NUCLEOSIDE DERIVATIVES AS INHIBITORS OF RNA-DEPENDENT RNA VIRAL POLYERMASE
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.
89 - 101 . (canceled)
102 . 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.
103 . The method of claim 102 , wherein the one or more reactants comprises a reactive phosphorous moiety.
104 . The method of claim 103 , wherein the reactive phosphorous moiety comprises a phosphorus oxychloride derivative.
105 . The method of claim 102 , wherein R 1 is CH 3 .
106 . The method of claim 105 , wherein R 3 is —OH.
107 . The method of claim 106 , wherein R 5 is H.
108 . The method of claim 107 , wherein R 6 is —OH.
109 . The method of claim 108 , wherein Y is —P(O)R 9 R 10 .
110 . The method of claim 109 , wherein R 9 and R 10 are each —OH.
111 . The method of claim 102 , 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.