Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases

Abstract

Disclosed are compounds which inhibit the activity of anti-apoptotic Bcl-2 proteins, compositions containing the compounds and methods of treating diseases during which is expressed anti-apoptotic Bcl-2 protein.

1 - 6 . (canceled) 
     
     
         7 . A compound having Formula (Ia), Formula (IIa), or Formula (IIIa): 
       
         
           
           
               
               
           
         
       
       or a therapeutically acceptable salt thereof, wherein
 A 1  is C(A 2 ); 
 A 2  is H 
 B 1  is OR 1  or NHR 1 , wherein R 1  is alkyl substituted with R 10 : 
 D 1  is H; 
 E 1  is H; 
 Y 1  is NO 2 ; 
 G 1  is R 1B , OR 1B , or NHR 1B , wherein R 1B  is alkyl substituted with OP(O)(OH)(OH) or with C 3 -C 10 -cycloalkyl substituted with OP(O)(OH)(OH); and 
 R 10  is C 3 -C 10 -cycloalkyl having one or two CH 2  moieties unreplaced or replaced with O; 
 wherein the moiety represented by R 10  is unsubstituted or substituted with one or two or three or four or five substituents independently selected from the group consisting of R 50 , OR 50 , F, Cl, Br or I; and 
 R 50  is alkyl. 
 
     
     
         8 - 11 . (canceled) 
     
     
         12 . A method of treating a cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the compound or therapeutically acceptable salt of  claim 7 . 
     
     
         13 . The method of  claim 12 , wherein the cancer is selected from the group consisting of bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, a lymphoid malignancy of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, and spleen cancer. 
     
     
         14 . The method of  claim 12 , wherein the cancer is acute lymphoblastic leukemia. 
     
     
         15 . The method of  claim 12  further comprising administering to the patient a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent. 
     
     
         16 . The method of  claim 12 , wherein the compound or therapeutically acceptable salt administered to the patient has Formula (Ia) 
       
         
           
           
               
               
           
         
       
       or a therapeutically acceptable salt thereof, wherein
 A 1  is C(A 2 ); 
 A 2  is H; 
 D 1  is H; 
 E 1  is H; 
 Y 1  is NO 2 ; and 
 G 1  is R 1B , OR 1B , or NHR 1B , wherein R 1B  is alkyl substituted with C 3 -C 10 -cycloalkyl, which is substituted with OP(O)(OH)(OH). 
 
     
     
         17 . The method of  claim 16 , wherein the compound or therapeutically acceptable salt is a compound selected from the group consisting of:
 3-[(4-{[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)benzoyl]sulfamoyl}-2-nitrophenyl)amino]-2,2-dimethylpropyl dihydrogen phosphate; and   trans-4-[(4-{[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)benzoyl]sulfamoyl}-2-nitrophenoxy)methyl]cyclohexyl dihydrogen phosphate,   or a therapeutically acceptable salt thereof.   
     
     
         18 . The method of  claim 12 , wherein the compound or therapeutically acceptable salt administered to the patient has Formula (IIIa) 
       
         
           
           
               
               
           
         
       
       or a therapeutically acceptable salt thereof, wherein
 A 1  is C(A 2 ); 
 A 2  is H; 
 B 1  is OR 1  or NHR 1 , wherein R 1  is alkyl substituted with R 10 ; 
 D 1  is H; 
 E 1  is H; 
 Y 1  is NO 2 ; 
 G 1  is R 1B , wherein R 1B  is alkyl substituted with OP(O)(OH)(OH); 
 R 10  is C 3 -C 10 -cycloalkyl having one or two CH 2  moieties unreplaced or replaced with O; 
 wherein the moiety represented by R10 is unsubstituted or substituted with one or two or three or four or five substituents independently selected from the group consisting of R 50 , OR 50 , F, Cl, Br or I; and 
 R 50  is alkyl. 
 
     
     
         19 . The method of  claim 18 , wherein the compound or therapeutically acceptable salt is a compound selected from the group consisting of:
 (5-{5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1 -yl]methyl}piperazin-1-yl)-2-[({3-nitro-4-[(tetrahydro-2H- pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenoxy}-7H-pyrrolo[2,3-b]pyridin-7-yl)methyl dihydrogen phosphate;   {5-[5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[(4-{[(trans-4- methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]carbamoyl}phenoxy]-7H-pyrrolo[2,3-b]pyridin-7-yl}methyl dihydrogen phosphate; and   (5-{5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[({4-[(4-fluorotetrahydro-2H- pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)carbamoyl]phenoxy}-7H-pyrrolo[2,3-b]pyridin-7-yl)methyl dihydrogen phosphate,   or a therapeutically acceptable salt thereof.   
     
     
         20 . A method of treating an autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the compound or therapeutically acceptable salt of  claim 7 .