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 .- 32 . (canceled) 
     
     
         33 . A compound having Formula (II) 
       
         
           
           
               
               
           
         
         or a therapeutically acceptable salt thereof, wherein 
         n is 0; 
         A 1  is C(A 2 ); 
         A 2  is H; 
         B 1  is NHR 1 ; 
         D 1  is H; 
         E 1  is H; and 
         Y 1  is NO 2 ; 
         R 1  is R 5 ; 
         R 5  is methyl, which is substituted with one R 7 ; 
         R 7  is R 10 ; 
         R 10  is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with R 10A ; R 10A  is benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
         wherein R 10  is unsubstituted or substituted with one or two or three or four or five of independently selected alkyl, OH, OR 57 , F, Cl, Br or I; 
         Z 2  is R 30 ; 
         R 30  is heterocycloalkylene which is fused or unfused with R 30A ; R 30A  is cycloalkane; 
         L 1  is R 37 ; 
         R 37  is a bond or R 37A ; 
         R 37A  is alkylene; 
         Z 3  is R 40 ; 
         R 40  is heterocycloalkyl or heterocycloalkenyl; 
         wherein R 40  is substituted with one or two or three R 57 ; 
         R 57  is R 58  or R 61 ; 
         R 58  is phenyl; 
         R 61  is alkyl; 
         wherein R 58  is substituted with chloro or one R 72 ; and 
         R 72  is alkyl. 
       
     
     
         34 . The compound of  claim 33  or a therapeutically acceptable salt thereof, wherein R 10  is cycloalkyl. 
     
     
         35 . The compound of  claim 34  or a therapeutically acceptable salt thereof, wherein R 10  is cyclohexyl. 
     
     
         36 . The compound of  claim 34  or a therapeutically acceptable salt thereof, wherein R 10  is substituted with one methyl and one OH. 
     
     
         37 . The compound of  claim 33  or a therapeutically acceptable salt thereof, wherein R 30  is heterocycloalkylene fused with R 30A ; R 30A  is cycloalkane. 
     
     
         38 . The compound of  claim 33  or a therapeutically acceptable salt thereof, wherein R 30  is heterocycloalkylene. 
     
     
         39 . The compound of  claim 33  or a therapeutically acceptable salt thereof, wherein R 37  is a bond. 
     
     
         40 . The compound of  claim 33  or a therapeutically acceptable salt thereof, wherein R 37A  is methylene. 
     
     
         41 . The compound of  claim 33  or a therapeutically acceptable salt thereof, wherein R 40  is heterocycloalkyl. 
     
     
         42 . The compound of  claim 33  or a therapeutically acceptable salt thereof, wherein R 40  is heterocycloalkenyl. 
     
     
         43 . The compound of  claim 33  or a therapeutically acceptable salt thereof, wherein R 40  is pyrrolidinyl. 
     
     
         44 . The compound of  claim 33  or a therapeutically acceptable salt thereof, wherein R 58  is substituted with R 72 , wherein R 72  is alkyl. 
     
     
         45 . The compound of  claim 33  or a therapeutically acceptable salt thereof, wherein R 58  is substituted with chloro. 
     
     
         46 . The compound of  claim 33  or a therapeutically acceptable salt thereof, wherein the compound is selected from
 4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-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-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; 
 and 
 Cis-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide. 
 
     
     
         47 . A pharmaceutical composition comprising the compound or therapeutically acceptable salt of any one of  claim 33  and a pharmaceutically acceptable excipient.