Chemical Compounds

Abstract

The present invention relates to compounds of Formula (I): and to their salts, pharmaceutical compositions, methods of use, and methods for their preparation. These compounds inhibit Bcl-2 and/or Bcl-X L activities and may be used for the treatment of cancer.

1 - 15 . (canceled) 
     
     
         16 . A process for preparing a compound of Formula (I), 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is selected from —CN, —OR 1a , and —N(R 1a ) 2 ; 
         R 1a  in each occurrence is independently selected from H, C 1-4 alkyl, —C(O)CH 2 NH 2 , —C(O)CH 2 NHCH 3 , and when R 1  is —OR 1a , then R 1a  is additionally selected from —P(═O)(OH)(OCH 3 ), —P(═O)(OCH 2 CH 3 ) 2 , —CH 2 OP(═O)(OH)[OC(CH 3 ) 3 ] and —CH 2 OP(═O)[OC(CH 3 ) 3 ] 2 ; 
         R 2  is selected from —N(O) 2  and —S(O) 2 CF 3 ; 
         R 3  is selected from H and C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted with one or more R 40 ; 
         R 4  is selected from H and C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted with one or more R 40 ; 
         or R 3  and R 4  together with the nitrogen to which they are attached form a 5- or 6-membered heterocyclic ring, wherein
 i) said 5- or 6-membered heterocyclic ring is optionally substituted on carbon with one or more R 40 ; and 
 ii) if said 5- or 6-membered heterocyclic ring contains a nitrogen, that nitrogen is optionally substituted with R 40 * to form a tertiary amine; 
 
         R 40 * is selected from C 1-4 alkyl and —(CH 2 ) 2 OP(═O)(O) 2 , wherein said C 1-4 alkyl is optionally substituted with one or more R a ; 
         R 40  in each occurrence is selected from —OR 40a , —N(R 40a ) 2 , —CH 2 OR 5a , —CH 2 N(R 5a ) 2 , —OP(═O)(OH) 2 , and —OP(═O)[OC(CH 3 ) 3 ] 2 ; 
         R 5a  in each occurrence is selected from H and C 1-3 alkyl; 
         R 40a  in each occurrence is independently selected from H and C 1-4 alkyl; and 
         R a  is selected from halo, —OR m , and —N(R m ) 2 ; and 
         R m  in each occurrence is independently selected from H and C 1-4 alkyl, 
         or a pharmaceutically acceptable salt thereof, wherein said process comprises: 
         (i) providing a carboxylic acid compound of formula (1-f): 
       
       
         
           
           
               
               
           
         
         (ii) providing a sulfonamide compound of formula (1-g): 
       
       
         
           
           
               
               
           
         
       
       and
 (iii) coupling the carboxylic acid compound of formula (1-f) with the sulfonamide compound of formula (1-g). 
 
     
     
         17 . A process for preparing a compound of formula (2-g) and (2-h), said process comprising: 
       
         
           
           
               
               
           
         
         performing enantioselective reduction to a compound of formula (3-c). 
       
     
     
         18 . A process for preparing a compound of formula (5-f), said process comprising: 
       
         
           
           
               
               
           
         
         selectively deprotecting a compound of formula (5-e). 
       
     
     
         19 . A process for preparing a compound of formula (M), said process comprising: 
       
         
           
           
               
               
           
         
         (i) converting a compound of formula (J) to a compound of formula (K); 
         (ii) reducing a compound of formula (K) to form a compound of formula (L); 
         (iii) performing a substitution reaction on a compound of formula (L) to form a corresponding thioether; 
         (iv) performing a deprotection on the thioether to form a corresponding amine; and 
         (v) performing an aromatic substitution reaction on the corresponding amine to form a compound of formula (M).