PURINE NUCLEOSIDE ANALOGUES FOR TREATING FLAVIVIRIDAE INCLUDING HEPATITIS C

• US 20090169507A1
• Filed: 11/13/2008
• Published: 07/02/2009
• Est. Priority Date: 07/25/2003
• Status: Active Grant

• Current Assignee: Centre National De La Recherche Scientifique, Idenix Pharmaceuticals (Merck & Co., Inc.), Universite Montpellier II
• Original Assignee: Centre National De La Recherche Scientifique, Idenix Pharmaceuticals (Merck & Co., Inc.)
• Inventors: Dukhan, David, Gosselin, Gilles, Leroy, Frederic, Storer, Richard
• Granted Patent: US 8,742,101 B2
• Time in Patent Office: Days
• US Class Current: 424/85.400
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/706 containing six-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• CPC Class Codes: C07H 19/044 Pyrrole radicals
• CPC Class Codes: C07H 19/052 Imidazole radicals
• CPC Class Codes: C07H 19/056 Triazole or tetrazole radicals
• CPC Class Codes: C07H 19/23 Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22

Abstract

This invention is directed to a method for treating a host, especially a human, infected with hepatitis C, flavivirus and/or pestivirus, comprising administering to that host an effective amount of an anti-HCV biologically active pentofuranonucleoside where the pentofuranonucleoside base is an optionally substituted 2-azapurine. The optionally substituted pentofuranonucleoside, or a salt or prodrug thereof, may be administered alone or in combination with one or more optionally substituted pentofuranonucleosides or other anti-viral agents.

Claims

1. A method of treating a host infected with a flavivirus or pestivirus, comprising administering an effective amount of an anti-pestivirus or anti-flavivirus biologically active ribofuranonucleoside of Formula (I):

or a pharmacologically acceptable salt or prodrug thereof, wherein;

R is H, mono-, di-, or triphosphate, a stabilized phosphate, or phosphonate;

X is O, S[O]_n, CH₂, CHOH, CH-alkyl, CH-alkenyl, CH-alkynyl, C-dialkyl, CH—

O-alkyl, CH—

O-alkenyl, CH—

O-alkynyl, CH—

S-alkyl, CH—

S-alkenyl, CH—

S-alkynyl, NH, N-alkyl, N-alkenyl, N-alkynyl, S(O)N-alkyl, S(O)N-alkenyl, S(O)N-alkynyl, SCH-halogen, or C-(halogen)₂, wherein alkyl, alkenyl or alkynyl may optionally be substituted;

n is 0-2;

such than when X is CH₂, CHOH, CH-alkyl, CH-alkenyl, CH-alkynyl, C-dialkyl, CH—

O-alkyl, CH—

O-alkenyl, CH—

O-alkynyl, CH—

S-alkyl, CH—

S-alkenyl, CH—

S-alkynyl, CH-halogen, or C-(halogen)₂,

then each R¹ and R^1′

is independently H, OH, optionally substituted alkyl, lower alkyl, azido, cyano, optionally substituted alkenyl or alkynyl, —

C(O)O-(alkyl), —

C(O)O(lower alkyl), —

C(O)O-(alkenyl), —

C(O)O-(alkynyl), —

O(acyl), —

O(lower acyl), —

O(alkyl), —

O(lower alkyl), —

O(alkenyl), —

O(alkynyl), halogen, halogenated alkyl, —

NO₂, —

NH₂, —

NH(lower alkyl), —

N(lower alkyl)₂, —

NH(acyl), —

N(acyl)₂, —

C(O)NH₂, —

C(O)NH(alkyl), —

C(O)N(alkyl)₂, S(O)N-alkyl, S(O)N-alkenyl, S(O)N-alkynyl, SCH-halogen, wherein alkyl, alkenyl, and/or alkynyl may optionally be substituted; and

such that when X is O, S[O]_n, NH, N-alkyl, N-alkenyl, N-alkynyl, S(O)N-alkyl, S(O)N-alkenyl, S(O)N-alkynyl, or SCH-halogen,

then each R¹ and R^1′

is independently H, optionally substituted alkyl, lower alkyl, azido, cyano, optionally substituted alkenyl or alkynyl, —

C(O)O-(alkyl), —

C(O)O(lower alkyl), —

C(O)O-(alkenyl), —

C(O)O-(alkynyl), halogenated alkyl, —

C(O)NH₂, —

C(O)NH(alkyl), —

C(O)N(alkyl)₂, —

C(H)═

N—

NH₂, C(S)NH₂, C(S)NH(alkyl), or C(S)N(alkyl)₂, wherein alkyl, alkenyl and/or alkynyl may optionally be substituted;

each R² and R³ independently is OH, NH₂, SH, F, Cl, Br, I, CN, NO₂, —

C(O)NH₂, —

C(O)NH(alkyl), and —

C(O)N(alkyl)₂, N₃, optionally substituted alkyl, lower alkyl, optionally substituted alkenyl or alkynyl, halogenated alkyl, —

C(O)O-(alkyl), —

C(O)O(lower alkyl), —

C(O)O-(alkenyl), —

C(O)O-(alkynyl), —

O(acyl), —

O(alkyl), —

O(alkenyl), —

O(alkynyl), —

OC(O)NH₂, NC, C(O)OH, SCN, OCN, —

S(alkyl), —

S(alkenyl), —

S(alkynyl), —

NH(alkyl), —

N(alkyl)₂, —

NH(alkenyl), —

NH(alkynyl), an amino acid residue or derivative, a prodrug or leaving group that provides OH in vivo, or an optionally substituted 3-7 membered heterocyclic ring having O, S and/or N independently as a heteroatom taken alone or in combination;

each R^2′

and R^3′

independently is H;

optionally substituted alkyl, alkenyl, or alkynyl;

—

C(O)O(alkyl), —

C(O)O(lower alkyl), —

C(O)O(alkenyl), —

C(O)O(alkynyl), —

C(O)NH₂, —

C(O)NH(alkyl), —

C(O)N(alkyl)₂, —

O(acyl), —

O(lower acyl), —

O(alkyl), —

O(lower alkyl), —

O(alkenyl), halogen, halogenated alkyl and particularly CF₃, azido, cyano, NO₂, —

S(alkyl), —

S(alkenyl), —

S(alkynyl), NH₂, —

NH(alkyl), —

N(alkyl)₂, —

NH(alkenyl), —

NH(alkynyl), —

NH(acyl), or —

N(acyl)₂, and R₃ at 3′

-C may also be OH; and

Base is selected from the group consisting of;

wherein

each R′ and

R″

independently is H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, halogen, halogenated alkyl, OH, CN, N₃, carboxy, C_1-4alkoxycarbonyl, NH₂, C_1-4 alkylamino, di(C_1-4 alkyl)amino, C_1-6 alkoxy, C_1-6 alkylsulfonyl, (C_1-4 alkyl)_0-2 aminomethyl;

each W is Cl, Br, I, F, halogenated alkyl, alkoxy, OH, SH, O-alkyl, S-alkyl, O-alkenyl, O-alkynyl, S-alkenyl, S-alkynyl, —

OC(O)NR⁴R⁴, O-acyl, S-acyl, CN, SCN, OCN, NO₂, N₃, NH₂, NH(alkyl), N(alkyl)₂, NH-cycloalkyl, NH-acyl, NH═

NH, CONH₂, CONH(alkyl), or CON(alkyl)₂; and

each R⁴ is independently H, acyl, or C_1-6 alkyl;

each Z is O, S, NH, N—

OH, N—

NH₂, NH(alkyl), N(alkyl)₂, N-cycloalkyl, alkoxy, CN, SCN, OCN, SH, NO₂, NH₂, N₃, NH═

NH, NH(alkyl), N(alkyl)₂, CONH₂, CONH(alkyl), or CON(alkyl)₂;

with the caveat that when X is S, then the compound is not 5-(4-amino-imidazo[4,5-d][1,2,3]triazin-7-yl)-2-hydroxymethyl-tetrahydro-thiophen-3-ol or 7-(4-hydroxy-5-hydroxy-methyl-tetrahydro-thiophen-2-yl)-3,7-dihydro-imidazo[4,5-d][1,2,3]triazin-4-one.

2. A method of treating a host infected with a flavivirus or pestivirus, comprising administering an effective amount of an anti-pestivirus or anti-flavivirus biologically active ribofuranonucleoside of Formula (II):

or a pharmacologically acceptable salt or prodrug thereof, wherein;

X* is CY³;

Y³ is hydrogen, alkyl, bromo, chloro, fluoro, iodo, azido, cyano, alkenyl, alkynyl, —

C(O)O(alkyl), —

C(O)O(lower alkyl), CF₃, —

CONH₂, —

CONH(alkyl), or —

CON(alkyl)₂;

R is H, mono-, di-, or triphosphate, a stabilized phosphate, or phosphonate;

R¹ is H, OH, optionally substituted alkyl, lower alkyl, azido, cyano, optionally substituted alkenyl or alkynyl, —

C(O)O-(alkyl), —

C(O)O(lower alkyl), —

C(O)O-(alkenyl), —

C(O)O-(alkynyl), —

O(acyl), —

O(lower acyl), —

O(alkyl), —

O(lower alkyl), —

O(alkenyl), —

O(alkynyl), halogen, halogenated alkyl, —

NO₂, —

NH₂, —

NH(lower alkyl), —

N(lower alkyl)₂, —

NH(acyl), —

N(acyl)₂, —

C(O)NH₂, —

C(O)NH(alkyl), or —

C(O)N(alkyl)₂, wherein an optional substitution on alkyl, alkenyl, and/or alkynyl may be one or more halogen, hydroxy, alkoxy or alkylthio groups taken in any combination;

each R² and R³ independently is OH, NH₂, F, Cl, Br, I, CN, NO₂, C(O)NH₂, —

C(O)NH(alkyl), —

C(O)N(alkyl)₂, N₃, optionally substituted alkyl, lower alkyl, optionally substituted alkenyl or alkynyl, halogenated alkyl, —

C(O)O-(alkyl), —

C(O)O(lower alkyl), —

C(O)O-(alkenyl), —

C(O)O-(alkynyl), an amino acid residue or derivative, a prodrug or leaving group that provides OH in vivo, or an optionally substituted 3-7 membered heterocyclic ring having O, S and/or N independently as a heteroatom taken alone or in combination;

each R^2′

and R^3′

independently is H;

optionally substituted alkyl, alkenyl, or alkynyl;

—

C(O)O(alkyl), —

C(O)O(lower alkyl), —

C(O)O(alkenyl), —

C(O)O(alkynyl), —

C(O)NH₂, C(O)NH(alkyl), and —

C(O)N(alkyl)₂, —

O(acyl), —

O(lower acyl), —

O(alkyl), —

O(lower alkyl), —

O(alkenyl), halogen, halogenated alkyl and particularly CF₃, azido, cyano, NO₂, —

S(alkyl), —

S(alkenyl), —

S(alkynyl), NH₂, —

NH(alkyl), —

N(alkyl)₂, —

NH(alkenyl), —

NH(alkynyl), —

NH(acyl), or —

N(acyl)₂, and R₃ at 3′

-C may also be OH; and

Base is selected from the group consisting of;

wherein

each R′ and

R″

independently is H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, halogen, halogenated alkyl, OH, CN, N₃, carboxy, C_1-4alkoxycarbonyl, NH₂, C_1-4 alkylamino, di(C_1-4 alkyl)amino, C_1-6 alkoxy, C_1-6 alkylsulfonyl, (C_1-4 alkyl)_0-2 aminomethyl;

each W is Cl, Br, I, F, halogenated alkyl, alkoxy, OH, SH, O-alkyl, S-alkyl, O-alkenyl, O-alkynyl, S-alkenyl, S-alkynyl, —

OC(O)NR⁴R⁴, O-acyl, S-acyl, CN, SCN, OCN, NO₂, N₃, NH₂, NH(alkyl), N(alkyl)₂, NH-cycloalkyl, NH-acyl, NH═

NH, CONH₂, CONH(alkyl), or CON(alkyl)₂; and

each R⁴ is independently H, acyl, or C_1-6 alkyl;

each Z is O, S, NH, N—

OH, N—

NH₂, NH(alkyl), N(alkyl)₂, N-cycloalkyl, alkoxy, CN, SCN, OCN, SH, NO₂, NH₂, N₃, NH═

NH, NH(alkyl), N(alkyl)₂, CONH₂, CONH(alkyl), or CON(alkyl)₂.

3. A method of treating a host infected with a flavivirus or pestivirus, comprising administering an effective amount of an anti-pestivirus or anti-flavivirus biologically active ribofuranonucleoside of Formula (III):

or a pharmacologically acceptable salt or prodrug thereof, wherein;

each R, R²*, and R³* independently is H, mono-, di-, or triphosphate, a stabilized phosphate, or phosphonate;

optionally substituted alkyl, lower alkyl, optionally substituted alkenyl or alkynyl, acyl, —

C(O)-(alkyl), —

C(O)(lower alkyl), —

C(O)-(alkenyl), —

C(O)-(alkynyl), lipid, phospholipid, carbohydrate, peptide, cholesterol, an amino acid residue or derivative, or other pharmaceutically acceptable leaving group that is capable of providing H or phosphate when administered in vivo;

X is O, S[O]_n, CH₂, CHOH, CH-alkyl, CH-alkenyl, CH-alkynyl, C-dialkyl, CH—

O-alkyl, CH—

O-alkenyl, CH—

O-alkynyl, CH—

S-alkyl, CH—

S-alkenyl, CH—

S-alkynyl, NH, N-alkyl, N-alkenyl, N-alkynyl, S(O)N-alkyl, S(O)N-alkenyl, S(O)N-alkynyl, SCH-halogen, or C-(halogen)₂, wherein alkyl, alkenyl or alkynyl optionally may be substituted;

n is 0-2;

each R^2′

independently is H;

optionally substituted alkyl, alkenyl, or alkynyl;

—

C(O)O(alkyl), —

C(O)O(lower alkyl), —

C(O)O(alkenyl), —

C(O)C(alkynyl), —

C(O)NH₂, —

C(O)NH(alkyl), —

C(O)N(alkyl)₂, —

OH, —

O(acyl), —

O(lower acyl), —

O(alkyl), —

O(lower alkyl), —

O(alkenyl), halogen, halogenated alkyl and particularly CF₃, azido, cyano, NO₂, —

S(alkyl), —

S(alkenyl), —

S(alkynyl), NH₂, —

NH(alkyl), —

N(alkyl)₂, —

NH(alkenyl), —

NH(alkynyl), —

NH(acyl), or —

N(acyl)₂; and

Base is selected from the group consisting of;

wherein

each R′ and

R″

independently is H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, halogen, halogenated alkyl, OH, CN, N₃, carboxy, C_1-4alkoxycarbonyl, NH₂, C_1-4 alkylamino, di(C_1-4 alkyl)amino, C_1-6 alkoxy, C_1-6 alkylsulfonyl, (C_1-4 alkyl)_0-2 aminomethyl;

each W is Cl, Br, I, F, halogenated alkyl, alkoxy, OH, SH, O-alkyl, S-alkyl, O-alkenyl, O-alkynyl, S-alkenyl, S-alkynyl, —

OC(O)NR⁴R⁴, O-acyl, S-acyl, CN, SCN, OCN, NO₂, N₃, NH₂, NH(alkyl), N(alkyl)₂, NH-cycloalkyl, NH-acyl, NH═

NH, CONH₂, CONH(alkyl), or CON(alkyl)₂; and

each R⁴ is independently H, acyl, or C_1-6 alkyl;

each Z is O, S, NH, N—

OH, N—

NH₂, NH(alkyl), N(alkyl)₂, N-cycloalkyl, alkoxy, CN, SCN, OCN, SH, NO₂, NH₂, N₃, NH═

NH, NH(alkyl), N(alkyl)₂, CONH₂, CONH(alkyl), or CON(alkyl)₂.

4. The method of claim 3, wherein R^2′

is an optionally substituted alkyl, alkenyl, or alkynyl;

halogen, halogenated alkyl, CH₃, CF₃, azido, or cyano.

5. The method of claim 3, wherein R^2′

is an optionally substituted alkyl, alkenyl, or alkynyl;

halogen, halogenated alkyl, CH₃, or CF₃.

6. The method of claim 3, wherein R^2′

is CH₃ or CF₃.

7. The method of claim 3, wherein each R, R²*, and R³* is independently H, mono-, di-, or triphosphate, a stabilized phosphate, or phosphonate.

8. The method of claim 3, wherein each R, R²*, and R³* is independently H.

9. The method of claim 3, wherein each R, R²*, and R³* is independently H, acyl, or an amino acid acyl residue.

10. The method of claim 3, wherein X is O or S.

11. The method of claim 3, wherein X is O.

12. A method of treating a host infected with a flavivirus or pestivirus, comprising administering an effective amount of an anti-pestivirus or anti-flavivirus biologically active ribofuranonucleoside of Formula (IV):

or a pharmacologically acceptable salt or prodrug thereof, wherein;

each R, R²*, and R³* independently is H, mono-, di-, or triphosphate, a stabilized phosphate, or phosphonate;

optionally substituted alkyl, lower alkyl, optionally substituted alkenyl or alkynyl, acyl, —

C(O)-(alkyl), —

C(O)(lower alkyl), —

C(O)-(alkenyl), —

C(O)-(alkynyl), lipid, phospholipid, carbohydrate, peptide, cholesterol, an amino acid residue or derivative, or other pharmaceutically acceptable leaving group that is capable of providing H or phosphate when administered in vivo;

X is O, S[O]_n, CH₂, CHOH, CH-alkyl, CH-alkenyl, CH-alkynyl, C-dialkyl, CH—

O-alkyl, CH—

O-alkenyl, CH—

O-alkynyl, CH—

S-alkyl, CH—

S-alkenyl, CH—

S-alkynyl, NH, N-alkyl, N-alkenyl, N-alkynyl, S(O)N-alkyl, S(O)N-alkenyl, S(O)N-alkynyl, SCH-halogen, or C-(halogen)₂, wherein alkyl, alkenyl or alkynyl optionally may be substituted;

n is 0-2;

each R^3′

independently is H;

optionally substituted alkyl, alkenyl, or alkynyl;

—

C(O)O(alkyl), —

C(O)O(lower alkyl), —

C(O)O(alkenyl), —

C(O)O(alkynyl), —

C(O)NH₂, —

C(O)NH(alkyl), —

C(O)N(alkyl)₂, —

OH, —

O(acyl), —

O(lower acyl), —

O(alkyl), —

O(lower alkyl), —

O(alkenyl), halogen, halogenated alkyl and particularly CF₃, azido, cyano, NO₂, —

S(alkyl), —

S(alkenyl), —

S(alkynyl), NH₂, —

NH(alkyl), —

N(alkyl)₂, —

NH(alkenyl), —

NH(alkynyl), —

NH(acyl), or —

N(acyl)₂; and

Base is selected from the group consisting of;

wherein

each R′ and

R″

independently is H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, halogen, halogenated alkyl, OH, CN, N₃, carboxy, C_1-4alkoxycarbonyl, NH₂, C_1-4 alkylamino, di(C_1-4 alkyl)amino, C_1-6 alkoxy, C_1-6 alkylsulfonyl, (C_1-4 alkyl)_0-2 aminomethyl;

each W is Cl, Br, I, F, halogenated alkyl, alkoxy, OH, SH, O-alkyl, S-alkyl, O-alkenyl, O-alkynyl, S-alkenyl, S-alkynyl, —

OC(O)NR⁴R⁴, O-acyl, S-acyl, CN, SCN, OCN, NO₂, N₃, NH₂, NH(alkyl), N(alkyl)₂, NH-cycloalkyl, NH-acyl, NH═

NH, CONH₂, CONH(alkyl), or CON(alkyl)₂; and

each R⁴ is independently H, acyl, or C_1-6 alkyl;

each Z is O, S, NH, N—

OH, N—

NH₂, NH(alkyl), N(alkyl)₂, N-cycloalkyl, alkoxy, CN, SCN, OCN, SH, NO₂, NH₂, N₃, NH═

NH, NH(alkyl), N(alkyl)₂, CONH₂, CONH(alkyl), or CON(alkyl)₂.

13. The method of claim 12, wherein R^3′

is an optionally substituted alkyl, alkenyl, or alkynyl;

halogen, halogenated alkyl, CH₃, CF₃, azido, or cyano.

14. The method of claim 12, wherein R^3′

is an optionally substituted alkyl, alkenyl, or alkynyl;

halogen, halogenated alkyl, CH₃, or CF₃.

15. The method of claim 12, wherein R^3′

is CH₃ or CF₃.

16. The method of claim 12, wherein each R, R²*, and R³* is independently H, mono-, di-, or triphosphate, a stabilized phosphate, or phosphonate.

17. The method of claim 12, wherein each R, R²*, and R³* is independently H.

18. The method of claim 12, wherein each R, R²*, and R³* is independently H, acyl, or an amino acid acyl residue.

19. The method of claim 12, wherein X is O or S.

20. The method of claim 12, wherein X is O.

21. The method of one of claims 3 or 12 wherein the host is a mammal.

22. The method of claim 21, wherein the mammal is a human.

23. The method of one of claims 3 or 12, further comprising administering an antivirally effective amount of the compound, or a pharmaceutically acceptable salt or prodrug thereof, in combination or alternation with one or more additional antivirally effective agents.

24. The method of claim 23 wherein the additional antivirally effective agent is selected from the group consisting of an interferon, ribavirin, an interleukin, an NS3 protease inhibitor, a cysteine protease inhibitor, phenanthrenequinone, a thiazolidine derivative, a thiazolidine and a benzanilide, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, gliotoxin, cerulenin, an antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependent translation, and a ribozyme.

25. The method of claim 24, wherein the additional antivirally effective agent is an interferon.

26. The method of claim 25 wherein the additional antivirally effective agent is selected from the group consisting of pegylated interferon alpha 2a, interferon alphacon-1, natural interferon, albuferon, interferon beta-1a, omega interferon, interferon alpha, interferon gamma, interferon tau, interferon delta and interferon gamma-1b.

27. The method of one of claims 3 and 12, wherein the compound is in the form of a dosage unit.

28. The method of claim 27 wherein the dosage unit contains 50 to 1000 mg of the compound.

29. The method of claim 28, wherein the said dosage unit is a tablet or capsule.

30. The method of one of claims 3 or 12, wherein the compound is in substantially pure form.

31. The method of claim 30 wherein the compound is at least 90% by weight of the β

-D-isomer.

32. The method of claim 30 wherein the compound is at least 95% by weight of the β

-D-isomer.

33. The method of claim 30 wherein the compound is at least 90% by weight of the β

-L-isomer.

34. The method of claim 30 wherein the compound is at least 95% by weight of the β

-L-isomer.

35. A compound of the general structure of Formula (I):

or a pharmacologically acceptable salt or prodrug thereof, wherein;

R is H, mono-, di-, or triphosphate, a stabilized phosphate, or phosphonate;

X is O, S[O]_n, CH₂, CHOH, CH-alkyl, CH-alkenyl, CH-alkynyl, C-dialkyl, CH—

O-alkyl, CH—

O-alkenyl, CH—

O-alkynyl, CH—

S-alkyl, CH—

S-alkenyl, CH—

S-alkynyl, NH, N-alkyl, N-alkenyl, N-alkynyl, S(O)N-alkyl, S(O)N-alkenyl, S(O)N-alkynyl, SCH-halogen, or C-(halogen)₂, wherein alkyl, alkenyl or alkynyl may optionally be substituted;

n is 0-2;

such than when X is CH₂, CHOH, CH-alkyl, CH-alkenyl, CH-alkynyl, C-dialkyl, CH—

O-alkyl, CH—

O-alkenyl, CH—

O-alkynyl, CH—

S-alkyl, CH—

S-alkenyl, CH—

S-alkynyl, CH-halogen, or C-(halogen)₂,

then each R¹ and R^1′

is independently H, OH, optionally substituted alkyl, lower alkyl, azido, cyano, optionally substituted alkenyl or alkynyl, —

C(O)O-(alkyl), —

C(O)O(lower alkyl), —

C(O)O-(alkenyl), —

C(O)O-(alkynyl), —

O(acyl), —

O(lower acyl), —

O(alkyl), —

O(lower alkyl), —

O(alkenyl), —

O(alkynyl), halogen, halogenated alkyl, —

NO₂, —

NH₂, —

NH(lower alkyl), —

N(lower alkyl)₂, —

NH(acyl), —

N(acyl)₂, —

C(O)NH₂, —

C(O)NH(alkyl), —

C(O)N(alkyl)₂, S(O)N-alkyl, S(O)N-alkenyl, S(O)N-alkynyl, SCH-halogen, wherein alkyl, alkenyl, and/or alkynyl may optionally be substituted; and

such that when X is O, S[O]_n, NH, N-alkyl, N-alkenyl, N-alkynyl, S(O)N-alkyl, S(O)N-alkenyl, S(O)N-alkynyl, or SCH-halogen,

then each R¹ and R^1′

is independently H, optionally substituted alkyl, lower alkyl, azido, cyano, optionally substituted alkenyl or alkynyl, —

C(O)O-(alkyl), —

C(O)O(lower alkyl), —

C(O)O-(alkenyl), —

C(O)O-(alkynyl), halogenated alkyl, —

C(O)NH₂, —

C(O)NH(alkyl), —

C(O)N(alkyl)₂, —

C(H)═

N—

NH₂, C(S)NH₂, C(S)NH(alkyl), or C(S)N(alkyl)₂, wherein alkyl, alkenyl and/or alkynyl may optionally be substituted;

each R² and R³ independently is OH, NH₂, SH, F, Cl, Br, I, CN, NO₂, C(O)NH₂, —

C(O)NH(alkyl), and —

C(O)N(alkyl)₂, N₃, optionally substituted alkyl, lower alkyl, optionally substituted alkenyl or alkynyl, halogenated alkyl, —

C(O)O-(alkyl), —

C(O)O(lower alkyl), —

C(O)O-(alkenyl), —

C(O)O-(alkynyl), —

O(acyl), —

O(alkyl), —

O(alkenyl), —

O(alkynyl), —

OC(O)NH₂, NC, C(O)OH, SCN, OCN, —

S(alkyl), —

S(alkenyl), —

S(alkynyl), —

NH(alkyl), —

N(alkyl)₂, —

NH(alkenyl), —

NH(alkynyl), an amino acid residue or derivative, a prodrug or leaving group that provides OH in vivo, or an optionally substituted 3-7 membered heterocyclic ring having O, S and/or N independently as a heteroatom taken alone or in combination;

each R^2′

and R^3′

independently is H;

optionally substituted alkyl, alkenyl, or alkynyl;

—

C(O)O(alkyl), —

C(O)O(lower alkyl), —

C(O)O(alkenyl), —

C(O)O(alkynyl), —

C(O)NH₂, —

C(O)NH(alkyl), —

C(O)N(alkyl)₂, —

O(acyl), —

O(lower acyl), —

O(alkyl), —

O(lower alkyl), —

O(alkenyl), halogen, halogenated alkyl and particularly CF₃, azido, cyano, NO₂, —

S(alkyl), —

S(alkenyl), —

S(alkynyl), NH₂, —

NH(alkyl), —

N(alkyl)₂, —

NH(alkenyl), —

NH(alkynyl), —

NH(acyl), or —

N(acyl)₂, and R₃ at 3′

-C may also be OH; and

Base is selected from the group consisting of;

wherein

each R′ and

R″

independently is H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, halogen, halogenated alkyl, OH, CN, N₃, carboxy, C_1-4alkoxycarbonyl, NH₂, C_1-4 alkylamino, di(C_1-4 alkyl)amino, C_1-6 alkoxy, C_1-6 alkylsulfonyl, (C_1-4 alkyl)_0-2 aminomethyl;

each W is Cl, Br, I, F, halogenated alkyl, alkoxy, OH, SH, O-alkyl, S-alkyl, O-alkenyl, O-alkynyl, S-alkenyl, S-alkynyl, —

OC(O)NR⁴R⁴, O-acyl, S-acyl, CN, SCN, OCN, NO₂, N₃, NH₂, NH(alkyl), N(alkyl)₂, NH-cycloalkyl, NH-acyl, NH═

NH, CONH₂, CONH(alkyl), or CON(alkyl)₂; and

each R⁴ is independently H, acyl, or C_1-6 alkyl;

each Z is O, S, NH, N—

OH, N—

NH₂, NH(alkyl), N(alkyl)₂, N-cycloalkyl, alkoxy, CN, SCN, OCN, SH, NO₂, NH₂, N₃, NH═

NH, NH(alkyl), N(alkyl)₂, CONH₂, CONH(alkyl), or CON(alkyl)₂;

with the caveat that when X is S, then the compound is not 5-(4-amino-imidazo[4,5-d][1,2,3]triazin-7-yl)-2-hydroxymethyl-tetrahydro-thiophen-3-ol or 7-(4-hydroxy-5-hydroxy-methyl-tetrahydro-thiophen-2-yl)-3,7-dihydro-imidazo[4,5-d][1,2,3]triazin-4-one.

36. A compound of the general structure of Formula (II):

or a pharmacologically acceptable salt or prodrug thereof, wherein;

X* is CY³;

Y³ is hydrogen, alkyl, bromo, chloro, fluoro, iodo, azido, cyano, alkenyl, alkynyl, —

C(O)O(alkyl), —

C(O)O(lower alkyl), CF₃, —

CONH₂, —

CONH(alkyl), or —

CON(alkyl)₂;

R is H, mono-, di-, or triphosphate, a stabilized phosphate, or phosphonate;

R¹ is H, OH, optionally substituted alkyl, lower alkyl, azido, cyano, optionally substituted alkenyl or alkynyl, —

C(O)O-(alkyl), c(O)O(lower alkyl), —

C(O)O-(alkenyl), —

(O)O-(alkynyl), —

O(acyl), —

O(lower acyl), —

O(alkyl), —

O(lower alkyl), —

O(alkenyl), —

O(alkynyl), halogen, halogenated alkyl, —

NO₂, —

NH₂, —

NH(lower alkyl), —

N(lower alkyl), —

NH(acyl), —

N(acyl)₂, —

C(O)NH₂, —

C(O)NH(alkyl), or —

C(O)N(alkyl)₂, wherein an optional substitution on alkyl, alkenyl, and/or alkynyl may be one or more halogen, hydroxy, alkoxy or alkylthio groups taken in any combination;

each R² and R³ independently is OH, NH₂, F, Cl, Br, I, CN, NO₂, —

C(O)NH₂, —

C(O)NH(alkyl), —

C(O)N(alkyl)₂, N₃, optionally substituted alkyl, lower alkyl, optionally substituted alkenyl or alkynyl, halogenated alkyl, —

C(O)O-(alkyl), —

C(O)O(lower alkyl), —

C(O)O-(alkenyl), —

C(O)O-(alkynyl), an amino acid residue or derivative, a prodrug or leaving group that provides OH in vivo, or an optionally substituted 3-7 membered heterocyclic ring having O, S and/or N independently as a heteroatom taken alone or in combination;

each R^2′

and R^3′

independently is H;

optionally substituted alkyl, alkenyl, or alkynyl;

—

C(O)O(alkyl), —

C(O)O(lower alkyl), —

C(O)O(alkenyl), —

C(O)O(alkynyl), —

C(O)NH₂, —

C(O)NH(alkyl), and —

C(O)N(alkyl)₂, —

O(acyl), —

O(lower acyl), —

O(alkyl), —

O(lower alkyl), —

O(alkenyl), halogen, halogenated alkyl and particularly CF₃, azido, cyano, NO₂, —

S(alkyl), —

S(alkenyl), —

S(alkynyl), NH₂, —

NH(alkyl), —

N(alkyl)₂, —

NH(alkenyl), —

NH(alkynyl), —

NH(acyl), or —

N(acyl)₂, and R₃ at 3′

-C may also be OH; and

Base is selected from the group consisting of;

wherein

each R′ and

R″

independently is H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, halogen, halogenated alkyl, OH, CN, N₃, carboxy, C_1-4alkoxycarbonyl, NH₂, C_1-4 alkylamino, di(C_1-4 alkyl)amino, C_1-6 alkoxy, C_1-6 alkylsulfonyl, (C_1-4 alkyl)_0-2 aminomethyl;

each W is Cl, Br, I, F, halogenated alkyl, alkoxy, OH, SH, O-alkyl, S-alkyl, O-alkenyl, O-alkynyl, S-alkenyl, S-alkynyl, —

OC(O)NR⁴R⁴, O-acyl, S-acyl, CN, SCN, OCN, NO₂, N₃, NH₂, NH(alkyl), N(alkyl)₂, NH-cycloalkyl, NH-acyl, NH═

NH, CONH₂, CONH(alkyl), or CON(alkyl)₂; and

each R⁴ is independently H, acyl, or C_1-6 alkyl;

each Z is O, S, NH, N—

OH, N—

NH₂, NH(alkyl), N(alkyl)₂, N-cycloalkyl, alkoxy, CN, SCN, OCN, SH, NO₂, NH₂, N₃, NH═

NH, NH(alkyl), N(alkyl)₂, CONH₂, CONH(alkyl), or CON(alkyl)₂.

37. A compound of the general structure of Formula (III):

or a pharmacologically acceptable salt or prodrug thereof, wherein;

each R, R²*, and R³* independently is H, mono-, di-, or triphosphate, a stabilized phosphate, or phosphonate;

optionally substituted alkyl, lower alkyl, optionally substituted alkenyl or alkynyl, acyl, —

C(O)-(alkyl), —

C(O)(lower alkyl), —

C(O)-(alkenyl), —

C(O)-(alkynyl), lipid, phospholipid, carbohydrate, peptide, cholesterol, an amino acid residue or derivative, or other pharmaceutically acceptable leaving group that is capable of providing H or phosphate when administered in vivo;

X is O, S[O]_n, CH₂, CHOH, CH-alkyl, CH-alkenyl, CH-alkynyl, C-dialkyl, CH—

O-alkyl, CH—

O-alkenyl, CH—

O-alkynyl, CH—

S-alkyl, CH—

S-alkenyl, CH—

S-alkynyl, NH, N-alkyl, N-alkenyl, N-alkynyl, S(O)N-alkyl, S(O)N-alkenyl, S(O)N-alkynyl, SCH-halogen, or C-(halogen)₂, wherein alkyl, alkenyl or alkynyl optionally may be substituted;

n is 0-2;

each R^2′

independently is H;

optionally substituted alkyl, alkenyl, or alkynyl;

—

C(O)O(alkyl), —

C(O)O(lower alkyl), —

C(O)O(alkenyl), —

C(O)O(alkynyl), —

C(O)NH₂, —

C(O)NH(alkyl), —

C(O)N(alkyl)₂, —

OH, —

O(acyl), —

O(lower acyl), —

O(alkyl), —

O(lower alkyl), —

O(alkenyl), halogen, halogenated alkyl and particularly CF₃, azido, cyano, NO₂, —

S(alkyl), —

S(alkenyl), —

S(alkynyl), NH₂, —

NH(alkyl), —

N(alkyl)₂, —

NH(alkenyl), —

NH(alkynyl), —

NH(acyl), or —

N(acyl)₂; and

Base is selected from the group consisting of;

wherein

each R′ and

R″

independently is H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, halogen, halogenated alkyl, OH, CN, N₃, carboxy, C_1-4alkoxycarbonyl, NH₂, C_1-4 alkylamino, di(C_1-4 alkyl)amino, C_1-6 alkoxy, C_1-6 alkylsulfonyl, (C_1-4 alkyl)_0-2 aminomethyl;

each W is Cl, Br, I, F, halogenated alkyl, alkoxy, OH, SH, O-alkyl, S-alkyl, O-alkenyl, O-alkynyl, S-alkenyl, S-alkynyl, —

OC(O)NR⁴R⁴, O-acyl, S-acyl, CN, SCN, OCN, NO₂, N₃, NH₂, NH(alkyl), N(alkyl)₂, NH-cycloalkyl, NH-acyl, NH═

NH, CONH₂, CONH(alkyl), or CON(alkyl); and

each R⁴ is independently H, acyl, or C_1-6 alkyl;

each Z is O, S, NH, N—

OH, N—

NH₂, NH(alkyl), N(alkyl)₂, N-cycloalkyl, alkoxy, CN, SCN, OCN, SH, NO₂, NH₂, N₃, NH═

NH, NH(alkyl), N(alkyl)₂, CONH₂, CONH(alkyl), or CON(alkyl)₂.

38. The compound of claim 37, wherein R^2′

is an optionally substituted alkyl, alkenyl, or alkynyl;

halogen, halogenated alkyl, CH₃, CF₃, azido, or cyano.

39. The compound of claim 37, wherein R^2′

is an optionally substituted alkyl, alkenyl, or alkynyl;

halogen, halogenated alkyl, CH₃, or CF₃.

40. The compound of claim 37, wherein R^2′

is CH₃ or CF₃.

41. The compound of claim 37, wherein each R, R²*, and R³* is independently H, mono-, di-, or triphosphate, a stabilized phosphate, or phosphonate.

42. The compound of claim 37, wherein each R, R²*, and R³* is independently H.

43. The compound of claim 37, wherein each R, R²*, and R³* is independently H, acyl, or an amino acid acyl residue.

44. The compound of claim 37, wherein X is O or S.

45. The compound of claim 37, wherein X is O.

55. A pharmaceutical composition comprising an anti-virally effective amount of a compound of one of claims 37 or 46, optionally with a pharmaceutically acceptable carrier, diluent or excipient.

56. The pharmaceutical composition of claim 55 wherein the compound, salt or prodrug thereof is in the form of a dosage unit.

57. The pharmaceutical composition of claim 56 wherein the dosage unit contains from about 0.01 to about 50 mg of the compound.

58. The pharmaceutical composition of claim 57, wherein said dosage unit is a tablet or capsule.

59. The pharmaceutical composition of claim 55, further comprising one or more additional anti-virally effective agents.

60. The pharmaceutical composition of claim 59, wherein the additional anti-virally agent is selected from the group consisting of an interferon, ribavirin, an interleukin, an NS3 protease inhibitor, a cysteine protease inhibitor, a thiazolidine derivative, a thiazolidine and a benzanilide, phenanthrenequinone, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, gliotoxin, cerulenin, an antisense oligodeoxynucleotide, an inhibitor of IRES-dependent translation, and a ribozyme.

61. The pharmaceutical composition of claim 60 wherein the additional anti-virally effective agent is an interferon.

62. The pharmaceutical composition of claim 61, wherein the additional anti-virally effective agent is selected from the group consisting of pegylated interferon alpha 2a, interferon alphacon-1, natural interferon, albuferon, interferon beta-1a, omega interferon, interferon alpha, interferon gamma, interferon tau, interferon delta and interferon gamma-1b.

63. The pharmaceutical composition of one of claims 37 or 46, wherein the compound is in substantially pure form.

64. The pharmaceutical composition of claim 63, wherein the compound is at least 90% by weight of the β

-D-isomer.

65. The pharmaceutical composition of claim 63, wherein the compound is at least 95% by weight of the β

-D-isomer.

66. The pharmaceutical composition of claim 63 wherein the compound is at least 90% by weight of the β

-L-isomer.

67. The pharmaceutical composition of claim 63 wherein the compound is at least 95% by weight of the β

-L-isomer.

46. A compound of the general structure of Formula (IV):

or a pharmacologically acceptable salt or prodrug thereof, wherein;

each R, R²*, and R³* independently is H, mono-, di-, or triphosphate, a stabilized phosphate, or phosphonate;

optionally substituted alkyl, lower alkyl, optionally substituted alkenyl or alkynyl, acyl, —

C(O)-(alkyl), —

C(O)(lower alkyl), —

C(O)-(alkenyl), —

C(O)-(alkynyl), lipid, phospholipid, carbohydrate, peptide, cholesterol, an amino acid residue or derivative, or other pharmaceutically acceptable leaving group that is capable of providing H or phosphate when administered in vivo;

X is O, S[O]_n, CH₂, CHOH, CH-alkyl, CH-alkenyl, CH-alkynyl, C-dialkyl, CH—

O-alkyl, CH—

C-alkenyl, CH—

O-alkynyl, CH—

S-alkyl, CH—

S-alkenyl, CH—

S-alkynyl, NH, N-alkyl, N-alkenyl, N-alkynyl, S(O)N-alkyl, S(O)N-alkenyl, S(O)N-alkynyl, SCH-halogen, or C-(halogen)₂, wherein alkyl, alkenyl or alkynyl optionally may be substituted;

n is 0-2;

each R^3′

independently is H;

optionally substituted alkyl, alkenyl, or alkynyl;

—

C(O)O(alkyl), —

C(O)O(lower alkyl), —

C(O)O(alkenyl), —

C(O)O(alkynyl), —

C(O)NH₂, —

C(O)NH(alkyl), —

C(O)N(alkyl)₂, —

OH, —

O(acyl), —

O(lower acyl), —

O(alkyl), —

O(lower alkyl), —

O(alkenyl), halogen, halogenated alkyl and particularly CF₃, azido, cyano, NO₂, —

S(alkyl), —

S(alkenyl), —

S(alkynyl), NH₂, —

NH(alkyl), —

N(alkyl)₂, —

NH(alkenyl), —

NH(alkynyl), —

NH(acyl), or —

N(acyl)₂; and

Base is selected from the group consisting of;

wherein

each R′ and

R″

independently is H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, halogen, halogenated alkyl, OH, CN, N₃, carboxy, C_1-4alkoxycarbonyl, NH₂, C_1-4 alkylamino, di(C_1-4 alkyl)amino, C_1-6 alkoxy, C_1-6 alkylsulfonyl, (C_1-4 alkyl)_0-2 aminomethyl;

each W is Cl, Br, I, F, halogenated alkyl, alkoxy, OH, SH, O-alkyl, S-alkyl, O-alkenyl, O-alkynyl, S-alkenyl, S-alkynyl, —

OC(O)NR⁴R⁴, O-acyl, S-acyl, CN, SCN, OCN, NO₂, N₃, NH₂, NH(alkyl), N(alkyl)₂, NH-cycloalkyl, NH-acyl, NH═

NH, CONH₂, CONH(alkyl), or CON(alkyl)₂; and

each R⁴ is independently H, acyl, or C_1-6 alkyl;

each Z is O, S, NH, N—

OH, N—

NH₂, NH(alkyl), N(alkyl)₂, N-cycloalkyl, alkoxy, CN, SCN, OCN, SH, NO₂, NH₂, N₃, NH═

NH, NH(alkyl), N(alkyl)₂, CONH₂, CONH(alkyl), or CON(alkyl)₂.

47. The compound of claim 46, wherein R^3′

is an optionally substituted alkyl, alkenyl, or alkynyl;

halogen, halogenated alkyl, CH₃, CF₃, azido, or cyano.

48. The compound of claim 46, wherein R^3′

is an optionally substituted alkyl, alkenyl, or alkynyl;

halogen, halogenated alkyl, CH₃, or CF₃.

49. The compound of claim 46, wherein R^3′

is CH₃ or CF₃.

50. The compound of claim 46, wherein each R, R²*, and R³* is independently H, mono-, di-, or triphosphate, a stabilized phosphate, or phosphonate.

51. The compound of claim 46, wherein each R, R²*, and R³* is independently H.

52. The compound of claim 46, wherein each R, R²*, and R³* is independently H, acyl, or an amino acid acyl residue.

53. The compound of claim 46, wherein X is O or S.

54. The compound of claim 46, wherein X is O.