MODIFIED FLUORINATED NUCLEOSIDE ANALOGUES

• US 20090004135A1
• Filed: 06/19/2008
• Published: 01/01/2009
• Est. Priority Date: 05/30/2003
• Status: Abandoned Application

• Current Assignee: Gilead Pharmasset LLC (Gilead Sciences Inc.)
• Original Assignee: Pharmasset Incorporated (Gilead Sciences Inc.)
• Inventors: Clark, Jeremy
• Application Number:
  US12/142,536
• Publication Number:
  US 20090004135A1
• Time in Patent Office: Days
• US Class Current: 424/85.200
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07H 19/00 Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• CPC Class Codes: C07H 19/048 Pyridine radicals
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/14 Pyrrolo-pyrimidine radicals
• CPC Class Codes: C07H 19/16 Purine radicals

Abstract

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

Claims

1-129. -129. (canceled)

130. A (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

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

wherein the base is a purine base represented by the following formula;

X is O, S, CH₂, Se, NH, N-alkyl, CHW (R, S, or racemic), C(W)₂, wherein W is F, Cl, Br, or I;

R¹ and R⁷ are independently H, phosphate, including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower alkyl, O-substituted carboxyalkylamino or its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid (or racemic mixture), a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R¹ is H or phosphate;

R² is H or phosphate;

R¹ and R² or R⁷ can also be linked with cyclic phosphate group;

R² and R^2′

are independently H, C_1-4 allyl, C_1-4 alkenyl, C_1-4 alkynyl, vinyl, N₃, CN, Cl, Br, F, I, NO2, C(O)O(C_1-4 alkyl), C(O)O(C_1-4 alkyl), C(O)O(C_1-4 alkynyl), C(O)O(C_1-4 alkenyl), O(C_1-4 acyl), O(C_1-4 alkyl), O(C_1-4 alkenyl), S(C_1-4 acyl), S(C_1-4 alkyl), S(C_1-4 alkynyl), S(C_1-4 alkenyl), SO(C_1-4 acyl), SO(C_1-4 alkyl), SO(C_1-4 alkynyl), SO(C_1-4 alkenyl), SO₂(C_1-4 acyl), SO₂(C_1-4 allyl), SO₂(C_1-4 alkynyl), SO₂(C_1-4 alkenyl), O₃S(C_1-4 acyl), O₃S(C_1-4 alkyl), O₃S(C_1-4 alkenyl), NH₂, NH(C_1-4 alkyl), NH(C_1-4 alkenyl), NH(C_1-4 alkynyl), NH(C_1-4 acyl), N(C_1-4 alkyl)₂, N(C_1-18 acyl)₂, wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N₃, CN, one to three halogen (Cl, Br, F, I), NO₂, C(O)O(C_1-4 alkyl), C(O)O(C_1-4 alkyl), C(O)O(C_1-4 alkynyl), C(O)O(C_1-4 alkenyl), O(C_1-4 acyl), O(C_1-4 alkyl), O(C_1-4 alkenyl), S(C_1-4 acyl), S(C_1-4 allyl), S(C_1-4 alkynyl), S(C_1-4 alkenyl), SO(C_1-4 acyl), SO(C_1-4 alkyl), SO(C_1-4 alkynyl), SO(C_1-4 alkenyl), SO₂(C_1-4 acyl), SO₂(C_1-4 alkyl), SO₂(C_1-4 alkynyl), SO₂(C_1-4 alkenyl), O₃S(C_1-4 acyl), O₃S(C_1-4 alkyl), O₃S(C_1-4 alkenyl), NH₂, NH(C_1-4 alkyl), NH(C_1-4 alkenyl), NH(C_1-4 alkynyl), NH(C_1-4 acyl), N(C_1-4 alkyl)₂, N(C_1-4 acyl)₂, OR⁷;

R² and R²′

can be linked together to form a vinyl optionally substituted by one or two of N₃, CN, Cl, Br, F, I, NO₂;

R⁶ is an optionally substituted alkyl (including lower alkyl), cyano (CN), CH₃, OCH₃, OCH₂CH₃, hydroxy methyl (CH₂OH), fluoromethyl (CH₂F), azido (N₃), CHCN, CH₂N₃, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkyne (optionally substituted), or fluoro;

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

, SH, SR′

, NH₂, NHR′

, NR′

₂, lower alkyl of C₁-C₆, halogenated (F, Cl, Br, I) lower allyl of C₁-C₆, lower alkenyl of C₂-C₆, halogenated (F, Cl, Br, I) lower alkenyl of C₂-C₆, lower alkynyl of C₂-C₆ such as C≡

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

, CONH₂, CONHR′

, CONR′

₂, CH═

CHCO₂H, CH═

CHCO₂R′

; and

R′

is an optionally substituted alkyl of C₁-C₁₂, cycloalkyl, optionally substituted alkynyl of C₂-C₆, optionally substituted lower alkenyl of C₂-C₆ or optionally substituted acyl.

when n is 1, then R⁴ is ═

O.

when n is 0, then a double bond exists between position 1 and position 6.

131. The (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) of claim 130 or its pharmaceutically acceptable salt thereof,

wherein the Base is represented by the following formula;

when n is 0, then R⁴ is NH₂, R⁵ is H and a double bond exists between position 1 and position 6;

when n is 1, then R⁴ is ═

O and R⁵ is NH₂.

138. A pharmaceutical composition comprising the nucleoside of claim 130 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

139. A pharmaceutical composition comprising the nucleoside of claim 131 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

146. A method for the treatment or prophylaxis of Hepatitis C infection comprising administering to a host an antivirally effective amount of the nucleoside of claim 130 or its pharmaceutically acceptable salt optionally in a pharmaceutically acceptable carrier.

147. A method for the treatment or prophylaxis of Hepatitis C infection comprising administering to a host an antivirally effective amount of the nucleoside of claim 131 or its pharmaceutically acceptable salt optionally in a pharmaceutically acceptable carrier.

154. A method for the treatment or prophylaxis of Rhinovirus infection comprising administering to a host an antivirally effective amount of the nucleoside of claim 130 or its pharmaceutically acceptable salt optionally in a pharmaceutically acceptable carrier.

155. A method for the treatment or prophylaxis of Rhinovirus infection comprising administering to a host an antivirally effective amount of the nucleoside of claim 131 or its pharmaceutically acceptable salt optionally in a pharmaceutically acceptable carrier.

162. A method for the treatment or prophylaxis of Yellow Fever Virus infection comprising administering to a host an antivirally effective amount of the nucleoside of claim 130 or its pharmaceutically acceptable salt optionally in a pharmaceutically acceptable carrier.

163. A method for the treatment or prophylaxis of Yellow Fever Virus infection comprising administering to a host an antivirally effective amount of the nucleoside of claim 131 or its pharmaceutically acceptable salt optionally in a pharmaceutically acceptable carrier.

170. A method for the treatment or prophylaxis of West Nile Virus infection comprising administering to a host an antivirally effective amount of the nucleoside of claim 130 or its pharmaceutically acceptable salt optionally in a pharmaceutically acceptable carrier.

171. A method for the treatment or prophylaxis of West Nile Virus infection comprising administering to a host an antivirally effective amount of the nucleoside of claim 131 or its pharmaceutically acceptable salt optionally in a pharmaceutically acceptable carrier.

178. A method for the treatment or prophylaxis of Dengue Virus infection comprising administering to a host an antivirally effective amount of the nucleoside of claim 130 or its pharmaceutically acceptable salt optionally in a pharmaceutically acceptable carrier.

179. A method for the treatment or prophylaxis of Dengue Virus infection comprising administering to a host an antivirally effective amount of the nucleoside of claim 131 or its pharmaceutically acceptable salt optionally in a pharmaceutically acceptable carrier.

186. The method of claim 146, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

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

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

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

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

levovirin;

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

a helicase inhibitor;

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

gliotoxin;

an IRES inhibitor, and antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazole;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

189. The method of claim 154, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

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

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

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

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

levovirin;

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

a helicase inhibitor;

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

gliotoxin;

an IRES inhibitor, and antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazole;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

192. The method of claim 162, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

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

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

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

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

levovirin;

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

a helicase inhibitor;

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

gliotoxin;

an IRES inhibitor, and antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazole;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

195. The method of claim 170, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

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

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

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

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

levovirin;

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

a helicase inhibitor;

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

gliotoxin;

an IRES inhibitor, and antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazole;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

198. The method of claim 178, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

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

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

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

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

levovirin;

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

a helicase inhibitor;

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

gliotoxin;

an IRES inhibitor, and antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazole;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

132. A (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

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

wherein the base is a purine base;

X is O, S, CH₂, Se, NH, N-alkyl, CHW (R, S, or racemic), C(W)₂, wherein W is F, Cl, Br, or I;

R¹ and R⁷ are independently H, phosphate, including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower allyl, O-substituted carboxyalkylamino or its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid (or racemic mixture), a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R¹ is H or phosphate;

R² is H or phosphate;

R¹ and R² or R⁷ can also be linked with cyclic phosphate group.

133. The (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D) of claim 132 or its pharmaceutically acceptable salt thereof,

wherein the Base is represented by the following formula;

when n is 0, then R⁴ is NH₂, R⁵ is H and a double bond exists between position 1 and position 6;

when n is 1, then R⁴ is ═

O and R⁵ is NH₂.

140. A pharmaceutical composition comprising the nucleoside of claim 132 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

141. A pharmaceutical composition comprising the nucleoside of claim 133 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

148. A method for the treatment or prophylaxis of Hepatitis C infection comprising administering to a host an antivirally effective amount of the nucleoside of claim 132 or its pharmaceutically acceptable salt optionally in a pharmaceutically acceptable carrier.

149. A method for the treatment or prophylaxis of Hepatitis C infection comprising administering to a host an antivirally effective amount of the nucleoside of claim 133 or its pharmaceutically acceptable salt optionally in a pharmaceutically acceptable carrier.

156. A method for the treatment or prophylaxis of Rhinovirus infection comprising administering to a host an antivirally effective amount of the nucleoside of claim 132 or its pharmaceutically acceptable salt optionally in a pharmaceutically acceptable carrier.

157. A method for the treatment or prophylaxis of Rhinovirus infection comprising administering to a host an antivirally effective amount of the nucleoside of claim 133 or its pharmaceutically acceptable salt optionally in a pharmaceutically acceptable carrier.

164. A method for the treatment or prophylaxis of Yellow Fever Virus infection comprising administering to a host an antivirally effective amount of the nucleoside of claim 132 or its pharmaceutically acceptable salt optionally in a pharmaceutically acceptable carrier.

165. A method for the treatment or prophylaxis of Yellow Fever Virus infection comprising administering to a host an antivirally effective amount of the nucleoside of claim 133 or its pharmaceutically acceptable salt optionally in a pharmaceutically acceptable carrier.

172. A method for the treatment or prophylaxis of West Nile Virus infection comprising administering to a host an antivirally effective amount of the nucleoside of claim 132 or its pharmaceutically acceptable salt optionally in a pharmaceutically acceptable carrier.

173. A method for the treatment or prophylaxis of West Nile Virus infection comprising administering to a host an antivirally effective amount of the nucleoside of claim 133 or its pharmaceutically acceptable salt optionally in a pharmaceutically acceptable carrier.

180. A method for the treatment or prophylaxis of Dengue Virus infection comprising administering to a host an antivirally effective amount of the nucleoside of claim 132 or its pharmaceutically acceptable salt optionally in a pharmaceutically acceptable carrier.

181. A method for the treatment or prophylaxis of Dengue Virus infection comprising administering to a host an antivirally effective amount of the nucleoside of claim 133 or its pharmaceutically acceptable salt optionally in a pharmaceutically acceptable carrier.

134. A (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

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

wherein

R¹ and R⁷ are independently H, phosphate, including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower alkyl, O-substituted carboxyalkylamino or its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid (or racemic mixture), a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R¹ or R⁷ is independently H or phosphate;

R¹ and R⁷ can also be linked with cyclic phosphate group; and

R⁶ is an optionally substituted alkyl (including lower allyl), cyano (CN), CH₃, OCH₃, OCH₂CH₃, hydroxy methyl (CH₂OH), fluoromethyl (CH₂F), azido (N₃), CHCN, CH₂N₃, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkyne (optionally substituted), or fluoro.

135. A (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

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

136. A (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

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

wherein

R¹ is H, phosphate, including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower alkyl, O-substituted carboxyalkylamino or its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid (or racemic mixture), a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R¹ is H or phosphate.

137. A (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

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

142. A pharmaceutical composition comprising a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

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

wherein

R¹ and R⁷ are independently H, phosphate, including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, allyl, including lower alkyl, O-substituted carboxyalkylamino or its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid (or racemic mixture), a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R¹ or R⁷ is independently H or phosphate;

R¹ and R⁷ can also be linked with cyclic phosphate group; and

R⁶ is an optionally substituted allyl (including lower alkyl), cyano (CN), CH₃, OCH₃, OCH₂CH₃, hydroxy methyl (CH₂OH), fluoromethyl (CH₂F), azido (N₃), CHCN, CH₂N₃, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkyne (optionally substituted), or fluoro.

143. A pharmaceutical composition comprising a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

-D or β

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

144. A pharmaceutical composition comprising a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

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

wherein

R¹ is H, phosphate, including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower alkyl, O-substituted carboxyalkylamino or its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid (or racemic mixture), a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R¹ is H or phosphate.

145. A pharmaceutical composition comprising a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

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

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

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

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

wherein

R¹ and R⁷ are independently H, phosphate, including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower alkyl, O-substituted carboxyalkylamino or its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid (or racemic mixture), a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R¹ or R⁷ is independently H or phosphate;

R¹ and R⁷ can also be linked with cyclic phosphate group; and

R⁶ is an optionally substituted alkyl (including lower alkyl), cyano (CN), CH₃, OCH₃, OCH₂CH₃, hydroxy methyl (CH₂OH), fluoromethyl (CH₂F), azido (N₃), CHCN, CH₂N₃, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkyne (optionally substituted), or fluoro.

optionally in a pharmaceutically acceptable carrier.

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

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

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

optionally in a pharmaceutically acceptable carrier.

187. The method of claim 151, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

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

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

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

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

levovirin;

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

a helicase inhibitor;

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

gliotoxin;

an IRES inhibitor, and antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazole;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

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

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

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

wherein

R¹ is H, phosphate, including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower alkyl, O-substituted carboxyalkylamino or its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid (or racemic mixture), a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R¹ is H or phosphate.

optionally in a pharmaceutically acceptable carrier.

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

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

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

optionally in a pharmaceutically acceptable carrier.

188. The method of claim 153, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

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

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

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

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

levovirin;

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

a helicase inhibitor;

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

gliotoxin;

an IRES inhibitor, and antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazole;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

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

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

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

wherein

R¹ and R⁷ are independently H, phosphate, including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower alkyl, O-substituted carboxyalkylamino or its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid (or racemic mixture), a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R¹ or R⁷ is independently H or phosphate;

R¹ and R⁷ can also be linked with cyclic phosphate group; and

R⁶ is an optionally substituted alkyl (including lower alkyl), cyano (CN), CH₃, OCH₃, OCH₂CH₃, hydroxy methyl (CH₂OH), fluoromethyl (CH₂F), azido (N₃), CHCN, CH₂N₃, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkyne (optionally substituted), or fluoro.

optionally in a pharmaceutically acceptable carrier.

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

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

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

optionally in a pharmaceutically acceptable carrier.

190. The method of claim 159, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

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

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

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

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

levovirin;

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

a helicase inhibitor;

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

gliotoxin;

an IRES inhibitor, and antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazole;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

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

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

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

wherein

R¹ is H, phosphate, including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower alkyl, O-substituted carboxyalkylamino or its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid (or racemic mixture), a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R¹ is H or phosphate.

optionally in a pharmaceutically acceptable carrier.

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

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

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

optionally in a pharmaceutically acceptable carrier.

191. The method of claim 161, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

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

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

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

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

levovirin;

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

a helicase inhibitor;

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

gliotoxin;

an IRES inhibitor, and antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazole;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

166. A method for the treatment or prophylaxis of Yellow Fever Virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

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

wherein

R¹ and R⁷ are independently H, phosphate, including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower allyl, O-substituted carboxyalkylamino or its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid (or racemic mixture), a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R¹ or R⁷ is independently H or phosphate;

R¹ and R⁷ can also be linked with cyclic phosphate group; and

R⁶ is an optionally substituted alkyl (including lower allyl), cyano (CN), CH₃, OCH₃, OCH₂CH₃, hydroxy methyl (CH₂OH), fluoromethyl (CH₂F), azido (N₃), CHCN, CH₂N₃, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkyne (optionally substituted), or fluoro.

optionally in a pharmaceutically acceptable carrier.

167. A method for the treatment or prophylaxis of Yellow Fever Virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

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

optionally in a pharmaceutically acceptable carrier.

193. The method of claim 167, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

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

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

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

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

levovirin;

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

a helicase inhibitor;

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

gliotoxin;

an IRES inhibitor, and antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazole;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

168. A method for the treatment or prophylaxis of Yellow Fever Virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

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

wherein

R¹ is H, phosphate, including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower alkyl, O-substituted Carboxyalkylamino or its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid (or racemic mixture), a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R¹ is H or phosphate.

optionally in a pharmaceutically acceptable carrier.

169. A method for the treatment or prophylaxis of Yellow Fever Virus infection comprising administering to a host an antivirally effective amount of a (2′

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

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

optionally in a pharmaceutically acceptable carrier.

194. The method of claim 169, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

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

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

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

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

levovirin;

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

a helicase inhibitor;

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

gliotoxin;

an IRES inhibitor, and antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazole;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

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

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

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

wherein

R¹ and R⁷ are independently H, phosphates including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower alkyl, O-substituted carboxyalkylamino or its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid (or racemic mixture), a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R¹ or R⁷ is independently H or phosphate;

R¹ and R⁷ can also be linked with cyclic phosphate group; and

R⁶ is an optionally substituted alkyl (including lower alkyl), cyano (CN), CH₃, OCH₃, OCH₂CH₃, hydroxy methyl (CH₂OH), fluoromethyl (CH₂F), azido (N₃), CHCN, CH₂N₃, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkyne (optionally substituted), or fluoro.

optionally in a pharmaceutically acceptable carrier.

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

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

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

optionally in a pharmaceutically acceptable carrier.

196. The method of claim 175, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

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

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

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

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

levovirin;

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

a helicase inhibitor;

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

gliotoxin;

an IRES inhibitor, and antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazole;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

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

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

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

wherein

R¹ is H, phosphate, including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower alkyl, O-substituted carboxyalkylamino or its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid (or racemic mixture), a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R¹ is H or phosphate.

optionally in a pharmaceutically acceptable carrier.

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

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

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

optionally in a pharmaceutically acceptable carrier.

197. The method of claim 177, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

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

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

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

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

levovirin;

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

a helicase inhibitor;

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

gliotoxin;

an IRES inhibitor, and antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazole;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

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

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

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

wherein

R¹ and R⁷ are independently H, phosphate, including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower alkyl, O-substituted carboxyalkylamino or its peptide derivatives, sulfonate ester, including allyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid (or racemic mixture), a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R¹ or R⁷ is independently H or phosphate;

R¹ and R⁷ can also be linked with cyclic phosphate group; and

R⁶ is an optionally substituted alkyl (including lower allyl), cyano (CN), CH₃, OCH₃, OCH₂CH₃, hydroxy methyl (CH₂OH), fluoromethyl (CH₂F), azido (N₃), CHCN, CH₂N₃, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkyne (optionally substituted), or fluoro.

optionally in a pharmaceutically acceptable carrier.

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

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

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

optionally in a pharmaceutically acceptable carrier.

199. The method of claim 183, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

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

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

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

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

levovirin;

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

a helicase inhibitor;

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

gliotoxin;

an IRES inhibitor, and antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazole;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.

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

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

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

wherein

R¹ is H, phosphate, including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower alkyl, O-substituted carboxyalkylamino or its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid (or racemic mixture), a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R¹ is H or phosphate.

optionally in a pharmaceutically acceptable carrier.

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

R)-2′

-deoxy-2′

-fluoro-2′

-C-methyl nucleoside (β

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

optionally in a pharmaceutically acceptable carrier.

200. The method of claim 185, wherein the antivirally effective amount of (2′

R)-2′

-deoxy-2′

-fluoro-2′

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

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

an interleukin, including interleukin 10 and interleukin 12;

ribavirin;

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

levovirin;

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

a helicase inhibitor;

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

gliotoxin;

an IRES inhibitor, and antisense oligonucleotide;

a thiazolidine derivative;

a benzanilide, a ribozyme;

another nucleoside, nucleoside prodrug or nucleoside derivative;

a 1-amino-alkylcyclohexane;

an antioxidant including vitamin E;

squalene;

amantadine;

a bile acid;

N-(phosphonoacetyl)-L-aspartic acid;

a benzenedicarboxamide;

polyadenylic acid;

a benzimidazole;

thymosin;

a beta tubulin inhibitor;

a prophylactic vaccine;

an immune modulator, an IMPDH inhibitor;

silybin-phosphatidylcholine phytosome; and

mycophenolate.