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US 2007/0179136 A1Published application
1h-benzimidazole-4-carboxamides substituted with phenyl at the 2-position are potent parp inhibitors
AssigneeAbbVie Inc.
InventorsThomas Penning, Sheela Thomas, Gui-Dong Zhu, Virajkumar Gandhi, Jianchun Gong, Vincent Giranda
Life of this patent
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Abstract
Compound having formula (I) inhibit the PARP enzyme and are useful for treating a disease or a disorder associated with PARP. Also disclosed are pharmaceutical compositions comprising compounds having formula (I), methods of treatment comprising compounds having formula (I), and methods of inhibiting the PARP enzyme comprising compounds having formula (I).
Claims15
A compound having formula (I)
- or a salt thereof, wherein
- R1, R2, and R3 are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, cyano, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, NRARB, and (NRARB)carbonyl;
- each R4 is independently selected from the group consisting of hydrogen, halogen, alkyl, and haloalkyl;
- m is 4;
- Z is a bond or alkylenyl;
- A is a nonaromatic 5 or 6-membered ring that contains 1 or 2 nitrogen atoms and, optionally, one sulfur or oxygen atom, wherein A is attached to Z through a carbon atom, and 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, alkylcarbonyl, alkylcarbonylalkyl, alkynyl, aryl, arylalkyl, carboxy, cycloalkyl, cycloalkylalkyl, cyano, haloalkoxy, haloalkyl, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, heterocyclesulfonyl, hydroxy, hydroxyalkyl, NRCRD, (NRD)alkyl, (NRD)carbonyl, (NRD)carbonylalkyl, (NRCRD)sulfonyl, and oxo;
- and
- RA, RB, RC, and RD are independently selected from the group consisting of hydrogen, alkyl, alkycarbonyl, and cycloalkyl.
5 more elements
A compound having formula (I)
- or a salt thereof, wherein
- R1, R2, and R3 are independently selected from the group consisting of hydrogen and halogen;
- each R4 is independently selected from the group consisting of hydrogen, halogen, and haloalkyl;
- m is 4;
- Z is a bond or alkylenyl;
- A is a nonaromatic 5 or 6-membered ring that contains 1 nitrogen atom, wherein A is attached to Z through a carbon atom, and wherein the nonaromatic ring is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkoxycarbonyl, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, and heterocyclealkyl.
3 more elements
A compound selected from the group consisting of
- 2-(4-piperidin-4-ylphenyl)-1H-b enzimidazole-4-carboxamide;
- 2-(4-piperidin-2-ylphenyl)-1H-b enzimidazole-4-carboxamide;
- 2-(4-(1-methyl-piperidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-(1-ethylpiperidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-(1-isopropyl-piperidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-pip eridin-3-ylphenyl)-1H-b enzimidazole-4-carboxamide;
- 2-(4-(1-isopropyl-piperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-(1-methyl-piperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-(1-ethyl-piperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-(1-benzyl-piperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-(1-phenethyl-piperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- benzyl 4-(3-(4-(4-carbamoyl-1H-benzimidazol-2-yl)phenyl)piperidin-1-ylmethyl)— 1-carboxylate;
- 2-(4-(1-(4-morpholin-4-yl-benzyl)piperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-(1-(4-piperidin-1-ylbenzyl)piperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-(1-piperidin-4-ylmethyl-piperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-(1-ethyl-piperidin-4-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- tert-butyl 4-(4-(4-carbamoyl-1H-benzimidazol-2-yl)piperidine-1-carboxylate;
- 2-(4-(1-methyl-piperidin-4-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-(1-isopropyl-piperidin-4-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-piperidin-4-ylmethylphenyl)-1H-b enzimidazole-4-carboxamide;
- tert-butyl 2-(4-(4-carbamoyl-1H-benzimidazol-2-yl)phenyl)pyrrolidine-1-carboxylate;
- 2-(4-(2-Piperidin-2-yl-ethyl)phenyl)-1H-b enzimidazole-4-carboxamide;
- 2-(4-(1-isopropylpyrrolidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-(1-cyclopentylpyrrolidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-(1-cyclohexylpyrrolidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(2-fluoro-4-piperidin-4-ylphenyl)-1H-benzimidazole-4-carboxamide;
- 2-(2-fluoro-4-piperidin-3-ylphenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-(1-isopropylpiperidin-4-ylmethyl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-(1-isopropylpyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-(1-cyclopropylmethylpyrrolidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-(1-cyclopentylpyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-(1-cyclohexylpyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-pyrrolidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-(1-propylpyrrolidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-(1-cyclopropylmethylpyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-(1-propylpyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(2-fluoro-4-piperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide;
- 3-(4-pyrrolidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-(1-methylpyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-(1-methylpyrrolidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(2-fluoro-4-( 1-isopropylpiperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-piperidin-3-yl-3-trifluoromethylphenyl)-1H-benzimidazole-4-carboxamide;
- 2-(2-fluoro-4-( 1-methylpiperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 6-chloro-2-(4-pyrrolidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide;
- 6-Fluoro-2-(4-pyrrolidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide;
- 6-chloro-2-(4-( 1-isopropyl-pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 6-chloro-2-(4-( 1-cyclopentyl-pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 6-Chloro-2-(4-( 1-methylpyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 6-fluoro-2-(4-(1-methylpyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(2-fluoro-4-pyrrolidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-(1-ethylpyrrolidin-2-yl)-2-fluorophenyl)-1H-benzimidazole-4-carboxamide;
- 2-(2-fluoro-4-( 1-isopropylpyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-(1—Cyclobutylpyrrolidin-2-yl)-2-fluorophenyl)-1H-benzimidazole-4-carboxamide;
- 2-(2-Fluoro-4-(1-propylpyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-(1-cyclopropylmethylpyrrolidin-2-yl)-2-fluorophenyl)-1H-benzimidazole-4carboxamide;
- 6-fluoro-2-(2-fluoro-4-pyrrolidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide;
- 6-fluoro-2-(2-fluoro-4-(1-isopropylpyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-(1-Ethylpyrrolidin-2-yl)-2-fluorophenyl)-6-fluoro-1H-benzimidazole-4-carboxamide;
- 6-Fluoro-2-(2-fluoro-4-( 1-methylpyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 6-fluoro-2-(2-fluoro-4-piperidin-3-ylphenyl)-1H-benzimidazole-4-carboxamide;
- 6-chloro-2-(2-fluoro-4-piperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide;
- 6-fluoro-2-(2-fluoro-4-piperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide;
- 6-fluoro-2-(2-fluoro-4-( 1-methylpiperidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-(1-ethylpiperidin-2-yl)-2-fluorophenyl)-6-fluoro-1H-benzimidazole-4-carboxamide;
- 6-fluoro-2-(2-fluoro-4-( 1-isopropyl-piperidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-(1-cyclobutylpiperidin-2-yl)-2-fluorophenyl)-6-fluoro-1H-benzimidazole-4-carboxamide;
- 6-chloro-2-(2-fluoro-4-(1-methylpiperidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 6-chloro-2-(4-( 1-ethylpiperidin-2-yl)-2-fluorophenyl)-1H-benzimidazole-4-carboxamide;
- 6-chloro-2-(4-( 1-cyclopropylmethyl-piperidin-2-yl)-2-fluorophenyl)-1H-benzimidazole-4-carboxamide;
- 2-(4-(1-ethylpiperidin-3-yl)-2-fluorophenyl)-6-fluoro-1H-benzimidazole-4-carboxamide;
- 2-(4-(1-cyclopropylmethylpiperidin-2-yl)-2-fluorophenyl)-6-fluoro-1H-benzimidazole-4-carboxamide;
- 6-fluoro-2-(2-fluoro-4-( 1-methylpiperidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 6-chloro-2-(2-fluoro-4-piperidin-3-ylphenyl)-1H-b enzimidazole-4-carboxamide;
- 6-chloro-2-(4-piperidin-4-ylphenyl)-1H-benzimidazole-4-carboxamide;
- 2-(2-fluoro-4-( 1-methylpiperidin-4-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 6-chloro-2-(4-piperidin-3-ylphenyl)-1H-benzimidazole-4-carboxamide;
- 6-fluoro-2-(4-pip eridin-3-ylphenyl)-1H-b enzimidazole-4-carboxamide;
- 2-(4-(1-ethylpiperidin-4-yl)-2-fluorophenyl)-1H-benzimidazole-4-carboxamide;
- 2-(2-fluoro-4-( 1-isopropylpiperidin-4-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 6-chloro-2-(4-( 1-cyclopropylmethylpiperidin-3-yl)-2-fluorophenyl)-1H-benzimidazole-4-carboxamide;
- 6-Fluoro-2-(2-fluoro-4-piperidin-4-ylphenyl)-1H-benzimidazole-4-carboxamide;
- 6-Chloro-2-(4-( 1-methylpiperidin-4-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 6-fluoro-2-(4-( 1-methylpiperidin-4-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- 6-fluoro-2-(4-piperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide;
- 6-fluoro-4-( 1-methylpiperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide;
- (S)-2-(2-fluoro-4-piperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide;
- (R)-2-(2-fluoro-4-piperidin-2-ylphenyl)-1H-b enzimidazole-4-carboxamide;
- 6-fluoro-2-(4-piperidin-4-ylphenyl)-1H-b enzimidazole-4-carboxamide;
- (S)-2-(4-piperidin-2-ylphenyl)-1H-b enzimidazole-4-carboxamide;
- (R)-2-(4-piperidin-2-ylphenyl)-1H-b enzimidazole-4-carboxamide;
- 6-fluoro-2-(4-( 1-methylpiperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide;
- (+) (R)-2-(2-fluoro-4-pyrrolidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide;
- and
- (−) (S)-2-(2-fluoro-4-pyrrolidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide.
91 more elements
A method of treating cancer in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula (I) or a salt thereof.
Dependencies are inferred from the claim text.