Bicyclic heteroaryl derivatives

Abstract

Disclosed are compounds, compositions and methods for treating Flaviviridae family virus infections.

1 - 107 . (canceled) 
   
   
       108 . A method for treating a viral infection in a mammal mediated at least in part by a virus in the flaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a pharmaceutical composition comprising a compound according to formula II 
     
       
         
         
             
             
         
       
       wherein: 
       W is CH; 
       Z′ is selected from the group consisting of carboxy and carboxy ester, 
       R 17  is selected from the group consisting of cycloalkyl and cycloalkyl substituted with 1 to 3 alkyl groups; 
       X and X′ are independently selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, halo, hydroxy, and nitro; 
       Ar 1  is selected from the group consisting of aryl, and substituted aryl; 
       and Ar 2  is selected from the group consisting of aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; 
       t is an integer equal to 0, 1 or 2; and 
       t′ is an integer equal to 0 or 1; 
       and pharmaceutically acceptable salts thereof. 
     
   
   
       109 . The method according to  claim 108 , wherein R 17  is cycloalkyl. 
   
   
       110 . The method according to  claim 109 , wherein R 17  is cyclohexyl. 
   
   
       111 . The method according to  claim 108 , wherein —Ar 1 —Ar 2  are selected from the group consisting of aryl-aryl, -aryl-substituted aryl, -substituted aryl-aryl, and -substituted aryl-substituted aryl. 
   
   
       112 . The method according to  claim 111 , wherein —Ar 1 —Ar 2  are selected from the group consisting of biphen-2-yl, biphen-4-yl, 4-amino-4′-chlorobiphen-2-yl, 4′-aminomethyl-4-methoxybiphen-2-yl, 4-carbamoyl-4′-methoxybiphen-2-yl, 4-carbamoyl-4′-fluorobiphen-2-yl, 4-carbamoyl-4′-methoxybiphen-2-yl, 4-carbamoyl-4′-nitrobiphen-2-yl, 4-(carbamoylmethyl-carbamoyl)biphen-2-yl, 4-(carbamoylmethylcarbamoyl)-4′-chlorobiphen-2-yl, 4-carboxy-4′-chlorobiphen-2-yl, 3-carboxy-4′-methoxybiphen-2-yl, 4-carboxy-4′-methoxybiphen-2-yl, 4′-carboxy-4-(pyrrolidin-1-ylcarbonyl)biphen-2-yl, 4-carboxymethoxybiphen-2-yl, 4-carboxymethoxy-4′-chlorobiphen-2-yl, 4′-chlorobiphen-2-yl, 4′-chloro-4-chlorobiphen-2-yl, 4′-chloro-4-(dimethylaminoethylcarbamoylbiphen-2-yl, 4′-chloro-4-(2-ethoxyethoxy)biphen-2-yl, 3′-chloro-4′-fluoro-4-methoxybiphen-2-yl, 4′-chloro-4-fluorobiphen-2-yl, 4′-chloro-4-hydroxybiphen-2-yl, 3′-chloro-4-methoxybiphen-2-yl, 4′-chloro-4-methylcarbamoylbiphen-2-yl, 4′-chloro-4-methoxybiphen-2-yl, 4′-chloro-4-(2-methoxyethoxy)biphen-2-yl, 4′-chloro-4-nitrobiphen-2-yl, 4′-chloro-4-(2-oxo-2-pyrrolidin-1-ylethoxy)biphen-2-yl, 4′-chloro-4-(pyrrolidin-1-ylcarbonyl)biphen-2-yl, 4′-chloro-4-(3-pyrrolidin-1-ylpropoxy)biphen-2-yl, 4′-cyano-4-methoxybiphen-2-yl, 3′,4_dichloro-4-methoxybiphen-2-yl, 4,4′-dimethoxybiphen-2-yl, 3′,4′-dimethoxy-4-(pyrrolidin-1-ylcarbonyl)biphen-2-yl, 4′-dimethylamino-4-methoxybiphen-2-yl, 4-(2-dimethylaminoethylcarbamoyl)biphen-2-yl, 4′-ethoxy-4-methoxybiphen-2-yl, 4′-fluoro-4-methoxybiphen-2-yl, 4-hydroxybiphenyl, 4-methoxybiphenyl, 4-methoxy-4′-hydroxybiphen-2-yl, 4-(2-methoxyethoxy)biphen-2-yl, 4-methoxy-4′-methylbiphen-2-yl, 4-methoxy-3′-nitrobiphen-2-yl, 4-methoxy-4′-nitrobiphen-2-yl, 4-methylcarbamoylbiphen-2-yl, 3′-methyl-4-methoxybiphen-2-yl, 4′-nitro-4-(pyrrolidin-1-ylcarbonyl)biphen-2-yl, 4-(2-oxo-2-pyrrolidin-1-ylethoxy)biphen-2-yl, 4-(3-pyrrolidin-1-ylpropoxy)biphen-2-yl, and 4′-trifluoromethyl-4-methoxybiphen-2-yl. 
   
   
       113 . The method according to  claim 108 , wherein —Ar 1 —Ar 2  are selected from the group consisting of -aryl-heteroaryl, -aryl-substituted heteroaryl, -substituted aryl-heteroaryl, and -substituted aryl-substituted heteroaryl. 
   
   
       114 . The method according to  claim 113 , wherein —Ar 1 —Ar 2  are selected from the group consisting of 2-furan-2-yl-5-methoxyphenyl, 4-(imidazol-1-yl)phenyl, 5-methoxy-2-thiophen-2-ylphenyl, 2-(2,4-dimethoxypyrimidin-5-yl)-4-methoxyphenyl, and 2-(pyrid-4-yl)phenyl. 
   
   
       115 . The method according to  claim 108 , wherein —Ar 1 —Ar 2  are selected from the group consisting of -aryl-cycloalkyl, -aryl-substituted cycloalkyl, -substituted aryl-cycloalkyl, -substituted aryl-substituted cycloalkyl, -aryl-heterocyclic, aryl-substituted heterocyclic, substituted aryl-heterocyclic, and substituted aryl-substituted heterocyclic. 
   
   
       116 . The method according to  claim 115 , wherein —Ar 1 —Ar 2  are selected from the group consisting of (4-piperazin-1-yl)phenyl, 2-cyclohexyl-5-methoxyphenyl, and 4-morpholinophenyl. 
   
   
       117 . The method according to  claim 108 , wherein the compound selected from the group consisting of 
     2-{2-[4′-chloro-4-(pyrrolidine-1-carbonyl)-biphen-2-yl]-quinolin-6-yl}-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     2-[2-(4′-chloro-4-methoxy-biphen-2-yl)-quinolin-6-yl]-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-{2-[4-(2-oxo-2-pyrrolidin-1-yl-ethoxy)-biphen-2-yl]-quinolin-6-yl}-1H-benzoimidazole-5-carboxylic acid; 
     2-{2-[4-(carbamoylmethyl-carbamoyl)-4′-chloro-biphen-2-yl]-quinolin-6-yl}-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-[2-(4-methylcarbamoyl-biphen-2-yl)-quinolin-6-yl]-1H-benzoimidazole-5-carboxylic acid; 
     2-[2-(4′-cyano-4-methoxy-biphen-2-yl)-quinolin-6-yl]-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     2-[2-(3′-chloro-4′-fluoro-4-methoxy-biphen-2-yl)-quinolin-6-yl]-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-[2-(4-methoxy-3′-methyl-biphen-2-yl)-quinolin-6-yl]-1H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-[2-(2-pyridin-4-yl-phenyl)-quinolin-6-yl]-1H-benzoimidazole-5-carboxylic acid; 
     2-[2-(4-carboxymethoxy-biphen-2-yl)-quinolin-6-yl]-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     2-{2-[4′-chloro-4-(2-oxo-2-pyrrolidin-1-yl-ethoxy)-biphen-2-yl]-quinolin-6-yl}-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     2-{2-[4-(carbamoylmethyl-carbamoyl)-biphen-2-yl]-quinolin-6-yl}-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     2-[2-(4′-chloro-4-methylcarbamoyl-biphen-2-yl)-quinolin-6-yl]-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     2-(2-biphen-2-yl-8-methyl-quinolin-6-yl)-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     2-[2-(4′-carbamoyl-4-methoxy-biphen-2-yl)-quinolin-6-yl]-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-[2-(4-methoxy-4′-nitro-biphen-2-yl)-quinolin-6-yl]-1H-benzoimidazole-5-carboxylic acid; 
     2-[2-(4′-aminomethyl-4-methoxy-biphen-2-yl)-quinolin-6-yl]-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     2-[2-(4′-chloro-biphen-2-yl)-quinolin-6-yl]-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     2-(2-biphen-2-yl-7-fluoro-quinolin-6-yl)-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     2-(2-biphenyl-4-yl-quinolin-6-yl)-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     2-(2-biphen-2-yl-quinolin-6-yl)-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-[2-(4′-dimethylamino-4-methoxy-biphen-2-yl)-quinolin-6-yl]-H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-[2-(3′,4′-dichloro-4-methoxy-biphen-2-yl)-quinolin-6-yl]-H-benzoimidazole-5-carboxylic acid; 
     2-[2-(4′-chloro-biphen-2-yl)-7-fluoro-quinolin-6-yl]-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     2-[2-(4-carboxy-4′-chloro-biphen-2-yl)-quinolin-6-yl]-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     2-[2-(4′-chloro-biphen-2-yl)-8-methyl-quinolin-6-yl]-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-{2-[3′,4′-dimethoxy-4-(pyrrolidine-1-carbonyl)biphen-2-yl]quinolin-6-yl}-1H-benzimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-[2-(4-methoxy-3′-nitro-biphen-2-yl)-quinolin-6-yl]1H-benzoimidazole-5-carboxylic acid; 
     2-[2-(4′-carboxy-4-methoxy-biphen-2-yl)-quinolin-6-yl]-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     2-[2-(3′-chloro-4-methoxy-biphen-2-yl)-quinolin-6-yl]-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-[2-(4-morpholin-4-yl-phenyl)-quinolin-6-yl]-1H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-{2-[4-(3-pyrrolidin-1-yl-propoxy)-biphen-2-yl]-quinolin-6-yl}-1H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-{2-[4′-nitro-4-(pyrrolidine-1-carbonyl)biphen-2-yl]quinolin-6-yl}-1H-benzimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-[2-(4-methoxy-4′-trifluoromethyl-biphen-2-yl)-quinolin-6-yl]-H-benzoimidazole-5-carboxylic acid; 
     2-[2-(3′-carboxy-4-methoxy-biphen-2-yl)-quinolin-6-yl]-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-[2-(4-methoxy-4′-methyl-biphen-2-yl)-quinolin-6-yl]-1H-benzoimidazole-5-carboxylic acid; 
     2-[2-(4′-chloro-4-nitro-biphen-2-yl)-quinolin-6-yl]-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     2-[2-(4′-chloro-biphen-2-yl)-3-phenyl-quinolin-6-yl]-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     2-{2-[4′-chloro-4-(3-pyrrolidin-1-yl-propoxy)-biphen-2-yl]-quinolin-6-yl}-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     2-{2-[4′-carboxy-4-(pyrrolidine-1-carbonyl)biphen-2-yl]quinolin-6-yl}-1-cyclohexyl-1H-benzimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-[2-(2-furan-2-yl-5-methoxy-phenyl)-quinolin-6-yl]-1H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-[2-(4′-fluoro-4-methoxy-biphen-2-yl)-quinolin-6-yl]-1H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-[2-(4′-ethoxy-4-methoxy-biphen-2-yl)-quinolin-6-yl]-1H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-{2-[4-(2-methoxy-ethoxy)-biphen-2-yl]-quinolin-6-yl}-1H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-[2-(4,4′-dimethoxy-biphen-2-yl)-quinolin-6-yl]-1H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-[2-(4′-hydroxy-4-methoxy-biphen-2-yl)-quinolin-6-yl]-1H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-[2-(5-methoxy-2-thiophen-2-yl-phenyl)-quinolin-6-yl]-1H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-[2-(4-imidazol-1-yl-phenyl)-quinolin-6-yl]-1H-benzoimidazole-5-carboxylic acid; 
     2-{2-[4′-chloro-4-(2-methoxy-ethoxy)-biphen-2-yl]-quinolin-6-yl}-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     2-[2-(4′-chloro-biphenyl-3-yl)-quinolin-6-yl]-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-{2-[2-(2,4-dimethoxy-pyrimidin-5-yl)-5-methoxy-phenyl]-quinolin-6-yl}-1H-benzoimidazole-5-carboxylic acid; 
     2-[2-(4′-chloro-biphen-2-yl)-4-methyl-quinolin-6-yl]-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-[2-(4-hydroxy-biphen-2-yl)-quinolin-6-yl]-1H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-[2-(4-piperazin-1-yl-phenyl)-quinolin-6-yl]-1H-benzoimidazole-5-carboxylic acid; 
     2-{2-[4′-chloro-4-(2-dimethylamino-ethylcarbamoyl)-biphen-2-yl]-quinolin-6-yl}-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-[2-(4-methoxy-biphen-2-yl)-quinolin-6-yl]-1H-benzoimidazole-5-carboxylic acid; 
     2-[2-(4′-chloro-4-hydroxy-biphen-2-yl)-quinolin-6-yl]-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-{2-[4-(2-dimethylamino-ethylcarbamoyl)-biphen-2-yl]-quinolin-6-yl}-1H-benzoimidazole-5-carboxylic acid; 
     2-{2-[4′-chloro-4-(2-ethoxy-ethoxy)-biphen-2-yl]-quinolin-6-yl}-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     2-[2-(4′-chloro-4-methoxy-biphen-2-yl)-quinolin-6-yl]-1-(4-methyl-cyclohexyl)-1H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-[2-(2′-fluoro-4-methoxy-biphen-2-yl)-quinolin-6-yl]-1H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-[2-(2-cyclohexyl-5-methoxy-phenyl)-quinolin-6-yl]-1H-benzoimidazole-5-carboxylic acid; 
     2-[2-(4′-chloro-4-methoxy-biphen-2-yl)-quinolin-6-yl]-1-(4-methyl-cyclohexyl)-1H-benzoimidazole-5-carboxylic acid; 
     2-(2-biphenyl-4-yl-quinolin-6-yl)-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-{2-[4′-fluoro-4-(pyrrolidine-1-carbonyl)biphen-2-yl]quinolin-6-yl}-1H-benzimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-[2-(4,2′-dimethoxy-biphen-2-yl)-quinolin-6-yl]-1H-benzoimidazole-5-carboxylic acid; 
     Ethyl 1-cyclohexyl-2-[2-(4′-fluoro-4-methoxy-biphen-2-yl)-quinolin-6-yl]-1H-benzoimidazole-5-carboxylic acid; 
     2-[2-(4′-chloro-4-methoxy-biphen-2-yl)-quinolin-6-yl]-1-(3,3,5-trimethyl-cyclohexyl)-1H-benzoimidazole-5-carboxylic acid; 
     2-[2-(4′-chloro-4-methoxy-biphen-2-yl)-quinolin-6-yl]-1-(2-methyl-cyclohexyl)-1H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-[2-(4′-ethyl-4-methoxy-biphen-2-yl)-quinolin-6-yl]-1H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-[2-(3′,4′-difluoro-4-methoxy-biphen-2-yl)-quinolin-6-yl]-H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-{2-[4′-methoxy-4-(pyrrolidine-1-carbonyl)biphen-2-yl]quinolin-6-yl}-1H-benzimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-[2-(3′,5′-dichloro-4-methoxy-biphen-2-yl)-quinolin-6-yl]-1H-benzoimidazole-5-carboxylic acid; 
     2-[2-(4′-chloro-4-fluoro-biphen-2-yl)-quinolin-6-yl]-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     2-{2-[8-(4-chloro-phenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-quinolin-6-yl}-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-[2-(4,4′-dichloro-biphen-2-yl)-quinolin-6-yl]-1H-benzoimidazole-5-carboxylic acid; 
     1-bicyclo[2.2.1]hept-2-yl-2-[2-(4′-chloro-4-methoxy-biphen-2-yl)-quinolin-6-yl]1H-benzoimidazole-5-carboxylic acid; 
     2-[2-(4-amino-4′-chloro-biphen-2-yl)-quinolin-6-yl]-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; 
     2-[2-(4′-chloro-4-methoxy-biphen-2-yl)-quinolin-6-yl]-1-cyclopropyl-1H-benzoimidazole-5-carboxylic acid; 
     2-[2-(4′-chloro-4-methoxy-biphen-2-yl)-quinolin-6-yl]-1-cyclopentyl-1H-benzoimidazole-5-carboxylic acid; 
     1-cyclohexyl-2-(2-(4-methoxy-2′-methylbiphenyl-2-yl)quinolin-6-yl)-1H-benzoimidazole-5-carboxylic acid; and 
     2-[2-(4-carbamoyl-5-hydroxy-4′-nitro-biphen-2-yl)-7-fluoro-quinolin-6-yl]-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid; and
 pharmaceutically acceptable tautomers or salts thereof. 
 
   
   
       118 . The method according to  claim 108 , wherein said virus is hepatitis C virus. 
   
   
       119 . The method according to  claim 118  in combination with the administration of a therapeutically effective amount of one or more agents active against hepatitis C virus. 
   
   
       120 . The method according to  claim 119  wherein said active agent against is ribavirin, levovirin, thymosin alpha-1, an inhibitor of NS3 serine protease, and inhibitor of inosine monophosphate dehydrogenase, interferon-alpha, pegylated interferon-alpha, alone or in combination with ribavirin or levovirin. 
   
   
       121 . The method according to  claim 120  wherein said agent active against HCV is interferon-alpha or pegylated interferon-alpha alone or in combination with ribavirin or levovirin.