Anti-Viral Compounds

Abstract

Compounds effective in inhibiting replication of Hepatitis C virus (“HCV”) are described. This invention also relates to processes of making such compounds, compositions comprising such compounds, and methods of using such compounds to treat HCV infection.

1 - 4 . (canceled) 
     
     
         5 . A process of making methyl {(2S,3R)-1-[(2S)-2-{5-[(2R,5R)-1-{3,5-difluoro-4-[4-(4-fluorophenyl)piperidin-1-yl]phenyl}-5-(6-fluoro-2-{(2S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-1H-benzimidazol-5-yl)pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methoxy-1-oxobutan-2-yl}carbamate, or a pharmaceutically acceptable salt thereof, the process comprising:
 reacting (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(4-fluorophenyl)piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole) with (2 S, 3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid.   
     
     
         6 . The process of  claim 5 , wherein the reacting step is performed in the presence of a peptide coupling reagent. 
     
     
         7 . The process of  claim 6 , wherein the peptide coupling reagent is selected from the group consisting of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride/1-hydroxybenzotriazole (EDAC/HOBT), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), propane phosphonic acid anhydride (T3P), and 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT). 
     
     
         8 . (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(4-fluorophenyl)piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole). 
     
     
         9 . A process of making methyl {(2S,3R)-1-[(2S)-2-{5-[(2R,5R)-1-{3,5-difluoro-4-[4-(4-fluorophenyl)piperidin-1-yl]phenyl}-5-(6-fluoro-2-{(2S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-1H-benzimidazol-5-yl)pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methoxy-1-oxobutan-2-yl}carbamate, or a pharmaceutically acceptable salt thereof, the process comprising:
 reacting a dimesylate with an amine to obtain a substituted pyrrolidine, wherein the dimesylate is (1S,4S)-1,4-bis(4-chloro-2-fluoro-5-nitrophenyl)butane-1,4-diyl dimethanesulfonate, the amine is 3,5-difluoro-4-(4-(4-fluorophenyl)piperidin-1-yl)aniline, and the substituted pryrrolidine is 1-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-(4-fluorophenyl)piperidine.   
     
     
         10 . The process of  claim 9 , further comprising:
 reacting the substituted pyrrolidine with tert-butyl-2-carbamoylpyrrolidine-1-carboxylate to obtain a protected intermediate.   
     
     
         11 . The process of  claim 10 , further comprising:
 reducing, cyclizing, and deprotecting the protected intermediate to obtain (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(4-fluorophenyl)piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole).   
     
     
         12 . The process of  claim 11 , further comprising:
 reacting (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(4-fluorophenyl)piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole) with (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid.   
     
     
         13 . (1S,4S)-1,4-bis(4-chloro-2-fluoro-5-nitrophenyl)butane-1,4-diyl dimethanesulfonate. 
     
     
         14 . 3,5-difluoro-4-(4-(4-fluorophenyl)piperidin-1-yl)aniline. 
     
     
         15 . 1-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-(4-fluorophenyl)piperidine. 
     
     
         16 . A process of making an HCV inhibitor, comprising reacting (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(4-fluorophenyl)piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole) with an intermediate acid which is selected from:
 (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid, 
 (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid, 
 (S)-2-cyclohexyl-2-(methoxycarbonylamino)acetic acid, 
 (S)-2-cyclopentyl-2-(methoxycarbonylamino)acetic acid, 
 (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid, 
 (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid, 
 (2S,3S)-3-methoxy-2-(methoxycarbonylamino)butanoic acid, 
 (S)-2-(methoxycarbonylamino)-2-((R)-tetrahydrofuran-3-yl)acetic acid, 
 (S)-2-(methoxycarbonylamino)-2-((S)-tetrahydrofuran-3-yl)acetic acid, 
 (S)-2-(2,3-dihydro-1H-inden-2-yl)-2-(methoxycarbonylamino)acetic acid, 
 2-(tert-butoxycarbonylamino)acetic acid, 
 2-(methoxycarbonylamino)-3-methylbut-2-enoic acid, 
 (S)-tetrahydrofuran-2-carboxylic acid, 
 (S)-3-ethyl-2-(methoxycarbonylamino)pentanoic acid, or 
 (S)-2-(ethoxycarbonylamino)-3-methylbutanoic acid. 
 
     
     
         17 . The process of  claim 16 , wherein said intermediate acid is (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid.