1H-benzimidazole-4-carboxamides substituted with a quaternary carbon at the 2-position 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;

A is a nonaromatic 4, 5, 6, 7, or 8-membered ring that contains 1 or 2 nitrogen atoms and, optionally, one sulfur or oxygen atom, wherein the nonaromatic ring is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, heteroaryl, heteroarylalkyl, hydroxy, hydroxyalkyl, nitro, 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. The compound according to claim 1 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;

A is selected from the group consisting of

R 5 is independently selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, NR C R D , and (NR C R D )carbonyl;

n is 0, 1, 2, or 3;

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

R C and R D are independently selected from the group consisting of hydrogen and alkyl.

3. The compound according to claim 2 wherein A is selected from the group consisting of

4. The compound according to claim 3 wherein

R 1 , R 2 , R 3 , and R 5 are hydrogen;

n is 0;

R 6 is selected from the group consisting of hydrogen, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heteroarylalkyl, and (NR C R D )sulfonyl; and

R C and R D are independently selected from the group consisting of hydrogen and alkyl.

5. The compound according to claim 2 wherein A is selected from the group consisting of

6. The compound according to claim 5 wherein

R 1 , R 2 , R 3 , and R 5 are hydrogen;

n is 0;

R 6 is selected from the group consisting of hydrogen, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heteroarylalkyl, and (NR C R D )sulfonyl; and

R C and R D are independently selected from the group consisting of hydrogen and alkyl.

7. The compound according to claim 2 wherein A is selected from the group consisting of

8. The compound according to claim 7 wherein

R 1 , R 2 , R 3 , and R 5 are hydrogen;

n is 0;

R 6 is selected from the group consisting of hydrogen, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heteroarylalkyl, and (NR C R D )sulfonyl; and

R C and R D are independently selected from the group consisting of hydrogen and alkyl.

9. The compound according to claim 2 wherein A is selected from the group consisting of

10. The compound according to claim 9 wherein

R 1 , R 2 , R 3 , and R 5 are hydrogen;

n is 0;

R 6 is selected from the group consisting of hydrogen, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heteroarylalkyl, and (NR C R D )sulfonyl; and

R C and R D are independently selected from the group consisting of hydrogen and alkyl.

11. A compound selected from the group consisting of

2-(2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide;

2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide;

2-[(2S)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide;

2-(1,2-dimethylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide;

2-(1-ethyl-2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide;

2-(2-methyl-1-propylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide;

2-(1-isopropyl-2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide;

2-(1-cyclobutyl-2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide;

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

2-(3-methyl-1-propylpyrrolidin-3-yl)-1H-benzimidazole-4-carboxamide;

2-[1-(cyclopropylmethyl)-3-methylpyrrolidin-3-yl]-1H-benzimidazole-4-carboxamide;

2-(1-isobutyl-3-methylpyrrolidin-3-yl)-1H-benzimidazole-4-carboxamide;

2-(1-isopropyl-3-methylpyrrolidin-3-yl)-1H-benzimidazole-4-carboxamide;

2-(1-cyclobutyl-3-methylpyrrolidin-3-yl)-1H-benzimidazole-4-carboxamide;

2-(1-cyclopentyl-3-methylpyrrolidin-3-yl)-1H-benzimidazole-4-carboxamide;

2-(1-cyclohexyl-3-methylpyrrolidin-3-yl)-1H-benzimidazole-4-carboxamide;

2-(3-methyl-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl)-1H-benzimidazole-4-carboxamide;

2-[3-methyl-1-(pyridin4-ylmethyl)pyrrolidin-3-yl]-1H-benzimidazole-4-carboxamide;

2-[3-methyl-1-(2-phenylethyl)pyrrolidin-3-yl]-1H-benzimidazole-4-carboxamide;

2-[3-methyl-1-(1-methyl-3-phenylpropyl)pyrrolidin-3-yl]-1H-benzimidazole-4-carboxamide;

2-(2-methylazetidin-2-yl)-1H-benzimidazole-4-carboxamide;

2-(1-isopropyl-2-methylazetidin-2-yl)-1H-benzimidazole-4-carboxamide;

2-(1-cyclobutyl-2-methylazetidin-2-yl)-1H-benzimidazole-4-carboxamide;

2-(1-cyclopentyl-2-methylazetidin-2-yl)-1H-benzimidazole-4-carboxamide;

2-(1-cyclohexyl-2-methylazetidin-2-yl)-1H-benzimidazole-4-carboxamide;

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

2-(3-methyl-1-propylazetidin-3-yl)-1H-benzimidazole-4-carboxamide;

2-[1-(cyclopropylmethyl)-3-methylazetidin-3-yl]-1H-benzimidazole-4-carboxamide;

2-(1-isobutyl-3-methylazetidin-3-yl)-1H-benzimidazole-4-carboxamide;

2-(1-cyclobutyl-3-methylazetidin-3-yl)-1H-benzimidazole-4-carboxamide;

2-(1-cyclopentyl-3-methylazetidin-3-yl)-1H-benzimidazole-4-carboxamide;

2-(1-cyclohexyl-3-methylazetidin-3-yl)-1H-benzimidazole-4-carboxamide;

2-(3-methyl-1-tetrahydro-2H-pyran-4-ylazetidin-3-yl)-1H-benzimidazole-4-carboxamide;

2-{1-[(dimethylamino)sulfonyl]-3-methylazetidin-3-yl}-1H-benzimidazole-4-carboxamide;

2-(2-methylpiperidin-2-yl)-1H-benzimidazole-4-carboxamide;

2-(2-methyl-1-propylpiperidin-2-yl)-1H-benzimidazole-4-carboxamide;

2-{1-[(dimethylamino)sulfonyl]-4-methylpiperidin-4-yl}-1H-benzimidazole-4-carboxamide;

2-(1-cyclobutyl-4-methylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide;

2-(1-isopropyl-4-methylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide;

2-(4-methyl-1-propylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide;

2-(4-methylazepan-4-yl)-1H-benzimidazole-4-carboxamide;

2-(1-cyclopentyl-4-methylazepan-4-yl)-1H-benzimidazole-4-carboxamide; and

2-(1-Cyclohexyl-4-methyl-azepane-4-yl)-H-benzoimidazole-4-carboxylic acid amide.

12. A compound selected from the group consisting of

2-[1-(2-fluorobenzyl)-3-methylpyrrolidin-3-yl]-1H-benzimidazole-4-carboxamide;

6-chloro-2-(3-methylpyrrolidin-3-yl)-1H-benzimidazole-4-carboxamide;

6-chloro-2-(1,3-dimethylpyrrolidin-3-yl)-1H-benzimidazole-4-carboxamide;

6-chloro-2-(1-isopropyl-3-methylpyrrolidin-3-yl)-1H-benzimidazole-4-carboxamide;

2-(2-methylpyrrolidin-2-yl)-6-(trifluoromethyl)-1H-benzimidazole-4-carboxamide;

2-(1,2-dimethylpyrrolidin-2-yl)-6-(trifluoromethyl)-1H-benzimidazole-4-carboxamide;

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

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

6-chloro-2-(2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide;

6-chloro-2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide;

6-chloro-2-[(2S)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide;

6-fluoro-2-[(2S)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide;

6-fluoro-2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide;

6-chloro-2-[(2R)-1,2-dimethylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide;

6-chloro-2-[(2R)-1-isopropyl-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide;

6-chloro-2-[(2R)-1-cyclopentyl-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide;

6-chloro-2-[(2S)-1,2-dimethylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide;

6-chloro-2-[(2S)-1-isopropyl-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide;

6-chloro-2-[(2S)-1-cyclopentyl-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide;

2-[(2S)-1,2-dimethylpyrrolidin-2-yl]-6-fluoro-1H-benzimidazole-4-carboxamide;

6-fluoro-2-[(2S)-1-isopropyl-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide;

2-[(2S)-1-cyclopentyl-2-methylpyrrolidin-2-yl]-6-fluoro-1H-benzimidazole-4-carboxamide;

2-[(2R)-1,2-dimethylpyrrolidin-2-yl]-6-fluoro-1H-benzimidazole-4-carboxamide;

6-fluoro-2-[(2R)-1-isopropyl-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide;

2-[(2R)-1-cyclopentyl-2-methylpyrrolidin-2-yl]-6-fluoro-1H-benzimidazole-4-carboxamide;

2-[(2R)-1-ethyl-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide;

2-[(2S)-1-ethyl-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide;

6-chloro-2-(1-ethyl-3-methylpyrrolidin-3-yl)-1H-benzimidazole-4-carboxamide;

2-[(2R)-1,2-dimethylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide; and

2-[(2R)-2-methyl-5-oxopyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide.

13. 2-(2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide or a therapeutically acceptable salt thereof.

14. The compound of claim 13 , wherein the compound is 2-((R)-2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide, or a therapeutically acceptable salt thereof.

15. The compound of claim 13 , wherein the compound is 2-[(2S)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide, or a therapeutically acceptable salt thereof.

16. The compound of claim 14 , wherein the therapeutically acceptable salt is hydrochloride.

17. A pharmaceutical composition comprising is 2-((R)-2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide in combination with a therapeutically acceptable carrier.