Nucleoside prodrugs and uses thereof

Abstract

Compounds having the formula I or II, wherein R 1 , R 2 , B, and V are as defined herein, are Hepatitis C virus NS5b polymerase inhibitors. Also disclosed are compositions and methods for treating an HCV infection and inhibiting HCV replication.

We claim: 
     
         1 . A compound of general formula I or II 
       
         
           
           
               
               
           
         
         wherein V is phenyl or pyridinyl said phenyl or pyridinyl optionally substituted with one to three substituents selected from the group consisting of halogen, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, or cyano; 
         B is 
       
       
         
           
           
               
               
           
         
         R 1  and R 2  are independently selected from H and/or COR 4 ; 
         Y is O or NH; 
         R 3  is C 1 -C 6  alkyl or COR 4 ; and 
         R 4  is C 1-6  alkyl, C 1-3  alkoxy-C 1-6  alkyl, C 3-6  cycloalkyl, C 3-6  cycloalkyl-C 1-3  alkyl, C 1-6  alkoxy or heteroaryl wherein the heteroaryl is a five-membered ring containing one or two heteroatoms selected from nitrogen, oxygen or sulfur or pyridine or a six-membered ring with one or two nitrogen atoms; or 
       
       a pharmaceutically acceptable salt thereof. 
     
     
         2 . A compound according to formula I of  claim 1 , wherein B is B-1. 
     
     
         3 . A compound according to  claim 2 , wherein V is optionally substituted phenyl, R 1  and R 2  are independently hydrogen or COR 4 , and R 4  is C 1-6  alkyl. 
     
     
         4 . A compound according to formula II of  claim 1 . 
     
     
         5 . A compound according to formula II of  claim 3 , wherein V is optionally substituted phenyl and B is B-1. 
     
     
         6 . A compound according to  claim 1 , wherein B is B-2. 
     
     
         7 . A compound according to  claim 6 , wherein V is optionally substituted phenyl. 
     
     
         8 . A compound according to  claim 1 , wherein B is B-3. 
     
     
         9 . A compound according to  claim 8 , wherein V is optionally substituted phenyl. 
     
     
         10 . A compound according to  claim 1  selected from the group consisting of:
 4′-azido-cis-5′-O-[4-(R,S)-(3-fluorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 4′-azido-cis-5′-O-[4-(R,S)-(3-bromophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 4′-azido-cis-5′-O-[4-(R,S)-(3-bromo-4-fluorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 4′-azido-cis-5′-O-[4-(R,S)-(3-chloro-4-fluorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 4′-azido-cis-5′-O-[4-(R,S)-phenyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 4′-azido-cis-5′-O-[4-(R,S)-(4-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 4′-azido-cis-5′-O-[4-(R,S)-(4-bromophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 4′-azido-cis-5′-O-[4-(R,S)-(2-bromophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 4′-azido-cis-5′-O-[4-(R,S)-(2-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 4′-azido-cis-5′-O-[4-(R,S)-(3-bromo-5-fluorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 4′-azido-cis-5′-O-[4-(R,S)-(2,4-dichlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 4′-azido-cis-5′-O-[4-(R,S)-(2-chloro-6-fluorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 4′-azido-cis-5′-O-[4-(R,S)-(2,5-dichlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 4′-azido-cis-5′-O-[4-(R,S)-(2,4-difluorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 4′-azido-cis-5′-O-[4-(R,S)-(3-bromo-6-fluorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 4′-azido-cis-5′-O-[4-(R,S)-(2-chloro-4-fluorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 4′-azido-cis-5′-O-[4-(R,S)-(2,3-difluorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 4′-azido-cis-5′-O-{4-(R,S)-[3,5-di-(trifluoromethyl)phenyl]-2-oxo-1,3,2-dioxaphosphorinan-2-yl}uridine; 
 4′-azido-cis-5′-O-[4-(R,S)-(3-trifluoromethylphenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 4′-azido-cis-5′-O-[4-(R,S)-(2-trifluoromethylphenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 4′-azido-cis-5′-O-[4-(R,S)-(3-cyanophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 4′-azido-cis-5′-O-[4-(R,S)-(4-trifluoromethylphenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 4′-azido-cis-5′-O-[4-(R,S)-(3,5-dichlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 4′-azido-cis-5′-O-[4-(S)-(3,5-difluorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 4′-azido-cis-5′-O-[4-(S)-(pyrid-4-yl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine, hydrochloride salt; 
 4′-azido-cis-5′-O-[4-(R,S)-(3,4-dichlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 4′-azido-cis-5′-O-[4-(R,S)-(pyrid-3-yl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine, hydrochloride salt 
 4′-azido-cis-5′-O-[4-(R,S)-(3-bromopyrid-5-yl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine, hydrochloride salt 
 4′-azido-cis-5′-O-[4-(R,S)-(2-fluorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 4′-azido-cis-5′-O-[4-(R,S)-(2,6-difluorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 4′-azido-cis-5′-O-[4-(R,S)-(2,6-dichlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 4′-azido-cis-5′-O-[4-(R,S)-(2-fluoro-4-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine 
 4′-azido-cis-5′-O-[4-(R,S)-(2-fluoro-4-bromophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 2′,3′-O-(3-methylbutanoyl)-4′-azido-cis-5′-O-[4-(R,S)-(3-cyanophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine 
 4′-azido-cis-5′-O-[4-(S)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine 2′,3′-O-bis-propionate; 
 4′-azido-cis-5′-O-[4-(S)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]-2′,3′-O-bis-pivaloyl-uridine; 
 4′-azido-cis-5′-O-[4-(S)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]-2′,3′-O-bis-pentanoyl-uridine; 
 2′,3′-O-(3-methylbutanoyl)-4′-azido-cis-5′-O-[4-(S)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 2′,3′-O-bis-isobutanoyl-4′-azido-cis-5′-O-[4-(S)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 2′,3′-O-bis-n-butanoyl-4′-azido-cis-5′-O-[4-(S)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 4′-azido-cis-5′-O-[4-(S)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]-2′,3′-O-bis-(cyclopropylcarbonyl)uridine; 
 4′-azido-cis-5′-O-[4-(S)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]-2′,3′-O-bis-(2-cyclopropylacetyl)-uridine; 
 2′,3′-O-bis-(oxazole-4-carbonyl)-4′-azido-cis-5′-o-[4-(S)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 2′,3′-O-bis-(furan-3-carbonyl)-4′-azido-cis-5′-o-[4-(S)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine; 
 4′-azido-cis-5′-O-[4-(S)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]-2′,3′-O-bis-(2-ethoxyacetyl)-uridine; 
 4′-azido-cis-5′-O-[4-(S)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]-2′,3′-O-bis-(2-methoxy-acetyl)-uridine; 
 4′-azido-cis-5′-O-[4-(S)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine 2′,3′-O-bis-(ethoxycarbonate); 
 4′-azido-cis-5′-O-[4-(S)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine 2′,3′-O-bis-(isopropoxycarbonate); 
 4′-Azido-cis-5′-O-[4-(S)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]-2′,3′-O-bis-(pyrrole-2-carboxyl)uridine; 
 4′-Azido-cis-5′-O-[4-(S)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]-2′,3′-O-bis-(pyrazol-5-carboxyl)-uridine; 
 4′-Azido-cis-5′-O-[4-(S)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]-2′,3′-O-bis-(pyridine-3-carboxyl)-uridine; 
 4′-Azido-cis-5′-O-[4-(S)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]-2′,3′-O-bis-(2-ethoxyacetyl)-uridine; 
 4′-Azido-cis-5′-O-[4-(S)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]-2′,3′-O-bis-(2-methoxy-acetyl)-uridine; 
 4′-Azido-cis-5′-O-[4-(S)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine 2′,3′-O-bis-(ethoxycarbonate); 
 4′-Azido-cis-5′-O-[4-(S)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine 2′,3′-O-bis-(isopropoxycarbonate); and 
 
       stereoisomers thereof. 
     
     
         11 . A compound according to  claim 1  which compound is:
 4′-Azido-cis-5′-O-[4-(S)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine 2′,3′-O-bis-propionate, 
 4′-azido-cis-5′-O-[4-(S)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine 2′,3′-O-bis-valeroate, or 
 4′-azido-cis-5′-O-[4-(S)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]uridine 2′,3′-O-bis-isovaleroate. 
 
     
     
         12 . A method for treating a disease caused by the Hepatitis C Virus (HCV) virus comprising administering to a patient in need thereof, a therapeutically effective quantity of a compound according to  claim 1 . 
     
     
         13 . The method of  claim 7  further co-comprising administering at least one immune system modulator and/or at least one antiviral agent that inhibits replication of HCV. 
     
     
         14 . The method of  claim 8 , wherein the immune system modulator is an interferon, interleukin, tumor necrosis factor or colony stimulating factor. 
     
     
         15 . The method of  claim 9 , wherein the immune system modulator is an interferon or chemically derivatized interferon. 
     
     
         16 . The method of  claim 8 , wherein the antiviral compound is selected from the group consisting of a HCV protease inhibitor, another HCV polymerase inhibitor, a HCV helicase inhibitor, a HCV primase inhibitor and a HCV fusion inhibitor. 
     
     
         17 . A method of inhibiting replication in HCV comprising administering a therapeutically effective quantity of a compound according to  claim 1 . 
     
     
         18 . A pharmaceutical composition comprising a therapeutically effective quantity of a compound according to  claim 1  admixed with at least one pharmaceutically acceptable carrier, diluent or excipient.