1′,4′-thio nucleosides for the treatment of HCV

1. A compound according to Formula 3001:

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

Base is

or tautomeric form thereof, wherein: R 4 is hydrogen, hydroxyl, alkoxyl, or amino; R 5 is hydrogen, hydroxyl, amino, or alkoxyl; R 6 is hydrogen, halogen, or alkyl; and R 7 is hydrogen, amino, or hydroxyl;

W is S or O;

each of X and Y is independently hydrogen, —OR 1 , —SR 1 , —NR 1 R 2 , or an N-linked or O-linked amino acid residue, or derivative thereof;

each N-linked amino acid residue or derivative thereof is —NR X -G(S C )—C(O)-Q 1 ;

each O-linked amino acid residue or derivative thereof is independently —OC(O)G(S C )-Q or —O—C(O)-G(S C )—NH-Q 2 ;

each G is independently unsubstituted C 1 -C 2 alkylene;

each S C is independently a side chain of a naturally occurring amino acid or S C is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted arylalkyl, unsubstituted heterocycloalkyl, -(unsubstituted alkyl)-C(O)OH, unsubstituted heteroarylalkyl, -(unsubstituted alkyl)-NH 2 , -(unsubstituted alkyl)-NH-(unsubstituted alkyl), -(unsubstituted alkyl)-N-(unsubstituted alkyl) 2 , hydroxylalkyl, -alkyl-NH—C(NH)—NH 2 , -(unsubstituted alkyl)-SH, -(unsubstituted alkyl)-C(O)—NH 2 , -(unsubstituted alkyl)-C(O)—NH-(unsubstituted alkyl), -(unsubstituted alkyl)-C(O)—N-(unsubstituted alkyl) 2 , -(unsubstituted alkyl)-S-(unsubstituted alkyl) and -(unsubstituted alkyl)-(unsubstituted aryl)-OH;

each Q is independently —SR, —NRR or alkoxyl, each R is independently hydrogen or alkyl;

each Q 1 is independently —SR Y , —NR Y R Y or alkoxyl; R Y is hydrogen or alkyl;

each R X is hydrogen;

each Q 2 is independently hydrogen or alkoxyl;

Z is hydrogen, hydroxyl, or halo; or, in the alternative, Y and Z, together with the atoms to which they are attached, combine to form a six-membered heterocyclic ring wherein Y and Z together represent a single divalent —O—;

R A is hydrogen, methyl, or halo;

R B is hydrogen, hydroxyl, or halo;

each R 1 is independently unsubstituted alkyl, substituted alkyl, unsubstituted aryl, substituted aryl, unsubstituted arylalkyl, substituted arylalkyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted -alkyl-S—C(O)-alkyl, or substituted -alkyl-S—C(O)-alkyl; and

each R 2 is independently hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted arylalkyl, or substituted arylalkyl; and

wherein each substituted alkyl is independently alkyl substituted with a moiety(ies) selected from the group consisting of halogen; oxo; epoxy; hydroxyl; unsubstituted cycloalkyl; unsubstituted aralkyl; sulfanyl; —NR 1′ R 2′ wherein R 1′ and R 2′ are independently hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocyclic, unsubstituted aryl, or unsubstituted heteroaryl; —O-(unsubstituted alkyl); —O-(unsubstituted cycloalkyl); unsubstituted aryloxy; nitro; cyano; sulfonic acid; sulfate; phosphonic acid; and phosphate;

wherein each substituted aryl, either alone or as part of another group, is independently aryl substituted with one or more moieties selected from the group consisting of halogen; unsubstituted alkyl; haloalkyl; hydroxyl; —NR 1′ R 2′ wherein R 1′ and R 2′ are independently hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocyclic, unsubstituted aryl, or unsubstituted heteroaryl; —O-(unsubstituted alkyl); —O-(unsubstituted cycloalkyl); unsubstituted aryloxy; nitro; cyano; sulfonic acid; sulfate; phosphonic acid; and phosphate;

wherein each substituted cycloalkyl is independently cycloalkyl substituted with a moiety(ies) selected from the group consisting of halogen; oxo; epoxy; hydroxyl; sulfanyl; —NR 1′ R 2′ wherein R 1′ and R 2′ are independently hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocyclic, unsubstituted aryl, or unsubstituted heteroaryl; —O-(unsubstituted alkyl); —O-(unsubstituted cycloalkyl); unsubstituted aryloxy; nitro; cyano; sulfonic acid; sulfate; phosphonic acid; and phosphate; and

wherein each substituted heterocycloalkyl is independently heterocycloalkyl substituted with a moiety(ies) selected from the group consisting of halogen; oxo; epoxy; hydroxyl; alkoxycarbonyl; alkoxycarbonylalkyl; —NR 1′ R 2′ wherein R 1′ and R 2′ are independently hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocyclic, unsubstituted aryl, or unsubstituted heteroaryl; —O-(unsubstituted alkyl); —O-(unsubstituted cycloalkyl); unsubstituted aryloxy; nitro; cyano; sulfonic acid; sulfate; phosphonic acid; and phosphate.

2. The compound of claim 1 , wherein:

X is —NH-G(S C )—C(O)-Q 1 ; and

S C is a side chain of a naturally occurring amino acid.

3. The compound of claim 1 , wherein:

X is —OR 1 ; and

R 1 is unsubstituted -alkyl-S—C(O)-alkyl.

4. The compound of claim 1 , wherein:

Y is hydrogen, —OR 1 , —SR 1 , —NR 1 R 2 , or an N-linked or O-linked amino acid residue, or derivative thereof; and

Z is hydrogen, hydroxyl, or halo.

5. The compound of claim 1 , wherein W is O.

6. The compound of claim 1 according to any of Formulas II-IV, or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof:

7. The compound of claim 1 , wherein Base is:

or a tautomeric form thereof, wherein:

R 4 is hydrogen, hydroxyl, unsubstituted alkoxyl, —NH 2 , —NH(unsubstituted alkyl), or —N(unsubstituted alkyl) 2 ;

R 5 is hydrogen, hydroxyl, —NH 2 , —NH(unsubstituted alkyl), —N(unsubstituted alkyl) 2 or unsubstituted alkoxyl;

R 6 is hydrogen, halogen, unsubstituted alkyl, or substituted alkyl; and

R 7 is hydrogen, hydroxyl, —NH 2 , —NH(unsubstituted alkyl), or —N(unsubstituted alkyl) 2 .

8. The compound of claim 7 wherein Base is:

wherein

Y is hydrogen, —OR 1 , —SR 1 , —NR 1 R 2 , or an N-linked or O-linked amino acid residue, or derivative thereof; and R 1 is unsubstituted alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted -alkyl-S—C(O)— alkyl;

X is —NH-G(S C )—C(O)-Q 1 ;

S C is a side chain of a naturally occurring amino acid;

G is methylene, and

Q 1 is unsubstituted alkoxyl.

9. The compound of claim 1 , wherein Base is uracil.

10. The compound of claim 1 , wherein R A is hydrogen or methyl.

11. The compound of claim 1 , wherein Z is hydroxyl.

12. The compound of claim 1 , wherein R B is hydroxyl.

13. The compound of claim 1 according to any of Formulas 1-4, or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof:

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

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

16. A method for the treatment of a human host infected with a hepatitis C virus, comprising administering to the host an effective amount of a compound of claim 1 .

17. The method of claim 16 comprising administering a second anti-viral agent in combination or alternation with the compound, 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.

18. The method of claim 17 , wherein the second anti-viral agent is samatasvir, simeprevir, sofosbuvir, telaprevir, boceprevir, interferon alfacon-1, interferon alfa-2b, pegylated interferon alpha 2a, pegylated interferon alpha 2b, or a combination thereof.

19. The method of claim 17 , wherein the second anti-viral agent is samatasvir, simeprevir, sofosbuvir, telaprevir, boceprevir, interferon alfacon-1, interferon alfa-2b, pegylated interferon alpha 2a, pegylated interferon alpha 2b, or a combination thereof, and further wherein the administration is not in combination or alternation with ribavirin.

20. A pharmaceutical composition comprising the compound of claim 8 and a pharmaceutically acceptable excipient, carrier, or diluent.

21. The pharmaceutical composition of claim 20 , wherein the composition is an oral formulation.

22. A method for the treatment of a human host infected with a hepatitis C virus, comprising administering to the host an effective amount of a compound of claim 8 .

23. The method of claim 22 comprising administering a second anti-viral agent in combination or alternation with the compound, 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.

24. A compound according to Formula (3001)

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

wherein:

Base is

or a tautomeric form thereof;

R 4 is hydrogen, hydroxyl, unsubstituted alkoxyl, —NH 2 , —NH(unsubstituted alkyl), or —N(unsubstituted alkyl) 2 ;

R 5 is hydrogen, hydroxyl, —NH 2 , —NH(unsubstituted alkyl), —N(unsubstituted alkyl) 2 or unsubstituted alkoxyl;

R 6 is hydrogen, halogen, unsubstituted alkyl;

R 7 is hydrogen, hydroxyl, —NH 2 , —NH(unsubstituted alkyl), or —N(unsubstituted alkyl) 2 ;

W is S or O;

each of X and Y is independently hydrogen, —OR 1 , —SR 1 , —NR 1 R 2 , or an N-linked or O-linked amino acid residue, or derivative thereof;

each N-linked amino acid residue or derivative thereof is —NR X -G(S C )—C(O)-Q 1 ;

each O-linked amino acid residue or derivative thereof is independently —OC(O)G(S C )-Q or —O—C(O)-G(S C )—NH-Q 2 ;

each G is independently unsubstituted C 1 -C 2 alkylene;

each S C is independently a side chain of a naturally occurring amino acid or S C is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted arylalkyl, unsubstituted heterocycloalkyl, -(unsubstituted alkyl)-C(O)OH, unsubstituted heteroarylalkyl, -(unsubstituted alkyl)-NH 2 , -(unsubstituted alkyl)-NH-(unsubstituted alkyl), -(unsubstituted alkyl)-N-(unsubstituted alkyl) 2 , hydroxylalkyl, -alkyl-NH—C(NH)—NH 2 , -(unsubstituted alkyl)-SH, -(unsubstituted alkyl)-C(O)—NH 2 , -(unsubstituted alkyl)-C(O)—NH-(unsubstituted alkyl), -(unsubstituted alkyl)-C(O)—N-(unsubstituted alkyl) 2 , -(unsubstituted alkyl)-S-(unsubstituted alkyl) and -(unsubstituted alkyl)-(unsubstituted aryl)-OH;

each Q is independently —SR, —NRR or alkoxyl, each R is independently hydrogen or alkyl;

each Q 1 is independently —SR Y , —NR Y R Y or alkoxyl; each R Y is independently hydrogen or alkyl;

each R X is hydrogen;

each Q 2 is independently hydrogen or alkoxyl;

Z is hydrogen, hydroxyl, or halo; or, in the alternative, Y and Z, together with the atoms to which they are attached, combine to form a six-membered heterocyclic ring wherein Y and Z together represent a single divalent —O—, and X is —OR 1 , —SR 1 , —NR 1 R 2 , or an N-linked or O-linked amino acid residue, or derivative thereof;

R A is hydrogen, methyl, or halo;

R B is hydrogen, hydroxyl, or halo;

each R 1 is independently unsubstituted alkyl, substituted alkyl, unsubstituted aryl, substituted aryl, unsubstituted arylalkyl, substituted arylalkyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted -alkyl-S—C(O)-alkyl, or substituted -alkyl-S—C(O)-alkyl;

each R 2 is independently hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted arylalkyl, or substituted arylalkyl;

each alkyl is independently a saturated straight or branched hydrocarbon having one to ten carbon atoms; and when substituted is substituted with a moiety(ies) selected from the group consisting of halogen; oxo; epoxy; hydroxyl; unsubstituted cycloalkyl; unsubstituted aralkyl; sulfanyl; —NR 1′ R 2′ wherein R 1′ and R 2′ are independently hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocyclic, unsubstituted aryl, or unsubstituted heteroaryl; —O-(unsubstituted alkyl); —O-(unsubstituted cycloalkyl); unsubstituted aryloxy; nitro; cyano; sulfonic acid; sulfate; phosphonic acid; and phosphate;

each alkenyl is independently an unsubstituted monovalent olefinically unsaturated, straight-chained or branched hydrocarbon group having 2 to 11 carbon atoms and having at least 1 site of olefinic unsaturation;

each alkynyl is independently an unsubstituted acetylenically unsaturated, straight-chained or branched hydrocarbon group having 2 to 11 carbon atoms and having at least 1 alkynyl unsaturation;

each aryl, either alone or as part of another group, is independently a C6-C12 aromatic ring; and when substituted is substituted with one or more moieties selected from the group consisting of halogen; unsubstituted alkyl; haloalkyl; hydroxyl; —NR 1′ R 2′ wherein R 1′ and R 2′ are independently hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocyclic, unsubstituted aryl, or unsubstituted heteroaryl; —O-(unsubstituted alkyl); —O-(unsubstituted cycloalkyl); unsubstituted aryloxy; nitro; cyano; sulfonic acid; sulfate; phosphonic acid; and phosphate;

each arylalkyl is independently an unsubstituted alkyl group with an unsubstituted or substituted aryl substituent;

each cycloalkyl is independently a saturated cyclic C 3-15 hydrocarbon which can be a bridged, non-bridged, and fused bicyclic group; and when substituted is substituted with a moiety(ies) selected from the group consisting of halogen; oxo; epoxy; hydroxyl; sulfanyl; NR 1′ R 2′ wherein R 1′ and R 2′ are independently hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocyclic, unsubstituted aryl, or unsubstituted heteroaryl; —O-(unsubstituted alkyl); —O-(unsubstituted cycloalkyl); unsubstituted aryloxy; nitro; cyano; sulfonic acid; sulfate; phosphonic acid; and phosphate;

each heterocyclic or heterocyclo is independently a monovalent monocyclic non-aromatic ring system having 3 to 20 ring atoms or a bicyclic, tricyclic, or tetracyclic ring system that contains at least one non-aromatic ring and which can be fused or bridged having 3 to 20 ring atoms; wherein one or more of the non-aromatic ring atoms is a heteroatom independently selected from O, S, and N and the remaining ring atoms are carbon atoms and in which the nitrogen or sulfur atoms are optionally oxidized and the nitrogen atoms are optionally quaternized; where the heterocyclic and heterocyclo are attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound; and when substituted is substituted with a moiety(ies) selected from the group consisting of halogen; oxo; epoxy; hydroxyl; alkoxycarbonyl; alkoxycarbonylalkyl; —NR 1′ R 2′ wherein R 1′ and R 2′ are independently hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocyclic, unsubstituted aryl, or unsubstituted heteroaryl; —O-(unsubstituted alkyl); —O-(unsubstituted cycloalkyl); unsubstituted aryloxy; nitro; cyano; sulfonic acid; sulfate; phosphonic acid; and phosphate;

each heterocycloalkyl is independently an unsubstituted alkyl group with an unsubstituted or substituted heterocyclo substituent;

each heteroaryl, either alone or as part of another group, is independently a monovalent monocyclic aromatic group or a multicyclic aromatic group that contains at least one aromatic ring; wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S and N in the ring provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom; wherein the heteroaryl is bonded to the rest of the molecule through the aromatic ring; and wherein the ring has 5 to 20 ring atoms; and

each heteroarylalkyl is independently an alkyl group with an heteroaryl substituent.