Substituted heterocyclic compounds

Abstract

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 R 1 , R 2 , R 3 , and R 4 are as described herein, to methods for the preparation and use of the compounds and to pharmaceutical compositions containing the same.

1 . A compound of Formula I: 
     
       
         
         
             
             
         
       
       wherein
 R 1  is
 a) hydrogen or C 1-6  alkyl, 
 b) —X—NR 5 R 6 , 
 c) —X—C(O)NR 5 R 6 , 
 d) —X—C(O)OR 7 , 
 e) —X—OR 7 , 
 f) —X—NR 8 —C(O)NR 5 R 6 , 
 g) —X—C(O)R 7 , or 
 h) —X-phenyl, wherein the phenyl group is optionally substituted by 1, 2, or 3 groups chosen from C 1-6  lower alkyl, C 1-6  lower alkoxy, halo, and trifluoromethyl; 
 wherein 
 R 5  is hydrogen or C 1-6  optionally substituted lower alkyl, and 
 R 6  is hydrogen, C 1-6  lower alkyl, aryl, heteroaryl, —C(NH)NH 2 , —C(O)R 7 , —C(O)(CH 2 ) n OR7, or —S(O) 2 R 7 , wherein
 n is 0 or 1, R 7  is hydrogen, hydroxyl, optionally substituted C 1-6  alkyl, C 1-6  alkoxy, optionally substituted monocyclic aryl, or 5 or 6 membered optionally substituted monocyclic heteroaryl, or 
 R 5  and R 6  along with the nitrogen to which they are attached join to form a 5 or 6 membered monocyclic heteroaryl or heterocyclyl ring; 
 R 7  is hydrogen, optionally substituted C 1-6  alkyl, optionally substituted C 1-6  alkenyl, optionally substituted monocyclic aryl, or 5 or 6 membered optionally substituted monocyclic heteroaryl; 
 R 8  is hydrogen or C 1-6  lower alkyl; 
 X is optionally substituted C 1-6  linear or branched alkylene; 
 
 
 R 2  is
 a) hydrogen, C 1-6  alkoxy, C 1-6  alkyl optionally substituted by halo, phenyl, heteroaryl, or cycloalkyl, in which said phenyl, heteroaryl, or cycloalkyl groups are optionally substituted by halo, hydroxyl, or alkoxy of 1-6 carbon atoms; 
 b) —Y—NR 24 R 25 , 
 c) —Y—C(O)NR 24 R 25 , 
 d) —Y—C(O)OR 27 , 
 e) —Y—OR 27 , or 
 f) —Y—NR 28 —C(O)NR 24 R 25 , or 
 g) —Y—C(O)R 27 , 
 wherein 
 R 24  is hydrogen or C 1-6  optionally substituted lower alkyl, and 
 R 25  is hydrogen, C 1-6  lower alkyl, aryl, heteroaryl, C 1-6  alkoxy, —C(NH)NH 2 , —C(O)R 26  or —S(O) 2 R 26 , wherein
 R 26  is hydrogen, optionally substituted C 1-6  alkyl, optionally substituted C 1-6  alkenyl, C 1-6  alkoxy, optionally substituted monocyclic aryl, or 5 or 6 membered optionally substituted monocyclic heteroaryl, or 
 
 R 24  and R 25  along with the nitrogen to which they are attached join to form a 5 or 6 membered monocyclic heteroaryl or heterocyclyl ring; 
 R 27  is hydrogen, optionally substituted C 1-6  alkyl, optionally substituted C 1-6  alkenyl, optionally substituted monocyclic aryl, or 5 or 6 membered optionally substituted monocyclic heteroaryl; 
 R 28  is hydrogen or C 1-6  lower alkyl; 
 Y is a covalent bond, optionally substituted C 1-6  linear or branched alkylene; 
 wherein the alkyl, cycloalkyl, aryl, or heteroaryl moiety is optionally substituted with from 1 to 3 substituents independently selected from the group consisting of heterocyclyl, aryl, heteroaryl, halo, NO 2 , CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , S(O) 3 R 20 , P(O)(OR 20 ) 2 , SO 2 NR 20 COR 22 , SO 2 NR 20 CO 2 R 22 , SO 2 NR 20 CON(R 20 ) 2 , NR 20 COR 22 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , NR 20 C(NR 20 )NHR 23 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , CONR 20 SO 2 R 22 , NR 20 SO 2 R 22 , SO 2 NR 20 CO 2 R 22 , OCONR 20 SO 2 R 22 , OC(O)R 20 , C(O)OCH 2 OC(O)R 20 , and OCON(R 20 ) 2 , and 
 further wherein each optional heteroaryl, aryl, and heterocyclyl substituent is further optionally substituted with halo, NO 2 , alkyl, CF 3 , amino, mono- or di-alkylamino, alkyl or aryl or heteroaryl amide, NR 20 COR 22 , NR 20 SO 2 R 22 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , NR 20 CON(R 20 ) 2 , OC(O)R 20 , OC(O)N(R 20 ) 2 , S(O) 3 R 20 , P(O)(OR 20 ) 2 , SR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , CN, or OR 20 ; 
 
 R 3  is optionally substituted mono or bicyclic heterocyclyl, mono or bicyclic aryl, or mono or bicyclic heteroaryl;
 wherein the aryl, heterocyclyl or heteroaryl moiety is optionally substituted with from 1 to 3 substituents independently selected from the group consisting of alkyl, heterocyclyl, aryl, aryloxy, heteroaryl, halo, NO 2 , CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , S(O) 3 R 20 , P(O)(OR 20 ) 2 , SO 2 NR 20 COR 22 , SO 2 NR 20 CO 2 R 22 , SO 2 NR 20 CON(R 2 ) 2 , NR 20 COR 22 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , NR 20 C(NR 20 )NHR 23 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , CONR 20 SO 2 R 22 , NR 20 SO 2 R 22 , SO 2 NR 20 CO 2 R 22 , OCONR 20 SO 2 R 22 , OC(O)R 20 , C(O)OCH 2 OC(O)R 20 , and)OCON(R 20 ) 2 , and 
 further wherein each optional alkyl, heteroaryl, aryl, and heterocyclyl substituent is further optionally substituted with halo, NO 2 , alkyl, CF 3 , amino, mono- or di-alkylamino, alkyl or aryl or heteroaryl amide, NR 20 COR 22 , NR 20 SO 2 R 22 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , NR 20 CON(R 2 ) 2 , OC(O)R 20 , OC(O)N(R 20 ) 2 , S(O) 3 R 20 , P(O)(OR 20 ) 2 , SR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , CN, or OR 20 ; 
 
 R 4  is hydrogen, halo, optionally substituted C 1-6  alkyl, optionally substituted C 1-6  alkenyl, C 1-6  alkoxy, or cycloalkyl, 
 R 20  and R 22  are independently selected from the group consisting of hydrogen, C 1-15  alkyl, C 2-15  alkenyl, C 2-15  alkynyl, heterocyclyl, aryl, and heteroaryl, 
 wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroaryl moieties are optionally substituted with from 1 to 3 substituents independently selected from halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, CN, O—C 1-6  alkyl, CF 3 , aryl, and heteroaryl; 
 
       or a pharmaceutically acceptable salt, ester, prodrug, or solvate thereof. 
     
   
   
       2 . The compound of  claim 1 , in which R 1  is alkyl of 1-6 carbon atoms optionally substituted by —OR, —C(O)OR, or —NH(CO)OR, in which R is hydrogen or alkyl of 1-6 carbon atoms. 
   
   
       3 . The compound of  claim 1 , in which R 2  is hydrogen, trifluoromethyl, or alkyl of 1-6 carbon atoms optionally substituted by hydroxyl, phenyl, or heteoaryl. 
   
   
       4 . The compound of  claim 1 , in which R 3  is phenyl optionally substituted by 1, 2 or 3 groups chosen from halo, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, phenyl, and phenoxy, said alkyl, alkoxy, phenyl, and phenoxy optionally substituted by halo or alkoxy of 1-6 carbon atoms. 
   
   
       5 . The compound of  claim 4 , in which R 4  is hydrogen, and halo is chloro or fluoro. 
   
   
       6 . The compound of  claim 5 , in which R 3  is phenyl optionally substituted by 1, 2, or 3 groups chosen from phenyl, phenoxy, difluoromethyl, trifluoromethyl, trifluoromethoxy, fluorine, and chlorine. 
   
   
       7 . The compound of  claim 6 , wherein R 1  is —CH 2 CH 2 CO(O)R, wherein R is hydrogen or lower alkoxy of 1-4 carbon atoms, and R 2  is t-butyl. 
   
   
       8 . The compound of  claim 7 , wherein R is hydrogen and R 3  is biphenyl, namely 3-(7-(biphenyl-3-yl)-3-tert-butyl-2-oxoquinoxalin-1(2H)-yl)propanoic acid. 
   
   
       9 . The compound of  claim 7 , wherein R is hydrogen and R 3  is 3-trifluoromethyl-4-chlorophenyl or 3-trifluoromethyl-2-chlorophenyl, namely 3-(3-tert-butyl-7-(4-chloro-3-(trifluoromethyl)phenyl)-2-oxoquinoxalin-1(2H)-yl)propanoic acid or 3-(3-tert-butyl-7-(2-chloro-3-(trifluoromethyl)phenyl)-2-oxoquinoxalin-1(2H)-yl)propanoic acid. 
   
   
       10 . The compound of  claim 7 , wherein R is hydrogen and R 3  is 3-trifluoromethylphenyl, namely 3-(3-tert-butyl-2-oxo-7-(3-(trifluoromethyl)phenyl)quinoxalin-1(2H)-yl)propanoic acid. 
   
   
       11 . The compound of  claim 7 , wherein R is hydrogen and R 3  is 4-phenoxyphenyl, namely 2-(3-tert-butyl-2-oxo-7-(4-phenoxyphenyl)quinoxalin-1(2H)-yl)acetic acid. 
   
   
       12 . The compound of  claim 6 , wherein R 1  is methyl, 2-hydroxyethyl, and R 2  is t-butyl, pyridyl, or benzyl. 
   
   
       13 . The compound of  claim 12 , wherein R 3  is 4-trifluoromethoxyphenyl or 3-trifluoromethoxyphenyl. 
   
   
       14 . The compound of  claim 13 , chosen from 3-benzyl-1-methyl-7-(4-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one, 3-tert-butyl-1-methyl-7-(3-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one, N-(2-(3-tert-butyl-2-oxo-7-(3-(trifluoromethoxy)phenyl)quinoxalin-1(2H)-yl)ethyl)-2-hydroxyacetamide, and 1-methyl-3-(pyridin-4-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one. 
   
   
       15 . The compound of  claim 1 , wherein:
 R 1  is alkyl of 1-6 carbon atoms optionally substituted by —X—NR 5 R 6 ;   R 2  is alkyl of 1-6 carbon atoms or trifluoromethyl;   R 3  is phenyl optionally substituted by 1, 2 or 3 groups chosen from halo, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, phenyl, and phenoxy, said alkyl, alkoxy, phenyl, and phenoxy optionally substituted by halo or alkoxy of 1-6 carbon atoms; and   R 4  is hydrogen.   
   
   
       16 . The compound of  claim 15  chosen from:
 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]-3-(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-methyl-7-[4-(trifluoromethoxy)phenyl]quinoxalin-2(1H)-one;   7-(3,4-difluorophenyl)-1-methylquinoxalin-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(1H)-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(1H)-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-methyl-7-(4-(trifluoromethoxy)phenyl)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-methyl-7-(4-(trifluoromethoxy)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)ethyl amino)ethyl acetate;   ethyl 4-methyl-3-oxo-6-(4-(trifluoromethoxy)phenyl)-3,4-dihydroquinoxaline-2-carboxylate;   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;   ethyl-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(1H)-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.   
   
   
       17 . A method of treating a disease state in a mammal that is alleviable by treatment with an agent capable of reducing late sodium current, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of  claim 1 . 
   
   
       18 . The method of  claim 17 , wherein the disease state is a cardiovascular disease selected from one or more of atrial and ventricular arrhythmias, heart failure (including congestive heart failure, diastolic heart failure, systolic heart failure, acute heart failure), Prinzmetal's (variant) angina, stable and unstable angina, exercise induced angina, congestive heart disease, ischemia, recurrent ischemia, reperfusion injury, myocardial infarction, acute coronary syndrome, peripheral arterial disease, and intermittent claudication. 
   
   
       19 . The method of  claim 17 , wherein the disease state is diabetes or diabetic peripheral neuropathy. 
   
   
       20 . The method of  claim 17 , wherein the compound of  claim 1  is chosen from 3-(7-(biphenyl-3-yl)-3-tert-butyl-2-oxoquinoxalin-1(2H)-yl)propanoic acid, 3-(3-tert-butyl-7-(4-chloro-3-(trifluoromethyl)phenyl)-2-oxoquinoxalin-1(2H)-yl)propanoic acid, 3-(3-tert-butyl-7-(2-chloro-3-(trifluoromethyl)phenyl)-2-oxoquinoxalin-1(2H)-yl)propanoic acid, 3-(3-tert-butyl-2-oxo-7-(3-(trifluoromethyl)phenyl)quinoxalin-1(2H)-yl)propanoic acid, and 2-(3-tert-butyl-2-oxo-7-(4-phenoxyphenyl)quinoxalin-1(2H)-yl)acetic acid. 
   
   
       21 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of  claim 1 .