C-purine nucleoside analogs as inhibitors of RNA-dependent RNA viral polymerase
View Patent ↗The present invention provides C-purine nucleoside analogs and certain derivatives thereof which are inhibitors of RNA-dependent RNA viral polymerase. These compounds are inhibitors 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 C-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 C-nucleoside compounds of the present invention.
1. A compound of the structural formula I:
or a pharmaceutically acceptable salt thereof; wherein
X is O, S, or NR 8 ;
Y is CR 11 or N;
R 1 is selected from the group consisting of hydrogen, fluoro, azido, amino, hydroxy, C 1-3 alkoxy, mercapto, and C 1-3 alkylthio;
R 2 and R 3 are each independently selected from the group consisting of hydrogen, methyl, C 1-16 alkylcarbonyl, C 2-18 alkenylcarbonyl, C 1-10 alkyloxycarbonyl, C 3-6 cycloalkylcarbonyl, C 3-6 cycloalkyloxycarbonyl, CH 2 O(C═O)C 1-4 alkyl, CH(C 1-4 alkyl)O(C═O)C 1-4 alkyl, or an amino acyl residue of structural formula
R 4 is hydrogen, azido, methyl, hydroxymethyl, or fluoromethyl;
R 5 is hydrogen, C 1-10 alkylcarbonyl, phosphoryl or a cyclic prodrug ester thereof, diphosphoryl, triphosphoryl, C 2-18 alkenylcarbonyl, C 1-10 alkyloxycarbonyl, C 3-6 cycloalkylcarbonyl, C 3-6 cycloalkyloxycarbonyl, CH 2 O(C═O)C 1-4 alkyl, CH(C 1-4 alkyl)O(C═O)C 1-4 alkyl, or an amino acyl residue of structural formula
R 6 and R 7 are each independently hydrogen, hydroxy, halogen, C 1-4 alkoxy, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 3-6 cycloalkylamino, di(C 3-6 cycloalkyl)amino, benzylamino, dibenzylamino, or C 4-6 heterocycloalkyl, wherein alkyl, cycloalkyl, benzyl, and heterocycloalkyl are unsubstituted or substituted with one to five groups independently selected from halogen, hydroxy, amino, C 1-4 alkyl, and C 1-4 alkoxy;
R 8 is hydrogen or C 1-4 alkyl;
R 9 is hydrogen, C 1-5 alkyl, or phenyl C 0-2 alkyl;
R 10 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; and
R 11 is hydrogen, methyl, halogen, azido, or amino;
and provided that when Y is CH and X is NH and R 1 =R 2 =R 3 =R 4 =R 5 =hydrogen, then R 6 is not OH.
2. The compound of claim 1 wherein Y is CH, and X is O, S, or NR 8 .
3. The compound of claim 2 wherein X is O.
4. The compound of claim 2 wherein X is NR 8 .
5. The compound of claim 4 wherein R 8 is hydrogen.
6. The compound of claim 1 wherein Y is N, and X is O, S, or NR 8 .
7. The compound of claim 6 wherein X is O.
8. The compound of claim 6 wherein X is NR 8 .
9. The compound of claim 8 wherein R 8 is hydrogen.
10. The compound of claim 1 wherein R 1 and R 4 are both hydrogen.
11. The compound of claim 10 wherein R 2 , R 3 , and R 5 are hydrogen.
12. The compound of claim 11 wherein R 6 and R 7 are each independently hydrogen, amino, fluoro, or hydroxy.
13. The compound of claim 1 wherein Y is N; X is NR 8 ; R 1 , R 2 , R 3 , R 4 , and R 5 are hydrogen; and R 6 and R 7 are each independently hydrogen, amino, fluoro, or hydroxy.
14. The compound of claim 13 wherein R 8 is hydrogen.
15. The compound of claim 1 wherein Y is CH; X is NR 8 ; R 1 , R 2 , R 3 , R 4 , and R 5 are hydrogen; and R 6 and R 7 are each independently hydrogen, amino, fluoro, or hydroxy.
16. The compound of claim 15 wherein R 8 is hydrogen, and R 6 is hydrogen, amino, or fluoro.
17. The compound of claim 1 wherein Y is N; X is O; R 1 , R 2 , R 3 , R 4 , and R 5 are hydrogen; and R 6 and R 7 are each independently hydrogen, amino, fluoro, or hydroxy.
18. The compound of claim 17 wherein R 8 is hydrogen.
19. The compound of claim 1 wherein Y is CH; X is O; R 1 , R 2 , R 3 , R 4 , and R 5 are hydrogen; and R 6 and R 7 are each independently hydrogen, amino, fluoro, or hydroxy.
20. The compound of claim 19 wherein R 8 is hydrogen.
21. The compound of claim 1 which is selected from the group consisting of:
4-amino-7-(2-C-methyl-β-D-ribofuranosyl)-furo[3,2-d]pyrimidine;
2-amino-7-(2-C-methyl-β-D-ribofuranosyl)-furo[3,2-d]pyrimidin-4(3H)-one;
4-amino-7-(2-C-methyl-β-D-ribofuranosyl)-thieno[3,2-d]pyrimidine;
2-amino-7-(2-C-methyl-β-D-ribofuranosyl)-thieno[3,2-d]pyrimidin-4(3H)-one;
4-amino-7-(2-C-methyl-β-D-ribofuranosyl)-5H-pyrrolo[3,2-d]pyrimidine;
7-amino-3-(2-C-methyl-β-D-ribofuranosyl)-isoxazolo[4,5-d]pyrimidine;
5-amino-3-(2-C-methyl-β-D-ribofuranosyl)-isoxazolo[4,5-d]pyrimidin-7(6H)-one;
7-amino-3-(2-C-methyl-β-D-ribofuranosyl)-1H-pyrazolo[4,3-d]pyrimidine; and
5-amino-3-(2-C-methyl-β-D-ribofuranosyl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one;
or a pharmaceutically acceptable salt thereof.
22. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
23. 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 according to claim 1 .