MX2007003039A - Methods and compositions for treating flaviviruses, pestiviruses and hepacivirus - Google Patents

Abstract

A method and composition for treating a host infected with flavivirus, pestivirus or hepacivirus comprising administering an effective flavivirus, pestivirus or hepacivirus treatment amount of a described base-modified nucleoside or a pharmaceutically acceptable salt or prodrug thereof, is provided.

Description

METHODS AND COMPOSITIONS FOR TREATING FLAVIVIRUS, PESTIVIRUS AND HEPACIVIRUS FIELD OF THE INVENTION This invention is found in the area of pharmaceutical chemistry, and in particular, it is a compound, method and composition for the treatment of flavivirus, pestivirus and hepacivirus, and in particular for hepatitis C virus infection. BACKGROUND OF THE INVENTION Pestiviruses and Flaviviruses belong to the family Flaviviridae of the viruses along with the hepatitis C virus. The genus pestivirus includes bovine viral diarrhea virus (BVDV), classical swine fever virus (also called porcine cholera virus) and borderline or tremor virus and hirsutism (BDV) of the. sheep (Moenning, V. et al., Adv. Vir. Res. 1992, 41, 53-98). Infections by livestock pestivirus (cattle, pig and sheep) domesticated cause significant economic losses worldwide. BVDV causes mucosal disease in cattle and is of significant economic importance to the livestock industry (Meyers, G. and Thiel, H.-J., Advances in Virus Research, 1996, 47, 53-118; Moenning V ., et al, Adv. Vir. Res. 1992, 41, 53-98).

Human pestiviruses have not been as extensively characterized as pestiviruses in animals. However, serological tests indicate considerable pestivirus exposure in humans. Pestivirus infections in humans have implicated several diseases including congenital brain injury, childhood gastroenteritis and chronic diarrhea in HIV-positive patients. M. Giangaspero et al., Arch. Virol. Suppl. , 1993, 7, 53-62, M. Giangaspero et al., Int. J. Std. Aids, 1993, 4 (5): 300-302. The genera of the flaviviruses include more than 68 members separated into groups based on the serological relationship (Calisher et al., J ", Gen. Virol, 1993, 70, 37-43) .The clinical symptoms vary and include fever, encephalitis and hemorrhagic fever Fields Virology, Editors: Fields, BN, Knipe, DM, and Howley, PM Publications, Lippincott-Raven, Philadelphia, PA, 1996, Chapter 31, 931-959 Flaviviruses of global concern that are associated with Human diseases include dengue hemorrhagic fever (DHF) viruses, yellow fever virus, shock syndrome and Japanese encephalitis virus Halstead, SB, Rev. Infect. Bis., 1984, 6, 251- 264; Halstead, S.B., Science, 239,476-481, 1988; Monta, T.P., New Eng. J. Med., 1988, 319, 641-643. Pestiviruses and hepaciviruses are closely related groups of viruses within the Flaviviridae family. Other closely related viruses in this family include GB viruses A, agents similar to GB viruses A, GB virus B, GB virus C (also called hepatitis G virus, HGV). The group of hepaciviruses (hepatitis C virus, HCV) consists of a number of closely related but genotypically distinguishable viruses that infect humans. There are approximately 6 HCV genotypes and more than 50 subtypes. Due to the similarities between pestiviruses and hepaciviruses, combined with the poor capacity of hepaciviruses to grow efficiently in cell culture, bovine viral diarrhea virus (BVDV) is frequently used as a substitute for studying the HCV virus. Hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide. (Boyer,? Et al., J. Hepatol, 32: 98-112, 2000) HCV causes a slow-growing viral infection and is the major cause of cirrhosis and hepatocellular carcinoma (Di Besceglie, AM and Bacon, BR. , Scientific American, Oct.: 80-85, (1999); Boyer,?., Et al., J. "Hepatol, 32: 98-112, 2000). An estimated 170 million people are infected with HCV worldwide. (Boyer, N. et al., J. Hepatol, 32: 98-112, 2000). Cirrhosis caused by chronic hepatitis C infection accounts for 8,000-12,000 deaths per year in the United States, and HCV infection is the main indication for liver transplantation. HCV is known to cause at least 80% of post-transfusion hepatitis and a substantial proportion of sporadic acute hepatitis. Preliminary evidence also implicates HCV in many cases of chronic "idiopathic" hepatitis, "cryptogenic" cirrhosis, and probably hepatocellular carcinoma unrelated to other hepatitis viruses, such as Hepatitis B virus (HBV). A small proportion of healthy people seem to be carriers of chronic HCV, varying with geography and other epidemiological factors. The numbers can substantially exceed those for the HBV, although the information is still preliminary; how many of these people have subclinical chronic liver disease is unclear. (The Merck Manual, ch 69, p.901, 16th ed., (1992)). HCV is a developed virus that contains a positive-sense single-strand KRN genome of approximately 9.4 kb. The viral genome consists of a 5 'untranslated region (UTR), a long, open reading frame that encodes a polyprotein precursor of approximately 3011 amino acids, and a short "3 UTR." The UTR 5"is the most highly conserved from the HCV genome and is important for the initiation and control of the transfer of the polyprotein. The transfer of the HCV genome is initiated by a mechanism independent of the termination known as internal ribosome entry. This mechanism involves the binding of ribosomes to an RNA sequence known as the internal ribosome entry site (IRES). Recently it has been determined that a structure of pseudoligadura of RNA is an essential structural element of the IRES of HCV. Viral structural proteins include a core protein (C) of nucleopside and two glycoproteins, El and E2. HCV also encodes two proteinases, a zinc-dependent metalloproteinase encoded by the NS2-NS3 region and a serine proteinase encoded in the NS3 region. These proteinases are required for the cleavage of specific regions of the precursor polyprotein in mature peptides. The carboxyl moiety of the non-structural protein 5, NS5B, contains the RNA-dependent RNA polymerase. The function of the remaining non-structural proteins, NS4A and NS4B, and that of NS5A (the amino-terminal half of non-structural protein 5) remains unknown. A significant approach to current antiviral research is directed towards the development of improved methods of treatment of chronic HCV infections in humans (Di Besceglie, AM and Bacon, BR, Scientific American, Oct.: 80-85, (1999) ). In view of the severity of the diseases associated with pestiviruses and hepaciviruses and their penetrability in animals and humans, it is an object of the present invention to provide a compound, method and composition for the treatment of a host infected with flavivirus, pestivirus or hepacivirus. BRIEF DESCRIPTION OF THE INVENTION Compounds, methods and compositions are described for the treatment of a host infected by flavi irus, pestivirus or a hepacivirus infection, those include an amount of the effective treatment of a modified nucleoside of the formulas (I) - (VI) ) or a pharmaceutically acceptable salt or prodrug thereof. In summary, the present invention includes the following features: Modified nucleosides of Formulas (I) - (VI) and pharmaceutically acceptable salts, esters and prodrugs thereof; Modified nucleosides of Formulas (I) (VI) and pharmaceutically acceptable salts, esters and prodrugs thereof for use in the treatment or prophylaxis of a flavivirus, pestivirus or hepacivirus infection, especially in individuals diagnosed as having a flavi infection. irus, pestivirus or hepacivirus or that are at risk of being infected by flavivirus, pestivirus or hepacivirus; The use of these modified nucleosides of Formulas (I) - (VI) and pharmaceutically acceptable salts, esters and prodrugs thereof in the manufacture of a medicament for the treatment of an infection by flavivirus, pestivirus or hepacivirus, Pharmaceutical formulations comprising the modified nucleosides of Formulas (I) (VI), and pharmaceutically acceptable salts, esters and prodrugs thereof together with a pharmaceutically acceptable carrier or diluent. (e) Modified nucleosides of Formulas (I) (VI) and salts, esters and prodrugs substantially in the absence of enantiomers of the described nucleoside or substantially isolated from other chemical entities; (f) Processes for the preparation of the modified nucleosides of Formulas (I) - (VI) and pharmaceutically acceptable salts, esters and prodrugs thereof. (g) Processes for the preparation of the modified nucleosides of Formulas (I) - (VI) and pharmaceutically acceptable salts, esters and prodrugs thereof substantially in the absence of enantiomers of the described nucleoside or substantially isolated from other chemical entities. In a first embodiment, a method is provided for the treatment of a host infected with an infection - flavivirus, pestivirus or hepacivirus, in particular with HCV, which comprises administering an effective treatment amount of a compound of the Formula (I) - (II): or a pharmaceutically acceptable salt or prodrug thereof: R1 is independently H, alkyl (including lower alkyl) optionally substituted, acyl (including lower acyl), phosphate (including mono-, di-, or triphosphate or a prodrug of stabilized phosphate), sulfonate ester including optionally substituted alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzoyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate, a peptide; cholesterol; or another pharmaceutically acceptable release group which when administered in vivo is capable of providing a compound wherein R1 is independently H or phosphate (including mono-, di-, or triphosphate); each A is independently an optionally substituted linear, branched or cyclic alkyl, CH3, CF3, C (Y3) 3, 2-Br-ethyl, C¾F, C¾C1, C¾CF3 / CF2CF3íC (Y3) 2C (Y3) 3, CH2OH , optionally substituted alkenyl, optionally substituted alkynyl, COOR4, COO-aryl, C0-0-alkoxyalkyl, CONHR4, C (NR4) N (R4) 2, C (S) N (R4) 2, CON (R) 2, chloro , bromine, fluorine, iodine, CN, N3, OH, OR4, NH2, NHR4, NR4R5, SH or SR5, -C (= S) N¾, -C (= H) N¾, -C- (5-membered heterocycle) having one or more O, S or N, -C-imidazole atoms; cycloalkyl, acyl, Br-vinyl, -O-alkyl, -O-alkenyl, -0-alkynyl, -O-aryl, -O-aralkyl, -O-acyl, -O-cycloalkyl, -NH-alkyl, -N -dialkyl, -H-acyl, -NH-aryl, -NH-aralkyl, -NH-cycloalkyl, SH, -S-alkyl, -S-acyl, -S-aryl, -S-cycloalkyl, -S-aralkyl, F, Cl, Br, I, -C02-alkyl, -CONH-alkyl, -CON-dialkyl, CF3, -CHmOH, - (C¾) mNH2, - (CH2) raC (0) OH, - (CH2) raCN, - (CH2) mN02, - (CH2) mCONH2, alkylamino of Ci-, (di (C1.4 alkyl) amino, cycloalkylamino of C3_6, alkoxycarbonyl of Ci_4, N3 or alkoxy of Ci_6; each B is independently H, straight-chain, branched or optionally substituted cyclic alkyl CH3, CF3, C (Y3) 3, 2-Br-ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, C (Δ3) 2C (Δ3) 3, CH2OH, alkenyl optionally substituted, optionally substituted alkynyl, COOR4, COO-aryl, -C0-0-alkoxyalkyl, -CONHR4, -C (NR4) N (R4) 2, -C (S) N (R4) 2, -CON (R) 2 / chlorine, bromine, fluorine, iodine, CN, N3 / OH, OR4, N¾, HR4, NR4R5, SH or SR5, -C (= S) NH2, -C (= H) H2, -C- (h 5-membered heterocycle) having one or more O, S or N, -C-imidazole atoms; cycloalkyl, acyl, Br-vinyl, -O-alkyl, -O-alkenyl, -0-alkynyl, -O-aryl, -O-aralkyl, -O-acyl, -O-cycloalkyl, -NH-alkyl, -N -dialkyl, -H-acyl, -NH-aryl, -NH-aralkyl, -NH-cycloalkyl, SH, -S-alkyl, -S-acyl, -S-aryl, -S-cycloalkyl, -S-aralkyl, F, Cl, Br, I, -C02-alkyl, -CONH-alkyl, -CON-dialkyl, CF3, -CHm0H, (CH2) mN¾, - (CH2) mC (0) 0H, - (CH2) mG, - (CH2) mN02, - (CH2) mC0NH2, alkylamino of Ci_4, di (Ci-4 alkyl) amino, cycloalkylamino of C3-e, alkoxycarbonyl of Cx.4r N3 or alkoxy of each? 3 is independently H, F , Cl, Br or I; each R 4 and R 5 is independently hydrogen, acyl (including lower acyl), alkyl (including but not limited to methyl, ethyl, propyl and cyclopropyl), lower alkyl, alkenyl, alkynyl, or cycloalkyl. X is O or CH;each R6 is independently an optionally substituted alkyl (including lower alkyl), C¾, CH 2 CN, CH 2 N 3, CH 2 N 2, CH 2 NHCH 3, CH 2 N (CH 3) 2, CH 2 OH, halogenated alkyl (including halogenated lower alkyl), CF 3, C (Y 3) 3 , 2-Br-ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, C (Y3) 2C (Y3) 3, optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, - (CH2) mC (0) OR4 , - (CH2) mC (0) NHR4, - (CH2) mC (0) N (R4) 2, C (O) OR4 or cyano; each R7 is independently OH, OR2, optionally substituted alkyl (including lower alkyl), CH3, C¾CN, CH2N3, CH2NH2, CH2 HCH3, CH2N (CH3) 2, CH20H, halogenated alkyl (including halogenated lower alkyl), CF3, C (Y3) 3, 2-Br-ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, C (Y3) 2C (Y3) 3, optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, carbocycle (typically a ring 3-7 membered carbocyclic) optionally substituted, heterocycle (typically a 3-7 membered heterocyclic ring having one or more O, S and / or N) optionally substituted, heteroaryl (typically a 3-7 membered heteroaromatic ring having one or more O, S and / or N) optionally substituted, - (CH2) mC (O) OR4, - (CH2) mC (O) SR4- (CH2) raC (0) NHR4, - (CH2) mC (0 ) N (R) 2, -C (0) 0R4, -C (0) SR4, -0 (R4), -S (R4), N02, -NR4R5, azido, cyano, SCN, OCN, NCO or halo; each R8 and R11 are independently hydrogen, an optionally substituted alkyl (including lower alkyl), CH3, CH2CN, CH2N3, CH2NH2, CH2 HCH3, CH2N (CH3) 2, CH2OH, halogenated alkyl (including halogenated lower alkyl), CF3, C (Y3) 3, 2-Br-ethyl, CH2F, C¾C1, CH2CF3, CF2CF3, C (Y3) 2C (Y3) 3, optionally substituted alkenyl, alkenyl, alkynyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, -CH2C (O) N (R4) 2, - (CH2) mC (O) OR4, - (CH2) mC (O) NHR4, -C (0) 0R4, cyano NH-acyl or N (acyl) 2; each of R9 and R10 are independently hydrogen, OH, OR2, optionally substituted alkyl (including lower alkyl), CH3, C¾CN, C¾N3, CH2NH2, CH2CH3, CH2N (CH3) 2, CH20H, alkyl (including halogenated lower alkyl ) halogenated,. CF3, C (Y3) 3, 2-Br-ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, C (Y3) 2C (Y3) 3, optionally substituted alkenyl, alkenyl, alkynyl, N02, haloalkenyl, Br-vinyl, alkynyl optionally substituted, haloalkynyl, carbocycle (typically a 3-7 membered carbocyclic ring) optionally substituted, heterocycle (typically a 3-7 membered heterocyclic ring having one or more O, S and / or N) optionally substituted, heteroaryl (typically a 3-7 membered heteroaromatic ring having one or more O, S and / or N) optionally substituted, - (CH2) mC (O) OR4- (CH2) mC (O) SR4, '- - (CH2) mC ( 0) N (R) 2, -C (0) 0R4, -C (0) SR4, -0 (R4), -O (aralguilo), -S (R4), M02, -NR4R5, -NH (aralkyl) ), azido, cyano, SCN, OCN, NCO or halo; each m is independently 1 or 2; and alternatively, R6 and R10, R7 and R9, R8 and R7 or R9 and R11 can go together to form a linked compound selected from the group consisting of a carbocycle (typically a 3-7 membered carbocyclic ring) optionally substituted or a heterocycle (typically a 3-7 membered heterocyclic ring having one or more 0, S and / or N) optionally substituted; or alternatively, Rs and R7 or R9 and R10 can go together to form a spiro compound selected from the group consisting of a carbocycle (typically an optionally substituted 3-7 membered carbocyclic ring) or a heterocycle (typically a 3- or 5- membered heterocyclic ring). 7 members having one or more O, S and / or N) optionally substituted; and each W is independently 0, S or CH. In another main embodiment, a method is provided for the treatment of a host infected with a flavivirus, pestivirus or hepacivirus infection, in particular with HCV, which comprises administering an effective treatment amount of a compound of Formula (III), ( IV) or (V): (??) (W) (V) or a pharmaceutically acceptable salt or prodrug thereof, wherein R1, R2 and R3 are each independently H, optionally substituted alkyl (including lower alkyl), acyl (including lower acyl), phosphate (including mono-, di- , or triphosphate or a stabilized phosphate prodrug), sulfonate ester including optionally substituted alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate, a peptide; cholesterol; or another pharmaceutically acceptable release group which when administered in vivo is capable of providing a compound wherein R1, R2 and R3 are independently H or phosphate (including mono-, di-, or triphosphate); wherein in an embodiment R2 and / or R3 is not phosphate (including mono-, di-, or triphosphate or a stabilized phosphate prodrug). each Rs is independently H, OH, N02, halo, azido, alkenyl, alkynyl and an optionally substituted alkyl (including lower alkyl), CH3, CH2CN, CH2N3, CH2NH2, CH2NHC¾, CH2N (CH3) 2, CH2OH, alkyl ( including halogenated lower alkyl) halogenated, CF3 / C (Y3) 3, 2- Br-ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, C (Y3) 2C (Y3) 3, optionally substituted alkenyl, haloalkenyl, Br-vinyl, alkynyl optionally substituted, haloalkynyl, - (CH2) mC (O) OR4, - (CH2) mC (O) NHR4, - (C¾) mC (0) N (R4) 2, C (O) OR4 or cyano; X and X * are independently O or CH; each R7 is independently OH, OR2, optionally substituted alkyl (including lower alkyl), CH3, CH2CN, C¾N3, CH2H2, CH2HCH3, CH2N (CH3) 2, CH2OH, halogenated alkyl (including halogenated lower alkyl), CF3, C (Y3) 3, 2-Br-ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, C (Y3) 2C (Y3) 3, optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, carbocycle (typically a 3-7 membered carbocyclic ring) optionally substituted, heterocycle (typically a 3-7 membered heterocyclic ring having one or more O, S and / or N) optionally substituted, heteroaryl (typically a 3-7 membered heteroaromatic ring which has one or more O, S and / or N) optionally substituted, - (C¾) mC (0) OR 4, - (C¾) mC (O) SR 4 - (CH 2) mC (0) NHR 4, - (CH 2) m C ( 0) N (R4) 2, -C (0) 0R4, -C (0) SR4, -O (R4), -S (R4), N02, -NR4RS, acid, cyano, SCM, OCM, NCO or halo; and alternatively, Rs and R7 can go together to form a spiro compound selected from the group consisting of a carbocycle (typically an optionally substituted 3-7 membered carbocyclic ring) or a heterocycle (typically a 3-7 membered heterocyclic ring having one or more O, S and / or N) optionally substituted; each m is independently 1 or 2; and the base is independently: where A, B and W are the same as defined above. In another main embodiment, a method is provided for the treatment of a host infected with a flavivirus, pestivirus or hepacivirus infection, and in particular with HCV, which comprises administering an effective treatment amount of a compound of the compound of the Formula (VI ): (VI) wherein A, R1, R6, R7, R8, R9, R10 and R11 are the same as defined above. The modified nucleosides of this invention can inhibit the activity of the polymerase of the flavivirus, pestivirus or hepacivirus. These nucleosides can be evaluated for their ability to inhibit in vitro the activity of the polymerase of the flavivirus, pestivirus or hepacivirus according to standard selection methods. In one embodiment, the efficacy of the anti-flavivirus, pestivirus or hepacivirus compound is measured according to the concentration of the compound necessary to reduce the number of the virus plate in vitro by 50% (ie, the EC50 of the compound). In a preferred embodiment, the compound has an EC50 of less than 15 or typically, less than 10 micromolar in vitro. In another embodiment, the active compound can be administered in combination or alternately with another anti-flavivirus, pestivirus or hepacivirus agent. A variety of known antiviral agents can be used in combination or alternatively with the compounds of the invention. In combinatorial therapy, effective dosages of two or more agents are administered together, while during alternate therapy, an effective dosage of each agent is administered serially. HCV is a member of the Flaviviridae family; however, now, HCV has been located in a new monotypic genus, hepacivirus. Therefore, in one embodiment, flavivirus, pestivirus is not HCV. However, in a separate modality, the virus is a hepacivirus and in one modality it is HCV. DETAILED DESCRIPTION OF THE INVENTION The invention is a compound, method and composition for the treatment of flavivirus, pestivirus or hepacivirus, and in particular, HCV infection in humans and other host animals, including the administration of a quantity of the treatment against the flavivirus, pestivirus or effective hepacivirus of a modified nucleoside as described herein or a pharmaceutically acceptable salt or prodrug thereof, optionally in a pharmaceutically acceptable carrier. The compounds of this invention possess either antiviral activity (ie, flavivirus, pestivirus or hepacivirus and HCV in particular) or are metabolized to a compound exhibiting such activity. I. Active Compound In a first major embodiment, a compound is provided for the treatment of a host infected with a flavivirus, pestivirus or hepacivirus and in particular by HCV, of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: R1 is independently H, optionally substituted alkyl (including lower alkyl), acyl (including lower acyl), phosphate (including mono-, di-, or triphosphate or a phosphate prodrug) stabilized), sulfonate ester including optionally substituted alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate, a peptide; cholesterol; or another pharmaceutically acceptable release group which when administered in vivo is capable of providing a compound wherein R 1 is independently H or phosphate (including mono-, di-, or triphosphate); each A is independently an optionally substituted straight, branched or cyclic chain alkyl, C¾, CF 3, C (Y 3) 3, 2-Br-ethyl, CH 2 F, C 1 C 1, CH 2 CF 3, CF 2 CF 3, C (Y 3) 2 C (Y 3) 3, CH20H, optionally substituted alkenyl, optionally substituted alkynyl, C00R4, COO-aryl, C0-0-alkoxyalkyl, CO HR4, C (NR4) N (R4) 2, C (S) N (R) 2, CON (R ) 2, chlorine, bromine, fluorine, iodine, CN, N3 / OH, OR4, H2, NHR4, NR4R5, SH or SR5, -C (= S) N¾, -C (= NH) N¾, -C- (heterocycle) of 5 members) having one or more O, S or N, -C-imidazole atoms; cycloalkyl, acyl, Br-vinyl, -0-alkyl, -0-alkenyl, -O-alkynyl, -0-aryl, -O-aralkyl, -0-acyl, -O-cycloalkyl, -NH-alkyl, -N -dialkyl, -NH-acyl, N-aryl, -N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl, S-aralkyl, F, Cl, Br, I , C02-alkyl, CO H-alkyl, CON-dialkyl, CF3, CHmOH, (CH2) mNH2, (C¾) mC (0) OH, (C¾) mCN, (C¾) mN02, (CH2) raCONH2, alkylamino of ¾ -4, (di (Ci-4) alkyl amino, C3_6 cycloalkylamino, Ci_4 alkoxycarbonyl, N3 or Ca_6 alkoxy each B is independently H, straight chained, branched or optionally substituted cyclic alkyl CH3, CF3, C (Y3) 3, 2-Br-ethyl, CH2F, CH2Cl, CH2CF3, CF2CF3, C (Y3) 2C (Y3) 3, CH2OH, optionally substituted alkenyl, optionally substituted alkynyl, COOR4, COO-aryl, CO-O-alkoxyalkyl , CONHR4, C (NR4) N (R4) 2, C (S) N (R4) 2, CON (R) 2, Chlorine, Bromine, Fluoro, Iodine, CN, N3, OH, OR4, NH2, NHR4, NRR5 , SH or SR5, -C (= S) NH2, -C (= NH) NH2, -C- (5-membered heterocycle) that has one or more O, S or N, -C-imidazole atoms; cycloalkyl, acyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, H-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl, S-aralkyl, F, Cl, Br, I, C02-alkyl, CONH-alkyl, CON-dialkyl, CF3, CHmOH, (CH2) mNH2, (CH2) mC (O) OH, (CH2) mCN, (CH2) mN02, (CH2) mCONH2, Ci-4 alkylamino, di (Ci_4 alkyl) amino, cycloalkylamino of C3_6, Ci-4 alkoxycarbonyl, N3 or Ci_6 alkoxy; each Y3 is independently H, F, Cl, Br or I; each R 4 and R 5 are independently hydrogen, acyl (including lower acyl), alkyl (including but not limited to methyl, ethyl, propyl and cyclopropyl), lower alkyl, alkenyl, alkynyl, or cycloalkyl. X is 0 or CH; each R6 is independently an optionally substituted alkyl (including lower alkyl), CH3, CH2CN, CH2N3, CH2H2 / C¾NHCH3, CH2N (CH3) 2, CH2OH, alkyl (including halogenated lower alkyl) halogenated, CF3, C (Y3) 3, 2-Br-ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, C (Y3) 2C (Y3) 3, optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, - (C¾) mC (0) OR4, - (CH2) mC (0) NHR4, - (C¾) raC (0) N (R4) 2, C (0) OR4 or cyano; each R7 is independently OH, OR2, optionally substituted alkyl (including lower alkyl), CH3, C¾CN, CH2N3, CH2NH2, CH2 HCH3, CH2N (CH3) 2, CH20H, halogenated alkyl (including halogenated lower alkyl), CF3, C (Y3) 3, 2-Br-ethyl, CH2F, CH2C1, C¾CF3, CF2CF3, C (Y3) 2C (Y3) 3, optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, carbocycle (typically a 3-7 membered carbocyclic ring) optionally substituted, heterocycle (typically a 3-7 membered heterocyclic ring having one or more O, S and / or N) optionally substituted, heteroaryl (typically a 3-7 membered heteroaromatic ring having one or more O, S and / or N) optionally substituted, - (C¾) mC (0) OR4, - (C¾) mC (0) SR4- - (CH2) mC (0) N (R) 2, -C (0) 0R4, -C (0) SR4, -0 (R4), -S (R4), N02, -NRR5 , azido, cyano, SCN, OCN, NCO or halo; each R8 and R11 are independently hydrogen, an optionally substituted alkyl (including lower alkyl), CH3, CH2CN, C¾N3, CH2H2, CH2NHCH3, CH2N (CH3) 2, C¾0H, halogenated alkyl (including halogenated lower alkyl), CF3 / C (Y3) 3, 2-Br-ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, C (Y3) 2C (Y3) 3, optionally substituted alkenyl, alkenyl, alkynyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, -CH2C (O) N (R4) 2, - (CH2) mC (O) OR4, - (CH2) mC (O) NHR4, -C (0) 0R4, cyano, NH-acyl or N (acyl) 2; each of R9 and R10 are independently hydrogen, OH, OR2, optionally substituted alkyl (including lower alkyl), CH3, CH2CN, CH2N3, CH2 H2, CH2NHCH3, C¾N (CH3) 2, CH20H, alkyl (including halogenated lower alkyl ) halogenated, CF3, C (Y3) 3, 2-Br-ethyl, CH2F, CH2C1, C¾CF3, CF2CF3, C (Y3) 2C (Y3) 3, optionally substituted alkenyl, alkenyl, alkynyl, N02, haloalkenyl, Br-vinyl , optionally substituted alkynyl, haloalkynyl, carbocycle (typically a 3-7 membered carbocyclic ring) optionally substituted, heterocycle (typically a 3-7 membered heterocyclic ring having one or more O, S and / or N) optionally substituted, heteroaryl (typically a 3-7 membered heteroaromatic ring having one or more 0, S and / or N) optionally substituted, - (CH2) mC (O) OR4- (CH2) mC (0) SR, - (C¾) mC (0) HR4, - (CH2) mC (0) N (R4) 2, -C (0) 0R4, -C (0) SR4, -0 (R4), -0 (aralkyl), -S (R4) , N02, -NRR5, - H (aralkyl), acid, cyano, SCN, OCN, NCO or halo; each m is independently 1 or 2; and alternatively, R6 and R10, R7 and R9, R8 and R7 or R9 and R11 can go together to form a linked compound selected from the group consisting of a carbocycle (typically a 3-7 membered carbocyclic ring) optionally substituted or a heterocycle (typically a 3-7 membered heterocyclic ring having one or more O, S and / or N) optionally substituted; or alternatively, R6 and R7 or R9 and R10 can go together to form a spiro compound selected from the group consisting of a carbocycle (typically an optionally substituted 3-7 membered carbocyclic ring) or a heterocycle (typically a heterocyclic ring of 3-7). 7 members having one or more O, S and / or N) optionally substituted; and W is 0, S or CH. In a sub-modality, the compound is provided for the treatment of a host infected with a flavi irus, pestivirus or hepacivirus, in particular with HCV, of Formula (I) or a pharmaceutically acceptable salt or prodrug thereof is provided, in wherein: R1 is independently H, optionally substituted alkyl; acyl; phosphate; a lipid, including a phospholipid; an amino acid; a carbohydrate, a peptide; cholesterol; or another pharmaceutically acceptable release group that when administered in vivo is capable of providing a compound wherein R1 is independently H or phosphate; A is independently an optionally substituted straight, branched or cyclic chain alkyl, CH3, CH20H, optionally substituted alkenyl, optionally substituted alkynyl, COOR4, COO-aryl, CO-0-alkoxyalkyl, CO HR4, C (R4) N ( R4) 2, C (S) N (R) 2, C0N (R) 2, -C (= S) NH2, -C (= NH) N¾, -C- (5-membered heterocycle) having one or more atoms of 0, S or N, acyl, CO H-alkylo, CON-dialkyl, (CH2) mC (O) OH, (C¾) mCN, (C¾) mN02, (CH2) mCO H2: each B is independently H, straight chained, branched or optionally substituted cyclic alkyl CH3, CF3, C (Y3) 3, C (Y3) 2C (Δ3) 3, CH2OH, optionally substituted alkenyl, optionally substituted alkynyl, COOR4, C00-aryl, CO -0-alkoxyalkyl, CO HR4, C (NR4) N (R4) 2, C (S) N (R) 2, CON (R4) 2, chlorine, bromine, fluorine, iodine, OH, OR4, NH2, HR4, NRR5, SH or SR5, CF3, CHmOH, (CH2) m H2, (CH2) mC (O) OH, (CH2) mCN, (CH2) mN02, (CH2) mCONH2, alkylamino of Ca_4 / or Ci_6 alkoxy; each? 3 is independently H, F, Cl, Br or I; each R 4 and R 5 are independently hydrogen, acyl, alkyl, alkenyl, alkynyl, or cycloalkyl. X is 0; each Rs is independently an optionally substituted alkyl, CH2CN, CH2N3, C¾NH2, CH2NHCH3, CH2N (CH3) 2, CH20H, halogenated alkyl, CF3, C (Y3) 3, 2-Br-ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, C (Y3) 2C (Y3) 3 or cyano; each R7 is independently OH, 0R2, optionally substituted alkyl, or halo; each R8 and R11 is independently hydrogen, an optionally substituted alkyl; each of R9 and R10 are independently hydrogen, OH, OR2, optionally substituted alkyl, CH3, CH2CN, CH2N3, CH2NH2, CH2NHCH3, CH2N (CH3) 2, CH2OH, halogenated alkyl, CF3, C (Y3) 3, 2 -Br-ethyl, CH2F, C¾C1, CH2CF3, CF2CF3, C (Y3) 2C (Y3) 3, optionally substituted alkenyl, alkenyl, alkynyl, N02, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted carbocycle, heterocycle (typically a 3-7 membered heterocyclic ring having one or more 0, S and / or N) optionally substituted, optionally substituted heteroaryl, - (CH2) raC (0) OR4- (CH2) raC (0) SR4, - (CH2) mC (O) NHR4, - (CH2) mC (O) N (R4) 2, -C (0) 0R4, -C (0) SR 4, -0 (R 4), - -O (aralkyl), -S (R 4), N 0 2, -NR 4 R 5, - H (aralkyl), azido, cyano, SCN, OCN, WCO or halo; each m is independently 1 or 2. In one embodiment, X is 0, each B is independently H or an optionally substituted straight, branched or cyclic chain alkyl or a halogen (Cl, Br, I, F), each R7 and R9 are independently OH or OR2 and R1 is H or phosphate. In another submodality, the compound of the Formula (I) or a pharmaceutically acceptable salt or prodrug thereof, wherein: R1 is H or phosphate; A is CONHR4; and B is H. In a second embodiment, a compound is provided for the treatment of a host infected with a flavivirus, pestivirus or hepacivirus, and HCV in particular, of Formula (II): . { 11) or a pharmaceutically acceptable salt or prodrug thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, A, B and W are the same as defined above. In a submodality, the compound of the Formula (II), or a pharmaceutically acceptable salt or prodrug thereof, wherein: R1 is H or phosphate; each A is independently H, C¾, CF3 or CH2CH3.

In a third major embodiment, a compound is provided for the treatment of a host infected with a flavivirus, pestivirus or hepacivirus, in particular with HCV, of Formula (III), (IV) or (V): (??) (IV) (V) or a pharmaceutically acceptable salt or prodrug thereof, wherein R1, R2 and R3 are each independently H, optionally substituted alkyl (including lower alkyl), acyl (including lower acyl), phosphate (including mono-, di-, or triphosphate or a stabilized phosphate prodrug), sulfonate ester including optionally substituted alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate, a peptide; cholesterol; or another pharmaceutically acceptable release group that when administered in vivo is capable of providing a compound wherein R1, R2 or R3 is independently H or phosphate (including mono-, di-, or triphosphate); wherein in an embodiment R2 and / or R3 is not phosphate (including mono-, di-, or triphosphate or a stabilized phosphate prodrug). each R6 is independently H, OH, N02, halo, azido, alkenyl, alkynyl and an optionally substituted alkyl (including lower alkyl), CH3, CH2CN, CH2N3, CH2NH2, CH2 HCH3, CH2N (CH3) 2, CH2OH, halogenated alkyl (including halogenated lower alkyl), CF3, C (Y3) 3/2-Br-ethyl, C¾F, C¾C1, C¾CF3, CF2CF3, C (Y3) 2C (Y3) 3, optionally substituted alkenyl, haloalkenyl, Br-vinyl , optionally substituted alkynyl, haloalkynyl, - (C¾) mC (O) OR 4, (CH2) mC (O) NHR4, - (CH2) mC (0) N (R) 2, C (O) OR4 or cyano; X and X * are independently O or CH; each R7 is independently OH, OR2, alkyl (including lower alkyl) optionally substituted, CH3, CH2CN, CH2N3, C¾NH2, CH2NHCH3, CH2N (CH3) 2, CH2OH, alkyl (including halogenated lower alkyl) halogenated, CF3, C (Y3) 3, 2-Br-ethyl, C¾F, CH2C1, CH2CF3, CF2CF3, C (Y3) 2C (Y3) 3, optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, carbocycle (typically a 3-7 membered carbocyclic ring) optionally substituted, heterocycle (typically a 3-7 membered heterocyclic ring having one or more O, S and / or N) optionally substituted, heteroaryl (typically a heteroaromatic ring of 3) -7 members having one or more O, S and / or N) optionally substituted, - (CH2) mC (O) OR4, - (CH2) mC (O) SR4- (C¾) mC (0) HR4, - ( CH2) mC (0) N (R4) 2, -C (0) OR4, -C (0) SR4, -0 (R4), -S (R4), N02, -NR4R5, acid, cyano, SCN, OCN , NCO or halo; and alternatively, Rs and R7 can go together to form a spiro compound selected from the group consisting of a carbocycle (typically an optionally substituted 3-7 membered carbocyclic ring) or a heterocycle (typically a 3-7 membered heterocyclic ring having one or more O, S and / or N) optionally substituted; each m is independently 1 or 2; and the Base is independently: where A, B and W are the same as defined above.

In another embodiment, the compound of Formula (VI), or pharmaceutically acceptable salts or prodrugs thereof, is provided: wherein A, R1, R6, R7, R8, R9, R10 and R11 are the same as defined above. In one embodiment of any of the formulas (I) - (VI), R2 and R3 are independently an amino acid. In a submodality of any of the Formulas (I) - (VI), R2 and R3 are independently valilo. In a particular embodiment, there is provided a compound of Formula (VI), or pharmaceutically acceptable salts or prodrugs thereof, wherein: X is O, and / or each R6 is independently an optionally substituted lower alkyl, optionally substituted alkenyl , optionally substituted alkynyl, optionally substituted cycloalkyl, CH 2 OH, CH 2 H 2 CH 2 HCH 3 / CH 2 N (CH 3) 2 / C¾F, CH 2 Cl, C¾N 3, CH 2 CN, C¾CF 3, CF 3, CF 2 CF 3; and / or each 7 is independently -OH, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl-O-alkyl, O-alkenyl, 0-alkynyl, O-aralkyl, O-cycloalkyl, -acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, N02, N¾, N 3 NH-acyl, NH-alkyl, N-dialkyl, H-alkenyl, H-alkynyl, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl, S-acyl, S-cycloalkyl, C02-alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH20H, CH2NH2 CH2NHCH3, CH2N (CH3) 2 / CH2F, CH2C1, CH2N3, CH2CN, CH2CF3, CF3, CF2CF3, (CH2) mC00H, (CH2) mCONH2, a carbocyclic ring of 3-7 member optionally substituted, and an optionally substituted 3-7 membered heterocyclic ring having o, S and / or N independently as a heteroatom taken alone in combination, and / or each R9 is independently hydrogen, alkyl optionally substituted lower, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -OH, -O-alkyl, -O-alkenyl, -0-alkynyl, -0-aralkyl, -0-cycloalkyl-, 0-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, N02, NH2, N3, H-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aralkyl, NH- cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl, S-acyl, S-cycloalkyl, C02-alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-alkynyl, CONH- aralkyl, CONH- cycloalkyl, - CH20H, CH2NH2, CH2NHC¾, CH2N (C¾) 2, CH2F, CH2C1, CH2N3, CH2CN, CH2CF3, CF3, CF2CF3, (CH2) mC00H, (CH2) mC0NH2, a carbocyclic ring of 3-7 optionally substituted member, and an optionally substituted 3-7 membered heterocyclic ring having 0, S, and / or N independently as a heteroatom terminated alone or in combination; and / or each R10 is independently hydrogen, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, CH2NH2, CH2NHCH3, CH2N (CH3) 2, CH2F, CH2C1, CH2N3, CH2CN, CH2CF3, CF3 , CF2CF3, (C¾) mC00H, (CH2) mC0NH; and / or each R8 and R11 are independently H, C¾, CH 2 OH, CH 2 F, CH 2 N 3, (CH 2) mCOOH, (CH 2) mCONH 2 and N-acyl; and / or A is CONH2; and each m is independently 1. II. Methods of Use In one embodiment, the modified nucleosides of Formulas (I) - (VI), salts, esters and pharmaceutically acceptable prodrugs thereof are provided for use in the treatment or prophylaxis of a flavivirus, pestivirus or hepacivirus infection, especially in individuals diagnosed as having a flavivirus, pestivirus or hepacivirus infection or who are at risk of becoming infected with flavivirus, pestivirus or hepacivirus. In one embodiment, a method is provided, which comprises administering an effective amount of the treatment of a compound of Formula (I) - (VI) to a host suffering from, or at risk of suffering from, a flavivirus infection. , pestivirus or hepacivirus, in particular by HCV. In a particular embodiment, a method of treating a host infected with hepatitis C virus is provided. In another embodiment, the use of a compound of the invention is provided for the treatment of a host infected with a flavivirus or pestivirus. In a certain modality, the virus is not HCV. The dosages of the given compound will depend on the absorption, inactivation and secretion rates of the drug in addition to other factors known to those skilled in the art. It should be noted that the dosage values will also vary with the severity of the condition to be alleviated. It is further understood that for any particular purpose, the specific dosage regimens and schedules should be adjusted during the course according to the need of the individual and the professional judgment of the person administering or overseeing the administration of the compositions. In some embodiments, an anti-hepacivirus, anti-pestivirus or anti-flavivirus compound having an EC50 of 10-15 μ ?, or typically less than 1-5 μ ?. The flaviviruses included within the scope of this invention are discussed generally in Fields Virology, Editors: Fields, BN, Knipe, DM, and Howley, PM, Lippincott-Raven Publishers, Philadelphia, ??, Chapter 31, 1996. Flavivirus-specific include, without limitation: Absettarov, Alfuy, Apoi, Aroa, Bagaza, Banzi, Bouboui, Bussuquara, Cacipacore, Carey Island, Dakar Bat, Dengue 1, Dengue 2, Dengue 3, Dengue 4, Edge Hill, Bat of Entebbe, Gadgets Gully, Hanzalova, Hypr, Ilheus, meningoencephalitis of the turkey of Israel, Japanese encephalitis, Jugra, Jutiapa, Kadam, Karshi, Kedougou, Kokobera, outango, Kumlinge, Kunjin, Kyasanur Forest disease, Langat, Louping ill, Meaban, Modoc, Montana myotis leukoencephalitis, Murray valley encephalitis, Naranjal, Negishi, Ntaya, Omsk hemorrhagic fever, Phnom-Penh bat, Powassan, Rio Bravo, Rocio, Royal Farm, Russian spring-summer encephalitis, Savoy, St. Louis, Sal Vieja, San Perlita, Saumarez Reef, Sepik, Sokuluk, Spondweni, Stratford, Tembusu, Tyuleniy, Uganda S, Usutu, Wesselsbron, West Nile, Yaounde, yellow fever and Zika. Pestiviruses included within the scope of this invention are discussed generally in Fields Virology, Editors: Fields, BN, Knipe, DM, and Howley, PM, Lippincott-Raven Publishers, Philadelphia, PA, Chapter 33, 1996. Specific viruses include , without limitation: bovine viral diarrhea virus ("BVDV"), classical swine fever virus ("CSFV," also called porcine cholera virus), and borderline or tremor and hirsutism virus ("BDV") ).

The hepacivirus group (hepatitis C virus, HCV) consists of a number of closely related but genotypically distinguishable viruses that infect humans. There are approximately 6 HCV genotypes and more than 50 subtypes. Due to the similarities between pestiviruses and hepaciviruses, combined with the poor capacity of hepaciviruses to grow efficiently in cell culture, bovine viral diarrhea virus (BVDV) is frequently used as a substitute for studying the HCV virus. The compounds of the invention can be administered via any convenient means. In one embodiment, the compounds of the invention are administered orally. In another embodiment, the compounds are administered parenterally. In yet another embodiment, the compounds are administered via intravenous infusion. In certain embodiments, the compounds of the invention are administered in a pharmaceutically acceptable carrier or excipient. The carrier or excipient can be useful for. The modified nucleosides of this invention may exhibit flavivirus, pestivirus or hepacivirus polymerase activity. The nucleosides can be selected for their ability to inhibit the activity of the polymerase of the flavi irus, pestiviruses or hepaciviruses in vitro according to selection methods established more particularly here. Some can easily determine the spectrum of activity by evaluating the compound in the assays described here or with another confirmatory assay. In one embodiment, the efficacy of the anti-flavivirus, pestivirus or hepacivirus compound is measured according to the concentration of the compound necessary to reduce the number of the virus plaque in vitro, according to methods more particularly set out herein, at 50 % (that is, the EC50 of the compound). In a preferred embodiment, the compound has an EC50 of less than 15 or typically, less than 10 micromolar in vitro. The active compound can be administered as any salt or prodrug which after administration to the container is capable of directly or indirectly providing the main compound, or which exhibits self-activity. Non-limiting examples are pharmaceutically acceptable salts (alternatively referred to as "physiologically acceptable salts") and a compound that has been alkylated or acylated at the 5 'position or on the basis of purine or pyrimidine (a type of "pharmaceutically acceptable prodrug") "). In addition, the modifications can affect the biological activity of the compound, increasing in some cases the activity in the main compound. This can easily be assayed by preparing the salt or prodrug and proven its antiviral activity according to the methods described herein, or to other methods known to those skilled in the art. III. Definitions The term "alkyl" as used herein, unless otherwise specified, refers to a straight, branched or cyclic primary, secondary or tertiary hydrocarbon of typically Ci to Ci0 and specifically includes methyl, trifluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl. The term includes both substituted and unsubstituted alkyl groups. The radicals with which the alkyl group can be substituted with one or more substituents are selected from the group consisting of halo (F, Cl, Br or I), (for example, CF3, 2-Br-ethyl, C¾F, CH2C1, CH2CF3 or CF2CF3), hydroxyl (e.g., CH20H), amino (e.g., CH2N¾, CH2 HCH3 or CH2N (CH3) 2), alkylamino, arylamino, alkoxy, aryloxy, nitro, azido (e.g., CH2N3), cyano (per example, CH2CN), sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected or protected as necessary, as is known to those skilled in the art., for example, as in Greene, et al, Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, which is incorporated herein by reference. When a range is referred to in the specification, the range refers to independently including each and every component of the range. As a non-limiting example of this, when a Ci-6 alkyl is listed, it means to independently include Cl7 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl. The term "lower alkyl" as used herein and unless otherwise specified refers to a linear, branched alkyl group, or if appropriate a cyclic (eg, cyclopropyl) of ¾ to saturated C4 including both substituted and non-substituted forms. replaced. Unless specifically stated otherwise in this application, when the alkyl is a convenient radical, the lower alkyl is typical. Similarly, when alkyl or lower alkyl is a convenient radical, unsubstituted alkyl or lower alkyl are typical. The term "alkylamino" or "arylamino" refers to an amino group having one or two alkyl or aryl substituents, respectively. The term amino acid includes amino acids a, β? or they are found naturally and synthetically and include but are not limited to amino acids found in proteins, ie, glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine , asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine. In one embodiment, the amino acid is in the L configuration. Alternatively, the amino acid can be a derivative of alanyl, valinyl, leucinyl, isoleuccinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoil, glutaroyl, lisinyl, argininyl, histidinyl, ß-alanyl, ß-valinyl, ß-leucinyl, ß-isoleuccinyl, ß-prolinyl, ß-phenylalaninyl, ß-tryptophanil, ß-methioninyl, ß-glycinyl, ß- serinyl, β-threoninyl, β-cysteinyl, β-tyrosinyl, β-asparaginyl, β-glutaminyl, β-aspartoyl, β-glutaroyl, β-lisinyl, β-argininyl or β-histidinyl. When the term amino acid is used, it is considered to be a specific and independent disclosure of each of the esters of a natural or synthetic amino acid including but not limited to glycine a, β? or alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine in configurations D and L. The term "protected" as used herein and unless otherwise defined refers to a group that is added to an oxygen, nitrogen or phosphorus atom to prevent its further reaction or for other purposes. A wide variety of oxygen and nitrogen protection groups are known to those skilled in the art of organic synthesis. The term "aryl", as used herein and unless otherwise specified, refers to phenyl, or naphthyl and typically phenyl. The term includes both substituted and unsubstituted radicals. The aryl group can be substituted with one or more radicals selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulphonic acid, sulfate, phosphonic acid, phosphate or phosphonate, whether protected or unprotected as necessary, as is known to those skilled in the art, as shown in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

The term "alkaryl" or "alkylaryl" refers to an alkyl group with an aryl substituent. The term "aralkyl" or "alkylaryl" refers to an aryl group with an alkyl substituent. The term "halo," as used herein, includes chlorine, bromine, iodine and fluoro. The term "acyl" refers to a carboxylic acid ester in which the non-carbonyl radical of the ester group is linear, branched or cyclic alkyl or lower alkyl, alkoxyalkyl including methoxymethyl, aralkyl including benzyl, aryloxyalkyl such as phenoxymethyl, aryl including phenyl optionally substituted with halogen, alkyl of ¾ to C, or alkoxy of Cx to C4, sulfonate esters such as aralkyl alkyl or sulfonyl including methanesulfonyl, the mono, di or triphosphate, trityl or monomethoxytrityl ester, substituted benzyl, trialkylsilyl (for example, dimethyl-t-butylsilyl) or diphenylmethylsilyl. The aryl groups in the esters optimally comprise a phenyl group. The term "lower acyl" refers to an acyl group in which the non-carbonyl radical is lower alkyl. As used herein, the term "substantially free of" or "substantially in the absence of" refers to a composition of the nucleoside that includes at least 85% or 90% by weight, typically 95% to 98% by weight and still most typical 99% to 100% by weight, of the designated enantiomer of that nucleoside. In one embodiment, in the methods and compounds of this invention, the compounds are substantially free of enantiomers. Similarly, "isolated" refers to a composition of the nucleoside that includes at least 85 or 90% by weight, typically 95% to 98% by weight and even more typically 99% to 100% by weight of the nucleoside, the remaining comprises other chemical species or enantiomers. The term "independently" is used here to indicate that the variable, which is applied independently, varies independently from application to application. Thus, in a compound such as R "XYR", where R "is" independently carbon or nitrogen "both R" can be carbon, both R "can be nitrogen, or one R" can be carbon and the another R "nitrogen.

The term "host" as used herein, refers to a unicellular or multicellular organism in which the virus can replicate, including cell lines and animals and typically a human. Alternatively, the host can be a carrier of a part of the flavivirus, pestivirus or hepacivirus genome whose replication or function can be altered by the compounds of the present invention. The term "host" refers specifically to infected cells, cells transfected with all or part of the flavivirus, pestivirus or hepacivirus genome and animals, in particular primates (including chimpanzees) and humans. In most of the animal applications of the present invention, the host is a human patient. Veterinary applications, in certain indications, however, are clearly anticipated by the present invention (such as chimpanzees). The term "pharmaceutically acceptable salt or prodrug" is used throughout the specification to describe any pharmaceutically acceptable form (such as an ester, phosphate ester, salt of an ester or a related group) of the compound of a nucleoside which after administration to a patient, provide the nucleoside compound. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable organic and inorganic acids and bases. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium among numerous other acids well known in the pharmaceutical art. "Pharmaceutically acceptable prodrugs" refers to a compound that is metabolized, hydrolyzed or oxidized for example in the host to form the compound of the present invention. Typical examples of prodrugs include compounds having biologically labile protecting groups in a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, be reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to produce the active compound. The compounds of this invention possess antiviral activity against flavivirus, pestivirus or hepacivirus or are metabolized to a compound exhibiting such activity. IV. Nucleotide Salt or Prodrug Formulations In cases where the compounds are sufficiently basic or acidic to form stable non-toxic basic salts or acids, administration of the compound as a pharmaceutically acceptable salt may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids, which form a physiologically acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, -glycerophosphate. D-ketoglutarate, and Q-benzoate, ascorbate, convenient inorganic salts including sulfate, nitrate, bicarbonate and carbonate salts can also be formed. Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting a basic compound sufficiently such as an amine with a convenient acid that provides a physiologically acceptable anion. Alkali metal salts (eg, sodium, potassium or lithium) or alkaline earth metals (eg, calcium) can also be made from carboxylic acids. Any of the nucleosides described herein can be administered as a nucleotide prodrug to increase the activity, bioavailability, stability or otherwise alter the properties of the nucleoside. A number of nucleoside prodrug ligands are known. In general, alkylation, acylation, or other lipophilic modification of the mono, di or triphosphate of the nucleoside will increase the stability of the nucleotide. Examples of substituent groups that can replace one or more hydrogens in the phosphate radical are alkyl, aryl, spheroids, carbohydrates, including sugars, 1,2-diacylglycerol and alcohols. Many are described in R. Jones and N. Bischofberger, Antiviral Research, 27 (1995) 1-17. Any of these can be used in combination with the nucleosides disclosed to achieve the desired effect. The active nucleoside can also be provided as a 5'-phosphoeter lipid or a 5'-ether lipid, as disclosed in the following references, which are incorporated herein by reference: Kucera, LS, N. Iyer, E. Leake , A. Raben, Modest EK, DLW, and C. Piantadosi, "Novel membrane-interactive ether lipid analogs that inhibit infectious HIV-I production and induces defective virus formation," AIDS Res. Hu. Retro Viruses, 1990, 6, 491-501; Piantadosi, C, J. Marasco CJ. , S. L. Morris-Natschke, K.L. Meyer, F. Gumus, J.R. Surles, K.S. Ishaq, L.S. Kucera, N. Iyer, CA. Wallen, S. Piantadosi, and EJ. Modest, "Synthesis and evaluation of novel ether lipid nucleoside conjugates for anti-HIV activity," J. Med. Chem., 1991, 34, 1408-1414; Hosteller, K.Y. , D.D. Richman, D.A. Carson, L.M. Stuhmiller, G.M. T. van Wijk, and H. van den Bosch, "Greatly enhanced inhibition of human immunodeficiency virus type 1 replication in CEM and HT4-6C cells by 3 '-deoxythymidine diphosphate dimyristoylglycerol, a lipid prodrug of 3, -deoxythymidine," Antimicrob. Agents Chemother., 1992, 36, 2025-2029; Hosetler, .Y., L.M. Stuhmiller, H.B. Lenting, H. van den Bosch, and D.D. Richman, "Synthesis and antiretroviral activity of phospholipid analogs of azidothymidine and other antiviral nucleosides." J ". Biol. Che., 1990, 265, 61127. Non-limiting examples of North American patents disclosing convenient lipophilic substituents that can be covalently incorporated in the nucleoside, typically at the 5-position of the nucleoside or the lipophilic preparations include U.S. Patent Nos. 5,149,794 (September 22, 1992, Yatvin et al.); 5,194,654 (March 16, 1993, Hostetler et al., 5,223,263 (June 29, 1993, Hostetler et al.), 5,256,641 (October 26, 1993, Yatvin et al.), 5,411,947 (May 2, 1995, Hostetler et al.), 5,463,092 (October 31, 1995, Hostetler et al. ), 5,543,389 (August 6, 1996, Yatvin et al.), 5,543,390 (August 6, 1996, Yatvin et al.), 5,543,391 (August 6, 1996, Yatvin et al.), And 5,554,728 (September. 10, 1996; Basava et al.), Which are incorporated herein by reference. to Patent Applications disclosing lipophilic substituents that can bind to the nucleosides of the invention of the present invention, or to lipophilic preparations, include WO 89/02733, WO 90/00555, WO 91/16920, WO 91/18914, WO 93/00910, WO 94/26273, WO 96/15132, EP 0 350 287, EP 93917054.4, and WO 91/19721. V. Combination and alternation therapy It has been recognized that drug-resistant HCV variants may emerge after prolonged treatment with an antiviral agent. The highest resistance to the drug typically occurs by mutation of a gene encoding an enzyme used in viral replication. The efficacy of a drug against HCV infection can be prolonged, increased or restored by administering the compound in combination or alternatively with a second and perhaps a third antiviral compound that induces a mutation different from that caused by the main drug. Alternatively, the pharmacokinetics, biodistribution or other parameter of the drug can be altered by such combination or alternation therapy. In general, combination therapy is typical of alternation therapy since it induces multiple simultaneous stress in the virus.

Any of the active compounds described herein can be used in combination or alternatively with another antiviral compound. Non-limiting examples include: (I) Interferon Interferons (IFNs) are compounds that have been commercially available for the treatment of chronic hepatitis for almost a decade. IFNs are glycoproteins produced by immune cells in response to viral infection. IFNs inhibit the viral replication of many viruses, including HCV, and when used as the sole treatment for hepatitis C infection, IFN suppresses RNA with HCV at undetectable levels. Additionally, IFN normalizes serum amino transferase levels. Unfortunately, the effects of IFN are temporary and a sustained response occurs in only 8% -9% of patients chronically infected with HCV (Gary L. Davis, Gastroenterology 118: S104-S114, 2000). A number of patents disclose HCV treatments using interferon-based therapies, for example, U.S. Patent No. 5,980,884 to Blatt et al., Discloses methods for the re-treatment of patients afflicted with HCV using interferon in consensus. The North American Patent No. ,942,223 by Bazer et al., Discloses an anti-HCV therapy using ovine or bovine interferon-tau. U.S. Patent No. 5,928,636 by Alber et al. Discloses the combination therapy of interleukin-12 and alpha interferon for the treatment of infectious diseases including HCV. U.S. Patent No. 5,908,621 to Glue et al. Discloses the use of polyethylene glycol modified interferon for the treatment of HCV. U.S. Patent No. 5,849,696 to Chretien et al. Discloses the use of thymosins, alone or in combination with interferon, to treat HCV. U.S. Patent No. 5,830,455 by Valtuena et al. Discloses a combination HCV therapy using interferon and a free radical scavenger. U.S. Patent No. 5,738,845 by Imakawa discloses the use of human interferon tau proteins to treat HCV. Other interferon-based treatments for HCV are disclosed in U.S. Patent No. 5,676,942 by Testa et al., U.S. Patent No. 5,372, 808 by Blatt et al., And U.S. Patent No. 5,849,696. (2) Ribavirin (Battaglia,?.?., Et al., Ann.Pharmacother, 2000, 34, 487-494); Berenguer, M. et al. Antivir. Ther. , 1998, 3 (Suppl 3), 125-136).

Ribavirin (1-D-D-ribofuranosyl-1-l, 2,4-triazole-3-carboxamide) is a broad-spectrum antiviral nucleoside analogue that is not induced by interferon, synthetic. It is sold under the Virazole ™ trademarks (The Merck Index, 11th edition, Publisher: Budavari, S., Merck &Co., Inc., Rahway, NJ, p304, 1989); Rebetol (Schering Plow) and Co-Pegasus (Roche). U.S. Patent No. 3,798,209 and RE29,835 (ICN Pharmaceuticals) disclose and claim ribavirin. Ribavirin is structurally similar to guanosine, and has in vitro activity against several DNA and RNA viruses including Flaviviridae (Gary L. Davis, Gastroenterology 118: S104-S114, 2000). U.S. Patent No. 4,211,771 (by ICN Pharmaceuticals) discloses the use of ribavirin as an antiviral agent. Ribavirin reduces serum amino transferase levels to normal in 40% of patients, but does not reduce serum levels of RNA with HCV (Gary L. Davis, Gastroenterology 118: S104-S114, 2000). In this way, ribavirin alone is not effective in reducing viral RNA levels. Additionally, ribavirin has significant toxicity and is known to induce anemia. Schering-Plow sells ribavirin as capsules (200 mg) of Rebetol® for administration to patients with HCV.

The United States FDA has approved Rebetol capsules to treat chronic HCV infection in combination with Intron® A and PEG-Intron ™ alpha interferon-2b products from Schering. Rebetol capsules have not been approved for monotherapy (ie, the independent administration of Intron® A or PEG-Intron), although the Intron A and the 'PEG-Intron are approved for monotherapy (ie, administration without ribavirin). Hoffman La Roche sells ribabirin under the name Co-Pegasus in Europe and the United States, also for use in combination with interferon for the treatment of HCV. Other alpha interferon products include Roferon-A (Hoffmann-La Roche), Infergen® (Intermune, formerly Amgen product), and Wellferon® (Wellcome Foundation) are currently approved by the FDA for HCV monotherapy. Interferon products currently under development for HCV include: Roferon-A (interferon alfa-2a) by Roche, PEGASYS (pegylated interferon alfa-2a) by Roche, INFERGEN (interferon alfacon-1) by InterMune, OMNIFERON (natural interferon) by Viragen, ALBUFERON by Human Genortie Sciences, REBIF (interferon beta-la) by Ares-Serono, Omega Interferon by BioMedicine, Oral Interferon Alpha by Amarillo Biosciences, and Interferon gamma-Ib by InterMune.

The combination of IFN and ribavirin for the treatment of HCV infection has been reported to be effective in the treatment of patients without involvement of IFN (for example, in Battaglia, AM et al., Ann.Pharmacother., 34: 487-494 , 2000). The combination treatment is effective, both, before the development of hepatitis and when histological disease is present (for example, in Berenguer, M. et al., Antivir., Ther. 3 (Suppl 3) -.125- 136, 1998). Currently, the most effective therapy for HCV is combination therapy of pegylated interferon with ribavirin (2002 NIH Consensus Development Conference on the Management of Hepatitis C). However, the side effects of the combination therapy may be significant and include hemolysis, flu-like symptoms, anemia, and fatigue (Gary L. Davis, Gastroenterology 118: S104-S114, 2000). (3) Protease inhibitors have been developed for the treatment of infections by Flaviviridae. Examples, include, but are not limited to the following. Substrate-based NS3 protease inhibitors (see, for example, Attwood et al, Antiviral peptide derivatives, PCT O 98/22496, 1998, Attwood et al, Antiviral Chemistry and Chemotherapy 1999, 10, 259-273; Attwood et al. , Preparation and use of amino acid derivatives as anti-viral agents, German Patent Pub. DE 19914474; Tung et al., Inhibitors of serine proteases, particularly hepatitis C virus NS3 protease, PCT WO 98/17679), including alpha-ketoamides and hydra-uoureas and inhibitors ending in an electrophile such as a boronic acid or phosphonate (see, for example, Llinas-Brunet et al, Hepatitis C inhibitor peptide analogues, PCT WO 99/07734); Non-substrate-based inhibitors such as 2, 4,6-trihydroxy-3-nitro-benzamide derivatives (see, for example, Sudo K. et al, Biochemical and Biophysical Research Communications, 1997, 238, 643). -647; Sudo K. et al Antiviral Chemistry and Chemotherapy, 1998, 9, 186), including RD3-4082 and RD3-4078, the former substituted in the amide with a chain of 14 carbons and the latter processing a group for -phenoxyphenyl; Fenantrenoquinones having activity against the protease, for example in an SDS-PAGE and / or autoradiography test, such as, for example Sch 68631, isolated from the fermentation culture broth of Streptomyces sp. , (see, for example, Chu M. et al, Tetrahedron Letters, 1996, 37, 7229-7232), and Sch 351633, isolated from the fungus Penicilliu griseofulvum, demonstrating activity in a scintillation proximity assay (see, for example. , Chu M. et al, Bioorganic and Medicinal Chemistry Letters 9, 1949-1952); and selective NS3 inhibitors, for example, based on the elgin c macromolecule, isolated from leech (see, for example, Qasim M.A. et al, Biochemistry, 1997, 36, 1598-1607). The nanomolar potency against the enzyme of the HCV NS3 protease has been achieved through the design of selective inhibitors based on the macromolecule elgin c. The elgin c, isolated from leech is a potent inhibitor of several serine proteases such as proteases? and B of S. griseus, D-chymotrypsin, chymase and subtilisin. Several US Patents disclose protease inhibitors for the treatment of HCV. Non-limiting examples include, but are not limited to the following. US Patent No. 6,004,933 by Spruce et al. Discloses a class of cistern protease inhibitors to inhibit HCV endopeptidase. U.S. Patent No. 5,990,276 by Zhang et al discloses synthetic inhibitors of the NS3 protease of hepatitis C virus. The inhibitor is a sequence of an NS3 protease substrate or a substrate of the NS4A cofactor. The use of restriction enzymes to treat HCV is disclosed in U.S. Patent No. 5,538,865 by Reyes et al.

Peptides as inhibitors of HCV NS3 serine protease are disclosed in WO 02/008251 by Corvas International, Inc, and in WO 02/08187 and WO 02/008256 by Schering Corporation. HCV inhibitor tripeptides are disclosed in U.S. Pat. Nos. 6, 534,523, 6,410,531, and 6,420,380 by Boehringer Ingelheim and WO 02/060926 by Bristol Myers Squibb. Diaryl peptides as inhibitors of HCV serine protease NS3 are disclosed in WO 02/48172 by Schering Corporation. Imidazoleidinones as inhibitors of HCV NS3 serine protease are disclosed in WO 02/08198 by Schering Corporation and WO 02/48157 by Bristol Myers Squibb. WO 98/17679 by Vértex Pharmaceuticals and WO 02/48116 by Bristol Myers Squibb also disclose HCV protease inhibitors. (4) Thiazolidine derivatives, for example, show relevant inhibition in a reverse phase HPLC assay with an NS3 / 4A fusion protein and an NS5A / 5B substrate (see, for example, Sudo K. et al, Antiviral Research, 1996, 32, 9-18), especially the compound RD-1-6250, which possesses a fused cinnamoyl radical substituted with a long alkyl chain, RD4 6205 and RD4 6193; (5) Thiazolidines and benzanilides, for example, as identified in Kakiuchi N. et al. J. EBS Letters 421, 217-220; Takeshita N. et al. Analytical Biochemistry, 1997, 247, 242-246; (6) Helicase inhibitors (see, for example, Diana GD et al, Compounds, compositions and methods for treatment of hepatitis C, US Patent No. 5,633,358, Diana GD et al., Piperidine derivatives, pharmaceutical compositions and their use in the treatment of hepatitis C, PCT WO 97/36554); (7) Polymerase inhibitors such as i) nucleotide analogs, such as gliotoxin (see, for example, Ferrari R. et al, Journal of Virology, 1999, 73, 1649-1654); ii) The natural product cerulenin (see, for example, Lohmann V. et al., Virology, 1998, 249, 108-118); and iii) non-nucleotide polymerase inhibitors, including, for example, compound R803 (see, for example, WO 04/018463 A2 and WO 03/040112 Al, both by Rigel Pharmaceuticals, Inc.); substituted diamine pyrimidines (see, for example, WO 03/063794 A2 by Rigel Pharmaceuticals, Inc.); benzimidazole derivatives (see, for example, Bioorg, Med Chem. Lett., 2004, 14: 119-124 and Bioorg, Med. Chem. Lett., 2004, 14: 967-911, both by Boehringer Ingelheim Corporation); β, β-disubstituted phenylalanines (see, for example, J. Biol. Chem., 2003, 278: 9495-98 and J. Med. Chem., 2003, 13: 1283-85, both, by Shire Biochem, Inc. ); substituted thiophene-2-carboxylic acids (see, for example, Bioorg, Med. Chem. Lett., 2004, 14: 793-796 and Bioorg, Med. Chem. Lett., 2004, 14: 797-800, both by Shire Biochem, Inc.); diketo acids (see, for example, J. "Med. Chem., 2004, 14-17 and WO 00/006529 Al, both by Merck & Co. , Inc.); and meconic acid derivatives (see, for example, Bioorg, Med. Chem. Lett., 2004, 3257-3261, WO 02/006246 Al and WO03 / 062211 Al, all by IRBM Merck &Co., Inc.); (8) Complementary antisense phosphorothioate (S-ODN) oligodeoxynucleotides, for example, stretches of the sequence in the 5"non-coding region of the virus (NCR) (see, eg, Alt M. et al, Hepatology, 1995 , 22, 707-717), or by nucleotides 326-348 comprising the 3 'end of the NCR and the nucleotides 371-388 located in the coding region of the HCV RNA core (see, for example, Alt M . et al, Archives of Virology, 1997, 142, 589-599; Galderisi U. et al, Journal of Cellular Physiology, 1999, 181, 251-257). (9) Inhibitors of IRES dependent movement (see, for example, Ikeda N et al, Agent for the prevention and treatment of hepatitis C, Japanese Patent Pub. JP-08268890; Kai Y. et al Prevention and treatment of viral diseases , Japanese Patent Pub. JP-10101591). (10) Nuclease resistant ribozymes (see, for example, Maccjak, DJ et al, Hepatology 1999, 30, abstract 995, US Patent No. 6,043,077 by Barber et al, and US Patent Nos. 5,869,253 and 5,610,054 by Draper et al.). 11. Nucleoside analogues have also been developed for the treatment of Flaviviridae infections. Idenix Pharmaceuticals, Ltd., discloses branched nucleosides, and their use in the treatment of HCV and flavivirus and pestiviruses in U.S. Patent No. 6,914,054, which was issued July 5, 2005, and U.S. Patent No. 6,812,219, issued November 2, 2004, which correspond to International Applications Nos. WO 01/90121 and WO 01/92282. A method for the treatment of hepatitis C infection (and flavivirus and pestivirus) in humans and other host animals is disclosed in the Idenix Requests which includes administering an effective amount of a DD or DL 1 ', 2', 3 'or nucleoside. Or a pharmaceutically acceptable salt or prodrug thereof, administered either alone or in combination, optionally in a pharmaceutically acceptable carrier. See also U.S. Patent Applications Nos. 2004/0006002 and 2004/0006007 in addition to WO 03/026589 and WO 03/026675. Idenix Pharmaceuticals, Ltd. also discloses in US Patent Application No. 2004/0077587 prodrugs of pharmaceutically acceptable nucleosides and their uses in the treatment of HCV and of flaviviruses and pestiviruses in the prodrugs. See also, PCT Applications Nos. WO 04/002422, WO 04/002999, WO 04/003000; WO 04/024095 and WO 05/009418. Biota Inc. discloses various nucleoside phosphate derivatives, including D-D or D-L 1 ', 2', 3 'or 4' -branched nucleosides, for the treatment of hepatitis C infection in International Patent Application WO 03/072757. Emory University and the University of Georgia Research Foundation, Inc. (UGARF) disclose the use of 2'-fluoronucleosides for the treatment of HCV in US Patent No. 6,348,587. See also U.S. Patent Application No. 2002/0198171 and International Patent Application WO 99/43691. BioChem Pharma Inc. (now Shire Biochem, Inc.) discloses the use of various 1, 3-dioxolane nucleosides for the treatment of an infection by Flaviviridae in US Patent No. 6,566,365. See also US Patents Nos. 6,340,690 and 6,605,614; U.S. Patent Applications Nos. 2002/0099072 and 2003/0225037, in addition to International Application No. WO 01/32153 and WO 00/50424. BioChem Pharma Inc. (now Shire Biochem, Inc.) also discloses several other 2'-halo, 2'-hydroxy and 2'-alkoxy nucleosides for the treatment of a Flaviviridae infection in US Patent Application No. 2002/0019363 in addition to International Application No. WO 01/60315 (PCT / CAOl / 00197, filed February 19, 2001). ICN Pharmaceuticals, Inc. discloses various nucleoside analogs that are useful in modulating the immune response in US Patent Nos. 6,495,677 and 6,573,248. See also WO 98/16184, WO 01/68663, and WO 02/03997.

U.S. Patent No. 6,660,721; US Patent Publications Nos. 2003/083307 Al, 2003/008841 Al, and 2004/0110718; in addition to International Patent Applications Nos. WO 02/18404; WO 02/100415, WO 02/094289, and WO 04/043159; filed by F. Hoffimann-La Roche AG, disclose several nucleoside analogs for the treatment of RNA replication with HCV. Pharmasset Ltd. discloses various nucleosides and antimetabolites for the treatment of a variety of viruses, including Flaviviridae, and in particular HCV, in US Patent Applications Nos. 2003/0087873, 2004/0067877, 2004/0082574, 2004/0067877, 2004/002479, 2003/0225029, and 2002/00555483, in addition to the US Pat. Applications Nos. WO 02/32920, WO 01/79246, WO 02/48165, WO 03/068162, WO 03/068164 and WO 2004 / 013298. Merck & Co. , Inc. and Isis Pharmaceuticals disclose in US Patent No. 6,777,395, issued August 17, 2004; U.S. Patent Application No. 2004/0072788, 2004/0067901, and 2004/0110717; in addition to the corresponding International Patent Applications Nos. WO 02/057425 (PCT / US02 / 01531; filed January 18, 2002) and WO 02/057287 (PCT / US02 / 03086; filed January 18, 2002) several nucleosides, and in particular several pyrrolopyrimidine nucleosides, for the treatment of viruses whose replication is dependent on AR-dependent RNA polymerase, including Flaviviridae, and in particular HCV. See also WO 2004/000858, WO. 2004/003138, WO 2004/007512, and WO 2004/009020. U.S. Patent Publication No. 2003/028013 Al in addition to International Patent Publications Nos. WO 03/051899, WO 03/061576, WO 03/062255 WO 03/062256, WO 03/062257, and WO 03/061385, presented by Ribapharm, are also directed to the use of certain nucleoside analogs to treat hepatitis C virus. Genelabs Technologies discloses in US Patent Publication No. 2004/0063658 in addition to International Patent Applications No. WO 03 / 093290 and WO 04/028481 various base nucleoside derivatives including DD or DL nucleosides 1 ', 2', 3 'or 4' -branched, for the treatment of hepatitis C infection. Eldrup et al. (Oral Session V, Hepatitis C Virus, Flaviviridae, 16th International Conference on Antiviral Research (April 27, 2003, Savannah, Ga.) P.A75) describes the relationship of the structure activity of the 2'-modified nucleosides the inhibition of HCV.

Bhat et al (Oral Session V, Hepatitis C Virus, Flaviviridae, 16th International Conference on Antiviral Research (April 27, 2003, Savannah, Ga.); p A75) describes the synthesis and pharmacokinetic properties of nucleoside analogs as possible inhibitors of RNA replication with HCV. The authors report that the modified "2" nucleosides demonstrate potent inhibitory activity in replication assays in cell bases Olsen et al. (Oral Session V, Hepatitis C Virus, Flaviviridae, 16th International Conference on Antiviral Research (April 27, 2003, Savannah, Ga.) P A76) also describes the effects of 2"-modified nucleosides on RNA replication with HCV. Anti-viral Purines having acyclic substituents are known and have been used to treat various viral infections. Examples of this class of compounds are acyclovir, ganciclovir, famciclovir, penciclovir, adefovir and adefovir dipivoxil, all of which are useful in the treatment of human syncytial virus (HSV), cytomegalovirus (CMV) and varicella-zoster virus (see EP 0 72027 by the Wellcome Foundation Ltd., UK, for the treatment of equine rhinopneumonitis virus, JP 06227982 by Aj inomoto KK, for the treatment of varicella-zoster virus and cytomegalovirus, S. Vittori et al., Deaza - and Deoxyadenosine Derivatives: Synthesis and Inhibition of Animal Viruses as Human Infection Models, in Nucleosides, Nucleotides & Nucleic Acids (2003) 22 (5-8): 877-881, for the treatment of bovine herpes virus 1 (BHV-I) and the Maedi-Visna virus of sheep (MW); R. ang et al., Synthesis and hiological activity of 2-aminopurine methylenecyclo-propane analogues of nucleosides, in Nucleosides, Nucleotides & Mucleic Acids (2003) 22 (2): 135-144, for the treatment of HSV-I and VZV; U.S. Patent 6,444,656 by BioChem Pharma, Inc., Canada, for the treatment of HIV and / or HBV infections; and WO 02/057288 by LG Chem Investment Ltd. for acyclic nucleoside phosphonate compounds for use as anti-HBV agents). (12) Other miscellaneous compounds including 1-amino-alkylcyclohexanes (for example, US Patent No. 6,034,134 by Gold et al), alkyl lipids (e.g., U.S. Patent No. 5,922,757 by Chojkier et al.), vitamin E and other antioxidants (for example, U.S. Patent No. 5,922,757 by Chojkier et al), squalene, amantadine, bile acids (e.g., U.S. Patent No. 5,846,964 by Ozeki et al), N- (phosphonoacetyl) - L-aspartic (e.g., U.S. Patent No. 5,830,905 by Diana et al), benzenedicarboxamides (e.g., U.S. Patent No. 5, 633,388 by Diana et al), polyadenylic acid derivatives (e.g., U.S. Patent No. 5,496,546 by Wang et al), 2 ', 3'-dideoxyinosine (e.g., U.S. Patent No. 5,026,687 by Yarchoan et al), benzimidazoles (e.g., U.S. Patent No. 5,891,874 by Colacino et al), extracts of plants (for example, the U.S. Patent No. 5,837,257 by Tsai et al, U.S. Patent No. 5,725,859 by Omer et al., And U.S. Patent No. 6,056,961), and piperidenes (e.g., U.S. Patent No. 5,830,905 by Diana et al.). (13) Other compounds include, for example: Interleukin-10 by Schering-Plow, IP-501 by Interneuron, Merimebodib VX-497 by Vertex, AMANTADINE® (Symmetrel) by Endo Labs Solvay, HEPTAZYME® by RPI, IDN-6556 by Idun Pharma., XTL-002 by XTL. , HCV / MF59 by Chiron, CIVACIR ® (Hepatitis C immune globulin) by NABI, LEVOVIRIN ® by ICN / Ribapharm, VIRAMIDINE ® by ICN / Ribapharm, ZADAXIN ® (thymosin alfa - 1) by Sci Clone, thymosin plus pegylated interferon by Sci Clone, CEPLENE ® (histamine dihydrochloride) by Maxim, VX 950 / LY 570310 by Vertex / Eli Lilly, ISIS 14803 by Isis Pharmaceutical / Elan, IDN-6556 by Idun, Pharmaceuticals, Inc., JT 003 by AKROS Pharma, BILN -2061 by Boehringer Ingelheim, CellCept (mycophenolate mofetil) by Roche, T67, an inhibitor of D-tubulin, by Tularik, a therapeutic vaccine directed to E2 by Innogenetics, FK788 by Fujisawa Healthcare, Inc., IdB 1016 (Siliphos, silibin -phosphatidylcholine oral phytosome), inhibitors of RNA replication (VP50406) by ViroPharma / Wyeth, therapeutic vaccine by Intercell, therapeutic vaccine by Epimmune / Genencor, inhibitor IRES by Anadys, ANA 245 and ANA 246 by Anadys, immunotherapy (Teraporo) by Avant, protease inhibitor by Corvas / SC hering, helicase inhibitor by Vertex, fusion inhibitor by Trimeris, T-cell therapy by CellExSys, polymerase inhibitor by Bxocryst, RNA chemistry directed by PTC Therapeutics, Dication by Immtech, Int., protease inhibitor by Agouron, inhibitor of protease by Chiron / Medivir, antisense therapy by AVI BioPharma, antisense therapy by Hybridon, hemopurifier by Aethlon Medical, therapeutic vaccine by Merix, inhibitor of protease by Bristol-Myers Squibb / Axys, Chron-VacC, a therapeutic vaccine, by Tripep, UT 23IB by United Therapeutics, Protease inhibitors, helicase and polymerase by Genelabs Technologies, IRES inhibitors by Immusol, R803 by Rigel Pharmaceuticals, INFERGEN ® (interferon alfacon-1) by InterMune, OMNIFERON ® (natural interferon) by Viragen, ALBUFERON ® by Human Genome Sciences, REBIF® (interferon beta-la) by Ares-Serono, Omega Interferon by BioMedicine, Alpha Oral Interferon by Amarillo Biosciences, interferon gamma, interferon tau, and interferon gamma-lb by InterMune. SAW . Pharmaceutical Compositions The hosts or hosts, including humans, infected with flavivirus, pestivirus or hepacivirus can be treated by administering to the patient an effective amount of the active compound or a prodrug or pharmaceutically acceptable salt, in the presence of a pharmaceutically acceptable carrier or solvent. . The active materials can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, in liquid or solid form. Non-limiting examples of the compound infection dose will be in the range of 1 to 80 mg / kg, 1 to 70 mg / kg, 1 to 60 mg / kg, 1 to 50 mg / kg, or 1 to 20 mg / kg, body weight per day, more usually 0.1 to about 100 mg per kilogram of container body weight per day. The effective dose range of the pharmaceutically acceptable salts and prodrugs can be calculated based on the weight of the major nucleoside to be delivered. If the salt or prodrug exhibits activity in itself, then the effective dose can be estimated as mentioned above using the weight of the salt or the prodrug, or by other means known to those skilled in the art. The compound is conveniently administered in unit of any suitable form of the dosage, including but not limited to one containing 7 to 3000 mg, typically 70 to 1400 mg of active ingredient per unit dosage form. An oral dose of 50-1000 mg is usually convenient. Ideally, the active ingredient should be administered to achieve maximum plasma concentrations of the active compound of about 0.2 to 70 μ,?, Typically about 1.0 to 10 μ.?. This can be achieved, for example, by the intravenous injection of a solution of 0.1 to 5% of the active ingredient, optionally in saline, or it can be administered as a bolus of the active ingredient. The concentration of the active compound in the drug composition will depend on the rates of absorption, deactivation, and excretion of the drug as well as other factors known to those of skill in the art. It should be noted that the dose values will also vary with the severity of the condition to be alleviated. It should be further understood that for any particular subject, the specific regimens of the dose should be adjusted over time according to the individual need and professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges described hereinafter are exemplary only and are not intended to limit the scope or practice of the claimed composition. The active ingredient can be administered in a single dose, or it can be divided into a number of smaller doses to be administered in intervals that vary with time. One mode of administration of the active compound is oral. Oral compositions will generally include an inert solvent or an edible carrier. They can be included in gelatin capsules or they can be compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and can be used in the form of tablets, troches or capsules. The pharmaceutically compatible agglutinating agents, and / or the adjuvant materials can be included as part of the composition.

Tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: A binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the unit dosage form is a capsule, it may contain, in addition to the material of the type cited above, a liquid carrier such as a fatty oil. In addition, dosage unit forms may contain various other materials that modify the physical form of the unit dose, for example, coatings of sugar, shellac, or other enteric agents. The compound can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colors and flavors.

The compound or a prodrug or pharmaceutically acceptable salts thereof can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antibiotics, antifungals, anti-inflammatories, or other antivirals, including other compounds of Nucleosides. Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application may include the following components: a sterile solvent such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for tonicity adjustment such as sodium chloride or dextrose. The parental preparation can be included in ampules, disposable syringes or multiple dose vials made of glass or plastic. If administered intravenously, typical carriers are physiological saline or phosphate buffered saline (PBS).

In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biodegradable polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid can be used. Methods for the preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation. Liposomal suspensions (including liposomes directed to cells infected with monoclonal antibodies to viral antigens) are also typical as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in US Patent No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, liposome formulations can be prepared by dissolving the appropriate lipid (s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, aracadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent which is then evaporated, leaving behind a thin film of dry lipid on the surface of the container. An aqueous solution of the active compound or its monophosphate derivatives is then introduced, diphosphate, and / or triphosphate in the container. The container is then swirled by hand to release the lipid material from the sides of the container and to disperse the lipid aggregates, thus forming the liposomal suspension. VII. Processes for the Preparation of Active Compounds. The nucleosides of the present invention can be synthesized by any means known in the art. In particular, the synthesis of the present nucleosides can be achieved by either the alkylation of the appropriately modified sugar, followed by the glycosylation or glycosylation followed by the alkylation of the nucleoside. The following non-limiting embodiments illustrate some general methodologies for obtaining the nucleosides of the present invention. General Synthesis of the 11 -C-Branched Nucleosides The 1'-C-branched ribonucleosides of the following structure: where the Base, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and, W1, W2, W3, X, X1, X2 and X3 are as defined herein, can be prepared by one of the following general methods. 1) Modification of the lactone The key starting material for this process is an appropriately substituted lactone. The lactone can be purchased or can be prepared by any known means including standard epimerization, substitution and cyclization techniques. The lactone can optionally be protected with a suitable protecting group, typically with an acyl or silyl group, by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synt esis. John Wiley and Sons, Second Edition, 1991. The protected lactone can then be coupled with a suitable coupling agent, such as an organometallic carbon nucleophile, such as a Grignard reagent, an organolithium, lithium dialkyl or R6-SiMe3 in TBAF with the appropriate non-protic solvent at a suitable temperature, to give the 1'-alkylated sugar. The optionally activated sugar can then be coupled to the BASE by methods well known to those skilled in the art, as taught by Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994. For example, an acylated sugar can be coupled to a silylated base with a lewis acid, such as tin tetrachloride, titanium tetrachloride or trimethylsilyltriflate in the appropriate solvent at a suitable temperature. Subsequently, the nucleoside can be deprotected by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Qrganic Synthesis, John Wiley and Sons, Second Edition, 1991. In a particular embodiment, the 1'-C-branched ribonucleoside is desired. The synthesis of a ribonucleoside is shown in Scheme 1. Alternatively, deoxyribo-nucleoside is desired. To obtain these Nucleosides, the ribonucleoside formed can optionally be protected by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Qrganic Synthesis. John Wiley and Sons, Second Edition, 1991, and subsequently 2'-OH can be reduced with a suitable reducing agent. Optionally, 2'-hydroxyl can be activated to facilitate reduction; that is, via the Barton reduction.

Scheme 1 i) Coupling 2 $ Beaprotección Optional. 2. Alternative method for the preparation of the nucleosides 1 r -C-ramifloados. The key starting material for this process is an appropriately substituted hexose. The hexose can be purchased or can be prepared by any known means including standard epimerization techniques (for example by alkaline treatment), substitution and coupling. The hexose can be selectively protected to give the appropriate hexafuranose, as taught by Townsend Chemistry of Niccides and Nucleotides, Plenum Press, 1994. The 1'-hydroxyl can be optionally activated to a suitable leaving group such as an acyl group or a halogen via acylation or halogenation, respectively. The optionally activated sugar can then be coupled to the BASE by methods well known to those skilled in the art, as taught by Townsend Chemistry of Niccides and Nucleotides, Plenum Press, 1994. For example, an acylated sugar can be coupled to a silylated base with a Lewis acid, such as tin tetrachloride, titanium tetrachloride or trimethylsilyltriphylate in the appropriate solvent at a suitable temperature. Alternatively, a halo-sugar can be coupled to a silylated base in the presence of trimethylsilyltriphyte. The -CH2-0H, if protected, can be selectively deprotected by methods well known in the art. The resulting primary hydroxyl can be functionalized to give several C-branched Nucleosides. For example, the primary hydroxyl can be reduced to the methyl, using a suitable reducing agent. Alternatively, the hydroxyl can be activated before reduction to facilitate the reaction; that is, via the Barton reduction. In an alternate embodiment, the primary hydroxyl can be oxidized to the aldehyde, then can be coupled with a carbon nucleophile, such as a Grignard reagent, an organolithium, lithium dialkyl or R6-SiMe3 in TBAF with the appropriate non-protic solvent at a temperature adequate In a particular embodiment, the 1'-C-branched ribonucleoside is desired. The synthesis of a ribonucleoside is shown in Scheme 2. Alternatively, deoxyribo-nucleoside is desired. To obtain these Nucleosides, the ribonucleoside formed can optionally be protected by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and subsequently 2'-OH can be reduced with a suitable reducing agent. Optionally, 2'-hydroxyl can be activated to facilitate reduction; that is, via the Barton reduction.

In addition, the L-enantiomers corresponding to the compounds of the invention can be prepared following the same general methods (1 or 2), starting with the L-sugar or L-enantiomer of the corresponding nucleoside as starting material. General synthesis of the 2'-C-branched Nucleosides The 2'-C-branched ribonucleosides of the following structure: where the Base, R1, R2, R3, R, R5, R6, R7, R9, R10, and, W1, W2, W3, X, X1, X2 and X3 are as defined herein can be prepared by one of the following general methods. I. Glycosylation of the nucleobase with an appropriately modified sugar. The key starting material for this process is a sugar appropriately substituted with a 2'-OH and 2'H, with the appropriate leaving group (LG), for example an acyl group or a halogen. Sugar can be purchased or can be prepared by any known means including standard epimerization, substitution, oxidation and reduction techniques. The substituted sugar can then be oxidized with the appropriate oxidizing agent in a compatible solvent at a suitable temperature to produce the 2'-modified sugar. Possible oxidizing agents are Jones reagent (a mixture of chromic acid and sulfuric acid), Collin reagent (Cr (VI) dipyridine oxide, Corey reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, permanganate. of potassium, Mn02, ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate supported on a polymer, Cl2-pyridine, H202-ammonium molybdate, NaBr02-CMT, NaOCl in HOAc, copper chromite, oxide of copper, Raney nickel, palladium acetate, Meerwin-Pondorf-Verley reagent (aluminum t-butoxide with another ketone) and N-bromosuccinimide, then the coupling of an organometallic carbon nucleophile, such as a Grignard reagent, an organolithium , lithium dialkyl copper or Rs-SiMe3 in TBAF with the ketone with the appropriate non-protic solvent at a suitable temperature, produces the 2'-alkylated sugar.The alkylated sugar can be optionally protected with A suitable protecting group, typically with an acyl or silyl group, by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991. The optionally protected sugar can then be coupled to the BASE by methods well known to those skilled in the art, as taught by Townsend Chemistry of Niccides and Nucleotides, Plenum Press, 1994. For example, an acylated sugar can be coupled to a silylated base with a lewis acid, such as tin tetrachloride, titanium tetrachloride or trimethylsilyltriflate in the appropriate solvent at a suitable temperature. Alternatively, a halo-sugar can be coupled to a silylated base in the presence of trimethylsilyltriflate.

Subsequently, the nucleoside can be deprotected by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synt esis. John Wiley and Sons, Second Edition, 1991. In a particular embodiment, the 2'-C-branched ribonucleoside is desired. The synthesis of a ribonucleoside is shown in Scheme 3. Alternatively, deoxyribo-nucleoside is desired. To obtain these nucleosides, the ribonucleoside formed can optionally be protected by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and subsequently 2'-OH can be reduced with a suitable reducing agent. Optionally, 2'-hydroxyl can be activated to facilitate reduction; that is, via the Barton reduction.

B_s¾tte. »A 3 1) Coupling 2 > Optional check out Optional on 2. Modification of a preformed nucleoside The key starting material for this process is a nucleoside appropriately substituted with a 2'-OH and 2 ?. The nucleoside can be purchased or can be prepared by any known means including standard coupling techniques. The nucleoside can optionally be protected with suitable protecting groups, typically with the acyl or silyl groups, by methods well known to those skilled in the art, as taught by Greene et al.

Protective Groups in Organic Synthesis, John ile and Sons, Second Edition, 1991. The appropriately protected nucleoside can then be oxidized with the appropriate oxidizing agent in a compatible solvent at a suitable temperature to produce the modified-21 sugar. Possible oxidizing agents are Jones reagent (a mixture of chromic acid and sulfuric acid), Collin reagent (Cr (VI) dipyridine oxide, Corey reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, permanganate potassium, Mn02, ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate supported on a polymer, Cl2-pyridine, H202-ammonium molybdate, NaBr02-CAN, NaOCl in HOAc, copper chromite, copper, Raney nickel, palladium acetate, Meerwin-Pondorf-Verley reagent (aluminum t-butoxide with another ketone) and N-bromosuccinimide Subsequently, the nucleoside can be deprotected by methods well known to those skilled in the art, such as taught by GreeneGreene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991. In a particular embodiment, the 2'-C-branched ribonucleoside is desired. ribonucleoside is shown in Scheme 4. Alternatively, deoxyribo-nucleoside is desired. To obtain these nucleosides, the ribonucleoside formed can optionally be protected by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and subsequently 2'-OH can be reduced with a suitable reducing agent. Optionally, 2'-hydroxyl can be activated to facilitate reduction; that is, via the Barton reduction.

Optional protection * Deproteooion; Optional In another embodiment of the invention, the L-enantiomers are desired. Accordingly, the L-enantiomers may be corresponding to the compounds of the invention and may be prepared by following the same general methods above, starting with the L-sugar or L-enantiomer of the corresponding nucleoside as starting material. General synthesis of the 3'-C-rairtified Nucleosides The 3'-C-branched ribonucleosides of the following structure: where the Base, R1, R2, R3, R, R5, R6, R7, R8, R9, and, W1, W2, W3, X, X1, X2 and X3 are as defined herein can be prepared by one of the following general methods. 1 Glycosylation of the nucleobase with a suitably modified sugar The key starting material for this process is a sugar appropriately substituted with a -OH and 3'-H, with the appropriate leaving group (LG), for example an acyl group or a halogen Sugar can be purchased or can be prepared by any known means including standard epimerization, substitution, oxidation and reduction techniques. The substituted sugar can then be oxidized with the appropriate oxidizing agent in a compatible solvent at a suitable temperature to produce the 3'-modified sugar. Possible oxidizing agents are Jones reagent (a mixture of chromic acid and sulfuric acid), Collin reagent (Cr (VI) dipyridine oxide, Corey reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, permanganate potassium, Mn02, ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate supported on a polymer, Cl2-pyridine, H202-ammonium molybdate, NaBr02-CA, NaOCl in HOAc, copper chromite, oxide copper, nickel nickel, palladium acetate, Meerwin-Pondorf-Verley reagent (aluminum t-butoxide with another ketone) and N-bromosuccinimide, subsequently the coupling of an organometallic carbon nucleophile, such as a Grignard reagent, an organolithium, lithium dialkyl or R6-SiMe3 in TBAF with the ketone with the appropriate non-protic solvent at a suitable temperature, produces the 31 -C-branched sugar. 3 '-C-branched sugar can optionally be protected with a suitable protecting group, typically with an acyl or silyl group, by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991. The optionally protected sugar can then be coupled to the BASE by methods well known to those skilled in the art, as taught by To nsend Chemistry of Niccides and Nucleotides. Plenum Press, 1994. For example, an acylated sugar can be coupled to a silylated base with a lewis acid, such as tin tetrachloride, titanium tetrachloride or trimethylsilyltriflate in the appropriate solvent at a suitable temperature. Alternatively, a halo-sugar can be coupled to a silylated base in the presence of trimethylsilyltriflate. Subsequently, the nucleoside can be deprotected by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis. John Wiley and Sons, Second Edition, 1991. In a particular embodiment, the 3'-C-branched ribonucleoside is desired. The synthesis of a ribonucleoside is shown in Scheme 5. Alternatively, deoxyribo-nucleoside is desired. To obtain these nucleosides, the ribonucleoside formed can optionally be protected by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis. John Wiley and Sons, Second Edition, 1991, and can subsequently be reduced to 2 '-0H with a suitable reducing agent. Optionally, 2'-hydroxyl can be activated to facilitate the reduction; that is, via the Barton reduction.

Esguema S 1) Coupling 2) Optional deprecation ase i) Gpeional Protection 2) Optional Reteam tion 2. Modification of a preformed nucleoside The key starting material for this process is a nucleoside appropriately substituted with a 3'-OH and 3'-H. The nucleoside can be purchased or can be prepared by any known means including standard coupling techniques. The nucleoside can optionally be protected with suitable protecting groups, typically with the acyl or silyl groups, by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991. The appropriately protected nucleoside can then be oxidized with the appropriate oxidizing agent in a compatible solvent at a suitable temperature to produce the modified 2'-sugar. Possible oxidizing agents are Jones reagent (a mixture of chromic acid and sulfuric acid), Collin reagent (Cr (VI) dipyridine oxide, Corey reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, permanganate. potassium, Mn02, ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate supported on a polymer, Cl2-pyridine, H202 molybdate-ammonium molybdate, NaBr02-CA, NaOCl in HOAc, copper chromite , copper oxide, nickel nickel, palladium acetate, Meerwin-Pondorf-Verley reagent (aluminum t-butoxide with another ketone) and N-bromosuccinimide.

Subsequently, the nucleoside can be deprotected by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991. In a particular embodiment, the 3'-C-branched ribonucleoside is desired. The synthesis of a ribonucleoside is shown in Scheme 6. Alternatively, deoxyribo-nucleoside is desired. To obtain these nucleosides, the ribonucleoside formed can optionally be protected by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and subsequently 2'-OH can be reduced with a suitable reducing agent. Optionally, el-2'-hydroxyl can be activated to facilitate reduction; that is, via the Barton reduction.

Es¾uema 6 Optional checkout In another embodiment of the invention, the L-enantiomers are desired. Accordingly, the L-enantiomers can be corresponding to the compounds of the invention can be prepared following the same general methods above, starting with the L-sugar or L-enantiomer of the corresponding nucleoside as starting material. General synthesis of the 4'-C-branched Nucleosides The 'C-branched' ribonucleosides of the following structure: wherein the Base, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, Y, W1, W2, W3, X, X1, X2 and X3 are as defined herein can be prepared by one of the following general methods. 1. Modification of the pentodialdo-furanose The key starting material for this process is an appropriately substituted pentodial-furanose. The pentodialdo-furanose can be purchased or can be prepared by any known means including standard epimerization, substitution and cyclization techniques. In one embodiment, the pentodial-furanose is prepared from the appropriately substituted hexose. The hexose can be purchased or can be prepared by any known means including standard epimerization techniques (eg via alkaline treatment), substitution and coupling techniques. The hexose may be either in the form of furanose, or cyclized by any means known in the art, such as the methodology taught by Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994, typically by selectively protecting hexose, to give the appropriate hexafuranose. The 4'-hydroxymethylene of the hexafuranose can then be oxidized with the appropriate oxidizing agent in a compatible solvent at a suitable temperature to produce the 4-aldo-modified sugar. Possible oxidizing agents are Swern's reagents, Jones's reagent (a mixture of chromic acid and sulfuric acid), Collin's reagent (Cr (VI) dipyridine oxide, Corey's reagent (pyridinium chlorochromate), pyridinium, acid dichromate, potassium permanganate, Mn02, ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate supported on a polymer, Cl2-pyridine, H202-ammonium molybdate, NaBr02-CAN, NaOCl in HOAc , copper chromite, copper oxide, Raney nickel, palladium acetate, Meerwin-Pondorf-Verley reagent (aluminum t-butoxide with another ketone) and N-bromosuccinimide, however typically using H3P04, DMSO and DCC in a mixture of benzene / pyridine at room temperature Subsequently, the pentodialdo-furanose can optionally be protected with a suitable protecting group, typically with an acyl or silyl group, by methods well known to those skilled in the art. ca, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991. In the presence of a base, such as sodium hydroxide, the protected pentodial-furanose can then be coupled with a suitable alkyl, halogen-alkyl (i.e. CF3), alkenyl or alkynyl (ie allyl), to obtain the 4'-alkylated sugar. Alternatively, the protected pentodial-furanose may be coupled with the corresponding carbonyl, such as formaldehyde, in the presence of a base, such as sodium hydroxide, with the appropriate polar solvent, such as dioxane, at a suitable temperature, which can then be reduced with an appropriate reducing agent to give the 4'-alkylated sugar. In one embodiment, the reduction is carried out using PhOC (S) Cl, DMAP, typically in acetonitrile at room temperature, followed by the treatment of ACCN and TMSS subjected to reflux in toluene. The optionally activated sugar can then be coupled to the BASE by methods well known to those skilled in the art, as taught by Townsend Chemistry of Nicleosides and Nucleotides. Plenum Press, 1994. For example, an acylated sugar can be coupled to a silylated base with a lewis acid, such as tin tetrachloride, titanium tetrachloride or trimethylsilyltriflate in the appropriate solvent at a suitable temperature. Subsequently, the nucleoside can be deprotected by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991. In a particular embodiment / the 4'-C-branched ribonucleoside is desired. Alternatively, deoxy ribonucleoside is desired. To obtain these deoxyribo-nucleosides, a ribo-nucleoside formed by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and subsequently 2'-OH can be reduced with a suitable reducing agent. Optionally, 2'-hydroxyl can be activated to facilitate the reduction; that is, via the Barton reduction. In another embodiment of the invention, the L-enantiomers are desired. Accordingly, the L-enantiomers may be corresponding to the compounds of the invention may be prepared following the same general methods above, starting with the corresponding L-pentodial-furanose as starting material. The following table shows a number of compounds that are prepared using the procedures described above: The present invention is described by way of illustration, in the following examples. It will be understood by one of ordinary skill in the art that these examples are not in any way limiting and that variations of detail can be made without departing from the spirit and scope of the present invention. VIII. Anti-Flavivirus, Pestivirus or Hepacivirus activity. The compounds may exhibit anti-flavivirus, pestivirus or hepacivirus activity by inhibiting the flavivirus polymerase, pestivirus or hepacivirus, by inhibiting other enzymes needed in the replication cycle, or by other routes. Example 1 Nucleoside Phosphorylation Test to activate Trifosphate. To determine the cellular metabolism of the compounds, HepG2 cells are obtained from the American Type Culture Collection (Rockville, MD), and grown in 225 cm2 tissue culture flasks in minimal essential medium supplemented with non-essential amino acids, 1 % penicillin-streptomycin. The medium is renewed every three days, and the cells are subcultured once a week. After detachment of the adherent monolayer with a 10-minute exposure to 30 mL of trypsin-EDTA and three consecutive washes with the medium, the HepG2 confluent cells are seeded at a density of 2.5 x 10 cells per well in a plate or dish. 6 wells and exposed to 10μ of active compound labeled [3H] (500 dpm / pmol) for the specified time periods. The cells are maintained at 37 ° C under a 5% C02 atmosphere. At the selected time points, the cells are washed three times with ice cold buffered saline (PBS). The intracellular active compound and its respective metabolites are extracted by incubating the cell pellet overnight at -20 ° C with 60% methanol, followed by extraction with 20 μl of additional cold methanol for one hour in a water bath. ice. The extracts are then combined, dried under filtered, gentle air flow and stored at -20 ° C until HPLC analysis. Example 2 Bioavailability Test in Cinomolgus Monkeys Within 1 week before the initiation of the study, the cynomolgus monkeys are surgically implanted with a chronic venous catheter and the subcutaneous venous access port (VAP) to facilitate blood collection and experience a physical examination including hematology and serum chemistry and body weight evaluations are recorded. Each monkey (six in total) receives approximately 250 μ? of activity 3H with each dose of active compound at a dose level of 10 mg / kg at a dose concentration of 5 mg / mL, either via an intravenous bolus (3 monkeys, IV), or via oral priming ( 3 monkeys, PO). Each dosing syringe is weighed before dosing to determine gravimetrically the amount of formulation administered. Urine tests are collected via crucible routes at the designated intervals (approximately 18-0 pre-dose, 0-4, 4-8 and 8-12 hours post-dose) and processed. Blood tests are also collected (pre-dose, 0.25, 0.5, 1, 2, 3, 6, 8, 12 and 24 hours post-dose) via the chronic venous catheter and VAP or from a peripheral container if the Chronic venous catheter was not possible. The blood and urine tests are analyzed for the maximum concentration (Cmax), the time when the maximum concentration (Tmax), the area under the curve (AUC), the half-life of the dose concentration (?? / 2), elimination (CL), volume at steady state and distribution (Vss) and bioavailability (F). Example 3 Bone Marrow Toxicity Test Human bone marrow cells are collected from healthy normal volunteers and the mononuclear population is separated by Ficoll-Hypaque gradient centrifugation as previously described by Sommadossi JP, Carlisle R. "Toxicity of 3 '-azido-3' -deoxythymidine and 9- (1,3-dihydroxy-2-propoxymethyl) guanine for normal human hematopoietic progenitor cells in vitro "Antimicrobial Agents and Chemotherapy 1987; 31: 452-454; and Sommadossi J-P, Schinazi RF, Chu CK, Xie M-Y. "Comparison of cytotoxicity of the (-) -and (+) -enantiomer of 21, 3 '-dideoxy-31 -thiacytidine in normal human bone marrow progenitor cells" Biochemical Pharmacology 1992; 44: 1921-1925. Culture tests for CFU-GM and BFU-E are performed using a mild bilayer agar or methylcellulose method. The drugs are diluted in the tissue culture medium and filtered. After 14 to 18 days at 37 ° C in a humidified atmosphere of 5% C02 in air, colonies of more than 50 cells are counted using an inverted microscope. The results are presented as the percent inhibition of colony formation in the presence of the drug compared to the control solvent cultures. Example 4 Mitochondria Toxicity Test HepG2 cells are cultured in 12-well dishes as described above and exposed to various concentrations of drugs as taught by Pan-Zhou XR, Cui L, Zhou XJ, Sommadossi JP, Darley -Usmer VM. "Differential effects of antiretroviral nucleoside analogs on mitochondrial function in HepG2 cells" Antimicrob Agents Chemother 2000; 44: 496-503. The levels of lactic acid in the culture medium after 4 days of exposure to the drug are measured using a Boehringer lactic acid test kit. The levels of lactic acid are normalized by the number of cells as measured by hemocytometer counting. Example 5 Cytotoxicity test Cells are sown in a ratio of 5 x 103 and 5xl04 / well in 96-well dishes in the growth medium overnight at 37 ° C in a humid atmosphere of C02 (5%). The new growth medium containing serial dilutions of the drugs is then added. After incubation for 4 days, the cultures are fixed in 50% TCA and stained with sulforhodamine B. The optical density is read at 550 nm. The cytotoxic concentration is expressed as the concentration required to reduce the number of cells by 50% (CC50). Example 6 Cell Protection Test (CPA) The test is performed essentially as described by Baginski, S. G.; Pevear, D. C; Seipel, M.; Sun, S.C. C .; Benetatos, C. A .; Chunduru, S. K.; Rice, CM and MS Collett "Mechanism of action of a pestivirus antiviral compound" PNAS USA 2000, 97 (14), 7981- 7986. MDBK cells (ATCC) are seeded in 96-well plates or culture dishes (4,000 cells per well) 24 hours before use. After infection with BVDV (strain NADL, ATCC) at a multiplicity of infection (MOI) of plaque-forming units (PFU) of 0.02 per cell, serial dilutions of the test compounds are added for both infected cells and uninfected in a final concentration of 0.5% DMSO in the growth medium. Each dilution is tested in quadruplicate. The cell densities and inocula of the virus are adjusted to ensure the continuous growth of the cell throughout the experiment and to achieve more than 90% of the cell destruction induced by the virus in the untreated controls after four years. post-infection days. After four days, the dishes are fixed with 50% TCA and stained or stained with sulforhodamine B. The optical density of the wells is read on a 550 nm microplate reader. The values of 50% effective concentration (EC50) are defined as the concentration of the compound that achieves 50% reduction of the cytopathic effect of the virus. Plate Reduction Test The effective concentration for each compound in plates or plates of 24 duplicate wells is determined by plaque reduction tests. The monolayers of the cell are infected with 100 PFU / well of virus. Subsequently, serial dilutions of test compounds in MEM supplemented with 2% deactivated serum and 0.75% methyl cellulose are added to the monolayers. The cultures are further incubated at 37 ° C for 3 days, then fixed with 50% ethanol and 0.8% Crystal Violet, washed and air dried. The plates are then counted to determine the concentration to obtain 90% virus suppression. Example 7 Performance Reduction Test The concentration is determined for each compound to obtain a 6-log reduction in viral load in 24-well duplicate plates, by performance reduction tests. The test is performed as described by Baginski, S. G.; Pevear, D. C; Seipel, M.; Sun, S.C. C .; Benetatos, C. A .; Chunduru, S. K.; Rice, C. M. and M. S. Collett "Mechanism of action of a pestivirus antiviral compound" PNAS USA 2000, 97 (14), 7981-7986, with minor modifications. Briefly, MDBK cells are seeded on 24-well dishes or plates (2 x 10 5 cells per well) 24 hours before infection with BVDV (NADL strain) at a multiplicity of infection (MOI) of 0.1 PFU per cell. Serial dilutions of the test compounds are added to the cells in a final concentration of 0.5% DMSO in the growth medium. Each dilution is tested in triplicate. After three days, cell cultures (cell monolayers and supernatants) are lysed by three freeze-thaw cycles, and the virus yield is quantified by the plaque test. Briefly, MDBK cells are seeded on 6-well plates (5 x 10 5 cells per well) 24 hours before use. The cells are inoculated with 0.2 mL of used test for 1 hour, they are washed and covered with a layer of 0.5% agarose in the growth medium. After 3 days, the monolayers of the cell are fixed with 3.5% formaldehyde and stained with 1% crystal violet (weight / volume in 50% ethanol) to visualize the plates. Plates are counted to determine the concentration to obtain a 6-log reduction in viral load. This invention has been described with reference to certain modalities. Variations and modifications of the invention will be obvious to those skilled in the art from the above detailed description of the invention.

Claims (27)

1. CLAIMS 1. A compound of Formula (I) or (II): or a pharmaceutically acceptable salt or prodrug thereof, characterized in that: R1 is independently H, optionally substituted alkyl, acyl, phosphate, sulfonate ester including optionally substituted alkyl or arylalkyl sulfonyl including methanesulfonyl and benzoyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a gravestone, including a phospholipid; an amino acid; a carbohydrate, a peptide; cholesterol; or another pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 is independently H or phosphate; each A is independently an optionally substituted linear, branched or cyclic alkyl, CH3, CF3, C (Y3) 3, 2-Br-ethyl, CH2F, C¾C1, CH2CF3 / CF2CF3, C (Y3) 2C (Y3) 3í CH2OH , optionally substituted alkenyl, optionally substituted alkynyl, C00R4, COO-aryl, C0-0-alkoxyalkyl, CONHR4, C (NR4) N (R4) 2, C (S) N (R4) 2 CON (R) 2, chlorine, bromine, fluorine, iodine, CN, N3, OH, OR4, H2, HR4, RR5, SH or SR5, -C (= S) H2, -C (= NH) NH2, -C- (5-membered heterocycle) has one or more O, S or N, -C-imidazole atoms; cycloalkyl, acyl, Br-vinyl, -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aryl, -O-aralkyl, -O-acyl, -O-cycloalkyl, -NH-alkyl, -N -dialkyl, -H-acyl, -NH-aryl, -NH-aralkyl, -NH-cycloalkyl, SH, -S-alkyl, -S-acyl, -S-aryl, -S-cycloalkyl, -S-aralkyl, -C02-alkyl, -CONH-alkyl, -CON-dialkyl, CF3, -CHmOH, - (CH2) mNH2, (CH2) mC (0) OH, - (CH2) mCN, - (C¾) mN02, - (CH2) mCONH2, Ci-4 alkylamino, (di (Ci-4) alkyl amino, C3-6 cycloalkylamino, alkoxycarbonyl of Cx_4, N3 or Ci_6 alkoxy, each B is independently H, an optionally substituted straight chain, branched or cyclic alkyl CH3, CF3, C (Y3) 3/2-Br-ethyl, C¾F, CH2C1, CH2CF3 , CF2CF3, C (Y3) 2C (Y3) 3, CH20H, optionally substituted alkenyl, optionally substituted alkynyl, COOR4, COO-aryl, -CO-0-alkoxyalkyl, -CONHR4, -C (NR4) N (R4) 2, -C (S) N (R) 2, -CON (R) 2, chlorine, bromine, fluorine, iodine, CN, N3, OH, OR4, NH2, HR4, NRR5, SH or SR5, -C (= S) NH2, -C (= NH) N¾, -C- (5-membered heterocycle) having one or more O, S or N, -C-imidazole atoms; cycloalkyl, acyl, Br-vinyl, -O-alkyl, -O-alkenyl, -0-alkynyl, -0-aryl, -0-aralkyl, -0-acyl, -0-cycloalkyl, -H-alkyl, -N-dialkyl, -NH-acyl, -H-aryl, -NH- aralkyl, -NH-cycloalkyl, SH, -S-alkyl, -S-acyl, -S- aryl, -S-cycloalkyl, -S-aralkyl, -C02-alky lo, -C0 H- alkyl, -CON-dialkyl, CF3, -CHmOH, - (CH2) mNH2, - (CH2) mC (0) 0H, - (CH2) mCN, - (CH2) mN02, - (CH2) mC0NH2, Ci-4 alkylamino, di (d-amino alkyl, C3-6 cycloalkylamino, alkoxycarbonyl Ci_4, N3 or Ci_6 alkoxy, each Y3 is independently H, F, Cl, Br or I, each R4 and R5 is independently hydrogen, acyl, alkyl, lower alkyl, alkenyl, alkynyl, or cycloalkyl. 0 or CH, each R6 is independently an optionally substituted alkyl, C¾, CH 2 CN, CH 2 N 3, CH 2 NH 2, CH 2 NHCH 3, CH 2 N (CH 3) 2, CH 2 OH, halogenated alkyl, CF 3, C (Y 3) 3, 2-Br-ethyl, CH2F, • CH2C1, CH2CF3, CF2CF3, C (Y3) 2C (Y3) 3, optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, - (G¾) mC (O) OR 4, - (CH 2) mC (O) NHR4, - (CH2) mC (0) N (R) 2, C (0) 0R4 or cyano; each R7 is independently OH, OR2, optionally substituted alkyl, CH3, C¾CN, CH2N3, CH2NH2, CH2 HCH3, CH2N (CH3) 2, CH2OH, halogenated alkyl, CF3, C (Y3) 3, 2-Br-ethyl, CH2F, C¾C1, C¾CF3, CF2CF3, C (Y3) 2C (Y3) 3, optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted heteroaryl, - (C¾) mC (0) OR4, - (CH2) mC (0) SR4- (CH2) mC (O) NHR4, - (C¾) mC (0) N (R4) 2, -C (0) 0R4, -C (0) SR4, -0 (R4), - S (R4), N02, -NRR5, azido, cyano, SCN, OCN, NCO or halo; each R8 and R11 are independently hydrogen, an optionally substituted alkyl, CH3, CH2CN, CH2N3, CH2NH2, CH2NHCH3, CH2N (CH3) 2 CH20H, halogenated alkyl, CF3, C (Y3) 3, 2-Br-ethyl, CH2F , CH2C1, CH2CF3, CF2CF3, C (Y3) 2C (Y3) 3, optionally substituted alkenyl, alkenyl, 'alkynyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, ~ CH2C (O) N (R4) 2, - (C¾) raC (0) OR, - (CH2) mC (O) NHR4, -C (0) 0R4, cyano, NH-acyl or N (acyl) 2; each of R9 and R10 are independently hydrogen, OH, OR2, optionally substituted alkyl, C¾, CH 2 CN, C¾N 3, C¾NH 2, CH 2 NHCH 3, CH 2 N (CH 3) 2, CH 2 OH, halogenated alkyl, CF 3, C (Y 3) 3, 2 -Br-ethyl, CH2F, C¾Cl, CH2CF3, CF2CF3, C (Y3) 2C (3 3) 3, optionally substituted alkenyl, alkenyl, alkynyl, N02, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted heteroaryl, - (CH2) mC (0) OR4- (CH2) mC (O) SR4, - (CH2) mC (0) NHR4, - (CH2) mC (0) N (R) 2, -C (0) 0R4, -C (0) SR4, -0 (R4), -O (aralkyl), -S (R4), N02 / -NR4R5, -H (aralkyl), azido, cyano, SCN, OCN, NCO or halo; each m is independently 1 or 2; and alternatively, R6 and R10, R7 and R9, R8 and R7 or R9 and R11 can go together to form a linked compound selected from the group consisting of an optionally substituted carbocycle or an optionally substituted heterocycle; or alternatively, R6 and R7 or R9 and R10 can go together to form a spiro compound selected from the group consisting of an optionally substituted carbocycle or an optionally substituted heterocycle; and each W is independently 0, S or CH.
2. 2. The compound of claim 1, characterized in that the compound is of Formula I.
3. 3. The compound of claim 1, characterized in that W is 0.
4. 4. The compound of claim 1, characterized in that each B is independently H or an optionally substituted straight, branched or cyclic chain alkyl.
5. 5. The compound of claim 3, characterized in that each B is H. The compound of claim 1, characterized in that R7 and R9 are independently OH or OR2. The compound of claim 1, characterized in that R1 is H or phosphate. 8. The compound of claim 1, characterized in that A is CONHR4. 9. A compound of Formula (III), (IV) or (V), or a pharmaceutically acceptable salt or ester thereof, characterized in that: R1, R2 and R3 are each independently H, optionally substituted alkyl, acyl, phosphate, sulfonate ester including optionally substituted alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given here; a lipid, including a phospholipid; an amino acid; a carbohydrate, a peptide; cholesterol; or another pharmaceutically acceptable release group that when administered in vivo is capable of providing a compound wherein R1, R2 or R3 is independently H or phosphate; wherein in an embodiment R2 and / or R3 is not phosphate; each R6 is independently H, OH, N02, halo, acid, alkenyl, alkynyl and an optionally substituted alkyl, CH3, CH2CN, CH2N3, CH2NH2, CH2NHCH3, CH2N (CH3) 2, C¾OH, halogenated alkyl, CF3, C ( Y3) 3, 2- Br-ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, C (Y3) 2C (Y3) 3, optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, - (CH2) mC ( 0) OR4, - (CH2) mC (0) HR4, - (CH2) mC (0) N (R) 2, C (0) OR4 or cyano; X and X * are independently 0 or CH; each R7 is independently OH, OR2, optionally substituted alkyl, CH3, CH2CN, CH2N3, CH2N¾, CH2NHC¾, CH2N (CH3) 2 / CH2OH, halogenated alkyl, CF3, C (Y3) 3, 2-Br-ethyl, CH2F , C¾C1, CH2CF3, CF2CF3, C (Y3) 2C (Y3) 3, optionally substituted alkenyl, haloalgenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted heteroaryl, - (CH2) mC (0) OR4, - (CH2) mC (0) SR4- (CH2) mC (0) RH, - (CH2) mC (O) N (R4) 2, -C (0) 0R4, -C (0) SR4, -0 (R4), -S (R4), N02, -NRR5, azido, cyano, SCN, OCN, NCO or halo; and alternatively, R6 and R7 can go together to form a spiro compound selected from the group consisting of an optionally substituted carbocycle or an optionally substituted heterocycle; each m is independently 1 or 2; and the base is independently: wherein each A is independently an optionally substituted linear, branched or cyclic alkyl, CH3, CF3, C (Y3) 3, 2-Br-ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, C (Y3) 2C (Y3) 3, C¾OH, optionally substituted alkenyl, optionally substituted alkynyl, COOR4, COO-aryl, C0-0-alkoxyalkyl, CONHR4, C (NR4) N (R4) 2, C (S) N (R4) 2, CON (R) 2, chlorine, bromine, fluorine, iodine, CN, N3, OH, OR4, NH2 / NHR4, NRR5, SH or SR5, -C (= S) NH2, -C (= NH) N¾, -C- (heterocycle of 5 members) having one or more O, S or N, -C-imidazole atoms; cycloalkyl, acyl, Br-vinyl, -O-alkyl, -0-alkenyl, -O-alkynyl, -0-aryl, -O-aralkyl, -O-acyl, -O-cycloalkyl, -NH-alkyl, -N -dialkyl, -H-acyl, -NH-aryl, -H-aralkyl, -NH-cycloalkyl, SH, -S-alkyl, -S-acyl, -S-aryl, -S-cycloalkyl, -S-aralkyl, -C02-alkyl, -CONH-alkyl, -CON-dialkyl, CF3, -CHm0H, - (C¾) mNH2, - (CH2) mC (0) 0H, - (CH2) mCN, - (CH2) mN02, - ( CH2) mC0N¾, C1 alkylamino. (di (Ci_4 alkyl) amino, C3_s alkylaminoalkyl, C1_4 alkoxycarbonyl, N3 or Ci_6 alkoxy, each B is independently H, an optionally substituted straight chain, branched or cyclic alkyl CH3, CF3, C (Y3) 3, 2-Br-ethyl, CH2F, CH2C1, C¾CF3, CF2CF3 / C (Y3) 2C (Y3) 3, CH20H, optionally substituted alkenyl, optionally substituted alkynyl, COOR4, COO-aryl, -C0-0- alkoxyalkyl, -CO HR, -C (NR4) N (R4) 2, -C (S) N (R4) 2, -CON (R) 2 chloro, bromo, fluoro, iodo, CN, N3, OH, OR4, H2, NHR4, MRR5, SH or SRS, -C (= S) H2, -C (= NH) H2, -C- (5-membered heterocycle) having one or more 0, S or N, -C atoms -imidazole, cycloalkyl, acyl, Br-vinyl, -0-alkyl, -O-alkenyl, -0-alkynyl, -0-aryl, -O-aralkyl, -0-acyl, -O-cycloalkyl, -H-alkyl , -N-dialkyl, - H-acyl, -NH-aryl, - H-aralkyl, - H-cycloalkyl, SH, -S-alkyl, -S-acyl, -S-aryl, -S-cycloalkyl, -S -aralkyl, -C02-alkyl, -CONH-alkyl, -CON-dialkyl, CF3, -CHm0H, - (CH2) m H2, - (CH2) mC (0) 0H, - (C¾) mCN, - (CH2) mN02, - (CH2) mC0 H2, alkylamino of Ci_4, di (Ci-4 alkyl) amino, cycloalkylamino of C3_6, alkoxycarbonyl of Ci -4, M3 or Ci_6 alkoxy; and each W is independently 0, S or CH. 10. A compound of Formula (VI), (VJ) or a pharmaceutically acceptable salt or ester thereof, characterized in that; R1 is independently H, optionally substituted alkyl, acyl, phosphate, sulfonate ester including optionally substituted alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aril given here; a lipid, including a phospholipid; an amino acid; a carbohydrate, a peptide; cholesterol; or another pharmaceutically acceptable release group that when administered in vivo is capable of providing a compound wherein R1 is independently H or phosphate; each A is independently an optionally substituted straight, branched or cyclic chain alkyl, CH3, CF3, C (Y3) 3, 2-Br-ethyl, C¾F, CH2C1, CH2CF3, CF2CF3, C (Y3) 2C (Y3) 3, CH20H, optionally substituted alkenyl, optionally substituted alkynyl, C00R4, COO-aryl, C0-0-alkoxyalkyl, CONHR4, C (NR4) N (R4), C (S) N (R4) 2, CON (R4) 2 , chlorine, bromine, fluorine, iodine, CN, N3, OH, OR4, N¾, HR4, NR4R5, SH or SR5, -C (= S) NH2, -C (= NH) N¾, -C- (heterocycle of 5) members) having one or more O, S or N, -C-imidazole atoms; cycloalkyl, acyl, Br-vinyl, -O-alkyl, -0-alkenyl, -O-alkynyl, -O-aryl, -O-aralkyl, -O-acyl, -O-cycloalkyl, -H-alkyl, -N -dialkyl, -H-acyl, -NH-aryl, -H-aralkyl, -NH-cycloalkyl, SH, -S-alkyl, -S-acyl, -S-aryl, -S-cycloalkyl, -S-aralkyl, -C02-alkyl, -CONH-alkyl, -CON-dialkyl, CF3, -CHmOH, - (C¾) mNH2, - (C¾) mC (0) OH, - (CH2) mCN, - (CH2) mN02, - ( C¾) mCONH2, Ci_4 alkylamino, (Ci_4 amino) diyl, C3_6 cycloalkylamino, Ci_4 alkoxy, N3 or Ci_6 alkoxy, each B is independently H, an optionally substituted straight, branched or cyclic alkyl chain CH 3, CF 3, C (Y 3) 3, 2-Br-ethyl, CH 2 F, CH 2 Cl, CH 2 CF 3, CF 2 CF 3, C (Y 3) 2 C (Y 3) 3, CH 2 OH, optionally substituted alkenyl, optionally substituted alkynyl, COOR 4, COO-aryl, -CO-O-alkoxyalkyl, -CO HR4, -C (NR4) N (R4) 2, -C (S) N (R4) 2, -CON (R4) 2, chlorine, bromine, fluorine, iodine, CN, N3, OH, OR4, H2, NHR4, NRR5, SH or SR5, -C (= S) NH2, -C (= NH) NH2, -C- (5-membered heterocycle) mbros) having one or more O, S or N, -C-imidazole atoms; cycloalkyl, acyl, Br-vinyl, -O-alkyl, -O-alkenyl, -0-alkynyl, -O-aryl, -O-aralkyl, -O-acyl, -O-cycloalkyl, -NH-alkyl, -N -dialkyl, -NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl, S-aralkyl, C02-alkyl, CONH-alkyl, CON-dialkyl, CF3, CHmOH, (CH2) mNH2, (CH2) mC (0) OH, (CH2) mCN, (CH2) mN02, (CH2) mCO H2, alkylamino of ¾_4, di (Cx-4 alkyl) amino, C3-6 cycloalkylamino, ¾_4 / N3 alkoxycarbonyl or Ci_6 alkoxy; each? 3 is independently H, F, Cl, Br or I; each 4 and Rs is independently hydrogen, acyl, alkyl, lower alkyl, alkenyl, alkynyl, or cycloalkyl. X is O or CH; each R6 is independently an optionally substituted alkyl, CH3, CH2CN, C¾N3, CH2NH2, C¾NHCH3, CH2N (C¾) 2, CH20H, halogenated alkyl, CF3 / C (Y3) 3, 2-Br-ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, C (Y3) 2C (Y3) 3, optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, - (CH2) mC (O) OR4, - (CH2) mC (O) NHR4, - (CH2) mC (O) N (R4) 2, C (0) 0R4 or cyano; each R7 is independently OH, OR2, optionally substituted alkyl, CH3, CH2CN, CH2N3, CH2NH2, CH2NHCH3, CH2N (CH3) 2, CH20H, halogenated alkyl, CF3, C (Y3) 3, 2-Br-ethyl, C¾F , CH2C1, CH2CF3, CF2CF3, C (Y3) 2C (Y3) 3, optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted heteroaryl, - (CH2) mC (0) 0R4, - (CH2) mC (0) SR4- (CH2) mC (0) NHR4, - (CH2) mC (O) N (R4) 2, -C (0) 0R4, -C (0) SR4, -0 (R4), -S (R4), M02, -NR4R5, azido, cyano, SCN, OCM, NCO or halo; each R8 and R11 are independently hydrogen, an optionally substituted alkyl, CH3, CH2CN, CH2N3, CH2H2, CH2HCH3, C¾N (C¾) 2, CH20H, halogenated alkyl, CF3, C (Y3) 3, 2-Br- ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, C (Y3) 2C (Y3) 3, optionally substituted alkenyl, alkenyl, alkynyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, -CH2C (O) N (R4) 2 , ~ (C¾) mC (0) OR 4, - (CH 2) mC (O) NHR 4, -C (0) 0R 4, cyano, NH-acyl or N (acyl) 2; each of R9 and R10 are independently hydrogen, OH, OR2, optionally substituted alkyl, CH3, CH2CN, C¾N3, C¾NH2, CH2NHCH3, CH2N (CH3) 2, CH20H, halogenated alkyl, CF3, C (Y3) 3, 2 -Br-ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, C (Y3) 2C (Y3) 3, optionally substituted alkenyl, alkenyl, alkynyl, N02, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted carbocycle, heterocycle optionally substituted, optionally substituted heteroaryl, - (CH2) mC (O) OR4- (CH2) mC (0) SR, - (CH2) mC (0) NHR4, - (CH2) mC (0) N (R) 2, -C (0) 0R4, -C (0) SR4, -0 (R4), -O (aralkyl), -S (R4), N02 / -NRR5, -H (aralkyl), azido, cyano, SCN, OCN, NCO or hale-each m is independently 1 or 2; and alternatively, R6 and R10, R7 and R9, R8 and R7 or R9 and R11 can go together to form a linked compound selected from the group consisting of an optionally substituted carbocycle or an optionally substituted heterocycle; or alternatively, R6 and R7 or R9 and R10 can go together to form a spiro compound selected from the group consisting of an optionally substituted carbocycle or an optionally substituted heterocycle. The compound of claim 10, characterized in that X is O. 12. The compound of claim 10, characterized in that each R6 is independently an optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, C¾0H, CH2NH2, CH2NHCH3, CH2N (CH3) 2, CH2F, CH2C1, CH2N3, CH2CN, CH2CF3, CF3 / CF2CF3. The compound of claim 10, characterized in that each R7 is independently -OH, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -O-alkyl, -O-alkenyl, -O- alkynyl, -O-aralkyl, -O-cycloalkyl, -O-acyl, F, Cl, Br, I, CN, CN, SCN, OCN, NCO, N02, NH2, N3 / H-acyl, NH-alkyl, N -dialkyl, NH-alkenyl, H-alkynyl, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl, S-acyl, S-cycloalkyl, C02-alkyl, CONH -alkyl, CON-dialkyl, CONH-alkenyl, CO H-alkynyl, CO H-aralkyl, CONH-cycloalkyl, CH2OH, CH2NH2, CH2 HCH3, CH2N (CH3) 2, C¾F, C¾C1, C¾N3, CH2CN, CH2CF3, CF3, CF2CF3, (CH2) mCOOH, (CH2) mCON¾, an optionally substituted 3-7 membered carbocyclic ring, and an optionally substituted 3-7 membered heterocyclic ring having o, S and / or N independently as a hetero atom taken alone in combination ation. The compound of claim 10, characterized in that each R9 is independently hydrogen, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -OH, -O-alkyl, -O-alkenyl, - 0-alkynyl, -O-aralkyl, -O-cycloalkyl, -O-acyl, F, Cl, Br, I, CN, CN, SCN, OCN, NCO, N02, N¾, N3, NH-acyl, NH-alkyl , N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl, S-acyl, S-cycloalkyl, C02-alkyl , CO H-alkyl, CON-dialkyl, CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH2OH, CH2NH2 CH2NHCH3, CH2N (CH3) 2, CH2F, CH2C1, CH2N3, CH2CN, CH2CF3, CF3 / CF2CF3 , (CH2) mGOOH, (CH2) mCONH2, an optionally substituted 3-7 membered carbocyclic ring, and an optionally substituted 3-7 membered heterocyclic ring having O, S and / or N independently as a heteroatom taken alone in combination. 15. The compound of claim 10, characterized in that each R10 is independently hydrogen, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, CH2OH, CH2NH2, CH2NHCH3, CH2N (CH3) 2, CH2F , CH2Cl, C¾N3, CH2CN, CH2CF3í CF3, CF2CF3, (CH2) mCOOH, (CH2) mC0NH. 16. The compound of claim 10, characterized in that each R8 and R11 are independently H, CH3, CH2OH, C¾F, CH2N3, (CH2) mC00H, (CH2) mCONH2 and N-acyl. 17. The compound of claim 10, characterized in that A is CONH2. 18. The compound of claim 10, characterized in that each m is independently 1. 19. A method for the treatment or prophylaxis of a host infected with a flavivirus or pestivirus or with a hepacivirus infection, characterized by comprising administering to a host or host an effective amount of the treatment of a compound of claim 1, 9 or 10, optionally in a pharmaceutically acceptable carrier. 20. The method of claim 19, characterized in that the infection is an HCV infection. 21. The method of claim 19, characterized in that the infection is not an HCV infection. 22. The method of claim 19, characterized in that the host or host is at risk of being infected by a flavivirus, pestivirus or hepacivirus. 23. The method of claim 19, characterized in that it further comprises administering at least one second antiviral agent. The method of claim 23, characterized in that the second antiviral agent is selected from the group consisting of Interferon; Ribavirin; protease inhibitors (such as substrate-based NS3 protease inhibitors, inhibitors that are not substrate-based, phenanthrenoquinones possessing protease activity and selective NS3 inhibitors); Thiazolidine derivatives; Thiazolidines and benzanilides; Helicasa; Inhibitors of the antisense phosphorothioate oligodeoxynucleotide polymerase; inhibitors of I ES dependent movement; nuclease-resistant ribozymes, nuclease analogues; 1-amino-alkylcyclohexanes; alkyl lipids; vitamin E and other antioxidants; squalene; amantadine; biliary acids; N- (phosphonoacetyl) -L-aspartic acid; benzenedicarboxamides; polyadenylic acid derivatives; 2", 3" -dideoxyinosine, benzimidazoles; plant extracts; and piperidenes. 25. A pharmaceutical composition for the treatment of a host infected with a flavivirus, pestivirus or hepacivirus infection, characterized in that it comprises an effective amount of the treatment of a compound of claim 1, 9 or 10 or a pharmaceutically acceptable salt or ester of the themselves and a pharmaceutically acceptable carrier. 26. The composition of claim 25, characterized in that it further comprises at least one second antiviral agent. The composition of claim 26, characterized in that the second antiviral agent is selected from the group consisting of Interferon; Ribavirin; protease inhibitors (such as substrate-based NS3 protease inhibitors, inhibitors that are not substrate-based, phenanthrenoquinones possessing protease activity and selective NS3 inhibitors); Thiazolidine derivatives; Thiazolidines and benzanilides; Helicasa; Polymerase inhibitors; antisense phosphorothioate oligodeoxynucleotides; inhibitors of I ES dependent movement; nuclease-resistant ribozymes, nuclease analogues; 1-amino-alkylcyclohexanes; alkyl lipids; vitamin E and other antioxidants; squalene; amantadine; bile acids; N- (phosphonoacetyl) -L-aspartic acid; benzenedicarboxamides; polyadenylic acid derivatives; 2", 3" -dideoxyinosine, benzimidazoles; plant extracts; and piperidenes.