Nucleoside derivatives as inhibitors of rna-dependent rna viral polymerase

Abstract

The present invention provides nucleoside compounds and certain derivatives thereof which are inhibitors of RNA-dependent RNA viral polymerase. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful for the treatment of RNA-dependent RNA viral infection. They are particularly useful as inhibitors of hepatitis C virus (HCV) NS5B polymerase, as inhibitors of HCV replication, and/or for the treatment of hepatitis C infection. The invention also describes pharmaceutical compositions containing such nucleoside compounds alone or in combination with other agents active against RNA-dependent RNA viral infection, in particular HCV infection. Also disclosed are methods of inhibiting RNA-dependent RNA polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection with the nucleoside compounds of the present invention.

1 - 88 . (canceled) 
     
     
         89 . A method of preparing a compound, the method comprising reacting: 
       
         
           
           
               
               
           
         
       
       with one or more reactants; wherein:
 B is: 
 
       
         
           
           
               
               
           
         
         W is O or S; 
         R 1  is CF 3  or C 1-4  alkyl and one of R 2  and R 3  is —OH, C 1-4  alkoxy, or a hydroxyl protecting group, and the other of R 2  and R 3  is fluoro; 
         R 6  is H, OH, SH, NH 2 , C 1-4  alkylamino, di(C 1-4  alkyl)amino, C 3-6  cycloalkylamino, halogen, C 1-4  alkyl, C 1-4  alkoxy, or —CF 3 ; 
         R 5  is H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-4  alkylamino, CF 3 , or halogen; and 
         R 9  and R 10  are each independently —OH, OCH 2 CH 2 SC(═O)t-butyl, OCH 2 O(C═O)iPr. 
       
     
     
         90 . The method of  claim 89 , wherein the one or more reactants comprises a reactive phosphorous moiety. 
     
     
         91 . The method of  claim 90 , wherein the reactive phosphorous moiety comprises a phosphorus oxychloride derivative. 
     
     
         92 . The method of  claim 91 , wherein R 1  is CH 3 . 
     
     
         93 . The method of  claim 92 , wherein R 3  is —OH. 
     
     
         94 . The method of  claim 93 , wherein R 5  is H. 
     
     
         95 . The method of  claim 94 , wherein R 6  is —OH. 
     
     
         96 . The method of  claim 95 , wherein Y is P(O)R 9 R 10 . 
     
     
         97 . The method of  claim 96 , wherein R 9  and R 10  are each —OH. 
     
     
         98 . The method of  claim 89 , wherein the compound is a compound of formula (III): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof 
       wherein Y is H, C 1-10  alkylcarbonyl, P 3 O 9 H 4 , P 2 O 6 H 3 , or P(O)R 9 R 10 ; and 
       wherein R 9  and R 10  are each independently —OH, OCH 2 CH 2 SC(═O)t-butyl, or OCH 2 O(C═O)iPr. 
     
     
         99 . A compound prepared by a process comprising reacting: 
       
         
           
           
               
               
           
         
       
       with one or more reactants; wherein
 B is: 
 
       
         
           
           
               
               
           
         
         W is O or S; 
         R 1  is —CF 3  or C 1-4  alkyl and one of R 2  and R 3  is —OH or C 1-4  alkoxy, and the other of R 2  and R 3  is fluoro; 
         R 6  is H, —OH, —SH, —NH 2 , C 1-4  alkylamino, di(C 1-4  alkyl)amino, C 3-6  cycloalkylamino, halogen, C 1-4  alkyl, C 1-4  alkoxy, or —CF 3 ; 
         R 5  is H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-4  alkylamino, CF 3 , or halogen; and 
         R 9  and R 10  are each independently —OH, OCH 2 CH 2 SC(═O)t-butyl, OCH 2 O(C═O)iPr. 
       
     
     
         100 . The compound of  claim 99 , wherein the one or more reactants comprises a reactive phosphorous moiety. 
     
     
         101 . The method of  claim 100 , wherein the reactive phosphorous moiety comprises a phosphorus oxychloride derivative.