6-alkynyl-pyridine derivatives

Abstract

6-Alkynyl-pyridine of general formula (I) their use as SMAC mimetics, pharmaceutical compositions containing them, and their use as a medicaments for the treatment and/or prevention of diseases characterized by excessive or abnormal cell proliferation and associated conditions such as cancer. An exemplary compound is

1 . A compound of formula I 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from the group consisting of hydrogen, —C 1-3 alkyl and halogen; 
 R 2  is selected from the group consisting of hydrogen, —C 1-3 alkyl and halogen; 
 R 3  is selected from the group consisting of phenyl or a 9- to 14-membered heteroaryl wherein each of these groups is optionally substituted with R 5  or 
 R 3  is a phenyl moiety fused with a 5-6 membered heterocycloalkyl, wherein each of these groups is optionally and independently substituted with one or more R 6 ; 
 R 4  is a 5- or 6-membered heteroaryl substituted with —C 1-3 alkyl or —O—C 1-3 alkyl; 
 R 5  is —C 1-3 alkyl; 
 R 6  is ═O or —C 1-3 alkyl; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . A compound according to  claim 1 , wherein R 1  is selected from the group consisting of hydrogen, —CH 3  and Cl. 
     
     
         3 . A compound according to  claim 1 , wherein R 2  is selected from the group consisting of hydrogen, —CH 3  and Cl. 
     
     
         4 . A compound according to  claim 1 , wherein R 1  is hydrogen and R 2  is selected from the group consisting of hydrogen, —CH 3  and Cl. 
     
     
         5 . A compound according to  claim 1 , wherein R 4  is a 6-membered heteroaryl substituted with —C 1-3 alkyl or —O—C 1-3 alkyl. 
     
     
         6 . A compound according to  claim 1 , wherein R 4  is selected from the group consisting of pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, each of which is independently substituted with —C 1-3 alkyl or —O—C 1-3 alkyl. 
     
     
         7 . A compound according to  claim 1 , wherein R 4  is selected from the group consisting of pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, each of which is independently substituted with —CH 3  or —O—CH 3 . 
     
     
         8 . A compound according to  claim 1 , wherein R 3  is selected from the group consisting of phenyl, 
       
         
           
           
               
               
           
         
       
     
     
         9 . A compound according to  claim 1 , selected from the group consisting of 
       
         
           
                 
                 
               
                     
                 
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                   Structure 
                 
                     
                 
                     
                 
                 
                 
               
                   1 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
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                   3 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   4 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   5 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   6 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   7 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   8 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   9 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   10 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   11 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
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                   15 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                 
               
                   and, 
                 
                     
                 
                 
                 
               
                   16 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
                
                
               
               
                
               
            
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
             
                
                
               
            
             
                
                
               
            
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         10 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         11 . A method for the treatment of cancer, which comprises administering to a host suffering from a cancer a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         12 . A method for the treatment of carcinomas of the breast, prostate, brain or ovary, non-small-cell lung carcinomas (NSCLC), melanomas, acute myeloid leukaemia (AML) or chronic lymphatic leukaemias (CLL), which comprises administering to a host suffering from one of said conditions a therapeutically effective amount of a compound according to  claim 1 .