Fused heterocyclic compounds as ion channel modulators

Abstract

The present invention relates to sodium channel inhibitors of Formula : in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as defined above, and to their use in the treatment of various disease states, including cardiovascular diseases and diabetes.

1 . A compound of Formula (I): 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1  is hydrogen or alkyl of 1-6 carbon atoms optionally substituted by 1, 2 or 3 groups chosen from hydroxyl, alkoxy, halo, —C(O)R, aryl, cycloalkyl, heterocyclyl, and heteroaryl, wherein said aryl, cycloalkyl, heterocyclyl, or heteroaryl groups are optionally substituted by one, two, or three groups independently chosen from halo, hydroxyl, alkyl, —C(O)R, haloalkyl, alkoxy, aryl, or cycloalkyl; in which R is hydroxy, alkoxy, or —NH 2 , 
 R 2  and R 3  are each independently hydrogen, halo, alkoxy of 1-6 carbon atoms, optionally substituted alkyl of 1-6 carbon atoms, —CF 3 , —O—CF 3 , or —CN, or 
 R 2  and R 3 , taken together with the carbon to which they are both attached form an optionally substituted cycloalkyl; 
 R 4  is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of alkyl of 1-6 carbon atoms, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, —NO 2 , —CF 3 , —O—CF 3 , —CN, —O—R 8 , —S—R 8 , —N(R 8 ) (R 9 ), —S(═O)—R 8 , —S(═O) 2 R 8 , —S(═O) 2 —N(R 8 )(R 9 ), —S(═O) 2 —O—R 8 , —N(R 8 )—C(O)—R 9 , —N(R 8 )—C(O)—O—R 9 , —N(R 8 )—C(O)—N(R 8 )(R 9 ), —C(O)—R 8 , —C(O)—O—R 8 , —C(O)—N(R 8 )(R 9 ), and —N(R 8 )—S(═O) 2 —R 9 , wherein each said alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is further optionally substituted with halo, —NO 2 , —CF 3 , —O—CF 3 , —N(R 8 )(R 9 ), —C(O)—R 8 , —C(O)—O—R 8 , —C(O)—N(R 8 )(R 9 ), —CN, or —O—R 8 , in which R 8  and R 9  are independently chosen from the group consisting of hydrogen, alkyl of 1-6 carbon atoms, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three substituents independently selected from halo, alkyl, mono- or dialkylamino, alkyl or aryl; 
 R 5  and R 6  are each independently hydrogen, halo, alkoxy, optionally substituted alkyl of 1-6 carbon atoms, —CF 3 , —O—CF 3 , or —CN, or 
 R 5  and R 6 , taken together with the carbon to which they are both attached form an optionally substituted cycloalkyl; 
 R 7  is hydrogen, halo, cyano, or alkyl of 1-6 carbon atoms optionally substituted by hydroxyl, alkoxy, halo, or —C(O)R, 
 X 1  and X 2  are independently —N═ or —C(R 10 )═, wherein R 10  is selected from hydrogen, halo, hydroxyl, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, —CF 3 , —O—CF 3 , —CN, or —N(R 8 )(R 9 ); 
 
     or a pharmaceutically acceptable salt, ester, prodrug, or solvate thereof. 
   
   
       2 . The compound of  claim 1 , wherein X 1  and X 2  are both —CH═. 
   
   
       3 . The compound of  claim 2 , wherein R 1  is hydrogen or alkyl of 1-6 carbon atoms optionally substituted by hydroxy, —C(O)R, trifluoromethyl, alkoxy of 1-6 carbon atoms, or phenyl optionally substituted by —C(O)R. 
   
   
       4 . The compound of  claim 3 , wherein R 2 , R 5 , and R 6  are hydrogen or lower alkyl of 1-6 carbon atoms. 
   
   
       5 . The compound of  claim 4 , wherein R 4  is phenyl optionally substituted by 1 or 2 substituents independently selected from halo, trifluoromethyl, trifluoromethoxy, cyano, or —C(O)R 8 , 
   
   
       6 . The compound of  claim 5 , wherein R 1  is hydrogen, R 2 , R 3 , R 5 , and R 6  are hydrogen, R 7  is methoxy, and R 4  is 6-(4-chlorophenyl), namely 6-(4-chlorophenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one. 
   
   
       7 . The compound of  claim 5 , wherein R 1  is 2-methoxyethyl, R 2 , R 3 , R 5 , R 6  and R 7  are hydrogen, and R 4  is 6-(4-trifluoromethylphenyl), namely 1-(2-methoxyethyl)-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one. 
   
   
       8 . The compound of  claim 5 , wherein R 1  is carboxymethyl, R 2 , R 3 , R 5 , R 6  and R 7  are hydrogen, and R 4  is 6-(4-trifluoromethoxyphenyl), namely 2-(2-oxo-6-(4-(trifluoromethoxy)phenyl)-3,4-dihydroquinolin-1(2H)-yl)acetic acid. 
   
   
       9 . The compound of  claim 5 , wherein R 1  is hydrogen, R 2 , R 3 , R 5 , R 6  and R 7  are hydrogen, and R 4  is 6-(3-fluorophenyl), namely 6-(3-fluorophenyl)-3,4-dihydroquinolin-2(1H)-one. 
   
   
       10 . The compound of  claim 5 , wherein R 1  is benzyl, R 2 , R 3 , R 5 , R 6  and R 7  are hydrogen, and R 4  is 6-(2,4-difluorophenyl), namely 1-benzyl-6-(2,4-difluorophenyl)-3,4-dihydroquinolin-2(1H)-one. 
   
   
       11 . The compound of  claim 5 , wherein R 1  is hydrogen, R 2 , R 3 , R 5  and R 6  are hydrogen, R 7  is methoxy, and R 4  is 6-(3-fluoro-4-trifluoromethylphenyl), namely 6-(3-fluoro-4-(trifluoromethyl)phenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one. 
   
   
       12 . The compound of  claim 5 , wherein R 1  is hydrogen or —C(O)OH, R 2  and R 3  are methyl, R 5 , R 6 , and R 7  are hydrogen, and R 4  is 6-(4-trifluoromethylphenyl), namely 4,4-dimethyl-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-2(1H)-one and {4,4-dimethyl-2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetic acid. 
   
   
       13 . The compound of  claim 3 , wherein R 1  is hydrogen, alkyl of 1-6 carbon atoms optionally substituted by 1, 2 or 3 groups chosen from —C(O)R, halo, hydroxy, heteroaryl substituted by optionally substituted phenyl, or phenyl optionally substituted by —C(O)R. 
   
   
       14 . The compound of  claim 13 , wherein R 1  is —C(O)OH, R 2 , R 3 , R 5 , and R 6  are hydrogen, R 7  is methoxy, and R 4  is 6-(4-chlorophenyl) or 6-(4-trifluoromethylphenyl), namely {7-methoxy-2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetic acid or [6-(4-chlorophenyl)-7-methoxy-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetic acid. 
   
   
       15 . The compound of  claim 13 , wherein R 1  is —C(O)R. 
   
   
       16 . The compound of  claim 15 , wherein the compound is selected from:
 2-{2-oxo-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetamide;   2-[6-(2,4-difluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetamide;   2-{2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetamide;   2-{6-[4-chloro-3-(trifluoromethyl)phenyl]-2-oxo-3,4-dihydroquinolin-1(2H)-yl}acetamide;   tert-butyl 2-(6-(3-fluoro-4-(trifluoromethyl)phenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate;   tert-butyl [6-(2,4-difluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate;   tert-butyl [6-(4-fluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate;   tert-butyl {2-oxo-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetate;   tert-butyl {6-[4-chloro-3-(trifluoromethyl)phenyl]-2-oxo-3,4-dihydroquinolin-1(2H)-yl}acetate;   ethyl {2-oxo-6-[3-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetate;   tert-butyl [6-(3-chlorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate;   tert-butyl {2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetate;   ethyl [6-(2,4-difluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate;   tert-butyl [6-(4-chlorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate;   ethyl [6-(3,4-difluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate;   {2-oxo-6-[3-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetic acid;   [6-(4-chlorophenyI)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetic acid;   {2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetic acid;   2-(6-(3-fluoro-4-(trifluoromethyl)phenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetic acid;   ethyl {2-oxo-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetate;   [6-(4-fluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetie acid;   [6-(3-chloro-4-fluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetic acid;   sodium {2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetate;   [6-(3,4-dichlorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetic acid;   {2-oxo-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetic acid;   [6-(4-chloro-3-fluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetic acid;   ethyl {2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetate;   [6-(3-fluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetic acid;   tert-butyl 2-(6-(3,4-dichlorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate; and   tert-butyl-2-(7-methoxy-2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)acetate.   
   
   
       17 . The compound of  claim 13 , wherein R 1  is alkyl optionally substituted by phenyl, heteroaryl or heterocyclyl. 
   
   
       18 . The compound of  claim 17 , wherein the compound is selected from:
 1-[(5-tert-butyl-1,2,4-oxadiazol-3-yl)methyl]-6-(4-fluorophenyl)-3,4-dihydroquinolin-2(1H)-one;   1-(pyridin-3-ylmethyl)-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-2(1H)-one;   1-[(5-methylisoxazol-3-yl)methyl]-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-2(1H)-one;   1-[2-(morpbolin-4-yl)-2-oxoethyl]-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-2(1H)-one;   1-{[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}-6-(2,4-difluorophenyl)-3,4-dihydroquinolin-2(1H)-one;   ethyl 3-((2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)methyl)benzoate;   methyl 4-((2-oxo-6-(4-(trifluoromethy)phenyl)-3,4-dihydroquinolin-1(2H)-yl)triethyl)benzoate; and   4-((2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)methyl)benzoic acid.   
   
   
       19 . The compound of  claim 13 , wherein R 1  is hydrogen. 
   
   
       20 . The compound of  claim 19 , wherein the compound is selected from
 7-methoxy-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-2(1H)-one;   8-bromo-6-(4-chlorophenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one;   6,8-bis(4-chlorophenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one;   [6,8-bis(4-chlorophenyl)-7-methoxy-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetic acid.   6-(3-fluorophenyl)-1-methyl-3,4-dihydroquinolin-2(1H)-one;   6-(2,4-difluorophenyl)-1-(2-methoxyethyl)-3,4-dihydroquinolin-2(1H)-one;   1-(2-hydroxypropyl)-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-2(1H)-one;   1-(2-hydroxyethyl)-6-[4-(frifluoromethoxy)phenyl]-3,4-dihydroquinolin-2(1H)-one;   6-(3,4-difluorophenyl)-1-(2-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one;   1-(2-hydroxyethyl)-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-2(1H)-one;   6-(2,4-difluorophenyl)-1-(2-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one;   6-(2,4-difluorophenyl)-1-(2,2,2-trifluoroethyl)-3,4-dihydroquinolin-2(1H)-one;   {2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetonitrile; and   6-(2,4-difluorophenyl)-1-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-3,4-dihydroquinolin-2(1H)-one.   6-[3-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-2(1H)-one;   6-[4-chloro-3-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-2(1H)-one;   6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-2(1H)-one;   6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-2(1H)-one:   6-(2,4-difluorophenyl)-3,4-dihydroquinolin-2(1H)-one;   6-(2-fluorophenyl)-3,4-dihydroquinolin-2(1H)-one;   6-phenyl-3,4-dihydroquinolin-2(1H)-one;   6-(4-chlorophenyl)-3,4-dihydroquinolin-2(1H)-one;   6-(3-fluoro-4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one;   4-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)benzonitrile;   6-(4-fluorophenyl)-3,4-dihydroquinolin-2(1H)-one;   2-fluoro-5-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)benzonitrile;   3-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)benzamide;   6-(3-acetylphenyl)-3,4-dihydroquinolin-2(1H)-one;   4-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)benzamide;   3-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)benzonitrile; and   6-[3-(morpholin-4-ylcarbonyl)phenyl]-3,4-dihydroquinolin-2(1H)-one.   
   
   
       21 . 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 . 
   
   
       22 . The method of  claim 21 , 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 isehemia, reperfusion injury, myocardial infarction, acute coronary syndrome, peripheral arterial disease, and intermittent claudication. 
   
   
       23 . The method of  claim 21 , wherein the disease state is diabetes or diabetic peripheral neuropathy. 
   
   
       24 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of  claim 1 .