Substituted 1H-benzimidazole-4-carboxamides are potent PARP inhibitors
View Patent ↗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, and halogen;
Ar 1 is aryl, wherein Ar 1 is optionally substituted with halogen;
X 1 is alkylenyl;
Z is heterocycle, wherein Z is substituted with 1, 2, 3, or 4 substituents selected from the group consisting of 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.
2. The compound according to claim 1 , wherein Ar 1 is phenyl.
3. The compound according to claim 1 , wherein Z is pyrrolidinyl, wherein the pyrrolidinyl is substituted with 1, 2, 3, or 4 substituents selected from the group consisting of 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.
4. The compound according to claim 1 , wherein Z is pyrrolidinyl substituted with NR C R D .
5. The compound according to claim 1 , wherein Z is pyrrolidinyl substituted with NR C R D alkyl.
6. The compound according to claim 1 , wherein Z is pyrrolidinyl substituted with hydroxyalkyl.
7. The compound according to claim 1 , wherein Ar 1 is phenyl and Z is pyrrolidinyl, wherein the pyrrolidinyl is substituted with 1, 2, 3, or 4 substituents selected from the group consisting of 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.
8. The compound according to claim 1 , wherein Ar 1 is phenyl substituted with halogen.
9. The compound according to claim 1 , wherein R 1 , R 2 , and R 3 are hydrogen.
10. The compound according to claim 1 selected from the group consisting of
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;
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-((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-((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-[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-(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-(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.
11. 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.