Nucleotide mimics and their prodrugs

• US 20070265224A1
• Filed: 06/14/2007
• Published: 11/15/2007
• Est. Priority Date: 02/28/2002
• Status: Active Grant

• Current Assignee: Biota Scientific Management Pty Limited (Vaxart, Inc.)
• Original Assignee: Biota Scientific Management Pty Limited (Vaxart, Inc.)
• Inventors: Jin, Yi, Wang, Guangyi, Prhavc, Marija, Rajwanshi, Vivek, Cook, Phillip, Leeds, Janet, Brooks, Jennifer, Ariza, Maria, Fagan, Patrick, Bruice, Thomas, Boyle, Nicholas, Tucker, Kathleen
• Granted Patent: US 7,807,653 B2
• Time in Patent Office: Days
• US Class Current: 514/46
• 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 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/14 Pyrrolo-pyrimidine radicals
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids

Abstract

The present invention relates to nucleoside diphosphate mimics and nucleoside triphosphate mimics, which contain diphosphate or triphosphate moiety mimics and optionally sugar-modifications and/or base-modifications. The nucleotide mimics of the present invention, in a form of a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug, or a pharmaceutical formulation, are useful as antiviral, antimicrobial, and anticancer agents. The present invention provides a method for the treatment of viral infections, microbial infections, and proliferative disorders. The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention optionally in combination with other pharmaceutically active agents.

Claims

1. A compound of Formula (I) which may be a D- or L-nucleotide:

2. The compound defined in claim 1 of Formula (V):

3. The compound defined in claim 1 of Formula (VI):

4. The compound defined in claim 1 of Formula (VII):

5. The compound defined in claim 4

wherein X² is O;

and

wherein X⁷ is SH, NH₂, ⁻

BH₃M⁺, alkyl, aryl, alkylamino, or arylamino.

6. The compound defined in claim 4

wherein X² is O;

and

wherein X⁷ is selected from the group consisting of SH, NH₂, ⁻

BH₃M⁺, R, and NHR.

7. The compound defined in claim 1 of Formula (VIII):

8. The compound defined in claim 1 of Formula (VIII):

wherein X⁹ and X¹⁰ are selected independently from the group consisting of acylthioethoxy, acyloxymethoxy, 1,2-O-diacylglyceroxy, 1,2-O-dialkylglyceroxy, and 1-O-alkyl-2-O-acylglyceroxy

9. The compound defined in claim 1 of Formula (VIII):

10. The compound defined in claim 8 wherein at least one of X⁹ and X¹⁰ is 1,2-O-dialkylglyceryloxy.

11. The compound defined in claim 1 of Formula (IX):

12. The compound defined in claim 1 of Formula (IX):

13. The compound defined in claim 1 of Formula (XIII):

14. The compound defined in claim 1 of Formula (XIII):

15. The compound defined in claim 1 of Formula (XIV):

16. The compound defined in claim 1 of Formula (XIV):

17. The compound defined in claim 1 of Formula (XV):

18. The compound defined in claim 1 of Formula (XV):

46. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1, a pharmaceutically acceptable salt thereof, optionally in combination with one or more other active ingredients and/or with a pharmaceutically acceptable carrier.

50. A method for the treatment of a microbial infection comprising administering a therapeutically effective amount of the compound defined in claim 1.

51. A method for the treatment of a proliferative disorder comprising administering a therapeutically effective amount of the compound defined in claim 1.

56. The compound of claim 1 where D is guanine.

19. A compound of Formula (XVI):

20. The compound defined in claim 19 where Nu is selected from the group consisting of:

adenosine,

guanosine,

2′

-deoxyadenosine,

2′

-deoxyguanosine,

inosine,

9-(β

-D-arabinofuranosyl)adenine,

9-(β

-D-arabinofuranosyl)guanine,

9-(β

-D-arabinofuranosyl)hypoxanthine,

3′

-azido-2′

,3′

-dideoxyadenosine,

3′

-azido-2′

,3′

-dideoxyguanosine,

3′

-azido-2′

,3′

-dideoxyinosine,

2′

,3′

-dideoxyinosine,

2′

,3′

-dideoxyadenosine,

2′

,3′

-dideoxyguanosine,

9-(2,3-dideoxy-1-β

-D-ribofuranosyl)-2,6-diaminopurine,

2′

,3′

-didehydro-2′

,3′

-dideoxyadenosine,

2′

,3′

-didehydro-2′

,3′

-dideoxyguanosine,

2′

,3′

-didehydro-2′

,3′

-dideoxyinosine,

3-deazaadenosine,

3-deazaguanosine,

3-deazainosine,

7-deazaadenosine,

7-deazaguanosine,

7-deazainosine,

9-(β

-D-ribofuranosyl)-6-thiopurine,

6-methylthio-9-(β

-D-ribofuranosyl)purine,

2-amino-9-(β

-D-ribofuranosyl)-6-thiopurine,

2-amino-6-methylthio-9-(β

-D-ribofuranosyl)purine,

2′

-C-methyladenosine,

2′

-C-methylguanosine,

2′

-C-methylinosine,

2′

-deoxy-2′

-fluoroadenosine,

2′

-deoxy-2′

-fluoroguanosine,

2′

-deoxy-2′

-fluoroinosine,

2′

-deoxy-2′

-fluoroarabinoadenosine,

2′

-deoxy-2′

-fluoroarabinoguanosine,

2′

-deoxy-2′

-fluoroarabinoinosine,

2′

-O-methyladenosine,

2′

-O-methylguanosine,

2′

-O-methylinosine,

2′

-C-ethynylguanosine,

2′

-C-ethynylinosine,

3′

-C-ethynyladenosine,

3′

-C-ethynylguanosine,

3′

-C-ethynylinosine,

3′

-deoxyadenosine,

3′

-deoxyguanosine,

3′

-deoxyinosine,

4′

-C-ethynyladenosine,

4′

-C-ethynylguanosine,

4′

-C-ethynylinosine,

4′

-C-methyladenosine,

4′

-C-methylguanosine,

4′

-C-methylinosine,

2′

-C-methyl-7-deazaadeno sine,

2′

-C-methyl-7-deazaguanosine,

2′

-C-methyl-3-deazaadenosine,

2′

-C-methyl-3-deazaguanosine,

2′

-O-methyl-7-deazaadenosine,

2′

-O-methyl-7-deazaguanosine,

2′

-O-methyl-3-deazaadenosine,

2′

-O-methyl-3-deazaguanosine,

2′

-C-methyl-2-chloroadenosine,

2′

-deoxy-7-deazaadenosine,

2′

-deoxy-3-deazaadenosine,

2′

-deoxy-7-deazaguanosine,

2′

-deoxy-3-deazaguanosine,

2′

-deoxy-2-chloroadenosine,

2′

-deoxy-2-fluoroadenosine,

3′

-deoxy-7-deazaadenosine,

3′

-deoxy-7-deazaguanosine,

3′

-deoxy-3-deazaadenosine,

3′

-deoxy-3-deazaguanosine,

3′

-deoxy-2-chloroadenosine,

2′

,3′

-dideoxy-7-deazaadenosine,

2′

,3′

-dideoxy-7-deazaguanosine,

2′

,3′

-dideoxy-3-deazaadenosine,

2′

,3′

-dideoxy-3-deazaguanosine,

2′

,3′

-dideoxy-2-chloroadenosine,

2′

,3′

-dideoxy-β

-L-adenosine,

2′

,3′

-dideoxy-β

-L-guanosine,

2′

-deoxy-β

-L-adenosine,

2′

-deoxy-β

-L-guanosine,

2′

-deoxy-β

-L-inosine,

β

-L-adenosine,

β

-L-guanosine,

β

-L-inosine,

2′

,3′

-didehydro-2′

,3′

-dideoxy-β

-L-adenosine,

2′

,3′

-didehydro-2′

,3′

-dideoxy-β

-L-guanosine,

9-(β

-D-arabinofuranosyl)-2-fluoroadenine,

2′

,3′

-dideoxy-3′

-fluoroguanosine,

(±

)-(1α

,2β

,3α

)-9-[2,3-bis(hydroxymethyl)-1-cyclobutyl]adenine,

(±

)-(1α

,2β

,3α

)-9-[2,3-bis(hydroxymethyl)-1-cyclobutyl]guanine,

(±

)-(1β

,2α

,3β

)-9-[2,3-bis(hydroxymethyl)-1-cyclobutyl]guanine,

(±

)-(1β

,2α

,3β

)-9-[2,3-bis(hydroxymethyl)-1-cyclobutyl]adenine,

(1R,3S,4R)-9-(3-hydroxy-4-hydroxymethylcyclopent-1-yl)guanine,

(1S,2R,4R)-9-(1-hydroxy-2-hydroxymethylcyclopent-4-yl)guanine,

(2R,4R)-9-(2-hydroxymethyl-1,3-dioxolan-4-yl)-2,6-diaminopurine,

(2R,4R)-9-(2-hydroxymethyl-1,3-dioxolan-4-yl)guanine,

(1R,2S,4S)-9-(4-hydroxy-3-hydroxymethyl-2-methylenecyclopent-4-yl]guanine, and

(1S,3R,4S)-9-(3-hydroxy-4-hydroxymethyl-5-methylenecyclopent-1-yl]guanine.

21. The compound defined in claim 19 of Formula (XVII):

22. The compound defined in claim 19 of Formula (XVII):

23. The compound defined in claim 21 where Nu is selected from the group consisting of:

adenosine,

guanosine,

2′

-deoxyadenosine,

2′

-deoxyguanosine,

inosine,

9-(β

-D-arabinofuranosyl)adenine,

9-(β

-D-arabino furanosyl)guanine,

9-(β

-D-arabinofuranosyl)hypoxanthine,

3′

-azido-2′

,3′

-dideoxyadenosine,

3′

-azido-2′

,3′

-dideoxyguanosine,

3′

-azido-2′

,3′

-dideoxyinosine,

2′

,3′

-dideoxyinosine,

2′

,3′

-dideoxyadenosine,

2′

,3′

-dideoxyguanosine,

9-(2,3-dideoxy-1-β

-D-ribofuranosyl)-2,6-diaminopurine,

2′

,3′

-didehydro-2′

,3′

-dideoxyadenosine,

2′

,3′

-didehydro-2′

,3′

-dideoxyguanosine,

2′

,3′

-didehydro-2′

,3′

-dideoxyinosine,

3-deazaadenosine,

3-deazaguanosine,

3-deazainosine,

7-deazaadenosine,

7-deazaguanosine,

7-deazainosine,

9-(β

-D-ribofuranosyl)-6-thiopurine,

6-methylthio-9-(β

-D-ribofuranosyl)purine,

2-amino-9-(β

-D-ribofuranosyl)-6-thiopurine,

2-amino-6-methylthio-9-(β

-D-ribofuranosyl)purine,

2′

-C-methyladenosine,

2′

-C-methylguanosine,

2′

-C-methylinosine,

2′

-deoxy-2′

-fluoroadenosine,

2′

-deoxy-2′

-fluoroguanosine,

2′

-deoxy-2′

-fluoroinosine,

2′

-deoxy-2′

-fluoroarabinoadenosine,

2′

-deoxy-2′

-fluoroarabinoguanosine,

2′

-deoxy-2′

-fluoroarabinoinosine,

2′

-O-methyladenosine,

2′

-O-methyl guano sine,

2′

-O-methylinosine,

2′

-C-ethynylguanosine,

2′

-C-ethynylinosine,

3′

-C-ethynyladenosine,

3′

-C-ethynylguanosine,

3′

-C-ethynylinosine,

3′

-deoxyadenosine,

3′

-deoxyguanosine,

3′

-deoxyinosine,

4′

-C-ethynyladenosine,

4′

-C-ethynylguanosine,

4′

-C-ethynylinosine,

4′

-C-methyladenosine,

4′

-C-methylguanosine,

4′

-C-methylinosine,

2′

-C-methyl-7-deazaadenosine,

2′

-C-methyl-7-deazaguanosine,

2′

-C-methyl-3-deazaadenosine,

2′

-C-methyl-3-deazaguanosine,

2′

-O-methyl-7-deazaadenosine,

2′

-O-methyl-7-deazaguanosine,

2′

-O-methyl-3-deazaadenosine,

2′

-O-methyl-3-deazaguanosine,

2′

-C-methyl-2-chloroadenosine,

2′

-deoxy-7-deazaadenosine,

2′

-deoxy-3-deazaadenosine,

2′

-deoxy-7-deazaguanosine,

2′

-deoxy-3-deazaguanosine,

2′

-deoxy-2-chloroadenosine,

2′

-deoxy-2-fluoroadenosine,

3′

-deoxy-7-deazaadenosine,

3′

-deoxy-7-deazaguanosine,

3′

-deoxy-3-deazaadenosine,

3′

-deoxy-3-deazaguanosine,

3′

-deoxy-2-chloroadenosine,

2′

,3′

-dideoxy-7-deazaadenosine,

2′

,3′

-dideoxy-7-deazaguanosine,

2′

,3′

-dideoxy-3-deazaadenosine,

2′

,3′

-dideoxy-3-deazaguanosine,

2′

,3′

-dideoxy-2-chloroadenosine,

2′

,3′

-dideoxy-β

-L-adenosine,

2′

,3′

-dideoxy-β

-L-guanosine,

2′

-deoxy-β

-L-adenosine,

2′

-deoxy-β

-L-guanosine,

2′

-deoxy-β

-L-inosine,

β

-L-adenosine,

β

-L-guanosine,

β

-L-inosine,

2′

,3′

-didehydro-2′

,3′

-dideoxy-β

-L-adenosine,

2′

,3′

-didehydro-2′

,3′

-dideoxy-β

-L-guanosine,

9-(β

-D-arabinofuranosyl)-2-fluoroadenine,

2′

,3′

-dideoxy-3′

-fluoroguanosine,

(±

)-(1α

,2β

,3α

)-9-[2,3-bis(hydroxymethyl)-1-cyclobutyl]adenine,

(±

)-(1α

,2β

,3α

)-9-[2,3-bis(hydroxymethyl)-1-cyclobutyl]guanine,

(±

)-(1β

,2α

,3β

)-9-[2,3-bis(hydroxymethyl)-1-cyclobutyl]guanine,

(±

)-(1β

,2α

,3β

)-9-[2,3-bis(hydroxymethyl)-1-cyclobutyl]adenine,

(1R,3S,4R)-9-(3-hydroxy-4-hydroxymethylcyclopent-1-yl)guanine,

(1S,2R,4R)-9-(1-hydroxy-2-hydroxymethylcyclopent-4-yl)guanine,

(2R,4R)-9-(2-hydroxymethyl-1,3-dioxolan-4-yl)-2,6-diaminopurine,

(2R,4R)-9-(2-hydroxymethyl-1,3-dioxolan-4-yl)guanine,

(1R,2S,4S)-9-(4-hydroxy-3-hydroxymethyl-2-methylenecyclopent-4-yl]guanine, and

(1S,3R,4S)-9-(3-hydroxy-4-hydroxymethyl-5-methylenecyclopent-1-yl]guanine.

24. The compound defined in claim 19 of Formula (XVIII):

25. The compound defined in claim 19 of Formula (XVIII):

26. The compound defined in claim 25 where Nu is selected from the group consisting of:

adenosine,

guanosine,

2′

-deoxyadenosine,

2′

-deoxyguanosine,

mosine,

9-(β

-D-arabinofuranosyl)adenine,

9-(β

-D-arabinofuranosyl)guanine,

9-(β

-D-arabinofuranosyl)hypoxanthine,

3′

-azido-2′

,3′

-dideoxyadenosine,

3′

-azido-2′

,3′

-dideoxyguanosine,

3′

-azido-2′

,3′

-dideoxyinosine,

2′

,3′

-dideoxyinosine,

2′

,3′

-dideoxyadenosine,

2′

,3′

-dideoxyguanosine,

9-(2,3-dideoxy-1-β

-D-ribofuranosyl)-2,6-diaminopurine,

2′

,3′

-didehydro-2′

,3′

-dideoxyadenosine,

2′

,3′

-didehydro-2′

,3′

-dideoxyguanosine,

2′

,3′

-didehydro-2′

,3′

-dideoxyinosine,

3-deazaadenosine,

3-deazaguanosine,

3-deazainosine,

7-deazaadenosine,

7-deazaguanosine,

7-deazainosine,

9-(β

-D-ribofuranosyl)-6-thiopurine,

6-methylthio-9-(β

-D-ribofuranosyl)purine,

2-amino-9-(β

-D-ribofuranosyl)-6-thiopurine,

2-amino-6-methylthio-9-(β

-D-ribofuranosyl)purine,

2′

-C-methyladenosine,

2′

-C-methylguanosine,

2′

-C-methylinosine,

2′

-deoxy-2′

-fluoroadenosine,

2′

-deoxy-2′

-fluoroguanosine,

2′

-deoxy-2′

-fluoroinosine,

2′

-deoxy-2′

-fluoroarabinoadenosine,

2′

-deoxy-2′

-fluoroarabinoguanosine,

2′

-deoxy-2′

-fluoroarabinoinosine,

2′

-O-methyladenosine,

2′

-O-methylguanosine,

2′

-O-methylinosine,

2′

-C-ethynylguanosine,

2′

-C-ethynylinosine,

3′

-C-ethynyladenosine,

3′

-C-ethynylguanosine,

3′

-C-ethynylinosine,

3′

-deoxyadenosine,

3′

-deoxyguanosine,

3′

-deoxyinosine,

4′

-C-ethynyladenosine,

4′

-C-ethynylguanosine,

4′

-C-ethynylinosine,

4′

-C-methyladenosine,

4′

-C-methylguanosine,

4′

-C-methylinosine,

2′

-C-methyl-7-deazaadenosine,

2′

-C-methyl-7-deazaguanosine,

2′

-C-methyl-3-deazaadenosine,

2′

-C-methyl-3-deazaguanosine,

2′

-O-methyl-7-deazaadenosine,

2′

-O-methyl-7-deazaguanosine,

2′

-O-methyl-3-deazaadenosine,

2′

-O-methyl-3-deazaguanosine,

2′

-C-methyl-2-chloroadenosine,

2′

-deoxy-7-deazaadenosine,

2′

-deoxy-3-deazaadenosine,

2′

-deoxy-7-deazaguanosine,

2′

-deoxy-3-deazaguanosine,

2′

-deoxy-2-chloroadenosine,

2′

-deoxy-2-fluoroadenosine,

3′

-deoxy-7-deazaadenosine,

3′

-deoxy-7-deazaguanosine,

3′

-deoxy-3-deazaadenosine,

3′

-deoxy-3-deazaguanosine,

3′

-deoxy-2-chloroadenosine,

2′

,3′

-dideoxy-7-deazaadenosine,

2′

,3′

-dideoxy-7-deazaguanosine,

2′

,3′

-dideoxy-3-deazaadenosine,

2′

,3′

-dideoxy-3-deazaguanosine,

2′

,3′

-dideoxy-2-chloroadenosine,

2′

,3′

-dideoxy-β

-L-adenosine,

2′

,3′

-dideoxy-β

-L-guanosine,

2′

-deoxy-β

-L-adenosine,

2′

-deoxy-β

-L-guano sine,

2′

-deoxy-β

-L-inosine,

β

-L-adenosine,

β

-L-guanosine,

β

-L-inosine,

2′

,3′

-didehydro-2′

,3′

-dideoxy-β

-L-adenosine,

2′

,3′

-didehydro-2′

,3′

-dideoxy-β

-L-guanosine,

9-(β

-D-arabinofuranosyl)-2-fluoroadenine,

2′

,3′

-dideoxy-3′

-fluoroguanosine,

(±

)-(1α

,2β

,3α

)-9-[2,3-bis(hydroxymethyl)-1-cyclobutyl]adenine,

(±

)-(1α

,2β

,3α

)-9-[2,3-bis(hydroxymethyl)-1-cyclobutyl]guanine,

(±

)-(1β

,2α

,3β

)-9-[2,3-bis(hydroxymethyl)-1-cyclobutyl]guanine,

(±

)-(1β

,2α

,3β

)-9-[2,3-bis(hydroxymethyl)-1-cyclobutyl]adenine,

(1R,3S,4R)-9-(3-hydroxy-4-hydroxymethylcyclopent-1-yl)guanine,

(1S,2R,4R)-9-(1-hydroxy-2-hydroxymethylcyclopent-4-yl)guanine,

(2R,4R)-9-(2-hydroxymethyl-1,3-dioxolan-4-yl)-2,6-diaminopurine,

(2R,4R)-9-(2-hydroxymethyl-1,3-dioxolan-4-yl)guanine,

(1R,2S,4S)-9-(4-hydroxy-3-hydroxymethyl-2-methylenecyclopent-4-yl]guanine, and

(1S,3R,4S)-9-(3-hydroxy-4-hydroxymethyl-5-methylenecyclopent-1-yl]guanine.

27. The compound defined in claim 19 of Formula (XIX):

28. The compound defined in claim 19 of Formula (XIX):

47. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 19, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable prodrug thereof, optionally in combination with one or more other active ingredients and/or with a pharmaceutically acceptable carrier.

52. The compound defined in claim 19,

wherein at least one of X⁷, X⁸ and/or X⁹ is ⁻

BH₃M⁺; and

at least one of X⁰, X⁵ or X⁶ is CY₂.

53. The compound defined in claim 52,

wherein at least one of X⁰, X⁵ or X⁶ is CF₂.

54. The compound defined in claim 52,

wherein X⁶ is CF₂ or CCl₂.

55. The compound defined in claim 52,

wherein X⁷ is ⁻

BH₃M⁺.

29. A compound of Formula (I) which may be a D- or L-nucleotide:

30. The compound defined in claim 29 of Formula (VI):

31. The compound defined in claim 29 of Formula (VII):

32. The compound defined in claim 31

wherein X² is O;

and

wherein X⁷ is selected from the group consisting of SH, NH₂, ⁻

BH₃M⁺, alkyl, aryl, alkylamino, and arylamino.

33. The compound defined in claim 31

wherein X² is O;

and

wherein X⁷ is selected from the group consisting of SH, NH₂, ⁻

BH₃M⁺, R, and NHR.

34. The compound defined in claim 29 of Formula (VIII):

35. The compound defined in claim 29 of Formula (IX):

36. The compound defined in claim 29 of Formula (XIII):

37. The compound defined in claim 29 of Formula (XIV):

38. The compound defined in claim 29 of Formula (XV):

48. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 29, a pharmaceutically acceptable salt thereof, optionally in combination with one or more other active ingredients and/or with a pharmaceutically acceptable carrier.

39. A compound of Formula (XVI):

40. The compound defined in claim 39 where Nu is selected from the group consisting of:

adenosine,

guanosine,

2′

-deoxyadenosine,

2′

-deoxyguanosine,

inosine,

9-(β

-D-arabinofuranosyl)adenine,

9-(β

-D-arabinofuranosyl)guanine,

9-(β

-D-arabinofuranosyl)hypoxanthine,

3′

-azido-2′

,3′

-dideoxyadenosine,

3′

-azido-2′

,3′

-dideoxyguanosine,

3′

-azido-2′

,3′

-dideoxyinosine,

2′

,3′

-dideoxyinosine,

2′

,3′

-dideoxyadenosine,

2′

,3′

-dideoxyguanosine,

9-(2,3-dideoxy-1-β

-D-ribofuranosyl)-2,6-diaminopurine,

2′

,3′

-didehydro-2′

,3′

-dideoxyadenosine,

2′

,3′

-didehydro-2′

,3′

-dideoxyguanosine,

2′

,3′

-didehydro-2′

,3′

-dideoxyinosine,

3-deazaadenosine,

3-deazaguanosine,

3-deazainosine,

7-deazaadenosine,

7-deazaguanosine,

7-deazainosine,

9-(β

-D-ribofuranosyl)-6-thiopurine,

6-methylthio-9-(β

-D-ribofuranosyl)purine,

2-amino-9-(β

-D-ribofuranosyl)-6-thiopurine,

2-amino-6-methylthio-9-(β

-D-ribofuranosyl)purine,

2′

-C-methyladenosine,

2′

-C-methylguanosine,

2′

-C-methylinosine,

2′

-deoxy-2′

-fluoroadenosine,

2′

-deoxy-2′

-fluoroguanosine,

2′

-deoxy-2′

-fluoroinosine,

2′

-deoxy-2′

-fluoroarabinoadenosine,

2′

-deoxy-2′

-fluoroarabinoguanosine,

2′

-deoxy-2′

-fluoroarabinoinosine,

2′

-O-methyladenosine,

2′

-O-methyl guano sine,

2′

-O-methylinosine,

2′

-C-ethynylguanosine,

2′

-C-ethynylinosine,

3′

-C-ethynyladenosine,

3′

-C-ethynylguanosine,

3′

-C-ethynylinosine,

3′

-deoxyadenosine,

3′

-deoxyguanosine,

3′

-deoxyinosine,

4′

-C-ethynyladenosine,

4′

-C-ethynylguanosine,

4′

-C-ethynylinosine,

4′

-C-methyladenosine,

4′

-C-methylguanosine,

4′

-C-methylinosine,

2′

-C-methyl-7-deazaadenosine,

2′

-C-methyl-7-deazaguanosine,

2′

-C-methyl-3-deazaadenosine,

2′

-C-methyl-3-deazaguanosine,

2′

-O-methyl-7-deazaadenosine,

2′

-O-methyl-7-deazaguanosine,

2′

-O-methyl-3-deazaadenosine,

2′

-O-methyl-3-deazaguanosine,

2′

-C-methyl-2-chloroadenosine,

2′

-deoxy-7-deazaadenosine,

2′

-deoxy-3-deazaadenosine,

2′

-deoxy-7-deazaguanosine,

2′

-deoxy-3-deazaguanosine,

2′

-deoxy-2-chloroadenosine,

2′

-deoxy-2-fluoroadenosine,

3′

-deoxy-7-deazaadenosine,

3′

-deoxy-7-deazaguanosine,

3′

-deoxy-3-deazaadenosine,

3′

-deoxy-3-deazaguanosine,

3′

-deoxy-2-chloroadenosine,

2′

,3′

-dideoxy-7-deazaadenosine,

2′

,3′

-dideoxy-7-deazaguanosine,

2′

,3′

-dideoxy-3-deazaadenosine,

2′

,3′

-dideoxy-3-deazaguanosine,

2′

,3′

-dideoxy-2-chloroadenosine,

2′

,3′

-dideoxy-β

-L-adenosine,

2′

,3′

-dideoxy-β

-L-guanosine,

2′

-deoxy-β

-L-adenosine,

2′

-deoxy-β

-L-guanosine,

2′

-deoxy-β

-L-inosine,

β

-L-adenosine,

β

-L-guanosine,

β

-L-inosine,

2′

,3′

-didehydro-2′

,3′

-dideoxy-β

-L-adenosine,

2′

,3′

-didehydro-2′

,3′

-dideoxy-β

-L-guanosine,

9-(β

-D-arabinofuranosyl)-2-fluoroadenine,

2′

,3′

-dideoxy-3′

-fluoroguanosine,

(±

)-(1α

,2β

,3α

)-9-[2,3-bis(hydroxymethyl)-1-cyclobutyl]adenine,

(×

)-(1α

,2β

,3α

)-9-[2,3-bis(hydroxymethyl)-1-cyclobutyl]guanine,

(±

)-(1β

,2α

,3β

)-9-[2,3-bis(hydroxymethyl)-1-cyclobutyl]guanine,

(±

)-(1β

,2α

,3β

)-9-[2,3-bis(hydroxymethyl)-1-cyclobutyl]adenine,

(1R,3S,4R)-9-(3-hydroxy-4-hydroxymethylcyclopent-1-yl)guanine,

(1S,2R,4R)-9-(1-hydroxy-2-hydroxymethylcyclopent-4-yl)guanine,

(2R,4R)-9-(2-hydroxymethyl-1,3-dioxolan-4-yl)-2,6-diaminopurine,

(2R,4R)-9-(2-hydroxymethyl-1,3-dioxolan-4-yl)guanine,

(1R,2S,4S)-9-(4-hydroxy-3-hydroxymethyl-2-methylenecyclopent-4-yl]guanine, and

(1S,3R,4S)-9-(3-hydroxy-4-hydroxymethyl-5-methylenecyclopent-1-yl]guanine.

41. The compound defined in claim 39 of Formula (XVII):

42. The compound defined in claim 41 where Nu is selected from the group consisting of:

adenosine,

guanosine,

2′

-deoxyadenosine,

2′

-deoxyguanosine,

mosine,

9-(β

-D-arabinofuranosyl)adenine,

9-(β

-D-arabinofuranosyl)guanine,

9-(β

-D-arabinofuranosyl)hypoxanthine,

3′

-azido-2′

,3′

-dideoxyadenosine,

3′

-azido-2′

,3′

-dideoxyguanosine,

3′

-azido-2′

,3′

-dideoxyinosine,

2′

,3′

-dideoxyinosine,

2′

,3′

-dideoxyadenosine,

2′

,3′

-dideoxyguanosine,

9-(2,3-dideoxy-1-β

-D-ribofuranosyl)-2,6-diaminopurine,

2′

,3′

-didehydro-2′

,3′

-dideoxyadenosine,

2′

,3′

-didehydro-2′

,3′

-dideoxyguanosine,

2′

,3′

-didehydro-2′

,3′

-dideoxyinosine,

3-deazaadenosine,

3-deazaguanosine,

3-deazainosine,

7-deazaadenosine,

7-deazaguanosine,

7-deazainosine,

9-(β

-D-ribofuranosyl)-6-thiopurine,

6-methylthio-9-(β

-D-ribofuranosyl)purine,

2-amino-9-(β

-D-ribofuranosyl)-6-thiopurine,

2-amino-6-methylthio-9-(β

-D-ribofuranosyl)purine,

2′

-C-methyladenosine,

2′

-C-methylguanosine,

2′

-C-methylinosine,

2′

-deoxy-2′

-fluoroadenosine,

2′

-deoxy-2′

-fluoroguanosine,

2′

-deoxy-2′

-fluoroinosine,

2′

-deoxy-2′

-fluoroarabinoadenosine,

2′

-deoxy-2′

-fluoroarabinoguanosine,

2′

-deoxy-2′

-fluoroarabinoinosine,

2′

-O-methyladenosine,

2′

-O-methylguanosine,

2′

-O-methylinosine,

2′

-C-ethynylguanosine,

2′

-C-ethynylinosine,

3′

-C-ethynyladenosine,

3′

-C-ethynylguanosine,

3′

-C-ethynylinosine,

3′

-deoxyadenosine,

3′

-deoxyguanosine,

3′

-deoxyinosine,

4′

-C-ethynyladenosine,

4′

-C-ethynylguanosine,

4′

-C-ethynylinosine,

4′

-C-methyladenosine,

4′

-C-methylguanosine,

4′

-C-methylinosine,

2′

-C-methyl-7-deazaadenosine,

2′

-C-methyl-7-deazaguano sine,

2′

-C-methyl-3-deazaadenosine,

2′

-C-methyl-3-deazaguanosine,

2′

-O-methyl-7-deazaadenosine,

2′

-O-methyl-7-deazaguanosine,

2′

-O-methyl-3-deazaadenosine,

2′

-O-methyl-3-deazaguanosine,

2′

-C-methyl-2-chloroadenosine,

2′

-deoxy-7-deazaadenosine,

2′

-deoxy-3-deazaadenosine,

2′

-deoxy-7-deazaguanosine,

2′

-deoxy-3-deazaguanosine,

2′

-deoxy-2-chloroadenosine,

2′

-deoxy-2-fluoroadenosine,

3′

-deoxy-7-deazaadenosine,

3′

-deoxy-7-deazaguanosine,

3′

-deoxy-3-deazaadenosine,

3′

-deoxy-3-deazaguanosine,

3′

-deoxy-2-chloroadenosine,

2′

,3′

-dideoxy-7-deazaadenosine,

2′

,3′

-dideoxy-7-deazaguanosine,

2′

,3′

-dideoxy-3-deazaadenosine,

2′

,3′

-dideoxy-3-deazaguanosine,

2′

,3′

-dideoxy-2-chloroadenosine,

2′

,3′

-dideoxy-β

-L-adenosine,

2′

,3′

-dideoxy-β

-L-guanosine,

2′

-deoxy-β

-L-adenosine,

2′

-deoxy-β

-L-guanosine,

2′

-deoxy-β

-L-inosine,

β

-L-adenosine,

β

-L-guanosine,

β

-L-inosine,

2′

,3′

-didehydro-2′

,3′

-dideoxy-β

-L-adenosine,

2′

,3′

-didehydro-2′

,3′

-dideoxy-β

-L-guanosine,

9-(β

-D-arabinofuranosyl)-2-fluoroadenine,

2′

,3′

-dideoxy-3′

-fluoroguanosine,

(±

)-(1α

,2β

,3α

)-9-[2,3-bis(hydroxymethyl)-1-cyclobutyl]adenine,

(±

)-(1α

,2β

,3α

)-9-[2,3-bis(hydroxymethyl)-1-cyclobutyl]guanine,

(±

)-(1β

,2α

,3β

)-9-[2,3-bis(hydroxymethyl)-1-cyclobutyl]guanine,

(±

)-(1β

,2α

,3β

)-9-[2,3-bis(hydroxymethyl)-1-cyclobutyl]adenine,

(1R,3S,4R)-9-(3-hydroxy-4-hydroxymethylcyclopent-1-yl)guanine,

(1S,2R,4R)-9-(1-hydroxy-2-hydroxymethylcyclopent-4-yl)guanine,

(2R,4R)-9-(2-hydroxymethyl-1,3-dioxolan-4-yl)-2,6-diaminopurine,

(2R,4R)-9-(2-hydroxymethyl-1,3-dioxolan-4-yl)guanine,

(1R,2S,4S)-9-(4-hydroxy-3-hydroxymethyl-2-methylenecyclopent-4-yl]guanine, and

(1S,3R,4S)-9-(3-hydroxy-4-hydroxymethyl-5-methylenecyclopent-1-yl]guanine.

43. The compound defined in claim 39 of Formula (XVIII):

44. The compound defined in claim 43 where Nu is selected from the group consisting of:

adenosine,

guanosine,

2′

-deoxyadenosine,

2′

-deoxyguanosine,

inosine,

9-(β

-D-arabinofuranosyl)adenine,

9-(β

-D-arabinofuranosyl)guanine,

9-(β

-D-arabinofuranosyl)hypoxanthine,

3′

-azido-2′

,3′

-dideoxyadenosine,

3′

-azido-2′

,3′

-dideoxyguanosine,

3′

-azido-2′

,3′

-dideoxyinosine,

2′

,3′

-dideoxyinosine,

2′

,3′

-dideoxyadenosine,

2′

,3′

-dideoxyguanosine,

9-(2,3-dideoxy-1-β

-D-ribofuranosyl)-2,6-diaminopurine,

2′

,3′

-didehydro-2′

,3′

-dideoxyadenosine,

2′

,3′

-didehydro-2′

,3′

-dideoxyguanosine,

2′

,3′

-didehydro-2′

,3′

-dideoxyinosine,

3-deazaadenosine,

3-deazaguanosine,

3-deazainosine,

7-deazaadenosine,

7-deazaguanosine,

7-deazainosine,

9-(β

-D-ribofuranosyl)-6-thiopurine,

6-methylthio-9-(β

-D-ribofuranosyl)purine,

2-amino-9-(β

-D-ribofuranosyl)-6-thiopurine,

2-amino-6-methylthio-9-(β

-D-ribofuranosyl)purine,

2′

-C-methyladenosine,

2′

-C-methylguanosine,

2′

-C-methylinosine,

2′

-deoxy-2′

-fluoroadenosine,

2′

-deoxy-2′

-fluoroguanosine,

2′

-deoxy-2′

-fluoroinosine,

2′

-deoxy-2′

-fluoroarabinoadenosine,

2′

-deoxy-2′

-fluoroarabinoguanosine,

2′

-deoxy-2′

-fluoroarabinoinosine,

2′

-O-methyladenosine,

2′

-O-methylguanosine,

2′

-O-methylinosine,

2′

-C-ethynylguanosine,

2′

-C-ethynylinosine,

3′

-C-ethynyladenosine,

3′

-C-ethynylguanosine,

3′

-C-ethynylinosine,

3′

-deoxyadenosine,

3′

-deoxyguanosine,

3′

-deoxyinosine,

4′

-C-ethynyladenosine,

4′

-C-ethynylguanosine,

4′

-C-ethynylinosine,

4′

-C-methyladenosine,

4′

-C-methylguanosine,

4′

-C-methylinosine,

2′

-C-methyl-7-deazaadenosine,

2′

-C-methyl-7-deazaguanosine,

2′

-C-methyl-3-deazaadenosine,

2′

-C-methyl-3-deazaguanosine,

2′

-O-methyl-7-deazaadenosine,

2′

-O-methyl-7-deazaguanosine,

2′

-O-methyl-3-deazaadenosine,

2′

-O-methyl-3-deazaguanosine,

2′

-C-methyl-2-chloroadenosine,

2′

-deoxy-7-deazaadenosine,

2′

-deoxy-3-deazaadenosine,

2′

-deoxy-7-deazaguanosine,

2′

-deoxy-3-deazaguanosine,

2′

-deoxy-2-chloroadenosine,

2′

-deoxy-2-fluoroadenosine,

3′

-deoxy-7-deazaadenosine,

3′

-deoxy-7-deazaguanosine,

3′

-deoxy-3-deazaadenosine,

3′

-deoxy-3-deazaguanosine,

3′

-deoxy-2-chloroadenosine,

2′

,3′

-dideoxy-7-deazaadenosine,

2′

,3′

-dideoxy-7-deazaguanosine,

2′

,3′

-dideoxy-3-deazaadenosine,

2′

,3′

-dideoxy-3-deazaguanosine,

2′

,3′

-dideoxy-2-chloroadenosine,

2′

,3′

-dideoxy-β

-L-adenosine,

2′

,3′

-dideoxy-β

-L-guanosine,

2′

-deoxy-β

-L-adenosine,

2′

-deoxy-β

-L-guanosine,

2′

-deoxy-β

-L-inosine,

β

-L-adenosine,

β

-L-guanosine,

β

-L-inosine,

2′

,3′

-didehydro-2′

,3′

-dideoxy-β

-L-adenosine,

2′

,3′

-didehydro-2′

,3′

-dideoxy-β

-L-guanosine,

9-(β

-D-arabinofuranosyl)-2-fluoroadenine,

2′

,3′

-dideoxy-3′

-fluoroguanosine,

(±

)-(1α

,2β

,3α

)-9-[2,3-bis(hydroxymethyl)-1-cyclobutyl]adenine,

(±

)-(1α

,2β

,3α

)-9-[2,3-bis(hydroxymethyl)-1-cyclobutyl]guanine,

(±

)-(1β

,2α

,3β

)-9-[2,3-bis(hydroxymethyl)-1-cyclobutyl]guanine,

(±

)-(1β

,2α

,3β

)-9-[2,3-bis(hydroxymethyl)-1-cyclobutyl]adenine,

(1R,3S,4R)-9-(3-hydroxy-4-hydroxymethylcyclopent-1-yl)guanine,

(1S,2R,4R)-9-(1-hydroxy-2-hydroxymethylcyclopent-4-yl)guanine,

(2R,4R)-9-(2-hydroxymethyl-1,3-dioxolan-4-yl)-2,6-diaminopurine,

(2R,4R)-9-(2-hydroxymethyl-1,3-dioxolan-4-yl)guanine,

(1R,2S,4S)-9-(4-hydroxy-3-hydroxymethyl-2-methylenecyclopent-4-yl]guanine, and

(1S,3R,4S)-9-(3-hydroxy-4-hydroxymethyl-5-methylenecyclopent-1-yl]guanine.

45. The compound defined in claim 39 Formula (XIX):

49. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 39, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable prodrug thereof, optionally in combination with one or more other active ingredients and/or with a pharmaceutically acceptable carrier.

57. A compound having the formula: