Substituted 1H-benzimidazole-4-carboxamides are potent PARP inhibitors

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;

X 1 is selected from the group consisting of aryl and heteroaryl, wherein X 1 is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of alkyl, cyano, halogen, and haloalkyl;

W is X 2 —Y—NR 6 R 7 or Y—NR 6 R 7 ;

X 2 is selected from the group consisting of aryl and heteroaryl, wherein X 2 is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of alkyl, cyano, halogen, and haloalkyl;

Y is alkylenyl;

R 6 is selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, heteroaryl, heteroarylalkyl, hydroxyalkyl, (NR C R D )alkyl, (NR C R D )carbonyl, (NR C R D )carbonylalkyl, and (NR C R D )sulfonyl;

R 7 is selected from the group consisting of cycloalkyl and cycloalkyl fused to phenyl, wherein R 7 may be optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkynyl, carboxy, cycloalkyl, cycloalkylalkyl, cyano, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, NR C R D , (NR C R D )alkyl, (NR C R D )carbonyl, (NR C R D )carbonylalkyl, (NR C R D )sulfonyl, and oxo; and

R A , R B , R C , and R D are independently selected from the group consisting of hydrogen, alkyl, and alkycarbonyl.

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;

X 1 is selected from the group consisting of aryl and heteroaryl, wherein X 1 is optionally substituted with halogen;

W is X 2 —Y—NR 6 R 7 or Y—NR 6 R 7 ;

X 2 is aryl;

Y is alkylenyl;

R 6 is selected from the group consisting of hydrogen and alkyl; and

R 7 is selected from the group consisting of cycloalkyl and cycloalkyl fused to phenyl.

3. A compound according to claim 1 , wherein R 1 , R 2 , and R 3 are hydrogen.

4. A compound according to claim 1 , wherein W is Y—NR 6 R 7 .

5. A compound according to claim 1 , wherein R 6 is hydrogen; and R 7 is cycloalkyl.

6. A compound according to claim 1 , wherein X 1 is thiophenyl.

7. A compound according to claim 1 , wherein X 1 is thiazolyl.

8. A compound according to claim 1 , wherein X 1 is phenyl.

9. A compound according to claim 1 , wherein X 1 is phenyl and X 2 is phenyl.

10. A compound according to claim 1 wherein R 2 is halogen.

11. A compound or a therapeutically acceptable salt, thereof, selected from the group consisting of

2-{4-[1-(cyclohexylmethylamino)ethyl]phenyl}-1H-benzimidazole-4-carboxamide;

2-[4-(1-cyclobutylaminoethyl)phenyl]-1H-benzimidazole-4-carboxamide;

2-{4′-[(cyclohexylmethylamino)methyl]biphenyl-4-yl}-1H-benzimidazole-4-carboxamide;

2-(4′-cyclopropylaminomethylbiphenyl-4-yl)-1H-benzimidazole-4-carboxamide;

2-(4′-cyclobutylaminomethylbiphenyl-4-yl)-1H-benzimidazole-4-carboxamide;

2-[5-(1-cyclopropylaminoethyl)thiophen-2-yl]-1H-benzimidazole-4-carboxamide;

2-{5-[1-(cyclohexylmethylamino)ethyl]thiophen-2-yl}-1H-benzimidazole-4-carboxamide;

2-(3′-cyclopropylaminomethylbiphenyl-4-yl)-1H-benzimidazole-4-carboxamide;

2-(2′-cyclopropylaminomethylbiphenyl-4-yl)-1H-benzimidazole-4-carboxamide;

2-[3-(2-cyclopropylaminoethyl)phenyl]-1H-benzimidazole-4-carboxamide;

2-(4-cyclopropylaminomethylphenyl)-1H-benzimidazole-4-carboxamide;

2-(4-cyclobutylaminomethylphenyl)-1H-benzimidazole-4-carboxamide;

2-(4-cyclopentylaminomethylphenyl)-1H-benzimidazole-4-carboxamide;

6-chloro-2-{4-[(1,2,3,4-tetrahydronaphthalen-1-ylamino)methyl]phenyl}-1H-benzimidazole-4-carboxamide;

2-(4-cyclopropylaminomethylphenyl)-6-fluoro-1H-benzimidazole-4-carboxamide;

2-(4-Cyclobutylaminomethylphenyl)-6-fluoro-1H-benzimidazole-4-carboxamide;

2-(4-Cyclopentylaminomethylphenyl)-6-fluoro-1H-benzimidazole-4-carboxamide;

2-[4-(2-cyclopropylaminoethyl)phenyl]-1H-benzimidazole-4-carboxamide;

2-[4-(2-cyclobutylaminoethyl)phenyl]-1H-benzimidazole-4-carboxamide;

2-(4-cyclopropylaminomethyl-2-fluorophenyl)-1H-benzimidazole-4-carboxamide;

2-[4-(1-cyclopropylaminoethyl)phenyl]-1H-benzimidazole-4-carboxamide;

2-(4-cyclobutylaminomethyl-2-fluorophenyl)-1H-benzimidazole-4-carboxamide;

2-(4-cyclohexylaminomethyl-2-fluorophenyl)-1H-benzimidazole-4-carboxamide;

2-(4-cyclopentylaminomethyl-2-fluorophenyl)-1H-benzimidazole-4-carboxamide;

2-{2-[(cyclopentylamino)methyl]-1,3-thiazol-4-yl}-1H-benzimidazole-4-carboxamide;

2-{2-[(cyclohexylamino)methyl]-1,3-thiazol-4-yl}-1H-benzimidazole-4-carboxamide; and

2-{2-[(cyclobutylamino)methyl]-1,3-thiazol-4-yl}-1H-benzimidazole-4-carboxamide.

12. 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.

13. A method of treating inflammation in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I) of claim 1 or a therapeutically acceptable salt thereof.

14. A method of treating sepsis in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I) of claim 1 or a therapeutically acceptable salt thereof.

15. A method of treating septic shock in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I) of claim 1 or a therapeutically acceptable salt thereof.