Modified fluorinated nucleoside analogues

• US 20050009737A1
• Filed: 04/21/2004
• Published: 01/13/2005
• Est. Priority Date: 05/30/2003
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Pharmasset Incorporated (Gilead Sciences Inc.)
• Inventors: Clark, Jeremy
• Granted Patent: US 7,429,572 B2
• Time in Patent Office: Days
• US Class Current: 514/49
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07H 19/00 Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• CPC Class Codes: C07H 19/048 Pyridine radicals
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/14 Pyrrolo-pyrimidine radicals
• CPC Class Codes: C07H 19/16 Purine radicals

Abstract

The disclosed invention provides compositions and methods of treating a Flaviviridae infection, including hepatitis C virus, West Nile Virus, yellow fever virus, and a rhinovirus infection in a host, including animals, and especially humans, using a (2′R)-2′-deoxy-2′-fluoro-2′-C-methyl nucleosides, or a pharmaceutically acceptable salt or prodrug thereof.

Claims

1. A (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) of the formula;

2. The (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) of claim 1 or its pharmaceutically acceptable salt or prodrug thereof, wherein Base is selected from the group consisting of;

3. The (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) of claim 1 or its pharmaceutically acceptable salt or prodrug thereof,

wherein Base is selected from the group consisting of (a) or (b);

and wherein R¹ is H, R² is OH, R^2′

is H, R³ is H, and R⁴ is NH₂ or OH, and R⁵ is NH₂.

4. A (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) of the formula;

5. The (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) of claim 4 or its pharmaceutically acceptable salt or prodrug thereof, wherein

Base is

and R¹ is H, R² is OH, R² is H, R³ is H, R⁴ is NH₂ or OH, and R⁶ is H.

6. A (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) or its pharmaceutically acceptable salt or prodrug thereof of the structure;

7. The (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) of claim 6 or its pharmaceutically acceptable salt or prodrug thereof,

wherein Base is selected from the group consisting of;

Y is N or CH;

R³, R⁴ and R⁵ are independently H, halogen including F, Cl, Br, I, OH, OR′

, SH, SR′

, NH₂, NHR′

, NR′

₂, lower alkyl of C₁-C₆, halogenated (F, Cl, Br, I) lower alkyl of C₁-C₆ such as CF₃ and CH₂CH₂F, lower alkenyl of C₂-C₆ such as CH═

CH₂, halogenated (F, Cl, Br, I) lower alkenyl of C₂-C₆ such as CH═

CHCl, CH═

CHBr and CH═

CHI, lower alkynyl of C₂-C₆ such as C≡

CH, halogenated (F, Cl, Br, I) lower alkynyl of C₂-C₆, lower alkoxy of C₁-C₆ such as CH₂OH and CH₂CH₂OH, halogenated (F, Cl, Br, I) lower alkoxy of C₁-C₆, CO₂H, CO₂R′

, CONH₂, CONHR′

, CONR′

₂, CH═

CHCO₂H, CH═

CHCO₂R′

; and

,

R′

is an optionally substituted alkyl of C₁-C₁₂ (particularly when the alkyl is an amino acid residue), cycloalkyl, optionally substituted alkynyl of C₂-C₆, optionally substituted lower alkenyl of C₂-C₆, or optionally substituted acyl.

8. The (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) of claim 6 or its pharmaceutically acceptable salt or prodrug thereof,

wherein Base is selected from the group consisting of (a) or (b);

and wherein R¹ and R⁷are H, R³ is H, and R⁴ is NH₂ or OH, and R⁵ is NH₂.

9. A (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) of the formula;

10. A (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) of the formula

11. A (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof of the formula;

12. A (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof of the formula;

13. A (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof of the formula;

14. A (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof of the formula;

15. A (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof of the formula;

16. A pharmaceutical composition comprising a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) of the formula;

17. The composition of claim 16, wherein Base is selected from the group consisting of:

18. The composition of claim 16, wherein

Base is selected from the group consisting of (a) or (b):

and wherein R¹ is H, R² is OH, R^2′

is H, R³ is H, and R⁴ is NH₂ or OH, and R⁵ is NH₂.

19. A pharmaceutical composition comprising a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) of the formula;

20. The composition of claim 19, wherein

Base is

and R¹ is H, R² is OH, R²′

is H, R³ is H, R⁴ is NH₂ or OH, and R⁶ is H.

21. A pharmaceutical composition comprising a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) or its pharmaceutically acceptable salt or prodrug thereof, in a pharmaceutically acceptable carrier, of the structure;

22. The composition of claim 21, wherein

Base is selected from the group consisting of:

Y is N or CH;

R³, R⁴ and R⁵ are independently H, halogen including F, Cl, Br, I, OH, OR′

, SH, SR′

, NH₂, NHR′

, NR′

₂, lower alkyl of C₁-C₆, halogenated (F, Cl, Br, I) lower alkyl of C₁-C₆ such as CF₃ and CH₂CH₂F, lower alkenyl of C₂-C₆ such as CH═

CH₂, halogenated (F, Cl, Br, I) lower alkenyl of C₂-C₆ such as CH═

CHCl, CH═

CHBr and CH═

CHI, lower alkynyl of C₂-C₆ such as C≡

CH, halogenated (F, Cl, Br, I) lower alkynyl of C₂-C₆, lower alkoxy of C₁-C₆ such as CH₂OH and CH₂CH₂OH, halogenated (F, Cl, Br, I) lower alkoxy of C₁-C₆, CO₂H, CO₂R′

, CONH₂, CONHR′

, CONR′

₂, CH═

CHCO₂H, CH═

CHCO₂R′

; and

,

R′

is an optionally substituted alkyl of C₁-C₁₂ (particularly when the alkyl is an amino acid residue), cycloalkyl, optionally substituted alkynyl of C₂-C₆, optionally substituted lower alkenyl of C₂-C₆, or optionally substituted acyl.

23. The composition of claim 21, wherein

Base is selected from the group consisting of (a) or (b):

and wherein R¹ and R⁷ are H, R³ is H, and R⁴ is NH₂ or OH, and R⁵ is NH₂.

24. A pharmaceutical composition comprising a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) of the formula;

25. A pharmaceutical composition comprising a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) of the formula;

26. A pharmaceutical composition comprising a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof, in a pharmaceutically acceptable carrier of the formula;

27. A pharmaceutical composition comprising a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L), or its pharmaceutically acceptable salt or prodrug thereof, in a pharmaceutically acceptable carrier, of the formula;

28. A pharmaceutical composition comprising a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof, in a pharmaceutically acceptable carrier, of the formula;

29. A pharmaceutical composition comprising a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof in a pharmaceutically acceptable carrier of the formula;

30. A pharmaceutical composition comprising a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof, in a pharmaceutically acceptable carrier, of the structure;

31. A method for the treatment or prophylaxis of hepatitis C infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) of the formula;

32. The method of claim 31,

wherein Base is selected from the group consisting of:

Y is N or CH.

R³, R⁴ and R⁵ are independently H, halogen including F, Cl, Br, I, OH, OR′

, SH, SR′

, NH₂, NHR′

, NR′

₂, lower alkyl of C₁-C₆, halogenated (F, Cl, Br, I) lower alkyl of C₁-C₆ such as CF₃ and CH₂CH₂F, lower alkenyl of C₂-C₆ such as CH═

CH₂, halogenated (F, Cl, Br, I) lower alkenyl of C₂-C₆ such as CH═

CHCl, CH═

CHBr and CH═

CHI, lower alkynyl of C₂-C₆ such as C≡

CH, halogenated (F, Cl, Br, I) lower alkynyl of C₂-C₆, lower alkoxy of C₁-C₆ such as CH₂OH and CH₂CH₂OH, halogenated (F, Cl, Br, I) lower alkoxy of C₁-C₆, CO₂H, CO₂R′

, CONH₂, CONHR′

, CONR′

₂, CH═

CHCO₂H, CH═

CHCO₂R′

; and

,

R′

is an optionally substituted alkyl of C₁-C₁₂ (particularly when the alkyl is an amino acid residue), cycloalkyl, optionally substituted alkynyl of C₂-C₆, optionally substituted lower alkenyl of C₂-C₆, or optionally substituted acyl.

33. The method of claim 31, wherein

Base is selected from the group consisting of (a) or (b):

and wherein R¹ is H, R² is OH, R^2′

is H, R³ is H, and R⁴ is NH₂ or OH, and R⁵ is NH₂.

34. A method for the treatment or prophylaxis of hepatitis C infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) of the formula;

35. The method of claim 34, wherein

Base is

and R¹ is H, R² is OH, R^2′

is H, R³ is H, R⁴ is NH₂ or OH, and R⁶ is H.

36. A method for the treatment or prophylaxis of hepatitis C infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) or its pharmaceutically acceptable salt or prodrug thereof of the structure;

37. The method of claim 36, wherein

Base is selected from the group consisting of:

Y is N or CH;

R³, R⁴ and R⁵ are independently H, halogen including F, Cl, Br, I, OH, OR′

, SH, SR′

, NH₂, NHR′

, NR′

₂, lower alkyl of C₁-C₆, halogenated (F, Cl, Br, I) lower alkyl of C₁-C₆ such as CF₃ and CH₂CH₂F, lower alkenyl of C₂-C₆ such as CH═

CH₂, halogenated (F, Cl, Br, I) lower alkenyl of C₂-C₆ such as CH═

CHCl, CH═

CHBr and CH═

CHI, lower alkynyl of C₂-C₆ such as C≡

CH, halogenated (F, Cl, Br, I) lower alkynyl of C₂-C₆, lower alkoxy of C₁-C₆ such as CH₂OH and CH₂CH₂OH, halogenated (F, Cl, Br, I) lower alkoxy of C₁-C₆, CO₂H, CO₂R′

, CONH₂, CONHR′

, CONR′

₂, CH═

CHCO₂H, CH═

CHCO₂R′

; and

,

R′

is an optionally substituted alkyl of C₁-C₁₂ (particularly when the alkyl is an amino acid residue), cycloalkyl, optionally substituted alkynyl of C₂-C₆, optionally substituted lower alkenyl of C₂-C₆, or optionally substituted acyl.

38. The method of claim 36, wherein

Base is selected from the group consisting of (a) or (b):

and wherein R¹ and R⁷ are H, R³ is H, and R⁴ is NH₂ or OH, and R⁵is NH₂.

39. A method for the treatment or prophylaxis of hepatitis C infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) of the formula;

40. A method for the treatment or prophylaxis of hepatitis C infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) of the formula;

41. A method for the treatment or prophylaxis of hepatitis C infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof of the formula;

42. A method for the treatment or prophylaxis of hepatitis C infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof of the formula;

43. A method for the treatment or prophylaxis of hepatitis C infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof of the formula;

44. A method for the treatment or prophylaxis of hepatitis C infection comprising administering to a host an antivirally effective amount of a (2R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof of the formula;

45. A method for the treatment or prophylaxis of hepatitis C infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof of the formula;

46. A method for the treatment or prophylaxis of a rhinovirus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (E-D or β

-L) of the formula;

47. The method of claim 46,

wherein Base is selected from the group consisting of:

Y is N or CH.

R³, R⁴ and R⁵ are independently H, halogen including F, Cl, Br, I, OH, OR′

, SH, SR′

, NH₂, NHR′

, NR′

₂, lower alkyl of C₁-C₆, halogenated (F, Cl, Br, I) lower alkyl of C₁-C₆ such as CF₃ and CH₂CH₂F, lower alkenyl of C₂-C₆ such as CH═

CH₂, halogenated (F, Cl, Br, I) lower alkenyl of C₂-C₆ such as CH═

CHCl, CH═

CHBr and CH═

CHI, lower alkynyl of C₂-C₆ such as C≡

CH, halogenated (F, Cl, Br, I) lower alkynyl of C₂-C₆, lower alkoxy of C₁-C₆ such as CH₂OH and CH₂CH₂OH, halogenated (F, Cl, Br, I) lower alkoxy of C₁-C₆, CO₂H, CO₂R′

, CONH₂, CONHR′

, CONR′

₂, CH═

CHCO₂H, CH═

CHCO₂R′

; and

,

R′

is an optionally substituted alkyl of C₁-C₁₂ (particularly when the alkyl is an amino acid residue), cycloalkyl, optionally substituted alkynyl of C₂-C₆, optionally substituted lower alkenyl of C₂-C₆, or optionally substituted acyl.

48. The method of claim 46, wherein

Base is selected from the group consisting of (a) or (b):

and wherein R¹ is H, R² is OH, R^2′

is H, R³is H, and R⁴ is NH₂ or OH, and R⁵ is NH₂.

49. A method for the treatment or prophylaxis of a rhinovirus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) of the formula;

50. The method of claim 49, wherein

Base is

and R¹ is H, R² is OH, R²′

is H, R³ is H, R⁴ is NH₂ or OH, and R⁶ is H.

51. A method for the treatment or prophylaxis of a rhinovirus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) or its pharmaceutically acceptable salt or prodrug thereof of the structure;

52. The method of claim 51, wherein

Base is selected from the group consisting of:

Y is N or CH;

R³, R⁴ and R⁵ are independently H, halogen including F, Cl, Br, I, OH, OR′

, SH, SR′

, NH₂, NHR′

, NR′

₂, lower alkyl of C₁-C₆, halogenated (F, Cl, Br, I) lower alkyl of C₁-C₆ such as CF₃ and CH₂CH₂F, lower alkenyl of C₂-C₆ such as CH═

CH₂, halogenated (F, Cl, Br, I) lower alkenyl of C₂-C₆ such as CH═

CHCl, CH═

CHBr and CH═

CHI, lower alkynyl of C₂-C₆ such as C≡

CH, halogenated (F, Cl, Br, I) lower alkynyl of C₂-C₆, lower alkoxy of C₁-C₆ such as CH₂OH and CH₂CH₂OH, halogenated (F, Cl, Br, I) lower alkoxy of C₁-C₆, CO₂H, CO₂R′

, CONH₂, CONHR′

, CONR′

₂, CH═

CHCO₂H, CH═

CHCO₂R′

; and

,

R′

is an optionally substituted alkyl of C₁-C₁₂ (particularly when the alkyl is an amino acid residue), cycloalkyl, optionally substituted alkynyl of C₂-C₆, optionally substituted lower alkenyl of C₂-C₆, or optionally substituted acyl.

53. The method of claim 51, wherein

Base is selected from the group consisting of (a) or (b):

and wherein R¹ and R⁷ are H, R³ is H, and R⁴ is NH₂ or OH, and R⁵ is NH₂.

54. A method for the treatment or prophylaxis of a rhinovirus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) of the formula;

55. A method for the treatment or prophylaxis of a rhinovirus infection comprising administering to a host an antivirally effective amount of a (2R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) of the formula;

56. A method for the treatment or prophylaxis of a rhinovirus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof of the formula;

57. A method for the treatment or prophylaxis of a rhinovirus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof of the formula;

58. A method for the treatment or prophylaxis of a rhinovirus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof of the formula;

59. A method for the treatment or prophylaxis of a rhinovirus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof of the formula;

60. A method for the treatment or prophylaxis of a rhinovirus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof of the formula;

61. A method for the treatment or prophylaxis of a yellow fever virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) of the formula;

62. The method of claim 61,

wherein Base is selected from the group consisting of:

Y is N or CH.

R³, R⁴ and R⁵ are independently H, halogen including F, Cl, Br, I, OH, OR′

, SH, SR′

, NH₂, NHR′

, NR′

₂, lower alkyl of C₁-C₆, halogenated (F, Cl, Br, I) lower alkyl of C₁-C₆ such as CF₃ and CH₂CH₂F, lower alkenyl of C₂-C₆ such as CH═

CH₂, halogenated (F, Cl, Br, I) lower alkenyl of C₂-C₆ such as CH═

CHCl, CH═

CHBr and CH═

CHI, lower alkynyl of C₂-C₆ such as C≡

CH, halogenated (F, Cl, Br, I) lower alkynyl of C₂-C₆, lower alkoxy of C₁-C₆ such as CH₂OH and CH₂CH₂OH, halogenated (F, Cl, Br, I) lower alkoxy of C₁-C₆, CO₂H, CO₂R′

, CONH₂, CONHR′

, CONR′

₂, CH═

CHCO₂H, CH═

CHCO₂R′

; and

,

R′

is an optionally substituted alkyl of C₁-C₁₂ (particularly when the alkyl is an amino acid residue), cycloalkyl, optionally substituted alkynyl of C₂-C₆, optionally substituted lower alkenyl of C₂-C₆, or optionally substituted acyl.

63. The method of claim 61, wherein

Base is selected from the group consisting of (a) or (b):

and wherein R¹ is H, R² is OH, R^2′

is H, R³ is H, and R⁴ is NH₂ or OH, and R⁵ is NH₂.

64. A method for the treatment or prophylaxis of a yellow fever virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) of the formula;

65. The method of claim 64, wherein

Base is

and R¹ is H, R² is OH, R is H, R³ is H, R⁴ is NH₂ or OH, and R⁶ is H.

66. A method for the treatment or prophylaxis of a yellow fever virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) or its pharmaceutically acceptable salt or prodrug thereof of the structure;

67. The method of claim 66, wherein

Base is selected from the group consisting of:

Y is N or CH;

R³, R⁴ and R⁵ are independently H, halogen including F, Cl, Br, I, OH, OR′

, SH, SR′

, NH₂, NHR′

, NR′

₂, lower alkyl of C₁-C₆, halogenated (F, Cl, Br, I) lower alkyl of C₁-C₆ such as CF₃ and CH₂CH₂F, lower alkenyl of C₂-C₆ such as CH═

CH₂, halogenated (F, Cl, Br, I) lower alkenyl of C₂-C₆ such as CH═

CHCl, CH═

CHBr and CH═

CHI, lower alkynyl of C₂-C₆ such as C≡

CH, halogenated (F, Cl, Br, I) lower alkynyl of C₂-C₆, lower alkoxy of C₁-C₆ such as CH₂OH and CH₂CH₂OH, halogenated (F, Cl, Br, I) lower alkoxy of C₁-C₆, CO₂H, CO₂R′

, CONH₂, CONHR′

, CONR′

₂, CH═

CHCO₂H, CH═

CHCO₂R′

; and

,

R′

is an optionally substituted alkyl of C₁-C₁₂ (particularly when the alkyl is an amino acid residue), cycloalkyl, optionally substituted alkynyl of C₂-C₆, optionally substituted lower alkenyl of C₂-C₆, or optionally substituted acyl.

68. The method of claim 66, wherein

Base is selected from the group consisting of (a) or (b):

and wherein R¹ and R⁷ are H, R³ is H, and R⁴ is NH₂ or OH, and R⁵ is NH₂.

69. A method for the treatment or prophylaxis of a yellow fever virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) of the formula;

70. A method for the treatment or prophylaxis of a yellow fever virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) of the formula;

71. A method for the treatment or prophylaxis of a yellow fever virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof of the formula;

72. A method for the treatment or prophylaxis of a yellow fever virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof of the formula;

73. A method for the treatment or prophylaxis of a yellow fever virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof of the formula;

74. A method for the treatment or prophylaxis of a yellow fever virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof of the formula;

75. A method for the treatment or prophylaxis of a yellow fever virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof of the formula;

76. A method for the treatment or prophylaxis of a West Nile virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) of the formula;

77. The method of claim 76,

wherein Base is selected from the group consisting of:

Y is N or CH.

R³, R⁴ and R⁵ are independently H, halogen including F, Cl, Br, I, OH, OR′

, SH, SR′

, NH₂, NHR′

, NR′

₂, lower alkyl of C₁-C₆, halogenated (F, Cl, Br, I) lower alkyl of C₁-C₆ such as CF₃ and CH₂CH₂F, lower alkenyl of C₂-C₆ such as CH═

CH₂, halogenated (F, Cl, Br, I) lower alkenyl of C₂-C₆ such as CH═

CHCl, CH═

CHBr and CH═

CHI, lower alkynyl of C₂-C₆ such as C≡

CH, halogenated (F, Cl, Br,

     1) lower alkynyl of C₂-C₆, lower alkoxy of C₁-C₆ such as CH₂OH and CH₂CH₂OH, halogenated (F, Cl, Br, I) lower alkoxy of C₁-C₆, CO₂H, CO₂R′

, CONH₂, CONHR′

, CONR′

₂, CH═

CHCO₂H, CH═

CHCO₂R′

; and

,

R′

is an optionally substituted alkyl of C₁-C₁₂ (particularly when the alkyl is an amino acid residue), cycloalkyl, optionally substituted alkynyl of C₂-C₆, optionally substituted lower alkenyl of C₂-C₆, or optionally substituted acyl.

78. The method of claim 76, wherein

Base is selected from the group consisting of (a) or (b):

and wherein R¹ is H, R² is OH, R^2′

is H, R³ is H, and R⁴ is NH₂ or OH, and R⁵ is NH₂.

79. A method for the treatment or prophylaxis of a West Nile virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) of the formula;

80. The method of claim 79, wherein

Base is

and R¹ is H, R² is OH, R^2′

is H, R³ is H, R⁴ is NH₂ or OH, and R⁶ is H.

81. A method for the treatment or prophylaxis of a West Nile virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) or its pharmaceutically acceptable salt or prodrug thereof of the structure;

82. The method of claim 81, wherein

Base is selected from the group consisting of:

Y is N or CH;

R³, R⁴ and R⁵ are independently H, halogen including F, Cl, Br, I, OH, OR′

, SH, SR′

, NH₂, NHR′

, NR′

₂, lower alkyl of C₁-C₆, halogenated (F, Cl, Br, I) lower alkyl of C₁-C₆ such as CF₃ and CH₂CH₂F, lower alkenyl of C₂-C₆ such as CH═

CH₂, halogenated (F, Cl, Br, I) lower alkenyl of C₂-C₆ such as CH═

CHCl, CH═

CHBr and CH═

CHI, lower alkynyl of C₂-C₆ such as C≡

CH, halogenated (F, Cl, Br, I) lower alkynyl of C₂-C₆, lower alkoxy of C₁-C₆ such as CH₂OH and CH₂CH₂OH, halogenated (F, Cl, Br, I) lower alkoxy of C₁-C₆, CO₂H, CO₂R′

, CONH₂, CONHR′

, CONR′

₂, CH═

CHCO₂H, CH═

CHCO₂R′

; and

,

R′

is an optionally substituted alkyl of C₁-C₁₂ (particularly when the alkyl is an amino acid residue), cycloalkyl, optionally substituted alkynyl of C₂-C₆, optionally substituted lower alkenyl of C₂-C₆, or optionally substituted acyl.

83. The method of claim 81, wherein

Base is selected from the group consisting of (a) or (b):

and wherein R¹ and R⁷ are H, R³ is H, and R⁴ is NH₂ or OH, and R⁵ is NH₂.

84. A method for the treatment or prophylaxis of a West Nile virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) of the formula;

85. A method for the treatment or prophylaxis of a West Nile virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) of the formula;

86. A method for the treatment or prophylaxis of a West Nile virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof of the formula;

87. A method for the treatment or prophylaxis of a West Nile virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof of the formula;

88. A method for the treatment or prophylaxis of a West Nile virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof of the formula;

89. A method for the treatment or prophylaxis of a West Nile virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof of the formula;

90. A method for the treatment or prophylaxis of a West Nile virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof of the formula;

91. A method for the treatment or prophylaxis of a Dengue virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) of the formula;

92. The method of claim 91,

wherein Base is selected from the group consisting of:

Y is N or CH.

R³, R⁴ and R⁵ are independently H, halogen including F, Cl, Br, I, OH, OR′

, SH, SR′

, NH₂, NHR′

, NR′

₂, lower alkyl of C₁-C₆, halogenated (F, Cl, Br, I) lower alkyl of C₁-C₆ such as CF₃ and CH₂CH₂F, lower alkenyl of C₂-C₆ such as CH═

CH₂, halogenated (F, Cl, Br, I) lower alkenyl of C₂-C₆ such as CH═

CHCl, CH═

CHBr and CH═

CHI, lower alkynyl of C₂-C₆ such as C≡

CH, halogenated (F, Cl, Br, I) lower alkynyl of C₂-C₆, lower alkoxy of C₁-C₆ such as CH₂OH and CH₂CH₂OH, halogenated (F, Cl, Br, I) lower alkoxy of C₁-C₆, CO₂H, CO₂R′

, CONH₂, CONHR′

, CONR′

₂, CH═

CHCO₂H, CH═

CHCO₂R′

; and

,

R′

is an optionally substituted alkyl of C₁-C₁₂ (particularly when the alkyl is an amino acid residue), cycloalkyl, optionally substituted alkynyl of C₂-C₆, optionally substituted lower alkenyl of C₂-C₆, or optionally substituted acyl.

93. The method of claim 91, wherein

Base is selected from the group consisting of (a) or (b):

and wherein R¹ is H, R² is OH, R^2′

is H, R³ is H, and R⁴ is NH₂ or OH, and R⁵ is NH₂.

94. A method for the treatment or prophylaxis of a Dengue virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) of the formula;

95. The method of claim 94, wherein

Base is

and R¹ is H, R² is OH, R^2′

is H, R³ is H, R⁴ is NH₂ or OH, and R⁶ is H.

96. A method for the treatment or prophylaxis of a Dengue virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) or its pharmaceutically acceptable salt or prodrug thereof of the structure;

97. The method of claim 96, wherein

Base is selected from the group consisting of:

Y is N or CH;

R³, R⁴ and R⁵ are independently H, halogen including F, Cl, Br, I, OH, OR′

, SH, SR′

, NH₂, NHR′

, NR′

₂, lower alkyl of C₁-C₆, halogenated (F, Cl, Br, I) lower alkyl of C₁-C₆ such as CF₃ and CH₂CH₂F, lower alkenyl of C₂-C₆ such as CH═

CH₂, halogenated (F, Cl, Br, I) lower alkenyl of C₂-C₆ such as CH═

CHCl, CH═

CHBr and CH═

CHI, lower alkynyl of C₂-C₆ such as C≡

CH, halogenated (F, Cl, Br, I) lower alkynyl of C₂-C₆, lower alkoxy of C₁-C₆ such as CH₂OH and CH₂CH₂OH, halogenated (F, Cl, Br, I) lower alkoxy of C₁-C₆, CO₂H, CO₂R′

, CONH₂, CONHR′

, CONR′

₂, CH═

CHCO₂H, CH═

CHCO₂R′

; and

,

R′

is an optionally substituted alkyl of C₁-C₁₂ (particularly when the alkyl is an amino acid residue), cycloalkyl, optionally substituted alkynyl of C₂-C₆, optionally substituted lower alkenyl of C₂-C₆, or optionally substituted acyl.

98. The method of claim 96, wherein

Base is selected from the group consisting of (a) or (b):

and wherein R¹ and R⁷ are H, R³ is H, and R⁴ is NH₂ or OH, and R⁵ is NH₂.

99. A method for the treatment or prophylaxis of a Dengue virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) of the formula;

100. A method for the treatment or prophylaxis of a Dengue virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) of the formula;

101. A method for the treatment or prophylaxis of a Dengue virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof of the formula;

102. A method for the treatment or prophylaxis of a Dengue virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof of the formula;

103. A method for the treatment or prophylaxis of a Dengue virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof of the formula;

104. A method for the treatment or prophylaxis of a Dengue virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof of the formula;

105. A method for the treatment or prophylaxis of a Dengue virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) or its pharmaceutically acceptable salt or prodrug thereof of the formula;

106. The method of 31, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside is administered in combination or alternation with at least one treatment selected from the group consisting of;

interferon, including interferon alpha 2a, interferon alpha 2b, a pegylated interferon, interferon beta, interferon gamma, interferon tau and interferon omega;

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

interferon alpha or pegylated interferon alpha in combination with ribavirin or levovirin;

levovirin;

a protease inhibitor including an NS3 inhibitor, a NS3-4A inhibitor;

a helicase inhibitor;

a polymerase inhibitor including HCV RNA polymerase and NS5B polymerase inhibitor;

gliotoxin;

an IRES inhibitor; and

antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazoles;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMDPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

107. The method of 41, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside is administered in combination or alternation with at least one treatment selected from the group consisting of;

interferon, including interferon alpha 2a, interferon alpha 2b, a pegylated interferon, interferon beta, interferon gamma, interferon tau and interferon omega;

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

interferon alpha or pegylated interferon alpha in combination with ribavirin or levovirin;

levovirin;

a protease inhibitor including an NS3 inhibitor, a NS3-4A inhibitor;

a helicase inhibitor;

a polymerase inhibitor including HCV RNA polymerase and NS5B polymerase inhibitor;

gliotoxin;

an IRES inhibitor; and

antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazoles;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

108. The method of 43, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside is administered in combination or alternation with at least one treatment selected from the group consisting of;

interferon, including interferon alpha 2a, interferon alpha 2b, a pegylated interferon, interferon beta, interferon gamma, interferon tau and interferon omega;

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

interferon alpha or pegylated interferon alpha in combination with ribavirin or levovirin;

levovirin;

a protease inhibitor including an NS3 inhibitor, a NS3-4A inhibitor;

a helicase inhibitor;

a polymerase inhibitor including HCV RNA polymerase and NS5B polymerase inhibitor;

gliotoxin;

an IRES inhibitor; and

antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazoles;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

109. The method of 45, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside is administered in combination or alternation with at least one treatment selected from the group consisting of;

interferon, including interferon alpha 2a, interferon alpha 2b, a pegylated interferon, interferon beta, interferon gamma, interferon tau and interferon omega;

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

interferon alpha or pegylated interferon alpha in combination with ribavirin or levovirin;

levovirin;

a protease inhibitor including an NS3 inhibitor, a NS3-4A inhibitor;

a helicase inhibitor;

a polymerase inhibitor including HCV RNA polymerase and NS5B polymerase inhibitor;

gliotoxin;

an IRES inhibitor; and

antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazoles;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

110. The method of 46, wherein the antivirally effective amount of (2′

R)-2′

deoxy-2′

-fluoro-2′

-C-methyl nucleoside is administered in combination or alternation with at least one treatment selected from the group consisting of;

interferon, including interferon alpha 2a, interferon alpha 2b, a pegylated interferon, interferon beta, interferon gamma, interferon tau and interferon omega;

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

interferon alpha or pegylated interferon alpha in combination with ribavirin or levovirin;

levovirin;

a protease inhibitor including an NS3 inhibitor, a NS3-4A inhibitor;

a helicase inhibitor;

a polymerase inhibitor including HCV RNA polymerase and NS5B polymerase inhibitor;

gliotoxin;

an IRES inhibitor; and

antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazoles;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

111. The method of 56, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside is administered in combination or alternation with at least one treatment selected from the group consisting of;

interferon, including interferon alpha 2a, interferon alpha 2b, a pegylated interferon, interferon beta, interferon gamma, interferon tau and interferon omega;

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

interferon alpha or pegylated interferon alpha in combination with ribavirin or levovirin;

levovirin;

a protease inhibitor including an NS3 inhibitor, a NS3-4A inhibitor;

a helicase inhibitor;

a polymerase inhibitor including HCV RNA polymerase and NS5B polymerase inhibitor;

gliotoxin;

an IRES inhibitor; and

antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazoles;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

112. The method of 58, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside is administered in combination or alternation with at least one treatment selected from the group consisting of;

interferon, including interferon alpha 2a, interferon alpha 2b, a pegylated interferon, interferon beta, interferon gamma, interferon tau and interferon omega;

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

interferon alpha or pegylated interferon alpha in combination with ribavirin or levovirin;

levovirin;

a protease inhibitor including an NS3 inhibitor, a NS3-4A inhibitor;

a helicase inhibitor;

a polymerase inhibitor including HCV RNA polymerase and NS5B polymerase inhibitor;

gliotoxin;

an IRES inhibitor; and

antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazoles;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

113. The method of 60, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside is administered in combination or alternation with at least one treatment selected from the group consisting of;

interferon, including interferon alpha 2a, interferon alpha 2b, a pegylated interferon, interferon beta, interferon gamma, interferon tau and interferon omega;

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

interferon alpha or pegylated interferon alpha in combination with ribavirin or levovirin;

levovirin;

a protease inhibitor including an NS3 inhibitor, a NS3-4A inhibitor;

a helicase inhibitor;

a polymerase inhibitor including HCV RNA polymerase and NS5B polymerase inhibitor;

gliotoxin;

an IRES inhibitor; and

antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazoles;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

114. The method of 61, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside is administered in combination or alternation with at least one treatment selected from the group consisting of;

interferon, including interferon alpha 2a, interferon alpha 2b, a pegylated interferon, interferon beta, interferon gamma, interferon tau and interferon omega;

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

interferon alpha or pegylated interferon alpha in combination with ribavirin or levovirin;

levovirin;

a protease inhibitor including an NS3 inhibitor, a NS3-4A inhibitor;

a helicase inhibitor;

a polymerase inhibitor including HCV RNA polymerase and NS5B polymerase inhibitor;

gliotoxin;

an IRES inhibitor; and

antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazoles;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

115. The method of 71, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside is administered in combination or alternation with at least one treatment selected from the group consisting of;

interferon, including interferon alpha 2a, interferon alpha 2b, a pegylated interferon, interferon beta, interferon gamma, interferon tau and interferon omega;

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

interferon alpha or pegylated interferon alpha in combination with ribavirin or levovirin;

levovirin;

a protease inhibitor including an NS3 inhibitor, a NS3-4A inhibitor;

a helicase inhibitor;

a polymerase inhibitor including HCV RNA polymerase and NS5B polymerase inhibitor;

gliotoxin;

an IRES inhibitor; and

antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazoles;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

116. The method of 73, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside is administered in combination or alternation with at least one treatment selected from the group consisting of;

interferon, including interferon alpha 2a, interferon alpha 2b, a pegylated interferon, interferon beta, interferon gamma, interferon tau and interferon omega;

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

interferon alpha or pegylated interferon alpha in combination with ribavirin or levovirin;

levovirin;

a protease inhibitor including an NS3 inhibitor, a NS3-4A inhibitor;

a helicase inhibitor;

a polymerase inhibitor including HCV RNA polymerase and NS5B polymerase inhibitor;

gliotoxin;

an IRES inhibitor; and

antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazoles;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

117. The method of 75, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside is administered in combination or alternation with at least one treatment selected from the group consisting of;

interferon, including interferon alpha 2a, interferon alpha 2b, a pegylated interferon, interferon beta, interferon gamma, interferon tau and interferon omega;

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

interferon alpha or pegylated interferon alpha in combination with ribavirin or levovirin;

levovirin;

a protease inhibitor including an NS3 inhibitor, a NS3-4A inhibitor;

a helicase inhibitor;

a polymerase inhibitor including HCV RNA polymerase and NS5B polymerase inhibitor;

gliotoxin;

an IRES inhibitor; and

antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazoles;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

118. The method of 76, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside is administered in combination or alternation with at least one treatment selected from the group consisting of;

interferon, including interferon alpha 2a, interferon alpha 2b, a pegylated interferon, interferon beta, interferon gamma, interferon tau and interferon omega;

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

interferon alpha or pegylated interferon alpha in combination with ribavirin or levovirin;

levovirin;

a protease inhibitor including an NS3 inhibitor, a NS3-4A inhibitor;

a helicase inhibitor;

a polymerase inhibitor including HCV RNA polymerase and NS5B polymerase inhibitor;

gliotoxin;

an IRES inhibitor; and

antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazoles;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

119. The method of 86, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside is administered in combination or alternation with at least one treatment selected from the group consisting of;

interferon, including interferon alpha 2a, interferon alpha 2b, a pegylated interferon, interferon beta, interferon gamma, interferon tau and interferon omega;

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

interferon alpha or pegylated interferon alpha in combination with ribavirin or levovirin;

levovirin;

a protease inhibitor including an NS3 inhibitor, a NS3-4A inhibitor;

a helicase inhibitor;

a polymerase inhibitor including HCV RNA polymerase and NS5B polymerase inhibitor;

gliotoxin;

an IRES inhibitor; and

antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazoles;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

120. The method of 88, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside is administered in combination or alternation with at least one treatment selected from the group consisting of;

interferon, including interferon alpha 2a, interferon alpha 2b, a pegylated interferon, interferon beta, interferon gamma, interferon tau and interferon omega;

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

interferon alpha or pegylated interferon alpha in combination with ribavirin or levovirin;

levovirin;

a protease inhibitor including an NS3 inhibitor, a NS3-4A inhibitor;

a helicase inhibitor;

a polymerase inhibitor including HCV RNA polymerase and NS5B polymerase inhibitor;

gliotoxin;

an IRES inhibitor; and

antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazoles;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

121. The method of 90, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside is administered in combination or alternation with at least one treatment selected from the group consisting of;

interferon, including interferon alpha 2a, interferon alpha 2b, a pegylated interferon, interferon beta, interferon gamma, interferon tau and interferon omega;

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

interferon alpha or pegylated interferon alpha in combination with ribavirin or levovirin;

levovirin;

a protease inhibitor including an NS3 inhibitor, a NS3-4A inhibitor;

a helicase inhibitor;

a polymerase inhibitor including HCV RNA polymerase and NS5B polymerase inhibitor;

gliotoxin;

an IRES inhibitor; and

antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazoles;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

122. The method of 91, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside is administered in combination or alternation with at least one treatment selected from the group consisting of;

interferon, including interferon alpha 2a, interferon alpha 2b, a pegylated interferon, interferon beta, interferon gamma, interferon tau and interferon omega;

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

interferon alpha or pegylated interferon alpha in combination with ribavirin or levovirin;

levovirin;

a protease inhibitor including an NS3 inhibitor, a NS3-4A inhibitor;

a helicase inhibitor;

a polymerase inhibitor including HCV RNA polymerase and NS5B polymerase inhibitor;

gliotoxin;

an IRES inhibitor; and

antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazoles;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

123. The method of 101, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside is administered in combination or alternation with at least one treatment selected from the group consisting of;

interferon, including interferon alpha 2a, interferon alpha 2b, a pegylated interferon, interferon beta, interferon gamma, interferon tau and interferon omega;

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

interferon alpha or pegylated interferon alpha in combination with ribavirin or levovirin;

levovirin;

a protease inhibitor including an NS3 inhibitor, a NS3-4A inhibitor;

a helicase inhibitor;

a polymerase inhibitor including HCV RNA polymerase and NS5B polymerase inhibitor;

gliotoxin;

an IRES inhibitor; and

antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazoles;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

124. The method of 103, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside is administered in combination or alternation with at least one treatment selected from the group consisting of;

interferon, including interferon alpha 2a, interferon alpha 2b, a pegylated interferon, interferon beta, interferon gamma, interferon tau and interferon omega;

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

interferon alpha or pegylated interferon alpha in combination with ribavirin or levovirin;

levovirin;

a protease inhibitor including an NS3 inhibitor, a NS3-4A inhibitor;

a helicase inhibitor;

a polymerase inhibitor including HCV RNA polymerase and NS5B polymerase inhibitor;

gliotoxin;

an IRES inhibitor; and

antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazoles;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

125. The method of 105, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside is administered in combination or alternation with at least one treatment selected from the group consisting of;

interferon, including interferon alpha 2a, interferon alpha 2b, a pegylated interferon, interferon beta, interferon gamma, interferon tau and interferon omega;

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

interferon alpha or pegylated interferon alpha in combination with ribavirin or levovirin;

levovirin;

a protease inhibitor including an NS3 inhibitor, a NS3-4A inhibitor;

a helicase inhibitor;

a polymerase inhibitor including HCV RNA polymerase and NS5B polymerase inhibitor;

gliotoxin;

an IRES inhibitor; and

antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazoles;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

126. A method of synthesizing a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) comprising glycosylation of a nucleobase with an intermediate structure;

127. A method of synthesizing a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L) comprising selective deprotection of either Pg in an intermediate of the structure;

128. An intermediate in the synthesis of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L), wherein the intermediate is of the structure;

129. An intermediate in the synthesis of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

-L), wherein the intermediate is of the structure;