Cyclopropyl polymerase inhibitors
Compounds of formula I: wherein: R 2 is hydrogen or C 1 -C 4 alkyl; R 3 and R 4 are hydrogen, —C(═O)R 5 , or —C(═O)CHR 6 —NH 2 ; or R 3 is hydrogen and R 4 is a monophosphate-, diphosphate-, or triphosphate ester; or R 3 is hydrogen, —C(═O)CHR 5 , or —C(═O)CHR 6 —NH 2 and R 4 is each R 5 is hydrogen, C 1 -C 6 alkyl, or C 3 -C 7 cycloalkyl; R 6 is hydrogen or C 1 -C 6 alkyl; R 7 is optionally substituted phenyl; naphthyl; or indolyl; R 8 and R 8′ are hydrogen, C 1 -C 6 alkyl, benzyl; or R 8 and R 8′ combined form C 3 -C 7 cycloalkyl; R 9 is C 1 -C 6 alkyl, benzyl, or optionally substituted phenyl; provided that R 2 , R 3 and R 4 are not all hydrogen; or a pharmaceutically acceptable salt or solvate thereof; pharmaceutical formulations with the compounds I; the use of compounds I, including the compounds of formula I wherein R 2 , R 3 and R 4 are all hydrogen, as HCV inhibitors.
1. A compound of formula I:
including any possible stereoisomers thereof, wherein:
R 2 is hydrogen or C 1 -C 4 alkyl;
R 3 and R 4 are independently selected from the group consisting of hydrogen, —C(═O)R 5 , and —C(═O)CHR 6 —NH 2 ; or
R 3 is hydrogen and R 4 is a monophosphate-, diphosphate-, or triphosphate ester; or R 3 is hydrogen, —C(═O)CHR 5 , or —C(═O)CHR 6 —NH 2 and R 4 is a group of formula
each R 5 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 3 -C 7 cycloalkyl;
R 6 is hydrogen or C 1 -C 6 alkyl;
R 7 is phenyl, optionally substituted with 1, 2 or 3 substituents each independently selected from halo, C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 1 -C 6 alkoxy, hydroxy, and amino, or R 7 is naphthyl; or R 7 is indolyl;
R 8 is hydrogen, C 1 -C 6 alkyl, benzyl;
R 8 is hydrogen, C 1 -C 6 alkyl, benzyl; or
R 8 and R 8′ together with the carbon atom to which they are attached form C 3 -C 7 cycloalkyl;
R 9 is C 1 -C 6 alkyl, benzyl, or phenyl, wherein said phenyl may be optionally substituted with 1, 2 or 3 substituents each independently selected from hydroxy, C 1 -C 6 alkoxy, amino, mono- and diC 1 -C 6 alkylamino;
provided that R 2 , R 3 and R 4 are not all hydrogen;
or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 , wherein R 2 is hydrogen.
3. The compound according to claim 1 , wherein R 3 and R 4 are hydrogen.
4. The compound according to claim 1 wherein R 3 is hydrogen and R 4 is a group of formula
5. The compound according to claim 1 wherein R 7 is phenyl, optionally substituted with halo, or C 1 -C 6 alkyl, or R 7 is naphthyl.
6. The compound according to claim 1 wherein R 8 is hydrogen, and R 8′ is hydrogen or C 1 -C 6 alkyl.
7. The compound according to claim 1 wherein one of R 3 and R 4 is —C(═O)R 5 and the other of R 3 and R 4 is hydrogen; or wherein both R 3 and R 4 are —C(═O)R 5 ; and wherein R 5 is C 1 -C 6 alkyl.
8. The compound of claim 7 wherein R 5 is isopropyl.
9. The compound according to claim 1 wherein R 9 is C 1 -C 6 alkyl or benzyl.
10. The compound of claim 1 , wherein the compound has the formula:
11. The compound of claim 10 , wherein the compound is in free form.
12. A pharmaceutical composition comprising an anti-virally effective amount of a compound of formula I as defined in claim 1 and a pharmaceutically acceptable carrier.
13. The method of inhibiting HCV in a subject in need of such inhibition comprising administering to said subject an effective amount of a compound of formula I,
including any possible stereoisomers thereof, wherein:
R 2 is hydrogen or C 1 -C 4 alkyl;
R 3 and R 4 are independently selected from the group consisting of hydrogen, —C(═O)R 5 , and —C(═O)CHR 6 —NH 2 ; or
R 3 is hydrogen and R 4 is a monophosphate-, diphosphate-, or triphosphate ester; or R 3 is hydrogen, —C(═O)CHR 5 , or —C(═O)CHR 6 —NH 2 and R 4 is a group of formula
each R 5 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 3 -C 7 cycloalkyl;
R 6 is hydrogen or C 1 -C 6 alkyl;
R 7 is phenyl, optionally substituted with 1, 2 or 3 substituents each independently selected from halo, C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 1 -C 6 alkoxy, hydroxy, and amino, or R 7 is naphthyl; or R 7 is indolyl;
R 8 is hydrogen, C 1 -C 6 alkyl, benzyl;
R 8′ is hydrogen, C 1 -C 6 alkyl, benzyl; or
R 8 and R 8′ to ether with the carbon atom to which the are attached form C 3 -C 7 cycloalkyl;
R 9 is C 1 -C 6 alkyl, benzyl, or phenyl, wherein said phenyl may be optionally substituted with 1, 2 or 3 substituents each independently selected from hydroxy, C 1 -C 6 alkoxy, amino, mono- and diC 1 -C 6 alkylamino;
provided that R 2 , R 3 and R 4 are not all hydrogen;
or a pharmaceutically acceptable salt thereof.
14. The method of claim 13 wherein the compound of formula 1 has R 2 , R 3 and R 4 all hydrogen.
15. The method of claim 14 in which the compound is in free form.
16. A pharmaceutical composition as defined in claim 12 in combination with another HCV inhibitor.