Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase
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. A compound having the formula:
or a pharmaceutically acceptable salt thereof,
wherein:
B is:
L is CH or N;
E is N or CR 5 ;
W is O or S;
R 1 is C 2-4 alkenyl, C 2-4 alkynyl, or C 1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms; R 3 is hydroxy or C 1-4 alkoxy; and R 2 is selected from the group consisting of
halogen,
C 1-4 alkyl, optionally substituted with 1 to 3 fluorine atoms,
C 1-10 alkoxy, optionally substituted with C 1-3 alkoxy or 1 to 3 fluorine atoms,
C 2-6 alkenyloxy,
C 1-4 alkylthio,
C 1-8 alkylcarbonyloxy,
aryloxycarbonyl,
azido,
amino,
C 1-4 alkylamino, and
di(C 1-4 alkyl)amino;
R 4 and R 6 are each independently 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;
R 12 and R 13 are each independently hydrogen or methyl.
2. A compound having the formula:
or a pharmaceutically acceptable salt thereof,
wherein:
B is:
L is CH or N;
E is N or CR 5 ;
W is O or S;
R 1 is C 2-4 alkenyl, C 2-4 alkynyl, or C 1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms; R 3 is hydroxy or C 1-4 alkoxy; and R 2 is selected from the group consisting of
halogen,
C 1-4 alkyl, optionally substituted with 1 to 3 fluorine atoms,
C 1-10 alkoxy, optionally substituted with C 1-3 alkoxy or 1 to 3 fluorine atoms,
C 2-6 alkenyloxy,
C 1-4 alkylthio,
C 1-8 alkylcarbonyloxy,
aryloxycarbonyl,
azido,
amino,
C 1-4 alkylamino, and
di(C 1-4 alkyl)amino;
R 4 and R 6 are each independently 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 12 and R 13 are each independently hydrogen or methyl.
3. A compound having the formula:
or a pharmaceutically acceptable salt or thereof,
wherein:
B is:
L is CH or N;
E is N or CR 5 ;
W is O or S;
R 1 is C 2-4 alkenyl, C 2-4 alkynyl, or C 1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms; R 3 is hydroxy or C 1-4 alkoxy; and R 2 is selected from the group consisting of
halogen,
C 1-4 alkyl, optionally substituted with 1 to 3 fluorine atoms,
C 1-10 alkoxy, optionally substituted with C 1-3 alkoxy or 1 to 3 fluorine atoms,
C 2-6 alkenyloxy,
C 1-4 alkylthio,
C 1-8 alkylcarbonyloxy,
aryloxycarbonyl,
azido,
amino,
C 1-4 alkylamino, and
di(C 1-4 alkyl)amino;
R 4 and R 6 are each independently 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 12 and R 13 are each independently hydrogen or methyl.
4. The compound of claim 1 , wherein B is:
5. The compound of claim 1 , wherein B is:
6. The compound of claim 2 , wherein B is:
7. The compound of claim 2 , wherein B is:
8. The compound of claim 3 , wherein B is:
9. A compound having the formula:
or a pharmaceutically acceptable salt thereof,
wherein:
B is
Y is P 3 O 9 H 4 or P 2 O 6 H 3 ;
R 1 is C 1-4 alkyl;
R 2 is fluoro;
R 3 is OH or C 1-4 alkoxy.
10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein Y is P 3 O 9 H 4 .
11. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein Y is P 2 O 6 H 3 .