Apoptosis signal-regulating kinase inhibitors

Abstract

The present invention relates to compounds of Formula (I): wherein X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , R 1 , R 2 , R 3 are as defined above. The compounds have apoptosis signal-regulating kinase (“ASK1”) inhibitory activity, and are thus useful in the treatment of ASK1-mediated conditions, including autoimmune disorders, inflammatory diseases, cardiovascular diseases and neurodegenerative diseases. The invention also relates to pharmaceutical compositions comprising one or more of the compounds of Formula (I), and to methods of preparing the compounds of Formula (I).

1 - 36 . (canceled) 
     
     
         37 . A method of treating a cardiovascular disorder in a mammal, comprising administering to the mammal a therapeutically effective dose of a compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is alkyl of 1-10 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-10 carbon atoms, alkynyl of 2-10 carbon atoms, aryl, heteroaryl or heterocyclyl, all of which are optionally substituted with 1, 2, or 3 substituents selected from halo, oxo, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, heterocyclyl, phenyl, phenoxy, halo, —CN, —O—R 6 , —C(O)—R 6 , —OC(O)—R 6 —C(O)—O—R 6 , —N(R 6 )—C(O)—O—R 7 , —N(R 6 )—C(O)—R 7 , —N(R 6 )—C(O)—N(R 6 )(R 7 ), and —C(O)—N(R 6 )(R 7 ), wherein alkyl, cycloalkyl, heterocyclyl, phenyl, and phenoxy are optionally substituted by 1, 2, or 3 substituents selected from alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxyl, and halo; 
         provided that R 1  is not methyl when R 3  is morpholinyl or furyl;
 wherein R 6  and R 7  are independently selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms, or cycloalkyl of 3-8 carbon atoms; or 
 R 6  and R 7  when taken together with the nitrogen to which they are attached form a heterocycle; 
 
         R 2  is hydrogen, halo, cyano, alkoxy, or alkyl optionally substituted by halo; 
         R 3  is aryl, heteroaryl, or heterocyclyl, all of which are optionally substituted with 1, 2 or 3 substituents selected from alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, haloalkoxy, oxo, —CN, —O—R 6 , —O—C(O)—R 6 , —O—C(O)—N(R 6 )(R 7 ), —S—R 6 , —N(R 6 )(R 7 ), —S(═O)—R 6 , —S(═O) 2 R 6 , —S(═O) 2 —N(R 6 )(R 7 ), —S(═O) 2 —O—R 6 , —N(R 6 )—C(O)—R 7 , —N(R 6 )—C(O)—O—R 7 , —N(R 6 )—C(O)—N(R 6 )(R 7 ), —C(O)—R 6 , —C(O)—O—R 6 , —C(O)—N(R 6 )(R 7 ), and —N(R 6 )—S(═O) 2 —R 7 , wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclyl is further optionally substituted with one or more substituents selected from halo, hydroxyl, oxo, —CN, and —O—R 6 ; 
         with the proviso that the heteroaryl or heterocyclyl moiety includes at least one ring nitrogen atom; 
         X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7  and X 8  are independently C(R 4 ) or N, in which each R 4  is independently hydrogen, hydroxyl, halo, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, or cycloalkyl of 3-8 carbon atoms, wherein the alkyl or cycloalkyl is further optionally substituted with one or more substituents selected from halo, hydroxyl, oxo, —CF 3 , —O—CF 3 , —N(R 6 )(R 7 ), —C(O)—R 6 , —C(O)—O—R 7 , —C(O)—N(R 6 )(R 7 ), —CN, —O—Re; or 
         X 5  and X 6  or X 6  and X 7  are joined to provide fused cycloalkyl, fused aryl, or fused heteroaryl, all of which are optionally substituted with alkyl of 1-6 carbon atoms, hydroxyl, or halo; and 
         with the proviso that at least one of X 2 , X 3 , and X 4  is C(R 4 );
 at least two of X 5 , X 6 , X 7 , and X 8  are C(R 4 ); and 
 at least one of X 2 , X 3 , X 4 , X 5 , X 6 , X 7  and X 8  is N; 
 or a pharmaceutically acceptable salt thereof. 
 
       
     
     
         38 . The method of  claim 37 , wherein X 1  and X 2  are N and X 3 , X 4 , X 5 , X 7 , and X 8  are (CR 4 ); R 2  is hydrogen; and R 3  is heteroaryl substituted with one substituents selected from alkyl of 1-6 carbon atoms. 
     
     
         39 . The method of  claim 37 , wherein the cardiovascular disorder is heart failure. 
     
     
         40 . The method of  claim 37 , wherein the cardiovascular disorder is congestive heart failure, diastolic heart failure, systolic heart failure, or acute heart failure. 
     
     
         41 . The method of  claim 37 , further comprising administration of one or more agents. 
     
     
         42 . The method of  claim 41 , wherein the one or more agents is selected from the group consisting of hydrochlorothiazide, metolazone, furosemide, bumetanide, spironolactone, and eplerenone. 
     
     
         43 . The method of  claim 41 , wherein the one or more agents is spironolactone.