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 - 11 . (canceled) 
     
     
         12 . A compound having Formula (42): 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein
 A 1  is C(A 2 ); 
 A 2  is H; 
 L is R 1 , OR 1 , or NHR 1 ; 
 D 1  is H; 
 E 1  is H; 
 Y 1  is NO 2 ; 
 R 1  is alkyl or cycloalkyl-alkyl; 
 R 30  is cycloalkyl or cycloalkenyl, each having one or two CH moieties unreplaced or replaced with N; 
 wherein R 30  is substituted with CH 2 R 37 ; 
 R 37  is R 40 , each of which is substituted with R 41 ; 
 R 40  is C 4 -C 8 -cycloalkenyl; 
 R 41  is R 42 ; 
 R 42  is phenyl; 
 wherein the moieties represented by R 40  and R 42  are independently unsubstituted or substituted with one or two or three or four or five substituents independently selected from R 50 , OR 50 , F, Cl, Br and I; 
 R 50  is R 54 ; and 
 R 54  is alkyl. 
 
     
     
         13 . A method preparing the compound or salt of  claim 12 , comprising:
 mixing a compound of Formula (39)   
       
         
           
           
               
               
           
         
       
       with di-tert-butyl diisopropylphosphoramidite and tetrazole in tetrahydrofuran;
 adding hydrogen peroxide to the mixture from the mixing step to produce a compound of Formula (41) 
 
       
         
           
           
               
               
           
         
       
       and
 coupling the compound of Formula (41) with a compound of Formula (41A) 
 
       
         
           
           
               
               
           
         
       
       to produce the compound or salt of  claim 12 ; 
       wherein in Formulas (39) and (41):
 A 1  is C(A 2 ); 
 A 2  is H; 
 L is R 1 , OR 1 , or NHR 1 ; 
 D 1  is H; 
 E 1  is H; 
 Y 1  is NO 2 ; and 
 R 1  is alkyl or cycloalkyl-alkyl; and 
 
       wherein in Formula (41A):
 R 30  is cycloalkyl or cycloalkenyl, each having one or two CH moieties unreplaced or replaced with N; 
 wherein R 30  is substituted with CH 2 R 37 ; 
 R 37  is R 40 , each of which is substituted with R 41 ; 
 R 40  is C 4 -C 8 -cycloalkenyl; 
 R 41  is R 42 ; 
 R 42  is phenyl; 
 wherein the moieties represented by R 40  and R 42  are independently unsubstituted or substituted with one or two or three or four or five substituents independently selected from R 50 , OR 50 , F, Cl, Br and I; 
 R 5  is R 54 ; and 
 R 54  is alkyl.