Ribonucleoside cyclic acetal derivatives for the treatment of RNA-dependent RNA viral infection
View Patent ↗The present invention provides ribonucleoside 2′,3′-cyclic acetals of structural formula I which are precursors or prodrugs of inhibitors of RNA-dependent RNA viral polymerase. These compounds are precursors of inhibitors of RNA-dependent RNA viral replication and are useful for the treatment of RNA-dependent RNA viral infection. They are particularly useful as precursors or prodrugs of inhibitors of hepatitis C virus (HCV) NS5B polymerase, as precursors or prodrugs of inhibitors of HCV replication, and/or for the treatment of hepatitis C infection. The invention also describes pharmaceutical compositions containing such ribonucleoside 2′,3′-cyclic acetals 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 ribonucleoside 2′,3′-cyclic acetals of the present invention.
1. A compound of structural formula I having the indicated stereochemical configuration:
or a pharmaceutically acceptable salt thereof;
wherein B is
Y is N or CR 10 ;
R 1 is selected from the group consisting of hydrogen, fluoro, amino, hydroxy, and methoxy;
R 2 is selected from the group consisting of
C 1-12 alkyl,
C 3-8 cycloalkyl,
aryl, and
heteroaryl;
wherein alkyl and cycloalkyl are unsustituted or substituted with one to three substituents independently selected from halogen, hydroxy, carboxy, and C 1-4 alkoxy; and aryl and heteroaryl are unsubstituted or substituted with one to five substituents independently selected from R 9 ;
R 3 is selected from the group consisting of hydrogen, C 1-16 alkylcarbonyl, C 2-18 alkenylcarbonyl, C 1-10 alkyloxycarbonyl, C 3-6 cycloalkylcarbonyl, C 3-6 cycloalkyloxycarbonyl, arylcarbonyl, aryloxycarbonyl, heteroarylcarbonyl, heteroaryloxycarbonyl, an amino acyl residue of structural formula:
or a residue of structural formula:
wherein alkylcarbonyl, alkyloxycarbonyl, cycloalkylcarbonyl, and cycloalkyloxycarbonyl are unsubstituted or substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, carboxy, C 1-4 alkoxy, amino, C 1-4 alkylamino, and di(C 1-4 alkyl)amino and wherein arylcarbonyl, aryloxycarbonyl, heteroarylcarbonyl, and heteroaryloxycarbonyl are unsubstituted or substituted with one to five substituents independently selected from R 9 ;
Ar is phenyl unsubstituted or substituted with one to three substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, cyano, nitro, amino, carboxy, trifluoromethyl, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkylcarbonyl, C 1-4 alkylcarbonyloxy, and C 1-4 alkyloxycarbonyl;
R 4 is hydrogen, halogen, methyl, azido, cyano, or amino;
R 5 , R 6 , and R 7 are each independently hydroxy, halogen, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 3-6 cycloalkylamino, or di(C 3-6 cycloalkyl)amino;
R 8 is hydrogen, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylamino, CF 3 , or halogen;
each R 9 is independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylsulfonyl, cyano, nitro, amino, phenyl, carboxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkylcarbonyl, C 1-4 alkylcarbonyloxy, and C 1-4 alkyloxycarbonyl;
R 10 is hydrogen, fluorine, cyano, C 1-3 alkyl, NHCONH 2 , C(═O)NR 15 R 15 , C(═S)NR 15 R 15 , C(═O)OR 15 , C(═NH)NH 2 , hydroxy, C 1-3 alkoxy, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 2-4 alkenyl, or C 2-4 alkynyl;
R 11 is hydrogen, C 1-5 alkyl, or phenyl C 0-2 alkyl;
R 12 is hydrogen, C 1-4 alkyl, C 1-4 acyl, benzoyl, C 1-4 alkyloxycarbonyl, phenyl C 0-2 alkyloxycarbonyl, C 1-4 alkylaminocarbonyl, phenyl C 0-2 alkylaminocarbonyl, C 1-4 alkylsulfonyl, or phenyl C 0-2 alkylsulfonyl;
R 13 is hydrogen, C 1-5 alkyl, phenyl or benzyl;
wherein alkyl is unsubstituted or substituted with one substituent selected from the group consisting of hydroxy, methoxy, amino, carboxy, carbamoyl, guanidino, mercapto, methylthio, 1H-imidazolyl, and 1H-indol-3-yl; and wherein phenyl and benzyl are unsubstituted or substituted with one to two substituents independently selected from the group consisting of halogen, hydroxy, and methoxy;
R 14 is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, or benzyl;
wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, carboxy, C 1-4 alkoxy; and wherein phenyl and benzyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, cyano, C 1-4 alkoxy, and trifluoromethyl; and
each R 15 is independently hydrogen or C 1-6 alkyl.
2. The compound of claim 1 wherein B is:
3. The compound of claim 2 wherein Y is N.
4. The compound of claim 3 wherein R 4 and R 6 are hydrogen and R 5 is amino.
5. The compound of claim 2 wherein Y is CR 10 .
6. The compound of claim 5 wherein R 4 and R 6 are hydrogen and R 5 is amino.
7. The compound of claim 1 wherein B is a pyrimidine base of the structural formula:
8. The compound of claim 7 wherein R 8 is hydrogen and R 7 is amino.
9. The compound of claim 1 wherein R 2 is phenyl unsubstituted or substituted with one to three substituents independently selected from R 9 .
10. The compound of claim 1 wherein R 2 is C 1-6 alkyl unsustituted or substituted with one to three substituents independently selected from fluoro, hydroxy, carboxy, and C 1-4 alkoxy.
11. The compound of claim 1 wherein R 3 is hydrogen, C 1-6 alkylcarbonyl, C 3-6 cycloalkylcarbonyl, phenylcarbonyl, or heteroarylcarbonyl wherein phenylcarbonyl and heteroarylcarbonyl are unsubstituted or substituted with one to three substituents independently selected from R 9 and wherein alkylcarbonyl and cycloalkylcarbonyl are unsubstituted or substituted with one to three substituents independently selected from fluorine, hydroxy, carboxy, C 1-4 alkoxy, amino, C 1-4 alkylamino, and di(C 1-4 alkyl)amino.
12. A compound which is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
14. A method for treating hepatitis C virus infection in a mammal, which comprises administering to the mammal a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
15. A method for treating hepatitis C virus infection in a mammal, which comprises administering to the mammal a pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.