Nitrogen-containing heteroaryl derivatives

Abstract

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

1 . A compound of the formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is selected from the group consisting of —OR 7 , and —NR 8 R 9 ; 
 where R 7  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; 
 R 8  and R 9  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic or, alternatively, R 8  and R 9 , together with the nitrogen atom pendent thereto, form a heterocyclic or substituted heterocyclic ring group; 
 R 2  and R 12  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; or, R 2  and R 12 , together with the carbon atom pendent thereto, form a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic ring group; 
 R 3  is selected from the group consisting of hydrogen and alkyl; or R 2  and R 3 , together with the nitrogen atom pendent to R 3 , form a heterocyclic or substituted heterocyclic ring group; 
 each R 4  is selected from the group consisting of halo, nitro, amino, substituted amino, cyano and hydroxyl; 
 Q is selected from the group consisting of oxygen, —S(O) q — where q is zero, one or two and —N(R 3 )— where R 3  is as defined above; 
 X is selected from the group consisting of oxygen, sulfur, and ═NR 11 , where R 11  is hydrogen or alkyl: 
 R 5  is alkylene or substituted alkylene; 
 R 6  is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; 
 n is 0 to 3; 
 or pharmaceutically acceptable salts thereof. 
 
     
     
         2 . A compound according to  claim 1  wherein said compound is represented by the Formula Ia: 
       
         
           
           
               
               
           
         
         wherein
 R 2 , R 3 , R 4 , R 67 , R 7  and n are as defined above; 
 or pharmaceutically acceptable salts thereof. 
 
       
     
     
         3 . A compound according to  claim 1  wherein said compound is represented by the Formula Ib: 
       
         
           
           
               
               
           
         
         wherein
 R 2 , R 3 , R 4 , R 7  and n are as previously defined; 
 p is 0 to 5; 
 each R 10  is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, carboxyl, carboxyl ester, —C(O)NR 8 R 9  where R 8  and R 9  are as previously defined; 
 or pharmaceutically acceptable salts thereof. 
 
       
     
     
         4 . A compound according to  claim 1  wherein said compound is represented by Formula II: 
       
         
           
           
               
               
           
         
         wherein
 R 2 , R 3 , R 4 , R 6 , R 8  and R 9  are as defined above; or 
 pharmaceutically acceptable salts thereof. 
 
       
     
     
         5 . A compound according to  claim 1  wherein said compound is represented by Formula III: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 4 R 6 R 8 , R 9  and n are as defined above; 
 Z is selected from the group consisting of hydrogen, hydroxy, halo, alkyl, and aryl; 
 Y is selected from the group consisting of —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 O—, —CH 2 CH 2 S—, and —CH 2 CH 2 NH—; or 
 pharmaceutically acceptable salts thereof. 
 
     
     
         6 . A compound according to  claim 1  wherein said compound is represented by Formula IV: 
       
         
           
           
               
               
           
         
         wherein Z, Y, R 4 , R 8 , R 10 , p and n are as defined above, or pharmaceutically acceptable salts thereof. 
       
     
     
         7 . A compound selected from the group consisting of: 
       2-{[2-(4-benzyloxy-phenyl)-1-cyclohexyl-1H-benzimidazole-5-carbonyl]-amino}-3-(5-hydroxy-1H-indol-3-yl)-propionic acid; 
       2-[(1-cyclohexyl-2-{2-fluoro-4-[3-(aminocarbonyl)-6-(4-chlorophenyl)benzyloxy]-phenyl}-1H-benzimidazole-5-carbonyl)-amino]-3-(5-hydroxy-1H-indol-3-yl)-propionic acid; 
       2-[(2-{4-[2-bromo-5-(4-hydroxyl-piperidine-1-carbonyl)-benzyloxy]-2-fluoro-phenyl}-1-cyclohexyl-1H-benzimidazole-5-carbonyl)-amino]-3-(5-hydroxy-1H-indol-3-yl)-propionic acid; 
       2-[(1-cyclohexyl-2-{2-fluoro-4-[3-(4-hydroxyl-piperidine-1-carbonyl)-benzyloxy]-phenyl}-1H-benzimidazole-5-carbonyl)-amino]-3-(5-hydroxy-1H-indol-3-yl)-propionic acid; 
       2-(4-benzyloxy-phenyl)-1-cyclohexyl-1H-benzimidazole-5-carboxylic acid [1-carbamoyl-2-(5-hydroxy-1H-indol-3-yl)-ethyl]-amide; 
       2-[(2-{4-[4′-chloro 4-(4-hydroxyl-piperidine-1-carbonyl)-biphen-2-ylmethoxy]-2-fluoro-phenyl}-1-cyclohexyl-1H-benzoimidazole-5-carbonyl)-amino]-3-(5-hydroxy-1H-indol-3-yl)-propionic acid; 
       2-({1-Cyclohexyl-2-[4-(naphthalene-2-ylmethoxy)-phenyl]-1H-benzimidazole-5-carbonyl}-amino)-3-(5-hydroxy-1H-indol-3-yl)-propionic acid; and 
       3-(4-{[1-({2-[4-(4-Carbamoyl-4′-chloro-biphen-2-ylmethoxy)-2-fluoro-phenyl]-1-cyclohexyl-1H-benzoimidazole-5-carbonyl}-amino)-cyclopentanecarbonyl]-amino}-phenyl)-acrylic acid; or
 pharmaceutically acceptable salts thereof. 
 
     
     
         8 . A pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound of any one of  claims 1 - 7  or a mixture of two or more of said compounds. 
     
     
         9 . A method of treating or preventing viral infections in mammals mediated at least in part by a member of the flaviviridae family viruses, comprising administering to a patient in need thereof, the pharmaceutical composition of  claim 8 . 
     
     
         10 . The method of  claim 9  wherein the member of the flaviviridae family viruses is HCV. 
     
     
         11 . The method of  claim 9  in combination with the administration of a therapeutically effective amount of one or more agents active against HCV. 
     
     
         12 . The method of  claim 11  wherein said agent 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. 
     
     
         13 . The method of  claim 12  wherein said agent is interferon-alpha or pegylated interferon-alpha alone or in combination with ribavirin or levovirin.