WO2022161496A1 - Sulfonyl benzamide derivatives as bcl-2 inhibitors - Google Patents

Sulfonyl benzamide derivatives as bcl-2 inhibitors Download PDF

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Publication number
WO2022161496A1
WO2022161496A1 PCT/CN2022/075239 CN2022075239W WO2022161496A1 WO 2022161496 A1 WO2022161496 A1 WO 2022161496A1 CN 2022075239 W CN2022075239 W CN 2022075239W WO 2022161496 A1 WO2022161496 A1 WO 2022161496A1
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Prior art keywords
cancer
compound
methyl
mmol
alkyl
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English (en)
French (fr)
Inventor
Dongbo Li
Jianyong Chen
Fang Liu
Hao Chen
Xianchan ZHA
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Ascentage Pharma Suzhou Co Ltd
Ascentage Pharma Group Co Ltd
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Ascentage Pharma Suzhou Co Ltd
Ascentage Pharma Group Co Ltd
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Priority to JP2023527410A priority Critical patent/JP2024504542A/ja
Priority to EP22745367.7A priority patent/EP4298098A4/en
Priority to US18/263,249 priority patent/US12577245B2/en
Publication of WO2022161496A1 publication Critical patent/WO2022161496A1/en
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • Apoptosis the process of programmed cell death, is an essential biological process for tissue homeostasis. In mammals, it has been shown to regulate early embryonic development. Later in life, cell death is a default mechanism by which potentially dangerous cells, e.g., cells carrying cancerous defects, are removed.
  • Several apoptotic pathways are known.
  • One of the major apoptotic pathways involves the Bcl-2 family of proteins which are key regulators of the mitochondrial (also called "intrinsic" ) pathway of apoptosis. See Danial and Korsmeyer, Cell 116: 205-219 (2004) .
  • the structural homology domains BH1, BH2, BH3 and BH4 are characteristic of Bcl-2 family proteins.
  • the Bcl-2 family of proteins can be further classified into three subfamilies depending on how many of the homology domains each protein contains and on its biological activity, i.e., whether it has pro-or anti-apoptotic function.
  • the first subgroup of Bcl-2 proteins contains proteins having all four homology domains, i.e., BH1, BH2, BH3 and BH4. Their general effect is anti-apoptotic, that is, to preserve a cell from starting a cell death process. Proteins such as Bcl-2, Bcl-w, Bcl-xL, Mcl-1, and Bfl-1/A1 are members of this first subgroup. Proteins belonging to the second subgroup of Bcl-2 proteins contain the three homology domains BH1, BH2, and BH3, and have a pro-apoptotic effect. The two main representative proteins of this second subgroup are Bax and Bak.
  • the BH3-only proteins are further categorized as either "activator, " e.g., Bim and Bid, or “sensitizer, " e.g., Bad, Bik, Noxa, Hrk, Bmf, and Puma, proteins depending on their regulatory function.
  • activator e.g., Bim and Bid
  • sensitizer e.g., Bad, Bik, Noxa, Hrk, Bmf, and Puma
  • BH3-only proteins are the primary inducers of an apoptotic cascade that includes, as one step, the activation of the pro-apoptotic proteins Bax and Bak on the mitochondrial membrane in cells.
  • Bax and/or Bak oligomerize to result in mitochondrial outer membrane permeabilization (MOMP) , the release of cytochrome C, and downstream activation of effector caspases, to ultimately result in cell apoptosis.
  • MOMP mitochondrial outer membrane permeabilization
  • BH3-only proteins e.g., Puma, Bim, Bid
  • activators are "activators” in that these proteins directly engage pro-apoptotic proteins Bax and Bak to initiate MOMP
  • other BH3-only proteins e.g., Bad, Bik and Noxa
  • dex and Bak oligomerization indirectly by binding anti-apoptotic proteins, e.g., Bcl-2, Bcl-xL, Bcl-w, Mcl-1, and displacing and "freeing-up" the "activator” BH3-only proteins, which subsequently bind to and activate pro-apoptotic proteins, e.g., Bax, Bak, to induce cell death.
  • Dysregulated apoptotic pathways have been implicated in the pathology of many significant diseases such as neurodegenerative conditions (up-regulated apoptosis) , such as for example, Alzheimer's disease; and proliferative diseases (down-regulated apoptosis) such as for example, cancer, autoimmune diseases and pro-thrombotic conditions.
  • neurodegenerative conditions up-regulated apoptosis
  • proliferative diseases down-regulated apoptosis
  • cancer autoimmune diseases and pro-thrombotic conditions.
  • Down-regulated apoptosis may be involved in the onset of cancerous malignancy.
  • Bcl-2 and Bcl-xL are over-expressed in many cancer cell types. See Zhang, Nature Reviews Drug Discovery 1: 101 (2002) ; Kirkin et al., Biochimica et Biophysica Acta 1644: 229-249 (2004) ; and Amundson et al., Cancer Research 60: 6101-6110 (2000) .
  • the effect of this deregulation is the survival of altered cells which would otherwise have undergone apoptosis in normal conditions. The repetition of these defects associated with unregulated proliferation is thought to be the starting point of cancerous evolution.
  • BH3-only proteins can act as tumor suppressors when expressed in diseased animals.
  • Small molecule BH3-only protein mimetics such as ABT-737 and ABT-263 bind strongly to a subset of anti-apoptotic Bcl-2 proteins including Bcl-2, Bcl-w and Bcl-xL, and weakly to Mcl-1 and A1.
  • These small molecules were tested in animal studies and demonstrated cytotoxic activity in certain xenograft models as single agents, as well as enhanced the effects of a number of chemotherapeutic agents on other xenograft models when used in combination. See Tse, C. et al., Cancer Res 68: 3421-3428 (2008) and van Delft, M.F. et al., Cancer Cell 10: 389-399 (2006) .
  • ABT-199 (Venetoclax) is a potent Bcl-2 inhibitor that has been approved by the U.S. Food and Drug Administration for the treatment of chronic lymphocytic leukemia. See Cang et al., Journal of Hematology &Oncology 8: 129 (2015) and Souers et al., Nature Medicine 19: 202–208 (2013) .
  • Bcl-2 family proteins members vary in different cell types. For example, in young platelets, Bcl-xL protein is highly expressed and plays an important role in regulating cell death (life span) of platelets. Also, in certain cancer cell types, the cancer cell's survival is attributed to the dysregulation of the apoptotic pathway caused by the over-expression of one or more anti-apoptotic Bcl-2 protein family members.
  • Bcl-2 family of proteins in regulating apoptosis in both cancerous and normal, i.e., non-cancerous, cells, and the recognized inter-cell type variability of Bcl-2 family protein expression, it is advantageous to have a small molecule inhibitor that selectively targets and preferably binds to one type or a subset of anti-apoptotic Bcl-2 protein (s) , for example, to an anti-apoptotic Bcl-2 family member that overexpressed in a certain cancer type.
  • s anti-apoptotic Bcl-2 protein
  • Such a selective compound also may confer certain advantages in the clinical setting, by providing, for example, the flexibility to select a dosing regimen, a reduced on-target toxic effect in normal cells, among others, e.g., lymphopenia has been observed in Bcl-2 deficient mice. See Nakayama, K. et al. PNAS 91: 3700-3704 (1994) .
  • Mutation of drug-binding sites is a common mechanism by which malignant cells evade therapies. Venetoclax was approved in 2016 and there is a limited understanding of potential resistance mechanisms. To predict potential resistance mutants, a mouse model was used to induce Venetoclax tolerance in cancer cells. See, e.g., Fresquet, V. et al., Blood 123, 4111–4119 (2014) . This study identified that a mutation of phenylalanine 104 (human numbering) to either leucine (F104L) or cysteine (F104C) , located within Bcl-2’s BH3-binding groove, rendered the lymphoma cell line resistant to Venetoclax. Subsequent work confirmed that these mutations can also confer resistance in models of human leukemia and lymphoma, but have not yet been observed in patients. See, Tahir, S.K. et al., BMC Cancer 17, 399 (2017) .
  • Bcl-2 G101V chronic lymphocytic leukemia
  • CLL chronic lymphocytic leukemia
  • BAX and BIM pro-apoptotic proteins
  • the present disclosure provides compounds represented by any one of the Formulae below, and the pharmaceutically acceptable salts and solvates, e.g., hydrates, thereof, collectively referred to herein as "Compounds of the Disclosure. "
  • One embodiment of the present disclosure includes a compound having Formula I:
  • Ring X is a 5-or 6-membered ring, containing one or more additional degrees of unsaturation
  • each R 1 independently is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and halogen;
  • p 0, 1, or 2;
  • each R 2 independently is selected from the group consisting of (CH 2 ) t -R 4 , CONH-R 4 , NHC (O) -R 4 , NHR 4 , and (C ⁇ C) -R 4 ;
  • each R 4 independently is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, aryl, C 3-10 heterocyclyl, heteroaryl;
  • each R 4 may be susbstituted with one or more of the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, C3-6 cycloalkyl, C3-6 heterocyclyl, OSO 2 CH 3 , NH 2 , NHC 1-6 alkyl, N (C 1-6 alkyl) , C 1-6 alkoxy, OH, C 1-6 alkyl-OH, C 2-6 alkyl (OH) (C 3-6 cycloalkyl) , C 1-6 haloalkyl-OH, C 3-6 cycloalkyl-OH, C 1-6 alkyl-COOH, C 1- 6 alkyl-O-C 1-6 alkyl, CN, C 1-6 alkyl-CN, C 1-6 alkyl-NHC (O) -C 1-6 alkyl, and C 1-6 alkyl-C (O) NH-C 1-6 alkyl;
  • q 1 or 2;
  • each t is 0, 1, 2, 3, 4, 5, or 6;
  • r 0, 1, or 2.
  • Ring Y is a thiophene.
  • S atom is located in an alpha position to Ring X and the compound is of Formula Iy:
  • One embodiment of the present disclosure includes having the depicted stereochemistry:
  • One embodiment of the present disclosure includes a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
  • One embodiment of the present disclosure includes a pharmaceutical composition comprising the compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • One embodiment of the present disclosure includes a pharmaceutical composition of the present disclosure wherein the cancer is selected from the group consisting of acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia mixed lineage leukaemia, NUT-midline carcinoma, multiple myeloma, small cell lung cancer, neuroblastoma, Burkitt's lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer, and breast cancer.
  • the cancer is selected from the group consisting of acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia mixed lineage leukaemia, NUT-midline carcinoma, multiple myeloma, small cell lung cancer, neuroblastoma, Burkitt's lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer
  • One embodiment of the present disclosure includes a kit comprising the compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, and instructions for administering the compound, or a pharmaceutically acceptable salt or solvate thereof, to a patient having a hyperproliferative disease.
  • the hyperproliferative disease is cancer.
  • the cancer is selected from one or more of the cancers of Table 2.
  • One embodiment of the present disclosure includes wherein the cancer is selected from the group consisting of acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia mixed lineage leukemia, NUT-midline carcinoma, multiple myeloma, small cell lung cancer, neuroblastoma, Burkitt's lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer, and breast cancer.
  • One embodiment of the present disclosure includes one or more additional therapeutic agents.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a Compound of the Disclosure and one or more pharmaceutically acceptable carriers.
  • the present disclosure provides a method of inhibiting Bcl-2 proteins, e.g., Bcl-2, Bcl-2 WT, Bcl-xL, Mcl-1, and Bfl-1/A1, or any combination thereof, in a subject, e.g., a human, comprising administering to the subject an effective amount of at least one Compound of the Disclosure.
  • this aspect provides a method of inhibiting Bcl-2 WT.
  • this aspect provides a method of inhibiting the G101V mutant.
  • the present disclosure provides methods for treating or preventing diseases, disorders, or conditions, e.g., a hyperproliferative disease, e.g., cancer, e.g., small cell lung cancer, non-Hodgkin's lymphoma (NHL) , acute myelogenous leukemia (AML) , chronic lymphoid (or lymphocytic) leukemia (CLL) , or acute lymphoblastic leukemia (ALL) , in a subject responsive to inhibition of Bcl-2 proteins, e.g., Bcl-2 WT and/or Bcl-2 G101V, comprising administering to the subject a therapeutically effective amount of a Compound of the Disclosure.
  • a hyperproliferative disease e.g., cancer, e.g., small cell lung cancer, non-Hodgkin's lymphoma (NHL) , acute myelogenous leukemia (AML) , chronic lymphoid (or lymphocytic)
  • the present disclosure provides the use of Compounds of the Disclosure as inhibitors of one or more Bcl-2 proteins, e.g., Bcl-2 WT and/or Bcl-2 G101V.
  • the present disclosure provides the use of Compounds of the Disclosure as inhibitors of Bcl-2 WT.
  • the present disclosure provides a pharmaceutical composition for treating diseases, disorders, or conditions responsive to inhibition of Bcl-2 proteins, e.g., Bcl-2 WT and/or Bcl-2 G101V, wherein the pharmaceutical composition comprises a therapeutically effective amount of a Compound of the Disclosure optionally admixed with one or more pharmaceutically acceptable carriers.
  • the present disclosure provides Compounds of the Disclosure for use in treating or preventing a disease, disorder, or condition, e.g., a hyperproliferative disease, e.g., cancer, in a subject, e.g., a human.
  • a disease, disorder, or condition e.g., a hyperproliferative disease, e.g., cancer
  • the present disclosure provides a Compound of the Disclosure for use in the manufacture of a medicament for treating a disease, disorder, or condition, e.g., a hyperproliferative disease, e.g., cancer, in a subject, e.g., a human.
  • a disease, disorder, or condition e.g., a hyperproliferative disease, e.g., cancer
  • the present disclosure provides kit comprising a Compound of the Disclosure.
  • the present disclosure provides a kit comprising a Compound of the Disclosure and a second therapeutic agent useful in the treatment of a disease, disorder, or condition of interest, and a package insert containing directions for use in the treatment of that disease, disorder, or condition.
  • the present disclosure provides a composition
  • a composition comprising: (a) a Compound of the Disclosure; (b) a second therapeutically active agent; and (c) optionally an excipient and/or pharmaceutically acceptable carrier.
  • Compounds of the Disclosure inhibit Bcl-2 proteins, e.g., Bcl-2 WT and/or Bcl-2 G101V.
  • Compounds of the Disclosure are useful for treating or preventing diseases, disorders, or conditions, e.g., a hyperproliferative disease, e.g., cancer, responsive to the inhibition of Bcl-2 proteins in a subject.
  • Cancers responsive to the inhibition of Bcl-2 proteins include, but are not limited to, small cell lung cancer, NHL, AML, CLL, and ALL.
  • halogen or “halo” as used by itself or as part of another group refers to -Cl, -F, -Br, or -I.
  • amino as used by itself or as part of another group refers to -NH 2 .
  • cycloalkyl refers to unsubstituted saturated or partially unsaturated, e.g., containing one or two double bonds, cyclic aliphatic hydrocarbons containing one to three rings having from three to twelve carbon atoms, i.e., C 3-12 cycloalkyl, or the number of carbons designated.
  • the cycloalkyl group has two rings.
  • the cycloalkyl group has one ring.
  • the cycloalkyl group is a C 3-8 cycloalkyl.
  • the cycloalkyl group is a C 3-6 cycloalkyl.
  • the term "optionally substituted aryl" as used herein by itself or as part of another group refers to an aryl that is either unsubstituted or substituted with one to five substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, alkyl, alkoxy, amino, alkylamino, dialkylamino, haloalkyl, and heterocyclo.
  • the optionally substituted aryl is an optionally substituted phenyl.
  • the optionally substituted phenyl has one substituent.
  • the optionally substituted phenyl is unsubstituted.
  • Non-limiting exemplary substituted aryl groups include 2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, and 4-chlorophenyl.
  • heterocyclo refers to unsubstituted saturated and partially unsaturated, e.g., containing one or two double bonds, cyclic groups containing one, two, or three rings having from three to fourteen ring members, i.e., a 3-to 14-membered heterocyclo, wherein at least one carbon atom of one of the rings is replaced with a heteroatom.
  • heterocyclo is meant to include cyclic ureido groups such as imidazolidinyl-2-one, cyclic amide groups such as ⁇ -lactam, ⁇ -lactam, ⁇ -lactam and ⁇ -lactam, and cyclic carbamate groups such as oxazolidinyl-2-one.
  • the heterocyclo group is a 4-, 5-, 6-, 7-or 8-membered cyclic group containing one ring and one or two oxygen and/or nitrogen atoms.
  • the heterocyclo group is a 5-or 6-membered cyclic group containing one ring and one or two nitrogen atoms.
  • the heterocyclo group is an 8-, 9-, 10-, 11-, or 12-membered cyclic group containing two rings and one or two nitrogen atoms. In one embodiment, the heterocyclo group is a 4-or 5-membered cyclic group containing one ring and one oxygen atom. The heterocyclo can be optionally linked to the rest of the molecule through a carbon or nitrogen atom.
  • dialkylamino as used by itself or as part of another group refers to -NR 11a R 11b , wherein R 11a and R 11b are each independently C 1-6 alkyl. In one embodiment, R 11a and R 11b are each independently C 1-4 alkyl.
  • Non-limiting exemplary dialkylamino groups include -N (CH 3 ) 2 and -N (CH 3 ) CH 2 CH (CH 3 ) 2 .
  • the -O-, -N (H) -, or -S- can independently be placed at any interior position of the aliphatic hydrocarbon chain so long as each -O-, N (H) -, or -S-group is separated by at least two -CH 2 -groups.
  • two -CH 2 -groups are replaced with two -O-groups.
  • three -CH 2 -groups are replaced with three -O-groups.
  • Non-limiting exemplary heteroalkyl groups include -CH 2 CH 2 OCH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 N (H) CH 3 , and -CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 3 .
  • chiral center or "asymmetric carbon atom” refers to a carbon atom to which four different groups are attached.
  • enantiomerically pure or “enantiopure” refer to a sample of a chiral substance all of whose molecules (within the limits of detection) have the same chirality sense.
  • Compounds of the Disclosure having one or more chiral centers are enantiopure.
  • the present disclosure encompasses the preparation and use of salts of the Compounds of the Disclosure, including non-toxic pharmaceutically acceptable salts.
  • pharmaceutically acceptable addition salts include inorganic and organic acid addition salts and basic salts.
  • the pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt and the like; inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulphate and the like; organic acid salts such as citrate, lactate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalate, formate and the like
  • Acid addition salts can be formed by mixing a solution of the particular Compound of the Disclosure with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, or the like.
  • Basic salts can be formed by mixing a solution of the compound of the present disclosure with a solution of a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate and the like.
  • solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid.
  • 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, ethanol, and the like, and it is intended that the disclosure includes both solvated and unsolvated forms of Compounds of the Disclosure.
  • the 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.
  • 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°C to about 25°C, 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 solvent in a crystal of the solvate.
  • the present disclosure is further directed to a method of inhibiting Bcl-2 in an animal, e.g., a human, in need thereof, the method comprising administering to the animal a therapeutically effective amount of at least one Compound of the Disclosure.
  • the present disclosure is further directed to a method of inhibiting Bcl-2 WT in an animal, e.g., a human, in need thereof, the method comprising administering to the animal a therapeutically effective amount of at least one Compound of the Disclosure.
  • the present disclosure is further directed to a method of inhibiting Bcl-2 G101V in an animal, e.g., a human, in need thereof, the method comprising administering to the animal a therapeutically effective amount of at least one Compound of the Disclosure.
  • 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.
  • 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.
  • 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.
  • prevent 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.
  • terapéuticaally effective amount 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 an individual in need thereof.
  • the therapeutically effective amount of the agent may reduce (i.e., retard to some extent and preferably stop) unwanted cellular proliferation; reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., retard to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., retard to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; modulate protein methylation in the target cells; and/or relieve, to some extent, one or more of the symptoms associated with the cancer.
  • the administered compound or composition prevents growth and/or kills existing cancer cells, it may be cytostatic and/or cytotoxic.
  • tainer means any receptacle and closure therefore suitable for storing, shipping, dispensing, and/or handling a pharmaceutical product.
  • insert means information accompanying a pharmaceutical product that provides a description of how to administer the product, along with the safety and efficacy data required to allow the physician, pharmacist, and patient to make an informed decision regarding use of the product.
  • the package insert generally is regarded as the "label" for a pharmaceutical product.
  • Bcl-2 proteins or “Bcl-2 family of proteins” refers to any one or more of the following proteins: Bax, Bak, Bid, Bcl-2, Bcl-xL, Mcl-1, Bcl-w or Bcl-2 WT, Bcl-2 G101V, Bfl-1/A1, Bim, Puma, Bad, Bik/Blk, Noxa, Bmf, Hrk/DP5, and Beclin-1.
  • disease or “condition” or “disorder” denotes disturbances and/or anomalies that as a rule are regarded as being pathological conditions or functions, and that can manifest themselves in the form of particular signs, symptoms, and/or malfunctions.
  • Compounds of the Disclosure inhibit Bcl-2 proteins, such as Bcl-2 WT and/or Bcl-2 G101V, and can be used in treating or preventing diseases, conditions, or disorders such as hyperproliferative diseases, wherein inhibition of Bcl-2 proteins provides a benefit.
  • the Compounds of the Disclosure can be used to treat a "Bcl-2 protein mediated disorder, " e.g., a Bcl-2-mediated disorder, a Bcl-2 WT-mediated disorder, and/or a Bcl-2 G101V-mediated disorder.
  • a Bcl-2 protein mediated disorder is any pathological condition in which a Bcl-2 protein is known to play a role.
  • a Bcl-2 mediated disorder is a hyperproliferative disease.
  • a Bcl-2 mediated disorder is cancer.
  • the cancer is breast, cervix, colon, kidney, liver, head and neck, skin, pancreas, ovary, esophagus, or prostate cancer.
  • the cancer is esophageal squamous cell carcinoma (ESCC) , bladder carcinoma, or cervical carcinoma.
  • ESCC esophageal squamous cell carcinoma
  • bladder carcinoma esophageal squamous cell carcinoma
  • cervical carcinoma esophageal squamous cell carcinoma
  • Compounds of the Disclosure can be administered to a subject in the form of a raw chemical without any other components present.
  • Compounds of the Disclosure can also be administered to a subject as part of a pharmaceutical composition containing the compound combined with one or more suitable pharmaceutically acceptable carriers.
  • Such carriers can be selected from pharmaceutically acceptable excipients and auxiliaries.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable vehicle” encompasses any of the standard pharmaceutical carriers, solvents, surfactants, or vehicles. Suitable pharmaceutically acceptable vehicles include aqueous vehicles and nonaqueous vehicles. Standard pharmaceutical carriers and their formulations are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995.
  • a Compound of the Disclosure or a pharmaceutical composition comprising a Compound of the Disclosure can be administered to any patient or subject that may experience the beneficial effects of a Compound of the Disclosure.
  • mammals e.g., humans and companion animals, although the disclosure is not intended to be so limited.
  • the patient or subject is a human.
  • one or more disintegrating agents can be added, such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • Possible pharmaceutical preparations for rectal administration include, for example, suppositories, which consist of a combination of one or more active compounds with a suppository base.
  • Suitable suppository bases include natural and synthetic triglycerides, and paraffin hydrocarbons, among others. It is also possible to use gelatin rectal capsules consisting of a combination of active compound with a base material such as, for example, a liquid triglyceride, polyethylene glycol, or paraffin hydrocarbon.
  • Step B 3-bromo-4-isopropylthiophene (Step B, 900 mg, 4.39 mmol) in dry THF (30 mL) was added nBuLi (2.6 mL, 2.5 M in hexane, 6.59 mmol) dropwise at -78 °C, and the mixture was stirred at -78 °C for 20 min.
  • Triisopropyl borate (1.65 g, 8.78 mmol) was added; the reaction mixture was stirred at -78 °C for 2 h, allowed to warm up to room temperature and stirred for 12 h.
  • Step E 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4-isopropylthiophen-3-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoic acid and 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4-isopropylthiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoic acid
  • Example 7 17 mg, 31%over 2 steps;
  • Example 8 4 mg, 7%over 2 steps
  • Examples 11 and 12 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (2-isopropylthiophen-3-yl) -4, 4-dimethylcyclohex-1-en-1-yl) -methyl) piperazin-1-yl) -N- ( (3-nitro-4- ( ( (tetrahydro-2H-pyran-4-yl) methyl) amino) -phenyl) sulfonyl) benzamide (Example 11) and 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (5-isopropylthiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (3-nitro-4- ( ( (tetrahydro-2H-pyran-4-yl) methyl) amino) pheny
  • Step B Methyl 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (2-isopropylthiophen-3-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoate and methyl 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (5-isopropylthiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoate
  • Step C 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (2-isopropylthiophen-3-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoic acid and 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (5-isopropylthiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoic acid
  • Step D 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (2-isopropylthiophen-3-yl) -4, 4-dimethylcyclohex-1-en-1-yl) -methyl) piperazin-1-yl) -N- ( (3-nitro-4- ( ( (tetrahydro-2H-pyran-4-yl) methyl) amino) -phenyl) sulfonyl) benzamide (Example 11) and 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (5-isopropylthiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (3-nitro-4- ( ( (tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl)
  • Examples 13 and 14 (S) -N- ( (4- ( ( (1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (2-isopropylthiophen-3-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide (Example 13) and (S) -N- ( (4- ( ( (1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (5-isopropylthiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl
  • Example 13 1.4 mg; Example 14: 0.5 mg
  • Example 15 (S) -N- ( (4- ( ( (1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (5- (4- fluorophenyl) -4, 5, 6, 7-tetrahydrothieno [3, 2-c] pyridin-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide
  • Step A 5- (4-Fluorophenyl) -4, 5, 6, 7-tetrahydrothieno [3, 2-c] pyridine
  • Step B (5- (4-fluorophenyl) -4, 5, 6, 7-tetrahydrothieno [3, 2-c] pyridin-2-yl) boronic acid
  • Step C Methyl 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (5- (4-fluorophenyl) -4, 5, 6, 7-tetrahydrothieno [3, 2-c] pyridin-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoate
  • Step D 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (5- (4-fluorophenyl) -4, 5, 6, 7-tetrahydrothieno [3, 2-c] pyridin-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoic acid
  • Step E (S) -N- ( (4- ( ( (1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (5- (4- fluorophenyl) -4, 5, 6, 7-tetrahydrothieno [3, 2-c] pyridin-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide (Example 15)
  • Example 16 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (5- (4-fluorophenyl) -4, 5, 6, 7-tetrahydrothieno [3, 2-c] pyridin-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Example 15 Essentially the same protocol of preparation of Example 15 was used to afford the example (5 mg) as a yellow solid.
  • Example 17 (S) -5- (2- ( (4- (4- ( ( (4- ( ( (4- ( ( (1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) carbamoyl) -3- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) phenyl) piperazin-1-yl) methyl) -5, 5-dimethylcyclohex-1-en-1-yl) -N-phenylthiophene-3-carboxamide
  • Step B N-phenyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiophene-3-carboxamide
  • Step C Methyl 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (4, 4-dimethyl-2- (4- (phenylcarbamoyl) thiophen-2-yl) cyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoate
  • Step D 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (4, 4-dimethyl-2- (4- (phenylcarbamoyl) thiophen-2-yl) cyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoic acid
  • Step E (S) -5- (2- ( (4- (4- ( ( (4- ( ( (4- ( ( (1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) carbamoyl) -3- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) phenyl) piperazin-1-yl) methyl) -5, 5-dimethylcyclohex-1-en-1-yl) -N-phenylthiophene-3-carboxamide (Example 17)
  • Example 18 (S) -N- ( (4- ( ( (1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4-benzamidothiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide
  • Step B N- (5-bromothiophen-3-yl) benzamide
  • Step C N- (5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiophen-3-yl) benzamide
  • Step D Methyl 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4-benzamidothiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoate
  • Step E 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4-benzamidothiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoic acid
  • Step F (S) -N- ( (4- ( ( (1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4-benzamidothiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide (Example 18)
  • Example 19 (S) -N- ( (4- ( ( (1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (4, 4-dimethyl-2- (4- (pyrimidin-2-ylamino) thiophen-2-yl) cyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide
  • Step A (4- ( (tert-Butoxycarbonyl) amino) thiophen-2-yl) boronic acid
  • Step B Methyl 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- ( (tert-butoxycarbonyl) amino) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoate
  • Step C Methyl 4- (4- ( (2- (4- ( (tert-butoxycarbonyl) amino) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -2- ( (1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) benzoate
  • Step D Methyl 4- (4- ( (2- (4-aminothiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -2- ( (1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) benzoate
  • Step E Methyl 4- (4- ( (4, 4-dimethyl-2- (4- (pyrimidin-2-ylamino) thiophen-2-yl) cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -2- ( (1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) benzoate
  • Step F 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (4, 4-dimethyl-2- (4- (pyrimidin-2-ylamino) thiophen-2-yl) cyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoic acid
  • Step G (S) -N- ( (4- ( ( (1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (4, 4-dimethyl-2- (4- (pyrimidin-2-ylamino) thiophen-2-yl) cyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide (Example 19)
  • Example 20 (S) -N- ( (4- ( ( (1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- ( (2, 4-difluorophenyl) amino) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide
  • Example 19 Essentially the same protocol of preparation of Example 19 was used to afford the example (2 mg) as a yellow solid.
  • Example 21 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (4, 4-dimethyl-2- (5- (morpholinomethyl) thiophen-3-yl) cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (3-nitro-4- ( ( (tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide
  • Step A 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2-bromo-4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoic acid
  • Step F 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (4, 4-dimethyl-2- (4- ( (6- (methylsulfonyl) -2, 6-diazaspiro [3.3] heptan-2-yl) methyl) thiophen-2-yl) cyclohexan-1-yl) methyl) piperazin-1-yl) benzoic acid
  • Step A Methyl 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (4, 4-dimethyl-2- (4- ( (4-morpholinopiperidin-1-yl) methyl) thiophen-2-yl) cyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoate
  • Step C (S) -N- ( (4- ( ( (1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (4, 4-dimethyl-2- (4- ( (4-morpholinopiperidin-1-yl) methyl) thiophen-2-yl) cyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide (Example 28)
  • Example 29 N- ( (4- ( ( ( (S) -1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (4, 4-dimethyl-2- (4- ( ( (3S, 5R) -3, 4, 5-trimethylpiperazin-1-yl) methyl) thiophen-2-yl) cyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide
  • Example 28 Essentially the same protocol of preparation of Example 28 was used to afford the example (8 mg) as a yellow solid.
  • Example 28 Essentially the same protocol of preparation of Example 28 was used to afford the example (10 mg) as a yellow solid.
  • Example 32 (S) -N- ( (4- ( ( (1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- ( (4, 4-difluoropiperidin-1-yl) methyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide
  • Example 33 (S) -N- ( (4- ( ( (1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (4-fluorophenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide
  • Step D 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (4-fluorophenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoic acid
  • Step E (S) -N- ( (4- ( ( (1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (4-fluorophenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide (Example 33)
  • Example 34 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (4, 4-dimethyl-2- (4-phenylthiophen-2-yl) cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (3-nitro-4- ( ( (tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide
  • Example 33 Essentially the same protocol of preparation of Example 33 was used to afford the example (7 mg) as a yellow solid.
  • Example 35 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (4, 4-dimethyl-2- (2-phenylthiophen-3-yl) cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (3-nitro-4- ( ( (tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide
  • Example 33 Essentially the same protocol of preparation of Example 33 was used to afford the example (7 mg) as a yellow solid.
  • Example 36 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (4-fluorophenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1s, 4s) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Example 33 Essentially the same protocol of preparation of Example 33 was used to afford the example (10 mg) as a yellow solid.
  • Example 33 Essentially the same protocol of preparation of Example 33 was used to afford the example (10 mg) as a yellow solid.
  • Example 38 (S) -N- ( (4- ( ( (1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (4-chlorophenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide
  • Example 39 (S) -N- ( (4- ( ( (1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2-isopropylphenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide
  • Example 33 Essentially the same protocol of preparation of Example 33 was used to afford the example (35 mg) as a yellow solid.
  • Example 40 (S) -N- ( (4- ( ( (1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (4, 4-dimethyl-2- (4- (4- (trifluoromethyl) phenyl) thiophen-2-yl) cyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide
  • Example 33 Essentially the same protocol of preparation of Example 33 was used to afford the example (11 mg) as a yellow solid.
  • Example 41 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (4, 4-dimethyl-2- (4- (4- (trifluoromethyl) phenyl) thiophen-2-yl) cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Example 33 Essentially the same protocol of preparation of Example 33 was used to afford the example (9 mg) as a yellow solid.
  • Example 42 (S) -N- ( (4- ( ( (1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2, 4-difluorophenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide
  • Step B Methyl 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2, 4-difluorophenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoate
  • Step C 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2, 4-difluorophenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoic acid
  • Step D (S) -N- ( (4- ( ( (1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2, 4-difluorophenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide (Example 42)
  • Example 43 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2, 4-difluorophenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Example 42 Essentially the same protocol of preparation of Example 42 was used to afford the example (9 mg) as a yellow solid.
  • Example 44 (S) -N- ( (4- ( ( (1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (4-chloro-2- fluorophenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide
  • Example 42 Essentially the same protocol of preparation of Example 42 was used to afford the example (6 mg) as a yellow solid.
  • Example 45 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (4, 4-dimethyl-2- (4- (3, 4, 5-trifluorophenyl) thiophen-2-yl) cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Example 42 Essentially the same protocol of preparation of Example 42 was used to afford the example (5.5 mg) as a yellow solid.
  • Example 46 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (4, 4-dimethyl-2- (4- (2, 3, 4-trifluorophenyl) thiophen-2-yl) cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Example 42 Essentially the same protocol of preparation of Example 42 was used to afford the example (13 mg) as a yellow solid.
  • Example 47 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (4, 4-dimethyl-2- (4- (2, 4, 6-trifluorophenyl) thiophen-2-yl) cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Example 42 Essentially the same protocol of preparation of Example 42 was used to afford the example (25 mg) as a yellow solid.
  • Example 48 (S) -N- ( (4- ( ( (1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (4- (difluoromethyl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide
  • Example 42 Essentially the same protocol of preparation of Example 42 was used to afford the example (18.8 mg) as a yellow solid.
  • Example 49 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (4- (difluoromethyl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Example 42 Essentially the same protocol of preparation of Example 42 was used to afford the example (9.3 mg) as a yellow solid.
  • Example 50 (S) -N- ( (4- ( ( (1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (3, 4-difluorophenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide
  • Example 42 Essentially the same protocol of preparation of Example 42 was used to afford the example (23.6 mg) as a yellow solid.
  • Example 51 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (3, 4-difluorophenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Example 42 Essentially the same protocol of preparation of Example 42 was used to afford the example (18 mg) as a yellow solid.
  • Example 52 (S) -N- ( (4- ( ( (1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (5-fluoropyridin-2-yl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide
  • Example 42 Essentially the same protocol of preparation of Example 42 was used to afford the example (1.5 mg) as a yellow solid. MS: 937.3 (M+H + ) .
  • Example 53 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (4, 4-dimethyl-2- (4- (2, 4, 5-trifluorophenyl) thiophen-2-yl) cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Example 42 Essentially the same protocol of preparation of Example 42 was used to afford the example (12.6 mg) as a yellow solid.
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ 11.65 (s, 1 H) , 8.54 –8.52 (m, 2 H) , 8.05 –8.02 (m, 1 H) , 7.88 –7.81 (m, 1 H) , 7.81 –7.74 (m, 2 H) , 7.63 –7.56 (m, 1 H) , 7.51 –7.47 (m, 3 H) , 7.28 –7.24 (m, 1 H) , 7.06 –7.04 (m, 1 H) , 6.71 –6.68 (m, 1 H) , 6.39 –6.35 (m, 1 H) , 6.23 –6.19 (m, 1 H) , 4.26 (s, 1 H) , 3.29 –3.26 (m, 2 H) , 3.10 –3.08 (m, 4 H) , 3.
  • Example 54 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (4, 4-dimethyl-2- (4- (2, 3, 6-trifluorophenyl) thiophen-2-yl) cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Step B 2-Chloro-4- (2, 3, 6-trifluorophenyl) thiophene
  • Step C 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (4, 4-dimethyl-2- (4- (2, 3, 6-trifluorophenyl) thiophen-2-yl) cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1 r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (Example 54)
  • Example 55 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (3-cyano-5-fluorophenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Step A 3- (5-chlorothiophen-3-yl) -5-fluorobenzonitrile
  • Step B tert-butyl 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2-bromo-4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoate
  • Step C tert-butyl 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (4, 4-dimethyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoate
  • Step D tert-butyl 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (3-cyano-5-fluorophenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoate
  • Step E 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (3-cyano-5-fluorophenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoic acid
  • Step F 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (3-cyano-5-fluorophenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (Example 55)
  • Example 56 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (4- (2-cyanopropan-2-yl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Step A 2- (4- (5-Chlorothiophen-3-yl) phenyl) -2-methylpropanenitrile
  • Step B 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (4- (2-cyanopropan-2-yl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1 r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (Example 56)
  • Example 57 (S) -N- ( (4- ( ( (1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (4, 6-difluoro-1H-indol-7-yl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide
  • Step A 4, 6-difluoro-7- (thiophen-3-yl) -1H-indole
  • Step B 4, 6-difluoro-7- (thiophen-3-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-indole
  • Step C (4- (4, 6-difluoro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-indol-7-yl) thiophen-2-yl) boronic acid
  • Step D Methyl 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (4, 6-difluoro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-indol-7-yl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoate
  • Step E 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (4, 6-difluoro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-indol-7-yl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoic acid
  • Step F (S) -N- ( (4- ( ( (1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (4, 6-difluoro-1- ( (2- (trimethylsilyl) ethoxy) -methyl) -1H-indol-7-yl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) -piperazin-1-yl) benzamide
  • Step G (S) -N- ( (4- ( ( (1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (4, 6-difluoro-1H-indol-7-yl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide (Example 57)
  • Example 58 (S) -N- ( (4- ( ( (1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2- (dimethylamino) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide
  • Step B (4- (2- (Dimethylamino) phenyl) thiophen-2-yl) boronic acid
  • N, N-dimethyl-2- (thiophen-3-yl) aniline (Step A, 0.32 g, 1.574 mmol) was dissolved into dry THF (10 mL) under argon at -78 °C to give a solution; LDA (1.2 mL, 2 M in THF, 2.36 mmol) was added at -78 °C and the mixture was stirred at -78 °C for 1 h; Triisopropyl borate (0.474 g, 2.52 mmol, 1.6) was followed dropwise; the reaction mixture was stirred at -78 °C for 0.5 h, allowed to warm up to room temperature gradually and stirred for 1 h.
  • Step C Methyl 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2- (dimethylamino) -phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoate
  • Step D 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2- (dimethylamino) phen-yl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoic acid
  • Step E (S) -N- ( (4- ( ( (1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2- (dimethylamino) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide (Example 58)
  • Example 59 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -N- ( (4- ( ( ( (1 r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ( (2- (4- (4- (2-hydroxypropan-2-yl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide
  • Example 58 Essentially the same protocol of preparation of Example 58 was used to afford the example (50 mg) as a yellow solid.
  • Example 60 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (4- (1, 1, 1, 3, 3, 3-hexafluoro-2-hydroxypropan-2-yl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1 r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Example 58 Essentially the same protocol of preparation of Example 58 was used to afford the example (70 mg) as a yellow solid.
  • Example 61 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- ( (4-fluorophenyl) ethynyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin- 1-yl) -N- ( (4- ( ( ( (1 r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Example 58 Essentially the same protocol of preparation of Example 58 was used to afford the example (2 mg) as a yellow solid.
  • Example 62 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2-fluoro-4- (2-hydroxypropan-2-yl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Step B 2- (3-Fluoro-4- (thiophen-3-yl) phenyl) propan-2-ol
  • methyl 3-fluoro-4- (thiophen-3-yl) benzoate (Step A, 1.1 g, 4.66 mmol) was dissolved into dry THF (30 mL) under argon at 0 °C to give a solution; MeMgBr (4.7 mL, 3M in 2-MeTHF, 14 mmol) was added dropwise at 0 °C; the reaction mixture was stirred at 0 °C for 0.5 h, allowed to warm up to room temperature gradually and stirred for 3 h. MeOH (10 mL) was slowly added to quench the reaction, the resulting mixture was partitioned with EA and aq. NH 4 Cl.
  • Step C (4- (2-Fluoro-4- (2-hydroxypropan-2-yl) phenyl) thiophen-2-yl) boronic acid
  • Step D 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2-fluoro-4- (2-hydroxypropan-2-yl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1 r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (Example 62)
  • Example 58 was used to afford the example (100 mg) as a yellow solid.
  • Example 63 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2, 6-difluoro-4- (2-hydroxypropan-2-yl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1 r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Example 62 Essentially the same protocol of preparation of Example 62 was used to afford the example (120 mg) as a yellow solid.
  • Example 64 (S) -N- ( (4- ( ( (1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2, 6-difluoro-4- (2-hydroxypropan-2-yl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide
  • Example 62 Essentially the same protocol of preparation of Example 62 was used to afford the example (90 mg) as a yellow solid.
  • Example 65 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ( (2- (4- (4- (2-hydroxypropan-2-yl) -2, 6-dimethylphenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide
  • Example 62 Essentially the same protocol of preparation of Example 62 was used to afford the example (31.2 mg) as a yellow solid.
  • Example 66 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2, 6-dichloro-4- (2-hydroxypropan-2-yl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Example 62 Essentially the same protocol of preparation of Example 62 was used to afford the example (17.7 mg) as a yellow solid.
  • Example 67 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2, 6-difluoro-4- (3-hydroxypentan-3-yl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Example 62 Essentially the same protocol of preparation of Example 62 was used to afford the example (51 mg) as a yellow solid.
  • Example 68 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2, 6-difluoro-4- (2-hydroxypropan-2-yl-1, 1, 1, 3, 3, 3-d6) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Example 62 Essentially the same protocol of preparation of Example 62 was used to afford the example (54 mg) as a yellow solid.
  • Example 69 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (4- (1-cyclopropyl-1-hydroxyethyl) -2, 6-difluorophenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Step A 1- (3, 5-Difluoro-4- (thiophen-3-yl) phenyl) ethan-1-one
  • Step B 1-Cyclopropyl-1- (3, 5-difluoro-4- (thiophen-3-yl) phenyl) ethan-1-ol
  • Step C (4- (2, 6-Difluoro-4- (3-hydroxypentan-3-yl) phenyl) thiophen-2-yl) boronic acid
  • Step D 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (4- (1-cyclopropyl-1-hydroxyethyl) -2, 6-difluorophenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1 r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (Example 69)
  • Example 62 Starting from Step C, essentially the same protocol of preparation of Example 62 was used to afford the example (20 mg) as a yellow solid.
  • Example 70 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ( (2- (4- (3- (2-hydroxypropan-2-yl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzamide
  • Example 58 Essentially the same protocol of preparation of Example 58 was used to afford the example (60 mg) as a yellow solid.
  • Example 71 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (3-fluoro-4- (2-hydroxypropan-2-yl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Example 62 Essentially the same protocol of preparation of Example 62 was used to afford the example (12 mg) as a yellow solid.
  • Example 72 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2-fluoro-4- (1-hydroxypropan-2-yl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Step B Methyl 2- (3-fluoro-4- (thiophen-3-yl) phenyl) propanoate
  • Step C 2- (3-Fluoro-4- (thiophen-3-yl) phenyl) propan-1-ol
  • Step D (4- (2-Fluoro-4- (1-hydroxypropan-2-yl) phenyl) thiophen-2-yl) boronic acid
  • Step E 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2-fluoro-4- (1-hydroxypropan-2-yl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1 r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (Example 72)
  • Example 62 Starting from Step D, essentially the same protocol of preparation of Example 62 was used to afford the example (10 mg) as a yellow solid.
  • Example 73 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2-fluoro-4- (2-hydroxy-2-methylpropyl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Step A Methyl 2- (3-fluoro-4- (thiophen-3-yl) phenyl) acetate
  • Step B 1- (3-Fluoro-4- (thiophen-3-yl) phenyl) -2-methylpropan-2-ol
  • Step C (4- (2-Fluoro-4- (2-hydroxy-2-methylpropyl) phenyl) thiophen-2-yl) boronic acid
  • Step D 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2-fluoro-4- (2-hydroxy-2-methylpropyl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1 r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (Example 73)
  • Example 62 Starting from Step C, essentially the same protocol of preparation of Example 62 was used to afford the example (20 mg) as a yellow solid.
  • Example 74 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2, 6-difluoro-4- (1-hydroxy-2-methylpropan-2-yl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Step A 2- (3, 5-Difluorophenyl) -2-methylpropanenitrile
  • Step B 2- (3, 5-Difluoro-4-iodophenyl) -2-methylpropanenitrile
  • Step C 2- (3, 5-Difluoro-4- (thiophen-3-yl) phenyl) -2-methylpropanenitrile
  • Step D 2- (3, 5-Difluoro-4- (thiophen-3-yl) phenyl) -2-methylpropanoic acid
  • Step E 2- (3, 5-Difluoro-4- (thiophen-3-yl) phenyl) -2-methylpropan-1-ol
  • Step F (4- (2, 6-Difluoro-4- (1-hydroxy-2-methylpropan-2-yl) phenyl) thiophen-2-yl) boronic acid
  • Step G 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2, 6-difluoro-4- (1-hydroxy-2-methylpropan-2-yl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1 r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (Example 74)
  • Example 62 Starting from Step F, essentially the same protocol of preparation of Example 62 was used to afford the example (8 mg) as a yellow solid.
  • Example 75 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2-fluoro-5- (2-hydroxypropan-2-yl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1- yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1 r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Example 62 Essentially the same protocol of preparation of Example 62 was used to afford the example (35 mg) as a yellow solid.
  • Example 76 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2-fluoro-4- (2-methoxypropan-2-yl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Step A 3- (2-Fluoro-4- (2-methoxypropan-2-yl) phenyl) thiophene
  • Step B (4- (2-Fluoro-4- (2-methoxypropan-2-yl) phenyl) thiophen-2-yl) boronic acid
  • Step C 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2-fluoro-4- (2-methoxypropan-2-yl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1 r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (Example 76)
  • Example 62 Starting from Step B, essentially the same protocol of preparation of Example 62 was used to afford the example (3 mg) as a yellow solid.
  • Example 77 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2, 6-difluoro-4- (1-hydroxycyclobutyl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Step A 1- (4-Bromo-3, 5-difluorophenyl) cyclobutan-1-ol
  • Step B 1- (3, 5-Difluoro-4- (thiophen-3-yl) phenyl) cyclobutan-1-ol
  • Step C (4- (2, 6-Difluoro-4- (1-hydroxycyclobutyl) phenyl) thiophen-2-yl) boronic acid
  • Step D 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2, 6-difluoro-4- (1-hydroxycyclobutyl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1 r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (Example 77)
  • Example 62 Starting from Step C, essentially the same protocol of preparation of Example 62 was used to afford the example (2.4 mg) as a yellow solid.
  • Example 78 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2-fluoro-4- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1 r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Step A 1- (3-Fluoro-4- (thiophen-3-yl) phenyl) ethan-1-one
  • Step B 1, 1, 1-trifluoro-2- (3-fluoro-4- (thiophen-3-yl) phenyl) propan-2-ol
  • Step C (4- (2-fluoro-4- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) phenyl) thiophen-2-yl) boronic acid
  • Step B 1, 1, 1-trifluoro-2- (3-fluoro-4- (thiophen-3-yl) phenyl) propan-2-ol (Step B, 290 mg, 1 mmol) was dissolved into dry THF (10 mL) under argon at 0 °C to give a solution; LDA (1.5 mL, 2 M in THF, 3 mmol) was added at 0 °C and the mixture was stirred for 1 h; Triisopropyl borate (564 mg, 3 mmol) was added dropwise; the reaction mixture was stirred at 0 °C for 0.5 h, allowed to gradually warm up to room temperature and stirred for 16 h.
  • LDA 1.5 mL, 2 M in THF, 3 mmol
  • Step D 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2-fluoro-4- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1 r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (Example 78)
  • Example 62 Starting from Step C, essentially the same protocol of preparation of Example 62 was used to afford the example (50 mg) as a yellow solid.
  • Example 79 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (1-hydroxy-1-methyl-2, 3-dihydro-1H-inden-5-yl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1 r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Example 69 Essentially the same protocol of preparation of Example 69 was used to afford the example (48 mg) as a yellow solid.
  • Example 80 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (4- (2-acetamidopropan-2-yl) -2, 6-difluorophenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1 r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Step A N- (2- (3, 5-difluoro-4- (thiophen-3-yl) phenyl) propan-2-yl) acetamide
  • Step B (4- (4- (2-Acetamidopropan-2-yl) -2, 6-difluorophenyl) thiophen-2-yl) boronic acid
  • N- (2- (3, 5-difluoro-4- (thiophen-3-yl) phenyl) propan-2-yl) acetamide (Step A, 200 mg, 0.68 mmol) was dissolved into dry THF (10 mL) under argon at 0 °C to give a solution; LDA (1 mL, 2 M in THF, 2 mmol) was added at 0 °C and the mixture was stirred for 1 h; triisopropyl borate (382 mg, 2.03 mmol) was added dropwise; the reaction mixture was stirred at 0 °C for 0.5 h, allowed to gradually warm up to room temperature and stirred for 16 h.
  • Step C 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (4- (2-acetamidopropan-2-yl) -2, 6-difluorophenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1 r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (Example 80)
  • Example 62 Starting from Step B, essentially the same protocol of preparation of Example 62 was used to afford the example (30 mg) as a yellow solid.
  • Example 81 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2, 6-difluoro-4- (2-hydroxypropan-2-yl) phenyl) -5-methylthiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
  • Example 63 Essentially the same protocol of preparation of Example 63 was used to afford the example (30 mg) as a yellow solid.
  • Example 82 2- (4- (5- (2- ( (4- (3- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- ( ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) carbamoyl) phenyl) piperazin-1-yl) methyl) -5, 5-dimethylcyclohex-1-en-1-yl) thiophen-3-yl) -3, 5-difluorophenyl) -2-methylpropanoic acid
  • Step A Methyl 2- (3, 5-difluoro-4- (thiophen-3-yl) phenyl) -2-methylpropanoate
  • Step B (4- (2, 6-Difluoro-4- (1-methoxy-2-methyl-1-oxopropan-2-yl) phenyl) thiophen-2-yl) boronic acid
  • Step C Methyl 2- (4- (5- (2- ( (4- (3- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- ( ( (4- ( ( ( (1 r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) carbamoyl) phenyl) piperazin-1-yl) methyl) -5, 5-dimethylcyclohex-1-en-1-yl) thiophen-3-yl) -3, 5-difluorophenyl) -2-methylpropanoate
  • Step D 2- (4- (5- (2- ( (4- (3- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- ( ( (4- ( ( ( (1 r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) carbamoyl) phenyl) piperazin-1-yl) methyl) -5, 5-dimethylcyclohex-1-en-1-yl) thiophen-3-yl) -3, 5-difluorophenyl) -2-methylpropanoic acid (Example 82)
  • Examples 83 and 84 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2, 6-difluoro-4- ( (R) -1-hydroxyethyl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (Example 83) and 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2, 6-difluoro-4- ( (S) -1-hydroxyethyl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1
  • Step A 1- (3, 5-Difluoro-4- (thiophen-3-yl) phenyl) ethan-1-ol
  • Step B (4- (2, 6-Difluoro-4- (1-hydroxyethyl) phenyl) thiophen-2-yl) boronic acid
  • Step C Methyl 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2, 6-difluoro-4- (1-hydroxyethyl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoate
  • Step D Methyl (R) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2, 6-difluoro-4- (1-hydroxyethyl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoate (P1) and methyl (S) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2, 6-difluoro-4- (1-hydroxyethyl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoate (P2)
  • Step E (R) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2, 6-difluoro-4- (1-hydroxyethyl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoic acid
  • Step F 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2, 6-difluoro-4- ( (R) -1-hydroxyethyl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1 r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (Example 83)
  • Step G 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (4- ( (2- (4- (2, 6-difluoro-4- ( (S) -1-hydroxyethyl) phenyl) thiophen-2-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ( (4- ( ( ( (1 r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (Example 84)
  • Example 83 Starting from P2 in Step D, essentially the same protocol of preparation of Example 83 was used to afford the example (185 mg, in salt form with AcOH, 25%over 2 steps) as a yellow solid.
  • Assay plate Greiner Bio-One 655209, Black, flat bottom 96 well Plate
  • Assay buffer 100 mM potassium phosphate, pH 7.5; 100 ⁇ g/ml bovine gamma globulin; 0.02%sodium azide, plus 0.01%Triton X (added right before assay)
  • Assay volume 100 ⁇ L
  • Assay solution preparations (a) Prepare the complex solution (Protein plus Flu-BIM) in following concentrations: 20.5 nM of Bcl2 protein and 5.1 nM Flu-BIM in the assay buffer; (b) Prepare the positive control which is the free Flu-BIM (5.1 nM) in the assay buffer. Note: concentrations here are adjusted to achieve final 20 and 5 nM for protein and tracer respectively after these solutions are mixed with compound solution later.
  • IC 50 values were determined by nonlinear regression fitting of the log (inhibitor) vs. response variable slope (four parameters) by Graphpad Prism 8.2.1 (mP values vs compound concentrations) .
  • RS4; 11Bcl-2-G101V, RS4; 11Bcl-2-D103E, RS4; 11 Bcl-2-V156D and RS4; 11Bcl-2-G101V-D103E cells were obtained from Cobioer Biosciences. Cells were maintained in the RPMI-1640 medium with 10%FBS, 1%P/S and puromycin (1 ⁇ g/mL) at 37 °C and an atmosphere of 5%CO 2 .

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