Hepatitis C Virus Inhibitors

Abstract

The present disclosure relates to compounds, compositions and methods for the treatment of hepatitis C virus (HCV) infection. Also disclosed are pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HCV infection.

What is claimed is: 
     
         1 . A compound of Formula (I) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 each m is independently 0 or 1; 
 each n is independently 0 or 1; 
 L is a bond or is selected from 
 
       
         
           
           
               
               
           
         
       
       wherein each group is drawn with its left end attached to the benzimidazole and its right end attached to R 1 ;
 R 1  is selected from 
 
       
         
           
           
               
               
           
         
         each R 2  is independently selected from alkyl and halo; 
         each R 3  is independently selected from hydrogen and —C(O)R 7 ; 
         R 4  is alkyl; 
         R 5  and R 6  are independently selected from hydrogen, alkyl, cyanoalkyl, and halo, or 
         R 5  and R 6 , together with the carbon atoms to which they are attached, form a six- or seven-membered ring optionally containing one heteroatom selected from nitrogen and oxygen and optionally containing an additional double bond; and 
         each R 7  is independently selected from alkoxy, alkyl, arylalkoxy, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, heterocyclylalkyl, (NR c R d )alkenyl, and (NR c R d )alkyl; 
       
       provided that when L is other than 
       
         
           
           
               
               
           
         
       
       and R 1  is other than 
       
         
           
           
               
               
           
         
       
       then either at least one of R 5  and R 6  is alkyl or cyanoalkyl, or at least one R 7  is arylalkoxy or (cycloalkyl)alkyl. 
     
     
         2 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein
 L is selected from   
       
         
           
           
               
               
           
         
       
       and
 R 1  is 
 
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein one of R 5  and R 6  is alkyl or cyanoalkyl. 
     
     
         4 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7  is selected from arylalkoxy and (cycloalkyl)alkyl. 
     
     
         5 . A compound selected from
 methyl ((1S)-1-(((2S)-2-(8-(4-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)phenyl)-1,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1,2-d]imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;   (1R)-2-((2R)-2-(7-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1H-naphtho[1,2-d]imidazol-2-yl)-1-pyrrolidinyl)-N,N-diethyl-2-oxo-1-phenylethanamine;   methyl ((1S)-1-(((2S)-2-(5-(4-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-naphtho[1,2-d]imidazol-7-yl)phenyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;   methyl ((1R)-2-((2S)-2-(7-(4-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate;   methyl ((1S)-1-(((2S)-2-(5-((4-(4-ethyl-2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)phenyl)ethynyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;   methyl ((1S)-1-(((2S)-2-(4-(cyanomethyl)-5-(4-((2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)ethynyl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;   methyl ((1R)-2-((2S)-2-(7-((2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)ethynyl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate;   methyl ((1R)-2-((2S)-2-(7-((2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)ethynyl)-1H-naphtho[1,2-d]imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate;   methyl ((1S)-1-(((1R,3S,5R)-3-(5-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)ethynyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate;   methyl ((1R)-2-((1R,3S,5R)-3-(7-((2-((1R,3S,5R)-2-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)ethynyl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-phenylethyl)carbamate;   methyl ((1R)-2-((1R,3S,5R)-3-(7-((2-((1R,3S,5R)-2-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)ethynyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-phenylethyl)carbamate;   methyl ((1S)-1-(4,4-difluorocyclohexyl)-2-((1R,3S,5R)-3-(7-((2-((1R,3S,5R)-2-((2S)-2-(4,4-difluorocyclohexyl)-2-((methoxycarbonyl)amino)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)ethynyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)carbamate;   methyl ((1S)-2-((1R,3S,5R)-3-(7-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)ethynyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate;   methyl ((1S)-2-((1R,3S,5R)-3-(7-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)ethynyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate;   methyl ((1S)-1-(((1R,3S,5R)-3-(4-fluoro-6-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo [3.1.0]hex-3-yl)-1H-naphtho [1,2-d]imidazol-7-yl)ethynyl)-1H-benzimidazol-2-yl)-2-azabicyclo [3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate;   benzyl (1R,3S,5R)-3-(7-((2-((1R,3S,5R)-2-(N-(methoxycarbonyl)-L-valyl)-2-azabicyclo [3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)ethynyl)-1H-naphtho [1,2-d]imidazol-2-yl)-2-azabicyclo [3.1.0]hexane-2-carboxylate;   methyl ((1S)-1-(((2S,5S)-2-(5-((2-((2S,5S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-methyl-2-pyrrolidinyl)-1H-naphtho [1,2-d]imidazol-7-yl)ethynyl)-1H-benzimidazol-2-yl)-5-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;   methyl ((1S)-2-((2S,5S)-2-(7-((2-((2S,5S)-1-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-5-methyl-2-pyrrolidinyl)-1H-benzimidazol-5-yl)ethynyl)-1H-naphtho [1,2-d]imidazol-2-yl)-5-methyl-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate;   methyl ((1S)-1-((1R,3S,5R)-3-(7-(2-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo [3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)ethyl)-1H-naphtho [1,2-d]imidazol-2-yl)-2-azabicyclo [3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate;   methyl ((1S)-2-((1R,3S,5R)-3-(7-(2-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo [3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)ethyl)-1H-naphtho [1,2-d]imidazol-2-yl)-2-azabicyclo [3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate;   methyl ((1S)-1-(((2S)-2-(4-((4-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)phenyl)ethynyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;   methyl ((1R)-1-(((2S)-2-(4-((4-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)phenyl)ethynyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;   methyl ((1S)-2-((2S)-2-(5-(4-((2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)ethynyl)phenyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate;   methyl ((1S,2R)-2-methoxy-1-(((2S)-2-(5-(4-((2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-threonyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)ethynyl)phenyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate;   methyl ((1R)-2-((2S)-2-(4-((4-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)phenyl)ethynyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate;   2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-5-(4-((2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)ethynyl)phenyl)-1H-benzimidazole;   methyl ((1S)-1-(((1R,3S,5R)-3-(7-(2-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)ethyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate;   methyl ((1S)-2-((1R,3S,5R)-3-(7-(2-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)ethyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate;   methyl ((1S)-1-(((2S)-2-(4-(2-(4-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)phenyl)ethyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;   1-(cyclopropylacetyl)-N-(3-(5-(2-((2S)-1-(cyclopropylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1,3-oxazol-2-yl)phenyl)-L-prolinamide; and   1-(cyclopropylacetyl)-N-(3-(2-(2-((2S)-1-(cyclopropylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1,3-oxazol-5-yl)phenyl)-L-prolinamide;   or a pharmaceutically acceptable salt thereof.   
     
     
         6 . A composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         7 . The composition of  claim 6  further comprising one or two additional compounds having anti-HCV activity. 
     
     
         8 . The composition of  claim 7  wherein at least one of the additional compounds is an interferon or a ribavirin. 
     
     
         9 . The composition of  claim 8  wherein the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau. 
     
     
         10 . The composition of  claim 7  wherein at least one of the additional compounds is selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5′-monophospate dehydrogenase inhibitor, amantadine, and rimantadine. 
     
     
         11 . The composition of  claim 7  wherein at least one of the additional compounds is effective to inhibit the function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and IMPDH for the treatment of an HCV infection. 
     
     
         12 . A method of treating an HCV infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         13 . The method of  claim 12  further comprising administering one or two additional compounds having anti-HCV activity prior to, after or simultaneously with the compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         14 . The method of  claim 13  wherein at least one of the additional compounds is an interferon or a ribavirin. 
     
     
         15 . The method of  claim 14  wherein the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau. 
     
     
         16 . The method of  claim 13  wherein at least one of the additional compounds is selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5′-monophospate dehydrogenase inhibitor, amantadine, and rimantadine. 
     
     
         17 . The method of  claim 13  wherein at least one of the additional compounds is effective to inhibit the function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and IMPDH for the treatment of an HCV infection.