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 - 21 . (canceled)  
   
   
       22 - 31 . (canceled)  
   
   
       32 . A method of treating hepatitis C virus (HCV) infection comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of structural formula III, or a pharmaceutically acceptable salt or acyl derivative thereof,  
     
       
         
         
             
             
         
       
       D is N;  
       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 ;  
       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 7  is hydrogen, amino, C 1-4  alkylamino, C 3-6  cycloalkylamino, or di(C 1-4  alkyl)amino;  
       R 8  is H, halogen, CN, carboxy, C 1-4  alkyloxycarbonyl, N 3 , amino, C 1-4  alkylamino, di(C 1-4  alkyl)amino, hydroxy, C 1-6  alkoxy, C 1-6  alkylthio, C 1-6  alkylsulfonyl, or (C 1-4  alkyl) 0-2  aminomethyl; and  
       R 9  and R 10  are each independently hydroxy, OCH 2 CH 2 SC(═O)t-butyl, or OCH 2 O(C═O)iPr.  
     
   
   
       33 . The method of  claim 32  wherein a compound of structural formula III, or a pharmaceutically acceptable salt or acyl derivative thereof, is in combination with a therapeutic amount of another agent active against HCV infection selected from the group consisting of ribavirin; levovirin; thymosin alpha-1; an inhibitor of NS3 serine protease; an inhibitor of inosine monophosphate dehydrogenase; interferon-α; and pegylated interferon-α.