MODIFIED FLUORINATED NUCLEOSIDE ANALOGUES

• US 20080253995A1
• Filed: 06/19/2008
• Published: 10/16/2008
• 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:
  US12/142,554
• Publication Number:
  US 20080253995A1
• Time in Patent Office: Days
• US Class Current: 424/85.2
• 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;

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;

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 alpha 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 alpha 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 alpha 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 anti sense 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 alpha 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 alpha 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;

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;

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;

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;

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;

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;

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;

151. A method for the treatment of 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;

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 alpha 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;

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;

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 alpha 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;

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;

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 alpha 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;

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;

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 alpha 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;

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;

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 alpha 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;

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;

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

an interleukin, including interleukin 10 and interlekin 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;

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;

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 alpha 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-alkylcylcyclohexane;

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;

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;

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 alpha 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;

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;

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 alpha 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;

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;

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 alpha 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.