Substituted heterocyclic compounds as ion channel modulators

Abstract

The present invention relates to sodium channel inhibitors of Formula (I): in which R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, and Z are as defined herein, and to their use in the treatment of various disease states, including cardiovascular diseases and diabetes. The invention also relates to methods for the preparation of the compounds, and to pharmaceutical compositions containing such compounds.

1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is amino or alkyl of 1-6 carbon atoms optionally substituted by halo, alkoxy of 1-6 carbon atoms, or phenoxy optionally substituted by 1, 2, or 3 substituents independently chosen from halo, alkyl of 1-6 carbon atoms, and alkoxy of 1-6 carbon atoms; or 
 R 1  is alkyl of 1-6 carbon atoms substituted by —NR 6 R 7 , in which R 6  and R 7  are independently chosen from hydrogen or alkyl of 1-6 carbon atoms, or R 6  and R 7  when combined with the nitrogen atom to which they are attached is a nitrogen-bearing heterocyclyl or heteroaryl group; 
 R 2  is alkyl of 1-6 carbon atoms, phenyl, or heteroaryl, all of which are optionally substituted by halo, alkyl of 1-6 carbon atoms, hydroxyl, cyano, alkoxy of 1-6 carbon atoms, or —C(O)R, in which R is alkoxy of 1-6 carbon atoms or —NR 6 R 7 , in which R 6  and R 7  are independently chosen from hydrogen or alkyl of 1-6 carbon atoms; 
 R 3 , R 4 , and R 5  are independently chosen from hydrogen, halo, alkyl of 1-6 carbon atoms, hydroxyl, cyano, or alkoxy of 1-6 carbon atoms; 
 X is a covalent bond, cyano, —C(O)—, —C(O)O—, —CH(OH)—, or —C(O)NR 6 R 7 ; 
 Y is a covalent bond, alkylene of 1-6 carbon atoms, heterocyclyl, or heteroaryl; 
 Z is a covalent bond, hydrogen, phenyl, benzyl, or cycloalkyl of 3-8 carbon atoms, all of which are optionally substituted by phenyl or heteroaryl, both of which are optionally substituted by 1, 2, or 3 substituents independently chosen from halo, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, and —C(O)R 8 , where le is alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, or —NR 6 R 7 , in which R 6  and R 7  are independently chosen from hydrogen or alkyl of 1-6 carbon atoms; or 
 Z is phenyl optionally substituted by 1, 2, or 3 substituents independently chosen from halo, alkyl of 1-6 carbon atoms optionally substituted by heteroaryl, and alkoxy of 1-6 carbon atoms; 
 with the proviso that X, Y and Z cannot all be covalent bonds; 
 or a pharmaceutically acceptable salt, ester, prodrug, or solvate thereof. 
 
     
     
         2 . The compound of claim. 1, wherein R 2  is alkyl of 1-3 carbon atoms or phenyl optionally substituted by halo. 
     
     
         3 . The compound of  claim 2 , wherein R 3 , R 4  and R 5  are independently chosen from hydrogen and halo. 
     
     
         4 . The compound of  claim 3 , wherein R 1  is alkyl of 1-6 carbon atoms. 
     
     
         5 . The compound of  claim 4 , wherein X is a covalent bond, —C(O)O—, or heteroaryl, Y is methylene, and Z is cycloalkyl or phenyl, both of which are optionally substituted by halo or heteroaryl. 
     
     
         6 . The compound of  claim 5 , wherein R 1  and R 2  are both methyl, R 3 , R 4 , and R 5  are all hydrogen, X is —C(O)O—, Y is methylene, and Z is 2-bromophenyl, namely 2-bromobenzyl 2,4-dimethylquinoline-3-carboxylate. 
     
     
         7 . The compound of  claim 5 , wherein R 1  is methyl, R 2  is phenyl, R 3 , R 4 , and R 5  are all hydrogen, X is —C(O)O—, Y is methylene, and Z is phenyl, namely benzyl 2-methyl-4-phenylquinoline-3-carboxylate. 
     
     
         8 . The compound of  claim 5 , wherein R 1  and R 2  are both methyl, R 3 , R 4 , and R 5  are all hydrogen, X is —C(O)O—, Y is methylene, and Z is 4-chlorophenyl, namely 4-chlorobenzyl 2,4-dimethylquinoline-3-carboxylate. 
     
     
         9 . The compound of  claim 5 , wherein R 1  and R 2  are both methyl, R 3 , R 4 , and R 5  are all hydrogen, X is a covalent bond, Y is 1,3,4-oxadiazole, and Z is (4-chlorophenyl)propan-2-yl), namely 2-(2-(4-chlorophenyl)propan-2-yl)-5-(2,4-dimethylquinolin-3-yl)-1,3,4-oxadiazole. 
     
     
         10 . The compound of  claim 5 , wherein R 1  is methyl, R 2  is phenyl, R 3  and R 4  are hydrogen, R 5  is 6-chloro, X is —C(O)O—, Y is methylene, and Z is cyclopropyl, namely cyclopropylmethyl 6-chloro-2-methyl-4-phenylquinoline-3-carboxylate. 
     
     
         11 . The compound of  claim 5 , wherein R 1  is methyl, R 2  is phenyl, R 3  and R 4  are hydrogen, R 5  is 6-chloro, X is —C(O)O—, Y is methylene, and Z is 4-((1H-pyrazol-1-yl)methyl)benzyl, namely 4-((1H-pyrazol-1-yl)methyl)benzyl 6-chloro-2-methyl-4-phenylquinoline-3-carboxylate. 
     
     
         12 . The compound of  claim 1 , wherein:
 R 1  is alkyl of 1-3 carbon atoms optionally substituted by alkoxy of 1-3 carbon atoms, phenoxy optionally substituted by 1 or 2 substituents independently chosen from halo and alkoxy of 1-3 carbon atoms; or R 1  is alkyl of 1-3 carbon atoms substituted by —NR 6 R 7 , in which R 6  and R 7  are independently chosen from hydrogen or alkyl of 1-6 carbon atoms, or R 6  and R 7  when combined with the nitrogen atom to which they are attached is a nitrogen-bearing heterocyclyl or heteroaryl group.   R 2  is alkyl of 1-3 carbon atoms or phenyl optionally substituted by halo;   R 3 , R 4  and R 5  are independently chosen from hydrogen and halo.   X is —CN, —C(O)—, —C(O)O—, or oxadiazolyl;   Y is alkylene of 1-4 carbon atoms, pyrrolidinyl, or piperidinyl;   Z is a covalent bond, hydrogen, or phenyl optionally substituted by halo or —C(O)R 8 , where R 8  is hydrogen, alkoxy of 1-3 carbon atoms, or amino.   
     
     
         13 . The compound of  claim 12 , wherein:
 R 1  is methyl substituted by ethoxy, 4-chloro-2-methoxyphenyl, or —NR 6 R 7 , where R 6  and R 7  are both methyl, or R 6  and R 7  when combined with the nitrogen atom to which they are attached are pyrrolidine-2,5-dione, isoindoline-1,3-dione, imidazolyl, or tetrazolyl;   R 2  is phenyl; and   X is —C(O)— or —C(O)O—.   
     
     
         14 . The compound of  claim 13 , chosen from:
 ethyl 6-chloro-2-((4-chloro-2-methoxyphenoxy)methyl)-4-phenylquinoline-3-carboxylate;   ethyl 6-chloro-2-((1,3-dioxoisoindolin-2-yl)methyl)-4-phenylquinoline-3-carboxylate;   ethyl 2-((1H-imidazol-1-yl)methyl)-6-chloro-4-phenylquinoline-3-carboxylate;   ethyl 6-chloro-2-((2,5-dioxopyrrolidin-1-yl)methyl)-4-phenylquinoline-3-carboxylate;   ethyl 2-((1H-tetrazol-1-yl)methyl)-6-chloro-4-phenylquinoline-3-carboxylate;   ethyl 6-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-4-phenylquinoline-3-carboxylate;   ethyl 6-chloro-2-(1H-imidazol-1-ylmethyl)-4-phenylquinoline-3-carboxylate;   ethyl 6-chloro-2-[(2,5-dioxopyrrolidin-1-yl)methyl]-4-phenylquinoline-3-carboxylate;   ethyl 6-chloro-4-phenyl-2-(1H-tetrazol-1-ylmethyl)quinoline-3-carboxylate;   ethyl 6-chloro-2-[(4-chloro-2-methoxyphenoxy)methyl]-4-phenylquinoline-3-carboxylate;   ethyl 6-chloro-2-[(dimethylamino)methyl]-4-phenylquinoline-3-carboxylate; and   ethyl 2-(ethoxymethyl)-4-methylquinoline-3-carboxylate.   
     
     
         15 . The compound of  claim 12 , wherein R 1  is methyl and R 2  is methyl or phenyl optionally substituted by halo. 
     
     
         16 . The compound of  claim 15 , chosen from:
 (6-chloro-2-methyl-4-phenylquinolin-3-yl)(piperidin-1-yl)methanone;   4-(1-(6-chloro-2-methyl-4-phenylquinoline-3-carbonyl)piperidin-4-yl)benzamide;   (R)-1-phenylethyl 6-chloro-2-methyl-4-phenylquinoline-3-carboxylate;   (S)-1-phenylethyl 6-chloro-2-methyl-4-phen ylquinoline-3-carboxylate;   4-((1H-pyrazol-1-yl)methyl)benzyl 6-chloro-2-methyl-4-phenylquinoline-3-carboxylate;   1-(6-chloro-2-methyl-4-phenylquinolin-3-yl)ethanol;   2-(2-(4-chlorophenyl)propan-2-yl)-5-(2,4-dimethylquinolin-3-yl)-1,3,4-oxadiazole;   benzyl 2-methyl-4-phenylquinoline-3-carboxylate;   tert-butyl 6-chloro-2-methyl-4-phenylquinoline-3-carboxylate;   6-chloro-N-(4-fluorobenzyl)-2-methyl-4-phenylquinoline-3-carboxamide;   6-chloro-3-[5-(4-chlorobenzyl)-1,3,4-oxadiazol-2-yl]-2-methyl-4-phenylquinoline;   cyclopropyl(phenyl)methyl 6-chloro-2-methyl-4-phenylquinoline-3-carboxylate;   (6-chloro-2-methyl-4-phenylquinolin-3-yl)(piperidin-1-yl)methanone;   (1S)-1-phenylethyl 6-chloro-2-methyl-4-phenylquinoline-3-carboxylate;   (1R)-1-phenylethyl 6-chloro-2-methyl-4-phenylquinoline-3-carboxylate;   cyclopropylmethyl 6-chloro-2-methyl-4-phenylquinoline-3-carboxylate;   4-{1-[(6-chloro-2-methyl-4-phenylquinolin-3-yl)carbonyl]piperidin-4-yl}benzamide;   4-(1H-pyrazol-1-ylmethyl)benzyl 6-chloro-2-methyl-4-phenylquinoline-3-carboxylate;   4-chlorobenzyl 2,4-dimethylquinoline-3-carboxylate;   tert-butyl 6-chloro-4-(2-chlorophenyl)-2-methylquinoline-3-carboxylate;   ethyl 6-chloro-4-(2-chlorophenyl)-2-methylquinoline-3-carboxylate;   tert-butyl 6-chloro-4-(2-fluorophenyl)-2-methylquinoline-3-carboxylate;   2-bromobenzyl 6-chloro-4-(2-chlorophenyl)-2-methylquinoline-3-carboxylate;   2-bromobenzyl 2,4-dimethylquinoline-3-carboxylate;   ethyl 6-chloro-2-methyl-4-phenylquinoline-3-carboxylate;   ethyl 6-chloro-4-(2-fluorophenyl)-2-methylquinoline-3-carboxylate; and   3-{5-[2-(4-chlorophenyl)propan-2-yl]-1,3,4-oxadiazol-2-yl}-2,4-dimethylquinoline.   
     
     
         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 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of  claim 1 .