3′,5′-cyclic phosphoramidate prodrugs for HCV infection

1. A compound of Formula I:

or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein:

X is alkoxyl, hydrogen, or hydroxyl;

Y is hydroxyl, acetoxyl, or fluoro;

Z is substituted alkyl; LC(O)O(L) p C(R) 3 , -LOC(O)(L) p C(R) 3 , -LC(O)O(L) p Cy, -L-S—S-(L p C(R) 3 , -LSC(O)(L) p C(R) 3 , L-S—S-(L) p C(R) 3 , or -LSC(O)(L) p C(R) 3 ;

each L is independently unsubstituted alkylene or substituted alkylene;

Cy is unsubstituted cycloalkyl; and

p is 0 or 1; and

R is hydrogen, alkyl, substituted alkyl, unsubstituted cycloalkyl, unsubstituted aryl, substituted aryl, or heteroaryl.

2. The compound of claim 1 wherein:

Z is -LC(O)O(L) p CR 3 , -LOC(O)(L) p CR 3 , or -LC(O)O(L) p Cy;

each L is independently alkylene or substituted alkylene;

Cy is unsubstituted cycloalkyl; and

p is 0 or 1.

3. The compound of claim 2 , wherein each L is independently C 1 -C 10 alkylene or C 1 -C 10 substituted alkylene.

4. The compound of claim 2 , wherein Cy is C 3 -C 10 unsubstituted cycloalkyl.

5. The compound of claim 1 wherein X is unsubstituted C 1 -C 10 alkoxyl.

6. The compound of claim 1 wherein X is hydroxyl.

7. The compound of claim 1 wherein Y is fluoro.

8. The compound of claim 1 wherein Y is acetoxyl.

9. The compound claim 1 wherein Y is hydroxyl.

10. The compound of claim 1 according to any of formulas II, III, or IV:

or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof.

11. The compound of claim 1 according to formula Ia or Ib:

or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof.

12. The compound of claim 1 wherein:

Z is -L-S—S-(L) p CR 3 ,or -LSC(O)(L) p CR 3 ;

each L is independently alkylene or substituted alkylene;

p is 0 or 1.

13. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient, carrier, or diluent.

14. A method for the treatment of a host infected with a hepatitis C virus, comprising the administration of an effective treatment amount of a compound of claim 1 .

15. The method of claim 14 , wherein the compound is administered in combination or alternation with a second anti-viral agent, wherein the second anti-viral agent is an interferon, a nucleotide analogue, a polymerase inhibitor, an NS3 protease inhibitor, an NS5A inhibitor, an entry inhibitor, a non-nucleoside polymerase inhibitor, a cyclosporine immune inhibitor, an NS4A antagonist, an NS4B-RNA binding inhibitor, a locked nucleic acid mRNA inhibitor, a cyclophilin inhibitor, or a combination thereof

16. The compound of claim 1 , wherein:

X is hydrogen, hydroxyl, or —OR′ wherein R′ is C 1 to C 10 unsubstituted alkyl;

Y is hydroxyl, acetoxyl, or fluoro;

Z is C 1 to C 10 alkyl substituted with:

fluoro, chloro, bromo, iodo, hydroxyl, —NH 2 , methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, phosphonate;

—NH 2 substituted with one or two C 1 to C 10 unsubstituted alkyl; or

—NH 2 substituted with one or two unsubstituted phenyl, unsubstituted biphenyl, or unsubstituted naphthyl; and

R is hydrogen, unsubstituted C 1 to C 10 alkyl, unsubstituted C 3 to C 15 cycloalkyl, unsubstituted phenyl, unsubstituted biphenyl, unsubstituted naphthyl, heteroaryl having from five to twenty ring atoms, or C 1 to C 10 alkyl substituted with:

fluoro, chloro, bromo, iodo, hydroxyl, —NH 2 , methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, phosphonate;

—NH 2 substituted with one or two unsubstituted C 1 to C 10 alkyl; or

—NH 2 substituted with one or two unsubstituted phenyl, unsubstituted biphenyl, or unsubstituted naphthyl.

17. The compound of claim 10 , wherein:

Y is hydroxyl, acetoxyl, or fluoro;

Z is C 1 to C 10 alkyl substituted with:

fluoro, chloro, bromo, iodo, hydroxyl, —NH 2 , methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, phosphonate;

—NH 2 substituted with one or two unsubstituted C 1 to C 10 alkyl; or

—NH 2 substituted with one or two unsubstituted phenyl, unsubstituted biphenyl, or unsubstituted naphthyl; and

R is hydrogen, unsubstituted C 1 to C 10 alkyl, unsubstituted C 3 to C 15 cycloalkyl, unsubstituted phenyl, unsubstituted biphenyl, unsubstituted naphthyl, heteroaryl having from five to twenty ring atoms, or C 1 to C 10 alkyl substituted with:

fluoro, chloro, bromo, iodo, hydroxyl, —NH 2 , methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, phosphonate;

—NH 2 substituted with one or two unsubstituted C 1 to C 10 alkyl; or

—NH 2 substituted with one or two unsubstituted phenyl, unsubstituted biphenyl, or unsubstituted naphthyl.

18. The compound of claim 11 , wherein:

X is hydrogen, hydroxyl, or —OR′ wherein R′ is unsubstituted C 1 to C 10 alkyl;

Y is hydroxyl, acetoxyl, or fluoro;

Z is C 1 to C 10 alkyl substituted with:

fluoro, chloro, bromo, iodo, hydroxyl, —NH 2 , methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, phosphonate;

—NH 2 substituted with one or two unsubstituted C 1 to C 10 alkyl; or

—NH 2 substituted with one or two unsubstituted phenyl, unsubstituted biphenyl, or unsubstituted naphthyl; and

R is hydrogen, unsubstituted C 1 to alkyl, unsubstituted C 3 to C 15 cycloalkyl, unsubstituted phenyl, unsubstituted biphenyl, unsubstituted naphthyl, heteroaryl having from five to twenty ring atoms, or C 1 to C 10 alkyl substituted with:

fluoro, chloro, bromo, iodo, hydroxyl, —NH 2 , methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, phosphonate;

—NH 2 substituted with one or two unsubstituted C 1 to C 10 alkyl; or

—NH 2 substituted with one or two unsubstituted phenyl, unsubstituted biphenyl, or unsubstituted naphthyl.

19. The compound of claim 10 , wherein:

R is H, and Z and Y are selected from one of the following combinations:

Z=(S)-iPrOC(O)CH(CH 3 )— and Y=F;

Z=(S)-iPrC(O)OCH 2 CH(CH 3 )— and Y=F;

Z=(S)-iBuOC(O)CH(CH 3 )— and Y=F;

Z=(S)-iPrOC(O)CH(CH 3 )— and Y=OH;

Z=EtOC(O)C(CH 3 ) 2 — and Y=F;

Z=(S)-iPrC(O)OCH 2 CH(Et)— and Y=F;

Z=EtC(O)O(CH 2 ) 2 — and Y=F;

Z=(S)-cPnOC(O)CH(CH 3 )— and Y=F;

Z=iPrOCO(CH 2 ) 2 — and Y=F; and

Z=tBuC(O)S(CH 2 ) 2 — and Y=F.

20. The compound of claim 19 , according to the formula:

wherein R is H, and Z and Y are selected from one of the following combinations:

Z=(S)-iPrOC(O)CH(CH 3 )— and Y=F;

Z=(S)-iPrC(O)OCH 2 CH(CH 3 )— and Y=F;

Z=(S)-iBuOC(O)CH(CH 3 )— and Y=F;

Z=(S)-iPrOC(O)CH(CH 3 )— and Y=OH;

Z=EtOC(O)C(CH 3 ) 2 — and Y=F;

Z=(S)-iPrC(O)OCH 2 CH(Et)— and Y=F;

Z=EtC(O)O(CH 2 ) 2 — and Y=F;

Z=(S)-cPnOC(O)CH(CH 3 )— and Y=F;

Z=iPrOCO(CH 2 ) 2 — and Y=F; and

Z=tBuC(O)S(CH 2 ) 2 — and Y=F;

or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof.

21. The compound according to claim 2 selected from

or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof.

22. The compound according to claim 12 selected from

or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof.

23. The compound of claim 1 according to formula (VII):

or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof.

24. The compound of claim 1 according to formula (VIII):

or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof.

25. A compound according to Formula V

or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof, wherein

X is unsubstituted alkoxyl, hydrogen, or hydroxyl;

Ring A is a 3-10 membered carbocyclic or heterocyclic ring;

R is hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted cycloalkyl, unsubstituted aryl, substituted aryl, or heteroaryl; and

Z is unsubstituted alkyl, substituted alkyl, unsubstituted arylalkyl, heteroarylalkyl, or unsubstituted cycloalkyl.

26. The compound of claim 25 where ring A is oxacyclopropyl or oxacyclobutyl.

27. A compound of Formula VI is provided:

or pharmaceutically acceptable salts, solvates, tautomeric forms or polymorphic forms thereof, wherein

X is unsubstituted alkoxyl, hydrogen, or hydroxyl;

Y is hydroxyl, acetoxyl, or fluoro;

Z is substituted alkyl; LC(O)O(L) p C(R) 3 , -LOC(O)(L) p C(R) 3 , -LC(O)O(L) p Cy, -L-S—S-(L) p C(R) 3 , -LSC(O)(L) p C(R) 3 , L-S—S-(L) p C(R) 3 , or -LSC(O)(L) p C(R) 3 ;

each L is independently unsubstituted alkylene or substituted alkylene;

Cy is unsubstituted cycloalkyl;

p is 0 or 1;

R is hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted cycloalkyl, unsubstituted aryl, substituted aryl, or heteroaryl;

W is independently hydrogen, fluoro, or methyl; and

each of R B and R C is independently hydrogen, halo, unsubstituted C 1 -C 10 alkyl, substituted C 1 -C 10 alkyl, unsubstituted C 5 -C 10 aryl, substituted C 5 -C 10 aryl, or C 5 -C 10 heteroaryl; or R B and R C are each independently selected from hydrogen, unsubstituted C 1-6 alkyl, substituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, substituted C 2-6 alkenyl, unsubstituted C 2-6 alkynyl, substituted C 2-6 alkynyl, and C 1-6 haloalkyl, where optionally at least one of R B and R C is not hydrogen; or R B and R C are taken together to form a group selected from unsubstituted C 3-6 cycloalkyl, C 3-6 cycloalkenyl, unsubstituted C 6 aryl, and C 3-6 heteroaryl.

28. The compound of claim 27 where R B and R C are methyl; or R B is hydrogen and R C is methyl.