Substituted 1h-benzimidazole-4-carboxamides are potent parp inhibitors

Abstract

The present invention relates to 1H-benzimidazole-4-carboxamides of formula (I), their preparation, and their use as inhibitors of the enzyme poly(ADP-ribose)polymerase for the preparation of drugs.

1 . A compound of Formula (I) 
     
       
         
         
             
             
         
       
     
     or a therapeutically acceptable salt thereof, wherein
 R 1 , R 2 , and R 3  are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, cyano, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, NR A R B , and (NR A R B )carbonyl; 
 Ar 1  is selected from the group consisting of aryl and heteroaryl, wherein Ar 1  is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of alkyl, cyano, halogen, and haloalkyl; 
 X 1  is alkylenyl; 
 Z is heterocycle, wherein Z is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of alkenyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkynyl, alkoxy, alkoxyalkyl alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylcarbonyl, cycloalkylcarbonylalkyl, halogen, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heteroarylcarbonylalkyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR C R D , NR C R D alkyl, (NR C R D )carbonyl, (NR C R D )carbonylalkyl, and oxo; 
 R A  and R B  are independently selected from the group consisting of hydrogen, alkyl, and alkycarbonyl, or R A  and R B  together with the nitrogen atom to which they are attached form a heterocycle; and 
 R C  and R D  are independently selected from the group consisting of hydrogen, alkyl, alkycarbonyl, cycloalkyl, and cycloalkylalkyl. 
 
   
   
       2 . A compound of Formula (I) 
     
       
         
         
             
             
         
       
     
     or a therapeutically acceptable salt thereof, wherein
 R 1 , R 2 , and R 3  are independently selected from the group consisting of hydrogen, and halogen; 
 Ar 1  is selected from the group consisting of aryl and heteroaryl, wherein Ar 1  is optionally substituted with halogen; 
 X 1  is alkylenyl; 
 Z is heterocycle, wherein Z is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, NR C R D , and NR C R D alkyl; and 
 R C  and R D  are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and cycloalkylalkyl. 
 
   
   
       3 . A compound according to  claim 1 , wherein Ar 1  is phenyl. 
   
   
       4 . A compound according to  claim 1 , wherein Z is pyrrolidinyl optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of alkenyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkynyl, alkoxy, alkoxyalkyl alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, NR C R D , NR C R D alkyl, (NR C R D )carbonyl, (NR C R D )carbonylalkyl, and oxo; and
 R C  and R D  are independently selected from the group consisting of hydrogen, alkyl, alkycarbonyl, cycloalkyl, and cycloalkylalkyl.   
   
   
       5 . A compound according to  claim 1 , wherein Z is pyrrolidinyl optionally substituted with NR C R D . 
   
   
       6 . A compound according to  claim 1 , wherein Z is pyrrolidinyl optionally substituted with alkyl. 
   
   
       7 . A compound according to  claim 1 , wherein Z is pyrrolidinyl optionally substituted with NR C R D alkyl. 
   
   
       8 . A compound according to  claim 1 , wherein Z is pyrrolidinyl optionally substituted with hydroxyalkyl. 
   
   
       9 . A compound according to  claim 1 , wherein Ar 1  is phenyl and Z is pyrrolidinyl. 
   
   
       10 . A compound according to  claim 1 , wherein Ar 1  is phenyl substituted with halogen. 
   
   
       11 . A compound according to  claim 1 , wherein R 1 , R 2 , and R 3  are hydrogen. 
   
   
       12 . A conmpound selected from the group consisting of 
     6-fluoro-2-[4-(2-methylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-carboxamide; 
     6-fluoro-2-[4-((S)-2-hydroxymethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-carboxamide; 
     6-fluoro-2-[4-(2-trifluoromethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-carboxamide; 
     2-[4-(2-ethylpyrrolidin-1-ylmethyl)phenyl]-6-fluoro-1H-benzimidazole-4-carboxamide; 
     6-fluoro-2-[4-(2-isopropylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-carboxamide; 
     6-fluoro-2-[4-((R)-2-hydroxymethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-carboxamide; 
     2-[4-((S)-2-hydroxymethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-carboxamide; 
     2-[4-(2-trifluoromethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-carboxamide; 
     2-[4-(2-isopropylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-carboxamide; 
     2-[4-(2-ethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-carboxamide; 
     2-[4-((R)-2-hydroxymethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-carboxamide; 
     6-chloro-2-[4-(2-trifluoromethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-carboxamide; 
     6-chloro-2-[4-(2-isopropylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-carboxamide; 
     6-chloro-2-[4-((S)-2-hydroxymethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-carboxamide; 
     6-chloro-2-[4-((R)-2-hydroxymethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-carboxamide; 
     2-{4-[2-(2-methylpyrrolidin-1-yl)-ethyl]phenyl}-1H-benzimidazole-4-carboxamide; 
     2-[2-fluoro-4-((S)-2-hydroxymethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-carboxamide; 
     2-{4-[(3-aminopyrrolidin-1-yl)methyl]phenyl}-1H-benzimidazole-4-carboxamide; 
     2-(4-{[3-(dimethylamino)pyrrolidin-1-yl]methyl}phenyl)-1H-benzimidazole-4-carboxamide; 
     2-(4-{[3-(isopropylamino)pyrrolidin-1-yl]methyl}phenyl)-1H-benzimidazole-4-carboxamide; 
     2-[4-({3-[(cyclopropylmethyl)amino]pyrrolidin-1-yl}methyl)phenyl]-1H-benzimidazole-4-carboxamide; 
     2-(4-{[3-(cyclobutylamino)pyrrolidin-1-yl]methyl}phenyl)-1H-benzimidazole-4-carboxamide; 
     2-(4-{[3-(dicyclobutylamino)pyrrolidin-1-yl]methyl}phenyl)-1H-benzimidazole-4-carboxamide; 
     2-(4-{[2-(aminomethyl)pyrrolidin-1-yl]methyl}phenyl)-1H-benzimidazole-4-carboxamide; 
     2-[4-({2-[(dimethylamino)methyl]pyrrolidin-1-yl}methyl)phenyl]-1H-benzimidazole-4-carboxamide; 
     2-{4-[(2-{[(cyclopropylmethyl)amino]methyl}pyrrolidin-1-yl)methyl]phenyl}-1H-benzimidazole-4-carboxamide; 
     2-[4-({2-[(dicyclobutylamino)methyl]pyrrolidin-1-yl}methyl)phenyl]-1H-benzimidazole-4-carboxamide; 
     2-[4-({2-[(isopropylamino)methyl]pyrrolidin-1-yl}methyl)phenyl]-1H-benzimidazole-4-carboxamide; 
     2-(4-{[(2S,5S)-2,5-bis(methoxymethyl)pyrrolidin-1-yl]methyl}phenyl)-1H-benzimidazole-4-carboxamide; 
     2-{2-fluoro-4-[(2-methylpyrrolidin-1-yl)methyl]phenyl}-1H-benzimidazole-4-carboxamide; 
     2-(4-{[3-(dimethylamino)pyrrolidin-1-yl]methyl}-2-fluorophenyl)-1H-benzimidazole-4-carboxamide; 
     2-{4-[(3-aminopyrrolidin-1-yl)methyl]-2-fluorophenyl}-1H-benzimidazole-4-carboxamide; 
     2-(2-fluoro-4-{[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}phenyl)-1H-benzimidazole-4-carboxamide; 
     2-[4-(1-pyrrolidin-1-ylethyl)phenyl]-1H-benzimidazole-4-carboxamide; 
     2-{4-[1-(4-methyl-[1,4]diazepan-1-yl)ethyl]phenyl}-1H-benzimidazole-4-carboxamide; 
     2-[4-(1-(azepan-1-yl-ethyl)phenyl]-1H-benzimidazole-4-carboxamide; 
     2-[4-(1-(morpholin-4-ylethyl)phenyl]-1H-benzimidazole-4-carboxamide; 
     2-{4-[1-(4-methyl-piperazin-1-yl)ethyl]phenyl}-1H-benzimidazole-4-carboxamide; 
     2-{4-[1-(4-isopropylpiperazin-1-yl)ethyl]phenyl}-1H-benzimidazole-4-carboxamide; 
     2-[4-(1-methyl-1-pyrrolidin-1-ylethyl)phenyl]-1H-benzimidazole-4-carboxamide; 
     2-[5-(1-morpholin-4-ylethyl)thiophen-2-yl]-1H-benzimidazole-4-carboxamide; 
     2-(2-fluoro-4-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]methyl}phenyl)-1H-benzimidazole-4-carboxamide; and 
     2-(2-fluoro-4-{[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]methyl}phenyl)-1H-benzimidazole-4-carboxamide. 
   
   
       13 . A pharmaceutical composition comprising a compound of Formula (I) of  claim 1  or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier. 
   
   
       14 . A method of inhibiting poly(ADP-ribose)polymerase (PARP) in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) of  claim 1  or a therapeutically acceptable salt thereof. 
   
   
       15 . A method of treating inflammation in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) of  claim 1  or a therapeutically acceptable salt thereof. 
   
   
       16 . A method of treating sepsis in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) of  claim 1  or a therapeutically acceptable salt thereof. 
   
   
       17 . A method of treating septic shock in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) of  claim 1  or a therapeutically acceptable salt thereof. 
   
   
       18 . A method of treating cancer in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a therapeutically acceptable salt thereof.