Solid dispersions containing an apoptosis-inducing agent

Abstract

A pro-apoptotic solid dispersion comprises, in essentially non-crystalline form, a Bcl-2 family protein inhibitory compound of Formula I as defined herein, dispersed in a solid matrix that comprises (a) a pharmaceutically acceptable water-soluble polymeric carrier and (b) a pharmaceutically acceptable surfactant. A process for preparing such a solid dispersion comprises dissolving the compound, the polymeric carrier and the surfactant in a suitable solvent, and removing the solvent to provide a solid matrix comprising the polymeric carrier and the surfactant and having the compound dispersed in essentially non-crystalline form therein. The solid dispersion is suitable for oral administration to a subject in need thereof for treatment of a disease characterized by overexpression of one or more anti-apoptotic Bcl-2 family proteins, for example cancer.

1 . A solid dispersion comprising, in essentially non-crystalline form, a compound of Formula I 
       
         
           
           
               
               
           
         
         where: 
         R 0  is halo; 
         R 1  and R 2  are H or are independently methyl or methoxy; 
         R 3  and R 4  are independently methyl or methoxy if R 1  and R 2  are H, or are H if R 1  and R 2  are independently methyl or methoxy; 
         A 1  and A 2  are each independently CH or N; 
         R 5  is C 1-4  alkyl or haloalkyl, C 1-4  alkylsulfonyl or haloalkylsulfonyl, halo, nitro or cyano; 
         X is —O— or —NH—; 
         Y is —(CH 2 ) n — where n is 0, 1, 2 or 3; and 
         R 6  is an unsubstituted or substituted 3- to 7-membered carbocyclic or heterocyclic ring as defined herein, or is NR 7 R 8 ;
 wherein, if R 6  is NR 7 R 8 , R 7  and R 8  are each independently H or R 9 —(CH 2 ) m — groups, no more than one of R 7  and R 8  being H, where each R 9  is independently a 3- to 7-membered carbocyclic or heterocyclic ring, optionally substituted with no more than two Z 1  groups as defined below, and each m is independently 0 or 1; and 
 wherein, if R 6  is a substituted carbocyclic or heterocyclic ring, substituents thereon are no more than two Z 1  groups and/or no more than one Z 2  group, Z 1  groups being independently selected from (a) C 1-4  alkyl, C 2-4  alkenyl, C 1-4  alkoxy, C 1-4  alkylthio, C 1-4  alkylamino, C 1-4  alkylsulfonyl, C 1-4  alkylsulfonylamino, C 1-4  alkylcarbonyl, C 1-4  alkylcarbonylamino and C 1-4  alkylcarboxy, each optionally substituted with one or more substituents independently selected from halo, hydroxy, C 1-4  alkoxy, amino, C 1-4  alkylamino, di-(C 1-4  alkyl)amino and cyano, (b) halo, (e) hydroxy, (f) amino and (g) oxo groups, and Z 2  being (i) a further 3- to 6-membered carbocyclic or heterocyclic ring, optionally substituted with no more than two Z 1  groups as defined above, or (ii) NR 7 R 8  where R 7  and R 8  are as defined above; 
 
       
       or a pharmaceutically acceptable salt thereof; dispersed in a solid matrix that comprises (a) at least one pharmaceutically acceptable water-soluble polymeric carrier and (b) at least one pharmaceutically acceptable surfactant. 
     
     
         2 . The solid dispersion of  claim 1 , wherein, in the compound of Formula I, R 0  is chloro. 
     
     
         3 . The solid disperson of  claim 2 , wherein, in the compound of Formula I, R 3  and R 4  are each methyl. 
     
     
         4 . The solid disperson of  claim 3 , wherein, in the compound of Formula I, R 1  and R 2  are each hydrogen. 
     
     
         5 . The solid disperson of  claim 4 , wherein, in the compound of Formula I, A 1  is N and A 2  is CH. 
     
     
         6 . The solid disperson of  claim 5 , wherein, in the compound of Formula I, R 5  is nitro. 
     
     
         7 . The solid disperson of  claim 6 , wherein, in the compound of Formula I, X is —NH—. 
     
     
         8 . The solid disperson of  claim 7 , wherein, in the compound of Formula I, Y is —(CH 2 ) n — where n is 1. 
     
     
         9 . The solid disperson of  claim 8 , wherein, in the compound of Formula I, R 6  is tetrahydropyran. 
     
     
         10 . The solid dispersion of  claim 9 , wherein the compound is 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide. 
     
     
         11 . The solid dispersion of  claim 1 , wherein, in the compound of Formula I, R 1  is methyl or methoxy, R 2  is methyl, and R 3  and R 4  are each H. 
     
     
         12 . The solid dispersion of  claim 1 , wherein, in the compound of Formula I, if A 2  is —CH— then R 5  is nitro; and if A 2  is —N— then R 5  is bromo. 
     
     
         13 . The solid dispersion of  claim 1 , wherein, in the compound of Formula I, R 6  is a 3- to 7-membered carbocyclic or heterocyclic ring, unsubstituted or substituted with no more than two Z 1  groups and/or no more than one Z 2  group. 
     
     
         14 . The solid dispersion of  claim 13 , wherein, in the compound of Formula I, said carbocyclic or heterocyclic ring is a saturated ring. 
     
     
         15 . The solid dispersion of  claim 14 , wherein, in the compound of Formula I, said saturated ring is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imazolidinyl, pyrazolidinyl, tetrahydrofuranyl, oxazolidinyl, isoxazolidinyl, thiophanyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, 1,4-dioxanyl, morpholinyl and tetrahydrothiopyranyl rings. 
     
     
         16 . The solid dispersion of  claim 1 , wherein the compound is selected from the group consisting of
 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   N-[(5-chloro-6-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3-yl)-sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   N-({5-bromo-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pyridin-3-yl}-sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   4-(4-{[2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}-sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(methylsulfonyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)-sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)-sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)-sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclopropyl(oxetan-3-yl)amino]propyl}amino)-3-nitrophenyl]-sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]methyl}-amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   N-[(5-chloro-6-{[1-(cyanomethyl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methoxytetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   
       and pharmaceutically acceptable salts thereof. 
     
     
         17 . The solid dispersion of  claim 1 , wherein the compound or salt is present in a parent-compound-equivalent amount of about 5% to about 40% by weight. 
     
     
         18 . The solid dispersion of  claim 1 , wherein the at least one polymeric carrier is present in an amount of about 40% to about 85% by weight and the at least one surfactant is present in an amount of about 5% to about 20% by weight. 
     
     
         19 . The solid dispersion of  claim 1 , wherein the at least one polymeric carrier is selected from the group consisting of homopolymers and copolymers of N-vinyl lactams, cellulose esters, cellulose ethers, high molecular weight polyalkylene oxides, polyacrylates, polymethacrylates, polyacrylamides, vinyl acetate polymers, graft copolymers of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate, oligo- and polysaccharides and mixtures thereof. 
     
     
         20 . The solid dispersion of  claim 1 , wherein the at least one polymeric carrier is selected from the group consisting of povidones, copovidones, HPMCs, polyethylene glycol/polyvinyl caprolactam/polyvinyl acetate graft copolymers and mixtures thereof. 
     
     
         21 . The solid dispersion of  claim 1 , wherein the at least one surfactant is non-ionic. 
     
     
         22 . The solid dispersion of  claim 1 , wherein the at least one surfactant is selected from the group consisting of polyoxyethylene glycerides, fatty acid monoesters of sorbitan, polysorbates, α-tocopheryl polyethylene glycol succinate (TPGS) and mixtures thereof. 
     
     
         23 . The solid dispersion of  claim 1 , wherein no more than about 5% of the compound of Formula I is crystalline as observed by X-ray diffraction analysis. 
     
     
         24 . The solid dispersion of  claim 1 , wherein no more than about 2% of the compound of Formula I is crystalline as observed by X-ray diffraction analysis. 
     
     
         25 . The solid dispersion of  claim 1 , wherein no more than about 1% of the compound of Formula I is crystalline as observed by X-ray diffraction analysis. 
     
     
         26 . A process for preparing a solid dispersion, comprising:
 (a) dissolving in a suitable solvent (i) an active pharmaceutical ingredient (API) comprising a compound of Formula I   
       
         
           
           
               
               
           
         
         
           where: 
           R 0  is halo; 
           R 1  and R 2  are H or are independently methyl or methoxy; 
           R 3  and R 4  are independently methyl or methoxy if R 1  and R 2  are H, or are H if R 1  and R 2  are independently methyl or methoxy; 
           A 1  and A 2  are each independently CH or N; 
         
         R 5  is C 1-4  alkyl or haloalkyl, C 1-4  alkylsulfonyl or haloalkylsulfonyl, halo, nitro or cyano; 
         X is —O— or —NH—; 
         Y is —(CH 2 ) n — where n is 0, 1, 2 or 3; and 
         R 6  is an unsubstituted or substituted 3- to 7-membered carbocyclic or heterocyclic ring as defined herein, or is NR 7 R 8 ;
 wherein, if R 6  is NR 7 R 8 , R 7  and R 8  are each independently H or R 9 —(CH 2 ) m — groups, no more than one of R 7  and R 8  being H, where each R 9  is independently a 3- to 7-membered carbocyclic or heterocyclic ring, optionally substituted with no more than two Z 1  groups as defined below, and each m is independently 0 or 1; and 
 wherein, if R 6  is a substituted carbocyclic or heterocyclic ring, substituents thereon are no more than two Z 1  groups and/or no more than one Z 2  group, Z 1  groups being independently selected from (a) C 1-4  alkyl, C 2-4  alkenyl, C 1-4  alkoxy, C 1-4  alkylthio, C 1-4  alkylamino, C 1-4  alkylsulfonyl, C 1-4  alkylsulfonylamino, C 1-4  alkylcarbonyl, C 1-4  alkylcarbonylamino and C 1-4  alkylcarboxy, each optionally substituted with one or more substituents independently selected from halo, hydroxy, C 1-4  alkoxy, amino, C 1-4  alkylamino, di-(C 1-4  alkyl)amino and cyano, (b) halo, (e) hydroxy, (f) amino and (g) oxo groups, and Z 2  being (i) a further 3- to 6-membered carbocyclic or heterocyclic ring, optionally substituted with no more than two Z 1  groups as defined above, or (ii) NR 7 R 8  where R 7  and R 8  are as defined above; 
 
          or a pharmaceutically acceptable salt thereof, (ii) at least one pharmaceutically acceptable water-soluble polymeric carrier and (iii) at least one pharmaceutically acceptable surfactant; and 
         (b) removing the solvent to provide a solid matrix comprising the at least one polymeric carrier and the at least one surfactant and having the compound or a salt thereof dispersed in an essentially non-crystalline form therein. 
       
     
     
         27 . The process of  claim 26 , wherein the API comprises a compound of Formula I in parent-compound form; and the process further comprises adding a pharmaceutically acceptable acid before removing the solvent. 
     
     
         28 . The process of  claim 26 , wherein the solvent is removed under heat and/or vacuum. 
     
     
         29 . The process of  claim 26 , wherein the solvent is removed by rotary evaporation or by spray-drying. 
     
     
         30 . The process of  claim 26 , wherein the solvent comprises one or more of methanol, ethanol, acetone, tetrahydrofuran and dichloromethane. 
     
     
         31 . The process of  claim 26 , wherein the solvent comprises a dichloromethane/methanol or THF/water mixture. 
     
     
         32 . The process of  claim 26 , wherein no more than about 5% of the compound of Formula I in the solid matrix is crystalline as observed by X-ray diffraction analysis. 
     
     
         33 . The process of  claim 26 , wherein no more than about 2% of the compound of Formula I in the solid matrix is crystalline as observed by X-ray diffraction analysis. 
     
     
         34 . The process of  claim 26 , wherein no more than about 1% of the compound of Formula I in the solid matrix is crystalline as observed by X-ray diffraction analysis. 
     
     
         35 . The process of  claim 26 , wherein API is 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide. 
     
     
         36 . The process of  claim 35 , wherein the polymeric carrier is a copovidone. 
     
     
         37 . The process of  claim 36 , wherein the surfactant is a polysorbate. 
     
     
         38 . An orally deliverable pharmaceutical dosage form comprising the solid dispersion of  claim 1 . 
     
     
         39 . A method for treating a neoplastic, immune or autoimmune disease, comprising orally administering to a subject having the disease a therapeutically effective amount of the solid dispersion of  claim 1 . 
     
     
         40 . The method of  claim 39 , wherein the disease is a neoplastic disease. 
     
     
         41 . The method of  claim 40 , wherein the neoplastic disease is selected from the group consisting of cancer, mesothelioma, bladder cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, bone cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal and/or duodenal) cancer, chronic lymphocytic leukemia, acute lymphocytic leukemia, esophageal cancer, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, testicular cancer, hepatocellular (hepatic and/or biliary duct) cancer, primary or secondary central nervous system tumor, primary or secondary brain tumor, Hodgkin's disease, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphoma, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, multiple myeloma, oral cancer, non-small-cell lung cancer, prostate cancer, small-cell lung cancer, cancer of the kidney and/or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system, primary central nervous system lymphoma, non-Hodgkin's lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, cancer of the spleen, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma and combinations thereof. 
     
     
         42 . The method of  claim 40 , wherein the neoplastic disease is a lymphoid malignancy. 
     
     
         43 . The method of  claim 42 , wherein the lymphoid malignancy is non-Hodgkin's lymphoma. 
     
     
         44 . The method of  claim 40 , wherein the neoplastic disease is chronic lymphocytic leukemia or acute lymphocytic leukemia. 
     
     
         45 . The method of  claim 39 , wherein the disease is an immune or autoimmune disease. 
     
     
         46 . The method of  claim 39 , wherein the solid dispersion is administered in a parent-compound-equivalent dose of about 50 to about 500 mg per day of the compound of Formula I or salt thereof at an average treatment interval of about 3 hours to about 7 days. 
     
     
         47 . The method of  claim 39 , wherein the solid dispersion is administered once daily in a parent-compound-equivalent dose of about 50 to about 500 mg per day of the compound of Formula I or salt thereof. 
     
     
         48 . The method of  claim 39 , wherein the compound is selected from the group consisting of
 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   N-[(5-chloro-6-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3-yl)-sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   N-({5-bromo-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pyridin-3-yl}-sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   4-(4-{[2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}-sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(methylsulfonyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)-sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)-sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)-sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclopropyl(oxetan-3-yl)amino]propyl}amino)-3-nitrophenyl]-sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]methyl}-amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   N-[(5-chloro-6-{[1-(cyanomethyl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methoxytetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;   
       and pharmaceutically acceptable salts thereof. 
     
     
         49 . The method of  claim 48 , wherein the compound is 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide.