Substituted heterocyclic compounds

摘要

The present invention relates to compounds that are late sodium channel inhibitors and to their use in the treatment of various disease states, including cardiovascular diseases and diabetes. In particular embodiments, the structure of the compounds is given by Formula (I):;
wherein R1, R2, R3, and R4 are as described herein, to methods for the preparation and use of the compounds and to pharmaceutical compositions containing the same.

主权项

1. A compound selected from the group consisting of:
1,3-dimethyl-7-(4-(trifluoromethoxy)phenyl)-quinoxalin-2(1H)-one; 1,3-dimethyl-6-[4-(trifluoromethoxy)phenyl]quinoxalin-2(1H)-one; 6-(3,4-difluorophenyl)-1,3-dimethylquinoxalin-2(1H)-one; 1-methyl-6-[4-(trifluoromethoxy)phenyl]-2-(trifluoromethyl)quinoxalin-2(1H)-one; 1,3-dimethyl-7-[4-(trifluoromethoxy)phenyl]quinoxalin-2(1H)-one; 1-methyl-7-[4-(trifluoromethoxy)phenyl]-3-(trifluoromethyl)quinoxalin-2(1H)-one; 1,3-dimethyl-7-[3-(trifluoromethyl)phenyl]quinoxalin-2(1H)-one; 1,3-dimethyl-7-[4-(trifluoromethyl)phenyl]quinoxalin-2(1H)-one; 3-tert-butyl-1-methyl-7-[4-(trifluoromethoxy)phenyl]quinoxalin-2(1H)-one; 3-tert-butyl-1-methyl-7-[3-(trifluoromethoxy)phenyl]quinoxalin-2(1H)-one; 1-methyl-3-(propan-2-yl)-7-[4-(trifluoromethoxy)phenyl]quinoxalin-2(H)-one; 1-methyl-3-(propan-2-yl)-7-[3-(trifluoromethoxy)phenyl]quinoxalin-2(1H)-one; 1,3-dimethyl-6-[3-(trifluoromethoxy)phenyl]quinoxalin-2(1H)-one; 1-methyl-6-[3-(trifluoromethoxy)phenyl]-3-(trifluoromethyl)quinoxalin-2(1H)-one; 1-methyl-3-(trifluoromethyl)-6-[3-(trifluoromethyl)phenyl]quinoxalin-2(1H)-one; 1-methyl-7-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)quinoxalin-2(1H)-one; 1,3-dimethyl-7-(4-(trifluoromethoxy)phenyl)quinoxalin-2(H)-one; 7-(3,4-difluorophenyl)-1,3-dimethylquinoxalin-2(1H)-one; 1,3-dimethyl-7-(4-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one; 7-(3,4-difluorophenyl)-1-methyl-3-(trifluoromethyl)quinoxalin-2(1H)-one; 1,3-dimethyl-7-(3-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one; 1,3-dimethyl-7-(4-(trifluoromethyl)phenyl)quinoxalin-2(1H)-one; 3-tert-butyl-1-methyl-7-(4-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one; 3-isopropyl-1-methyl-7-(4-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one; 3-isopropyl-1-methyl-7-(3-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one; 1-methyl-7-(3-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)quinoxalin-2(1H)-one; 1-methyl-3-(trifluoromethyl)-6-(3-(trifluoromethyl)phenyl)quinoxalin-2(1H)-one; 3-tert-butyl-1-methyl-6-(3-(trifluoromethyl)phenyl)quinoxalin-2(1H)-one; 3-isobutyl-1-methyl-7-(4-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one; 2-hydroxy-N-(2-{2-oxo-7-[4-(trifluoromethoxy)phenyl]-3-(trifluoromethyl)quinoxalin-1(2H)-yl}ethyl)acetamide; ethyl 4-methyl-3-oxo-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinoxaline-2-carboxylate; ethyl 4-methyl-3-oxo-6-[3-(trifluoromethoxy)phenyl]-3,4-dihydroquinoxaline-2-carboxylate; N-(2-{3-tert-butyl-2-oxo-7-[3-(trifluoromethoxy)phenyl]quinoxalin-1(2H)-yl}ethyl)-2-hydroxyacetamide; 3-(2-hydroxypropan-2-yl)-1-methyl-7-[4-(trifluoromethoxy)phenyl]quinoxalin-2(1H)-one; 2-hydroxy-N-(2-(2-oxo-7-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)quinoxalin-1(2H)-yl)ethyl)acetamide; 2-oxo-2-(2-(2-oxo-7-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)quinoxalin-1(2H)-yl)ethylamino)ethyl acetate; 2-hydroxy-N-(2-(3-t-butyl-2-oxo-7-(3-(trifluoromethoxy)phenyl)quinoxalin-1(2H)-yl)ethyl)acetamide; 3-(2-hydroxypropan-2-yl)-1-methyl-7-(4-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one; tert-butyl 2-(3-tert-butyl-2-oxo-7-(3-(trifluoromethoxy)phenyl)quinoxalin-1(2H)-yl)acetate; tert-butyl 2-(3-tert-butyl-2-oxo-7-(4-(trifluoromethoxy)phenyl)quinoxalin-1(2H)-yl)acetate; 2-hydroxy-N-(2-(3-isopropyl-2-oxo-7-(4-(trifluoromethoxy)phenyl)quinoxalin-1(2H)-yl)ethyl)acetamide; 2-hydroxy-N-(2-(3-isopropyl-2-oxo-7-(3-(trifluoromethoxy)phenyl)quinoxalin-1(2H)-yl)ethyl)acetamide; 3-benzyl-1-methyl-7-(3-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one; 3-tert-butyl-1-(2-methoxyethyl)-7-(4-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one; 3-tert-butyl-1-(2-methoxyethyl)-7-(3-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one; 1-methyl-3-phenyl-7-(4-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one; 1-methyl-3-phenyl-7-(3-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one; 3-isopropyl-1-(2-methoxyethyl)-7-(3-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one; 3-isopropyl-1-(2-methoxyethyl)-7-(4-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one; ethyl 2-(4-methyl-3-oxo-6-(4-(trifluoromethoxy)phenyl)-3,4-dihydroquinoxalin-2-yl)propanoate; ethyl 2-(4-methyl-3-oxo-6-(3-(trifluoromethoxy)phenyl)-3,4-dihydroquinoxalin-2-yl)propanoate; 2-(3-methyl-2-oxo-7-(4-(trifluoromethoxy)phenyl)quinoxalin-1(2H)-yl)acetic acid; 3-(3-tert-butyl-2-oxo-7-(3-(trifluoromethoxy)phenyl)quinoxalin-1(2H)-yl)propanoic acid; 2-(3-tert-butyl-2-oxo-7-(3-(trifluoromethoxy)phenyl)quinoxalin-1(2H)-yl)acetic acid; 3-tert-butyl-1-(2-hydroxyethyl)-7-(3-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one; tert-butyl 3-(3-tert-butyl-2-oxo-6-(3-(trifluoromethyl)phenyl)quinoxalin-1(2H)-yl)propanoate; 3-(3-tert-butyl-2-oxo-6-(3-(trifluoromethyl)phenyl)quinoxalin-1(2H)-yl)propanoic acid; 1-(2-hydroxyethyl)-3-isopropyl-7-(3-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one; ethyl 4-(2,4-dimethoxybenzyl)-3-oxo-6-(3-(trifluoromethoxy)phenyl)-3,4-dihydroquinoxaline-2-carboxylate; 1-(2-hydroxyethyl)-3-isopropyl-7-(4-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one; 3-(3-isopropyl-2-oxo-7-(4-(trifluoromethoxy)phenyl)quinoxalin-1(2H)-yl)propanoic acid; 3-tert-butyl-1-(2-hydroxyethyl)-6-(3-(trifluoromethyl)phenyl)quinoxalin-2(1H)-one; ethyl 6-(3-bromophenyl)-4-(2,4-dimethoxybenzyl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate; 1-methyl-3-phenethyl-7-(4-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one; 3-(indolin-3-yl)-1-methyl-7-(4-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one; 3-(4-methyl-3-oxo-6-(4-(trifluoromethoxy)phenyl)-3,4-dihydroquinoxalin-2-yl)propanoic acid; 3-(3-tert-butyl-7-(3-chlorophenyl)-2-oxoquinoxalin-1(2H)-yl)propanoic acid; 3-(3-tert-butyl-2-oxo-7-(4-phenoxyphenyl)quinoxalin-1(2H)-yl)propanoic acid; 4-((3-tert-butyl-2-oxo-7-(4-(trifluoromethoxy)phenyl)quinoxalin-1(2H)-yl)methyl)benzoic acid; 2-(2-(3-isopropyl-2-oxo-7-(4-(trifluoromethoxy)phenyl)quinoxalin-1(2H)-yl)ethoxy)acetic acid; 4-(3-methyl-2-oxo-7-(4-(trifluoromethoxy)phenyl)quinoxalin-1(2H)-yl)butanoic acid; N-methyl-3-(4-methyl-3-oxo-6-(4-(trifluoromethoxy)phenyl)-3,4-dihydroquinoxalin-2-yl)propanamide; 3-(3-isopropyl-2-oxo-7-(3-(trifluoromethoxy)phenyl)quinoxalin-1(2H)-yl)propanoic acid; 3-(3-methyl-2-oxo-7-(3-(trifluoromethoxy)phenyl)quinoxalin-1(2H)-yl)propanoic acid; 3-benzoyl-1-methyl-7-(4-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one; 3-isonicotinoyl-1-methyl-7-(4-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one; 3-(3-benzoyl-2-oxo-7-(3-(trifluoromethoxy)phenyl)quinoxalin-1(2H)-yl)propanoic acid; 4-(3-methyl-2-oxo-7-(4-phenoxyphenyl)quinoxalin-1(2H)-yl)butanoic acid; 3-tert-butyl-1-methyl-7-(4-phenoxypiperidin-1-yl)quinoxalin-2(1H)-one; 3-hydroxy-1-methyl-7-(4-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one; 3-(3-benzyl-2-oxo-7-(4-(trifluoromethoxy)phenyl)quinoxalin-1(2H)-yl)propanoic acid; 3-(dimethylamino)-1-methyl-7-(4-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one; 4-(3-tert-butyl-2-oxo-7-(3-(trifluoromethoxy)phenyl)quinoxalin-1(2H)-yl)butanoic acid; 3-(3-methyl-2-oxo-7-(3-(trifluoromethyl)phenyl)quinoxalin-1(2H)-yl)propanoic acid; 1-methyl-3-(methyl(phenyl)amino)-7-(4-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one; 1-methyl-3-(phenylthio)-7-(4-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one; 1-methyl-3-phenoxy-7-(4-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one; 1-methyl-3-(phenylamino)-7-(4-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one; N-(2-(3-methyl-2-oxo-7-(4-(trifluoromethoxy)phenyl)quinoxalin-1(2H)-yl)ethyl)methanesulfonamide; N-(2-(3-isopropyl-2-oxo-7-(4-(trifluoromethoxy)phenyl)quinoxalin-1(2H)-yl)ethyl)methanesulfonamide; 3-(1H-imidazol-2-ylthio)-1-methyl-7-(4-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one; 3-(3-tert-butyl-2-oxo-7-(4-(trifluoromethyl)phenyl)quinoxalin-1(2H)-yl)propanoic acid; 3-(3-tert-butyl-2-oxo-7-(3-phenoxyphenyl)quinoxalin-1(2H)-yl)propanoic acid; 3-(3-tert-butyl-7-(4-fluoro-3-(trifluoromethyl)phenyl)-2-oxoquinoxalin-1(2H)-yl)propanoic acid; 3-(3-tert-butyl-7-(2-methoxy-5-(trifluoromethyl)phenyl)-2-oxoquinoxalin-1(2H)-yl)propanoic acid; 3-(7-(3,5-bis(trifluoromethyl)phenyl)-3-tert-butyl-2-oxoquinoxalin-1(2H)-yl)propanoic acid; 3-tert-butyl-1-(2-hydroxyethyl)-7-(3-(trifluoromethyl)phenyl)quinoxalin-2(H)-one; 2-(3-tert-butyl-2-oxo-7-(3-phenoxyphenyl)quinoxalin-1(2H)-yl)acetic acid; 3-(3-tert-butyl-7-(3-(difluoromethoxy)phenyl)-2-oxoquinoxalin-1(2H)-yl)propanoic acid; 4-(3-tert-butyl-7-(4-chloro-3-(trifluoromethyl)phenyl)-2-oxoquinoxalin-1(2H)-yl)butanoic acid; 3-(3-tert-butyl-6-methoxy-2-oxo-7-(3-(trifluoromethyl)phenyl)quinoxalin-1(2H)-yl)propanoic acid; 3-(3-tert-butyl-7-(2-chloro-5-(trifluoromethyl)phenyl)-2-oxoquinoxalin-1(2H)-yl)propanoic acid; (R)-3-(3-tert-butyl-2-oxo-7-(3-(trifluoromethyl)phenyl)quinoxalin-1(2H)-yl)butanoic acid; 3-(2-oxo-3-(2-phenylpropan-2-yl)-7-(3-(trifluoromethoxy)phenyl)quinoxalin-1(2H)-yl)propanoic acid; 3-(3-tert-butyl-6-methyl-2-oxo-7-(3-(trifluoromethyl)phenyl)quinoxalin-1(2H)-yl)propanoic acid; and ethyl 4-(2,4-dimethoxybenzyl)-3-oxo-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydroquinoxaline-2-carboxylate, or a pharmaceutically acceptable salt thereof.