 mL) was added LiHMDS (1.04 g, 6.22 mmol) at -70 ℃ dropwise. Then the mixture was stirred at -70 ℃ for 1 h, the solution of 3-chloro-2- (chloromethyl) prop-1-ene (0.777 g, 6.22 mmol) in THF (5 mL) was added dropwise at -70 ℃. At last, the temperature was rised to room temperature slowly overnight. Quenched with saturated NH₄Cl solution and extracted with ethyl acetate three times. The combined organic layeres were washed with brine, dried with anhydrous sodium sulfate, concentrated in vauoc to give a residual, which was purified by silica gel column and eluted with EA/PE from 0 to 20%to afford the title compound (1.03 g, 75 %) as a colorless oil. HNMR (CDCl3, 400M) : 5.39-5.37 (m, 1H) , 5.13-5.11 (m, 1H) , 4.10 (s, 2H) , 3.70 (s, 3H) , 3.34-3.15 (m, 2H) , 2.66-2.51 (m, 2H) , 2.18-2.11 (m, 1H) , 1.49-1.41 (m, 10H) , 1.04-1.00 (m, 1H) , 0.80-0.66 (m, 1H) .

Step 2: methyl (1aR, 5aS, 6aR) -4-methylenehexahydrocyclopropa [b] pyrrolizine-5a (3H) -carboxylate

Under Ar, the mixture of 2- (tert-butyl) 3-methyl (1R, 3S, 5R) -3- (2- (chloromethyl) allyl) -2-azabicyclo [3.1.0] hexane-2, 3-dicarboxylate (1.03 g, 3.12 mmol) in DCM (3 mL) and HCl/dioxane (3 mL) was stirred at rt for 1h. The volatiles were removed under reduced pressure to give a residua, which was redissolved in CAN (5 mL) , and then K₂CO₃ (2.158 g, 15.61 mmol) was added to the above mixture, and the resulting mixture was stirred at rt overnight. The mixture was filtered, the filtrates was concentrated in vacuo to give a residue, which was purified by silica gel column and eluted with MeOH/DCM from 0 to 5%to give the title compound (587 mg, 97 %) as a light brown oil. MS: 194.31 (M+H⁺)

Step 3: ( (1aR, 5aS, 6aR) -4-methylenehexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methanol

underAr, to a solution of methyl (1aR, 5aS, 6aR) -4-methylenehexahydrocyclopropa [b] pyrrolizine-5a (3H) -carboxylate (100 mg, 0.517 mmol) in THF (5 mL) was added LiAlH4 (39.3 mg, 1.035 mmol) at 0 ℃, then the mixture was stirred at rt for 1h. Quenched with Na₂SO₄.10H₂O an the resulting mixture was filtered, the filtrates were concentrated in vacuo to give the crude tilte compound (82mg) as a colorless oil, which was used in next step directly. MS: 166.3 (M+H⁺) .

Step 4: 4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1aR, 5aS, 6aR) -4-methylenehexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol

The title compound was prepared essentially the same protocol described in example1 to afford 2.8 mg as light yellow solid. MS: 607.5 (M+H⁺) .

Example 10

3- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1aR, 5aR, 6aR) -hexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) aniline (Cpd. NO. 10)

Step 1: 2- (3-bromo-5-chloro-4- (trifluoromethyl) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane

Under Ar, the mixture of 1-bromo-3-chloro-2- (trifluoromethyl) benzene (2.0 g, 7.71 mmol) , 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (3.92 g, 15.42 mmol) , 4, 4'-di-tert-butyl-2, 2'-bipyridine (210 mg, 0.77 mmol) and [Ir (OMe) (1, 5-cod) ] 2 (250 mg, 0.385 mmol) in dry THF (60 mL) was stirred at 70℃for 3h. The volatiles were removed under reduced pressure to give a residue, which was purified by silical gel column and eluted with EA/Hex from 0 to 10%to afford the titlte compound (2.96 g, 100 %) as colorless oil.

Step 2: 3-bromo-5-chloro-4- (trifluoromethyl) phenol

To a solution of (trifluoromethyl) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (2.96 g, 7.71 mmol) in ACE (40 mL) and water (15 mL) was added Oxone (2.65 g, 5.44 mmol) at ice-water condition. Then the mixture was stirred at rt for 1h. Diluted with water and extracted with EA for 3 times. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo to give a residue, which was purified by silica gel columna and eluted with EA/Hex from 0 to 20%to afford the title compound (1.5 g, 70.6 %) as colorless oil. ¹H NMR (400 MHz, DMSO) δ 11.26 (s, 1H) , 7.24 (d, J = 2.0 Hz, 1H) , 7.07 (d, J = 2.0 Hz, 1H) .

Step 3: 3-bromo-5-chloro-4- (trifluoromethyl) phenyl trifluoromethanesulfonate

Undeer Ar, to a solution of 3-bromo-5-chloro-4- (trifluoromethyl) phenol (1.5 g, 5.45 mmol) and DIEA (2.1 g, 16.34 mmol) in dry DCM (40 mL) was added Tf₂O (2.61 g, 9.26 mmol) at 0℃. The reaction mixture was stirred at 0℃ for 1h. Diluted with DCM, washed with water, brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by flash chromatography eluted with Hex/EA=20: 1 to afford the title compound (1.5 g, 67.6 %) as colorless oil.

Step 4: N- (3-bromo-5-chloro-4- (trifluoromethyl) phenyl) -1, 1-diphenylmethanimine

Under Ar, the mixture of 3-bromo-5-chloro-4- (trifluoromethyl) phenyl trifluoromethanesulfonate (1.5 g, 3.68 mmol) , diphenylmethanimine (213 mg, 0.368 mmol) , Pd₂ (dba) ₃ (170 mg, 0.184 mmol) , Xantphos (1.5 g, 5.45 mmol) and Cs₂CO₃ (1.5 g, 5.45 mmol) in Toluene (40 mL) was stirred at 100℃ for 3h. Filtered and the filtrates was concentrated in vacuo give a residue, which was purified by silica gel column and eluted with EA/Hex from 0 to 5%to afford the title compound (750 mg, 46.4 %) as a yellow oil MS: 438.2 (M+H⁺) .

Step 5: N- (3-chloro-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4- (trifluoromethyl) phenyl) -1, 1-diphenylmethanimine

Under Ar, the mixture of N- (3-bromo-5-chloro-4- (trifluoromethyl) phenyl) -1, 1-diphenylmethanimine (350 mg, 0.798 mmol) , 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (405 mg, 1.596 mmol) , Pd (dppf) Cl₂ (59 mg, 0.08 mmol) and potassium acetate (392 mg, 3.99 mmol) in Tol (15 mL) was stirred at 110℃ for 3h. After cooling down to RT, diluted with EA, washed with water and brine. Dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by silica gel column and eluted with EA/Hex from 0 to 5%to afford the title compound (60 mg, 15.5 %) as a yellow oil. MS: 486.6 (M+H⁺) .

Step 6: tert-butyl (1R, 5S) -3- (7- (3-chloro-5- ( (diphenylmethylene) amino) -2- (trifluoromethyl) phenyl) -8-fluoro-2- ( ( (1aR, 5aR, 6aR) -hexahydrocyclopropa [b] pyrroliz in-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

Under Ar, the mixture of N- (3-chloro-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4- (trifluoromethyl) phenyl) -1, 1-diphenylmethanimine (60 mg, 0.124 mmol) , tert-butyl (1R, 5S) -3- (7-chloro-8-fluoro-2- ( ( (1aR, 5aR, 6aR) -hexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (68 mg, 0.124 mmol) , Pd (dppf) Cl₂ (14 mg, 0.02 mmol) and CS₂CO₃ (201 mg, 0.618 mmol) in dioxane (4 mL) and water (1 mL) was stirred at 100℃ for 8h. After cooling down to RT, diluted with water, extracted with EA for 3 times. The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by flash chromatography eluted with DCM/MeOH=20: 1-10: 1 to afford the title compound (50 mg, 46.6 %) as brown oil. MS:868.4 (M+H⁺)

Step 7: 3- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1aR, 5aR, 6aR) -hexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) aniline

Under Ar, the mixture of tert-butyl (1R, 5S) -3- (7- (3-chloro-5- (methoxymethoxy) -2- (trifluoromethyl) phenyl) -8-fluoro-2- ( ( (1aR, 5aR, 6aR) -hexahydrocyclopropa [b] pyrr olizin-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane -8-carboxylate (50 mg, 0.124 mmol) in EA (4 mL) and 4M HCl/Dioxane (2 mL) was stirred at rt for 3h. Quenched with NaHCO₃ aq, extracted with EA for 3 times. The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated in vacuo to give a residual, which was purified by Pre-HPLC to afford the title compound (8.0 mg, 28.8 %) as a white solid. ¹H NMR (400 MHz, DMSO) δ 9.09 (s, 1H) , 7.22 (d, J = 2.0 Hz, 1H) , 6.82 (d, J = 2.0 Hz, 1H) , 4.45 (d, J = 12.4 Hz, 2H) , 4.10-3.99 (m, 2H) , 3.70-3.60 (m, 5H) , 3.10-3.00 (m, 1H) , 2.86-2.80 (m, 1H) , 2.68-2.60 (m, 1H) , 2.05-1.89 (m, 3H) , 1.85-1.60 (m, 7H) , 1.55-1.45 (m, 1H) , 0.6-0.5 (m, 1H) , 0.36-0.30 (m, 1H) . MS: 604.3 (M+H⁺) .

Example 11:

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1aS, 6aS, 6bR) -5-methy lenehexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Cpd. NO. 11)

Under Ar, to a solution of (1R, 2R, 5S) -3- (tert-butoxycarbonyl) -3-azabicyclo [3.1.0] hexane-2-carboxylic acid (5 g, 22.0 mmol) in DMF (20 mL) were added potassium carbonate (6.08 g, 44.0 mmol) and followed by iodomethane (9.37 g, 66.0 mmol) at 0 ℃. After stirred at RT for 2 hours, the mixture was filtered, and the filtrate was concentrated in vacuo to give a residual, which was purified by silica gel column and eluted with EA/PE from 0 to25%to afford the title product (5.2g, 98 %) as a colorless oil. HNMR (CDCl₃, 400 MHz) : 4.39-4.27 (m, 1H) , 3.74 (s, 3H) , 3.59-3.54 (m, 2H) , 1.61-1.39 (m, 11H) , 0.78-0.71 (m, 1H) , 0.35-0.30 (m, 1H) .

Step2 : 3- (tert-butyl) 2-methyl (1R, 2S, 5S) -2- (2- (chloromethyl) allyl) -3-azabicyclo [3.1.0] hexane-2, 3-dicarboxylate and 3- (tert-butyl) 2-methyl (1R, 2R, 5S) -2- (2- (chloromethyl) allyl) -3-azabicyclo [3.1.0] hexane-2, 3-dicarboxylate

Under Ar, to a solution of 3- (tert-butyl) 2-methyl (1R, 2R, 5S) -3-azabicyclo [3.1.0] hexane-2, 3-dicarboxylate (5.2 g, 21.55 mmol) in THF (15 mL) was added lithium bis (trimethylsilyl) amide (32.3 mmol) at -78 ℃, then the mixture was stirred at -78℃ for 1 hour. At last, the THF solution of 3-chloro-2- (chloromethyl) prop-1-ene (4.04 g, 32.3 mmol) was added to the aboved mixture at -78 ℃ dropwise, after addition, the mixture was warm to room temperature gradually and stirred at RT overnight. Quenched with saturated NH₄Cl aqueous, and the resulting mixture was extracted with ethyl acetate (200 mL x 3) . The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtrated and concentrated in vacuo to give a resiudal, which was purified by silica gel column and eluted with EA/PE from 0 to 20%to give two eluting stereoisomers as colorless oil . The stereochemistry of the asymmetric quaternary carbon atom of these compounds has not been determined.

The first eluting stereoisomer (3.23 g, 45.4 %) was arbitrarily designated as 3- (tert-butyl) 2-methyl (1R, 2S, 5S) -2- (2- (chloromethyl) allyl) -3-azabicyclo [3.1.0] hexane-2, 3-dicarboxylate.

MS: 230.2 (M-100+H⁺) .

The second eluting stereoisomer (1.73 g, 24.34 %) was arbitrarily designated as 3- (tert-butyl) 2-methyl (1R, 2R, 5S) -2- (2- (chloromethyl) allyl) -3-azabicyclo [3.1.0] hexane-2, 3-dicarboxylate.

MS: 230.2 (M-100+H⁺) .

Step 3: methyl (1aS, 6aS, 6bR) -5-methylenehexahydrocyclopropa [a] pyrrolizine-6a (4H) -carboxylate

Under Ar, The mixture of 3- (tert-butyl) 2-methyl (1R, 2S, 5S) -2- (2- (chloromethyl) allyl) -3-azabicyclo [3.1.0] hexane-2, 3-dicarboxylate (310 mg, 0.940 mmol) in DCM (3 mL) and HCl/dioxane (4 N, 3.00 mL) was stirrd at rt for 1h. LC-MS showed the start material disappeared, the volatiles were removed under reduced pressure to give a residual, which redissolved in the suspension of K₂CO₃ (649 mg, 4.70 mmol) in ACN (5 mL) at RT. The resulting mixture was stirred at rt for 1h. The filtrate was concentrated in vacuo to give a residual, which was purified by silica gel column and eluted with MeOH/DCM from 0 to 5%to afford the title compound (160 mg, 88 %) as a light brown oil. HNMR (CDCl₃, 400 MHz) : 4.91-4.82 (m, 2H) , 3.90-3.80 (m, 1H) , 3.75 (s, 3H) , 3.54-3.40 (m, 1H) , 3.31-3.22 (m, 1H) , 3.06-2.77 (m, 3H) , 1.91-1.85 (m, 1H) , 1.6-1.53 (m, 1H) , 0.64-0.50 (m, 1H) , 0.24-0.13 (m, 1H) . MS: 194.2 (M+H⁺) .

Step 4: ( (1aS, 6aS, 6bR) -5-methylenehexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methanol

Under Ar, The mixture of methyl

(1aS, 6aS, 6bR) -5-methylenehexahydrocyclopropa [a] pyrrolizine-6a (4H) -carboxylate (160 mg, 0.828 mmol) inTHF (5 mL) was added LiAlH4 (62.8 mg, 1.656 mmol) at 0 ℃, then the mixture was stirrd at rt for 1h. Quenched with Na₂SO₄.10H₂O, the filtrate was concentrated in vacuo to afford the title compound (120 mg, 88 %) as a colorless oil which was used in next step directly. MS: 166.2 (M+H⁺) .

Step 5: 4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1aS, 6aS, 6bR) -5-methy lenehexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol

The title compound was prepared essentially the same protocol described in example 6 with ( (1aS, 6aS, 6bR) -5-methylenehexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methanol instead of ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methanol to afford 4.1 mg as a light yellow solid.

HNMR (DMSO, 400 MHz) : 10.15 (s, 1H) , 9.04 (s, 1H) , 8.01 (dd, J = 8.5, 5.9 Hz, 1H) , 7.49-7.46 (m, 1H) , 7.39 (d, J = 2.4Hz, 1H) , 7.23-7.18 (m, 1H) , 4.90 (s, 1H) , 4.86 (s, 1H) , 4.64-4.53 (m, 1H) , 4.46-4.37 (m, 1H) , 4.13-3.24 (m, 10H) , 2.88-2.77 (m, 1H) , 2.67-2.33 (m, 3H) , 1.90-1.74 (m, 5H) , 1.59-1.47 (m, 1H) , 0.67-0.56 (m, 1H) , 0.20-0.11 (m, 1H) . MS: 607.4 (M+H⁺) .

Example 12:

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1aS, 6aR, 6bR) -5-methy lenehexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Cpd. NO. 12)

Step 1: methyl (1aS, 6aR, 6bR) -5-methylenehexahydrocyclopropa [a] pyrrolizine-6a (4H) -carboxylate

Under Ar, The mixture of 3- (tert-butyl) 2-methyl (1R, 2R, 5S) -2- (2- (chloromethyl) allyl) -3-azabicyclo [3.1.0] hexane-2, 3-dicarboxylate (1.73 g, 5.25 mmol; from exampel 11-step 2) in DCM (3.0 mL) and HCl/dioxane (3.0 mL) was stirrd at rt for 1h. LC-MS showed the start material disappeared, the volatiles were removed under reduced pressure to give a residual, which redissolved in the suspension of K₂CO₃ (3.62 g, 26.2 mmol) in ACN (20 mL) at RT. The resulting mixture was stirred at rt for 1h. The filtrate was concentrated in vacuo to give a residual, which was purified by silica gel column and eluted with MeOH/DCM from 0 to 5%to afford the title compound (972 mg, 96 %) a light brown oil. HNMR (CDCl₃, 400 MHz) : 5.00 (s, 1H) , 4.91 (s, 1H) , 3.74 (s, 3H) , 3.66-3.53 (m, 1H) , 3.40-3.20 (m, 2H) , 3.05-2.93 (m, 1H) , 2.76-2.68 (m, 1H) , 2.60-2.50 (m, 1H) , 1.84-1.70 (m, 1H) , 1.56-1.48 (m, 1H) , 0.96-0.85 (m, 1H) , 0.61-0.49 (m, 1H) . MS: 194.2 (M+H⁺) .

Step 2: ( (1aS, 6aR, 6bR) -5-methylenehexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methanol

Under Ar, the mixture of methyl (1aS, 6aR, 6bR) -5-methylenehexahydrocyclopropa [a] pyrrolizine-6a (4H) -carboxylate (200 mg, 1.035 mmol) in THF (5 mL) was added LiAlH₄ (79 mg, 2.070 mmol) at 0 ℃, then the mixture was stirred at rt for 1h. Quenched with Na₂SO₄.10H₂O. The filtrate was concentrated in vacuo to afford the title compound (160 mg, 94 %) as a colorless oil which was used in next step directly. MS: 166.2 (M+H⁺) .

Step 3: 4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1aS, 6aR, 6bR) -5-methy lenehexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol

The title compound was prepared essentially the same protocol described in example 6 with ( (1aS, 6aR, 6bR) -5-methylenehexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methanol instead of ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methanol to afford 18 mg as a light yellow solid.

HNMR (DMSO, 400 MHz) : 10.16 (s, 1H) , 9.04 (s, 1H) , 8.06-7.96 (m, 1H) , 7.53-7.46 (m, 1H) , 7.39 (d, J=2.4Hz, 1H) , 7.17 (d, J=2.4Hz, 1H) , 5.03 (s, 1H) , 4.94 (s, 1H) , 4.56-4.46 (m, 1H) , 4.38-4.28 (m, 1H) , 4.19-3.03 (m, 11H) , , 2.72-2.33 (m, 3H) , 1.73-1.66 (m, 5H) , 1.56-1.51 (m, 1H) , 0.71-0.60 (m, 1H) , 0.50-0.42 (m, 1H) . MS: 607.4 (M+H⁺) .

Example 13:

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1aS, 6aS, 6bR) -5-methy lhexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Cpd. NO. 13)

Step 1: ( (1aS, 6aS, 6bR) -5-methylhexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methanol

The mixture of ( (1aS, 6aS, 6bR) -5-methylenehexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methanol (60 mg, 0.363 mmol; example 11, step 4) and Pd/C (38.6 mg, 10%) in MeOH (5 mL) was stirred at rt under H₂ for18hours. After the reaction, the filtrate was concentrated in vacuo to afford the title product (60 mg, 99 %) as a colorless oil, which was used in next step directly. MS: 168.4 (M+H⁺) .

Step 2: 4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1aS, 6aS, 6bR) -5-methylhexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol

The title compound was prepared essentially the same protocol described in example 6 with ( (1aS, 6aS, 6bR) -5-methylhexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methanol instead of ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methanol to afford 3.1 mg as a light yellow solid. HNMR (DMSO, 400 MHz) : 10.16 (s, 1H) , 9.04 (s, 1H) , 7.99-7.96 (m, 1H) , 7.49-7.44 (m, 1H) , 7.39 (s, 1H) , 7.17 (s, 1H) , 4.51-4.34 (m, 2H) , 4.19-3.93 (m, 3H) , 3.67-3.59 (m, 4H) , 3.20-3.17 (m, 1H) , 2.97-2.94 (m, 1H) , 2.72-2.67 (m, 2H) , 2.32-2.04 (m, 3H) , 1.72-1.67 (m, 5H) , 1.55-1.50 (m, 1H) , 1.37-1.31 (m, 1H) , 0.95 (d, J=6.4Hz, 3H) , 0.65-0.61 (m, 1H) , 0.09-0.06 (m, 1H) . MS: 609.4 (M+H⁺) .

Example 14:

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1a'S, 6a'S, 6b'R) -tetrahydro-4'H-spiro [cyclopropane-1, 5'-cyclopropa [a] pyrrolizin] -6a' (6'H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Cpd. NO. 14)

Step 1: methyl

(1a'S, 6a'S, 6b'R) -tetrahydro-4'H-spiro [cyclopropane-1, 5'-cyclopropa [a] pyrrolizine] -6a' (6'H) -carboxylate

Under Ar, to a mixture of methyl (1aS, 6aS, 6bR) -5-methylenehexahydrocyclopropa [a] pyrrolizine-6a (4H) -carboxylate (500 mg, 2.59 mmol, example 11, step 3) and CH₂I₂ (6.93 g, 25.9 mmol) in dry Tol (20 mL) was added diethylzinc (28.5 mmol) at 0℃. The reaction mixture was stirred at 0℃ -RT for 16h. Quenched with NH₄Cl aq, extracted with EA for 3 times. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo to afford the desired compound (500 mg, crude) as a light yellow oil, which was directly used in next step without purification. MS: 208.5 (M+H⁺) .

Step 2:

( (1a'S, 6a'S, 6b'R) -tetrahydro-4'H-spiro [cyclopropane-1, 5'-cyclopropa [a] pyrrolizin] -6a' (6'H) -yl) methanol

Under Ar, to a solution of methyl (1a'S, 6a'R, 6b'R) -tetrahydro-4'H-spiro [cyclopropane-1, 5'-cyclopropa [a] pyrrolizine] -6a' (6'H) -carboxylate (500 mg, crude) in dry THF (20 mL) was added LiAlH₄ (458 mg, 12.05 mmol) in portions at 0℃. The reaction mixture was stirred at rt for 1h. Quenched with Na₂SO₄.10H₂O and stirred at rt for 30min. Filtered and the filtrate was concentrated in vacuo to afford the title compound (300 mg, crude) as colorless oil, which was directly used in next step without purification.

MS: 180.4 (M+H⁺)

Step 3:

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1a'S, 6a'S, 6b'R) -tetrahydro-4'H-spiro [cyclopropane-1, 5'-cyclopropa [a] pyrrolizin] -6a' (6'H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol

The title compound was prepared essentially the same protocol described in example 6 with ( (1a'S, 6a'S, 6b'R) -tetrahydro-4'H-spiro [cyclopropane-1, 5'-cyclopropa [a] pyrrolizin] -6a' (6'H) -yl) methanol instead of ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methanol to afford 38 mg as a light yellow solid. ¹H NMR (400 MHz, DMSO) δ 10.15 (s, 1H) , 9.04 (s, 1H) , 8.00-7.95 (m, 1H) , 7.49-7.44 (m, 1H) , 7.39 (d, J = 2.4Hz, 1H) , 7.17 (d, J = 2.4 Hz, 1H) , 4.55-4.42 (m, 1H) , 4.40-4.28 (m, 2H) , 4.09 (d, J = 10.4Hz, 1H) , 3.94 (d, J = 9.2 Hz, 1H) , 3.70-3.55 (m, 4H) , 3.27-2.45 (m, 5H) , 2.10-2.02 (m, 1H) , 1.78-1.65 (m, 5H) , 1.60-1.50 (m, 2H) , 0.70-0.60 (m, 1H) , 0.55-0.40 (m, 4H) , 0.22-0.15 (m, 1H) . MS: 621.4 (M+H⁺)

Example 15:

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1a'S, 6a'R, 6b'R) -tetrahydro-4'H-spiro [cyclopropane-1, 5'-cyclopropa [a] pyrrolizin] -6a' (6'H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Cpd. NO. 15)

The title compound was prepared essentially the same protocol described in example 14 with methyl (1aS, 6aR, 6bR) -5-methylenehexahydrocyclopropa [a] pyrrolizine-6a (4H) -carboxylate methanol instead of methyl (1aS, 6aS, 6bR) -5-methylenehexahydrocyclopropa [a] pyrrolizine-6a (4H) -carboxylate to afford 3.8 mg as a light yellow solid. ¹H NMR (400 MHz, DMSO) δ 10.18 (s, 1H) , 9.06 (s, 1H) , 8.00-7.96 (m, 1H) , 7.50-7.44 (m, 1H) , 7.39 (d, J=2.4Hz, 1H) , 7.18 (d, J=2.4Hz, 1H) , 4.56-4.52 (d, J=12.8Hz, 1H) , 4.40-4.34 (m, 2H) , 4.20-4.10 (m, 1H) , 3.96 (d, J=2.0Hz, 1H) , 3.75-3.60 (m, 5H) , 3.14-3.11 (d, J=8.8Hz, 1H) , 2.99-2.88 (m, 2H) , 1.99-1.86 (m, 2H) , 1.80-1.55 (m, 7H) , 0.65-0.46 (m, 4H) , 0.44-0.32 (m, 2H) . MS: 621.4 (M+H⁺)

Example 16:

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1aR, 5aR, 6aR) -hexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-amine (Cpd. NO. 16)

Step 1: tert-butyl (1R, 5S) -3- (8-fluoro-7- (7-fluoro-3-hydroxy-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( ( (1aR, 5aR, 6aR) -hexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

Under Ar, the mixture of tert-butyl (1R, 5S) -3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( ( (1aR, 5aR, 6aR) -hexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (170 mg, 0.19 mmol) in HCl/Dioxane (2 mL) and ACN (4 mL) was stirred at rt for 2h. The volatiles were removed under reduced pressure to give a crude intermediate, which was redissolved in the solution of DIEA (123 mg, 0.95 mmol) and DCM (8 mL) , and Boc₂O (62 mg, 0.285 mmol) was added at ice-water condition. The reacion mixture was stirred at rt for 1h. Water was added and neutralized with 1N HCl aq. Extracted with DCM for 3 times, the combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo to give a residue, which was purified by silica gel columna and eluted with MeOH/DCM from 0 to 5%to afford the tilte compound (140 mg, 87 %) as light yellow oil.

MS: 851.7 (M+H⁺) .

Step 2: tert-butyl (1R, 5S) -3- (8-fluoro-7- (7-fluoro-3- ( ( (trifluoromethyl) sulfonyl) oxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( ( (1aR, 5aR, 6aR) -hexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

Under Ar, to a solution of DIEA (106 mg, 0.822 mmol) and tert-butyl (1R, 5S) -3- (8-fluoro-7- (7-fluoro-3-hydroxy-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( ( (1aR, 5aR, 6aR) -hexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (140 mg, 0.164 mmol) in dry DCM (4 mL) was added Tf₂O (70 mg, 0.247 mmol) at 0℃. The reaction mixture was stirred at 0℃ for 1h. Diluted with DCM, washed with water, brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo to give a residue, which was purified by silica gel column and eluted with MeOH/DCM from 0 to 5%to afford the desired product (100 mg, 61.8 %) as yellow oil. MS: 983.4 (M+H⁺) .

Step 3: tert-butyl (1R, 5S) -3- (7- (3- ( (diphenylmethylene) amino) -7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -8-fluoro-2- ( ( (1aR, 5aR, 6aR) -hexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

Under Ar, the mixture of tert-butyl

(1R, 5S) -3- (8-fluoro-7- (7-fluoro-3- ( ( (trifluoromethyl) sulfonyl) oxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( ( (1aR, 5aR, 6aR) -hexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (100 mg, 0.102 mmol) , diphenylmethanimine (37 mg, 0.204 mmol) , Pd₂ (dba) ₃ (9.3 mg, 0.01 mmol) , Xantphos (11.8 mg, 0.02 mmol) and Cs₂CO₃ (166 mg, 0.51 mmol) in dry Tol (4 mL) was stirred at 100℃ for 8h. Filtered and the filtrate was concentrated in vacuo to give a residue, which was purified by silica gel column and eluted with MeOH/DCM from 0 to 5%to afford the title compound (45 mg, 43.6 %) as brown oil. MS: 1014.7 (M+H⁺) .

Step 4: tert-butyl

(1R, 5S) -3- (7- (3- ( (diphenylmethylene) amino) -8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ( ( (1aR, 5aR, 6aR) -hexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

Under Ar, the mixture of tert-butyl

(1R, 5S) -3- (7- (3- ( (diphenylmethylene) amino) -7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -8-fluoro-2- ( ( (1aR, 5aR, 6aR) -hexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (40 mg, 0.039 mmol) and CsF (60 mg, 0.39 mmol) in dry DMF (1 mL) was stirred at rt for 1h. Diluted with EA, washed with water, brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo to afford the title compound (34 mg, crude) as brown oil, which was used in next step without purification directly. MS: 858.6 (M+H⁺) .

Step 5:

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1aR, 5aR, 6aR) -hexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-amine

Under Ar, the mixture of tert-butyl

(1R, 5S) -3- (7- (3- ( (diphenylmethylene) amino) -8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ( ( (1aR, 5aR, 6aR) -hexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (34 mg, crude) in EA (2 mL) and 4N HCl/Dioxane (1 mL) was stirred at rt for 3h. Quenched with NaHCO₃ aq, extracted with EA for 3 times. The combined organic layers were concentrated in vacuo and purified by pre-HPLC to afford the title compoun (2.6 mg, 11.1 %) as a white solid.

MS: 594.5 (M+H⁺) .

Example 17:

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1aS, 6aR, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyn yl-6-fluoronaphthalen-2-amine (Cpd. NO. 17A)

and

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1aR, 6aS, 6bS) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-amine (Cpd. NO. 17B)

The mixtured title compound was prepared essentially the same protocol described in example 16 with (rac) -tert-butyl (1R, 5S) -3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( ( (1aS, 6aR, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate in place of tert-butyl (1R, 5S) -3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) na phthalen-1-yl) -2- ( ( (1aR, 5aR, 6aR) -hexahydrocyclopropa [b] pyrrolizin-5a (3H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate to afford (20 mg) as a light yellow solid. ¹H NMR (400 MHz, DMSO) δ 9.04 (s, 1H) , 7.79-7.75 (m, 1H) , 7.35-7.30 (m, 1H) , 7.05-7.00 (m, 2H) , 5.65-5.60 (m, 2H) , 4.60-4.50 (m, 1H) , 4.43-4.25 (m, 1H) , 4.18-4.02 (m, 2H) , 3.86 (d, J=5.6 Hz, 1H) , 3.85-3.60 (m, 4H) , 3.34 -2.51 (m, 5H) , 2.00-1.62 (m, 9H) , 1.56-1.50 (m, 1H) , 0.65-0.55 (m, 1H) , 0.13-0.07 (m, 1H) . MS: 594.5 (M+H⁺) .

Example 18:

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-amine (Cpd. NO. 18)

The title compound was prepared essentially the same protocol described in example 16 to afford the title compound (90 mg) as a light yellow solid. ¹H NMR (400 MHz, DMSO) δ 9.05 (s, 1H) , 7.82-7.77 (m, 1H) , 7.39-7.33 (m, 1H) , 7.08-7.00 (m, 2H) , 5.67 (s, 2H) , 4.55-4.45 (m, 1H) , 4.38-4.30 (m, 1H) , 4.20-4.03 (m, 2H) , 3.89 (d, J = 5.6 Hz, 1H) , 3.70-3.50 (m, 4H) , 3.33-2.55 (m, 5H) , 2.00-1.60 (m, 9H) , 1.60-1.50 (m, 1H) , 0.68-0.60 (m, 1H) , 0.13-0.08 (m, 1H) . MS: 594.5 (M+H⁺) .

Example 19:

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) -8-methoxypyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Cpd. NO. 19)

Step 1: tert-butyl

(1R, 5S) -3- (7-chloro-2- ( ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) -8-methoxypyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

Under Ar, to a suspension of methanol (32 mg, 1.10 mmol) and NaH (80 mg, 2.20 mmol) in dry THF (5 mL) was added tert-butyl (1R, 5S) -3- (7-chloro-8-fluoro-2- ( ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (200 mg, 0.367 mmol) at 40℃. The reaction mixture was stirred at 40℃ for 4h.Quenched with NH₄Cl aq at ice-water condition, extracted with EA for 3 times. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo to give a residue, which was purified by silica gel column and eluted with MeOH/DCM from 0 to 5%to afford the title compound (150 mg, 77 %) as a yellow solid. MS: 557.4 (M+H⁺)

Step 2:

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) -8-methoxypyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol

The title compound was prepared essentially the same protocol described in example 6 to afford the title compound (38 mg) as a light yellow solid. ¹H NMR (400 MHz, DMSO) δ 10.07 (s, 1H) , 8.92 (s, 1H) , 7.98-7.92 (m, 1H) , 7.48-7.40 (m, 1H) , 7.34 (d, J = 2.4Hz, 1H) , 7.09 (d, J = 2.4 Hz, 1H) , 4.51 (d, J = 12.0 Hz, 1H) , 4.25 (d, J = 12.0 Hz, 1H) , 4.20-4.06 (m, 2H) , 3.90 (s, 1H) , 3.85 (s, 3H) , 3.68-3.63 (m, 1H) , 3.57-3.50 (m, 3H) , 3.38-3.35 (m, 1H) , 3.30-3.23 (m, 1H) , 2.98-2.92 (m, 1H) , 2.76 (d, J = 11.2 Hz, 1H) , 2.60-2.55 (m, 1H) , 1.99-1.80 (m, 3H) , 1.80-1.65 (m, 6H) , 1.60-1.50 (m, 1H) , 0.68-0.60 (m, 1H) , 0.13-0.07 (m, 1H) . MS: 607.4 (M+H⁺) .

Example 20:

4- (4- (azepan-1-yl) -8-fluoro-2- ( ( (1aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Cpd. NO. 20)

Step 1: 4- (azepan-1-yl) -2, 7-dichloro-8-fluoropyrido [4, 3-d] pyrimidine

Under Ar, to the solution of azepane (0.864 g, 8.71 mmol) in DCM (20 mL) were added N-ethyl-N-isopropylpropan-2-amine (3.07 g, 23.77 mmol) and 2, 4, 7-trichloro-8-fluoropyrido [4, 3-d] pyrimidine (2 g, 7.92 mmol) at 0℃, then the mixture was stirred at room temperature for 0.5h. Water was added, the resulting mixture was partitioned between DCM/H₂O and the separated organic layer was rinsed with brine, dried over Na₂SO₄, filtered, concentrated under reduced pressure to give a residual, which was purified by silica gel column to give the title compound (1.8 g, 72.1 %) as an yellow solid. MS: 315.2 (M+H⁺) .

Step 2:

(1aS, 6aS, 6bR) -6a- ( ( (4- (azepan-1-yl) -7-chloro-8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) octahydrocyclopropa [a] pyrrolizine

Under Ar, to the mixture of ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methanol (0.25g, 1.632 mmol; example 6, step 4) in THF (5 ml) was added sodium hydride (0.117 g, 4.89 mmol) at 0 ℃, then the mixture was stirred at RT for 0.5h. 4- (azepan-1-yl) -2, 7-dichloro-8-fluoropyrido [4, 3-d] pyrimidine (0.514 g, 1.632 mmol) was added to the above mixture at RT, then the mixture was stirred at RT for 4h. Quenched with extracted with NH₄Cl solution, extracted with EA for three times, the combined orgainc layers were washed with brine, dried over Na₂SO₄, filterd, the filtrate was concentrated in vacuo to give a residual, which was purified by silica gel column and eluted with MeOH/DCM from 0 to 5%to give the title compound (520mg, 73.8 %) as a yellow solid. MS: 432.3 (M+H⁺) .

Step 3: (1aS, 6aS, 6bR) -6a- ( ( (4- (azepan-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) pyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) octahydrocyclopropa [a] pyrrolizine

Under Ar, the mixture of (1aS, 6bR) -6a- ( ( (4- (azepan-1-yl) -7-chloro-8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) octahydrocyclopropa [a] pyrrolizine (170mg, 0.394 mmol) , ( (2-fluoro-6- (methoxymethoxy) -8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) napht halen-1-yl) ethynyl) triisopropylsilane (242 mg, 0.472 mmol) , Cs₂CO₃ (385 mg, 1.181 mmol) , Pd (dppf) Cl₂ (28.8 mg, 0.039 mmol) in Water (2 mL) and 1, 4-Dioxane (16 mL) was stirred at 100 ℃ for 16h. After cooling down to RTto rt, EA was added, the separared organic layer was washed with brine, dried over Na₂SO₄, filtered, concentrated in vacuo to give a residual which was purified by silica gel column and eluted with MeOH/DCM from 0 to 2%to give the title compound (115mg, 37.4 %) as a brown solid. MS: 782.6 (M+H⁺) .

Step 4:

4- (4- (azepan-1-yl) -8-fluoro-2- ( ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol

Under Ar, the mixture of (1aS, 6bR) -6a- ( ( (4- (azepan-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) pyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) octahy drocyclopropa [a] pyrrolizine (105mg, 0.134 mmol) and CsF in dry DMF (1 mL) was stirred at rt for 2h. EA was added, the separated organic layer was washed with brine and concentrated in vacuo to give a residual. which was redissolved in 4N HCl/Dioxane solution and stirred at rt for 2h. Quenched with NH₃/MeOH, the resulting mixture was concentrated under reduced pressure to give a residual, which was purified by pre-HPLC to afford the title compound (12mg, 15.37 %) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.24 (s, 1H) , δ 9.08 (s, 1H) , 8.05 –7.91 (m, 1H) , 7.51 –7.33 (m, 2H) , 7.18 (d, J = 2.5 Hz, 1H) , 4.13 –1.54 (m, 25H) 0.67 –0.55 (m, 1H) , 0.18 –0.01 (m, 1H) . MS: 582.4 (M+H⁺)

Example 21:

(R) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- ( ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3-methylpiperidin-3-ol (Cpd. NO. 21)

The title compound was prepared essentially the same protocol described in example 20 with (R) -3-methylpiperidin-3-ol in place of azepane to afford (2.2 mg) as a brown solid. MS: 598.4 (M+H⁺) .

Example 22:

5-ethynyl-6-fluoro-4- (8-fluoro-2- ( ( (1aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) -4- (1, 4-oxazepan-4-yl) pyrido [4, 3-d] pyrimidin-7-yl) naphthalen-2-ol (Cpd. NO. 22)

Step 1: 4- (2, 7-dichloro-8-fluoropyrido [4, 3-d] pyrimidin-4-yl) -1, 4-oxazepane

Under Ar, to a solution of 2, 4, 7-trichloro-8-fluoropyrido [4, 3-d] pyrimidine (2.5 g, 9.9 mmol) and DIPEA (3.84 g, 29.7 mmol) in dry THF (50 ml) was added 1, 4-oxazepane (1.0 g, 9.9 mmol) at 0℃. Then the mixture was stirred at 0℃ for 1h. Water was added, the resulting mixture was extracted with EA for 3 times. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo to give a residual, which was purified by silica gel column and eluted with EA/Hex from 0 to20%to afford the title compound (2.5 g, 80 %) as a yellow solid. MS: 317.2 (M+H+) .

Step 2: 5-ethynyl-6-fluoro-4- (8-fluoro-2- ( ( (1aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4 H) -yl) methoxy) -4- (1, 4-oxazepan-4-yl) pyrido [4, 3-d] pyrimidin-7-yl) naphthalen-2-ol

The title compound was prepared essentially the same protocol described in example 20 with 4- (2, 7-dichloro-8-fluoropyrido [4, 3-d] pyrimidin-4-yl) -1, 4-oxazepane in place of 4- (azepan-1-yl) -2, 7-dichloro-8-fluoropyrido [4, 3-d] pyrimidine (step 1) to afford (36 mg) as a brown solid. ¹H NMR (400 MHz, DMSO) δ 10.19 (s, 1H) , 9.14 (s, 1H) , 8.04-7.98 (m, 1H) , 7.53-7.48 (m, 1H) , 7.30 (d, J=2.4Hz, 1H) , 7.22 (d, J=2.4Hz, 1H) , 4.22-3.96 (m, 9H) , 3.83-3.76 (m, 2H) , 3.28-3.22 (m, 1H) , 2.98-2.91 (m, 1H) , 2.80-2.74 (m, 1H) , 2.60-2.55 (m, 1H) , 2.18-2.11 (m, 2H) , 2.00-1.70 (m, 5H) , 1.58-1.52 (m, 1H) , 0.68-0.60 (m, 1H) , 0.16-0.10 (m, 1H) . MS: 584.5 (M+H⁺) .

Example 23:

5-ethynyl-6-fluoro-4- (8-fluoro-4- (5-fluoro-3, 6-dihydropyridin-1 (2H) -yl) -2- ( ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) naphthalen-2-ol (Cpd. NO. 23)

Step 1: tert-butyl 5-fluoro-3, 6-dihydropyridine-1 (2H) -carboxylate and tert-butyl 3, 3-difluoropiperidine-1-carboxylate

Under Ar, to the solution of tert-butyl 3-oxopiperidine-1-carboxylate (8.0 g, 40.2 mmol) in THF (100 mL) was added DAST (19.42 g, 120 mmol) at 0℃, then the mixture was stirred at 60℃ for 6h. The TLC showed the reation was completed. Iced Water was added, the resulting mixture was partitioned between EA/H₂O, and the organic layers were rinsed with brine, dried over Na₂SO₄, filtered, and concentrated and purified on flash chromatography column to afford the title mixture (8.90g) .

Step 2: 5-fluoro-1, 2, 3, 6-tetrahydropyridine and 3, 3-difluoropiperidine

Under Ar, to a mixture of tert-butyl 5-fluoro-3, 6-dihydropyridine-1 (2H) -carboxylate and tert-butyl 3, 3-difluoropiperidine-1-carboxylate (8.9 g) in DCM (100 mL) was added TFA (30 mL) at r. t. After stirred at room temperature for 1 h, the volatiles were removed in reduced pressure to afford the title crude mixture, which was used in next step directly without further purification.

Step 3:

2, 7-dichloro-8-fluoro-4- (5-fluoro-3, 6-dihydropyridin-1 (2H) -yl) pyrido [4, 3-d] pyrimidine and 2, 7-dichloro-4- (3, 3-difluoropiperidin-1-yl) -8-fluoropyrido [4, 3-d] pyrimidine

Under Ar, the mixture of 5-fluoro-1, 2, 3, 6-tetrahydropyridine and 3, 3-difluoropiperidine (0.9 g) and 2, 4, 7-trichloro-8-fluoropyrido [4, 3-d] pyrimidine (1.5 g, 5.94 mmol) and DIPEA (1.536 g, 11.88 mmol) in THF (20 mL) was stirred at RT for 2h. After the reaction, the mixture was partitioned between EA/Water, the separated organic layer was washed with brine, dried over Na₂SO₄, concentrated under reduced pressure to give a residual, which was purified by silica gel column to give 2, 7-dichloro-4- (3, 3-difluoropiperidin-1-yl) -8-fluoropyrido [4, 3-d] pyrimidine (650mg) as a yellow solid. MS: 337.2 (M+H⁺) . and 2, 7-dichloro-8-fluoro-4- (5-fluoro-3, 6-dihydropyridin-1 (2H) -yl) pyrido [4, 3-d] pyrimidine (1.0 g) as a yellow solid. MS: 317.2 (M+H⁺) .

Step 3: 5-ethynyl-6-fluoro-4- (8-fluoro-4- (5-fluoro-3, 6-dihydropyridin-1 (2H) -yl) -2- ( ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) naphthalen-2-ol

The title compound was prepared essentially the same protocol described in example 20 with 2, 7-dichloro-8-fluoro-4- (5-fluoro-3, 6-dihydropyridin-1 (2H) -yl) pyrido [4, 3-d] pyrimidi ne in place of 4- (azepan-1-yl) -2, 7-dichloro-8-fluoropyrido [4, 3-d] pyrimidine to afford (14 mg) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.17 (s, 1H) , 9.05 (s, 1H) , 7.98 (dd, J = 9.2, 5.9 Hz, 1H) , 7.46 (t, J = 9.0 Hz, 1H) , 7.40 (d, J = 2.6 Hz, 1H) , 7.20 (d, J = 2.6 Hz, 1H) , 5.64 (d, J = 16.4 Hz, 1H) , 4.55-4.41 (m, 2H) , 4.24 –4.15 (m, 1H) , 4.14-4.06 (m, 2H) , 4.02 (dd, J = 4.8, 1.0 Hz, 1H) , 3.92-3.81 (m, 1H) , 3.25-1.48 (m, 12H) , 0.68 –0.52 (m, 1H) , 0.13-0.06 (m, 1H) . MS: 584.5 (M+H⁺) .

Example 24:

5-ethynyl-6-fluoro-4- (8-fluoro-4- ( ( (1R, 2R) -2-fluorocyclopropyl) (methyl) amino) -2- ( ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) naphthalen-2-ol (Cpd. NO. 24A) and 5-ethynyl-6-fluoro-4- (8-fluoro-4- ( ( (1S, 2S) -2-fluorocyclopropyl) (methyl) amino) -2- ( ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) naphthalen-2-ol (Cpd. NO. 24B)

Step 1: 2, 7-dichloro-8-fluoro-N- ( (1R, 2R) -2-fluorocyclopropyl) pyrido [4, 3-d] pyrimidin-4-amine and 2, 7-dichloro-8-fluoro-N- ( (1S, 2S) -2-fluorocyclopropyl) pyrido [4, 3-d] pyrimidin-4-amine

Under Ar, to the mixture of trans-2-fluorocyclopropan-1-amine hydrochloride (750 mg, 6.72 mmol) , DIPEA (4345 mg, 33.6 mmol) in DCM (10 mL) was added 2, 4, 7-trichloro-8-fluoropyrido [4, 3-d] pyrimidine (1697 mg, 6.72 mmol) at -40 ℃, then the mixture was stirred at rt for 2h. Water was added, extracted three times with DCM, the combined organic layers were washed with brine. dried over Na₂SO₄, filtered, concentrated in vacuo to give a residue which was purified by silica gel column and eluted with PE/DCM=1: 1 to afford the title compound (1.75g, 89 %) as a yellow solid.

MS:291.1, 293.1 (M+H⁺) .

Step 2:

2, 7-dichloro-8-fluoro-N- ( (1R, 2R) -2-fluorocyclopropyl) -N-methylpyrido [4, 3-d] pyrimidin-4-amine and

2, 7-dichloro-8-fluoro-N- ( (1S, 2S) -2-fluorocyclopropyl) -N-methylpyrido [4, 3-d] pyrimidin-4-amine

Under Ar, to the mixture of 2, 7-dichloro-8-fluoro-N- ( (1R, 2R) -2-fluorocyclopropyl) pyrido [4, 3-d] pyrimidin-4-amine and 2, 7-dichloro-8-fluoro-N- ( (1S, 2S) -2-fluorocyclopropyl) pyrido [4, 3-d] pyrimidin-4-amine (650 mg, 2.233 mmol) in dry THF (10 mL) was added NaH (179 mg, 4.47 mmol) at 0 ℃, after stirred at rt for 30mins, MeI (1268 mg, 8.93 mmol) was added at ice-water condition, then the mixture was stirred at rt for 2h. Quenched with water, extracted with EA for three times, the combined organic layers were washed with brine. dried over Na₂SO₄, filtered, concentrated in vacuo to give a residue which was purified by silica gel column and eluted with PE/DCM=3: 1 to afford the title mixture compound (110mg, 16.15 %) as a white solid. MS: 305.2 (M+H⁺) .

Step 3: 5-ethynyl-6-fluoro-4- (8-fluoro-4- ( ( (1R, 2R) -2-fluorocyclopropyl) (methyl) amino) -2- ( ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) naphthalen-2-ol and 5-ethynyl-6-fluoro-4- (8-fluoro-4- ( ( (1S, 2S) -2-fluorocyclopropyl) (methyl) amino) -2- ( ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) naphthalen-2-ol

The title compound was prepared essentially the same protocol described in example 20 to afford (11 mg) as a yellow solid. ¹H-NMR (DMSO-d₆, 400M) : 10.14 (s, 1H) , 9.48 (d, J=15.6Hz, 1H ) , 8.00-7.96 (m, 1H) , 7.47 (t, J=8.8Hz, 1H) , 7.39 (d, J=2.4Hz, 1H) , 7.20 (d, J=2.4Hz, 1H) , 5.09-4.83 (m, 1H) , 4.17-3.97 (m, 4H) , 3.34-2.52 (m, 7H) , 1.93-1.22 (m, 8H) , 0.63-0.57 (m, 1H) , 0.10-0.06 (m, 1H) . MS: 572.6 (M+H⁺) .

Example 25:

5-ethynyl-6-fluoro-4- (8-fluoro-4- ( ( (1R, 2R) -2-fluorocyclopropyl) (methyl-d3) amino) -2- ( ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) naphthalen-2-ol (Cpd. NO. 25A) and 5-ethynyl-6-fluoro-4- (8-fluoro-4- ( ( (1S, 2S) -2-fluorocyclopropyl) (methyl-d3) amino) -2- ( ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) naphthalen-2-ol (Cpd. NO. 25B)

Step 1: 2, 7-dichloro-8-fluoro-N- ( (1R, 2R) -2-fluorocyclopropyl) -N- (methyl-d3) pyrido [4, 3-d] pyrimidin-4-amine and 2, 7-dichloro-8-fluoro-N- ( (1S, 2S) -2-fluorocyclopropyl) -N- (methyl-d3) pyrido [4, 3-d] pyrimidin-4-amine

Under Ar, to the mixture of 2, 7-dichloro-8-fluoro-N- ( (1R, 2R) -2-fluorocyclopropyl) pyrido [4, 3-d] pyrimidin-4-amine and 2, 7-dichloro-8-fluoro-N- ( (1S, 2S) -2-fluorocyclopropyl) pyrido [4, 3-d] pyrimidin-4-amine (2.31 g, 7.94 mmol, example 24, step 1) in dry DMF (20 mL) was added sodium hydride (0.381 g, 15.87 mmol) at 0 ℃, then the mixture was stirred at rt for 30mins. Iodomethane-d₃ (4.60 g, 31.7 mmol) was added at rt, the resulting mixture was stirred at rt for 2h. Quenched with water, extracted three times with EA. The combined organic layers were washed with brine, dried over Na₂SO₄, concentrated under reduced pressure to give a residual, which was purified by silica gel column to afford the title compound (780mg, 31.9 %) as a yellow solid. MS: 308.2 (M+H⁺) .

Step 2: 5-ethynyl-6-fluoro-4- (8-fluoro-4- ( ( (1R, 2R) -2-fluorocyclopropyl) (methyl-d3) amino) -2- ( ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) naphthalen-2-ol and 5-ethynyl-6-fluoro-4- (8-fluoro-4- ( ( (1S, 2S) -2-fluorocyclopropyl) (methyl-d3) amino) -2- ( ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) naphthalen-2-ol

The title compound was prepared essentially the same protocol described in example 20 to afford (40 mg) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.15 (s, 1H) , 9.55 –9.37 (m, 1H) , 7.98 (dd, J = 9.2, 5.9 Hz, 1H) , 7.46 (t, J = 9.0 Hz, 1H) , 7.40 (d, J = 2.5 Hz, 1H) , 7.20 (d, J = 2.5 Hz, 1H) , 5.14 –4.80 (m, 1H) , 4.21 –3.91 (m, 4H) , 3.22 (dd, J = 11.4, 4.1 Hz, 1H) , 2.95-2.88 (m, 1H) , 2.73 (d, J = 11.3 Hz, 1H) , 2.54 –1.17 (m, 9H) , 0.63-0.56 (m, 1H) , 0.11-0.05 (m, 1H) . MS: 575.6 (M+H⁺) .

Example 26:

4- (4- (5-oxa-2-azabicyclo [5.1.0] octan-2-yl) -8-fluoro-2- ( ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Cpd. NO. 26)

Step 1: benzyl 5-oxo-1, 4-oxazepane-4-carboxylate

Under Ar, to a solution of 1, 4-oxazepan-5-one (5 g, 43.4 mmol) in THF (130 mL) was added butyllithium (2.79 g, 43.5 mmol) dropwise at -78 ℃. After the addition, the mixture stirred at -78 ℃ for 30 mins, benzyl carbonochloridate (7.42 g, 43.5 mmol) in THF (50 mL) was added dropwise at -78 ℃. After 4 hours later, the mixture was quenched with saturated NH₄Cl, the resulting mixture was extracted three time with EA, and the combined organic layers were washed with brine, dried over MgSO₄, concentrated in vacuo to give a residual, which was purified by silica gel column to afford the title compound (7.4 g, 68.4 %) as a colorless oil.

Step 2: benzyl 2, 3-dihydro-1, 4-oxazepine-4 (7H) -carboxylate

Under Ar, to a solution of benzyl 5-oxo-1, 4-oxazepane-4-carboxylate (3.2 g, 12.84 mmol) in toluene (30 mL) was added lithium triethylhydroborate (1.632 g, 15.41 mmol) at -78 ℃ and then the mixture was stirred at this temperature for 2 hours. DIPEA (8.30 g, 64.2 mmol) , DMAP (0.157 g, 1.284 mmol) and TFAA (3.24 g, 15.41 mmol) were added at -78 ℃. Then the resulting mixture was stirred at RT for 12 hours. Quenched with f saturated NH4Cl solution, the resulting mixture was extracted three times with EA, the combined organic layers were washed with brine, dried over MgSO4, concentrated in vacuo to give a residual, which was purified by silica gel column to afford the title compound (1.7 g, 56.8 %) as oil. 1H NMR (400 MHz, CDCl3) δ 7.40 –7.33 (m, 5H) , 6.74 (s, 1H) , 5.19 (s, 2H) , 4.94 (d, J = 9.0 Hz, 1H) , 4.22 (dd, J = 4.4, 1.5 Hz, 2H) , 3.85 (d, J = 30.0 Hz, 4H) .

Step 3: benzyl 5-oxa-2-azabicyclo [5.1.0] octane-2-carboxylate

Under Ar, to a solution of benzyl 2, 3-dihydro-1, 4-oxazepine-4 (7H) -carboxylate (1.7 g, 7.29 mmol) in DCM (10 mL) was ZnEt₂ (22 mmol) at RT, and then the mixture was stirre at rt for 30mins. CH₂I₂ (9.6 g, 36 mmol) was added to the above mixture at 0 ℃. At last the mixture was stirred at RT for 16h. Quenched with NH₄Cl aq, the resulting mixture was extracted three times with EA, the combined organic layers were washed with brine, dried over MgSO4, concentrated in vacuo to give a residual, which was purified by silica gel column to afford the title compound (1.55 g, 86 %) . MS: 248.3 (M+H⁺)

Step 4: 5-oxa-2-azabicyclo [5.1.0] octane

The mixture of benzyl 5-oxa-2-azabicyclo [5.1.0] octane-2-carboxylate (1.3 g, 5.26 mmol) and Pd-C (90mg ) in MeOH (20 mL) was stirred at hydrogen condition for 48 hours at RT. The filtrate was concentrated in vacuo to give the title compound (0.4 g, 67.2 %) as colorless oil.

MS: 114.2 (M+H⁺)

Step 5: 4- (4- (5-oxa-2-azabicyclo [5.1.0] octan-2-yl) -8-fluoro-2- ( ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol

The title compound was prepared essentially the same protocol described in example 20 with 5-oxa-2-azabicyclo [5.1.0] octane in place of 4- (azepan-1-yl) -2, 7-dichloro-8-fluoropyrido [4, 3-d] pyrimidine (step 1) to afford (19 mg) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.20–6.91 (m, 7H) , 5.50–1.35 (m, 20H) , 0.91–-0.25 (m, 4H) . MS: 596.4 (M+H⁺) .

Example 27:

4- (4- (3-azabicyclo [4.1.0] heptan-3-yl) -8-fluoro-2- ( ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Cpd. NO. 27)

The title compound was prepared essentially the same protocol described in example 20 with 3-azabicyclo [4.1.0] heptane in place of azepane to afford (40 mg) as a brown solid. MS: 580.4 (M+H⁺) .

Example 28:

4- (4- (cyclopropyl (methyl) amino) -8-fluoro-2- ( ( (1aS, 6aS, 6bR) -hexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Cpd. NO. 28)

The title compound was prepared essentially the same protocol described in example 20 with 3-azabicyclo [4.1.0] heptane in place of azepane to afford (2 mg) as a brown solid. MS: 554.4 (M+H⁺) .

Eaample 29:

5-ethynyl-6-fluoro-4- (8-fluoro-2- ( ( (1aS, 6aS, 6bR) -5-methylenehexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) -4- (1, 4-oxazepan-4-yl) pyrido [4, 3-d] pyrimidin-7-yl) naphthalen-2-ol (Cpd. NO. 29)

Step 1: 4- (7-chloro-8-fluoro-2- ( ( (1aS, 6aS, 6bR) -5-methylenehexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -1, 4-oxazepane

Under Ar, to a solution of

( (1aS, 6aS, 6bR) -5-methylenehexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methanol (0.157 g, 0.952 mmol; example 11, step 4) in THF (5 mL) was added NaH (0.114 g, 2.86 mmol) at RT. After stirred for 10mins, 4- (2, 7-dichloro-8-fluoropyrido [4, 3-d] pyrimidin-4-yl) -1, 4-oxazepane (0.3 g) was added and then the mixture was stirred at rt overnight. Quenched with NH₄Cl solution, the resulting mixture was extracted three time with EA, the combined organic layers were washed with brine, dried over Na₂SO₄, concentrated in vacuo to give a residual, which was purified by silica gel column and eluted with MeOH/DCM from 0 to 5%to afford the title compound (0.105 g) as a yellow solid. MS: 446.4 (M+H⁺) .

Step 2: 5-ethynyl-6-fluoro-4- (8-fluoro-2- ( ( (1aS, 6aS, 6bR) -5-methylenehexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) -4- (1, 4-oxazepan-4-yl) pyrido [4, 3-d] pyrimidin-7-yl) naphthalen-2-ol

The title compound was prepared essentially the same protocol described in example 20 with 4- (7-chloro-8-fluoro-2- ( ( (1aS, 6aS, 6bR) -5-methylenehexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -1, 4-oxazepane in place of (1aS, 6aS, 6bR) -6a- ( ( (4- (azepan-1-yl) -7-chloro-8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) octahydrocyclopropa [a] pyrrolizine (example 20, step 2) to afford the (20 mg) as a yellow solid. ¹H NMR (400 MHz, DMSO) δ 10.21 (s, 1H) , 9.13 (s, 1H) , 8.00 (dd, J = 9.1, 6.0 Hz, 1H) , 7.49 (t, J = 9.0 Hz, 1H) , 7.42 (d, J = 2.0 Hz, 1H) , 7.21 (d, J = 1.9 Hz, 1H) , 4.88 (d, J = 18.3 Hz, 2H) , 4.28 –2.54 (m, 15H) , 2.19 –1.19 (m, 6H) , 0.68 –0.55 (m, 1H) , 0.22 –0.06 (m, 1H) . MS: 596.4 (M+H⁺) .

Example 30:

5-ethynyl-6-fluoro-4- (8-fluoro-4- (5-fluoro-3, 6-dihydropyridin-1 (2H) -yl) -2- ( ( (1aS, 6aS, 6bR) -5-methylenehexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) naphthalen-2-ol (Cpd. NO. 30)

The title compound was prepared essentially the same protocol described in example 29 with 5-fluoro-1, 2, 3, 6-tetrahydropyridine in place of 1, 4-oxazepane to afford 13 mg as a yellow solid. MS: 596.4 (M+H⁺) .

¹H NMR (400 MHz, DMSO-d₆) δ 10.17 (s, 1H) , 9.05 (s, 1H) , 7.98 (dd, J = 9.2, 6.0 Hz, 1H) , 7.55 –7.37 (m, 2H) , 7.21 (dd, J = 5.1, 2.6 Hz, 1H) , 5.64 (d, J = 16.5 Hz, 1H) , 4.85 (d, J = 18.6 Hz, 2H) , 4.52-3.30 (m, 11H) , 2.86 –1.43 (m, 6H) , 0.63-0.55 (m, 1H) , 0.17-0.10 (m, 1H) .

Example 31:

4- (4- (3, 3-difluoropiperidin-1-yl) -8-fluoro-2- ( ( (1aS, 6aS, 6bR) -5-methylenehexahydroc yclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Cpd. NO. 31)

The title compound was prepared essentially the same protocol described in example 29 to afford 4 mg as a yellow solid. MS: 616.5 (M+H⁺) .

Example 32:

5-ethynyl-6-fluoro-4- (8-fluoro-4- ( ( (1R, 2R) -2-fluorocyclopropyl) (methyl-d3) amino) -2 - ( ( (1aS, 6aS, 6bR) -5-methylenehexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) naphthalen-2-ol (Cpd. NO. 32A) and

5-ethynyl-6-fluoro-4- (8-fluoro-4- ( ( (1S, 2S) -2-fluorocyclopropyl) (methyl-d3) amino) -2- ( ( (1aS, 6aS, 6bR) -5-methylenehexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) naphthalen-2-ol (compound 32) . (Cpd. NO. 32B)

The title compound was prepared essentially the same protocol described in example 29 with 2, 7-dichloro-8-fluoro-N- ( (1R, 2R) -2-fluorocyclopropyl) -N- (methyl-d3) pyrido [4, 3-d] pyrimidin-4-amine and 2, 7-dichloro-8-fluoro-N- ( (1S, 2S) -2-fluorocyclopropyl) -N- (methyl-d3) pyrido [4, 3-d] pyrimidin-4-amine (example 25, step 1) in place of 4- (2, 7-dichloro-8-fluoropyrido [4, 3-d] pyrimidin-4-yl) -1, 4-oxazepane to afford 18 mg as a yellow solid. MS: 587.5 (M+H⁺) . ¹H NMR (400 MHz, DMSO-d₆) δ 10.15 (s, 1H) , 9.48 (d, J = 14.9 Hz, 1H) , 7.98 (dd, J = 9.2, 5.9 Hz, 1H) , 7.47 (t, J = 9.0 Hz, 1H) , 7.40 (d, J = 2.6 Hz, 1H) , 7.20 (d, J = 2.5 Hz, 1H) , 5.1-4.9 (m, 1H) , 4.85 (d, J = 17.7 Hz, 2H) , 4.18 –3.92 (m, 5H) , 3.56 (d, J = 13.1 Hz, 1H) , 3.23 (s, 2H) , 2.78 (d, J = 11.4 Hz, 1H) , 2.68-2.54 (m, 2H) , 1.81 –1.57 (m, 3H) , 1.53-1.47 (m, 1H) , 1.35-1.26 (m, 1H) , 0.59 (q, J = 7.1 Hz, 1H) , 0.18-0.09 (m, 1H) .

Example 33:

5-ethynyl-6-fluoro-4- (8-fluoro-4- ( ( (1R, 2R) -2-fluorocyclopropyl) (methyl) amino) -2- ( ( (1aS, 6aS, 6bR) -5-methylenehexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) naphthalen-2-ol (Cpd. NO. 33A) and

5-ethynyl-6-fluoro-4- (8-fluoro-4- ( ( (1S, 2S) -2-fluorocyclopropyl) (methyl) amino) -2- ( ( (1aS, 6aS, 6bR) -5-methylenehexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) naphthalen-2-ol (Cpd. NO. 33B)

The title compound was prepared essentially the same protocol described in example 29 with

2, 7-dichloro-8-fluoro-N- ( (1R, 2R) -2-fluorocyclopropyl) -N-methylpyrido [4, 3-d] pyrimi din-4-amine and

2, 7-dichloro-8-fluoro-N- ( (1S, 2S) -2-fluorocyclopropyl) -N-methylpyrido [4, 3-d] pyrimi din-4-amine (example 24, step 2) in place of

4- (2, 7-dichloro-8-fluoropyrido [4, 3-d] pyrimidin-4-yl) -1, 4-oxazepane to afford 18 mg as a yellow solid. MS: 584.5 (M+H⁺) .

Example 34:

(R) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- ( ( (1aS, 6aS, 6bR) -5-methylenehexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3-methylpiperidin-3-ol (Cpd. NO. 34)

The title compound was prepared essentially the same protocol described in example 29 to afford 10 mg as a yellow solid. MS: 610.4 (M+H⁺) .

Example 35:

5-ethynyl-6-fluoro-4- (8-fluoro-4- (1, 4-oxazepan-4-yl) -2- ( ( (1a'S, 6a'S, 6b'R) -tetrahydro-4'H-spiro [cyclopropane-1, 5'-cyclopropa [a] pyrrolizin] -6a' (6'H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) naphthalen-2-ol (Cpd. NO. 35)

The title compound was prepared essentially the same protocol described in example 29 with ( (1a'S, 6a'S, 6b'R) -tetrahydro-4'H-spiro [cyclopropane-1, 5'-cyclopropa [a] pyrrolizin] -6a' (6'H) -yl) methanol (example 14, step 2) in place of ( (1aS, 6aS, 6bR) -5-methylenehexahydrocyclopropa [a] pyrrolizin-6a (4H) -yl) methanol to afford 17 mg as a yellow solid. MS: 610.4 (M+H⁺) .

Example 36:

5-ethynyl-6-fluoro-4- (8-fluoro-4- (5-fluoro-3, 6-dihydropyridin-1 (2H) -yl) -2- ( ( (1a'S, 6a' S, 6b'R) -tetrahydro-4'H-spiro [cyclopropane-1, 5'-cyclopropa [a] pyrrolizin] -6a' (6'H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) naphthalen-2-ol (Cpd. NO. 36)

The title compound was prepared essentially the same protocol described in example 29 to afford 30 mg as a yellow solid. MS: 610.4 (M+H⁺) .

Example 37:

5-ethynyl-6-fluoro-4- (8-fluoro-4- ( ( (1R, 2R) -2-fluorocyclopropyl) (methyl-d3) amino) -2 - ( ( (1a'S, 6a'S, 6b'R) -tetrahydro-4'H-spiro [cyclopropane-1, 5'-cyclopropa [a] pyrrolizin] -6 a' (6'H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) naphthalen-2-ol (Cpd. NO. 37A) and 5-ethynyl-6-fluoro-4- (8-fluoro-4- ( ( (1S, 2S) -2-fluorocyclopropyl) (methyl-d3) amino) -2- ( ( (1a'S, 6a'S, 6b'R) -tetrahydro-4'H-spiro [cyclopropane-1, 5'-cyclopropa [a] pyrrolizin] -6a' (6'H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) naphthalen-2-ol (Cpd. NO. 37B)

The title compound was prepared essentially the same protocol described in example 29 to afford 24 mg. ¹H NMR (400 MHz, DMSO) δ 10.17 (s, 1H) , 9.57 –9.41 (m, 1H) , 8.01 (dd, J = 9.2, 5.9 Hz, 1H) , 7.49 (t, J = 9.0 Hz, 1H) , 7.43 (d, J = 2.5 Hz, 1H) , 7.23 (d, J = 2.4 Hz, 1H) , 5.16 –4.80 (m, 1H) , 4.48 –4.28 (m, 1H) , 4.23 –3.95 (m, 3H) , 2.98 –2.66 (m, 2H) , 2.20 –2.04 (m, 1H) , 1.84 –1.52 (m, 4H) , 1.40 –1.12 (m, 3H) , 0.67 (dd, J = 12.9, 7.9 Hz, 1H) , 0.58 –0.39 (m, 4H) , 0.21 (d, J = 3.7 Hz, 1H) . MS: 601.4 (M+H+) .

Cellular proliferation assay

Cellular proliferation assay in GP2d cells (KRAS G12D)

The inhibitory effect of test compounds on cellular proliferation was determined usingluminescent cell viability assay (Promega) following manufactur er’s instruction.

GP2d cells (ECACC #95090715) were cultured in DMEM medium supplemented with 10%fetal bovine serum, 10 U/ml penicillin and 10 ug/ml streptomycin. Cells were plated in 96-well plates at a density of 2000 cells/well and allowed attach for 120-24 hours. Then the cells were treated with various concentrations of test compounds for 72 hours. Reagent was added to wells and incubated for 10 minutes at room temperature. The plates were read on 96 Microplate Luminometer or compatible microplate readers. The percentage of cellular viability was calculated as:

Cellular viability = (mean RLU sample –mean RLU blank) / (RLU cell control -RLU blank) × 100. IC₅₀ value was calculated using GraphPad Prism (San Diego, CA) . The assays were carried out in triplicates.

Cellular proliferation assay in SW620 cells (KRAS G12V) :

1. Cell Culture

The cancer cell line SW620 was maintained in culture conditions (L-15 medium with 10%FBS ) at 37℃ in an atmosphere of 5%CO2 in air. The tumor cells were routinely subcultured. The cells growing in an exponential growth phase were harvested and counted for plating.

2. Cell Plating

(1) . Count cells by cell counter.

(2) . Adjust the cell concentration to 1 ×10⁴ cell/ml.

(3) . Plate 95 μl of cell suspension (about 1×10³ cells/well) into the assay plates according to the plate map. Add 95 μl of assay medium into the Blank wells.

(4) . Incubate the plates at 37℃, 5%CO₂, 95%air and 100%relative humidity for 4 hours.

3. Compound stock plate preparation

Preparation of compound stock plate (400X stock plates) : Serially dilute the stock solution from highest concentration down to lowest in DMSO according to the plate map (table 1) .

4. Compound Plate (20X) Preparation and Compound Treatment

(1) . 20X concentrate compound plate preparation: add 95 μl of assay medium into each well of the V-bottom plate; then transfer 5 μl of the stock compound solution of each concentration from the stock plate (400X stock) . Add 5 μl of DMSO into the Blank and Control wells. Pipette up and down to mix well. This V-plate is designated as the 20X concentrate compound plate.

(2) . Compound treatment: add 5 μl of the compound-medium of each well from the 20X concentrate compound plate into the cells in 96-well assay plate according to the plate map. Add 5 μl of the DMSO-medium into the Blank and Control wells. The final DMSO concentration was 0.25%.

(3) . Return the assay plate into incubator and incubate for 3 days

5. CTG Cell Viability Assay

(1) . Add 30 μl CTG Reagent in each well.

(2) . Mix contents for 2 minutes on an orbital shaker. Allow the plate to incubate at room temperature for 15mins to stabilize signal.

(3) . Record RLU on the Biotek plate reader.

6. Data analysis

Cell vialibity of the tested compounds was determined by the following formula:

(RLU_compound-RLU_blank) / (RLU_control-RLU_blank) *100%

All the cell vialibity of different dose of compound were calculated in Excel file, and then were used to plot curve and evaluate related parameters, such as Min, Max and IC50. The data were interpreted by GraphPad Prism. The results are provided in Table 1.

Table 1

na: no available

p-ERK Assay

The expression of p-ERK was detected in this assay. At first, the AGS cells (40000 cells/well) were seeded in 96-well plate culture overnight and treated with KRAS-G12D compounds inhibitors at concentrations of 1, 0.33, 0.11, 0.03, 0.01, 0.004, 0.001, 0.0004, 0.0001 μM for 3 h at 37 ℃. Then, add an equal volume (100 μL) of 8%paraformaldehyde solution to fix and crosslink the cells to the microplate for 15 minutes. Add 100 μL of 1X permeabilization solution to wells for 30 min and add 100 μL of 1X blocking solution for 2 h. Wash with PBS 3 times after each reaction. At last, Incubation with primary antibody (Anti-mouse β-Actin and Anti-rabbit p-ERK) and secondary antibody (Goat anti-Mouse IgG H&L IRDye 800CW and Goat anti-Rabbit IgG H&L IRDye 680RW ) for 2 h, As appropriate, image the microplate with an IR scanner or develop the HRP labeled microplate and read it with a spectrophotometer. The fluorescence signal was monitored using a microplate reader (Azure biosystems, Sapphire biomolecular imager) using excitation and emission wavelengths of 680 and 800 nm, respectively. Export data. The inhibitor dose-reponse curves were analyzed using normalized IC₅₀ regression curve fitting with control based normalization.

Table 2

Mouse Pharmacokinetic Study

The pharmacokinetic (PK) profile of representative Compounds of the Disclosure following single i.v. and p.o. administration in ICR (CD1, male) mouse. The results are provided in Table 6

All procedures performed on animals will be in accordance with established guidelines and reviewed and approved by an independent institutional review board. The study design is summarized in Table 4.

Table 4. Animal Treatment Schedule

The animals will be weighed prior to dosing and dose volume for each animal will be calculated using the formula below:

Dose Volume (mL) = [Nominal Dose (mg/kg) /Dose Concentration (mg/mL) ] ×Animal Body Weight (kg)

The actual body weight and dosing volume will be recorded accordingly.

Table 5. Sample Collection Information

Blood: Blood samples (～100μL) will be collected at different time points into anticoagulant tubes (coated with EDTA-K₂) . The blood sampling time will be recorded accordingly. The tubes will be gently inverted several times to ensure mixing. Whole blood will be processed by centrifugation at 1500-1600 g for 10 min. Plasma samples will be collected and kept below -90～ -60 ℃ prior to analysis. The blood sampling time will be recorded according

IV administration: T 1/2 (terminal half-life) , C0, AUClast, AUCinf, MRTinf, Cl, Vss, Number of Points for Regression.

PO administration: T 1/2 (terminal half-life) , Cmax, Tmax, MRTinf, AUCinf, AUClast, F%, Number of Points for Regression. The pharmacokinetic data was described using descriptive statistics such as mean, standard deviation.

Table 6:

Claims

A compound of Formula I:

or a pharmaceutically acceptable salt or solvate thereof,

wherein:

R₁ represents C₃-C₆ cycloalkyl or 5-6-membered heterocyclyl or heteroaryl containg 1, 2 or 3 N atoms, and R₂ represents H, C₁-C₆ alkyl or deuterated C₁-C₆ alkyl, wherein the C₃-C₆ cycloalkyl or 5-6-membered heterocyclyl or heteroaryl is optionally substituted with one or more of C₁-C₄ alkyl, amino, halogen, or OH; or

R₁ and R₂ taken together with the nitrogen atom to which they are attached form a N-containing heterocyclic, wherein the N-containing heterocyclic is optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, amino, OH, CN, halogen, or -C₁-C₆ alkyl-CN;

L is selected from the group consisting of -O-, -S-, and -N (R₆) -; or L is a bond;

R₆ is selected from the group consisting of hydrogen, C₁-C₆ alkyl and C₁-C₆ haloalkyl;

A and Q are independently selected from the group consisting of =C (R₇) -and =N-;

R₇ is selected from the group consisting of hydrogen, CN, C₁-C₆ alkyl, C₁-C₆ haloalkyl and C₃-C₆ cycloalkyl;

R₃ is - (CH₂) _n-heterocycle, wherein the heterocycle is a optionally substituted 7-12 membered heterocycle comprising at least two rings bridged to each other; and n is 0, 1, 2 or 3;

R₄ is selected from the group consisting of C₆-C₁₀ aryl, C₆-C₁₀ heteraryl, C₆-C₁₀ heterocyclic, and C₃-C₆ cycloalkyl, wherein the aryl, heteraryl, heterocyclic, and cycloalkyl is optionally substituted with one or more R₈;

wherein each R₈ may be the same or different, and is independent selected from the group consisting of C₁-C₆ alkyl, -S-C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, C₂-C₆ alkenyl; C₂-C₆ alkynyl, -C₁-C₆ alkyl- (CO) -N (C₁-C₆ alkyl) ₂, C₂-C₄hydroxyalkynyl, and -N (C₁-C₆ alkyl) ₂,

R₅ is selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, and halogen.
A compound of Formula I:

or a pharmaceutically acceptable salt or solvate thereof,

wherein:

R₁ and R₂ taken together with the nitrogen atom to which they are attached form a N-containing heterocyclic, wherein the N-containing heterocyclic is optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, amino, OH, CN, halogen, or -C₁-C₆ alkylene-CN;

L is selected from the group consisting of -O-, -S-, and -N (R₆) -; or L is a bond;

R₆ is selected from the group consisting of hydrogen, C₁-C₆ alkyl and C₁-C₆ haloalkyl;

A and Q are independently selected from the group consisting of =C (R₇) -and =N-;

R₇ is selected from the group consisting of hydrogen, CN, C₁-C₆ alkyl, C₁-C₆ haloalkyl and C₃-C₆ cycloalkyl;

R₃ is - (CH₂) _n-heterocycle, wherein the heterocycle is a optionally substituted 7-12 membered heterocycle comprising at least two rings bridged to each other; and n is 0, 1, 2 or 3;

R₄ is selected from the group consisting of C₆-C₁₀ aryl, C₆-C₁₀ heteraryl, C₆-C₁₀ heterocyclic, and C₃-C₆ cycloalkyl, wherein the aryl, heteraryl, heterocyclic, and cycloalkyl is optionally substituted with one or more R₈;

wherein each R₈ may be the same or different, and is independent selected from the group consisting of C₁-C₆ alkyl, -S-C₁-C₆ alkyl, O-C₁-C₆ alky, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, C₂-C₆ alkenyl; C₂-C₆ alkynyl, -C₁-C₆ alkyl- (CO) -N (C₁-C₆ alkyl) ₂, C₂-C₄hydroxyalkynyl, and -N (C₁-C₆ alkyl) ₂,

R₅ is selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, and halogen.
The compound of claim 1 or 2, wherein R₁ and R₂ taken together with the nitrogen atom to which they are attached form a 5-8 membered N-containing heterocyclic.
The compound of claim 1, wherein R₁ is cyclopropyl optionally substituted with one or more of C₁-C₄ alkyl, amino, halogen, or OH.
The compound of any one of claims 1-3, wherein R₁ and R₂ taken together with the nitrogen atom to which they are attached form a N-containing heterocycle optionally substituted with one or more Rb groups as follow:

whereinrepresents a single bond or a double bond; whenis a single bond, then U represents O, NH or CH₂; and whenis a double bond, then U represents N or CH;

t is 0, 1, 2, or 3;

each Rb may be the same or different, and is independently selected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, -C₁-C₆ alkyl-CN, amino, OH, CN, halogen;

or two R_b on the same carbon atom together with the carbon atom to which they are attached form C=CH₂, C=CH-C₁-C₆ alkyl, C=O, C₃-C₆ haloalkyl, or C₃-C₆ heterocycle; wherein the C₃-C₆ haloalkyl, or C₃-C₆ heterocycle is optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, amino, OH, CN, and halogen;

or two R_b on the different carbon atoms are linked together to form a - (CH₂) _s- (CH=CH) _p-linker, wherein s is 0, 1, 2 or 3; and p is 0, 1, 2 or 3.
The compound of any one of claims 1-3, wherein R₁ and R₂ taken together with the nitrogen atom to which they are attached form a N-containing heterocycle optionally substituted with one or more Rb groups as follow:

wherein U represents O, NH or CH₂;

t is 0, 1, 2, or 3;

each Rb may be the same or different, and is independently selected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, -C₁-C₆ alkyl-CN, amino, OH, CN, halogen;

or two R_b on the same carbon atom together with the carbon atom to which they are attached form C=CH₂, C=CH-C₁-C₆ alkyl, C=O, C₃-C₆ haloalkyl, or C₃-C₆ heterocycle; wherein the C₃-C₆ haloalkyl, or C₃-C₆ heterocycle is optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, amino, OH, CN, and halogen;

or two R_b on the different carbon atoms are linked together to form a - (CH₂) _s- (CH=CH) _p-linker, wherein s is 0, 1, 2 or 3; and p is 0, 1, 2 or 3.
The compound of any one of claims 1-3, wherein the N-containing heterocyclic is

wherein, R^2a, R^2b, R^2c and R^2d independently represent H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, -C₁-C₆ alkylene-CN, amino, OH, CN, halogen; or any one of R^2a, R^2b, R^2c and R^2d are linked together to form a - (CH₂) _s- (CH=CH) _p-linker, wherein s is 0, 1, 2 or 3; and p is 0, 1, 2 or 3.
The compound of any one of claims 1-3, wherein the N-containing heterocyclyl is selected from:

represents a single or double bond,

wherein the N-containing heterocyclyl is optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy_, amino, OH, CN, halogen, or -C₁-C₆ alkylene-CN.
The compound of any one of claims 1-3, wherein the N-containing heterocyclyl is selected from:

represents a single or double bond,

wherein the N-containing heterocyclyl is optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy_, amino, OH, CN, halogen, or -C₁-C₆ alkylene-CN.
The compound of any one of claims 1-3, wherein the N-containing heterocyclyl is selected from:

represents a single or double bond,

wherein the N-containing heterocyclyl is optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy_, amino, OH, CN, halogen, or -C₁-C₆ alkylene-CN.
The compound of any one of claims 1-3, wherein the N-containing heterocyclyl is selected from:

represents a single or double bond.

wherein the heterocyclyl is optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl , C₁-C₆ alkoxy_, amino, OH, CN, halogen, or -C₁-C₆ alkylene-CN.
The compound of any one of claims 1-3, wherein the N-containing heterocyclyl is selected from:

represents a single or double bond.

wherein the heterocyclyl is optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl , C₁-C₆ alkoxy_, amino, OH, CN, halogen, or -C₁-C₆ alkylene-CN.
The compound of any one of claims 1-12_, wherein R₃ is selected from:

wherein the R₃ is optionally substituted with one or more R_a, each R_a may be the same or different, and is independent selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, -C₁-C₆ alkyl- (CO) -N (C₁-C₆ alkyl) ₂, C₂-C₄hydroxyalkynyl, -N (C₁-C₆ alkyl) ₂, -CH₂O-CO-N (C₁-C₆ alkyl) ₂, and -CH₂NH-CO-N (C₁-C₆ alkyl) ₂; or two R_a on the same carbon atom form C=CH₂, C=CH-C₁-C₆ alkyl, or C=O.
The compound of any one of claims 1-12_, wherein R₃ is selected from:

wherein each Ra may be the same or different, and is independent represents C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, -C₁-C₆ alkyl- (CO) -N (C₁-C₆ alkyl) ₂, C₂-C₄hydroxyalkynyl, -N (C₁-C₆ alkyl) ₂, -CH₂O-CO-N (C₁-C₆ alkyl) ₂, and -CH₂NH-CO-N (C₁-C₆ alkyl) ₂; or two R_a on the same carbon atom form C=CH₂, C=CHF, C=CF₂, C=CH-C₁-C₆ alkyl, C=O, cyclopropyl or cyclobutyl; or two R_a on the adjacent carbon atoms together with the carbon atoms to which they are attached form a cyclopropyl or cyclobutyl optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, amino, OH, CN, halogen; and n is 0, 1, 2 or 3.
The compound of any one of claims 1-12_, wherein R₃ is selected from:

wherein each Ra may be the same or different, and is independent represents C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, -C₁-C₆ alkyl- (CO) -N (C₁-C₆ alkyl) ₂, C₂-C₄hydroxyalkynyl, -N (C₁-C₆ alkyl) ₂, -CH₂O-CO-N (C₁-C₆ alkyl) ₂, and -CH₂NH-CO-N (C₁-C₆ alkyl) ₂; or two R_a on the same carbon atom form C=CH₂, C=CH-C₁-C₆ alkyl, C=O, cyclopropyl or cyclobutyl; or two R_a on the adjacent carbon atoms together with the carbon atoms to which they are attached form a cyclopropyl or cyclobutyl optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, amino, OH, CN, halogen; and n is 0, 1, 2 or 3.
The compound of any one of claims 1-12_, wherein R₃ is selected from:

wherein the R₃ is optionally substituted with one or more R_a, each R_a may be the same or different, and is independent selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, -C₁-C₆ alkyl- (CO) -N (C₁-C₆ alkyl) ₂, C₂-C₄hydroxyalkynyl, -N (C₁-C₆ alkyl) ₂, -CH₂O-CO-N (C₁-C₆ alkyl) ₂, and -CH₂NH-CO-N (C₁-C₆ alkyl) ₂; or two R_a on the same carbon atom form C=CH₂, C=CH-C₁-C₆ alkyl, C=O, cyclopropyl or cyclobutyl.
The compound of any one of claims 1-12, wherein R₃ is selected from:
The compound of any one of claims 1-17, wherein R₅ is F.
The compound of any one of claims 1-18, wherein A and Q are both =N-.
The compound of any one of claims 1-19, wherein R₄ is selected from:

wherein M is selected from the group consisting of =C (R₇) -and =N-; and R₇ is selected from the group consisting of hydrogen, CN, C₁-C₆ alkyl, C₁-C₆ haloalkyl and C₃-C₆ cycloalkyl;

each R₈ may be the same or different, and is independent selected from the group consisting of C₁-C₆ alkyl, -S-C₁-C₆ alkyl, O-C₁-C₆ alky, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, C₂-C₆ alkenyl; C₂-C₆ alkynyl, -C₁-C₆ alkyl- (CO) -N (C₁-C₆ alkyl) ₂, C₂-C₄hydroxyalkynyl, and -N (C₁-C₆ alkyl) ₂; or two R₈ on the adjacent carbon atoms together with the carbon atoms to which they are attached form a fused phenyl optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, amino, OH, CN, halogen, C₂-C₆ alkenyl and C₂-C₆ alkynyl.
The compound of any one of claims 1-19 of Formula II:

or a pharmaceutically acceptable salt or solvate thereof,

wherein:

L is selected from the group consisting of -O-, -S-, and -N (R₆) -; or L is a bond;

R₆ is selected from the group consisting of hydrogen, C₁-C₆ alkyl and C₁-C₆ haloalkyl;

A, Q and M are independently selected from the group consisting of =C (R₇) -and =N-; R₇ is selected from the group consisting of hydrogen, CN, C₁-C₆ alkyl, C₁-C₆ haloalkyl and C₃-C₆ cycloalkyl;

n is 0, 1, 2 or 3; represents a single or double bond,

each R_a may be the same or different, and independent represents C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, -C₁-C₆ alkyl- (CO) -N (C₁-C₆ alkyl) ₂, C₂-C₄hydroxyalkynyl, -N (C₁-C₆ alkyl) ₂, -CH₂O-CO-N (C₁-C₆ alkyl) ₂, and -CH₂NH-CO-N (C₁-C₆ alkyl) ₂; or two R_a on the same carbon atom form C=CH₂, C=CH-C₁-C₆ alkyl, C=O, cyclopropyl or cyclobutyl; or two R_a on the adjacent carbon atoms together with the carbon atoms to which they are attached form a cyclopropyl or cyclobutyl optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, amino, OH, CN, halogen;

R₅ is selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, and halogen;

each R₈ may be the same or different, and is independent selected from the group consisting of C₁-C₆ alkyl, -S-C₁-C₆ alkyl, O-C₁-C₆ alky, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, C₂-C₆ alkenyl; C₂-C₆ alkynyl, - (CO) -, -C₁-C₆ alkyl- (CO) -N (C₁-C₆ alkyl) ₂, C₂-C₄hydroxyalkynyl, and -N (C₁-C₆ alkyl) ₂; or two R₈ on the adjacent carbon atoms together with the carbon atoms to which they are attached form a fused phenyl optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, amino, OH, CN, halogen, C₂-C₆ alkenyl and C₂-C₆ alkynyl.
The compound of claim 21 of Formula III:

wherein each R₉ may be the same or different, and is independent selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, C₂-C₆ alkenyl; and C₂-C₆ alkynyl; and other substituents and parameters are as defined in claim 19.
The compound of any one of claims 1-2, wherein the N-containing heterocyclyl is selected from:

wherein the N-containing heterocyclyl is optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, amino, OH, CN, halogen, or -C₁-C₆ alkylene-CN.
The compound of claim 23 of Formula IV:

or a pharmaceutically acceptable salt or solvate thereof,

wherein:

L is selected from the group consisting of -O-, -S-, and -N (R₆) -; or L is a bond;

R₆ is selected from the group consisting of hydrogen, C₁-C₆ alkyl and C₁-C₆ haloalkyl;

A, Q and M are independently selected from the group consisting of =C (R₇) -and =N-;

R₇ is selected from the group consisting of hydrogen, CN, C₁-C₆ alkyl, C₁-C₆ haloalkyl and C₃-C₆ cycloalkyl;

each n is independent 0, 1, 2 or 3;

each R_a may be the same or different, and independent represents C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, -C₁-C₆ alkyl- (CO) -N (C₁-C₆ alkyl) ₂, C₂-C₄hydroxyalkynyl, -N (C₁-C₆ alkyl) ₂, -CH₂O-CO-N (C₁-C₆ alkyl) ₂, and -CH₂NH-CO-N (C₁-C₆ alkyl) ₂; or two R_a on the same carbon atom form C=CH₂, C=CH-C₁-C₆ alkyl, C=O, cyclopropyl or cyclobutyl; or two R_a on the adjacent carbon atoms together with the carbon atoms to which they are attached form a cyclopropyl or cyclobutyl optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, amino, OH, CN, halogen;

R₅ is selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, and halogen;

R₈ is independent selected from the group consisting of C₁-C₆ alkyl, -S-C₁-C₆ alkyl, O-C₁-C₆ alky, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, C₂-C₆ alkenyl; C₂-C₆ alkynyl, - (CO) -, -C₁-C₆ alkyl- (CO) -N (C₁-C₆ alkyl) ₂, C₂-C₄hydroxyalkynyl, and -N (C₁-C₆ alkyl) ₂; or two R₈ on the adjacent carbon atoms together with the carbon atoms to which they are attached form a fused phenyl optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, amino, OH, CN, halogen, C₂-C₆ alkenyl and C₂-C₆ alkynyl;

each R₉ may be the same or different, and is independent selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, C₂-C₆ alkenyl; and C₂-C₆ alkynyl;

each R₁₀ may be the same or different, and may be on the same carbon atom or different carbon atoms, and is independent selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy_, amino, OH, CN, halogen, and -C₁-C₆ alkylene-CN.
The compound of claim 23 or 24, wherein the piperidine ring is
The compound of claim 1 of Formula V:

or a pharmaceutically acceptable salt or solvate thereof,

wherein:

L is selected from the group consisting of -O-, -S-, and -N (R₆) -; or L is a bond;

R₆ is selected from the group consisting of hydrogen, C₁-C₆ alkyl and C₁-C₆ haloalkyl;

A, Q and M are independently selected from the group consisting of =C (R₇) -and =N-;

R₇ is selected from the group consisting of hydrogen, CN, C₁-C₆ alkyl, C₁-C₆ haloalkyl and C₃-C₆ cycloalkyl;

each n is independent 0, 1, 2 or 3;

each R_a may be the same or different, and independent represents C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, -C₁-C₆ alkyl- (CO) -N (C₁-C₆ alkyl) ₂, C₂-C₄hydroxyalkynyl, -N (C₁-C₆ alkyl) ₂, -CH₂O-CO-N (C₁-C₆ alkyl) ₂, and -CH₂NH-CO-N (C₁-C₆ alkyl) ₂; or two R_a on the same carbon atom form C=CH₂, C=CHF, C=CF₂, C=CH-C₁-C₆ alkyl, C=O, cyclopropyl or cyclobutyl; or two R_a on the adjacent carbon atoms together with the carbon atoms to which they are attached form a cyclopropyl or cyclobutyl optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, amino, OH, CN, halogen; R₅ is selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, and halogen;

R₈ is independent selected from the group consisting of C₁-C₆ alkyl, -S-C₁-C₆ alkyl, O-C₁-C₆ alky, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, C₂-C₆ alkenyl; C₂-C₆ alkynyl, - (CO) -, -C₁-C₆ alkyl- (CO) -N (C₁-C₆ alkyl) ₂, C₂-C₄hydroxyalkynyl, and -N (C₁-C₆ alkyl) ₂; or two R₈ on the adjacent carbon atoms together with the carbon atoms to which they are attached form a fused phenyl optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, amino, OH, CN, halogen, C₂-C₆ alkenyl and C₂-C₆ alkynyl;

each R₉ may be the same or different, and is independent selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, C₂-C₆ alkenyl; and C₂-C₆ alkynyl;

U represents O, NH or CH₂;

t is 0, 1, 2, or 3;

each Rb may be the same or different, and is independently selected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, -C₁-C₆ alkyl-CN, amino, OH, CN, halogen;

or two R_b on the same carbon atom together with the carbon atom to which they are attached form C=CH₂, C=CH-C₁-C₆ alkyl, C=O, C₃-C₆ haloalkyl, or C₃-C₆ heterocycle; wherein the C₃-C₆ haloalkyl, or C₃-C₆ heterocycle is optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, amino, OH, CN, and halogen;

or two R_b on the different carbon atoms are linked together to form a - (CH₂) _s- (CH=CH) _p-linker, wherein s is 0, 1, 2 or 3; and p is 0, 1, 2 or 3.
The compound of claim 1 of Formula VI:

or a pharmaceutically acceptable salt or solvate thereof,

wherein:

L is selected from the group consisting of -O-, -S-, and -N (R₆) -; or L is a bond;

R₂ represents H, C₁-C₆ alkyl or deuterated C₁-C₆ alkyl;

R₆ is selected from the group consisting of hydrogen, C₁-C₆ alkyl and C₁-C₆ haloalkyl;

A, Q and M are independently selected from the group consisting of =C (R₇) -and =N-;

R₇ is selected from the group consisting of hydrogen, CN, C₁-C₆ alkyl, C₁-C₆ haloalkyl and C₃-C₆ cycloalkyl;

each n is independent 0, 1, 2 or 3;

each R_a may be the same or different, and independent represents C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, -C₁-C₆ alkyl- (CO) -N (C₁-C₆ alkyl) ₂, C₂-C₄hydroxyalkynyl, -N (C₁-C₆ alkyl) ₂, -CH₂O-CO-N (C₁-C₆ alkyl) ₂, and -CH₂NH-CO-N (C₁-C₆ alkyl) ₂; or two R_a on the same carbon atom form C=CH₂, C=CHF, C=CF₂, C=CH-C₁-C₆ alkyl, C=O, cyclopropyl or cyclobutyl; or two R_a on the adjacent carbon atoms together with the carbon atoms to which they are attached form a cyclopropyl or cyclobutyl optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, amino, OH, CN, halogen;

R₅ is selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, and halogen;

R₈ is independent selected from the group consisting of C₁-C₆ alkyl, -S-C₁-C₆ alkyl, O-C₁-C₆ alky, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, C₂-C₆ alkenyl; C₂-C₆ alkynyl, - (CO) -, -C₁-C₆ alkyl- (CO) -N (C₁-C₆ alkyl) ₂, C₂-C₄hydroxyalkynyl, and -N (C₁-C₆ alkyl) ₂; or two R₈ on the adjacent carbon atoms together with the carbon atoms to which they are attached form a fused phenyl optionally substituted with one or more of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, amino, OH, CN, halogen, C₂-C₆ alkenyl and C₂-C₆ alkynyl;

each R₉ may be the same or different, and is independent selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, C₂-C₆ alkenyl; and C₂-C₆ alkynyl;

j is 1, 2, 3 or 4;

R₁₁ represents hydrogen, C₁-C₄ alkyl, amino, halogen, or OH.
A compound selected from:

wherein A is selected from the group consisting of =C (R₇) -and =N-;

R₇ is selected from the group consisting of hydrogen, CN, C₁-C₆ alkyl, C₁-C₆ haloalkyl and C₃-C₆ cycloalkyl;

R₁ is selected from the group consisting of hydrogen, C₁-C₆ alkyl, -S-C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, C₂-C₆ alkenyl; C₂-C₆ alkynyl, -C₁-C₆ alkyl- (CO) -N (C₁-C₆ alkyl) ₂, C₂-C₄hydroxyalkynyl, and -N (C₁-C₆ alkyl) ₂; and

X is selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, C₂-C₆ alkenyl; and C₂-C₆ alkynyl, or a pharmaceutically acceptable salt or solvate thereof.
A compound selected from:

wherein A is selected from the group consisting of =C (R₇) -and =N-;

R₇ is selected from the group consisting of hydrogen, CN, C₁-C₆ alkyl, C₁-C₆ haloalkyl and C₃-C₆ cycloalkyl;

R₁ is selected from the group consisting of hydrogen, C₁-C₆ alkyl, -S-C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, C₂-C₆ alkenyl; C₂-C₆ alkynyl, -C₁-C₆ alkyl- (CO) -N (C₁-C₆ alkyl) ₂, C₂-C₄hydroxyalkynyl, and -N (C₁-C₆ alkyl) ₂; and

X is selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, NH₂, OH, CN, halogen, C₂-C₆ alkenyl; and C₂-C₆ alkynyl, or a pharmaceutically acceptable salt or solvate thereof.
A compound selected from:

or a pharmaceutically acceptable salt or solvate thereof.
A compound selected from:

or a pharmaceutically acceptable salt or solvate thereof.
A compound selected from:

or a pharmaceutically acceptable salt or solvate thereof.
A compound selected from:

or a pharmaceutically acceptable salt or solvate thereof.
A compound selected from:

or a pharmaceutically acceptable salt or solvate thereof.
A pharmaceutical composition comprising the compound of any one of claims 1-34, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
A method for inhibiting KRAS G12D or KRAS G12V activity in a cell, comprising contacting the cell in which inhibition of KRAS G12D or KRAS G12V activity is desired with an effective amount of a compound of any one of claims 1-34, or a pharmaceutically acceptable salt or solvate thereof; or the pharmaceutical composition of claim 35.
A method for treating a KRAS G12D or G12V-associated cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-34, or a pharmaceutically acceptable salt or solvate thereof; or the pharmaceutical composition of claim 35.
The method of claim 37, wherein the therapeutically effective amount of the compound is between about 0.01 to 100 mg/kg per day.
The method of claim 37 or 38, wherein the KRAS G12D or G12V -associated cancer is selected from the group consisting of Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma) , myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma) , alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma) , stomach (carcinoma, lymphoma, leiomyosarcoma) , pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma) , small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma) , large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma) ; Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma) , lymphoma, leukemia) , bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma) , prostate (adenocarcinoma, sarcoma) , testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma) ; Liver: hepatoma (hepatocellular carcinoma) , cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma) , fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma) , multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses) , benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans) , meninges (meningioma, meningiosarcoma, gliomatosis) , brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma) , glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors) , spinal cord neurofibroma, meningioma, glioma, sarcoma) ; Gynecological: uterus (endometrial 'carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma) , granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma) , vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma) , vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma) , fallopian tubes (carcinoma) ; Hematologic: blood (myeloid leukemia (acute and chronic) , acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome) , Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma) ; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.
The method of claim 39, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.
A method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with a KRAS G12D or G12V mutation (e.g., a KRAS G12D or G12V-associated cancer) ; and (b) administering to the patient a therapeutically effective amount of a compound of any one of claims 1-34, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of claim 35.
A compound of any one of claims 1-34, or a pharmaceutically acceptable salt or solvate thereof, for use in inhibiting KRAS G12D or KRAS G12V activity in a cell.
A compound of any one of claims 1-34, or a pharmaceutically acceptable salt or solvate thereof, for use in treating a KRAS G12D or G12V -associated cancer.
Use of a compound of any one of claims 1-34, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of claim 35, in the manufacture of a medicament for inhibiting KRAS G12D or KRAS G12V activity in a cell.
Use of a compound of any one of claims 1-34, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of claim 35, in the manufacture of a medicament for treating a KRAS G12D or G12V-associated cancer.
A kit comprising a compound of any one of claims 1-34, or a pharmaceutical composition of claim 35, and instructions for administering the compound, or a pharmaceutically acceptable salt or solvate thereof, to a subject having cancer.