Purine nucleoside analogues for treating Flaviviridae including hepatitis C

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 , CH 2 , 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 CH 2 , 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 R 1 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, —NO 2 , —NH 2 , —NH(lower alkyl), —N(lower alkyl) 2 , —NH(acyl), —N(acyl) 2 , —C(O)NH 2 , —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 R 1 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)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl) 2 , —C(H)═N—NH 2 , C(S)NH 2 , C(S)NH(alkyl), or C(S)N(alkyl) 2 , wherein alkyl, alkenyl and/or alkynyl may optionally be substituted;

each R 2 and R 3 independently is OH, NH 2 , SH, F, Cl, Br, I, CN, NO 2 , —C(O)NH 2 , —C(O)NH(alkyl), and —C(O)N(alkyl) 2 , N 3 , 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)NH 2 , 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)NH 2 , —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 CF 3 , azido, cyano, NO 2 , —S(alkyl), —S(alkenyl), —S(alkynyl), NH 2 , —NH(alkyl), —N(alkyl) 2 , —NH(alkenyl), —NH(alkynyl), —NH(acyl), or —N(acyl) 2 , and R 3 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, N 3 , carboxy, CN 4 alkoxycarbonyl, NH 2 , 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)NR 4 R 4 , O-acyl, S-acyl, CN, SCN, OCN, NO 2 , N 3 , NH 2 , NH(alkyl), N(alkyl) 2 , NH-cycloalkyl, NH-acyl, NH═NH, CONH 2 , CONH(alkyl), or CON(alkyl) 2 ; and

each R 4 is independently H, acyl, or C 1-6 alkyl;

each Z is O, S, NH, N—OH, N—NH 2 , NH(alkyl), N(alkyl) 2 , N-cycloalkyl, alkoxy, CN, SCN, OCN, SH, NO 2 , NH 2 , N 3 , NH═NH, NH(alkyl), N(alkyl) 2 , CONH 2 , 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 CY 3 ;

Y 3 is hydrogen, alkyl, bromo, chloro, fluoro, iodo, azido, cyano, alkenyl, alkynyl, —C(O)O(alkyl), —C(O)O(lower alkyl), CF 3 , —CONH 2 , —CONH(alkyl), or —CON(alkyl) 2 ;

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

R 1 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, —NO 2 , —NH 2 , —NH(lower alkyl), —N(lower alkyl) 2 , —NH(acyl), —N(acyl) 2 , —C(O)NH 2 , —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 R 2 and R 3 independently is OH, NH 2 , F, Cl, Br, I, CN, NO 2 , —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl) 2 , N 3 , 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)NH 2 , —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 CF 3 , azido, cyano, NO 2 , —S(alkyl), —S(alkenyl), —S(alkynyl), NH 2 , —NH(alkyl), —N(alkyl) 2 , —NH(alkenyl), —NH(alkynyl), —NH(acyl), or —N(acyl) 2 , and R 3 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, N 3 , carboxy, C 1-4 alkoxycarbonyl, NH 2 , 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)NR 4 R 4 , O-acyl, S-acyl, CN, SCN, OCN, NO 2 , N 3 , NH 2 , NH(alkyl), N(alkyl) 2 , NH-cycloalkyl, NH-acyl, NH═NH, CONH 2 , CONH(alkyl), or CON(alkyl) 2 ; and

each R 4 is independently H, acyl, or C 1-6 alkyl;

each Z is O, S, NH, N—OH, N—NH 2 , NH(alkyl), N(alkyl) 2 , N-cycloalkyl, alkoxy, CN, SCN, OCN, SH, NO 2 , NH 2 , N 3 , NH═NH, NH(alkyl), N(alkyl) 2 , CONH 2 , 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, R 2* , and R 3* 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 , CH 2 , 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)NH 2 , —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 CF 3 , azido, cyano, NO 2 , —S(alkyl), —S(alkenyl), —S(alkynyl), NH 2 , —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, N 3 , carboxy, C 1-4 alkoxycarbonyl, NH 2 , 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)NR 4 R 4 , O-acyl, S-acyl, CN, SCN, OCN, NO 2 , N 3 , NH 2 , NH(alkyl), N(alkyl) 2 , NH-cycloalkyl, NH-acyl, NH═NH, CONH 2 , CONH(alkyl), or CON(alkyl) 2 ; and

each R 4 is independently H, acyl, or C 1-6 alkyl;

each Z is O, S, NH, N—OH, N—NH 2 , NH(alkyl), N(alkyl) 2 , N-cycloalkyl, alkoxy, CN, SCN, OCN, SH, NO 2 , NH 2 , N 3 , NH═NH, NH(alkyl), N(alkyl) 2 , CONH 2 , 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, CH 3 , CF 3 , azido, or cyano.

5 . The method of claim 3 , wherein R 2′ is an optionally substituted alkyl, alkenyl, or alkynyl; halogen, halogenated alkyl, CH 3 , or CF 3 .

6 . The method of claim 3 , wherein R 2′ is CH 3 or CF 3 .

7 . The method of claim 3 , wherein each R, R 2 *, and R 3 * is independently H, mono-, di-, or triphosphate, a stabilized phosphate, or phosphonate.

8 . The method of claim 3 , wherein each R, R 2 *, and R 3 * is independently H.

9 . The method of claim 3 , wherein each R, R 2 *, and R 3 * 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, R 2 *, and R 3 * 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 , CH 2 , 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)NH 2 , —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 CF 3 , azido, cyano, NO 2 , —S(alkyl), —S(alkenyl), —S(alkynyl), NH 2 , —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, N 3 , carboxy, C 1-4 alkoxycarbonyl, NH 2 , 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)NR 4 R 4 , O-acyl, S-acyl, CN, SCN, OCN, NO 2 , N 3 , NH 2 , NH(alkyl), N(alkyl) 2 , NH-cycloalkyl, NH-acyl, NH═NH, CONH 2 , CONH(alkyl), or CON(alkyl) 2 ; and

each R 4 is independently H, acyl, or C 1-6 alkyl;

each Z is O, S, NH, N—OH, N—NH 2 , NH(alkyl), N(alkyl) 2 , N-cycloalkyl, alkoxy, CN, SCN, OCN, SH, NO 2 , NH 2 , N 3 , NH═NH, NH(alkyl), N(alkyl) 2 , CONH 2 , 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, CH 3 , CF 3 , azido, or cyano.

14 . The method of claim 12 , wherein R 3′ is an optionally substituted alkyl, alkenyl, or alkynyl; halogen, halogenated alkyl, CH 3 , or CF 3 .

15 . The method of claim 12 , wherein R 3′ is CH 3 or CF 3 .

16 . The method of claim 12 , wherein each R, R 2 *, and R 3 * is independently H, mono-, di-, or triphosphate, a stabilized phosphate, or phosphonate.

17 . The method of claim 12 , wherein each R, R 2 *, and R 3 * is independently H.

18 . The method of claim 12 , wherein each R, R 2 *, and R 3 * 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 , CH 2 , 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 CH 2 , 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 R 1 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, —NO 2 , —NH 2 , —NH(lower alkyl), —N(lower alkyl) 2 , —NH(acyl), —N(acyl) 2 , —C(O)NH 2 , —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 R 1 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)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl) 2 , —C(H)═N—NH 2 , C(S)NH 2 , C(S)NH(alkyl), or C(S)N(alkyl) 2 , wherein alkyl, alkenyl and/or alkynyl may optionally be substituted;

each R 2 and R 3 independently is OH, NH 2 , SH, F, Cl, Br, I, CN, NO 2 , —C(O)NH 2 , —C(O)NH(alkyl), and —C(O)N(alkyl) 2 , N 3 , 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)NH 2 , 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)NH 2 , —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 CF 3 , azido, cyano, NO 2 , —S(alkyl), —S(alkenyl), —S(alkynyl), NH 2 , —NH(alkyl), —N(alkyl) 2 , —NH(alkenyl), —NH(alkynyl), —NH(acyl), or —N(acyl) 2 , and R 3 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, N 3 , carboxy, C 1-4 alkoxycarbonyl, NH 2 , 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)NR 4 R 4 , O-acyl, S-acyl, CN, SCN, OCN, NO 2 , N 3 , NH 2 , NH(alkyl), N(alkyl) 2 , NH-cycloalkyl, NH-acyl, NH═NH, CONH 2 , CONH(alkyl), or CON(alkyl) 2 ; and

each R 4 is independently H, acyl, or C 1-6 alkyl;

each Z is O, S, NH, N—OH, N—NH 2 , NH(alkyl), N(alkyl) 2 , N-cycloalkyl, alkoxy, CN, SCN, OCN, SH, NO 2 , NH 2 , N 3 , NH═NH, NH(alkyl), N(alkyl) 2 , CONH 2 , 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 CY 3 ;

Y 3 is hydrogen, alkyl, bromo, chloro, fluoro, iodo, azido, cyano, alkenyl, alkynyl, —C(O)O(alkyl), —C(O)O(lower alkyl), CF 3 , —CONH 2 , —CONH(alkyl), or —CON(alkyl) 2 ;

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

R 1 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, —NO 2 , —NH 2 , —NH(lower alkyl), —N(lower alkyl) 2 , —NH(acyl), —N(acyl) 2 , —C(O)NH 2 , —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 R 2 and R 3 independently is OH, NH 2 , F, Cl, Br, I, CN, NO 2 , —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl) 2 , N 3 , 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)NH 2 , —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 CF 3 , azido, cyano, NO 2 , —S(alkyl), —S(alkenyl), —S(alkynyl), NH 2 , —NH(alkyl), —N(alkyl) 2 , —NH(alkenyl), —NH(alkynyl), —NH(acyl), or —N(acyl) 2 , and R 3 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, N 3 , carboxy, C 1-4 alkoxycarbonyl, NH 2 , 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)NR 4 R 4 , O-acyl, S-acyl, CN, SCN, OCN, NO 2 , N 3 , NH 2 , NH(alkyl), N(alkyl) 2 , NH-cycloalkyl, NH-acyl, NH═NH, CONH 2 , CONH(alkyl), or CON(alkyl) 2 ; and

each R 4 is independently H, acyl, or C 1-6 alkyl;

each Z is O, S, NH, N—OH, N—NH 2 , NH(alkyl), N(alkyl) 2 , N-cycloalkyl, alkoxy, CN, SCN, OCN, SH, NO 2 , NH 2 , N 3 , NH═NH, NH(alkyl), N(alkyl) 2 , CONH 2 , 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, R 2 *, and R 3 * 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 , CH 2 , 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)NH 2 , —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 CF 3 , azido, cyano, NO 2 , —S(alkyl), —S(alkenyl), —S(alkynyl), NH 2 , —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, N 3 , carboxy, C 1-4 alkoxycarbonyl, NH 2 , 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)NR 4 R 4 , O-acyl, S-acyl, CN, SCN, OCN, NO 2 , N 3 , NH 2 , NH(alkyl), N(alkyl) 2 , NH-cycloalkyl, NH-acyl, NH═NH, CONH 2 , CONH(alkyl), or CON(alkyl) 2 ; and

each R 4 is independently H, acyl, or C 1-6 alkyl;

each Z is O, S, NH, N—OH, N—NH 2 , NH(alkyl), N(alkyl) 2 , N-cycloalkyl, alkoxy, CN, SCN, OCN, SH, NO 2 , NH 2 , N 3 , NH═NH, NH(alkyl), N(alkyl) 2 , CONH 2 , 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, CH 3 , CF 3 , azido, or cyano.

39 . The compound of claim 37 , wherein R 2′ is an optionally substituted alkyl, alkenyl, or alkynyl; halogen, halogenated alkyl, CH 3 , or CF 3 .

40 . The compound of claim 37 , wherein R 2′ is CH 3 or CF 3 .

41 . The compound of claim 37 , wherein each R, R 2 *, and R 3 * is independently H, mono-, di-, or triphosphate, a stabilized phosphate, or phosphonate.

42 . The compound of claim 37 , wherein each R, R 2 *, and R 3 * is independently H.

43 . The compound of claim 37 , wherein each R, R 2 *, and R 3 * 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.

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

or a pharmacologically acceptable salt or prodrug thereof, wherein:

each R, R 2 *, and R 3 * 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 , CH 2 , 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)NH 2 , —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 CF 3 , azido, cyano, NO 2 , —S(alkyl), —S(alkenyl), —S(alkynyl), NH 2 , —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, N 3 , carboxy, C 1-4 alkoxycarbonyl, NH 2 , 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)NR 4 R 4 , O-acyl, S-acyl, CN, SCN, OCN, NO 2 , N 3 , NH 2 , NH(alkyl), N(alkyl) 2 , NH-cycloalkyl, NH-acyl, NH═NH, CONH 2 , CONH(alkyl), or CON(alkyl) 2 ; and

each R 4 is independently H, acyl, or C 1-6 alkyl;

each Z is O, S, NH, N—OH, N—NH 2 , NH(alkyl), N(alkyl) 2 , N-cycloalkyl, alkoxy, CN, SCN, OCN, SH, NO 2 , NH 2 , N 3 , NH═NH, NH(alkyl), N(alkyl) 2 , CONH 2 , 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, CH 3 , CF 3 , azido, or cyano.

48 . The compound of claim 46 , wherein R 3′ is an optionally substituted alkyl, alkenyl, or alkynyl; halogen, halogenated alkyl, CH 3 , or CF 3 .

49 . The compound of claim 46 , wherein R 3′ is CH 3 or CF 3 .

50 . The compound of claim 46 , wherein each R, R 2 *, and R 3 * is independently H, mono-, di-, or triphosphate, a stabilized phosphate, or phosphonate.

51 . The compound of claim 46 , wherein each R, R 2 *, and R 3 * is independently H.

52 . The compound of claim 46 , wherein each R, R 2 *, and R 3 * 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.

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.