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

1. A compound of Formula (VIII):

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

each Base is independently

each X is independently alkoxyl, hydrogen, or hydroxyl;

each Y is independently hydroxyl, acetoxyl, or fluoro;

each Z is independently -LC(O)O(L) p C(R) 3 , -L-Ar—C(O)O(L) p C(R) 3 , —C(R)(E)(L) p OC(O)O(L) p C(R) 3 , -LSC(O)LOH, -LSC(O)LOC(O)(L) p C(R) 3 , -LSC(O)LOC(O)(L) p N(R) 2 , -LS-S(L) p C(R) 3 , -LS-SLOH, -LN(R)C(O)O(L) p C(R) 3 , -LSC(O)LN(R)C(O)O(L) p C(R) 3 , —Ar—B, -L-B, -LN(R)C(O)D, -LN(R)C(O)CH(OH)(C(R) 2 ) 2 OH, -(L) p C(R)(R A )C(O)O(L) p C(R) 3 , or -LSC(O)LC(O)O(L) p C(R) 3 ;

each B is independently an alkyl group substituted with aminocarboxylene, carboxylene, or both;

each D is independently

each E is independently alkyl, aryl, or heteroaryl;

each Ar is independently an arylene or heteroarylene;

each L is independently alkylene;

each R is independently hydrogen, alkyl, aryl, or heteroaryl; each R A is independently a carbocyclic or heterocyclic ring; and

each p is independently 0 or 1.

2. The compound of claim 1 , wherein each Z is independently —(C 1-10 )alkylene-SC(O)(C 1-10 )alkyleneC(O)O [(C 1-10 )alkylene] p C(R) 3 , —(C 1-10 )alkylene-SC(O)(C 1-10 )alkyleneN(R)C(O)O [(C 1-10 )alkylene] p C(R) 3 , —(C(R) 2 ) m C(O)O(C(R) 2 ) n C(R) 3 , —(C(R) 2 ) m ArC(O)O(C(R) 2 ) n C(R) 3 , —C(R)(E)(C(R) 2 ) n OC(O)O(C(R) 2 ) n C(R) 3 , —(C(R) 2 ) m SC(O)(C(R) 2 ) m OH, —(C(R) 2 ) m SC(O)(C(R) 2 ) m OC(O)(C(R) 2 )—C(R) 3 , —(C(R) 2 ) m S—S(C(R) 2 ) n C(R) 3 , —(C(R) 2 ) m S—S(C(R) 2 ) m OH, —(C(R) 2 ) m N(R)C(O)O(C(R) 2 )—C(R) 3 ,

—(C(R) 2 ) n B, —(C(R) 2 ) m N(R)C(O)D, —(C(R) 2 ) m N(R)C(O)CH(OH)(C(R) 2 ) 2 OH, or —(C(R) 2 ) n C(R)(R A )C(O)O(C(R) 2 ) n C(R) 3 ; wherein each m is 1-10, each n is 0-10, and each p is 0 or 1.

3. The compound of claim 1 , wherein:

each B is independently C(R) 3 (C(R) 2 ) n OC(O)C(R)(B—)N(R)C(O)O(C(R) 2 ) n C(R) 3 ;

where B— denotes the attachment position to Ar or L; and

each n is independently an integer selected over the range of 0 to 10.

4. The compound of claim 1 , wherein each E is independently C 1 -C 10 alkyl, C 5 -C 10 aryl, or C 5 -C 10 heteroaryl.

5. The compound of claim 1 , wherein each Ar is independently C 5 -C 10 arylene or C 5 -C 10 heteroarylene.

6. The compound of claim 1 , wherein each R is independently hydrogen, C 1 -C 10 alkyl, C 5 -C 10 aryl, or C 5 -C 10 heteroaryl.

7. The compound of claim 1 , wherein each R A is independently a 3-20 membered carbocyclic or heterocyclic ring.

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

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

10. The compound of claim 1 wherein Y is hydroxyl.

11. The compound of claim 1 according to Formula (IX):

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

12. The compound of claim 11 , wherein each Z is independently -LSC(O)LC(O)O(L) p C(R) 3 or -LSC(O)LN(R)C(O)O(L) p C(R) 3 .

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

14. The pharmaceutical composition of claim 13 , wherein the composition is an oral formulation.

15. 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 or composition of claim 1 .

16. The method of claim 15 , wherein the host is a human.

17. The method of claim 15 , wherein the administration directs a substantial amount of the compound or pharmaceutically acceptable salt thereof, to a liver of the host.

18. The method of claim 15 , wherein the compound or composition is administered in combination or alternation with a second anti-viral agent selected from the group consisting of 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, and combinations thereof.

19. A compound of Formula (VIII):

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

each Base is independently

each X is alkoxyl of formula —OR′, wherein R′ is C 1-10 alkyl or C 3-15 cycloalkyl;

each Y is independently hydroxyl, acetoxyl, or fluoro;

each E is independently C 1-10 unsubstituted alkyl, C 1-10 substituted alkyl, aryl, or heteroaryl;

each Ar is independently C 5 -C 10 arylene or C 5 -C 10 heteroarylene;

each L is independently straight-chained or branched C 1 -C 10 unsubstituted alkylene or C 1 -C 10 substituted alkylene;

each R is independently C 1-10 unsubstituted alkyl, C 1-10 substituted alkyl, aryl, or heteroaryl;

each Z is independently -LC(O)O(L) p C(R) 3 , -L-Ar—C(O)O(L) p C(R) 3 , —C(R)(E)(L) p OC(O)O(L) p C(R) 3 , -LSC(O)LOH, -LSC(O)LOC(O)(L) p C(R) 3 , -LSC(O)LOC(O)(L) p N(R) 2 , -LS-S(L) p C(R) 3 , -LS-SLOH, -LN(R)C(O)O(L) p C(R) 3 , -LSC(O)LN(R)C(O)O(L) p C(R) 3 , —Ar—B, -L-B, -LN(R)C(O)D, -LN(R)C(O)CH(OH)(C(R) 2 ) 2 OH, or -(L) p C(R)(R A )C(O)O(L) p C(R) 3 ; wherein each p is 0 or 1;

wherein

each C 1-10 substituted alkyl is independently C 1-10 alkyl substituted by a moiety which is halogen, fluoro, chloro, bromo, iodo, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

each aryl is independently phenyl, biphenyl, and naphthyl, unsubstituted or substituted by a moiety which is halogen fluoro, chloro, bromo, iodo, alkyl, haloalkyl, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate

each heteroaryl is independently furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, thienopyridyl, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, or xanthenyl.

20. The compound of claim 19 , wherein each straight-chained or branched C 1-10 unsubstituted alkylene is independently methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, t-butylene, pentylene, isopentylene, neopentylene, hexylene, isohexylene, 3-methylpentylene, 2,2-dimethylbutylene, or 2,3-dimethylbutylene.

21. The compound of claim 19 , wherein

each X is alkoxyl of formula —OR′, wherein R′ is C 1-10 alkyl or C 3-15 cycloalkyl;

each E is independently C 1-10 unsubstituted alkyl, C 1-10 substituted alkyl, aryl, or heteroaryl;

each Ar is independently C 5 -C 10 arylene or C 5 -C 10 heteroarylene;

each L is independently C 1 -C 10 substituted alkylene;

each R is independently C 1-10 unsubstituted alkyl, C 1-10 substituted alkyl, aryl, or heteroaryl;

wherein

each C 1-10 substituted alkyl is independently C 1-10 alkyl substituted by a moiety which is halogen, fluoro, chloro, bromo, iodo, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

each C 1-10 substituted alkylene is independently C 1-10 alkylene substituted by a moiety which is halogen, fluoro, chloro, bromo, iodo, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

each aryl is independently phenyl, biphenyl, and naphthyl, unsubstituted or substituted by a moiety which is halogen fluoro, chloro, bromo, iodo, alkyl, haloalkyl, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

each heteroaryl is independently furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, thienopyridyl, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, or xanthenyl.