Cyclic phosphate diesters of 1,3-propane-1-aryl diols and their use in preparing prodrugs

1. A method of making a compound of Formula II.A or Formula II.B or salt thereof

said method comprising:

(a) isomerizing a mixture of trans/cis isomers of the compound of Formula I to give a ratio of trans/cis of about 85/15 or greater;

wherein:

V and L are trans relative to one another;

V is selected from the group consisting of heteroaryl, and phenyl, all optionally substituted with 1–4 substituents;

L is selected from the group consisting of halogen, and aryloxy optionally substituted with 1–2 substituents; and

(b) reacting the compound of Formula I having the ratio of trans/cis isomers of about 85/15 or greater, or salt thereof, with MH, wherein:

MH is selected from the group consisting of protected and unprotected oncolytic agents and antiviral agents and wherein:

H is attached to O, S, or N of said oncolytic and antiviral agents; and

M is attached to phosphorus via an oxygen, nitrogen or sulfur atom.

2. The method of claim 1 , wherein said isomerizing comprises treating the mixture of trans/cis isomers of the compound of Formula I with L − to give the ratio of trans/cis isomers of about 85/15 or greater.

3. The method of claim 1 , wherein said isomerizing comprises heating the mixture of trans/cis isomers of the compound of Formula I to give the ratio of trans/cis isomers of about 85/15 or greater.

4. The method of claim 3 , wherein said heating is from 40° C. to 70° C.

5. The method of claim 1 , wherein said isomerizing comprises isolating the cis isomer from the mixture of trans/cis isomers of Formula I and treating the cis isomer with L − to give the ratio of trans/cis isomers of about 85/15 or greater.

6. The method of claim 1 , wherein M is attached to phosphorus via an oxygen present in a primary hydroxyl on MH.

7. The method of claim 1 , wherein M is attached to phosphorus via an oxygen present in a hydroxyl group on an acyclic sugar in MH.

8. The method of claim 1 , wherein MH is reacted with the compound of Formula I in the presence of a base.

9. The method of claim 1 , wherein MH is a protected nucleoside and further comprising the steps of:

forming an anion of MH with a base; and

adding the compound of Formula I or salt thereof to said anion.

10. The method of claim 1 , wherein MH is an unprotected nucleoside, and wherein the compound of Formula I or salt thereof is added to MH or salt thereof.

11. The method of claim 8 , wherein said base is R′MgX′ wherein:

R′ is selected from the group consisting of C1–C5 alkyl, and aryl optionally substituted with 1–3 substituents; and

X′ is halogen.

12. The method of claim 11 , wherein said base is selected from the group consisting of tert-BuMgCl, and phenylMgCl.

13. The method of claim 11 , wherein said base is tert-BuMgCl.

14. The method of claim 1 , further comprising:

forming an anion of a protected nucleoside with a base;

adding a Lewis acid; and

adding the compound of Formula I.

15. The method of claim 1 , wherein MH is a nucleoside, and further comprising:

forming an anion of MH with a base;

adding a Mg salt; and

generating the Mg salt of said anion.

16. The method of claim 15 , wherein said base is selected from the group consisting of alkali hydride, organometallic base, trialkylamine, and N-containing heteroaryl base.

17. The method of claim 15 , wherein:

said base is selected from the group consisting of sodium hydride (NaH), lithium hydride (LiH), lithium diethylamide (LDA), lithium hexamethyldisilazide (LHMDS), potassium t-butoxide (t-BuOK), butyl lithium (BuLi), triethylamine (Et 3 N), diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), diazabicyclo[2.2.2]octane (DABCO), and pyridine.

18. The method of claim 15 , wherein said salt is selected from the group consisting of MgCl 2 , MgBr 2 , and MgI 2 .

19. The method of claim 15 , wherein said base is NaH and said salt is MgCl 2 .

20. The method of claim 15 , wherein said base is t-BuOK and said salt is MgCl 2 .

21. The method of claim 15 , wherein said base is BuLi and said salt is MgCl 2 .

22. The method of claim 15 , wherein said base is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and said salt is MgCl 2 .

23. The method of claim 15 , wherein said base is Et 3 N and said salt is MgCl 2 .

24. The method of claim 1 , wherein said oncolytic agent or antiviral agent is selected from the group consisting of araA (9-β-D-arabinofuranosyladenine); AZT (3′-azido-2′,3′-dideoxythymidine); d4T (2′,3′-didehydro-3′-deoxythymidine); ddI (2′,3′-dideoxyinosine); ddA (2′,3′-dideoxyadenosine); ddC (2′,3′-dideoxycytidine); L-ddC (L-2′,3′-dideoxycytidine); L-FddC (L-2′,3′-dideoxy-5-fluorocytidine); L-d4C (β-L-2′,3′-didehydro-2′,3′-dideoxy-cytidine); L-Fd4C (β-L-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine); 3TC ((−)-2′,3′-dideoxy-3′-thiacytidine); ribavirin (1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide); 5-fluoro-2′-deoxyuridine; FIAU (1-(2′-deoxy-2′-fluoro-β-D-arabinofuranosyl)-5-iodouridine); FIAC (1-(2′-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-iodocytosine); BHCG ((±)-(1α,2α,3α)-9-[2′,3′-bis(hydroxymethyl)cyclobutyl]-guanine); L-FMAU (2′-Fluoro-5-methyl-β-L-arabinofuranosyluracil); BvaraU (1′-β-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil); E-5-(2-bromovinyl)-2′-deoxyuridine); TFT (Trifluorothymidine); 5-propynyl-1′-arabinofuranosyluracil; CDG (carbocyclic 2′-deoxyguanosine); DAPD ((−)-β-D-2,6-diaminopurine dioxolane); FDOC ((−)-β-D-5-fluoro-1-[2′-(hydroxymethyl)-1′,3′-dioxolane]cytosine); d4C (-2′,3′-didehydro-2′,3′-dideoxy-cytidine); DXG (dioxolane guanosine); FEAU (2′-deoxy-2′-fluoro-1′-β-D-arabinofuranosyl-5-ethyluracil); FLG (2′,3′-dideoxy-3′-fluoroguanosine); FTC ((−)-cis-5-fluoro-1-[2′-(hydroxymethyl)-1′,3′-oxathiolan-5′-yl]-cytosine); L-dC (β-L-2′-deoxycytosine); L-dT (β-L-2′-deoxythymidine); 5-yl-carbocyclic-2′-deoxyguanosine; oxetanocin A (9-(2′-deoxy-2′-hydroxymethyl-β-D-erythro-oxetanosyl)adenine); oxetanocin G (9-(2′-deoxy-2′-hydroxymethyl-β-D-erythro-oxetanosyl)guanine); Cyclobut A ((+/−)-9-[(1′-β,2′-α,3′-β)-2′,3′-bis(hydroxymethyl)-1′-cyclobutyl]adenine); Cyclobut G ((+/−)-9-[(1′-β,2′-α,3′-β)-2,3-bis(hydroxymethyl)-1-cyclobutyl]guanine); dFdC (2′,2′-difluoro-2′-deoxycytidine); araC (arabinofuranosylcytosine); bromodeoxyuridine; IDU (5-iodo-2′-deoxyuridine); CdA (2-chloro-2′-deoxyadenosine); FaraA (2-fluoroarabinofuranosyladenosine); Coformycin; 2′-deoxycoformycin; araT (1-β-D-arabinofuranoside thymidine); tiazofurin; ddAPR (2,6-diaminopurine-2′,3′-dideoxyriboside); 9-(arabinofuranosyl)-2,6-diaminopurine; 9-(2′-deoxyribofuranosyl)-2,6-diaminopurine; 9-(2′-deoxy-2′-fluororibofuranosyl)-2,6-diaminopurine; 9-(arabinofuranosyl)guanine; 9-(2′-deoxyribofuranosyl)guanine; 9-(2′-deoxy-2′-fluororibofuranosyl)guanine; FMDC ((E)-2′-deoxy-2′(fluoromethylene)cytidine); DMDC (2′-deoxy-2′-methyledene-cytidine); 4′-thio-araC (4′-thio-arabinofuranosyl-cytidine); 5,6 dihydro-5-azacytidine; 5-azacytidine; 5-aza-2′-deoxycytidine; AICAR (5-aminoimidazole-4-carboxamido-1-ribofuranosyl); NK-84-0218; AM365; MCC 478 ; ICN 2001; Fluor L and D nucleosides; Famoiclovir (2-[2-(2-amino-9H-purin-9-yl)ethyl]-1,3-propanediol diacetate); ACV (9-(2′-hydroxyethoxylmethyl)guanine); GCV (9-(1′,3′-dihydroxy-2′-propoxymethyl)guanine); penciclovir (9-(4′-hydroxy-3′-hydroxymethylbut-1′-yl)guanine); (R)-9-(3′,4′-dihydroxybutyl)guanine, cytallene (1-(4′-hydroxy-1′,2′-butadienyl)cytosine), and 2′-β-methyl-ribofuranosyl nucleosides of Formula III:

wherein:

B is selected from the group consisting of

wherein:

A, G, and L′ are each independently CH or N;

D is N, CH, C—CN, C—NO 2 , C—C 1-3 alkyl, C—NHCONH 2 , C—CONR 11 R 11 , C—CSNR 11 R 11 , C—COOR 11 , C—C(═NH)NH 2 , C-hydroxy, C—C 1-3 alkoxy, C-amino, C—C 1-4 alkylamino, C-di(C 1-4 alkyl)amino, C-halogen, C-(1,3oxazol-2-yl), C-(1,3-thiazol-2-yl), or C-(imidazol-2-yl); wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, amino, hydroxy, carboxy, and C 1-3 alkoxy;

E is N or CR 5 ;

W is O or S;

R 5 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkylamino, CF 3 , or halogen;

R 6 is H, OH, SH, NH 2 , C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 3-6 cycloalkylamino, halogen, C 1-4 alkyl, C 1-4 alkoxy, or CF 3 ;

R 7 is H, amino, C 1-4 alkylamino, C 3-6 cycloalkylamino, or di(C 1-4 alkyl)amino;

R 8 is H, halogen, CN, carboxy, C 1-4 alkyloxycarbonyl, N 3 , amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulfonyl, or (C 1-4 alkyl) 0-2 aminomethyl;

R 11 is H or C 1-6 alkyl; and

R 14 is H, CF 3 , C 1-4 alkyl, amino, C 1-4 alkylamino, C 3-6 cycloalkylamino, or di(C 1-4 alkyl)amino.

25. A method of making a compound of Formula II.A or Formula II.B or salt thereof, said method comprising:

(a) isomerizing a mixture of trans/cis isomers of the compound of Formula I to give a ratio of trans/cis of about 85/15 or greater;

wherein:

V and L are trans relative to one another;

V is selected from the group consisting of heteroaryl, and phenyl, all optionally substituted with 1–4 substituents;

L is selected from the group consisting of halogen, and aryloxy optionally substituted with 1–2 substituents; and

(b) reacting the compound of Formula I having the ratio of trans/cis isomers of about 85/15 or greater, or salt thereof, with MH, wherein M is a nucleoside residue of Formula III;

wherein:

B is selected from the group consisting of

wherein:

A, G, and L′ are each independently CH or N;

D is N, CH, C—CN, C—NO 2 , C—C 1-3 alkyl, C—NHCONH 2 , C—CONR 11 R 11 , C—CSNR 11 R 11 , C—COOR 11 , C—C(═NH)NH 2 , C-hydroxy, C—C 1-3 alkoxy, C-amino, C—C 1-4 alkylamino, C-di(C 1-4 alkyl)amino, C-halogen, C-(1,3oxazol-2-yl), C-(1,3-thiazol-2-yl), or C-(imidazol-2-yl); wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, amino, hydroxy, carboxy, and C 1-3 alkoxy;

E is N or CR 5 ;

W is O or S;

R 5 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkylamino, CF 3 , or halogen;

R 6 is H, OH, SH, NH 2 , C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 3-6 cycloalkylamino, halogen, C 1-4 alkyl, C 1-4 alkoxy, or CF 3 ;

R 7 is H, amino, C 1-4 alkylamino, C 3-6 cycloalkylamino, or di(C 1-4 alkyl)amino;

R 8 is H, halogen, CN, carboxy, C 1-4 alkyloxycarbonyl, N 3 , amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulfonyl, or (C 1-4 alkyl) 0-2 aminomethyl;

R 11 is H or C 1-6 alkyl; and

R 14 is H, CF 3 , C 1-4 alkyl, amino, C 1-4 alkylamino, C 3-6 cycloalkylamino, or di(C 1-4 alkyl)amino.

26. The method of claim 25 , wherein said isomerizing comprises treating the compound of Formula I with L − to give the ratio of trans/cis isomers of about 85/15 or greater.

27. The method of claim 25 , wherein said isomerizing comprises heating the compound of Formula I to give the ratio of trans/cis isomers of about 85/15 or greater.

28. The method of claim 27 , wherein said heating is from 40° C. to 70° C.

29. The method of claim 25 , wherein said isomerizing comprises isolating the cis isomer from the mixture of trans/cis isomers of Formula I and treating the cis isomer with L − to give the ratio of trans/cis isomers of about 85/15 or greater.

30. The method of claim 25 , wherein B is selected from the group consisting of

wherein:

D is N, CH, C—CN, C—NO 2 , C—C 1-3 alkyl, C—NHCONH 2 , C—CONR 11 R 11 , C—COOR 11 , C-hydroxy, C—C 1-3 alkoxy, C-amino, C—C 1-4 alkylamino, C-di(C 1-4 alkyl)amino, or C-halogen;

E is N or CR 5 ;

R 5 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkylamino, CF 3 , or halogen;

R 6 is H, OH, SH, NH 2 , C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 3-6 cycloalkylamino, halogen, C 1-4 alkyl, C 1-4 alkoxy, or CF 3 ;

R 7 is H, amino, C 1-4 alkylamino, C 3-6 cycloalkylamino, or di(C 1-4 alkyl)amino;

R 8 is H, halogen, CN, carboxy, C 1-4 alkyloxycarbonyl, N 3 , amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulfonyl, or (C 1-4 alkyl) 0-2 aminomethyl;

R 11 is H or C 1-6 alkyl.

31. The method of claim 25 , wherein B is selected from the group consisting of

wherein:

D is N, CH, or C-halogen

E is N or C-Me;

R 6 is OH, or NH 2 ;

R 7 is H or amino;

R 8 is H or halogen.

32. The method of claim 25 , wherein B is selected from the group consisting of

33. A method for the preparation of a compound of Formula V, said method comprising:

(a) isomerizing a mixture of trans/cis isomers of the compound of Formula IV to give the compound of Formula IV wherein the ratio of trans/cis isomers is about 85/15 or greater;

wherein L is selected from the group consisting of chloro and 4-nitrophenoxy, and

(b) coupling the compound of Formula IV having the ratio of trans/cis isomers of about 85/15 or greater, with optionally protected cytarabine.

34. The method of claim 33 , wherein said isomerizing comprises treating the mixture of trans/cis isomers of the compound of Formula IV with L − to give the ratio of trans/cis isomers of about 85/15 or greater.

35. The method of claim 33 , wherein said isomerizing comprises heating the mixture of trans/cis isomers of the compound of Formula IV to give the ratio of trans/cis isomers of about 85/15 or greater.

36. The method of claim 35 , wherein said heating is from 40° C. to 70° C.

37. The method of claim 33 , wherein said isomerizing comprises isolating the cis isomer from the mixture of trans/cis isomers of Formula IV and treating the cis isomer with L − to give the ratio of trans/cis isomers of about 85/15 or greater.

38. The method of claim 33 , wherein a base is used in the coupling reaction in (b).

39. The method of claim 38 , wherein said base is RMgX wherein:

R is C1–C5 alkyl; and

X is halogen.

40. The method of claim 39 , wherein said base is t-BuMgCl.

41. The method of claim 33 , wherein the hydroxyl groups and 4-amino group of cytarabine are protected.

42. The method of claim 41 , wherein the 4-amino of cytarabine is protected as a dimethylformamidine.

43. The method of claim 33 , wherein a protecting group for the 2′ and 3′ hydroxyl groups of cytarabine is selected from the group consisting of trialkylsilyl ether, optionally substituted methoxy methyl (MOM) ether, and optionally substituted 2-methoxyethoxy methyl (MEM) ether.

44. The method of claim 33 , wherein said protecting group for 2′ and 3′ hydroxyl groups of cytarabine is t-butyldimethylsilyl ether.

45. The method of claim 33 , wherein the hydroxyl groups and 4-amino group of cytarabine are not protected.

46. The method of claim 45 , wherein L is chloro.

47. The method of claim 33 , further comprising: forming an anion of said optionally protected cytarabine with a base; adding a Mg salt; and generating the Mg salt of the anion of said optionally protected cytarabine.

48. The method of claim 47 , wherein said base is selected from the group consisting of alkali hydride, organometallic base, trialkylamine, and N-containing heteroaryl base.

49. The method of claim 47 , wherein said salt is selected from the group consisting of MgCl 2 , MgBr 2 , and MgI 2 .

50. The method of claim 47 , wherein said base is NaH and said salt is MgCl 2 .

51. The method of claim 47 , wherein said base is t-BuOK and said salt is MgCl 2 .

52. The method of claim 47 , wherein said base is BuLi and said salt is MgCl 2 .

53. The method of claim 47 , wherein said base is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and said salt is MgCl 2 .

54. The method of claim 47 , wherein said base is Et 3 N and said salt is MgCl 2 .

55. The method of claim 33 , further comprising:

using t-BuMgCl as a base;

using the compound of Formula IV

wherein:

L is 4-nitrophenoxy; and

said optionally protected cytarabine has the 2′ and 3′ hydroxyl groups protected as t-butyldimethylsilyl ethers and the 4 amino group protected as dimethylformamidine.

56. A method of making a compound of Formula II.A or Formula II.B or salt thereof

said method comprising:

(a) isomerizing a mixture of trans/cis isomers of the compound of Formula I to give a ratio of trans/cis of about 85/15 or greater;

wherein:

V and L are trans relative to one another;

V is selected from the group consisting of heteroaryl, and phenyl, all optionally substituted with 1–4 substituents;

L is selected from the group consisting of halogen, and aryloxy optionally substituted with 1–2 substituents; and

(b) reacting the compound of Formula I having the ratio of trans/cis isomers of about 85/15 or greater, or salt thereof, with MH, wherein:

MH is a nucleoside, and wherein:

H is attached to O, S, or N of said nucleoside; and

M is attached to phosphorus via an oxygen, nitrogen or sulfur atom.

57. The method of claim 56 , wherein said isomerizing comprises treating the mixture of trans/cis isomers of the compound of Formula I with L − to give the ratio of trans/cis isomers of about 85/15 or greater.

58. The method of claim 56 , wherein said isomerizing comprises heating the mixture of trans/cis isomers of the compound of Formula I to give the ratio of trans/cis isomers of about 85/15 or greater.

59. The method of claim 58 , wherein said heating is from 40° C. to 70° C.

60. The method of claim 56 , wherein said isomerizing comprises isolating the cis isomer from the mixture of trans/cis isomers of Formula I and treating the cis isomer with L − to give the ratio of trans/cis isomers of about 85/15 or greater.

61. The method of claim 56 , wherein M is attached to phosphorus via an oxygen present in a primary hydroxyl on MH.

62. The method of claim 56 , wherein M is a nucleoside in which the sugar is acyclic.

63. The method of claim 62 , wherein M is attached to phosphorus via an oxygen present in a hydroxyl group on the acyclic sugar in MH.

64. The method of claim 56 , wherein MH is reacted with the compound of Formula I in the presence of a base.

65. The method of claim 56 , wherein MH is a protected nucleoside and further comprising the steps of:

forming an anion of MH with a base; and

adding the compound of Formula I or salt thereof to said anion.

66. The method of claim 56 , wherein MH is an unprotected nucleoside, and wherein the compound of Formula I or salt thereof is added to MH or salt thereof.

67. The method of claim 64 , wherein said base is R′MgX′ wherein:

R′ is selected from the group consisting of C1–C5 alkyl, and aryl optionally substituted with 1–3 substituents; and

X′ is halogen.

68. The method of claim 67 , wherein said base is selected from the group consisting of tert-BuMgCl, and phenylMgCl.

69. The method of claim 67 , wherein said base is tert-BuMgCl.

70. The method of claim 56 , further comprising:

forming an anion of a protected nucleoside with a base;

adding a Lewis acid; and

adding the compound of Formula I.

71. The method of claim 56 , wherein MH is a nucleoside, and further comprising:

forming an anion of MH with a base;

adding a Mg salt; and

generating the Mg salt of said anion.

72. The method of claim 71 , wherein said base is selected from the group consisting of alkali hydride, organometallic base, trialkylamine, and N-containing heteroaryl base.

73. The method of claim 71 , wherein:

said base is selected from the group consisting of sodium hydride (NaH), lithium hydride (LiH), lithium diethylamide (LDA), lithium hexamethyldisilazide (LHMDS), potassium t-butoxide (t-BuOK), butyl lithium (BuLi), triethylamine (Et 3 N), diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), diazabicyclo[2.2.2]octane (DABCO), and pyridine.

74. The method of claim 71 , wherein said salt is selected from the group consisting of MgCl 2 , MgBr 2 , and MgI 2 .

75. The method of claim 71 , wherein said base is NaH and said salt is MgCl 2 .

76. The method of claim 71 , wherein said base is t-BuOK and said salt is MgCl 2 .

77. The method of claim 71 , wherein said base is BuLi and said salt is MgCl 2 .

78. The method of claim 71 , wherein said base is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and said salt is MgCl 2 .

79. The method of claim 71 , wherein said base is Et 3 N and said salt is MgCl 2 .

80. The method of claim 56 , wherein said nucleoside is selected from the group consisting of araA (9-β-D-arabinofuranosyladenine); AZT (3′-azido-2′,3′-dideoxythymidine); d4T (2′,3′-didehydro-3′-deoxythymidine); ddI (2′,3′-dideoxyinosine); ddA (2′,3′-dideoxyadenosine); ddC (2′,3′-dideoxycytidine); L-ddC (L-2′,3′-dideoxycytidine); L-FddC (L-2′,3′-dideoxy-5-fluorocytidine); L-d4C (β-L-2′,3′-didehydro-2′,3′-dideoxy-cytidine); L-Fd4C (β-L-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine); 3TC ((−)-2′,3′-dideoxy-3′-thiacytidine); ribavirin (1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide); 5-fluoro-2′-deoxyuridine; FIAU (1-(2′-deoxy-2′-fluoro-β-D-arabinofuranosyl)-5-iodouridine); FIAC (1-(2′-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-iodocytosine); BHCG ((±)-(1α,2α,3α)-9-[2′,3′-bis(hydroxymethyl)cyclobutyl]-guanine); L-FMAU (2′-Fluoro-5-methyl-β-L-arabinofuranosyluracil); BvaraU (1′-β-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil); E-5-(2-bromovinyl)-2′-deoxyuridine); TFT (Trifluorothymidine); 5-propynyl-1′-arabinofuranosyluracil; CDG (carbocyclic 2′-deoxyguanosine); DAPD ((−)-β-D-2,6-diaminopurine dioxolane); FDOC ((−)-β-D-5-fluoro-1-[2′-(hydroxymethyl)-1′,3′-dioxolane]cytosine); d4C (-2′,3′-didehydro-2′,3′-dideoxy-cytidine); DXG (dioxolane guanosine); FEAU (2′-deoxy-2′-fluoro-1′-β-D-arabinofuranosyl-5-ethyluracil); FLG (2′,3′-dideoxy-3′-fluoroguanosine); FTC ((−)-cis-5-fluoro-1-[2′-(hydroxymethyl)-1′,3′-oxathiolan-5′-yl]-cytosine); L-dC (β-L-2′-deoxycytosine); L-dT (β-L-2′-deoxythymidine); 5-yl-carbocyclic-2′-deoxyguanosine; oxetanocin A (9-(2′-deoxy-2′-hydroxymethyl-β-D-erythro-oxetanosyl)adenine); oxetanocin G (9-(2′-deoxy-2′-hydroxymethyl-β-D-erythro-oxetanosyl)guanine); Cyclobut A ((+/−)-9-[(1′-β,2′-α,3′-β)-2′,3′-bis(hydroxymethyl)-1′-cyclobutyl]adenine); Cyclobut G ((+/−)-9-[(1′-β,2′-α,3′-β)-2,3-bis(hydroxymethyl)-1-cyclobutyl]guanine); dFdC (2′,2′-difluoro-2′-deoxycytidine); araC (arabinofuranosylcytosine); bromodeoxyuridine; IDU (5-iodo-2′-deoxyuridine); CdA (2-chloro-2′-deoxyadenosine); FaraA (2-fluoroarabinofuranosyladenosine); Coformycin; 2′-deoxycoformycin; araT (1-β-D-arabinofuranoside thymidine); tiazofurin; ddAPR (2,6-diaminopurine-2′,3′-dideoxyriboside); 9-(arabinofuranosyl)-2,6-diaminopurine; 9-(2′-deoxyribofuranosyl)-2,6-diaminopurine; 9-(2′-deoxy-2′-fluororibofuranosyl)-2,6-diaminopurine; 9-(arabinofuranosyl)guanine; 9-(2′-deoxyribofuranosyl)guanine; 9-(2′-deoxy2′-fluororibofuranosyl)guanine; FMDC ((E)-2′-deoxy-2′(fluoromethylene)cytidine); DMDC (2′-deoxy-2′-methyledene-cytidine); 4′-thio-araC (4′-thio-arabinofuranosyl-cytidine); 5,6 dihydro-5-azacytidine; 5-azacytidine; 5-aza-2′-deoxycytidine; AICAR (5-aminoimidazole-4-carboxamido-1-ribofuranosyl); NK-84-0218; AM365; MCC 478 ; ICN 2001; Fluor L and D nucleosides; Famciclovir (2-[2-(2-amino-9H-purin-9-yl)ethyl]-1,3-propanediol diacetate); ACV (9-(2′-hydroxyethoxylmethyl)guanine); GCV (9-(1′,3′-dihydroxy-2′-propoxymethyl)guanine); penciclovir (9-(4′-hydroxy-3′-hydroxymethylbut-1′-yl)guanine); (R)-9-(3′,4′-dihydroxybutyl)guanine, cytallene (1-(4′-hydroxy-1′,2′-butadienyl)cytosine), and 2′-β-methyl-ribofuranosyl nucleosides of Formula III:

wherein:

B is selected from the group consisting of

wherein:

A, G, and L′ are each independently CH or N;

D is N, CH, C—CN, C—NO 2 , C—C 1-3 alkyl, C—NHCONH 2 , C—CONR 11 R 11 , C—CSNR 11 R 11 , C—COOR 11 , C—C(═NH)NH 2 , C-hydroxy, C—C 1-3 alkoxy, C-amino, C—C 1-4 alkylamino, C-di(C 1-4 alkyl)amino, C-halogen, C-(1,3oxazol-2-yl), C-(1,3-thiazol-2-yl), or C-(imidazol-2-yl); wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, amino, hydroxy, carboxy, and C 1-3 alkoxy;

E is N or CR 5 ;

W is O or S;

R 5 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkylamino, CF 3 , or halogen;

R 6 is H, OH, SH, NH 2 , C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 3-6 cycloalkylamino, halogen, C 1-4 alkyl, C 1-4 alkoxy, or CF 3 ;

R 7 is H, amino, C 1-4 alkylamino, C 3-6 cycloalkylamino, or di(C 1-4 alkyl)amino;

R 8 is H, halogen, CN, carboxy, C 1-4 alkyloxycarbonyl, N 3 , amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulfonyl, or (C 1-4 alkyl) 0-2 aminomethyl;

R 11 is H or C 1-6 alkyl; and

R 14 is H, CF 3 , C 1-4 alkyl, amino, C 1-4 alkylamino, C 3-6 cycloalkylamino, or di(Ci 1-4 alkyl)amino.