Nucleoside phosphoramidate prodrugs

1. A compound of formula IA:

or a stereoisomer thereof, wherein:

R 1 is naphthyl;

R 2 is H or C 1-10 alkyl, or R 2 together with R 3a or R 3b are (CH 2 ) n so as to form a cyclic ring that includes the adjoining N and C atoms, where n is 2 to 4;

R 3a and R 3b are (i) independently selected from H, C 1-10 alkyl, cycloalkyl, —(CH 2 ) c (NR 3′ ) 2 , C 1-6 hydroxyalkyl, —CH 2 SH, —(CH 2 ) 2 S(O) d Me, —(CH 2 ) 3 NHC(═NH)NH 2 , (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, —(CH 2 ) e COR 3″ , aryl and aryl C 1-3 alkyl, said aryl groups optionally substituted with a group selected from hydroxyl, C 1-10 alkyl, C 1-6 alkoxy, halogen, nitro and cyano; (ii) R 3a and R 3b both are C 1-6 alkyl; (iii) R 3a and R 3b together are (CH 2 ) f so as to form a spiro ring; (iv) R 3a is hydrogen and R 3b and R 2 together are (CH 2 ) n so as to form a cyclic ring that includes the adjoining N and C atoms; (v) R 3b is hydrogen and R 3a and R 2 together are (CH 2 ) n so as to form a cyclic ring that includes the adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, f is 2 to 5, n is 2 to 4, and where R 3′ is independently hydrogen or C 1-6 alkyl and R 3″ is —OR′ or —N(R 3′ ) 2 ; (vi) R 3a is H and R 3b is H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 Ph, CH 2 -indol-3-yl, —CH 2 CH 2 SCH 3 , CH 2 CO 2 H, CH 2 C(O)NH 2 , CH 2 CH 2 COOH, CH 2 CH 2 C(O)NH 2 , CH 2 CH 2 CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 NHC(NH)NH 2 , CH 2 -imidazol-4-yl, CH 2 OH, CH(OH)CH 3 , CH 2 ((4′-OH)-Ph), CH 2 SH, or lower cycloalkyl; or (viii) R 3a is CH 3 , —CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 Ph, CH 2 -indol-3-yl, —CH 2 CH 2 SCH 3 , CH 2 CO 2 H, CH 2 C(O)NH 2 , CH 2 CH 2 COOH, CH 2 CH 2 C(O)NH 2 , CH 2 CH 2 CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 NHC(NH)NH 2 , CH 2 -imidazol-4-yl, CH 2 OH, CH(OH)CH 3 , CH 2 ((4′-OH)-Ph), CH 2 SH, or lower cycloalkyl and R 3b is H, where R 3′ is independently H or alkyl and R 3″ is —OR′ or —N(R 3′ ) 2 ;

R 4 is H or C 1-10 alkyl optionally substituted with a lower alkyl, alkoxy, di(lower alkyl)amino, or halogen, C 1-10 haloalkyl, C 3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, optionally substituted aryl or optionally substituted heteroaryl;

R 5 is CH 2 CN, CH 2 NH 2 , CH 2 NHCH 3 or CH 2 N(CH 3 ) 2 ;

R 6 is H, CH 3 , CH 2 F, CHF 2 , CF 3 , F or CN;

X is H, OH, OCH 3 , halogen, NH 2 , or N 3 ;

Y is OH, H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, vinyl, N 3 , CN, Cl, Br, F, I, NO 2 , OC(O)O(C 1-4 alkyl), OC(O)O(C 1-4 alkyl), OC(O)O(C 2-4 alkynyl), OC(O)O(C 2-4 alkenyl), OC 1-10 haloalkyl, O(aminoacyl), O(C 1-10 acyl), O(C 1-4 alkyl), O(C 2-4 alkenyl), S(C 1-4 acyl), S(C 1-4 alkyl), S(C 2-4 alkynyl), S(C 2-4 alkenyl), SO(C 1-4 acyl), SO(C 1-4 alkyl), SO(C 2-4 alkynyl), SO(C 2-4 alkenyl), SO 2 (C 1-4 acyl), SO 2 (C 1-4 alkyl), SO 2 (C 2-4 alkynyl), SO 2 (C 2-4 alkenyl), OS(O) 2 (C 1-4 acyl), OS(O) 2 (C 1-4 alkyl), OS(O) 2 (C 2-4 alkenyl), NH 2 , NH(C 1-4 alkyl), NH(C 2-4 alkenyl), NH(C 2-4 alkynyl), NH(C 1-4 acyl), N(C 1-4 alkyl) 2 , N(C 1-18 acyl) 2 , wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N 3 , CN, one to three halogen, NO 2 , C(O)O(C 1-4 alkyl), C(O)O(C 1-4 alkyl), C(O)O(C 2-4 alkynyl), C(O)O(C 2-4 alkenyl), O(C 1-4 acyl), O(C 1-4 alkyl), O(C 2-4 alkenyl), S(C 1-4 acyl), S(C 1-4 alkyl), S(C 2-4 alkynyl), S(C 2-4 alkenyl), SO(C 1-4 acyl), SO(C 1-4 alkyl), SO(C 2-4 alkynyl), SO(C 2-4 alkenyl), SO 2 (C 1-4 acyl), SO 2 (C 1-4 alkyl), SO 2 (C 2-4 alkynyl), SO 2 (C 2-4 alkenyl), OS(O) 2 (C 1-4 acyl), OS(O) 2 (C 1-4 alkyl), OS(O) 2 (C 2-4 alkenyl), NH 2 , NH(C 1-4 alkyl), NH(C 2-4 alkenyl), NH(C 2-4 alkynyl), NH(C 1-4 acyl), N(C 1-4 alkyl) 2 or N(C 1-4 acyl) 2 ; and

R 7 , R 8 and R 9 are independently H, F, Cl, Br, I, OH, OR′, SH, SR′, NH 2 , NHR′, NR′ 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, CO 2 H, CO 2 R′, CONH 2 , CONHR′, CONR′ 2 , CH═CHCO 2 H, or CH═CHCO 2 R′,

wherein R′ is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted C 2-6 alkynyl, an optionally substituted C 2-6 alkenyl, or an optionally substituted acyl, or in the instance of NR′ 2 , each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms.

2. The compound of claim 1 represented by formula 1B:

or a stereoisomer thereof.

3. The compound of claim 2 , wherein R 2 is H or C 1-10 alkyl.

4. The compound of claim 2 , wherein one of R 3a and R 3b is H and the other is C 1-10 alkyl.

5. The compound of claim 2 , wherein R 4 is C 1-10 alkyl.

6. The compound of claim 2 , wherein R 6 is methyl.

7. The compound of claim 2 , wherein each of R 7 and R 8 is H.

8. The compound of claim 2 , wherein X is halogen.

9. The compound of claim 2 , wherein Y is OH.

10. The compound of claim 2 , wherein the compound is represented by formula IC:

or a stereoisomer thereof.

11. The compound of claim 10 , wherein R 2 is H.

12. The compound of claim 10 represented by formula ID:

or a stereoisomer thereof.

13. The compound of claim 12 , wherein R 4 is i Pr, n Pr, n Bu, 2-butyl, t Bu or benzyl.

14. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.

15. A method of treating HCV comprising administering a therapeutically effective amount of a compound according to claim 1 to a human in need thereof.

16. The method of claim 15 further comprising administering to the human a therapeutically effective amount of a second antiviral agent.

17. The method of claim 16 wherein the second antiviral agent is an NS5A inhibitor.

18. The method of claim 16 wherein the second antiviral agent is an NS3 protease inhibitor.

19. The method of claim 15 further comprising administering to the human subject therapeutically effective amounts of an NS5A inhibitor and an NS3 protease inhibitor.