AU2013203966B2 - Methods and compositions for treating hepatitis C virus - Google Patents

Abstract

H:IUflnLCfvoveNmPomtbI\JLKXNG657U5_1.IDUL;-VA /2V13 A method and composition for treating a host infected with hepatitis C comprising administering an effective hepatitis C treatment amount of a described 1, 2' or 3'-modified nucleoside or a pharmaceutically acceptable salt or prodrug thereof, is provided.

Description

H:\rxsnierwoven\NRPorbl\DCC\RXS\5065705_1.DOC-10/04/2l13 METHODS AND COMPOSITIONS FOR TREATING HEPATITIS C VIRUS This is a divisional of Australian Patent Application No. 2012233015, the entire contents of which are incorporated herein by reference. FIELD OF THE INVENTION This invention is in the area of pharmaceutical chemistry, and is in particular, is a compound, method and composition for the treatment of hepatitis C virus. This application claims priority to U.S. provisional application no. 60/206,585, filed on May 23, 2000. BACKGROUND OF THE INVENTION The hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide. (Boyer, N. 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 Besoeglie, A. M. and Bacon, B. R., Scientfic American, Oct.: 80-85, (1999); Boyer, N. et al. J HepatoL 32:98 112, 2000). An estimated 170 million persons 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 leading indication for liver transplant. HCV is known to cause at least 80% of posttransfusion hepatitis and a substantial proportion of sporadic acute hepatitis. Preliminary evidence also implicates HCV in many cases of "idiopathic" chronic hepatitis, "cryptogenic" cirrhosis, and probably hepatocellular carcinoma unrelated to other hepatitis viruses, such as Hepatitis B Virus (HBV). A small proportion of healthy persons appear to be chronic HCV carriers, varying with geography and other epidemiological factors. The numbers may substantially exceed those for HBV, though information is still preliminary; how many of these persons have subclinical chronic liver disease is unclear. (The Merck Manual, ch. 69, p. 901, 16th ed., (1992)), HCV has been classified as a member of the virus family Flaviviridae that includes the genera flaviviruses, pestiviruses, and hapaceiviruses which includes hepatitis C viruses (Rice, C. M., Flaviviridae: The viruses and their replication. In: Fields Virology, Editors: Fields, B. N., Knipe, D. M., and Howley, P. M., Lippincott-Raven Publishers, Philadelphia, PA, Chapter 30, 931-959, 1996). HCV is an enveloped virus containing a positive-sense single-stranded RNA genome of approximately 9.4kb. The viral genome consists of a 5' untranslated region (UTR), a long open reading frame encoding a polyprotein precursor of WO 01/90121 PCT/US01/16671 approximately 3011 amino acids, and a short 3' UTR, The 5' UTR is the most highly conserved part of the HCV genome and is important for the initiation and control of polyprotein translation. Translation of the HCV genome is initiated by a cap-independent mechanism known as internal ribosome entry. This mechanism involves the binding of 5 ribosomes to an RNA sequence known as the internal ribosome entry site fires) . An RNA pseudoknot structure has recently been determined to be an essential structural element of the HCV IRES. Viral structural proteins include a nucleocapsid core protein (C) and two envelope glycoproteins, El and E2. HCV also encodes two proteinases, a zinc-dependent metallopoteinase encoded by the NS2-NS3 region and a serine proteinase encoded in the 10 NS3 region. These proteinases are required for cleavage of specific regions of the precursor polyprotein into mature peptides. The carboxyl half of nonstructural protein 5, NS5B, contains the RNA-dependent RNA polymerase. The function of the remaining nonstructural proteins, NS4A and NS4B, and that of NSSA (the amino-terminal half of nonstructural protein 5) remain unknown. 15 A significant focus of current antiviral research is directed toward the development of improved methods of treatment of chronic HCV infections in humans (Di Besceglie, A. M. and Bacon, B. R., Scientific American, Oct.: 80-85, (1999)). Currently, there are two primary antiviral compounds, Ribavirin and interferon-alpha, which are used for the treatment of chronic HCV infections in humans. 20 Treatment of HCV Infection with Ribivarin Ribavirin (1-#-D-iibofuranosyl-1-1,2,4-triazole-3-carboxanide) is a synthetic, non interferon-inducing, broad spectrum antiviral nucleoside analog sold under the trade name, Virazole (The Merck Index, 11th edition, Editor: Budavari, S., Merck & Co., Inc., Rahway, NJ, p1304, 1989). United States Patent No. 3,798,209 and RE29,835 disclose and claim 25 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). Ribavirin reduces serum amino transferase levels to normal in 40% or patients, but it does not lower serum levels of HCV-RNA (Gary L. Davis. Gastroenterology 1I1S104 30 S114, 2000). Thus, Ribavirin alone is not effective in reducing viral RNA levels. Additionally, Ribavirin has significant toxicity and is known to induce anemia. 2 WO 01/90121 PCT/US01/16671 Treatment of HCV Infection with Interferon Interferons (IFNs) are compounds that have been commercially available for the treatment of chronic hepatitis for nearly a decade. IFNs are glycoproteins produced by immune cells in response to viral infection. IFNs inhibit viral replication of many viruses, 5 including HCV, and when used as the sole treatment for hepatitis C infection, IFN suppresses seram HCV-RNA to 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 118:8104-S114, 2000). 10 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 retreatment of patients afflicted with HCV using consensus interferon. U.S. Patent No. 5,942,223 to Bazer et al. discloses an anti-HCV therapy using ovine or bovine interferon-tau. U.S. Patent No. 5,928,636 to Alber et al discloses the combination therapy of interleukin-12 and interferon 15 alpha 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, for treating HCV. U.S. Patent No. 5,830,455 to Valtuena et al. discloses a combination HCV therapy employing interferon and a free radical scavenger. 20 U.S. Patent No. 5,738,845 to Imakawa discloses the use of human interferon tau proteins for treating HCV. Other interferon-based treatments for HCV are disclosed in US. Patent No. 5,676,942 to Testa et al., U.S. Patent No. 5,372,808 to Blatt et al., and U.S. Patent No. 5,849,696. Combination of Interferon and Ribavirin 25 The combination of IFN and Ribavirin for the treatment of HCV infection has been reported to be effective in the treatment of IFN naive patients (Battaglia, A.M. et al, Ann. Pharmacother. 34:487-494, 2000), Results are promising for this combination treatment both before hepatitis develops or when histological disease is present (Berenguer, M. et al Antivir. Ther. 3(Suppl. 3):125-136, 1998). Side effects of combination therapy include 3 WO 01/90121 PCT/US01/16671 hemolysis, flu-like symptoms, anemia, and fatigue. (Gary L. Davis. Gastroenterology 118:S104-S114, 2000). Additional References Disdosing Methods to Treat HCV Infections A number of HCV treatments are reviewed by Bymock et at. in Antiviral Chemistry 5 & Chemotherapy, 11:2; 79-95 (2000). Several substrate-based NS3 protease inhibitors have been identified in the literature, in which the scissile amide bond of a cleaved substrate is replaced by an electrophile, which interacts with the catalytic serine. Attwood et al. (1998) Antiviral peptide derivatives, 98122496; Attwood et al. (1999), Antiviral Chemistry and 10 Chemotherapy 10.259-273; Attwood et al. (1999) Preparation and use of amino acid derivatives as anti-viral agents, German Patent Publication DE 19914474; Tung et al. (1998) Inhibitors of serine proteases, particularly hepatitis C virus NS3 protease, WO 98/17679. The reported inhibitors terminate in an electrophile such as a boronic acid or phosphonate. Llinas-Brunet et al. (1999) Hepatitis C inhibitor peptide analogues, WO 15 99/07734. Two classes of electrophile-based inhibitors have been described, alphaketoamides and bydrazinoureas. The literature has also described a number of non-substrate-based inhibitors. For example, evaluation of the inhibitory effects of 2,4,6-trihydroxy-3-nitro-beazamide derivatives against HCV protease and other serine proteases has been reported. Sudo, K. et 20 al., (1997) Biochemical and Biophysical Research Communications, 23 8:643-647; Sudo, K. et al. (1998) Antiviral Chemistry and Chemotherapy 9;186. Using a reverse-phase HPLC assay, the two most potent compounds identified were RD3-4082 and RD3-4078, the former substituted on the amide with a 14 carbon chain and the latter processing a para phenoxyphenyl group. 25 Thiazolidine derivatives have been identified as micromolar inhibitors, using a reverse-phase HPLC assay with an NS3/4A fusion protein and NS5A/5B substrate. Sudo, K. at al. (1996) Antiviral Research 32:9-18. Compound RD-1-6250, possessing a fused cinnamoyl moiety substituted with a long alkyl chain, was the most potent against the isolated enzyme. Two other active examples were RD4 6205 and RD4 6193. 4 WO 01/90121 PCT/US01/16671 Other literature reports screening of a relatively small library using an ELISA assay and the identification of three compounds as potent inhibitors, a thiazolidine and two benzanilides. Kakiuchi N. et al. J. EBS Letters 421:217-220; Takeshita N. et al,, Analytical Biochemistry 247:242-246, 1997. Several U.S. patents disclose protease inhibitors for the 5 treatment of HCV. For example, U.S. Patent No. 6,004,933 to Spruce et al. discloses a class of cysteine protease inhibitors for inhibiting HCV endopeptidase 2. U.S. Patent No. 5,990,276 to Zhang et al. discloses synthetic inhibitors of hepatitis C virus NS3 protease, The inhibitor is a subsequence of a substrate of the NS3 protease or a substrate of the NS4A cofactor. The use of restriction enzymes to treat HCV is disclosed in U.S. Patent No. 10 5,538,865 to Reyes et al. Isolated from the fermentation culture broth of Streptomyces sp., Sch 68631, a phenan-threnequinone, possessed micromolar activity against HCV protease in a SDS PAGE and autoradiography assay. Chu M. et al., Tetrahedron Letters 37:7229-7232, 1996. In another example by the same authors, Sch 351633, isolated from the fungus Penicillium 15 griscofuluum, demonstrated micromolar activity in a scintillation proximity assay. Chu M. et al., Bloorganic and Medicinal Chemistry Letters 9:1949-1952. Nanomolar potency against the HCV NS3 protease enzyme has been achieved by the design of selective inhibitors based on the macromolecule eglin c. Eglin c, isolated from leech, is a potent inhibitor of several serine proteases such as S. griseus proteases A and B, a-chymotrypsin, 20 chymase and subtilisin. Qasim MA. et al., Biochemistry 36:1598-1607, 1997. HCV helicase inhibitors have also been reported. U.S. Patent No. 5,633,358 to Diana G.D. et al,; PCT Publication No. WO 97/36554 of Diana G.D. et al. There are a few reports of HCV polymerase inhibitors: some nucleotide analogues, gliotoxin and the natural product cerulenin. Ferrari R. et at, Journal of Virology 73:1649-1654, 1999; Lohmann V. 25 et a., Virology 249:108-118, 1998. Antisense phosphorothioate oligodeoxynucleotides complementary to sequence stretches in the 5' non-coding region of the HCV, are reported as efficient inhibitors of HCV gene expression in in vitro translation and IcpG2 IICV-luciferase cell culture systems. Alt M. et al., Hepatology 22:707-717, 1995. Recent work has demonstrated that 30 nucleotides 326-348 comprising the 3' end of the NCR and nucleotides 371-388 located in the core coding region of the HCV RNA are effective targets for antisense-mediated inhibition of viral translation. Alt M. et al., Archives of Virology 142:589-599, 1997. U.S. 5 WO 01/90121 PCT/USOI/16671 Patent No. 6,001,990 to Wands et al. discloses oligonucleotides for inhibiting the replication of HCV. PCT Publication No. WO 99/29350 discloses compositions and methods of treatment for hepatitis C infection comprising the administration of antisense oligonucleotides that are complementary and hybridizable to HCV-RNA. U.S. Patent No. 5 5,922,857 to Han et al, disclose nucleic acids corresponding to the sequence of the pestivirus homology box IV area for controlling the translation of HCV. Antisense oligonucleotides as therapeutic agents have been recently reviewed (Galderisi U. et al., Journal of Cellular Physiology 181:251-257, 1999). Other compounds have been reported as inhibitors of IRES-dependent translation in 10 HCV. Japanese Patent Publication JP-08268890 of Ikeda N et al.; Japanese Patent Publication JP-10101591 of Kai, Y. et al. Nuclease-resistant ribozytnes have been targeted at the IRES and recently reported as inhibitors in an HCV-poliovirus chimera plaque assay. Maccjak D.J. et al., Hepatology 30 abstract 995, 1999, The use of ribozymes to treat HCV is also disclosed in U.S. Patent No. 6,043,077 to Barber et aL, and U.S. Patent Nos. 15 5,869,253 and 5,610,054 to Draper et aL Other patents disclose the use of immune system potentiating compounds for the treatment of HCV. For example, U.S. Patent No. 6,001,799 to Chretien et al. discloses a method of treating hepatitis C in non-responders to interferon treatment by administering an immune system potentiating dose of thymosin or a thymosin fragment. U.S. Patent Nos. 20 5,972,347 to Eder et al. and 5,969,109 to Bona et al. disclose antibody-based treatments for treating HCV. U.S. Patent No. 6,034,134 to Gold et al. discloses certain NMDA receptor agonists having immunodulatory, antimalarial, anti-Boma virus and anti-Hepatitis C activities. The disclosed NNMA receptor agonists belong to a family of 1-amino-alkylcyclohexanes. U.S, 25 Patent No. 6,030,960 to Morris-Natschce et al. discloses the use of certain alkyl lipids to inhibit the production of hepatitis-induced antigens, including those produced by the HCV virus. U.S. Patent No. 5,922,757 to Chojkier et al. discloses the use of vitamin E and other antioxidants to treat hepatic disorders including HCV. U.S. Patent No. 5,858,389 to Elsherbi et al. discloses the use of squalene for treating hepatitis C. U.S. Patent No. 30 5,849,800 to Smith et al discloses the use of amantadine for treatment of Hepatitis C. U.S. Patent No. 5,846,964 to Ozeki et al. discloses the use of bile acids for treating HCV. U.S. 6 WO 01/90121 PCT/US01/16671 Patent No. 5,491,135 to Blough et al discloses the use of N-(phosphonoacetyl)-L-aspartic acid to treat flaviviruses such as HCV. Other compounds proposed for treating HCV include plant extracts (U.S. Patent No. 5,837,257 to Tsai et al, U.S. Patent No. 5,725,859 to Omer et al, and U.S. Patent No. 5 6,056,961), piperidenes (U.S. Patent No, 5,830,905 to Diana et al.), benzenedicarboxamides (U.S. Patent No. 5,633,388 to Diana et aL), polyadenylic acid derivatives (U.S. Patent No. 5,496,546 to Wang et at), 2',3'-dideoxyinosine (U.S. Patent No. 5,026,687 to Yarchoan et at), benzimidazoles (U.S. Patent No. 5,891,874 to Colacino et aL). In light of the fact that the hepatitis C virus has reached epidemic levels worldwide, 10 and has tragic effects on the infected patient, there remains a strong need to provide new effective pharmaceutical agents to treat hepatitis C that has low toxicity to the host. Therefore, it is an object of the present invention to provide a compound, method and composition for the treatment of a host infected with hepatitis C virus. SUMMARY OF THE INVENTION 15 Compounds, methods and compositions for the treatment of hepatitis C infection are described that include an effective hepatitis C treatment amount of a #-D- or #-L-nucleoside of the Formulas (1) - (XVIII), or a phannaceutically acceptable salt or prodrug thereof. In a first principal embodiment, a compound of Formula I, or a pharmaceutically acceptable salt or prodrug thereof, is provided: Y N N N X CH$ 20

OR

2 OR () wherein: R', R 2 and R 3 are independently H, phosphate (including mono-, di- or triphosphate and a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); 7 WO 01/90121 PCT/USO1/16671 sulfonate ester including 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; a cholesterol; or other phannaceutically acceptable leaving 5 group which when administered in vivo is capable of providing a compound wherein R', R2 or R 3 is independently H or phosphate; Y is hydrogen, bromo, chloro, fluoro, iodo, OR 4 , NR 4

R

5 or SR;

X

1 and X 2 are independently selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, 10 OR 4 , NR 4 NR' or SR; and

R

4 and R 3 are independently hydrogen, acyl (including lower acyl), or alkyl (including but not limited to methyl, ethyl, propyl and cyclopropyl). In a second principal embodiment, a compound of Formula II, or a pharmaceutically acceptable salt or prodrug thereof, is provided: Y N N

R

1 O 0I 15 OR' OR' (II) wherein: R', R 2 and R3 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl 20 (including lower ailcyl); sulfonate ester including 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; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of 25 providing a compound wherein Ri, R or R 3 is independently H or phosphate; and Y is hydrogen, bromo, chloro, fluoro, iodo, OR4, NR 4

R

5 or SR4; 8 WO 01/90121 PCT/USO1I/16671 X' and X 2 are independently selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, brono, fluoro, iodo,

OR

4 , NR 4 Nt 5 or SR 5 ; and

R

4 and R 5 are independently hydrogen, acyl (including lower acyl), or alkyl (including but 5 not limited to methyl, ethyl, propyl and cyclopropyl). In a third principal embodiment, a compound of Formula III, or a pharmaceutically acceptable salt or prodrug thereof, is provided: Y N

R

1 1 R'N N x2 CH, (III) 10 wherein: R', R 2 and R3 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or 15 more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a 'peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1, R 2 or R 3 is independently H or phosphate; and Y is hydrogen, bromo, chloro, fluoro, iodo, OR 4 , NR 4

R

5 or SR4; 20 X1 and X 2 are independently selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-ailcoxyalkyl, chloro, bromo, fluoro, iodo,

OR

4 , NR4NR or SR 5 ; and

R

4 and R 5 are independently hydrogen, acyl (including lower acyl), or alkyl (including but not limited to methyl, ethyl, propyl and cyclopropyl). 9 WO 01/90121 PCT/US01/16671 In a fourth principal embodiment, a compound of Formula IV, or a pharmaceutically acceptable salt or prodrug thereof, is provided: Y xi Nt N o R'o 0

C'.

3

OR

1 OR (IV) 5 wherein: R, R 2 and R3 are independently H, phosphate (including mono-, di- or triphosphate and a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as 10 described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R', R 2 or R3 is independently H or phosphate; Y is hydrogen, bromo, chloro, fluoro, iodo, OR 4 , NR4R 5 or SR 4 ; 15 X 1 is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alcoxyalkyl, chloro, bromo, fluoro, iodo, OR 4 , NR 4 NR or SR5; and R and W are independently hydrogen, acyl (including lower acyl), or alkyl (including but not limited to methyl, ethyl, propyl and cyclopropyl). In a fifth principal embodiment, a compound of Formula V, or a phannaceutically 20 acceptable salt or prodrug thereof, is provided: 10 WO 01/90121 PCT/US01/16671 Y XN RIO 0~

OR

2

OR

3 wherein: R', R2 and R? are independently H; phosphate (including monophosphate, diphosphate, 5 triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including 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; a cholesterol; or other 10 pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R 1 , R2 or R3 is independently H or phosphate; and Y is hydrogen, bromo, chloro, fluoro, iodo, OR 4 , N 4

R

5 or SR 4 ;

X

1 is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, O , NR 4 NR' or SR; and 15 R4 and R are independently hydrogen, acyl (including lower acyl), or alkyl (including but not limited to methyl, ethyl, propyl and cyclopropyl). In a sixth principal embodiment, a compound of Formula VI, or a pharmaceutically acceptable salt or prodrug thereof, is provided: y R'O OR OR 3 20 (VI) 11 WO 01/90121 PCT[USOI/16671 wherein: R, R2 and R 3 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including 5 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; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R', R2 or R 3 is independently H or phosphate; and 10 Y is hydrogen, bromo, chloro, fluoro, iodo, OR 4 , NR 4 Rs or SR 4 ;

X

1 is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR 4 , NR 4 NR or SR; and RW and R 5 are independently hydrogen, acyl (including lower acyl), or alkyl (including but not limited to methyl, ethyl, propyl and cyclopropyl). 15 In a seventh principal embodiment, a compound selected from Formulas VII, VIII and IX, or a pharmaceutically acceptable salt or prodrug thereof, is provided: Base Base Base R'O R'O R'O x x x

OR

2 Of 0Rz (VII) (VIII) (IX wherein: 20 Base is a purine or pyrimidine base as defined herein; R', R 2 and R3 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); ailcyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or 25 more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1, R2 or R 3 is independently H or phosphate; 12 WO 01/90121 PCT/US01I/16671 R is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br vinyl, 2-Br-ethyl, -C(O)O(alkyl), -C(O)O(lower alkyl), -O(acyl), -O(lower acyl), -O(alkyl), -O(lower alkyl), -O(alkenyl), CF 3 , chloro, bromo, fluoro, iodo, NO 2 , NH 2 , -NH(lower alkyl), -NH(acyl), -N(lower alkyl) 2 , -N(acyl)2; and 5 X is 0, ,SO 2 or CH 2 In a eighth principal embodiment, a compound of Formulas X, XI and XII, or a pharmaceutically acceptable salt or prodrug thereof, is provided: R'O Base Rio Base R o Base X-' x

OR

2

OR

3 R (X (XI) (XII) 10 wherein: Base is a purine or pyriindine base as defined herein;

R

1 , R 2 and R 3 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower-alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including 15 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; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R', R 2 or R 3 is independently H or phosphate; 20 R is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br vinyl, -C(O)O(alcyl), -C(0)O(lower alkyl), -O(acyl), -O(lower acyl), -O(alkyl), -O(lower alkyl), -O(alkenyl), chloro, bromo, fluoro, iodo, NO 2 , NH 2 , -NH(lower alkyl), -NH(acyl), N(lower alkyl)2, -N(acyl) 2 ;

R

7 is hydrogen, OR 3 , hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, 25 Br-vinyl, -C(O)O(alkyl), -C(0)O(lower alkyl), -O(acyl), -O(lower acyl), -O(alkyl), O(lower alkyl), -O(alkenyl), chlorine, bromine, iodine, NO 2 , NH 2 , -NH(lower alkyl), NH(acyl), -N(lower alkyl) 2 , -N(acyl)2; and 13 WO 01/90121 PCT/US01/16671 X is 0, S, S02 or CH 2 . In a ninth principal embodiment a compound selected from Formulas XIII, XIV and XV, or a pharmaceutically acceptable salt or prodrug thereof, is provided: RIO Base RIO Base RIO Base -x

OR

2

O

3 0( 5 (XIII) (XIV) (XV) wherein: Base is a purine or pyrimidine base as defined herein; R', R2 and R3 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl 10 (including lower alkyl); sulfonate ester including 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; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of 15 providing a compound wherein R, R2 or R3 is independently H or phosphate; R6 is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br vinyl, -C(O)O(alkyl), -C(O)O(lower alkyl), -O(acyl), -O(lower acyl), -O(alkyl), -0(lower alkyl), -Q(alkenyl), chloro, bromo, fluoro, iodo, NO 2 , NHl 2 , -NH(lower alkyl), -NH(acyl), N(lower alkyl) 2 , -N(acyl) 2 ; and 20 X is 0, S, SO 2 or CH 2 . In a tenth principal embodiment the invention provides a compound of Formula XVI, or a pharmaceutically acceptable salt or prodrug thereof: R O Base R0 R R6 R R7 (XVI) 14 WO 01/90121 PCTUSU1/16671 wherein: Base is a purine or pyrimidine base as defined herein; R' and R 2 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl 5 (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and beuzyl, 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; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of 10 providing a compound wherein R' or R2 is independently H or phosphate;

R

6 is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br vinyl, -C(O)O(alkyl), -C(O)O(lower alkyl), -O(acyl), -O(lower acyl), -O(alkyl), -O(lower alkyl), -O(alkenyl), chloro, bromo, fluoro, iodo, NO 2 , NH 2 , -NH(lower alkyl), -NH(acyl), N(lower alky1) 2 , -N(acyl)2; 15 R7 and Re are independently hydrogen, OR 2 , hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(O)O(alkyl), -C(O)O(lower alkyl), -O(acyl), -O(lower acyl), -O(alkyl), -O(lower alkyl), -O(alkenyl), chlorine, bromine, iodine, NO 2 , NH 2 , -NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, -N(acyl) 2 ; R and R 0 are independently H, alkyl (including lower alkyl), chlorine, bromine or iodine; 20 alternatively, R 7 and R, R 7 and R, Ra and R9, or R 8 and R 10 can come together to form a pi bond; and X is 0, S, SO 2 or CH 2 . In a eleventh principal embodiment the invention provides a compound of Formula XVII, or a pharmaceutically acceptable salt or prodrug thereof: R'O Base R10 6 25 7S (XVII) 15 WO 01/90121 PCT/US01/16671 wherein: Base is a purine or pyrimidine base as defined herein; R' and R 2 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); ailcyl 5 (including lower alkyl); sulfonate ester including 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 heroin; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of 10 providing a compound wherein R' or R 2 is independently H or phosphate;

R

6 is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br vinyl, -C(0)O(alkyl), -C(O)O(lower alkyl), -O(acyl), -O(Iower acyl), -O(alkyl), -O(lower alkyl), -O(alkenyl), chloro, bromo, fluoro, iodo, NO 2 , NH2, -NH(lower alkyl), -NH(acyl), N(lower alkyl) 2 , -N(acyl) 2 ; 15 R and R9 are independently hydrogen, OR 2 , hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(0)O(alkyl), -C(O)O(lower alkyl), -O(acyl), -O(lower acyl), -O(alkyl), -O(lower alkyl), -O(alkenyl), chlorine, bromine, iodine, NO 2 , NH2, NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, -N(acyl)2;

R'

0 is H, alkyl (including lower alkyl), chlorine, bromine or iodine; 20 alternatively, R7 and R9, or R 7 and R1 0 can come together to form a pi bond; and X is 0, S, SO 2 or CH 2 . In an twelfth principal embodiment, the invention provides a compound of Formula XVIII, or a phannaceutically acceptable salt or prodrug thereof: Io Base x R R 25 (XVTII) 16 WO 01/90121 PCT/USG1/16671 wherein: Base is a purine or pyrimidine base as defined herein;

R

1 and R2 independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl 5 (including lower alkyl); sulfonate ester including 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; a cholesterol; or other phamaceutically acceptable leaving group which when administered in vivo is capable of 10 providing a compound wherein R' or R2 is independently H or phosphate; R6 is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br vinyl, -C(0)O(alkyl), -C(O)O(lower alkyl), -O(acyl), -Oclower acyl), -O(alkyl), -O(lower alkyl), -O(alkenyl), chloro, bromo, fluoro, iodo, NO 2 , NI 2 , -NH(lower alkyl), -NH(acyl), N(lower alkyl) 2 , -N(acyl)z; 15 R7 and R9 are independently hydrogen, OR 2 , alkyl (including lower alkyl), alkenyl, alcynyl, Br-vinyl, 0-alkenyl, chlorine, bromine, iodine, NO 2 , amino, loweralkylamino or di(lower alkyl)amino; R8 is H, alkyl (including lower alkyl), chlorine, bromine or iodine; alternatively, R? and R?, or R! and R9 can come together to form a pi bond; 20 X is 0, S, SO 2 or CH 2 . The #-D- and #-L-nucleosides of this invention may inhibit HCV polymerase activity. Nucleosides can be screened for their ability to inhibit HCV polymerase activity in vitro according to screening methods set forth more particularly herein. One can readily 25 determine the spectrum of activity by evaluating the compound in the assays described herein or with another confirmatory assay. In one embodiment the efficacy of the anti-HCV compound is measured according to the concentration of compound necessary to reduce the plaque number of the virus in vitro, according to methods set forth more particularly herein, by 50% (i.e. the compound's 17 WO 01190121 PCT/US01/16671

EC

5 0). In preferred embodiments the compound exhibits an EC 50 of less than 25, 15, 10, 5, or 1 micromolar. In another embodiment, the active compound can be administered in combination or alternation with another anti-HCV agent. In combination therapy, an effective dosage of 5 two or more agents are administered together, whereas during alternation therapy an effective dosage of each agent is administered serially. The dosages will depend on absorption, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated, It is to be fiuther understood that for any particular 10 subject, specific dosage regimens and schedules should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. Nonlimiting examples of antiviral agents that can be used in combination with the compounds disclosed herein include: 15 (1) an interferon and/or ribavirin (Battaglia, A.M. et al, Ann. Pharnacother. 34:487 494, 2000); Berenguer, M. et al Antivir. Ther. 3(Suppl. 3):125-136, 1998); (2) Substrate-based NS3 protease inhibitors (Attwood et al, Antiviral peptide derivatives, PCT WO 98/22496, 1998; Attwood et al, Antiviral Chemistry and Chemotherapy 10.259-273, 1999; Attwood et al., Preparation and use of amino acid 20 derivatives as anti-viral agents, German Patent Publication DE 19914474; Tung et al. Inhibitors of serine proteases, particularly hepatitis C virus NS3 protease, PCT WO 98/17679), including alphaketoamides and hydrazinoureas, and inhibitors that terminate in an electrophile such as a boronic acid or phosphonate. Llinas-Brunet et al, Hepatitis C inhibitor peptide analogues, PCT WO 99/07734. 25 (3) Non-substrate-based inhibitors such as 2,4,6-trihydroxy-3-nitro-benzamide derivatives (Sudo K. et al., Biochemical and Biophysical Research Communications, 238:643-647, 1997; Sudo K. et al. Antiviral Chemistry and Chemotherapy 9:186, 1998), including RD3-4082 and RD3-4078, the former substituted on the amide with a 14 carbon chain and the latter processing apara-phenoxyphenyl group; 30 (4) Thiazolidine derivatives which show relevant inhibition in a reverse-phase HPLC assay with an NS3/4A fusion protein and NS5A/5B substrate (Sudo K. et al., 18 WO 01/90121 PCT[US01/16671 Antiviral Research 32:9-18, 1996), especially compound RD-1-6250, possessing a fused cinnamoyl moiety substituted with a long alkyl chain, RD4 6205 and RD4 6193; (5) Thiazolidines and benzanilides identified in Kakiuchi N. et al. J. EBS Letters 421:217-220; Takeshita N. et al. Analytical Biochemistry 247:242-246, 1997; 5 (6) A phenan-threnequinone possessing activity against HCV protease in a SDS PAGE and autoradiography assay isolated from the fermentation culture broth of Streptomyces sp., Sch 68631 (Chu M. et al., Tetrahedron Letters 37:7229-7232, 1996), and Sch 351633, isolated from the fungus Penicillium griscofdluum, which demonstrates activity in a scintillation proximity assay (Chu M. et al., Bioorganic and Medicinal 10 Chemistry Letters 9:1949-1952); (7) Selective NS3 inhibitors based on the macromolecule elgin c, isolated from leech (Qasim M.A. et al., Biochemistry 36:1598-1607, 1997); (8) HCV helicase inhibitors (Diana G.D. et al., Compounds, compositions and methods for treatment of hepatitis C, U.S. Patent No. 5,633,358; Diana G.D. et al., 15 Piperidine derivatives, pharmaceutical compositions thereof and their use in the treatment ofhepatitis C, PCT WO 97/36554); (9) HCV polymerase inhibitors such as nucleotide analogues, gliotoxin (Ferrari R. et al. Journal of Virology 73:1649-1654, 1999), and the natural product cerulenin (Lohmann V. et al., Virology 249:108-118, 1998); 20 (10) Antisense phosphorothioate oligodeoxynucleotides (S-ODN) complementary to sequence stretches in the 5' non-coding region (NCR) of the HCV (Alt M. et al., Hepatology 22:707-717, 1995), or nucleotides 326-348 comprising the 3' end of the NCR and nucleotides 371-388 located in the core coding region of the IICV RNA (Alt M. et al., Archives of Virology 142:589-599, 1997; Galderisi U. et al, Journal of Cellular Physiology 25 181:251-257, 1999); (11) Inhibitors of IRES-dependent translation (Ikeda N et al., Agent for the prevention and treatment of hepatitis C, Japanese Patent Publication JP-08268890; Kai Y. et al. Prevention and treatment of viral diseases, Japanese Patent Publication JP 10101591); 19 - WO 01/90121 PCT/US01/16671 (12) Nuclease-resistant ribozymes (Macojak DJ. et a[., Hepatology 30 abstract 995, 1999); and (13) Other miscellaneous compounds including 1-amino-alkylcyclohexanes (U.S. Patent No. 6,034,134 to Gold et aL), alkyl lipids (U.S. Patent No. 5,922,757 to Chojkier et 5 al.), vitamin E and other antioxidants (U.S. Patent No. 5,922,757 to Chojkier et al.), squalene, amantadine, bile acids (U.S. Patent No. 5,846,964 to Ozeki et al.), N (phosphonoacetyl)-L-aspartic acid, (U.S. Patent No. 5,830,905 to Diana et al.), benzenedicarboxamides (U.S. Patent No. 5,633,388 to Diana et al.), polyadenylic acid derivatives (U.S. Patent No. 5,496,546 to Wang et al.), 2',3'-dideoxyinosine (U.S. Patent 10 No. 5,026,687 to Yarchoan et al.), and benzimidazoles (U.S. Patent No. 5,891,874 to Colacino et al.). BRIEF DESCRIPTION OF THE FIGURES Figure 1 provides the structure of various non-limiting examples of nucleosides of the present invention, as well as other known nucleosides, FIAU and Ribavirin, which are 15 used as comparative examples in the text. Figure 2 is a line graph of the pharmacokinetics (plasma concentrations) of p-D-2'

CH

3 -riboG administered to six Cynonolgus Monkeys over time after administration. Figure 3a and 3b are line graphs of the pharmacokinetics (plasma concentrations) of p-D-2'-CH 3 -riboG administered to Cynomolgus Monkeys either intravenously (3a) or 20 orally (3b) over time after administration. DETAILED DESCRIPTION OF THE INVENTION The invention as disclosed herein is a compound, method and composition for the treatment of hepatitis C in humans or other host animals, that includes administering an effective HCV treatment amount of a #-D- or #-L-nucleoside as described herein or a 25 phannaceutically acceptable salt or prodrug thereof, optionally in a pharmaceutically acceptable carrier. The compounds of this invention either possess antiviral (i.e., anti-HCV) activity, or are metabolized to a compound that exhibits such activity. 20 WO 01/90121 PCT/USOI/16671 In summary, the present invention includes the following features: (a) j-D- and -L-nucleosides, as described herein, and pharmaceutically acceptable salts and prodrugs thereof; (b) O-D- and I-L-nucleosides as described herein, and pharmaceutically 5 acceptable salts and prodrugs thereof for use in the treatment or prophylaxis of an HCV infection, especially in individuals diagnosed as having an HCV infection or being at risk for becoming infected by HCV; (c) use of these j-D- and f-L-nucleosides, and pharmaceutically acceptable salts and prodrugs thereof in the manufacture of a medicament for treatment of an HCV 10 infection; (d) pharmaceutical formulations comprising the O-D- or f-L-nucleosides or pharmaceutically acceptable salts or prodrugs thereof together with a pharmaceutically acceptable carrier or diluent; (e) #-D- and fl-L-nucleosides as described herein substantially in the absence of 15 enantiomers of the described nucleoside, or substantially isolated from other chemical entities; (f) processes for the preparation of f-D- and I-L-nucleosides, as described in more detail below; and (g) processes for the preparation of f-D- and #-L-nucleosides substantially in the 20 absence of enantioiners of the described nucleoside, or substantially isolated from other chemical entities. L Active Comound, and Phsiologleally Acceptable Salts and Prodrugs Thereof In a first principal embodiment, a compound of Formula I, or a pharmaceutically acceptable salt or prodrug thereof, is provided: 21 WO 01/90121 PCTIUS01/16671 Y N N RIO 0 cH, ORz OR 3 (I) wherein:

R

1 , R2 and R3 are independently H, phosphate (including mono-, di- or triphosphate and a 5 stabilized phosphate prodnmg); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including 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; a cholesterol; or other pharmaceutically acceptable leaving 10 group which when administered in vivo is capable of providing a compound wherein R], R2 or R 3 is independently H or phosphate; Y is hydrogen, bromo, chloro, fluoro, iodo, OR4, NR 4 R or SRi; X1 and X2 are independently selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, 15 OR, NR 4 NR or SR 5 ; and R4 and RW are independently hydrogen, acyl (including lower acyl), or alkyl (including but not limited to methyl, ethyl, propyl and cyclopropyl). In a preferred subenbodiment, a compound of Formula I, or a pharmaceutically acceptable salt or prodrug thereof, is provided wherein: 20 R 1 , R2 and R 3 are independently H or phosphate (preferably H); X1 is H;

X

2 is H or NH 2 ; and Y is hydrogen, bromo, chloro, fluoro, iodo, NH 2 or OH. 22 WO 01/90121 PCTIUS01/16671 In a second principal embodiment, a compound of Fonnula II, or a pharmaceutically acceptable salt or prodrug thereof, is provided: y N N N Xz R, 0 5 wherein:

R

1 , R2 and R 3 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or 10 more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R 1 , R 2 or R 3 is independently H or phosphate; and Y is hydrogen, bromo, chioro, fluoro, iodo, OR 4 , NRR 5 or SR 4 ; 15 X' and X 2 are independently selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo,

OR

4 , NR 4

NR

5 or SR 5 ; and R4 and R are independently hydrogen, acyl (including lower acyl), or alkyl (including but not limited to methyl, ethyl, propyl and cyclopropyl). 20 In a preferred subembodiment, a compound of Formula U, or a pharmaceutically acceptable salt or prodrug thereof, is provided wherein: R', R2 and R 3 are independently H or phosphate (preferably H); X1 is H;

X

2 is H or NH 2 ; and 23 WO 01/90121 PCT/US01/16671 Y is hydrogen, bromo, chloro, fluoro, iodo, NH 2 or OH. In a third principal embodiment, a compound of Formula III, or a pharmaceutically acceptable salt or prodrug thereof, is provided: Y XN N N X 2

R

1 O

OR

2 OR 5 (III) wherein: R1, R2 and R3 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including 10 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; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1, R2 or R3 is independently H or phosphate; and 15 Y is hydrogen, bromo, chloro, fluoro, iodo, OR 4 , NR 4

R

5 or SR 4 ' X' and X 2 are independently selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo,

OR

4 , NR 4 NR or SR 5 ; and R4 and R5 are independently hydrogen, acyl (including lower acyl), or alkyl (including but 20 not limited to methyl, ethyl, propyl and cyclopropyl). In a preferred subenbodiment, a compound of Fonmula III, or a pharmaceutically acceptable salt or prodrug thereof, is provided wherein: R', R2 and R3 are independently H or phosphate (preferably H); X' is H; 24 WO 01/90121 PCT/US01/16671

X

2 is H or NH 2 ; and Y is hydrogen, bromo, chloro, fluoro, iodo, NH 2 or OH. In a fourth principal embodiment, a compound of Formula IV, or a pharmaceutically acceptable salt or prodrug thereof, is provided: Y N 0

CH

1 5 OR OR 3 wherein: R', R 2 and R 3 are independently H, phosphate (including mono-, di- or triphosphate and a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); 10 sulfonate ester including 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; a cholesterol; or other phannaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R', R2 15 or R 3 is independently H or phosphate; Y is hydrogen, bromo, chloro, fluoro, iodo, OR 4 , NR 4

R

5 or SR 4 ;

X

1 is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR 4 , NR 4 NR or SRW; and R and R are independently hydrogen, acyl (including lower acyl), or alkyl (including but 20 not limited to methyl, ethyl, propyl and cyclopropyl). In a preferred subembodiment, a compound of Formula IV, or a pharmaceutically acceptable salt or prodrug thereof, is provided wherein: R1, R 2 and R 3 are independently H or phosphate (preferably H); X1 is H or CH 3 ; and 25 WO 01/90121 PCT/USO1/16671 Y is hydrogen, bromo, chloro, fluoro, iodo, NH 2 or OH. In a fifth principal embodiment, a compound of Formula V, or a pharmaceutically acceptable salt or prodrug thereof, is provided: Y No Rio

H

3 C 0a 2 o& 5 (V) wherein: R', R2 and R are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including 10 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; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R 2 , R2 or R3 is independently H or phosphate; and 15 Y is hydrogen, bromo, chloro, fluoro, iodo, OR 4 , NR 4 R or SR ; X1 is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR 4 , NR4NR or SR; and Ri and R are independently hydrogen, acyl (including lower acyl), or alkyl (including but not limited to methyl, ethyl, propyl and cyclopropyl). 20 In a preferred subembodiment, a compound of Formula V, or a pharmaceutically acceptable salt or prodrug thereof, is provided wherein:

R

3 , R2 and R are independently I-I or phosphate (preferably H);

X

1 is H or CH 3 ; and Y is hydrogen, broino, chloro, fluoro, iodo, NH 2 or OH. 26 WO 01/90121 PCT/US01/16671 In a sixth principal embodiment, a compound of Fomula VI, or a phannaceutically acceptable salt or prodrag thereof, is provided: Y N N 0 Ao CH,

OR

1

O

3 (VI) 5 wherein:

R

1 , R2 and R2 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or 10 more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R 1 , R2 or R3 is independently H or phosphate; and Y is hydrogen, bromo, chloro, fluoro, iodo, OR 4 , NR 4

R

5 or SR 4 ; 15 X 1 is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR 4 , NR 4

NR

5 or SR5; and R4 and R? are independently hydrogen, acyl (including lower acyl), or alkyl (including but not limited to methyl, ethyl, propyl and cyclopropyl). In a preferred subembodinient, a compound of Forraula Vt or a pharmaceutically 20 acceptable salt or prodrag thereof, is provided wherein:

R

1 , R2 and R are independently H or phosphate (preferably H);

X

1 is H or CH 3 ; and Y is hydrogen, bromo, chloro, fluoro, iodo, NH2 or OH. 27 WO 01/90121 PCTfUS01/16671 In a seventh principal embodiment, a compound selected from Formulas VII, VIII and IX, or a pharmaceutically acceptable salt or prodrug thereof, is provided: Base Base Base RIO RIO RIO x x x

OR

2 OR3 OR2 (VII) (VHI) (IX) 5 wherein: Base is a pine or pyrimidine base as defined herein; R1, R2 and R 3 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including 10 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; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R 1 , R 2 or R3 is independently H or phosphate; 15 R 6 is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br vinyl, 2-Br-ethyl, -C(O)O(alkyl), -C(0)O(lower alkyl), -O(acyl), -OQower acyl), -O(alkyl), -O(lower alkyl), -O(alkenyl), CF 3 , chloro, bromo, fluoro, iodo, NO 2 , NH 2 , -NH(lower alkyl), -NH(acyl), -N(lower alkyl) 2 , -N(acyl) 2 ; and X is 0, S, SO 2 , or CHz. 20 In a first preferred subembodiment, a compound of Formula VII, VIII or IX, or a pharmaceutically acceptable salt or prodrug thereof, is provided wherein: Base is a purine or pyrimidine base as defined herein; R', R2 and R3 are independently hydrogen or phosphate; R is alkyl; and 25 X is 0, S, SO 2 or CH 2 . 28 WO 01/90121 PCT/USO1/16671 In a second preferred subembodiment, a compound of Fornula VII, VIII or IX, or a pharmaceutically acceptable salt or prodrug thereof, is provided wherein: Base is a purine or pyrimidine base as defined herein; R1, R 2 and R 3 are hydrogens; 5 R 6 is alkyl; and X is 0, S, S02 or CH 2 . In a third preferred subembodinent, a compound of Formula VII, VIII or IX, or a pharmaceutically acceptable salt or prodrug thereof, is provided wherein: Base is a purine or pyrimidine base as defined herein; 10 R', R 2 and R 3 are independently hydrogen or phosphate;

R

6 is alkyl; and X is 0. In a eighth principal embodiment, a compound of Formula X, XI or XII, or a pharmaceutically acceptable salt or prodrag thereof, is provided: R'o Base R o Base RtO Base 15 2 OR' R' 7 R6 (X) (XI) (XII) wherein: Base is a purine or pyrimidine base as defined herein; R', R2 and R 3 are independently H; phosphate (including monophosphate, diphosphate, 20 triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including 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; a cholesterol; or other 29 WO 01/90121 PCT/US01/16671 pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R', R2 or R3 is independently H or phosphate; R6 is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br vinyl, -C(O)O(alkyl), -C(O)Q(lower alkyl), -O(acyl), -O(lower acyl), -O(alkyl), -O(lower 5 alkyl), -O(alkenyl), chloro, bromo, fluoro, iodo, NO 2 , NH 2 , -NH(lower alkyl), -NH(acyl), N(lower alky1) 2 , -N(acyl) 2 ; R7 is hydrogen, OR3, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(O)O(alkyl), -C(O)O(lower alkyl), -O(acyJ), -OD(ower acyl), -O(alkyl), O(lower alkyl), -O(alkenyl), chlorine, bromine, iodine, NO 2 , NH 2 , -NH(lower alkyl), 10 NH(acyl), -N(loweralky) 2 , -N(acyl) 2 ; and X is 0, S, S02 or CH 2 . In a first preferred subembodiment, a compound of Formula X, XI or XII, or a pharmaceutically acceptable salt or prodrug thereof, is provided wherein: Base is a purine or pyrimidine base as defined herein; 15 R', R2 and R3 are independently hydrogen or phosphate; R6 is alkyl; and X is 0, S, S02 or CH 2 . In a second preferred subembodiment, a compound of Formula X, XI or XII, or a pharmaceutically acceptable salt or prodrug thereof, is provided wherein: 20 Base is a purine or pyrimidine base as defined herein; R1, R 2 and R3 are hydrogens;

R

6 is alkyl; and X is 0, S, SO 2 or CH 2 . In a third preferred subembodiment, a compound of Formula X, XI or XII, or a 25 pharmaceutically acceptable salt or prodrug thereof, is provided wherein: Base is a purine or pyrimidine base as defined herein; R1, R2 and R3 are independently H or phosphate; 30 WO 01/90121 PCT/USO1/16671

R

6 is alkyl; and X is 0. In even more preferred subembodiments, a compound of Formula XI, or its pharmaceutically acceptable salt or prodrug, is provided: R'O Base HaC 5 OR 2 (XI) wherein: Base is a purine or pyrimidine base as defined herein; optionally substituted with an amine or cyclopropyl (e.g., 2-amino, 2,6-diamino or cyclopropyl guanosine); and 10 RI and R2 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including 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 15 phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 or R2 is independently H or phosphate. In a ninth principal embodiment a compound selected from Formula XIII, XIV or XV, or a pharmaceutically acceptable salt or prodrug thereof, is provided: R10 Base RIO Base Base R, Re x x x 20 OR 2 OR'

OR

2 R, (XIII) (XIV) (XV) wherein: Base is a purine or pyrimidine base as defined herein; 31 WO 01/90121 PCT/USO1/16671 Ri, R2 and R3 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or 5 more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein Ri, R2 or R 3 is independently H or phosphate;

R

6 is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br 10 vinyl, -C(0)0(alkyl), -C(O)0(lower alkyl), -O(acyl), -O(lower acyl), -O(alkyl), -O(lower alkyl), -0(alkenyl), chloro, bromo, fluoro, iodo, NO 2 , NH2, -NH(lower alkyl), -NH(acyl), N(lower alkyl) 2 , -N(acyl)2; and X is 0, S, S02 or CH2. In a first preferred subembodiment, a compound of Formula XIII, XIV or XV, or a 15 pharmaceutically acceptable salt or prodrug thereof, is provided wherein: Base is a purine or pyrimidine base as defined herein; Ri', and R 3 are independently hydrogen or phosphate; R is alkyl; and X is 0, S, S02 or CH 2 . 20 In a second preferred subembodiment, a compound of Formula XIII, XIV or XV, or a phannaceutically acceptable salt or prodrug thereof, is provided wherein: Base is a purine or pyrimidine base as defined herein;

R

1 , R2 and R3 are hydrogens; R is alkyl; and 25 X is 0, S, SO2 or CH 2 . In a third preferred subembodiment, a compound of Formula XIII, XIV or XV, or a pharmaceutically acceptable salt or prodrug thereof, is provided wherein: Base is a purine or pyrimidine base as defined herein; 32 WO 01/90121 PCT/US01/16671

R

1 , R 2 and R 3 are independently hydrogen or phosphate; R is alkyl; and Xis O. In a tenth principal embodiment the invention provides a compound of Formula 5 XVL or a pharmaceutically acceptable salt or prodrug thereof: RO Base R X R (XVI) wherein: Base is a purine or pyrimidine base as defined herein; 10 R' and R 2 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including 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 15 phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R 1 and R2 are independently H or phosphate; R 6 is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br vinyl, -C(O)Q(alkyl), -C(O)O(lower alkyl), -O(acyl), -O(iower acyl), -O(alkyl), -O(lower 20 alkyl), -O(alkenyl), chloro, bromo, fluoro, iodo, NO 2 , NH 2 , -NH(lower alkyl), -NH(acyl), N(lower alkyl) 2 , -N(acyl) 2 ; R7 and R are independently hydrogen, OR 2 , hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(0)Q(alkyl), -C(O)O(lower alkyl), -O(acyl), -O(lower acyl), -O(alkyl), -O(lower alkyl), -O(alkenyl), chlorine, bromine, iodine, NO 2 , NH 2 , 25 -NH(lower alkyl), -NH(acyl), -N(lower alkyl) 2 , -N(acyl) 2 ;

R

8 and R' 0 are independently H, alkyl (including lower alkyl), chlorine, bromine or iodine; 33 WO 01/90121 PCT/US01/16671 alternatively, R7 and R?, R 7 and RI", R and R 9 , or R 8 and Rio can come together to form a pi bond; and X is 0, S, SO 2 or CH2. In a first preferred subembodiment, a compound of Formula XVI, or its 5 pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R' is independently H or phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is 10 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; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R' is independently H or phosphate; (3)

R

6 is alkyl; (4) R7 and R 9 are independently OR 2 , alkyl, alkenyl, alkynyl, Br-vinyl, 0 15 alkenyl, chlorine, bromine, iodine, NO 2 , amino, loweralkylamino or di(loweralkyl)amino; (5) R8 and R1 0 are independently H, alkyl (including lower alkyl), chlorine, bromine, or iodine; and (6) X is 0, S, S02 or CH 2 . In a second preferred subembodiment, a compound of Formula XVI, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or 20 pyrimidine base as defined herein; (2) R' is independently H or phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including 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 25 given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered In vivo is capable of providing a compound wherein R' is independently H or phosphate; (3) Re is alkyl, alkenyl, alkynyl, Br-vinyl, hydroxy, 0-alkyl, 0-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, loweralkylamino, or di(loweralkyl)amino; (4) R7 and R? are 30 independently OR 2 ; (5) R 8 and R 0 are independently H, alkyl (including lower alkyl), chlorine, bromine, or iodine; and (6) X is 0, S, SO 2 or CH 2 . 34 WO 01/90121 PCT[US0I/16671 In a third preferred subembodiment, a compound of Formula XVI, or its phannacentically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R' is independently H or phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl 5 (including lower acyl); alkyl (including lower alkyl); sulfonate ester including 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; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in 10 vivo is capable of providing a compound wherein R' is independently H or phosphate; (3) R is alkyl, alkenyl, alkynyl, Br-vinyl, hydroxy, 0-alkyl, 0-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, loweralkylamino or di(loweralkyl)amino; (4) Rt and R 9 are independently OR 2 , alkyl, alkenyl, alkynyl, Br-vinyl, 0-alkenyl, chlorine, bromine, iodine,

NO

2 , amino, loweralkylamino or di(loweralkyl)amino; (5) R 8 and R are H; and (6) X is 0, 15 S, SO 2 or CH 2 . In a fourth preferred subembodiment, a compound of Formula XVI, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R' is independently H or phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl 20 (including lower acyl); alkyl (including lower alkyl); sulfonate ester including 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; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in 25 vivo is capable of providing a compound wherein R' is independently H or phosphate; (3)

R

6 is alkyl, alkenyl, alkynyl, Br-vinyl, hydroxy, 0-alkyl, 0-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, loweralkylamino, or di(loweralkyl)aiino; (4) RI and R9 are independently OR 2 , alkyl, alkenyl, alkynyl, Br-vinyl, 0-alkenyl, chlorine, bromine, iodine,

NO

2 , amino, loweralkylamino, or di(loweralkyl)amino; (5) R8 and R 10 are independently H, 30 alkyl (including lower alkyl), chlorine, bromine, or iodine; and (6) X is 0. In a fifth preferred subembodiment, a compound of Formula XVI, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R' is independently H or phosphate (including 35 WO 01/90121 PCTfUSO1/16671 monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including 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 5 given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R' is independently H or phosphate; (3)

R

6 is alkyl; (4) R 7 and R 9 are independently OR'; (5) R and R' 0 are independently H, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is 0, 5, S02 or CH 2 . 10 In a sixth preferred subembodiment, a compound of Formula XVI, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R' is independently H or phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or 15 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; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R' is independently H or phosphate; (3) 20 R 6 is alkyl; (4) R' and R are independently OR 2 , alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, 0-alkenyl, chlorine, bromine, iodine, NO 2 , amino, loweralkylamino, or di(loweralkyl)amino; (5) R and R1 0 are H; and (6) X is 0, S, SO 2 , or CH 2 . hi a seventh preferred subembodiment, a compound of Formula XVI, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or 25 pyrimidine base as defined herein; (2) R' is independently H or phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyi (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the defiition of aryl 30 given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R' is independently H or phosphate; (3)

R

6 is alkyl; (4) R7 and R9 are independently OR 2 , alkyl (including lower alkyl), alkenyl, 36 WO 01/90121 PCT/USOI/16671 alkynyl, Br-vinyl, 0-alkenyl, chlorine, bromine, iodine, NO 2 , amino, loweralkylamino or di(loweralkyl)amino; (5) RW and R1 0 are independently H, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is 0. In a eighth preferred subembodiment, a compound of Fonnula XVI, or its 5 pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R' is independently H or phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is 10 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; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R' is independently H or phosphate; (3) RW is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, 15 chloro, bromo, fluoro, iodo, NO 2 , amino, loweralkylamino or di(loweralkyl)amino; (4) RW and R9 are independently OR2; (5) RW and RP are hydrogen; and (6) X is 0, S, SO 2 or CH 2 . In a ninth preferred subembodiment, a compound of Formula XVI, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R' is independently H or phosphate (including 20 monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including 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; a 25 cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R 1 is independently H or phosphate; (3) R is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, 0-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, loweralkylamino or di(loweralkyl)amino; (4) R 7 and R 9 are independently OR 2 ; (5) R 8 and RP are independently H, alkyl (including lower 30 alkyl), chlorine, bromine or iodine; and (6) X is 0. In a tenth preferred subembodiment, a compound of Formula XVI, or its pharmaceutically acceptable salt or prodrTug, is provided in which: (1) Base is a purine or 37 WO 01/90121 PCTrUS01/16671 pyrimidine base as defined herein; (2) R] is independently H or phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is 5 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; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R is independently H or phosphate; (3)

R

6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, 0-alkenyl, 10 chloro, bromo, fluoro, iodo, NO 2 , amino, loweralkylamino or di(loweralkyl)amino; (4) R7 and R9 are independently OR 2 , alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, 0 alkenyl, chlorine, bromine, iodine, NO 2 , amino, loweralkylamaino, or di(loweralkyl)amino; (5) R 8 and R1 0 are hydrogen; and (6) X is 0. In an eleventh preferred subembodiment, a compound of Formula XVI, or its 15 pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R' is independently H or phosphate; (3) R is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, 0-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, loweralkylamino or di(loweralkyl)amino; (4) R7 and R9 are independently OR 2 ; (5) R8 and R' 0 are hydrogen; and (6) X is 0, S, S02 or CH 2 . 20 In a twelfth preferred subembodiment, a compound of Formula XVI, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R' is independently H or phosphate; (3) R 6 is alkyl; (4) R7 and R 9 are independently OR 2 ; (5) R 8 and Ri 0 are hydrogen; and (6) X is 0, S, S02, or CH 2 . 25 In a thirteenth preferred subembodinent, a compound of Formula XVI, or its phannaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R' is independently H or phosphate; (3) R 6 is alkyl; (4) R 7 and R 9 are independently OR 2 ; (5) R' and R" are independently H, alkyl (including lower alkyl), chlorine, bromine, or iodine; and (6) X is 0. 30 In a fourteenth preferred subembodiment, a compound of Formula XVI, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R' is independently H or phosphate; (3) RP is alkyl; 38 WO 01/90121 PCTUS01/16671 (4) R and R 9 are independently OR 2 , alkyl (including lower alkyl), alkeny, alkynyl, Br vinyl, 0-alkenyl, chlorine, bromine, iodine, NO 2 , amino, loweralkylamino or di(loweralkyl)amino; (5) R 8 and R' 0 are hydrogen; and (6) X is 0. In even more preferred subembodiments, a compound of Formula XVI, or its 5 phannaceutically acceptable salt or prodrug, is provided in which: (1) Base is adenine; (2) R' is hydrogen; (3) R 6 is methyl; (4) R7 and R 9 are hydroxyl; (5) R 8 and R' 0 are hydrogen; and (6) X is 0; (1) Base is guanine; (2) R' is hydrogen; (3) R 6 is methyl; (4) R 7 and R9 are hydroxyl; (5) R 8 and R 1 O are hydrogen; and (6) X is 0; 10 (1) Base is cytosine; (2) R' is hydrogen; (3) Ri is methyl; (4) RI and R 9 are hydroxyl; (5) Rs and R 10 are hydrogen; and (6) X is 0; (1) Base is thymine; (2) R t is hydrogen; (3) R 6 is methyl; (4) R7 and R9 are hydroxyl; (5) R' and R'O are hydrogen; and (6) X is 0; (1) Base is uracil; (2) R' is hydrogen; (3) R is methyl; (4) RW and R9 are hydroxyl; 15 (5) R 8 and R1 0 are hydrogen; and (6) X is 0; (1) Base is adcniie; (2) R' is phosphate; (3) R 6 is methyl; (4) R 7 and R9 are hydroxyl; (5) RB and R' are hydrogen; and (6) X is 0; (1) Base is adenine; (2) R 1 is hydrogen; (3) R 6 is ethyl; (4) R 7 and R? are hydroxyl; (5) R8 and R1 0 are hydrogen; and (6) X is 0; 20 (1) Base is adenine; (2) R' is hydrogen; (3) R 6 is propyl; (4) R 7 and R 9 are hydroxyl; (5) R and R 0 are hydrogen; and (6) X is 0; (1) Base is adenine; (2) R 1 is hydrogen; (3) R 6 is butyl; (4) R7 and R 9 are hydroxyl; (5) R 8 and R1 0 are hydrogen; and (6) X is 0; (1) Base is adenine; (2) R' is hydrogen; (3) R6 is methyl; (4) R 7 is hydrogen and R 9 25 is hydroxyl; (5) R! and R' 0 are hydrogen; and (6) X is 0; (1) Base is adenine; (2) R' is hydrogen; (3) R 6 is methyl; (4) R and R 9 are hydroxyl; (5) R 8 and R1 0 are hydrogen; and (6) X is S; (1) Base is adenine; (2) R is hydrogen; (3) R( is methyl; (4) R and R 9 are hydroxyl; (5) R8 and R1 0 are hydrogen; and (6) X is SO 2 ; 39 WO 01/90121 PCT/USO1/16671 (1) Base is adenine; (2) R 1 is hydrogen; (3) R6 is methyl; (4) R 7 and R 9 are hydroxyl; (5) R8 and R' 0 are hydrogen; and (6) X is CH 2 ; In a eleventh principal embodiment the invention provides a compound of Formula XVII, or a pharmaceutically acceptable salt or prodrug thereof: R'O Base R10 R Rx 5 9 7 (XVII) wherein: Base is a purine or pyrimidine base as defined herein; R' is H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized 10 phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including 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; a cholesterol; or other pharmaceutically acceptable leaving group 15 which when administered in vivo is capable of providing a compound wherein R' is independently H or phosphate;

R

6 is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br vinyl, -C(O)O(alkyl), -C(O)O(lower alkyl), -O(acyl), -O(lower acyl), -O(alkyl), -O(lower alkyl), -O(alkenyl), chloro, bromo, fluoro, iodo, NO 2 , NH 2 , -NH(lower alkyl), -NH(acyl), 20 N(lower alkyl) 2 , -N(acyl) 2 ;

R

7 and R 9 are independently hydrogen, OR 2 , hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(O)O(alkyl), -C(O)O(lower alkyl), -O(acyl), -O(lower acyl), -O(alkyl), -O(lower alkyl), -O(alkenyl), chlorine, bromine, iodine, NO 2 , NH 2 , NH(Jower alkyl), -NH(acyl), -N(lower alkyl) 2 , -N(acy) 2 ; 25 R 1 0 is H, alkyl (including lower alkyl), chlorine, bromine, or iodine; alternatively, R7 and RP, or R 7 and R1 0 can come together to form a pi bond; and 40 WO 01/90121 PCT/US01/16671 X is O, S, SO 2 or CH 2 . In a first preferred subembodiment, a compound of Formula XVII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H; phosphate (including 5 monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including 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; a 10 cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R' is independently H or phosphate; (3)

R

6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, 0-alkyl, 0-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, loweralkylamino, or di(loweralkyl)amino; (4) R7 and R 9 are independently hydrogen, OR 2 , alkyl (including lower alkyl), alkenyl, alkynyl, 15 Br-vinyl, 0-alkenyl, chlorine, bromine, iodine, NO 2 , amino, loweralkylamino or di(loweralkyl)-amino; (5) R 10 is H; and (6) X is 0, S, S02, or CH2. In a second preferred subembodiment, a compound of Formula XVII, or its phannaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) Rt is independently H; phosphate (including 20 monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including 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 ary] given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a 25 cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R' is independently H or phosphate; (3) R is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, 0-alkyl, 0-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, loweralkylamino or di(loweralkyl)amino; (4) R7 and R9 are independently OR 2 ; (5) R1 0 is H, alkyl (including lower alkyl), chlorine, 30 bromine, or iodine; and (6) X is 0, S, S02 or CH 2 . In a third preferred subembodiment, a compound of Formula XVII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or 41 WO 01/90121 PCT[USO1/16671 pyrimidine base as defined herein; (2) R 1 is independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is 5 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; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R 1 is independently H or phosphate; (3) R6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, 0-alkyl, 0-alkenyl, 10 chloro, bromo, fluoro, iodo, NO 2 , amino, loweralkylamino, or di(loweralkyl)amino; (4) R7 and R 9 are independently hydrogen, OR 2 , alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, 0-alkenyl, chlorine, bromine, iodine, NO 2 , amino, loweralkylanino or di(loweralkyl)-amino; (5) R1 0 is H, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is 0. 15 In a fourth preferred subembodiment, a compound of Formula XVII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R' is independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or 20 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; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R' is independently H or phosphate; (3) 25 R6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, 0-alkyl, 0-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, lowerallylamino or di(loweralkyl)amino; (4) R 7 and R 9 are independently oRW; (5) R 10 is H; and (6) X is C, 8, 80 2 or CH 2 . In a fifth preferred subenbodiment, a compound of Formula XVII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or 30 pyrimidine base as defined herein; (2) R' is independently H; phosphate (including nonophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is 42 WO 01/90121 PCT[USO1/16671 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; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R' is independently H or phosphate; (3) 5 R 6 is alkyl (including lower alkyl), alkenyl, aflynyl, Br-vinyl, hydroxy, 0-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, loweralkylamino or di(loweralkyl)amino; (4) R7 and R 9 are independently OR 2 ; (5) R 10 is H, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is 0. In a sixth preferred subembodiment, a compound of Formula XVII, or its 10 phannaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R' is independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is 15 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; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R' is independently H or phosphate; (3) R6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, 0-alkyl, 0-alkenyl, 20 chloro, bromo, fluoro, iodo, NO 2 , amino, loweralkylamino, or di(loweralkyl)amino; (4) R7 and R 9 are independently hydrogen, OR 2 , alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO 2 , amino, loweralkylamino, or di(loweralkyl)amino; (5) R is H; and (6) X is 0. In a seventh preferred subembodiment, a compound of Formula XVII, or its 25 pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R' is independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is 30 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; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R' is independently H or phosphate; (3) 43 WO 01/90121 PCT/USOI/16671 R6 is alkyl (including lower alkyl), alkeny, alkynyl, Br-vinyl, hydroxy, O-alkyl, 0-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, loweralkylamino, or di(loweralkyl)amino; (4) IC and R? are independently OR 2 ; (5) R10 is H; and (6) X is O. In an eighth preferred subembodiment, a compound of Formula XVII, or its 5 pharmaceutically acceptable. salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R is independently H or phosphate; (3) R 6 is alkyl; (4) R 7 and R? are independently hydrogen, OR2, alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, 0-alkenyl, chlorine, bromine, iodine, NO 2 , amino, loweralkylamino or di(loweralkyl)-amino; (5) Rio is H, alkyl (including lower alkyl), chlorine, bromine or 10 iodine; and (6) X is 0, S, SO 2 , or CH2. In a ninth preferred subembodiment, a compound of Formula XVI, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R 1 is independently H or phosphate; (3) R5 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, 0-alkyl, 0-alkenyl, chloro, 15 bromo, fluoro, iodo, NO 2 , amino, loweralkylamino, or di(loweralkyl)amino; (4) R 7 and R9 are independently OR 2 ; (5) Rio is H; and (6) X is 0, S, SO2, or CH 2 . In a tenth preferred subenbodiment, a compound of Formula XVII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R t is independently H or phosphate; (3) R 6 is alkyl; 20 (4) R 7 mid R 9 are independently OR 2 ; (5) R' 0 is H; and (6) X is 0, S, SO 2 , or CH 2 . In even more preferred subernbodiments, a compound of Formula XVII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is adenine; (2) R 1 is hydrogen; (3) R6 is methyl; (4) R7 and R9 are hydroxyl; (5) R1 0 is hydrogen; and (6) X is 0; 25 (1) Base is guanine; (2) R' is hydrogen; (3) R6 is methyl; (4) R7 and R 9 are hydToxyI; (5) R 10 is hydrogen; and (6) X is 0; (1) Base is cytosine; (2) Ri is hydrogen; (3) R6 is methyl; (4) R 7 and R 9 are hydroxyl; (5) R' is hydrogen; and (6) X is 0; (1) Base is thymine; (2) R' is hydrogen; (3) R 6 is methyl; (4) R7 and R 9 are 30 hydroxyl; (5) R 0 is hydrogen; and (6) X is 0; 44 WO 01/90121 PCTfUSO1/16671 (1) Base is uracil; (2) R 1 is hydrogen; (3) R6 is methyl; (4) R( and R9 are hydroxyl; (5) R 10 is hydrogen; and (6) X is 0; (1) Base is adenine; (2) R1 is phosphate; (3) R6 is methyl; (4) R 7 and R9 are hydroxyl; (5) R 10 is hydrogen; and (6) X is 0; 5 (1) Base is adenine; (2) R 1 is hydrogen; (3) Ri is ethyl; (4) R7 and R9 are hydroxyl; (5) R1 0 is hydrogen; and (6) X is 0; (1) Base is adenine; (2) R' is hydrogen; (3) R6 is propyl; (4) R7 and R are hydroxyl; (5) RO is hydrogen; and (6) X is 0; (1) Base is adenine; (2) R 1 is hydrogen; (3) R 6 is butyl; (4) R7 and R are hydroxyl; 10 (5) R' 0 is hydrogen; and (6) X is 0; (1) Base is adenine; (2) R' is hydrogen; (3) Ri is methyl; (4) R7 and R are hydroxyl; (5) R1 0 is hydrogen; and (6) X is S; (1) Base is adenine; (2) R 1 is hydrogen; (3) Ri is methyl; (4) R! and R9 are hydroxyl; (5) R 10 is hydrogen; and (6) X is SO 2 ; or 15 (1) Base is adenine; (2) R' is hydrogen; (3) Ri is methyl; (4) K 7 and R9 are hydroxyl; (5) R1 0 is hydrogen; and (6) X is CH 2 In an twelfth principal embodiment the invention provides a compound of Formula XVIII, or a pharmaceutically acceptable salt or prodrug thereof: R'O Base R, Ra 20 (XVI1) wherein: Base is a purine or pyrimidine base as defined herein;

R

1 is independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); 25 sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, 45 WO 01/90121 PCTUS01/16671 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; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R' is 5 independently H or phosphate; R is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br vinyl, -C(O)O(alkyl), -C(0)O(lower alkyl), -O(acyl), -O(Iower acyl), -O(alkyl), -O(lower alkyl), -O(alkenyl), chloro, bromo, fluoro, iodo, NO 2 , NH 2 , -NH(lower alkyl), -NH(acyl), N(lower alkyl) 2 , -N(acyl) 2 ; 10 R 7 and R9 are independently hydrogen, OR 2 , alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, 0-alkenyl, chlorine, bromine, iodine, NO 2 , amino, lower alkylamino, or di(loweralkyl)amino; R8 is H, alkyl (including lower alkyl), chlorine, bromine or iodine-; alternatively, R7 and R9, or R and R 9 can come together to form a pi bond; 15 X is 0, S, SO 2 or CH 2 . In a first preferred subembodiment, a compound of Formula XVIII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R 1 is independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl 20 (including lower acyl); alkyl (including lower alkyl); sulfonate ester including 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; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in 25 vivo is capable of providing a compound wherein R is independently H or phosphate; (3)

R

6 is alkyl; (4) RW and R! are independently hydrogen, OR 2 , alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, 0-alkenyl, chlorine, bromine, iodine, NO 2 , amino, loweralkylamino or di(loweralkyl)amino; (5) RY is H, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is 0, S, S02 or CH2. 30 In a second preferred subembodiment, a compound of Formula XVIII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or 46 WO 01/90121 PCT/US01/16671 pyrimidine base as defined herein; (2) R' is independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower ailcyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is 5 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; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R' is independently H or phosphate; (3) R6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, 0-alkenyl, 10 chloro, bromo, fluoro, iodo, NO 2 , amino, loweralkylamino or di-(Ioweralkyl)amino; (4) R7 and R 9 are independently OR 2 ; (5) R 8 is H, alkyl (including lower alkyl), chlorine, bromine, or iodine; and (6) X is 0, S, SO 2 or CH 2 . hi a third preferred subembodiment, a compound of Formula XVIIH, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or 15 pyrimidine base as defined herein; (2) R' is independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alcyl); sulfonate ester including 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 20 given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R' is independently H or phosphate; (3) R6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO2, amino, loweralkylamino, or di(lower-alkyl)amino; (4) R7 25 and R 9 are independently hydrogen, OR 2 , alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, 0-alkenyl, chlorine, bromine, iodine, NO 2 , amino, loweralkylamino, or di(loweralkyl)amino; (5) R 8 is H; and (6) X is 0, S, SO 2 or CH 2 . In a fourth preferred subembodiment, a compound of Formula XVIII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or 30 pyrimidine base as defined herein; (2) R' is independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is 47 WO 01/90121 PCT/USO1/16671 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; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R' is independently H or phosphate; (3) 5 R6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, 0-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, loweralkylamino, or di(loweralkyl)amino; (4) R 7 and R 9 are independently hydrogen, OR 2 , alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, 0-alkenyl, chlorine, bromine, iodine, NO 2 , amino, loweralkylamino, or di(loweralkyl)amino; (5) R 5 is H, alkyl (including lower alkyl), chlorine, bromine, or iodine; 10 and (6) X is O. In a fifth preferred subembodiment, a compound of Formula XVIII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R 1 is independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl 15 (including lower acyl); alkyl (including lower alkyl); sulfonate ester including 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; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in 20 vivo is capable of providing a compound wherein R' is independently H or phosphate; (3) R6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, 0-alkyl, 0-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, loweralkylamino, or di(loweralkyl)amino; (4) R7 and R are independently OR 2 ; (5) R8 is H; and (6) X is 0, S, S02, or CH2. In a sixth preferred subembodiment, a compound of Formula XVIII, or its 25 pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R' is independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrag); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is 30 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; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R' is independently H or phosphate; (3) 48 WO 01/90121 PCTUS01/16671 R6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, 0-alkenyl, chloro, bromo-, fluoro, iodo, NO 2 , amino, loweralkylamino, or di(loweralkyl)amino; (4) R7 and R9 are independently OR 2 ; (5) R 8 is H, alkyl (including lower alkyl), chlorine, bromine, or iodine; and (6) X is 0. 5 In a seventh preferred subembodiment, a compound of Formula XVIH, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R' is independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or 10 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; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R' is independently H or phosphate; (3) 15 R 6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, 0-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino. loweralkylamino, or di(loweralkyl)amino; (4) R7 and R 9 are independently hydrogen, OR 2 , alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, 0-alkenyl, chlorine, bromine, iodine, NO 2 , amino, loweralkylamino, or di(loweralkyl)anino; (5) R 8 is H; and (6) X is 0. 20 In an eighth preferred subembodiment, a compound of Formula XVffl, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R 1 is independently H or phosphate; (3) R 6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, 0-alkyl, 0-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, loweralkylamino or di(loweralkyl)amino; (4) R 7 and R 9 25 are independently OR 2 ; (5) R 8 is H; and (6) X is 0, S, SO 2 or CH 2 . In a ninth preferred subembodiment, a compound of Formula XVIII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R' is independently H or phosphate; (3) R6 is alkyl; (4) R 7 and R 9 are independently OR 2 ; (5) R8 is H; and (6) X is 0, S, S02, or CH 2 . 30 In a tenth preferred subembodiment, a compound of Formula XVIII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or 49 WO 01/90121 PCT/USOI/16671 pyrinidine base as defined herein; (2) R1 is independently H or phosphate; (3) R 6 is alkyl; (4) R7 and R9 are independently OR 2 ; (5) R 8 is H; and (6) X is O. In even more preferred subembodiments, a compound of Formula XVIII, or its phannaceutically acceptable salt or prodrug, is provided in which: 5 (1) Base is adenine; (2) R' is hydrogen; (3) R 6 is methyl; (4) R 7 and R9 are hydroxyl; (5) R8 is hydrogen; and (6) X is 0; (1) Base is guanine; (2) R' is hydrogen; (3) R6 is methyl; (4) RC and RB are hydroxyl; (5) R8 is hydrogen; and (6) X is 0; (1) Base is cytosine; (2) R' is hydrogen; (3) RP is methyl; (4) RC and R 9 are 10 hydroxyl; (5) R' is hydrogen; and (6) X is 0; (1) Base is thymine; (2) R is hydrogen; (3) R! is methyl; (4) R and R 9 are hydroxyl; (5) R' is hydrogen; and (6) X is 0; (1) Base is uracil; (2) R' is hydrogen; (3) R6 is methyl; (4) R 7 and R 9 are hydroxyl; (5) R8 is hydrogen; and (6) X is 0; 15 (1) Base is adenine; (2) R' is phosphate; (3) R6 is methyl; (4) R and R 9 are hydroxyl; (5) R is hydrogen; and (6) X is 0; (1) Base is adenine; (2) R' is hydrogen; (3) R6 is ethyl; (4) R7 and R9 are hydroxyl; (5) R 8 is hydrogen; and (6) X is 0; (1) Base is adenine; (2) R' is hydrogen; (3) R6 is propyl; (4) R7 and R? are hydroxyl; 20 (5) R8 is hydrogen; and (6) X is 0; (1) Base is adenine; (2) R' is hydrogen; (3) R6 is butyl; (4) R 7 and R 9 are hydroxyl; (5) R8 is hydrogen; and (6) X is 0; (1) Base is adenine; (2) R is hydrogen; (3) R is methyl; (4) R7 and R9 are hydroxyl; (5) Ra is hydrogen; and (6) X is S; 25 (1) Base is adenine; (2) R' is hydrogen; (3) R6 is methyl; (4) R 7 and R9 are hydroxyl; (5) R is hydrogen; and (6) X is SO 2 ; or (1) Base is adenine; (2) R' is hydrogen; (3) R6 is methyl; (4) R7 and R9 are hydroxyl; (5) R 8 is hydrogen; and (6) X is CH 2 . 50 WO 01/90121 PCT/US01/16671 The (-D- and #-L-nucleosides of this invention may inhibit HCV polymerase activity. Nucleosides can be screened for their ability to inhibit HCV polymerase activity in vitro according to screening methods set forth more particularly herein. One can readily 5 determine the spectrum of activity by evaluating the compound in the assays described herein or with another confirmatory assay. In one embodiment the efficacy of the anti-HCV compound is measured according to the concentration of compound necessary to reduce the plaque number of the virus in vitro, according to methods set forth more particularly herein, by 50% (i.e. the compound's 10 ECso). In preferred embodiments the compound exhibits an BC 50 of less than 15 or 10 micromolar, when measured according to the polymerase assay described in Ferrari et at, nL. of Vir, 73:1649-1654, 1999; Ishii et at, Hepatology, 29:1227-1235,1999; Lohmann et al., An. of Bio. Chem., 274:10807-10815, 1999; or Yamashita et al, Jnl. of Bio. Chem., 273:15479-15486, 1998. 15 The active compound can be administered as any salt or prodrug that upon administration to the recipient is capable of providing directly or indirectly the parent compound, or that exhibits activity itself Nonlimiting examples are the 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 purine or 20 pyrimidine base (a type of "pharmaceutically acceptable prodrug"). Further, the modifications can affect the biological activity of the compound, in some cases increasing the activity.over the parent compound. This can easily be assessed by preparing the salt or prodrug and testing its antiviral activity according to the methods described herein, or other methods known to those skilled in the art. 25 Il. Definitions The term alkyl, as used herein, unless otherwise specified, refers to a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbon of typically C 1 to CIO, and specifically includes methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 51 WO 01/90121 PCT/USO1/16671 cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl, The term includes both substituted and unsubstituted alkyl groups. Moieties with which the alkyl group can be substituted are selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic 5 acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et aL, Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, hereby incorporated by reference. The term lower alkyl, as used herein, and unless otherwise specified, refers to a C 1 to 10 C 4 saturated straight, branched, or if appropriate, a cyclic (for example, cyclopropyl) alkyl group, including both substituted and unsubstituted forms, Unless otherwise specifically stated in this application, when alkyl is a suitable moiety, lower alkyl is preferred. Similarly, when alkyl or lower alkyl is a suitable moiety, unsubstituted alkyl or lower alkyl is preferred. 15 The term alkylamino or arylamino refers to an amino group that has one or two alkyl or aryl substituents, respectively. 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 protecting groups are known to 20 those skilled in the art of organic synthesis. The term aryl, as used herein, and unless otherwise specified, refers to phenyl, biphenyl, or naphthyl, and preferably phenyl. The term includes both substituted and unsubstituted moieties. The aryl group can be substituted with one or more moieties selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, 25 aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught 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 30 term aralkyl or arylalkyl refers to an aryl group with an alkyl substituent. The term halo, as used herein, includes chloro, bromo, iodo, and fluoro. 52 WO 01/90121 PCT/US01/16671 The term purine or pyrimidine base includes, but is not limited to, adenine, N 6 alkylpurines, N 6 -acylpurines (wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl), N 6 benzylpurine, N 6 -halopurine, N 6 -vinylpurine, N-acetylenic purine, N 6 -acyl purine,

N

6 -hydroxyalkyl purine, N 6 -thioalkyl purine, N 2 -alkylpurines, N 2 -alkyl-6-thiopurines, 5 thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2- and/or 4-mercaptopyrmidine, uracil, 5-halouracil, including 5-fluorouracil,

C

5 -alkylpyrimidines, C5-benzylpyrimidines, C 5 -halopyrimidines, Ctvinylpyrimidine, C acetylenic pyrimidine, C 5 -acyl pyrimidine, C 5 -hydroxyalkyl purine, C 5 -amidopyrimidine,

C

5 -cyanopyrimidine, C&-nitropyrimidine, C 5 -aminopyrimidine, N 2 -alkylpurines, N-alkyl 10 6-thiopurines, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, and pyrazolopyrimidinyl. Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine, Functional oxygen and nitrogen groups on the base can be protected as necessary or desired. Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, 15 dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl, alkyl groups, and acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl. The term acyl refers to a carboxylic acid ester in which the non-carbonyl moiety of the ester group is selected from straight, branched, or cyclic alkyl or lower alkyl, alkoxyalkyl including methoxymethyl, aralkyl including benzyl, aryloxyalkyl such as 20 phenoxymethyl, aryl including phenyl optionally substituted with chloro, bromo, fluoro, iodo, C1 to C 4 alkyl or C 1 to C 4 alkoxy, sulfonate esters such as alkyl or aralcyl sulphonyl including methanesulfonyl, the mono, di or triphosphate ester, trityl or monomethoxytrityl, substituted benzyl, trialkylsilyl (e.g. dimethyl-t-butylsilyl) or diphenyhnethylsilyl. Aryl groups in the enters optimally comprise a phenyl group. The term "lower acyl" refers to an 25 acyl group in which the non-carbonyl moiety is a lower alkyl. As used herein, the term "substantially free of' or "substantially in the absence of' refers to a nucleoside composition that includes at least 85 or 90% by weight, preferably 95% to 98 % by weight, and even more preferably 99% to 100% by weight, of the designated enantiomer of that nucleoside. In a preferred embodiment, in the methods and 30 compounds of this invention, the compounds are substantially free of enantiomers. 53 WO 01/90121 PCT/USQ1/16671 Similarly, the term "isolated" refers to a nucleoside composition that includes at least 85 or 90% by weight, preferably 95% to 98 % by weight, and even more preferably 99% to 100% by weight, of the nucleoside, the remainder comprising other chemical species or enantiomers. 5 The term "independently" is used herein to indicate that the variable which is independently applied varies independently from application to application. Thus, in a compound such as R"XYR", wherein R" is "independently carbon or nitrogen," both R" can be carbon, both R" can be nitrogen, or one R" can be carbon and the other R"nitrogen. The term host, as used herein, refers to an unicellular or multicellular organism in 10 which the virus can replicate, including cell lines and animals, and preferably a human. Alternatively, the host can be carrying a part of the hepatitis C viral genome, whose replication or function can be altered by the compounds of the present invention. The term host specifically refers to infected cells, cells transfected with all or part of the HCV genome and animals, in particular, primates (including chimpanzees) and humans, In most 15 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 fom (such as an ester, phosphate 20 ester, salt of an ester or a related group) of a nucleoside compound which, upon administration to a patient, provides the nucleoside compound. Phannaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, among 25 numerous other acids well known in the pharmaceutical art. Pharmaceutically acceptable prodrugs refer to a compound that is metabolized, for example hydrolyzed or oxidized, in the host to form the compound of the present invention. Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, 30 aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to produce the active 54 WO 01/90121 PCT/US0]/16671 compound. The compounds of this invention possess antiviral activity against HCV, or are metabolized to a compound that exhibits such activity. HI. Nucleotide Salt or Prodrug Formulations In cases where compounds are sufficiently basic or acidic to form stable nontoxic 5 acid or base salts, 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 physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, a-ketoglutarate, and a-glycerophosphate. Suitable inorganic salts may also be 10 formed, including, sulfate, nitrate, bicarbonate, and carbonate salts. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts 15 of carboxylic acids can also be made. 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 nucleotide prodrug ligands are known. In general, alkylation, acylation or other lipophilic modification of the mono, di or triphosphate of the nuclcoside 20 will increase the stability of the nucleotide. Examples of substituent groups that can replace one or more hydrogens on the phosphate moiety are alkyl, aryl, steroids, 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 disclosed nucleosides to achieve a desired effect. 25 The active nucleoside can also be provided as a 5'-phosphoether lipid or a 5'-ether lipid, as disclosed in the following references, which are incorporated by reference herein: Kucora, L.S., N. Iyer, E. Leake, A. Raben, Modest E.K., D.L.W., and C. Piantadosi. 1990. "Novel membrane-interactive ether lipid analogs that inhibit infectious HIV-1 production and induce defective virus formation." AIDS Ras. Hum. Retro Viruses. 6:491-501; 30 Piantadosi, C., J. Marasco C.J., S.L. Morris-Natschke, K.L. Meyer, F. Gumus, J.R. Surles, 55 WO 01/90121 PCT/USUI/16671 K.S. Ishaq, L.S. Kucera, N. Iyer, C.A. Wallen, S. Piantadosi, and EJ. Modest. 1991. "Synthesis and evaluation of novel ether lipid nucleoside conjugates for anti-HIV activity." J Med. Chem. 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. 1992. "Greatly enhanced inhibition 5 of human immunodeficiency virus type 1 replication in CEM and HT4-6C cells by 3' deoxythymidine diphosphate dimyristoylglycerol, a lipid prodrug of 3,-deoxythymidine." Antitnicrob. Agents Chenother. 36:2025.2029; Hosetler, K.Y., L.M, Stuhmiller, H.B. Lenfing, H. van den Bosch, and D.D. Richman, 1990. "Synthesis and antiretroviral activity of phospholipid analogs of azidothymidine and other antiviral nucleosides." J Biol. Chem. 10 265:61127. Nonlimiting examples of U.S. patents that disclose suitable lipophilic substituents that can be covalently incorporated into the nuoleoside, preferably at the 5'-OH position of the nucleoside or lipophilic preparations, include U.S. Patent Nos. 5,149,794 (Sep. 22, 1992, Yatvin et at.); 5,194,654 (Mar. 16, 1993, Hostetler et al., 5,223,263 (June 29, 1993, 15 Hostetler et al); 5,256,641 (Oct. 26, 1993, Yatvin et al.); 5,411,947 (May 2, 1995, Hostetler et al.); 5,463,092 (Oct. 31, 1995, Hostetler et al.); 5,543,389 (Aug. 6, 1996, Yatvin et al); 5,543,390 (Aug. 6, 1996, Yatvin et al.); 5,543,391 (Aug. 6, 1996, Yatvin et al); and 5,554,728 (Sep. 10, 1996; Basava et al.), all of which are incorporated herein by reference. Foreign patent applications that disclose lipophilic substituents that can be attached to the 20 nucleosides of the present invention, or 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. IV. Combination and Alternation Therapy It has been recognized that drug-resistant variants of HCV can emerge after 25 prolonged treatment with an antiviral agent. Drug resistance most typically occurs by mutation of a gene that encodes for an enzyme used in viral replication, The efficacy of a drug against HCV infection can be prolonged, augmented, or restored by administering the compound in combination or alternation with a second, and perhaps third, antiviral compound that induces a different mutation from that caused by the principle drug. 30 Alternatively, the pharmacokinetics, biodistribution or other parameter of the drug can be altered by such combination or alternation therapy. In general, combination therapy is 56 WO 01/90121 PCT/USO1/16671 typically preferred over alternation therapy because it induces multiple simultaneous stresses on the virus. Nonlimiting examples of antiviral agents that can be used in combination with the compounds disclosed herein include: 5 (1) an interferon and/or ribavirin (Battaglia, A.M. et al., Ann. Pharmacother. 34:487 494, 2000); Berenguer, M. et al. Antivir. 3(Suppl. 3):125-136, 1998); (2) Substrate-based NS3 protease inhibitors (Attwood et al., Antiviral peptide derivatives, PCT WO 98/22496, 1998; Attwood et al., Antiviral Chemistry and Chemotherapy 10.259-273, 1999; Attwood et al., Preparation and use of amino acid 10 derivatives as anti-viral agents, German Patent Publication DE 19914474; Tung et al. Inhibitors of serine proteases, particularly hepatitis C virus N1S3 protease, PCT WO 98/17679), including alphaketoamides and hydrazinoureas, and inhibitors that terminate in an electrophile such as a boronic acid or phosphonate. Llinas-Brunet et al, Hepatitis C inhibitor peptide analogues, PCT WO 99/07734. 15 (3) Non-substrate-based inhibitors such as 2,4,6-trihydroxy-3-nitro-benzamide derivatives(Sudo K. et al., Biochemical and Biophysical Research Communications, 238:643-647, 1997; Sudo K. et at. Antiviral Chemistry and Chemotherapy 9:186, 1998), including RD3-4082 and RD3-4078, the former substituted on the amide with a 14 carbon chain and the latter processing apara-phenoxyphenyl group; 20 (4) Thiazolidine derivatives which show relevant inhibition in a reverse-phase HPLC assay with an NS3/4A fusion protein and NS5A/5B substrate (Sudo K. et al., Antiviral Research 32:9-18, 1996), especially compound RD-1-6250, possessing a fused cinnamoyl moiety substituted with a long alkyl chain, RD4 6205 and RD4 6193; (5) Thiazolidines and benzanilides identified in Kakiuchi N. et al. J. EBS Letters 25 421:217-220; Takeshita N. et al. Analytical Biochemistry 247:242-246, 1997; (6) A phenan-threnequinone possessing activity against -ICV protease in a SDS PAGE and autoradiography assay isolated from the fermentation culture broth of Streptomyces sp., Sch 68631 (Chu M. et al, Tetrahedron Letters 37:7229-7232, 1996), and Sch 351633, isolated from the fungus Penicillium griscofuluum, which demonstrates 30 activity in a scintillation proximity assay (Chu M. et al., Bioorganic and Medicinal Chemistry Letters 9:1949-1952); 57 WO 01/90121 PCT/US01/16671 (7) Selective NS3 inhibitors based on the macromolecule elgin c, isolated from leech (Qasim M.A. et a., Biochemistry 36:1598-1607, 1997); (8) HCV helicase inhibitors (Diana G.D. et al, Compounds, compositions and methods for treatment of hepatitis C, U.S, Patent No. 5,633,358; Diana G.D. et at, 5 Piperidine derivatives, pharmaceutical compositions thereof and their use in the treatment of hepatitis C, PCT WO 97/36554); (9) HCV polymerase inhibitors such as nucleotide analogues, gliotoxin (Ferrari R. et al. Journal of Virology 73:1649-1654, 1999), and the natural product cerulenin (Lohmann V. et al., Virology 249:108-118, 1998); 10 (10) Antisense phosphorothioate oligodeoxynucleotides (S-ODN) complementary to sequence stretches in the 5' non-coding region (NCR) of the HCV (Alt M. et at, Hepatology 22:707-717, 1995), or nucleotides 326-348 comprising the 3' end of the NCR and nucleotides 371-388 located in the core coding region of the IICV RNA (Alt M. et at, Archives of Virology 142:589-599, 1997; Galderisi U. et al, Journal of Cellular Physiology 15 181:251-257, 1999); (11) Inhibitors of IRES-dependent translation (Ikeda N et at, Agent for the prevention and treatment of hepatitis C, Japanese Patent Publication JP-08268890; Kai Y. et al. Prevention and treatment of viral diseases, Japanese Patent Publication JP 10101591); 20 (12) Nuclease-resistant ribozymes. (Maccjak D.J. et al., Hepatology 30 abstract 995, 1999); and (13) Other miscellaneous compounds including 1-amino-alkylcyclohexanes (U.S. Patent No. 6,034,134 to Gold et al,), alkyl lipids (U.S. Patent No. 5,922,757 to Chojkier et al.), vitamin E and other antioxidants (U.S. Patent No. 5,922,757 to Chojkier et al.), 25 squalene, amantadine, bile acids (U.S. Patent No. 5,846,964 to Ozeki et al.), N (phosphonoacetyl)-L-aspartic acid, (U.S. Patent No. 5,830,905 to Diana et al.), benzenedicarboxamides (U.S. Patent No. 5,633,388 to Diana et al,), polyadenylic acid derivatives (U.S. Patent No. 5,496,546 to Wang et al.), 2',3'-dideoxyinosine (U.S. Patent No. 5,026,687 to Yarchoan et al.), and benzimidazoles (U.S. Patent No. 5,891,874 to 30 Colacino et a.). 58 WO 01/90121 PCT/US01/16671 V. Pharmaceutical Comuositions Hosts, including humans, infected with HCV, or a gene fragment thereof, can be treated by administering to the patient an effective amount of the active compound or a pharmaceutically acceptable prodirug or salt thereof in the presence of a pharmaceutically 5 acceptable carrier or diluent. The active materials can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, in liquid or solid form. A preferred dose of the compound for HCV will be in the range from about 1 to 50 mg/kg, preferably 1 to 20 mg/kg, of body weight per day, more generally 0.1 to about 100 10 mg per kilogram body weight of the recipient per day. The effective dosage range of the phannaceutically acceptable salts and prodrugs can be calculated based on the weight of the parent nucleoside to be delivered. If the salt or prodrug exhibits activity in itself, the effective dosage can be estimated as above using the weight of the salt or prodrug, or by other means known to those skilled in the art, 15 The compound is conveniently administered in unit any suitable dosage form, including but not limited to one containing 7 to 3000 mg, preferably 70 to 1400 mg of active ingredient per unit dosage form. A oral dosage of 50-1000 mg is usually convenient. Ideally the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.2 to 70 gM, preferably about 1.0 to 20 10 pM. This may be achieved, for example, by the intravenous injection of a 0.1 to 5% solution of the active ingredient, optionally in saline, or administered as a bolus of the active ingredient. The concentration of active compound in the drug composition will depend on absorption, inactivation and excretion rates of the drug as well as other factors known to 25 those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are 30 exemplary only and are not intended to limit the scope or practice of the claimed composition. The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time. 59 WO 01/90121 PCT/USOI/16671 A preferred mode of administration of the active compound is oral. Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the 5 form of tablets, troches, or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The 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 10 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 dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other 15 materials which modify the physical form of the dosage unit, 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 colorings and flavors. 20 The compound or a pharmaceutically acceptable prodrug or 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 nucleoside compounds. Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following 25 components; a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, 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 the adjustment of tonicity such as sodium 30 chloride or dextrose. The parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. 60 WO 01/90121 PCT/USO1/16671 If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS). In a preferred embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release 5 formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation. 10 Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) are also preferred as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, liposome formulations may be prepared by 15 dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin fihn of dried lipid on the surface of the container. An aqueous solution of the active compound or its monophosphate, diphosphate, and/or triphosphate derivatives is then introduced into the container. The container is then 20 swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension. V. 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 25 alkylating the appropriately modified sugar, followed by glycosylation or glycosylation followed by alkylation of the nucleoside. The following non-limiting embodiments illustrate some general methodology to obtain the nucleosides of the present invention. A. General Synthesis of 1'-C-Branched Nucleosides l'-C-Branched ribonucleosides of the following structure: 61 WO 01/90121 PCT/US01/16671 BASE R10 Ri 8 R .- Xs, R6

R

9 R( wherein BASE is a purine or pyrimidine base as defined herein; R7 and R 9 are independently hydrogen, OR 2 , hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(O)O(alkyl), -C(O)O(lower ailcyl), -O(acyl), -O(lower 5 acyl), -O(alkyl), -O(lower ailcyl), -O(alkenyl), chlorine, bromine, iodine, NO 2 , NHz, -NH(lower alkyl), -NH(acyl), -N(Iower alkyl)2, -N(acyl) 2 ;

R

8 and R 10 are independently H, alkyl (including lower alkyl), chlorine, bromine or iodine; alternatively, R 7 and R?, R7 and R 10 , R 8 and R', or R' and RO can come together to form a pi bond; 10 Ri and R2 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrag); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including 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 15 phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R 1 or R2 is independently H or phosphate; R6 is an alkyl, chloro-, bromo-, fluoro-, or iodo-alkyl (i.e. CF 3 ), alkenyl, or alkynyl (i.e. allyl); and 20 X is 0, S, SO 2 or CH 2 can be prepared by one of the following general methods. 1) Modification from the lactone The key starting material for this process is an appropriately substituted lactone. 25 The lactone can be purchased or can be prepared by any known means including standard epimerization, substitution and cyclization techniques. The lactone can be optionally 62 WO 01/90121 PCTfUS01/16671 protected with a suitable protecting group, preferably 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 protected lactone can then be coupled with a suitable coupling agent, such as an organometallic carbon 5 nucleophile, such as a Grignard reagent, an organolithium, lithiun dialkylcopper or R6 SiMe3 in TBAF with the appropriate non-protic solvent at a suitable temperature, to give the l'-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 10 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 15 Wiley and Sons, Second Edition, 1991. In a particular embodiment, the l'-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 formed ribonucleoside can optionally be protected by methods well known to those skilled in the art, as taught by Greene et aL. Protective 20 Groups in Organic Synthesis. John Wiley and Sons, Second Edition, 1991, and then the 2' OI can be reduced with a suitable reducing agent. Optionally, the 2'-hydroxyl can be activated to facilitate reduction; i.e. via the Barton reduction. 63 WO 01/90121 PCT/USOI/16671 Scheme I HO 0 Optional RIO o 1) R 6 -M R LO O-LG OH OH Protection OR 2

OR

3 2) Optional OR 2 Oe Activation 1) Coupling 2) Optional Deprotection R 1 ASE 1) Optional BASE Protection H

OR

2 2) Optional R Reduction OH OH Optional Deprotection BASE R6 2. Alternative method for the preparation of I'-C-branched nucleosides 5 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, such as alkaline treatment, substitution and coupling techniques, The hexose can be selectively protected to give the appropriate hexa-furanose, as taught by Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994. 10 The 1'-hydroxyl can be optionally activated to a suitable leaving group such as an acyl group or a chloro, bromo, fluoro, iodo via acylation or halogenation, respectively. The optionally activated sugar can then be coupled to the BASE by methods well known to those slduled 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 15 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 with the presence of trimethylsilyltriflate. 64 WO 01/90121 PCT/USO1/16671 The I'-CH 2 -OH, if protected, can be selectively deprotected by methods well known in the art. The resultant primary hydroxyl can be functionalized to yield various C-branched nucleosides. For example, the primary hydroxyl can be reduced to give the methyl, using a suitable reducing agent. Alternatively, the hydroxyl can be activated prior to reduction to 5 facilitate the reaction; i.e. via the Barton reduction. In an alternate embodiment, the primary hydroxyl can be oxidized to the aldehyde, then coupled with a carbon nucleophile, such as a Grignard reagent, an organolithitum, lithium dialkylcopper or R 6 -SiMe 3 in TBAF with the appropriate non-protic solvent at a suitable temperature. In a particular embodiment, the l'-C-branched ribonucleoside is desired. The 10 synthesis of a ribonucleoside is shown in Scheme 2. Alternatively, deoxyribo-nucleoside is desired. To obtain these nucleosides, the formed ribonucleoside can optionally be protected by methods well known to those skilled in the art, as taught by Greene et al. Protective Gimups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then the 2' OH can be reduced with a suitable reducing agent. Optionally, the 2'-hydroxyl can be 15 activated to facilitate reduction; i.e. via the Barton reduction. Scheme 2

OR

4 Alkaline treatment Protection RIO 0 1) Halogenation D-fmactose D-psicose - . - 4 OH 2) Nucleohase gfycosylation R20 OR 3 HO 1) Barton reduction R 1 0 Selective R 1 0 C13 2) Deprotection OH Deprotection Q14 OH OH R 2 0 OR 3

R

2 0 OR 3 In addition, the L-enantiomers corresponding to the compounds of the invention can 20 be prepared following the same general methods (1 or 2), beginning with the corresponding L-sugar or nucleoside L-enantiomer as starting material. 65 WO 01/90121 PCT/USO1/16671 B. General Synthesis of 2'-C-Branched Nucleosides 2'-C-Branched ribonucleosides of the following structure: BASE

R

10

R

6 -X

R

9 R7 wherein BASE is a purine or pyrimidine base as defined herein; 5 R7 and R? are independently hydrogen, OR 2 , hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(O)O(alkyl), -C(O)O(lower alkyl), -O(acyl), -O(lower acyl), -O(alkyl), -O(lower alkyl), -O(alkenyl), chlorine, bromine, iodine, NO 2 , NH 2 , -NH(lower alkyl), -NH(acyl), -N(lower alky1) 2 , -N(acyl) 2 ;

R

10 is H, alkyl (including lower alkyl), chlorine, bromine or iodine; 10 alternatively, R7 and R9, or R! and R 0 can come together to form a pi bond; R' and R2 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfbnyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or 15 more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R or R2 is independently H or phosphate; R6 is an alkyl, chloro-, bromo-, fluoro-, iodo-alkyl (i.e. CF 3 ), alkenyl, or alkynyl (i.e. allyl); 20 and X is 0, S, S2 or CH2 can be prepared by one of the following general methods. 1. Glycosylation of the nucleobase with an appropriately modified sugar 25 The key starting material for this process is an appropriately substituted sugar with a 2'-OH and 2'-H, with the appropriate leaving group (LG), for example an acyl group or a 66 WO 01/90121 PCT/US01/16671 chloro, bromo, fluoro or iodo. The 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 yield the 2'-modified sugar. Possible 5 oxidizing agents are Tones reagent (a mixture of chronic acid and sulfuric acid), Collins's reagent (dipyridine Cr(VI) oxide, Corey's reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, potassium permanganate, MnO 2 , ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate supported on a polymer, Cl 2 pyridine, H 2 0 2 -amonium molybdate, NaBrO 2 -CAN, NaOCI in HOAc, copper chromite, 10 copper oxide, Raney nickel, palladium acetate, Meerwin-Pondorf-Verley reagent (aluminum t-butoxide with another ketone) and N-bromosuccinimide. Then coupling of an organometallic carbon nucleophile, such as a Grignard reagent, an organolithium, lithium dialkylcopper or R 6 -SiMe 3 in TBAF with the ketone with the appropriate non-protic solvent at a suitable temperature, yields the 2'-alkylated sugar. The 15 alkylated sugar can be optionally protected with a suitable protecting group, preferably 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 E dition, 1991. The optionally protected sugar can then be coupled to the BASE by methods well 20 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. Alternatively, a halo-sugar can be coupled to a silylated base with the presence of trinethylsilyltriflate. 25 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 2'-C-branched ribonucleoside is desired. The synthesis of a ribonucleoside is shown in Scheme 3. Alternatively, deoxyribo-nucleoside is 30 desired. To obtain these nucleosides, the formed ribonucleoside 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 then the 2' 67 WO 01/90121 PCT/US01/16671 OH can be reduced with a suitable reducing agent. Optionally, the 2'-hydroxyl can be activated to facilitate reduction; i.e. via the Barton reduction. Scheme 3 OL Ox1idation L 1) R 6 -M Io ROLG OH OH OH o 2) Optional ORZ OR 3 Protection 1) Coupling 2) Optional Deprotection BASE 1) Optional BASE Protection HO OR2 2) Optional OH OH Reduction Optional Deprotection HO OH 5 2. Modification of a pre-formed nucleoside The key starting material for this process is an appropriately substituted nucleoside with a 2'-OH and 2'-H. The nucleoside can be purchased or can be prepared by any known means including standard coupling techniques, The nucleoside can be optionally protected 10 with suitable protecting groups, preferably with 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 yield the 2'-modified 15 sugar. Possible oxidizing agents are Jones reagent (a mixture of chromic acid and sulfuric acid), Collins's reagent (dipyridine Cr(VI) oxide, Corey's reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, potassium permanganate, MnO 2 , 68 WO 01/90121 PCTUSO1/16671 ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate supported on a polymer, C 2 -pyridine, H20 2 -aMMonium molybdate, NaBrO 2 -CAN, NaOCl in HOAc, copper chromite, copper oxide, Raney nickel, palladium acetate, Meerwin Pondorf-Verley reagent (aluminum t-butoxide with another ketone) and N 5 bromosuccinimide. Subsequently, the nucleoside can be deprotected by methods well known to those skilled in the art, as taught by GreeneGreene et at Protective Groups in Organic Synthesis John Wiley and Sons, Second Edition, 1991. In a particular embodiment, the 2'-C-branched ribonucleoside is desired. The 10 synthesis of a ribonucleoside is shown in Scheme 4. Alternatively, deoxyribo-nucleoside is desired. To obtain these nucleosides, the formed ribonucleoside can optionally be protected by methods well known to those skilled in the art, as taught by Greene et at. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then the 2' OH can be reduced with a suitable reducing agent, Optionally, the 2'-hydroxyl can be 15 activated to facilitate reduction; i.e. via the Barton reduction. 69 WO 01/90121 PCT/US0I/16671 Scheme 4 BASE BASE BASE 1) Optional Rio R 10 Protection R 6 -M OH OH 2) Oxidation OR 2 O O Optional Deprotection BASE 1) Optional 3ASE S 0 ProtectionO

OR

2 2) Optional Reduction Optional Deprotection HO_ BASE OH in another embodiment of the invention, the L-enantiomers are desired. 5 Therefore, the L-enantiomers can be corresponding to the compounds of the invention can be prepared following the same foregoing general methods, beginning with the corresponding L-sugar or nucleoside L-enantiomer as starting material. C. General Synthesis of 3'-C-Branched Nucleosides 3'-C-Branched ribonucleosides of the following structure: BASE R O R 10

R

9 R wherein BASE is a purine or pyrimidine base as defined herein; R' and R 9 are independently hydrogen, OR 2 , hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(0)O(alkyl), -C(O)O(lower alkyl), -O(acyl), -O(lower 70 WO 01/90121 PCT/USO1/16671 acyl), -O(alkyl), -O(lower alkyl), -O(alkenyl), chlorine, bromine, iodine, NO 2 , NH 2 , -NH(lower alkyl), -NH(acyl), -N(lower alkyl) 2 , -N(acyl)2;

R

8 is H, alkyl (including lower alkyl), chlorine, bromine or iodine; alternatively, R and R 9 , or R 8 and R9 can come together to form a pi bond; 5 R' and R 2 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methauesulfonyl and beuzyl, 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 10 phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 or R 2 is independently H or phosphate; Ri is an alkyl, chloro-, fluoro-, bromo-, iodo-alkyl (i.e. CF 3 ), alkenyl, or alkynyl (i.e. allyl); and 15 X is 0, S, SO 2 or CH2 can be prepared by one of the following general methods. 1 Glycosylation of the nucleobase with an appropriately modified sugar The key starting material for this process is an appropriately substituted sugar 20 with a 3'-OH and 3'-H, with the appropriate leaving group (LG), for example an acyl group or a chloro, bromo, fluoro, iodo. The 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 25 yield the 3'-modified sugar. Possible oxidizing agents are Jones reagent (a mixture of chromic acid and sulfuric acid), Collins's reagent (dipyridine Cr(VI) oxide, Corey's reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, potassium permanganate, MnO 2 , ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate supported on a polymer, C1 2 71 WO 01/90121 PCT/US01/16671 pyridine, H 2 0 2 -ammonium molybdate, NaBrO 2 -CAN, NaOCI in HOAc, copper chromite, copper oxide, Raney nickel, palladium acetate, Meerwin-Pondorf-Verley reagent (aluminum t-butoxide with another ketone) and N-bromosuccinimide. Then coupling of an organometallic carbon nucleophile, such as a Grignard 5 reagent, an organolithium, lithium dialkylcopper or R 6 -SiMe 3 in TBAF with the ketone with the appropriate non-protic solvent at a suitable temperature, yields the 3'-C-branched sugar. The 3'-C-branched sugar can be optionally protected with a suitable protecting group, preferably 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 10 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 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 15 tetrachloride or trimethylsilyltriflate in the appropriate solvent at a suitable temperature. Alternatively, a halo-sugar can be coupled to a silylated base with 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 20 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 formed ribonucleoside can optionally be protected by methods well known to those skilled in the art, as taught 25 by Greene et aL Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then the 2'-OH can be reduced with a suitable reducing agent. Optionally, the 2'-hydroxyl can be activated to facilitate reduction; i.e. via the Barton reduction. 72 WO 01/90121 PCTUSO1I/16671 Scheme 5 Ho 1) Optional R'O 1RO 1 C L Protection l 1) R-M VL HO OH 2) Oxidation o OR 3 2) Optional OR 2 ORG Protection 1) Coupling 2) Optional Deprotection Ri 6 SE 1) Optional HO 6 ASE R6 Protection i -0 -- -- -- --- OR2 2) Optional OH oH Reduction Optional Deprotection HO 6 A OH 2. Modification of apre-formed nucleoside 5 The key starting material for this process is an appropriately substituted nucleoside 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 be optionally protected with suitable protecting groups, preferably with acyl or silyl groups, by methods well known to those skilled in the art, as taught 10 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 yield the 2'-modified sugar. Possible oxidizing agents are Jones reagent (a mixture of 15 chronic acid and sulfuric acid), Collins's reagent (dipyridine Cr(VI) oxide, Corey's reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, potassium permanganate, MnO 2 , ruthenium tetroxide, phase transfer catalysts such 73 WO 01/90121 PCT[USO1/16671 as chromic acid or permanganate supported on a polymer, C1 2 -pyridine, H202 ammonium molybdate, NaBrO 2 -CAN, NaOCI in HOAc, copper chromite, copper oxide, Raney nickel, palladium acetate, Meerwin-Pondorf-Verley reagent (aluminum t-butoxide with another ketone) and N-bromosuccinimide. 5 Subsequently, the nucleoside can be deprotected by methods well known to those skilled in the art, as taught by GreeneGreene 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 10 nucleoside is desired. To obtain these nucleosides, the formed ribonucleoside 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 then the 2'-OH can be reduced with a suitable reducing agent. Optionally, the 2'-hydroxyl can be activated to facilitate reduction; i.e. via the 15 Barton reduction. Scheme 6 BASE MASE AsE HO,( BS 1) Optional R'O 6A'S R'o R' S Protection o R-M 0 Ho 2) Oxidation 0 R 3 H OR 3 Optional Deprotection R 6 ASB 1) Optional HO B ASE R _o0 1)Protection O 0 -* ---- oR2 2) Optional OH OH Reduction Optional Deprotection Ho ASB OH 74 WO 01/90121 PCT/USOI/16671 In another embodiment of the invention, the L-enantiomers are desired. Therefore, the L-enantiomers can be corresponding to the compounds of the invention can be prepared following the same foregoing general methods, beginning with the corresponding L-sugar or nucleoside L-enantiomer as starting material. 5 Examples Example 1: Preparation of 1'-C-methvlriboadenine via 6-amino-9-(1-deoxy-sD psicofuranosyllpurine As another alternative method of preparation, the title compound could also be prepared according to a published procedure (I. Farkas, and F. Sorm, "Nucleic acid 10 components and their analogues. XCIV. Synthesis of 6-amino-9-(1-deoxy--D psicofuranosyl)purine", Collect. Czech. Chem. Commun. 1967, 2, 2663-2667. J. Farkas", Collect. Czech. Chem. Commun. 1966, 31 1535) (Scheme 7), Scheme 7 0

NH

</ N Br 6-Benzamidopurine NlN( i p--ToIO Br chloromercuri salt p-ToO 0 Br Br p-ToIO Op-Tol p-ToO Op-Tol 1) BuSnH, A1BN

NH

2 2) (MeO) 2 Ba / MeOH N no 'N2 HO CH3 OH OH 15 In a similar manner, but using the appropriate sugar and pyrimidine or purine bases, the following nucleosides of Formula I are prepared. 75 WO 01/90121 PCT/US01/16671 y N N X RIO 0 CH3 oi9 OR 3 (I) wherein: R R2 R3 X1 X2 y H H H H H H H H H H H NH 2 H H H H H NH-cyclopropyl H H H H H NH-methyl H H H H H NH-ethyl H H H H H NH-acetyl H H H H H OH H H H H H OMe H H H H H OEt H H H H H O-cyclopropyl H H H H H O-acetyl H H H H H SH H H H H H SMe H H H H H SEt H H H H H S-cyclopropyl H H II H H F H H H H II Cl H H H H H Br H H H H H I monophosphate H H H H NH2 monophosphate H H H H NH-acetyl monophosphate H H H H NH-cyclopropyl 76 WO 01/90121 PCT[US01/16671 RR R X X2 y monophosphate H H H H NH-methyl monophosphate H H H H NH-ethyl monophosphate H H H H OH monophosphate H H H H 0-acetyl monophosphate H H H H OMe monophosphate H H H H OEt monophosphate H H H H O-cyclopropyl monophosphate H H H H SH monophosphate H H H H SMe monophosphate H H H H SEt monophosphate H H H H 8-cyclopropyl monophosphate H H H H F monophosphate H H H H CI monophosphate H H H H Br monophosphate H H H H I diphosphate H H H H NH2 diphosphate H H H H NH-acetyl diphosphate H H H H NH-cyclopropyl diphosphate H H H H NH-methyl diphosphate H H H H NH-ethyl diphosphate H H H H OH diphosphate H H H H 0-acetyl diphosphate H H H H OMe diphosphate H H H H OEt diphosphate H H H H O-cyclopropyl diphosphate H H H H SH diphosphate H H H H SMe diphosphate H H H H SEt diphosphate H H H H S-cyclopropyl diphosphate H H H H F diphosphate H H H H Cl 77 WO 01/90121 PCT/US01/16671 Rf 2 R X 0 X2 diphosphate H H H H Br diphosphate H H H H I triphosphate H H H H NH2 triphosphate H H H H NH-acetyl triphosphate H H H H NH-cyclopropyl triphosphate H I H H NH-methyl triphosphate H H H H NH-ethyl triphosphate H H H H OH triphosphate H H H H OMe triphosphate H H H H OR triphosphate H H H H 0-cyclopropyl triphosphate H H H H O-acetyl triphosphate H H H H SH triphosphate H H H H SMe triphosphato H H H H SEt triphosphate H H H H S-cyclopropyl triphosphate H H H H F triphosphate H H H H Cl triphosphate H H H H Br triphosphate H H H H I monophosphate monophosphate monophosphate H H NH2 monophosphate monophosphate monophosphate H H NH-cyclopropyl monophosphate monophosphate monophosphate H H OHf monophosphate monophosphate monophosphate H H F monophosphate monophosphate monophosphate H H Cl diphosphate diphosphate diphosphate H H NH2 diphosphate diphosphate diphosphate H H NH-cyclopropyl diphosphate diphosphate diphosphate H H OH diphosphate diphosphate diphosphate H H F diphosphate diphosphate diphosphate H H Cl triphosphate triphosphate triphosphate H H NH2 78 WO 01/90121 PCTIUSO1/16671 Rt R2R X X Y triphosphate triphosphate triphosphate H H NH-cyclopropyl triphosphate triphosphate triphosphate H H OH triphosphate triphosphate triphosphate H H F triphosphate triphosphate triphosphate H H Cl H H H F H NH 2 H H H F H NH-cyclopropyl H H H F H OH H H H F H F H H H F H Cl H H H Cl H NH 2 H H H Cl H NH-cyclopropyl H H H Cl H OH H H H Cl H F H H H Cl H Cl II H H BT H NH2 H H H Br H NH-cyclopropyl H H H Br H OH H H H Br H F H H H Br H Cl H H H NH 2 H NH2 H H H NH2 H NH-cyclopropyl H H H NH 2 H OH H H H NH 2 H F H H H NH2 H Cl H H H SIT H NH 2 H H H SH H NH-cyclopropyl H H H SI H OH H H H SH H F H H H SH H Cl acetyl H H H NH 2 acetyl H H H H NH-cyclopropyl 79 WO 01/90121 PCT/USU1/16671 acetyl HHH H OH acetyl H H H H F acetyl H H H H Cl acetyl H H F H NH2 acetyl H H F H NH-cyclopropyl a etyl H H F H OH acetyl H H F H F acetyl H H F H C1 H acetyl acetyl H H NH2 H acetyl acetyl H H NH-cyclopropyl H acetyl acetyl H H OH H acetyl acetyl H H F H acetyl acetyl H H Cl acetyl acetyl acetyl H H NH 2 acetyl acetyl acetyl H H NH-cyclopropyl acetyl acetyl acetyl H I OH acetyl acetyl acetyl H H F acetyl acetyl acetyl H H CI monophosphate acetyl acetyl H H NH 2 monophosphate acetyl acetyl H H NH-cyclopropyl monophosphate acetyl acetyl H H OH monophosphate acetyl acetyl H H F monophosphate acetyl acetyl H H Cl diphosphate acetyl acetyl H H NH2 diphosphate acetyl acetyl H H NH-cyclopropyl diphosphate acetyl acetyl H H OH diphosphate acetyl acetyl H H F diphosphate acetyl acetyl H H Cl triphosphate acetyl acetyl H H NH2 triphosphate acetyl acetyl H H NH-cyclopropyl triphosphate acetyl acetyl H H OH 80 WO 01/90121 PCT/US01/16671 RR RVX X2 y triphosphate acetyl acetyl H H F triphosphate acetyl acetyl H H Cl H H H H NH 2 H H H H H NH2 NH 2 H H H H NH 2 NH-cyclopropyl H H H H NH2 NH-methyl H H H H NH 2 NH-ethyl H H H H NH 2 NH-acetyl H H H H NH 2 OH H H H H NH 2 OMe H H H H NH 2 OEt H H H H NH 2 0-cyclopropyl H H H H NH 2 0-acetyl H H H H NH 2 SH H H H H NH 2 SMe H H H H NH2 SEt H H H H NH2 S-cyclopropyl H H H H NH 2 F H H H H NH 2 Cl H H H H NH 2 Br H H H H NH 2 I monophosphato H H H NH 2 NH2 monophosphate H H H NH 2 NH-acetyl monophosphate H H H NH2 NH-cyclopropyl monophosphate H H H NH 2 NH-methyl monophosphate H H H NH 2 NH-ethyl monophosphate H H H NH2 OH monophosphate H H H NH 2 O-acetyl monophosphate H H H NH2 OMe monophosphate H H H NH 2 OEt monophosphate H H H NHT 2 0-cyclopropyl 81 WO 01/90121 PCTfUS01/16671 monophosphate H H H NH 2 SH monophosphate H H H NH 2 SMe monophosphate H H H NH 2 SEt monophosphate H H H NH 2 S-cyclopropyl monophosphate H H H NH 2 F monophosphate H H H NH 2 Cl monophosphate H H H NH 2 Br monophosphate H H H NH 2 I diphosphate H H HI NH 2

NH

2 diphosphate H H H NH 2 NH-acetyl diphosphate H H H NH2 NH-cyclopropyl diphosphate H H H NH 2 NH-methyl diphosphate H H H NH 2 NH.-ethyl diphosphate H H H NH2 OH diphosphate H H H NH2 0-acetyl diphosphate H H H NH 2 OMe diphosphate H H H NiH 2 OEt diphosphate H H H NH 2 0-cyclopropyl diphosphate H H H NH2 SH diphosphate H H H NH 2 SMe diphosphate H H H NH 2 SEt diphosphate H H H NH 2 S-cyclopropyl diphosphate H H H NH 2 F diphosphate H H H NH 2 Cl diphosphate H H H NH2 Br diphosphate H H H NH 2 I triphosphate H H H NH 2

NH

2 triphosphate H H H NH 2 NH-acetyl triphosphate H H H NH 2 NH-cyclopropyl triphosphate H H H NH 2 NH-methyl triphosphate H H H NH 2 NH-ethyl 82 WO 01/90121 PCT/US1I/16671 R 2 R Y triphosphate H H H NH2 OH triphosphate H H H NH 2 OMe triphosphate H H H NH2 OEt triphosphate H H H Nit O-cyclopropyl triphosphate H H H NH 2 0-acetyl triphosphate H H H NH2 SH triphosphate H H H NH 2 SMe triphosphate H H H NH 2 SEt triphosphate H H H NH 2 S-cyclopropyl triphosphate H H H NH 2 F trphosphate H H H NH2 Cl triphosphate H H H NH2 Br triphosphate H H H NH 2 I monophosphate monophosphate monophosphate H NH 2

NH

2 monophosphate monophosphate monophosphate H NH2 NH-cyclopropyl monophosphate monophosphate monophosphate H NH 2 OH monophosphate monophosphate monophosphate H NH 2 F monophosphate nonophosphate monophosphate H NH 2 Cl diphosphate diphosphate diphosphate H NH 2

NH

2 diphosphate diphosphate diphosphate H NH 2 NH-cyclopropyl diphosphate diphosphate diphosphate Hl NHI 2 OH diphosphate diphosphate diphosphate H NH 2 F diphosphate diphosphate diphosphate H NH 2 Cl triphosphate triphosphate triphosphate H NH 2

NH

2 triphosphate triphosphate triphosphate H NH 2 NH-cyclopropyl triphosphate triphosphate triphosphate H NH 2 OH triphosphate triphosphate triphosphate H NH 2 F triphosphate triphosphate triphosphate H NH 2 Cl H H H F NH 2

NH

2 H H H F NH 2 NH-cyclopropyl H H H F NH 2 OH 83 WO 01/90121 PCT/US01/16671 R2R X1 :Xe Y H H H F NH 2 F H H H F NH 2 Cl H H H Cl NH2 NH 2 H H H Cl NH 2 NH- cyclopropyl H H H Cl NH2 OH H H H Cl NH2 F H H H Cl NH 2 Cl H H Br NH2 NH2 H H H Br NH2 NH-cyclopropyl H H H Br NH 2 OH H H H Br NH2 F H H H Br NH 2 Cl H H H NH2 NH2 NH2 H NH 2

NH

2 NH-cyclopropyl H I H NH2 NH 2 OH H H H NH2 NH 2 F H H H NH2 NH2 Cl H H H SH Ni NH2 HH H SH NH 2 NH-cyclopropyl H HSH NH 2 OH H H H SH NH2 F H H H SH NH2 C1 acetyl H H H NH2 NH2 acetyl H H H NH2 NH-cyclopiopyl acotyl H H H NH2 OH acetyl H H H NH2 F acetyl H H H NH2 C1 acetyl H H F NHz NHz acetyl H H F NH 2 NH-cyclopropyl acetyl H H F NH2 OH acetyl H H F NHz F 84 WO 01/90121 PCT/US01/16671 RZ"x x, y acety H HF Ni2 Cl H acetyl acetyl H NH 2

NH

2 acetyl acetyl H NH 2 NH-cyclopropyl acetyl acetyl H NH 2 OH acetyl acetyl H NH2 F acetyl acetyl H NH 2 Cl acetyl acetyl H NN2 NH 2 acetyl acetyl acetyl H NH 2 NH-cyclopropyl acetyl acetyl acetyl H NH 2 OH acetyl acetyl acetyl H NH 2 F acetyl acetyl acetyl H Ni2 Cl monophosphate acetyl acetyl H NH 2

NH

2 monophosphate acetyl acetyl H NH 2 NH-cyclopropyl monophosphate acetyl acetyl H NH 2 OH monophosphate acetyl acetyl H NH 2 F monophosphate acetyl acetyl H NHz Cl diphosphate acetyl acetyl H NH 2

NH

2 dphosphate acetyl acetyl H NH 2 NH-cyclopropyl diphosphate acetyl acetyl H NH 2 OH diphosphate acetyl acetyl H NH 2 F diphosphate acetyl acetyl H NH 2 Cl triphosphate acetyl acetyl H NH 2

NH

2 triphosphate acetyl acetyl H NH 2 NH-cyclopropyl triphosphate acetyl acetyl H NH 2 OH triphosphate acetyl acetyl H NHz F triphosphate acetyl acetyl H NH 2 Cl NHH Cl H H H H H Cl H SH HH Cl NH2 H H Cl NH-cyclopropyl H H H H Cl NH-methyl 85 WO 01/90121 PCT/USO1/16671 Rw 2 RX X 2 y H H H H Cl NH-ethyl H H H H Cl NH-acetyl H H H H C1 OH H H H H Cl OMe H H H H Cl OEt H H H H C1 0-cyclopropy1 H H H H C1 0-acetyl H H H H Cl SH H H H H Cl SMe H H H H Cl SEt H H H H Cl S-cyclopropyl monophosphate H H H Cl NH 2 monophosphate H H H Cl NH-acetyl monophosphate H H H Cl NH-cyclopropyl monophosphate H H H Cl NH-methyl monophosphate H H H Cl NH-ethyl monophosphate H H H Cl OH monophosphate H H H Cl 0-acetyl monophosphate H H H Cl OMe monophosphate H H H Cl OEt monophosphate H H H Cl 0-cyclopropyl monophosphate H H H Cl SH monophosphate H H H Cl SMe monophosphate H H H Cl SEt monophosphate H H H Cl S-cyclopropyl diphosphate H H H Cl NH 2 diphosphate H H H Cl NH-acetyl diphosphate H H H Cl NH-cyclopropyl diphosphate H H H Cl NH-methyl diphosphate H H H Cl NH-ethyl diphosphate H H H Cl OH 86 WO 01/90121 PCT/USOI/16671 diphosphate H H H Cl 0-acetyl diphosphate H H H Cl OMe diphosphate H H H C1 OEt diphosphate H H H CI 0-cyclopropyl diphosphate H H H Cl SH diphosphate H H H Cl SMe diphosphate H H H Cl SEt diphosphate H H H Cl S-cyclopropyl triphosphate H H H Cl NH2 triphosphate H1 H H Cl NH-acetyl triphosphate H H H Cl NH-cyclopropyl triphosphate H H H Cl NH-methyl triphosphate H H H Cl NH-ethyl triphosphate H H H Cl OH triphosphate H H H Cl OMe triphosphate H H H Cl OEt triphosphate H H H C1 0-cyclopropyl triphosphate H H H C1 0-acetyl triphosphate H H H C1 SH triphosphate H H H C1 SMe triphosphato H H H Cl SEt triphosphate l H H Cl S-cyclopropyl monophosphate monophosphate monophosphate H Cl NH2 monophosphate. monophosphate nionophosphate H Cl NH-cyclopropyl monophosphate monophosphate monophosphate H Cl OH diphosphate diphosphate diphosphate H Cl NH 2 diphosphate diphosphate diphosphate H1 Cl NH-cyclopropyl diphosphate diphosphate diphosphate H Cl OH triphosphate triphosphate triphosphate H Cl NH 2 triphosphate triphosphate triphosphate H Cl NH-cyclopropyl triphosphate triphosphate triphosphate H Cl OH 87 WO 01/90121 PCT/US01/16671 i R2 iR 3 X X2 y H H H F Cl NH2 H H H F Cl NH-cyclopropyl H H H F Cl OH H H H C1 Cl NH 2 H H H Cl C1 NH-cyclopropyl H H H Cl Cl OH H H H Br C1 NH 2 H H H Br C1 NH-cyclopropyl H H H Br Cl OH H H H NH 2 Cl NH2 H H H NH2 Cl NH-cyclopropyl H H H NH 2 Cl OH H H H SH Cl NH2 H H H SH Cl NH-cyclopropyl H H H SH Cl OH acetyl H H H Cl NH2 acetyl H H H Cl NH-cyclopropyl acetyl H H H Cl OH acetyl H H F Cl NH2 acetyl H H F Cl NH-cyclopropyl acetyl H II F Cl OH H acetyl acetyl H Cl NH 2 H acetyl acetyl H Cl NH-cyclopropyl H acetyl acetyl H C1 OH acetyl acetyl acetyl H Cl NH2 acetyl acetyl acetyl H Cl NH-cyclopropyl acetyl acetyl acetyl H Cl OH monophosphate acetyl acetyl H Cl NH2 monophosphate acetyl acetyl H Cl NH-cyclopropyl monophosphate acetyl acetyl H Cl OH diphosphate acetyl acetyl H Cl NH 2 88 WO 01/90121 PCTrUSO1/16671 R RX- X Y diphosphate acetyl acetyl H Cl NH-cyclopropyl diphosphate acetyl acetyl H C1 OH triphosphate acetyl acetyl H C NH 2 triphospbate acetyl acetyl H Cl NH-cyclopropyl triphosphate acetyl acetyl H C1 OH H H H H Cl NH2 H H H H Cl NH-cyclopropyl H H H H Cl OH H H H H Br NH2 H H H H Br NH-cyclopropyl H H H H Br OH Alternatively, the following nucleosides of Formula IV are prepared, using the appropriate sugar and pyrimidine or purine bases. y x1 NX N R 2O CHa OR2 OR 5 (IV) wherein: X Y H H H H H H H H H NH 2 H H H H NH-cyclopropy H H H H NH-methyl H H H H NH-ethyl H H H I NH-acetyl 89 WO 01190121 FCTUSO1I/16671 R R R X1 Y H H H H OH H H H H OMe H H H H OEt H H H H 0-cyclopropyl H H H H O-acetyl H4 H H H SH H H H H SMe H H H H SEt H H H H S-cyclopropyl monophosphate H H H NH 2 monophosphate H H H NH-acetyl monophosphate H H H NHl-cyclopropyl monophosphate H H H NiH-methyl monophosphate H H H NH-ethyl monophosphate H H H OH monophosphate H H H O-acetyl monophosphate H H H OMe monophosphate H H H O~t monophosphate H H H 0-cyclopropyl monophosphate H H H SH monophosphate H H H SMe monophosphate H H H SEt monophosphate H H H S-cyclopropyl diphosphate H H H NH 2 diphosphate H H H NH-acetyl diphosphate H H H NH-cyclopropyl diphosphate H H H NH-methyl diphosphate H H H NH-ethyl diphosphate H H H OH diphosphate H H H O-acetyl diphosphate H H H OMe 90 WO 01/90121 PCT/US01/16671 R R Y diphosphate H H H OEt diphosphate H H H 0-cyclopropyl diphosphate H H H SH diphosphate H H H SMe diphosphate H H H SEt diphosphate H H H S-cyclopropyl triphosphate H H H NH 2 triphosphate H H H NH-acetyl triphosphate H H H NH-cyclopropy triphosphate H H H Ni-methyl triphosphate H H H N-ethyl triphosphate H H H OH triphosphate H H H OMe triphosphate H H H Ot triphosphate H H H O-cyclopropyl triphosphate H H H 0-acetyl triphosphate H H H SH triphosphate H H H SMe triphosphate H H H SEt triphosphate H H H S-cyclopropyl monophosphate mionophosphate monophosphate H NH 2 monophosphate monophosphate monophosphate H NH-cyclopropyl monophosphate monophosphate monophosphate H OH diphosphate diphosphate diphosphate H NH2 diphosphate diphosphate diphosphate H NH-cyclopropyl diphosphate diphosphate diphosphate H OH triphosphate triphosphate triphosphate H NH 2 triphosphate triphosphate triphosphate H NH-cyclopropyl triphosphate triphosphate triphosphate H OH H H H F NH 2 H H H F NH-cyclopropyl 91 WO 01/90121 PCT/US01/16671 | I R12 Ra X Y H H H F OH H H H Cl NH2 H H H Cl NH-cyclopropyl H H H C1 OH H H H Br NH 2 H H H Br NH-cyclopropyl H1 H H Br OH H H H NH 2 NH2 H H H NH 2 NH-cyclopropyl H H H NH 2 OH H H H SH NH 2 H H H SH NH-cyclopropyl H H H SH OH acetyl H H H NH2 acetyl H H H NH-cyclopropyl acetyl H H H OH acetyl H H F NH2 acetyl H H F NH-cyclopropyl acetyl H1 H F OH H acetyl acetyl H NH 2 H acetyl acetyl H NH-cyclopropyl H acetyl acetyl H OH acetyl acetyl acetyl H NH2 acetyl acetyl acetyl H NH-cyclopropyl acetyl acetyl acetyl H OH monophosphate acetyl acetyl H NH 2 monophosphate acetyl acetyl H NH-cyclopropyl monophosphate acetyl acetyl H OH diphosphate acetyl acetyl H NH2 diphosphate acetyl acetyl H NH-cyclopropyl diphosphate acetyl acetyl H OH 92 WO 01/90121 PCT[USOI/16671 triphosphate acetyl acetyl H Ni2 triphosphate acetyl acetyl H NH-cyclopropyl triphosphate acetyl acetyl H OH Alternatively, the following nucleosides of Formula VU are prepared, using the appropriate sugar and pyrimidine or purine bases. Base RIO x OR 5 (VII) wherein: RR X Base H H H CH 3 0 2,4-0 Diacetyluracil H H H CH3 0 Hypoxanthine H H H CH 3 0 2,4-0 Diacetyithymine H H H CH3 0 Thymine H H H CH 3 0 Cytosine H H H CH 3 0 4-(N-mono acetyl)cytosine H H H CH 3 0 4-(N,N diacetyl)cytosine H H H CH 3 0 Uracil H H H CH 3 0 5-Fluorouracil H H H CH 3 S 2,4-0 Diacetyluraci H H H CH 3 S Hypoxanthine 93 WO 01/90121 PCT/USO1/16671 RR R' X Base H H H C113 S 2,4-0 Diacetylthymine H H H CH3 S Thymine H H H CH3 S Cytosine H H H CH3 S 4-(N-mono acetyl)cytosine H H H CH3 S 4-(NN diacetyl)cytosine H H H CH3 S, Uracil H H H CH 3 S 5-Fluorouracil monophosphate H H CH3 0 2,4-0 Diacetyluracil monqphosphate H H CH 3 0 Hypoxanthine monophosphate H H CH3 O 2,4-0 Diacetylthym monophosphate H H CH3 O Thymine monophosphate H H CH 3 0 Cytosine monophosphate H H CH 3 0 4-(N-mono acetyl)cytosine monophosphate H H CH3 0 4-(NN diacetyl)cytosine monophosphate H H CH 3 0 Uracil monophosphate H H CH3 0 5-Fluorouracil monophosphate H H CH3 S 2,4-0 Diacetyluracil monophosphate H H CH 3 S Hypoxanthine monophosphate H H CH 3 S 2,4-0 Diacetylthym monophosphate H H C3 S Thymine monophosphate H H CH3 S Cytosine monophosphate H H CH3 S 4-(N-mono acetyl)cytosine 94 WO 01/90121 PCT/US01/16671 RR RRwX Base monophosphate H H CH 3 S 4-(NN diacetyl)cytosine monophosphate H H CH 3 S Uracil monophosphate H H CH 3 S 5-Fluorouracil diphosphate H H CH 3 0 2,4-0 Diacetyluracil diphosphate H H CH 3 0 Hypoxanthine diphosphate H H CH3 0 2,4-0 Diacetyithymine diphosphate H H CH 3 0 Thymine diphosphate H H CH 3 0 Cytosine diphosphate U H CH3 0 4-(N-mono acetyl)cytosine diphosphate H H CH 3 0 4-(NN diacetyl)cytosine diphosphate H H CH 3 0 Uracil diphosphate H H CH 3 0 5-Fluorouracil diphosphate N H CH3 S 2,4-0 Diacetyluracil diphosphate H H CH3 S Hypoxanthine diphosphate H H CH 3 S 2,4-0 Diacetylthym diphosphate H H CH 3 S Thymine diphosphate H H CH 3 S Cytosine triphosphate 1 H CH 3 0 2,4-0 Diacetyluracil triphosphate H H CH 3 0 Hypoxanthine triphosphate H H CH 0 2,4-0 Diacetylthymine triphosphate 1- H CH3 0 Thymine triphosphate H H Cit 0 Cytosine 95 WO 01/90121 PCTfUS01/16671 RR R X Base triphosphate H H CH3 0 4-(N-mono acetyl)cytosine triphosphate H H CH3 0 4-(N,N diacetyl)cytosine triphosphate H H CH 3 0 Uracil triphosphate H H CH 3 0 5-Fluorouracil triphosphate i H CH 3 S 2,4-0 Diacetyluracil triphosphate H H CH S Hypoxanthine triphosphate H H CH 3 S 2,4-0 Diacetylthymine triphosphate H H CH 3 S Thynine triphosphate H H CH 3 S Cytosine monophosphate monophosphate monophosphate CF3 0 2,4-0 Diacetyluracil monophosphate monophosphate monophosphate CF 3 0 Hypoxanthine monophosphate monophosphate monophosphate CF 3 0 2,4-0 Diacetylthymine monophosphate monophosphate monophosphate CF 3 0 Thymine monophosphate monophosphate monophosphate CF 3 0 Cytosine monophosphate monophosphate monophosphate CF 3 0 4-(N-mono acetyl)cytosine monophosphate monophosphate monophosphate CF 3 0 4-(NN diacetyl)cytosine monophosphate monophosphate monophosphate CF 3 0 Uracil monophosphate monophosphate monophosphate CF 3 0 5-Fluorouracil monophosphate monophosphate monophosphate CF 3 S 2,4-0 Diacetyluracil monophosphate monophosphate monophosphate CF 3 S Hypoxanthine monophosphate monophosphate monophosphate CF 3 S 2,4-0 Diacetyithymine monophosphate monophosphate monophosphate CF 3 S Thymine 96 WO 01/90121 PCT/USO1/16671 R1 RR' X Base monophosphate monophosphate monophosphate CF 3 S Cytosine monophosphate mionophosphate monophosphate CF 3 S 4-(N-mono acetyl)cytosine monophosphate monophosphate monophosphate CF 3 S 4-(NN diacetyl)cytosine monophosphate ionophosphate monophosphate CF 3 S Uracil monophosphate monophosphate monophosphate CF 3 S 5-Fluorouracil acetyl acetyl acetyl CF 3 0 4-(NN diacetyl)cytosinc acetyl acetyl acetyl CF 3 S 4-(NN diacetyl)cytosine acetyl acetyl acetyl 2-bromo- 0 4-(NN vinyl diacetyl)cytosine acetyl acetyl acetyl 2-bromo- S 4-(NN vinyl diacetyl)cytosine H H CH 3 0 2-(N,N-diacetyl) guanine H H H CH3 0 6-0-acetyl guanine SH CH3 0 8-fluoroguanine H H H CH3 0 guanine SH CH3 0 6-(N,N-diacetyl) adenine H H H CH 3 0 2-fluoroadenine H H H CH 3 0 8-fluoroadenine H H H CH 3 0 2,8-difluoro adenine H H H CH 3 0 adenine H H H CH 3 S 2-(N,N-diacetyl) guanine H H H CH 3 S 6-0-acetyl guanine 97 WO 01/90121 PCT/US01/16671 R!2 RX Base H H H CH 3 S 8-fluoroguanine H H H CH 3 S guanine H H H CH 3 S 6-(NN-diacetyl) adenine H H H CH 3 S 2-fluoroadenine H H H CH 3 S 8-fluoroadenine H H H CH 3 S 2,8-difluoro adenine H H H CH3 S adenine monophosphate H H CH 3 0 2-(N,N-diacetyl) guanine monophosphate H H CH3 0 6-0-acetyl guanine maonophosphate H H CH3 0 8-fluoroguanine monophosphate H H CH 3 0 guanine monophosphate H H CH 3 0 6-(NN-diacetyl) adenine monophosphate H H CHf 3 0 2-fluoroadenine monophosphate H H CH3 0 8-fluoroadenine monophosphate H H CH 3 0 2,8-difluoro adenine monophosphate H H CH 3 0 adenine monophosphate H H CH 3 S 2-(NN-diacetyl) guanine monophosphate H H CH 3 S 6-0-acetyl guanine monophosphate H H CH3 S 8-fluoroguanine monophosphate H H CH 3 S guanine monophosphate H H CH3 S 6-(N,N-diacetyl) adenine monophosphate H H CH 3 S 2-fluoroadenine monophosphate H H CH3 S 8-fluoroadenine 98 WO 01/90121 PCT/USO1I/16671 Rw Rw R 3 R X Base monophosphate H H CH 3 S 2,8-difluoro adenine monophosphate H H CH 3 S adenine diphosphate H H CH 3 0 2-(NN-diacetyl) guanine diphosphate H H CH 3 0 6-0-acetyl guanine diphosphate H H CH 3 0 8-fluoroguanine diphosphate H H CH 3 0 guanine diphosphate H H CH 3 0 6-(N,N-diacetyl) adenine diphosphate H H Cs 0 2-fluoroadenine diphosphate H H CH3 0 8-fluoroadenine diphosphate H H CH 3 0 2,8-difluoro adenine diphosphate H H CH 3 0 adenine diphosphate H H CH 3 S 2-(NN-diacety1) guanine diphosphate H H CH 3 S 6-0-acetyl guanine diphosphate H H CH3 S 8-fluoroguanine diphosphate H H CH 3 S guamne diphosphate II H CH 3 S 6-(N,N-diacetyl) adenine diphosphate H H CH 3 S 2-fluoroadenine diphosphate H H Cl 3 S 8-fluoroadenine diphosphate H H CH 3 S 2,8-difluoro adenine diphosphate H H CH 3 S adenine triphosphate H H CH 3 0 2-(NN-diacetyl) guanine 99 WO 01/90121 PCT[US01/16671 R R 2 Ri Re -X Base triphosphate H H CH 3 0 6-0-acetyl guanine triphosphate H H CH 3 0 8-fluoroguanine triphosphate H H CH3 0 guanine triphosphate H H CH 3 C 6-(NN-diacetyl) adenine triphosphate H H CH3 0 2-fluoroadenine triphosphate H H CH 3 0 8-fluoroadenine triphosphate H1 H CH3 0 2,8-difluoro adenine triphosphate H H CH3 0 2-(NN-diacetyl) guanine triphosphate H H CH3 S 6-0-acetyl guanine triphosphate H H CH 3 S 8-fluoroguanine triphosphate H H CH 3 S guanine triphosphate H H CH 3 S 6-(N,N-diacetyl) adenine triphosphate H H CH 3 S 2-fluoroadenine triphosphate H H CH3 S 8-fluoroadenine triphosphate H H CH 3 S 2,8-difluoro adenine triphosphate H H CH 3 S adenine monophosphate monophosphate monophosphate CF 3 0 2-(NN-diacetyl) guanine monophosphate monophosphate monophosphate CF 3 0 6-0-acetyl guanine monophosphate monophosphate monophosphate CF 3 0 8-fluoroguanine monophosphate monophosphate monophosphate CF 3 0 guanine monophosphate monophosphate monophosphate CF 3 0 6-(N,N-diacetyl) adenine monophosphate monophosphate monophosphate CF 3 0 2-fluoroadenine 100 WO 01/90121 PCT/USOI/16671 R2i RI X Base monophosphate monophosphate monophosphate CF 3 0 8-fluoroadenine monophosphate monophosphate monophosphate CF 3 0 2,8-difluoro adenine monophosphate monophospbate monophosphate CF 3 0 adenine monophosphate monophosphate monophosphate CF 3 S 2-(NN-diacetyl) guanine monophosphate monophosphate monophosphate CF 3 S 6-0-acetyl guanine monophosphate monophosphate monophosphate CF 3 S 8-fluoroguanine monophosphate monophosphate monophosphate CF 3 S guanine monophosphate monophosphate monophosphate CF 3 S 6-(NN-diacetyl) adenine monophosphate monophosphate monophosphate CF 3 S 2-fluoroadenine monophosphate monophosphate monophosphate CF 3 S 8-fluoroadenine monophosphate monophosphate monophosphate CF 3 S 2,8-difluoro adenine monophosphate monophosphate monophosphate CF 3 S adenine acetyl acetyl acetyl CF 3 0 guanine acetyl acetyl acetyl CF 3 S guanine acetyl acetyl acetyl 2-bromo- 0 guanine vinyl acetyl acetyl acetyl 2-bromo- S guanine vinyl Alternatively, the following nucleosides of Formula VIII are prepared, using the appropriate sugar and pyrimidine or purine bases. Base R'O x

OR

2 5 (VIII) 101 WO 01/90121 PCT/US01/16671 wherein R RBase H H CH3 0 2,4-0-Diacetyluracil H H OH 3 0 Hypoxanthine H H CH13 0 2,4-0-Diacetylthymine H H CH 3 0 Thymine H H CH 3 0 Cytosine H H CH 3 0 4-(N-mono-acetyl)cytosine H H CH 3 0 4-(NN-diacetyl)cytosine H H CH 3 0 Uracil H H CH 3 0 5-Fluorouracil H H CH 3 S 2,4-0-Diacetyluracil H H CH 3 S Hypoxanthine H H CH 3 S 2,4-0-Diacetylthymine H H CH3 S Thymine H H C113 S Cytosine H H C3 S 4-(N-mono-acetyl)cytosine H H CH 3 S 4-(N,N-diacetyl)cytosine H H CH 3 S Uracil H H CH 3 S 5-Fluorouracil monophosphate H CH 3 0 2,4-0-Diacetyluracil nonophosphate H CH 3 0 Hypoxanthine monophosphate H CH 3 0 2,4-0-Diacetylthymine monophosphate H CH3 O Thymine monophosphate H CH3 0 Cytosine monophosphate H CH 3 0 4-(N-mono-acetyl)cytosine monophosphate H CH 3 0 4-(NN-diacetyl)cytosine monophosphate H CH3 0 Uracil monophosphate H CH 3 0 5-Fluorouracil monophosphate H CH 3 S 2,4-0-Diacetyluracil monophosphate H CH 3 S Hypoxanthine monophosphate H C113 S 2,4-0-Diacetylthymine 102 WO 01/90121 PCT/US01/16671 R2 X Base monophosphate H CH 3 S Thymine monophosphate H CH 3 S Cytosine monophosphate H CH 3 S 4-(N-mono-acetyl)cytosine monophosphate H CH 3 S 4-(NN-diacetyl)cytosine monophosphate H CH 3 S Uracil monophosphate H CH 3 S 5-Fluorouracil diphosphate H CH 3 0 2,4-0-Diacetyluracil diphosphate H CH 3 0 Hypoxanthine diphosphate H CH3 0 2,4-0-Diacetylthyniine diphosphate H C13 0 Thymine diphosphate H CH 3 O Cytosine diphosphate H CH 3 0 4-(N-mono-acetyl)cytosine diphosphate H CH 3 0 4-(NN-diacetyl)cytosine diphosphate H CH3 0 Uracil diphosphate H CH 3 0 5-Fluorouracil diphosphate H CH 3 S 2,4-0-Diacetyluracil diphosphate H CH 3 S Hypoxanthine diphosphate H CH 3 S 2,4-0-Diacetylthymine diphosphate H CH3 S Thymine diphosphate H CH3 S Cytosine diphosphate H CH 3 S 4-(N-mono-acetyl)cytosine diphosphate H CHI S 4-(NN-diacetyl)cytosine diphosphate H CH3 S Uracil diphosphate H CH% S 5-Fluorouracil triphosphate H CH 3 0 2,4-0-Diacetyluracil triphosphate H CH 3 0 Hypoxanthine triphosphate H CH 3 0 2,4-0-diacethylthymine triphosphate H CH 3 0 Thymine triphosphate H CI 0 Cytosine triphosphate H CH3 0 4-(N-mono-acetyl)cytosine triphosphate H CH 3 0 4-(N,N-diacetyl)cytosine 103 WO 01/90121 PCTfUS01/16671 i R2R X Base triphosphate H CH 3 0 Uracil triphosphate H CH 3 0 5-Fluorouracil triphosphate H CH 3 S 2,4-0-Diacetyluracil triphosphate H CH3 S Hypoxanthine triphosphate H CH 3 S 2,4-0-Diacetythynine triphosphate H CH 3 S ThyMine triphosphate H CH 3 S Cytosine triphosphate H CH-a S 4-(N-mono-acetyl)cytosine triphosphate H CH 3 S 4-(NN-diacetyl)cytosine triphosphate H CH 3 S Uracil triphosphate H CH 3 S 5-Fluorouracil monophosphate monophosphate CF 3 0 2,4-0-Diacetyluracil monophosphate monophosphate CF 3 0 Hypoxanthine monophosphate monophosphate CF 3 0 2,4-0-Diacetylthymine monophosphate monophosphate CF 3 0 Thymine nionophosphate monophosphate CF 3 0 Cytosine monophosphate monophosphate CF 3 0 4-(N-mono-acetyl)cytosine monophosphate monophosphate CF 3 0 4-(NN-diacetyl)cytosine monophosphate monophosphate CF 3 0 Uracil monophosphate monophosphate CF 3 0 5-Fluorouracil monophosphate monophosphate CF 3 S 2,4-O-Diacetyluracil monophosphate monophosphate CF 3 S Hypoxanthino monophosphate monophosphate CF 3 S 2,4-0-Diacetylthymine monophosphate monophosphate CF 3 S Thymine monophosphate monophosphate CF 3 S Cytosine monophosphate monophosphate CF 3 S 4-(N-mono-acetyl)cyto sine monophosphate monophosphate CF 3 S 4-(N,N-diacetyl)cytosine monophosphate monophosphate CF 3 S Uracil monophosphate monophosphate CF 3 S 5-Fluorouracil acetyl acetyl CF 3 0 4-(NN--diacetyl)cytosine acetyl acetyl CF 3 S 4-(NN-diacetyl)cytosine 104 WO 01/90121 PCTUSO1/16671 i R2 X Base acetyl acetyl 2-bromo- ) 4-(N,N-diacetyl)cytosine vinyl acetyl acetyl 2-bromo- S 4-(NN-diacetyl)cytosine vinyl H H CH 3 0 2-(NN-diacety)-guanine H H CH 3 0 6-0-acetyl guanine H H C13 0 8-fluoroguanine H H CH 3 0 guanine H H CH 3 0 6-(N,N-diacetyl)-adenine H H CH3 0 2-fluoroadenine H H CH3 0 8-fluoroadenine H H C113 0 2,8-difluoro-adenine H H CH3 0 adenine H H CH3 S 2-(NN-diacetyl)-guanine H H CH 3 S 6-0-acetyl guanine H H CH3 S 8-fluoroguanine H H CH3 S guanine H H CH3 S 6-(NN-diacetyl)-adenine H H CH 3 S 2-fluoroadenine H H CH 3 S 8-fluoroadenine H H CH3 S 2,8-difluoro-adenine H H CH 3 S adenine monophosphate H CH3 0 2-(N,N-diacetyl)-guanine monophosphate H CH3 0 6-0-acetyl guanine monophosphate H CH3 0 8-fluoroguanine monophosphate H CH3 0 guanine monophosphate H CH3 0 6-(NN-diacetyl)-adenine monophosphate H CH3 0 2-fluoroadenine monophosphate H CH3 0 8-fluoroadenine monophosphate H C13 0 2,8-difluoro-adenine monophosphate H CH3 0 adenine 105 WO 01/90121 PCT/USO1/16671 R Rw R X Base monophosphate H CH 3 S 2-(N,N-diacetyl)-guanine monophosphate H CH 3 S 6-0-acetyl guanine monophosphate H CH 3 S 8-fluoroguanine monophosphate H CH 3 8 guanine monophosphate H CH3 S 6-(NN-diacetyl)-adenine monophosphate H CH 3 S 2-fluoroadenine monophosphate H CH 3 S 8-fluoroadenine monophosphate H CH 3 S 2,8-difluoro-adenine monophosphate H CH 3 S adenine diphosphate H CH 3 0 2-(NN-diacetyl)-guanine diphosphate H CH 3 0 6-0-acetyl guanine diphosphate H CH3 0 8-fluoroguanine diphosphate H CH3 0 guanine diphosphate H CH 3 0 6-(NN-diacetyl)-adenine diphosphate H CH 3 0 2-fluoroadenine diphosphate H CH 3 0 8-fluoroadenine diphosphate H CH 0 2,8-difluoro-adenine diphosphate H CH3 O adenine diphosphate H CH3 S 2-(NN-diacetyl)-guanine diphosphate H CH 3 s 6-0-acetyl guanine diphosphate H CH3 S 8-fluoroguanine diphosphate H CH3 s guanine diphosphate H CH3 S 6-(NN-diacetyl)-adenine diphosphate H CHt S 2-fluoroadenine diphosphate H CH 3 S 8-fluoroadenine diphosphate H CH3 S 2,8-difluoro-adenine diphosphate H CH 3 S adenine triphosphate H CH 3 0 2-(N,N-diacetyl)-guanine triphosphate H CH3 0 6-0-acetyl guanine triphosphate H CH 3 0 8-fluoroguanine triphosphate H CH3 O ganine 106 WO 01/90121 PCT/US01/16671 Rw R R X Base triphosphate H CH3 0 6-(NN-diacetyl)-adenine triphosphate H CH 3 0 2-fluoroadenine triphosphate H CH 3 0 8-fluoroadenine triphosphate H CH 3 0 2,8-difluoro-adenine triphosphate H C93 0 adenine triphosphate H CH3 S 2-(NN-diacetyl)-guanine triphosphate H CH3 S 6-0-acetyl guanine triphosphate H CH 3 S 8-fluoroguanine triphosphate H CH3 S guanine triphosphate H CH 3 S 6-(NN-diacetyl)-adenine triphosphate H CH 3 S 2-fluoroadenine triphosphate H CH 3 S 8-fluoroadenine triphosphate H Ci3 S 2,8-difluoro-adenine triphosphate H CH3 S adenine monophosphate monophosphate CF 3 0 2-(NN-dLiacetyl)-guanine monophosphate monophosphate CF 3 0 6-0-acetyl guanine monophosphate monophosphate CF 3 0 8-fluoroguanine monophosphate monophosphate CF3 0 guanine monophosphate monophosphate CF 3 0 6-(NN-diacetyl)-adenin1e monophosphate monophosphate CF 3 0 2-fluoroadenine monophosphate monophosphate CF 3 0 8-fluoroadenine monophosphate monophosphate CF 3 0 2,8-difluoro-adenine monophosphate monophosphate CF 3 0 adenine monophosphate monophosphate CF 3 S 2-(NN-diacetyl)-guanine monophosphate monophosphate CF 3 S 6-0-acetyl guanine monophosphate monophosphate CF 3 S 8-fluoroguanine monophosphate monophosphate CF 3 S guanine monophosphate monophosphate CF 3 S 6-(N,N-diacetyl)-adenine monophosphate monophosphate CF 3 S 2-fluoroadenine monophosphate monophosphate CF 3 S 8-fluoroadenine monophosphate monophosphate CF 3 S 2,8-difluoro-adenine 107 WO 01/90121 PCTIUSQI/16671 R2 R - X Base monophosphate monophosphate CFa S adenine acetyl acetyl CF 3 0 guanine acetyl acetyl CF 3 S guanine acetyl acetyl 2-bromo- 0 guanine vinyl acetyl acetyl 2-bromo- S gaanine vinyl Alternatively, the following nucleosides of Formula IX are prepared, using the appropriate sugar and pyrimidine or purine bases. Base R 5 (IX) wherein: R]R X Base H CH 3 0 2,4-0-Diacetyluracil H CH3 0 Hypoxanthine H CH3 0 2,4-0-Diacetylthymine H CH 3 0 Thymine H CH 3 0 Cytosine H CH 3 0 4-(N-mono-acetyl)cytosine HI CH3 0 4-(NN-diacetyl)cytosine H CH 3 0 Uracil H CU 3 0 5-Fluorouracil H CU 3 S 2,4-0-Diacetyluracil H CH 3 S Hypoxanthine H CH 3 S 2,4-0-Diacetylthymine 108 WO 01/90121 PCT/US01/16671 R' R' X Base H CH 3 S Thymine H CH3 S Cytosine H CH3 S 4-(N-mono-acetyl)cytosine H CH 3 S 4-(NN-diacetyl)cytosine H CH3 S Uracil H CH 3 S 5-Fluorouracil monophosphate CH 3 0 2,4-O-Diacetyluracil monophosphate CH 3 0 Hypoxanthine monophosphate CH 3 0 2,4-0-Diacetylthymine monophosphate CH 3 0 Thymine monophosphate CH 3 0 Cytosine monophosphate CH3 0 4-(N-mono-acetyl)cytosine monophosphate CH 3 0 4-(NN-diaetyl)cytosine monophosphate CH3 0 Uracil monophosphate CH 3 0 5-Fluorouracil monophosphate CH 3 S 2,4-0-Diacetyluracil monophosphate CH 3 S Hypoxanthine monophosphate CH 3 S 2,4-0-Diacetylthymine monophosphate CH3 S Thymine monophosphate CH 3 S Cytosine monophosphate CH 3 S 4-(N-mono-acetyl)cytosine monophosphate CH 3 S 4-(NN-diacetyl)cytos monophosphate CH3 S Uracil monophosphate CH 3 S 5-Fluorouracil diphosphate CI3 0 2,4-0-Diacetyluxacil diphosphate CH 3 0 Hypoxanthine diphosphate CH 3 0 2,4-0-Diacetylthymine diphosphate CH 3 0 Thyxnine diphosphate CH 3 0 Cytosine diphosphate CH 3 0 4-(N-mono-acetyl)cytosine diphosphate CH 3 0 4-(N,N-diacetyl)cytosine 109 WO 01/90121 PCT[US01/16671 RRX Base diphosphate CH 3 0 Uracil diphosphate CH 3 0 5-Fluorouracil diphosphate CH 3 S 2,4-0-Diacetyluracil diphosphate CH 3 8 Hypoxanthine diphosphate CH 3 S 2,4-0-Diacetylthymine diphosphate CH 3 S Thymine diphosphate CH 3 S Cytosine triphosphate CH 3 0 2,4-0-Diacetyluracil triphosphate CH 3 0 Hypoxanthine triphosphate CH 3 0 2,4-0-Diacetylthymine triphosphate CH 3 0 Thymine triphosphate CH3 0 Cytosine triphosphate CH5 0 4-(N-mono-acetyl)cytosine triphosphate CH 0 4-(N,N-diacetyl)cytosine triphosphate CH 3 0 Uracil triphosphate CH 3 0 5-Fluorouracil triphosphate CH 3 S 2,4-O-Diacetyluracil triphosphate CH 3 S Hypoxanthine triphospahate CH 3 S 2,4-0-Diacetylthymine triphospahate CH 3 S Thymine triphospahate CH 3 S Cytosine monophosphate CF 3 0 2,4-0-Diacetyluracil monophosphate CF 3 0 Hypoxanthine monophosphate CF 3 0 2,4-0-Diacetylthymine monophosphate CF3 0 Thymine monophosphate CF 3 0 Cytosine monophosphate CF 3 0 4-(N-xnono-acetyl)cytosine monophosphate CF 3 0 4-(N,N-diacetyl)cytos monophosphate CF 3 0 Uracil inonophosphate CF 3 0 5-Fluorouracil inonophosphate CF 3 S 2,4-0-Diacetyluracil 110 WO 01/90121 PCT/USO1/16671 Rt R X Base monophosphate CF 3 S Hypoxanthine monophosphate CF 3 S 2,4-0-Diacetylthymine monophosphate CF 3 S Thymine monophosphate CF 3 S Cytosine monophosphate CF 3 S 4-(N-mono-acetyl)oytosine monophosphate CF 3 S 4-(N,N-diacetyl)cytosine monophosphate CF 3 S Uracil monophosphate CF 3 S 5-Fluorouracil acetyl CF 3 0 4-(NN-diacetyl)cytosine acetyl CF 3 S 4-(NN-diacetyl)cytosine acetyl 2-bromo-vinyl 0 4-(N,N-diacetyl)cytosine acetyl 2-bromo-vinyl S 4-(N,N-diacetyl)cytosine Alternatively, the following nucleosides of Formula XVI are prepared, using the appropriate sugar and pyrimidine or purine bases. R0 Base R1 0 x R 8 Rs

R

9

R

7 5 (XVI) wherein: W R7R X Base R R H CH3 H H 0 2,4-0-Diacetyluracil OH Me H CH 3 H H 0 Hypoxanthine OH Me H CH 3 H H 0 2,4-0-Diacetylthymine OH Me H CH 3 H H 0 Thymine OH Me H CH3 H H 0 Cytosine OH Me H CH 3 H- H 0 4-(N-mono-acetyl)cytosine OH Me H CH 3 TH H1 0 4-(N,N-diacetyl)cytosine OH Me 111 WO 01/90121 PCT/US01/16671 RW R R" X Base R R' H CH 3 H H 0 Uracil OH Me H CH 3 H H 0 5-Fluorouracil OH Me H CH 3 H H S 2,4-0-Diacetyluracil OH Me H CH 3 H H S Hypoxanthine OH Me H CH 3 H H S 2,4-0-Diacetylthymine OH Me H CH 3 H H S Thymine OH Me H CH3 H H S Cytosine OH Me H CH 3 H H S 4-(N-mono-acetyl)cytosine OH Me H CH 3 H H S 4-(N,N-diacetyl)cytosine OH Me H CH 3 H H S Uracil OH Me H CH 3 H H S 5-Fluorouracil OH Me monophosphate CH 3 H H 0 2,4-0-Diacetyluracil OH Me monophosphate CH 3 H H 0 Hypoxanthine OH Me monophosphate CH 3 H H 0 2,4-O-Diacetylthymine OH Me monophosphate CH 3 H H 0 Thymine OH Me monophosphate CH 3 H H 0 Cytosine OH Me monophosphate CH 3 H H 0 4-(N-mono-acetyl)cytosine OH Me monophosphate CH 3 H H 0 4-(NN-diacetyl)cytosine OH Me monophosphate CH 3 H H 0 Uracil OH Me monophosphate CH 3 H H 0 5-Fluorouracil OH Me monophosphate CH3 H H S 2,4-0-Diacetyluracil OH Me monophosphate CH 3 H H S Hypoxanthine OH Me monophosphate CH3 H H S 2,4-0-Diacetylthymine OH Me monophosphate CH 3 H H S Thymine OH Me monophosphate CH 3 H H S Cytosine OH Me monophosphate CH 3 H H S 4-(N-rnono-acetyl)cytosine OH Me monophosphate CH 3 H H S 4-(NN-diacetyl)oytosine OH Me monophosphate CH 3 H H S Uracil OH Me monophosphate CH 3 H H S 5-Fluorouracil OH Me diphosphate CI 3 H H 0 2,4-0-Diacetyluracil OH Me diphosphate CH 3 H H 0 Hypoxantbine OH Me 112 WO 1/90121 PCTJUSOV116671 RW R R X Base R i R diphosphate CH 3 H H 0 2,4-0-Diacetylthymine OH Me diphosphate CH3 H H 0 Thymine OH Me diphosphate CH 3 H H 0 Cytosine OH Me diphosphate Ci3 H H 0 4-(N-mono-acetyl)cytosine OH Me diphosphate CH 3 H H 0 4-(NN-diacetyl)cytosine OH Me diphosphate CH 3 H H 0 Uracil OH Me diphosphate CH 3 H H 0 5-Fluorouracil OH Me diphosphate CH 3 H H S 2,4-0-Diacetyluracil OH Me diphosphate CH3 H H S Hypoxanthine OH Me diphosphate CH 3 H H S 2,4-O-Diacetylthymine OH Me diphosphate CH3 H H -S Thymine OH Me diphosphate CH 3 H H S Cytosine OH Me triphosphate CH 3 H H O 2,4-0-Diacetyluracil OH Me triphosphate CH3 H H 0 Hypoxanthine OH Me triphosphate CH3 H H 0 2,4-O-Diacetylthymine OH Me triphosphate CH 3 H H 0 Thymine OH Me triphosphate CH 3 H H 0 Cytosine OH Me triphosphate CH 3 H H 0 4-(N-mono-acetyl)cytosine OH Me triphosphate CH 3 H H 0 4-(NN-diacetyl)cytosine OH Me triphosphate CH 3 H H 0 Uracil OH Me triphosphate CH 3 H H 0 5-Fluorouracil OH Me triphosphate CH 3 H H S 2,4-0-Diacetyluracil OH Me triphosphate CH 3 H H S Hypoxanthine OH Me triphosphate CH 3 H H S 2,4-O-Diacetylthymine OH Me triphosphate CH 3 H H S Thymine OH Me triphosphate CH3 H H S Cytosine OH Me monophosphate CF 3 H H 0 2,4-0-Diacetyluracil 01- Me monophosphate CF 3 H H 0 Hypoxanthine OH Me monophosphate CF 3 H H 0 2,4-0-Diacetylthymine OH Me monophosphate CF 3 H H 0 Thymine OH Me monophosphate CF 3 H H 0 Cytosine OH Me 113 WO 01/90121 PCTUSO1I/16671 RW RIRX Base R R monophosphate CF 3 H H 0 4-(N-mono-acetyl)cytosine OH Me monophosphate CF 3 H H 0 4-(NN-diacetyl)cytosine OH Me monophosphate CF 3 H H 0 Uracil OH Me monophosphate CF 3 H H 0 5-Fluorouracil OH Me monophosphate CF 3 H H S 2,4-0-Diacetyuracil OH Me monophosphate CF H H S Hypoxanthine OH Me monophosphate CF 3 H H S 2,4-0-Diacetylthymine OH Me monophosphate CF 3 H H S Thymine OH Me monophosphate CF 3 H H S Cytosine OH Me monophosphate CF 3 H H S 4-(N-mono-acetyl)cytosine OH Me monophosphate CF3 H 11 S 4-(NN-diacetyl)cytosine OH Me monophosphate CF 3 H H S Uracil OH Me monophosphate CF 3 H H S 5-Fluorouracil OH Me acetyl CH3 H H 0 4-(N,N-diacetyl)cytosine H Br acetyl CH 3 H H S 4-(NN-diacetyl)cytosine H Br acetyl CH3 OH H 0 4-(NN-diacety1)cytosine H Br acetyl CH OH H S 4-(NN-diacety1)cytosine H Br Example 2: Preparation of 2'-C-methylriboadenine The title compound was prepared according to a published procedure (RB. Harry O'kuru, J.M. Smith, and M.S. Wolfe, "A short, flexible route toward 2T-C-branched 5 ribonucleosides", J.Org. Chem. 1997, 2, 1754-1759) (Scheme 8). Scheme 8 BrO a ~ m B3o--bq IzO R 1z d t+OBz FV- OBz 14 BzO OH BzO 0 BrO OBz

NH

2 NHBz HO Ne B0 N BZ0 BZQ OH OH BzO BzO 114 WO 01/90121 PCT/US01/16671 (a) Dess-Martin periodinane; (b) MeMgBr / TiC1 4 ; (c) BzC1, DMAP, EtsN; (d) bis(trimethylsilyl)acetamide, N 6 -benzoyl adenine, TMSOTZ (e) NH 3 / MeOH In a similar manner, but using the appropriate sugar and pyrimidine or purine bases, the following nucleosides of Formula I are prepared. y N X 12 R!O HC ~j X 5

OR

2

OR

3 (11) wherein: RI R2 R0 Xy W Y H H H H H H H H H H H NH 2 H H H H H NH-cyclopropyl H H H H H NH--methyl H H H H H NH-ethyl H H H H H NH-acetyl H H H H H OH H H H H H OMe H H H H H OMt H H H H H O-cyclopropyl H H H H 0-acetyl H H H H H SH H H H H H SMe H H H H H SEt H H H H H S-cyclopropyl H H H H H F H H H H H Cl 115 WO 01190121 PCT/USU1/16671 Re R2 1w % - V X Y H H H H Br H H H H H I monophosphate H H H H NH 2 monophosphate H H H H NH-acetyl monophosphate H H H H NH-cyclopropyl monophosphate H H H H NH-methyl monophosphate H H H H NH-ethyl monophosphate H H H H OH monophosphate H H H H O-acetyl monophosphate H H H H OMe monophosphate H H H H OEt monophosphate H H H H 0-cyclopropyl monophosphate H H H H SH monophosphate H H H H SMe monophosphate H H H H SEt monophosphate H H H H S-cyclopropyl monophosphate H H H H F monophosphate H H H H Cl monophosphate H H H H Br monophosphate H H H H I diphosphate H H H H NH 2 diphosphate H H H H NH-acetyl diphosphate H H H H NH-cyclopropyl diphosphate H H H H NH-methyl diphosphate H H H H NH-ethyl diphosphate H H H H OH diphosphate H H H H O-acetyl diphosphate H H H H OMe diphosphate H H H H OEt diphosphate H H I-I H 0-cyclopropyl diphosphate H H H H SH 116 WO 01/90121 PCT/USO1/16671 i R 2 R 'Y diphosphate H H H H SMe diphosphate H H H H SEt diphosphate H H H H S-cyclopropyl diphosphate H H H H F diphosphate H H H H Cl diphosphate H H H H1 Br diphosphate H H H H I triphosphate H H H H NH 2 triphosphate H H H H NH-acetyl triphosphate H H H H NH-cyclopropyl triphosphate H H H H NH-methyl triphosphate H H H H NH-ethyl triphosphate H H H H OH triphosphate H H H H OMe triphosphate H H H H OEt triphosphate H H H H 0-cyclopropyl triphosphate H H H H O-acetyl triphosphate H H H H SH triphosphate H H H H SMe triphosphate H H H H SBt triphosphate H H H H S-cyclopropyl triphosphate H H H H F triphosphate H H H H Cl triphosphate H H H H Br triphosphate H H H H I monophosphate monophosphate monophosphate H H NH 2 monophosphate monophosphate monophosphate H -i NH-cyclopropyl monophosphate monophosphate monophosphate H H OH monophosphate monophosphate monophosphate H H F monophosphate monophosphate monophosphate H H Cl diphosphate diphosphate diphosphate H H NH 2 117 WO 01/90121 PCT/USO1/16671 diphosphate diphosphate diphosphate H H NH-cyclopropyl diphosphate diphosphate diphosphate H H OH diphosphate diphosphate diphosphate H H F diphosphate diphosphate diphosphate H H Cl triphosphate triphosphate triphosphate H H NiH2 triphosphate triphosphate triphosphate H H NH-cyclopropyl triphosphate triphosphate triphosphate H H OH triphosphate triphosphate triphosphate H H F triphosphate triphosphate triphosphate H H Cl H H H F HI NH2 H H H F H NH-cyclopropyl H H H F H OH H H H F H F H H H F H Cl H H H Cl H NH 2 H H H Cl H NH-cyclopropyl H H H Cl H OH H H' H C1 H F H H H C1 H Cl H H H Br H NH2 H N H Br H NI-cyclopropyl H H H Br H OH H H H Br H F H H H Br H Cl H H H NH2 H NH 2 H H H NH 2 H NH-cyclopropyl H H H NH 2 H OH H H H NH 2 H F H H H NH 2 H Cl 14 H H Sf1 H NH2 H H H SH H NHI-cyclopropyl 118 WO 01/90121 PCT/US01/16671 RRI R XI X2 V H H H S i OH H H H SH (H F H H H SH H Cl acetyl H a H H NH2 H acetyl H H H H NH-cyclopropyl acetyl a H H H NH acetyl H H H H F acetyl H H H .H C acetyl H H FI H NH2 acetyl H H F H NH-Cyclopropyl acetyl H H H H OH acetyl H H F H F acetyl H H H H C1 H acetyl acetyl H H NH2 H acetyl acetyl H H NH-cyclopropyl H acetyl acetyl H H OH H acetyl acetyl H H P H ~ acetyl acetyl H HIf Cl acetyl acetyl acetyl H H NH2 acetyl acetyl acetyl H H NH-cyclopropyl acetyl acetyl acetyl H H OH acetyl acetyl acetyl H HT F acetyl acetyl acetyl H -H C1 monophosphate acetyl acetyl H H NH2 monophosphate acetyl acetyl HH NH-cyclopropy monophosphate acetyl acetyl H H OH monophosphate, acetyl acetyl H H F mo-nophosphate acetyl acetyl H H C1 diphosphate acetyl acetyl H H NH2 diphosphate acetyl acetyl H H NH-cyclopropyl diphosphate acetyl acetyl H H O 119 WO 01/90121 PCT/USO1/16671 iR X, XY Y diphosphate acetyl acetyl H H F diphosphate acetyl acetyl H H Cl triphosphate acetyl acetyl H H NH2 triphosphate acetyl acetyl H H NH-cyclopropyl triphosphate acetyl acetyl H H OH triphosphate acetyl acetyl H I F triphosphate acetyl acetyl H H Cl H H H H NH 2 H H H H H NH 2 NH2 H H H H Ni2 NH-cyclopropyl H H H H NH2 NH-methyl H H H H NH 2 NH-ethyl H H H H -NH 2 NH-acetyl H H H H NH 2 OH H 1I H H NI2 OMe H H H H NH2 OFt H H H H NH2 0-cyclopropyl H H H H NH 2 0-acetyl H H H H NH 2 SH H H H H Ni2 SMe H H H H NH2 SEt H H H H NH2 S-cyclopropyl H H H H NH 2 F H H H H NH 2 C1 H H H H NH 2 Br H H H H NH 2 I monophosphate H H H NH2 NH2 monophosphate H H H NH 2 NH-acetyl monophosphate H H H NH 2 NH-cyclopropyl monophosphate H H H NH2 NH-methyl monophosphate -T H H NH 2 NH-ethyl 120 WO 01/90121 PCT/USO1/16671 SR X y monophosphate H H H NH2 OH monophosphate H H H NH 2 0-acetyl monophosphate H H H NHz OMe monophosphate H H H NH2 OEt monophosphate H H H NH 2 0-cyclopropy1 monophosphate H H H NH 2 SH monophosphate H H H NH2 SMe monophosphate H H1 H NH2 SEt monophosphate H H H NH2 S-cyclopropyl monophosphate H H H NH2 F monophosphate H H H NH2 Cl monophosphate H H H NH 2 Br monophosphate H H H NH I diphosphate H H H NH2 NH2 diphosphate H H H NH2 NH-acetyl diphosphate H H H NH 2 NH-cyclopropyl diphosphate H H H NH2 NH-methyl diphosphate H H H NH2 NH-ethyl diphosphate H H H NH2 OH diphosphate H H H NH 2 0-acetyl diphosphate H H H NH2 OMe diphosphate H H H NH2 OEt diphosphate II II H NH2 0-cyclopropyl diphosphate H H H NH2 SH diphosphate II H H NH2 SMe diphosphate H H II NH2 SEt diphosphate H H H NH 2 S-cyclopropyl diphosphate H H H NH 2 F diphosphate H H H NH 2 Cl diphosphate H H H Nt Br diphosphate H H H NH 2 I 121 WO 01/90121 PCT/USOI/16671 R RX Y triphosphate H H H NH2 NH 2 triphosphate H H H NH 2 NHI-acetyl triphosphate H H H Ni 2 NH-cyclopropyl triphosphate H H H NH 2 NH-methyl triphosphate H H H NH 2 NH-ethyl triphosphate H H H NH 2 OH triphosphate H H H NH 2 OMe triphosphate H H H NH 2 OEt triphosphate H H H NH 2 0-cyclopropyl triphosphate H H H . NH2 0-acetyl triphosphate H H H NH 2 SH triphosphate H H H NH2 SMe triphosphate H H H NH 2 SPt triphosphate H H H NH 2 S-cyclopropyl triphosphate H H H NH 2 F triphosphate H H H NH2 Cl triphosphate H H H NH2 Br triphosphate H H H NH2 I monophosphate monophosphate monophosphate H NH 2

NH

2 monophosphate monophosphate monophosphate H NH2 N-cyCIopropyl monophosphate monophosphate monophosphate H NH 2 OH monophosphate imonophosphate monophosphate H NH 2 P monophosphate monophosphate monophosphate H NH 2 Cl diphosphate diphosphate diphosphate H NH 2 NiH2 diphosphate diphosphate diphosphate H NH 2 NH-cyclopropyl diphosphate diphosphate diphosphate H NH2 OH diphosphate diphosphate diphosphate H NH 2 F diphosphate diphosphate diphosphate H NH 2 Cl triphosphate triphosphate triphosphate H NH2 NH 2 triphosphate triphosphate triphosphate H NH2 NH-cyclopropyl triphosphate triphosphate triphosphate H NH 2 OH 122 WO 01/90121 PCT/USO1/16671 RI R 2 R tiphosphate Uiphosphate triphosphate H NH 2 F triphosphate triphosphate triphosphate H NH 2 Cl H H H F NH2 NH2 H H H F NH 2 NH-cyclopropyl H H H F NH2 OH H H H F NH2 F H H H F NH2 C1 H H H C1 NH2 NH2 H H H Cl NH2 NH-cyclopropyl H H H C) NH2 OH H H H C1 NH2 F H H H C1 NH2 C1 H HH Br NH2 NH2 H H H Br NH 2 NH-cyclopropyl H H H Br NH2 OH H H H Br NH2 F H H H Br NH2 C1 H H H NH2 NH2 NH2 H H H NH 2 NH2 NH-cyclopropyl H H H NH2 NH2 OH H H H NH2 NH2 F H H H NH2 NH2 C1 H H H SH NH2 NH2 H H H SH NH 2 NH-cyclopropyl H H H SH NH2 OH H H H SH NH2 F H H H SH NH 2 CI acetyl H H H NH 2

NH

2 acetyl H H H NH 2 NH-cyclopropyl acetyl H H H NH2 OH acetyl H H H NH 2 F 123 WO 01/90121 PCT/USO1/16671 acetyl H H IT NH 2 Cl acetyl H H F NH 2

NH

2 acetyl H F NH 2 NH-cyclopropyl acetyl H H F NH 2 OH acetyl H H F NH 2 F acetyl H H F Ni2 Cl H acetyl acetyl H NH 2 NH2 H acetyl acetyl H NH 2 NH-cyclopropyl H acetyl acetyl H NH 2 OH H acetyl acetyl H NH 2 F H acetyl acetyl H NH2 Cl acetyl acetyl acetyl H NH 2 NH1 2 acetyl acetyl acetyl H NH 2 NH-cyclopropyl acetyl acetyl acetyl H NH 2 OH acetyl acetyl acetyl H NH 2 F acetyl acetyl acetyl H NH 2 Cl monophosphate acetyl acetyl H NH 2 NH2 monophosphate acetyl acetyl H NH 2 NH-cyclopropyl monophosphate acetyl acetyl H NH 2 OH monophosphate acetyl acetyl H NH 2 F monophosphate acetyl acetyl H NH 2 Cl diphosphate acetyl acetyl H NH2 NH 2 diphosphate acetyl acetyl H NH 2 NH-cyclopropyl diphosphate acetyl acetyl H NH 2 OH diphosphate acetyl acetyl H NH 2 F diphosphate acetyl acetyl H NH 2 Cl triphosphate acetyl acetyl H NH 2

NH

2 triphosphate acetyl acetyl HT NH 2 NH-cyclopropyl triphosphate acetyl acetyl H NH 2 OH triphosphate acetyl acetyl H NH 2 F triphosphate acetyl acetyl H NH 2 Cl 124 WO 01/90121 PCTfUS01/16671 R Ry H H H H Cl H H H H H Cl H H H H H Cl NH2 H H H H Cl NII-cyclopropyl H H H H Cl NH-methyl H H H H Cl NH-ethyl H H H H Cl NH-acetyl H H H H Cl OH H H H H Cl OMe H H H H Cl OEt H H H H Cl 0-cyclopropyl H H H H Cl 0-acetyl H H H H Cl SH H H H H Cl SMe H H H H Cl SEt H H H H Cl S-cyclopropyl monophosphate H H H Cl NH2 monophosphate H H H Cl NH-acetyl monophosphate H H H Cl NH-cyclopropyl monophosphate H H H Cl NH-methyl monophosphate H H H Cl NH-ethyl monophosphate H H H Cl OH monophosphate H H H Cl 0-acetyl monophosphate H H H Cl OMe monophosphate H H H Cl OEt monophosphate H H H Cl 0-cyclopropyl monophosphate H H H Cl SH monophosphate H H H C SMe monophosphate H H H Cl SEt monophosphate H H H Cl S-cyclopropyl diphosphate H H H Cl NH 2 125 WO 01/90121 PCTUSO1/16671 I R2 y diphosphate H H H Cl NH-acetyl diphosphate H H H Cl NH-cyclopropyl diphosphate H H H Cl NH-methyl diphosphate H H H Cl NH-ethyl diphosphate H H H Cl OH diphosphate H H H CI 0-acetyl diphosphate H H H Cl OMe diphosphate H H H Cl OEt diphosphate H H H Cl 0-cyclopropyl diphosphate H H H Cl SH diphosphate H H H Cl SMe diphosphate H H H C1 SEt diphosphate H H H Cl S-cyclopropyl triphosphate H H H Cl NH 2 triphosphate H H H Cl NH-acetyl triphosphate H H H Cl NH-cyclopropyl triphosphate H H H Cl NH-methyl triphosphate H H H C1 NH-ethyl triphosphate H H H C1 OH triphosphate H H H Cl OMe triphosphate H H H Cl OEt triphosphate H H H Cl 0-cyclopropyl triphosphate H H H Cl 0-acetyl triphosphate H H H Cl SH triphosphate H H H Cl SMe triphosphate H H H Cl SEt triphosphate H H H Cl S-cyclopropyl monophosphate monophosphate monophosphate H Cl NH 2 monophosphate monophosphate monophosphate H Cl NH-cyclopropyl monophosphate monophosphate monophosphate H Cl OH diphosphate diphosphate diphosphate H Cl NH 2 126 WO 01/90121 PCT/USO1/16671 R R R X X y dipliosphate diphosphate diphosphate H Cl NH-cyclopropyl diphosphate diphosphate diphosphate H Cl OH triphosphate triphosphate triphosphate H Cl NH 2 triphosphate triphosphate triphosphate H Cl NH-cyclopropyl triphosphate triphosphate triphosphate H Cl OH H H H F Cl NH 2 H H H F Cl NHi-cyclopropyl H H F cl OH SH Cl Cl NH 2 SH Cl Cl NH-cyclopropyl SH Cl Cl OH H H H Br Cl NH 2 H H H Br Cl NH-cyclopropyl H H H Br Cl OH H H H NH 2 Cl NH 2 H H H NH 2 Cl NH-cyclopropyl H H H NH 2 Cl OH H H H SH Cl NH 2 H H H SH Cl NH-cyclopropyl H H H SH Cl OH acetyl H H H Cl NH 2 acetyl H H H Cl NH-cyclopropyl acetyl H H H Cl OH acetyl H H F Cl NH 2 acetyl H H F Cl NH-cyclopropyl acetyl H H F Cl OH H acetyl acetyl H Cl NH2 H acetyl acetyl H Cl NH-cyclopropyl H acetyl acetyl H Cl OH acetyl acetyl acetyl H Cl NH 2 acetyl acetyl acetyl H Cl NH-cyclopropyl 127 WO 01/90121 PCT/US01/16671

R

2 R3 o X2 Y acetyl acetyl acetyl H Cl OH monophosphate acetyl acetyl H Cl NH2 monophosphate acetyl acetyl H Cl NH-cyclopropyl monophosphate acetyl acetyl H Cl OH diphosphate acetyl acetyl H Cl NH2 diphosphate acetyl acetyl H Cl NH-cyclopropyl diphosphate acetyl acetyl H Cl OH triphosphate acetyl acetyl H Cl NH 2 triphosphate acetyl acetyl H Cl NH-cyclopropyl triphosphate acetyl acetyl H Cl OH H H H H Cl NH 2 H H H H C1 NH-cyclopropy H H H H Cl OH H H H H Br NH2 H H H H Br NH-cyclopropyl H H H H Br OH Alternatively, the following nucleosides of Formula V are prepared, using the appropriate sugar and pyrimidine or purine bases. y R'O RO H,C 0-H.C OR, 3 5 (V) wherein:

R

2 RX Y H H H H H H H H NH 2 128 WO 01/90121 PCT/USO1/16671 Re R R X 'Y H H H H NH-cyclopropyl H H H H NH-methyl H H H H NH-ethyl H H H H NH-acetyl H H H H OH H H H H OMe H H H H Ot H H H H O-cyclopropyl H H H H O-acetyl H H H H SH H H H H SMe H H H H SEt H H H H S-cyclopropyl monophosphate H H H NH 2 monophosphate H H H NH-aoetyl monophosphate H H H NH-cyclopropyl monophosphate H H H NH-methyl monophosphate H H H NH-ethyl monophosphate H H H OH monophosphate H H H O-acetyl monophosphate H H H OMe monophosphate H H H OEt monophosphate H H H O-cyclopropyl monophosphate H H H SH monophosphate H H H SMe monophosphate H H H SEt monophospliate H H H S-cyclopropyl diphosphate H H H NH 2 diphosphate H H H NH-acetyl diphosphate H H H NH-cyclopropyl diphosphate H H H NH-methyl 129 WO 01/90121 PCTUS01/16671 R R 2 R X Y diphosphate H H H NH-ethyl diphosphate H H H OH diphosphate H H H O-acetyl diphosphate H H H OMe diphosphate H H H OEt diphosphate H H H O-cyclopropyl, diphosphate H H H SH diphosphate H H H SMe diphosphate H H H SEt diphosphate H H H S-cyclopropyl triphosphate H H H NH2 triphosphate H H H NH-acetyl triphosphate H H H NH-cyclopropyl triphosphate H H H NH-methyl triphosphate H H H NH-ethyl triphosphate H H H OH triphosphate H H H OMe triphosphate H H H OEt tiphosphate H H H 0-cyclopropyl triphosphate H H H O-acetyl triphosphate H H H SH triphosphate H H H SMe triphosphate H H H SEt triphosphate H H H S-cyclopropyl monophosphate monophosphate monophosphate H NH 2 monophosphate monophosphate monophosphate H NH-cyclopropyl monophosphate monophosphate monophosphate H OH diphosphate diphosphate diphosphate H NH 2 diphosphate diphosphate diphosphate H NH-cyclopropyl diphosphate diphosphate diphosphate H OH triphosphate triphosphate triphosphate H NH 2 130 WO 01/90121 PCT/US01/16671 R R2 R' X5 IY triphosphate triphosphate triphosphate H NH-cyclopropyl triphosphate triphosphate triphosphate H OH H H H F NH2 H H H F NE-cyclopropy H H H F OH H H H Cl NH2 H H H CI NH-cyclopropyl H H |H Cl OH H H H Br NH2 H H H Br NH-cyclopropyl H H H Br OH H H H NH 2 N2 H H H NH 2 NH-cyclopropyl H H H NH2 OH H H H SH NH 2 H H H SH NH-cyclopropyl H H H SH OH acetyl H H H NH2 acetyl H H H NH-cyclopropyl acetyl H H H OH acetyl H H F NH2 acetyl H H F NI-cyclopropyl acetyl H H F OH H acetyl acetyl H NH2 H acetyl acetyl H NII-cyclopropyl H acetyl acetyl H OH acetyl acetyl acetyl H NH 2 acetyl acetyl acetyl H NH-cyclopropyl acetyl acetyl acetyl H OH monophosphate acetyl acetyl H NH2 monophosphate acetyl acetyl H NH-cyclopropyl 131 WO 01/90121 PCT/USOI/16671 Ri' i 2 iX Y monophosphate acetyl acetyl H OH diphosphate acetyl acetyl H NH 2 diphosphate acetyl acetyl H NH-cyclopropyl diphosphate acetyl acetyl H OH triphosphate acetyl acetyl H NH 2 triphosphate acetyl acetyl H NH-cyclopropyl triphosphate acetyl acetyl H OH Alternatively, the following nucleosides of Formula X are prepared, using the appropriate sugar and pyrimidine or purine bases. R O Base x

OR

2

OR

3 5 (X) wherein: i- VX Base H H H CH 3 0 2,4-0 Diacetyluracil H H H CH 3 0 Hypoxanthine H H H CH3 0 2,4-0 Diacetythymine H H H CH3 0 Thymine H H H CH 3 0 Cytosine H H H CH3 0 4-(N-mono acetyl)cytosine H H H CH 3 0 4-(N,N diacetyl)cytosine H H H CH 3 0 UTacil 132 WO 01/90121 PCTfUS01/16671 3 2 RR X Base H H H CH3 0 5-Fluorouracil H H H CH 3 S 2,4-0 Diacetyluraci H H H CH 3 S Hypoxanthine H H H CH 3 S 2,4-0 Diacetyithymine H H H CH3 S Thyimine H H H CH 3 S Cytosine H H H CH3 S 4-(N-mono acetyl)cytosine H H H CH 3 S 4-(NN diacetyl)cytosine Hf H H CH 3 S Uracil H H H CH 3 S 5-Fluorouracil monophosphate H H CH 3 0 2,4-0 Diacetyluracil monophosphate H H CH 3 0 Hypoxanthine monophosphate H H CH 3 0 2,4-0 Diacetylthym monophosphate H H CH 3 O Thymine monophosphate H H CH 3 O Cytosine monophosphate H H CH3 0 4-(N-mono acetyl)oytosine monophosphate H H CH 3 0 4-(N,N diacetyl)cytosine monophosphate H H CH 3 0 Uracil monophosphate H H CH 3 0 5-Fluorouracil monophosphate H H CH 3 S 2,4-0 Diacetyluracil monophosphate H H CH 3 S Hypoxanthine monophosphate H H4 CH3 S 2,4-0 Diacetylthym 133 WO 01/90121 PCT'US01/16671 Re R R R X Base monophosphate H H CH 3 S Thymine monophosphate H H CH3 S Cytosine monophosphat H H CN3 S 4-(N-mono acetyl)cytosine monophosphate H H CH 3 S 4-(NN diacetyl)oytosine monophosphate H H CH3 S Uracil monophosphate H H CH 3 S 5-Fluorouracil diphosphate H H CH 3 0 2,4-0 Diacetyluracil diphosphate H H CH3 0 Hypoxanthine diphosphate H H CH 3 0 2,4-0 Diacetylthymine diphosphate H H CH3 0 Thymine diphosphate H H CH 3 0 Cytosine diphosphate H H CH 3 ) 4-(N-mono acetyl)cytosine diphosphate H H CH 3 0 4-(N,N diacetyl)cytosine diphosphate H H CH3 0 Uracil diphosphate H H CH 3 0 5-Fluorouracil diphosphate H H CH3 S 2,4-0 Diacetyluracil diphosphate H H CH 3 S Ilypoxanthine diphosphate H H CH 3 S 2,4-0 Diacetylthym diphosphate H H CH3 S Thymine diphosphate H H CH3 S Cytosine triphosphate H H CH 3 0 2,4-0 Diacetyluracil triphosphate H H C113 O Hypoxanthine 134 WO 01/90121 PCTIUSO1/16671 R '2 R X Base triphosphate H H CH3 0 2,4-0 Diacetylthymine triphosphate H H CH 3 0 Thymine triphosphate H H CH 3 0 Cytosine triphosphate H H CH3 O 4-(N-mono acetyl)cytosine triphosphate H H CH3 O 4-(NN diacetyl)cytosine triphosphate H H CH3 0 Uracil triphosphate H H Ci3 0 5-Fluorouracil triphosphate H H CH 3 S 2,4-0 Diacetyluracil triphosphate H H CH 3 S Hypoxanthine triphosphate H H CH 3 S 2,4-0 Diacetylthymine triphosphate H H CH 3 S Thymine triphosphate H H CH3 S Cytosine monophosphate monophosphate monophosphate CF 3 0 2,4-0 Diacetyluracil monophosphate monophosphate monophosphate CF 3 0 Hypoxanthine monophosphate monophosphate monophosphate CF 3 0 2,4-0 Diacetylthymine nonophosphate monophosphate monophosphate CF 3 0 Thymine monophosphate monophosphate monophosphate CF 3 0 Cytosine monophosphate monophosphate monophosphate CF 3 0 4-(N-mono acetyl)cytosine monophosphate monophosphate monophosphate CF 3 0 4-(NN diacetyl)cytosine monophosphate imonophosphate monophosphate CF 3 0 Uracil monophosphate monophosphate monophosphate CF 3 0 5-Fluorouracil monophosphate monophosphate monophosphate CF 3 S 2,4-0 Diacetyluracil 135 WO 01/90121 PCT/US01/16671 R R - R R X Base monophosphate monophosphate monophosphate CF 3 S Hypoxanthine monophosphate monophosphate monophosphate CF 3 S 2,4-0 Diacetylthymine monophosphate monophosphate monophosphate CF 3 S Thymine monophosphate monophosphate monophosphate CF 3 S Cytosine monophosphate monophosphate monophosphate CF 3 S 4-(N-mono acetyl)cytosine monophosphate monophosphate monophosphate CF 3 S 4-(N,N diacetyl)cytosine inonophosphate monophosphate monophosphate CF 3 S Uracil monophosphate monophosphate monophosphate CF 3 S 5-Fluorouracil acetyl acetyl acetyl CF 3 0 4-(N,N diacetyl)cytosine acetyl acetyl acetyl CF 3 S 4-(N,N diacetyl)cytosine acetyl acetyl acetyl 2-bromo- 0 4-(NN vinyl diacetyl)cytosine acetyl acetyl acetyl 2-bromo- S 4-(N,N vinyl diacetyl)cytosine H H H CH 3 0 2-(N,N-diacetyl) guanine H H H CH3 0 6-0-acetyl guanine H H H CH 3 0 8-fluoroguanine H H H CH3 0 guanine H H H CH3 0 6-(NN-diacetyl) adenine H H H CH3 0 2-fluoroadenine H H H CH 3 0 8-fluoroadenine H H H CH 3 0 2,8-difluoro adenine H H H C-I 3 0 adenine 136 WO 01/90121 FCTtUS01/16671 R' -R 2 -RW X Base H H H CH 3 S 2-(NN-diacetyl) guamne H H H CH 3 S 6-0-acetyl guanine H H H CH3 S 8-fluoroguanine H H H CH3 S guanine H H H CH 3 S 6-(NN-diacetyl) adenine H H H CH 3 S 2-fluoroadenine H H H CH 3 S 8-fluoroadenine H H H CIt S 2,8-difluoro adenine H H H CH 3 S adenine monophosphate H H CH 3 0 2-(NN-diacetyl) guanine monophosphate H H CH 3 0 6-0-acetyl guanine monophosphate H H CH3 0 8-fluoroguanine monophosphate H H CH3 O guanine monophosphate H H CH 3 0 6-(NN-diaetyl) adenine monophosphate H H CH 3 0 2-fluoroadenine monophosphate H H CH 3 0 8-fluoroadenine monophosphate Hf H CH3 O 2,8-difluoro Sadenin monophosphate H H CH 3 0 adenine monophosphate H H CH 3 S 2-(NN-diacetyl) guanine monophosphate H H CH 3 S 6-0-acetyl guanine monophosphate H H CH3 S 8-fluoroguanine monophosphate H H CH 3 S guanine 137 WO 01/90121 PCT/US01/16671 RR R* X Base monophosphate H H CH 3 S 6-(NN-diacetyl) adenine monophosphate H H CH 3 S 2-fluoroadenine monophosphate H H CH3 S 8-fluoroadenine monophosphate H H CH 3 S 2,8-difluoro adenine monophosphate H H CH3 S adenine diphosphate H H CH 3 0 2-(NN-diacetyl) guanine diphosphate H H CH 3 0 6-0-acetyl guanine diphosphate H H CH 3 0 8-fluoroguanine diphosphate T H CH 3 0 guanine diphosphate H H CH3 0 6-(NN-diacetyl) adenine diphosphate H H CH 3 0 2-fluoroadenine diphosphate H H CH 3 0 8-fluoroadenine diphosphate H H CH3 0 2,8-difluoro adenine diphosphate H H CH3 0 adenine diphosphate H H CH 3 S 2-(NN-diacety) guanine diphosphate H H CH 3 S 6-0-acetyl guanine diphosphate H H CH 3 S 8-fluoroguanine diphosphate H H CH 3 S guanine diphosphate H H CH3 S 6-(NN-diacetyl) adenine diphosphate H H CH3 S 2-fluoroadenine diphosphate H H CH3 S 8-fluoroadenine diphosphate H H C113 S 2,8-difluoro adenine 138 WO 01/90121 PCTIUS01/16671 R 2 Rr X Base diphosphate H H CH 3 S adenine triphosphate H H CH3 0 2-(NN-diacetyl) guanine triphosphate H H CH 3 0 6-0-acetyl guanine triphosphate H H CH 3 0 8-fluoroguanine triphosphate H H CH 3 0 guanine triphosphate H H CH 3 0 6-(NN-diacetyl) adenine triphosphate H H CH 3 0 2-fluoroadenine triphosphate H H CH 3 0 8-fluoroadenine triphosphate H H CH 3 0 2,8-difluoro adenine triphosphate H H CH 3 0 2-(NN-diacetyl) guanine triphosphate H H CH 3 S 6-0-acetyl guanine triphosphate H H CH 3 S 8-fluoroguanine triphosphate H H CH3 S guanine triphosphate H H CH 3 S 6-(NN-diacetyl) adenine triphosphate H H CH 3 S 2-fluoroadenine triphosphate H H CH3 S 8-fluoroadenine triphosphate H H CH 3 S 2,8-difluoro adenine triphosphate H H CH 3 S adenine monophosphate monophosphate monophosphate CF 3 0 2-(N,N-diacety1) guanine monophosphate monophosphate monophosphate CF 3 0 6-0-acetyl guanine monophosphate monophosphate monophosphate CF 3 0 8-fluoroguanine monophosphate monophosphate monophosphate CF 3 0 guanine 139 WO 01/90121 PCTIUS01/16671 2 .R R X Base monophosphate monophosphate monophosphate CF 3 0 6-(NN-diacetyl) adenine monophosphate monophosphate monophosphate CF 3 0 2-fluoroadenine monophosphate monophosphate monophosphate CF 3 0 8-fluoroadenine monophosphate monophosphate monophosphate CF 3 0 2,8-difluoro adenine monophosphate monophosphate monophosphate CF 3 0 adenine monophosphate monophosphate monophosphate CF 3 S 2-(NN-diacetyl) guanine monophosphate monophosphate monophosphate CF 3 S 6-0-acetyl guanine monophosphate monophosphate monophosphate CF 3 S 8-fluoroguanine monophosphate monophosphate monophosphate CF 3 S guanine monophosphate monophosphate monophosphate CF 3 S 6-(NN-diacetyl) adenine monophosphate monophosphate monophosphate CF 3 S 2-fluoroadenine monophosphate monophosphate monophosphate CF 3 S 8-fluoroadenine monophosphate monophosphate monophosphate CF3 S 2,8-difluoro adenine monophosphate monophosphate monophosphate CF 3 S adenine acetyl acetyl acetyl CF 3 0 guanine acetyl acetyl acetyl CF 3 S guanine acetyl acetyl acetyl 2-brono- 0 guanine vinyl acetyl acetyl acetyl 2-bromo- S guanine vinyl Alternatively, the following nucleosides of Formula XI are prepared, using the appropriate sugar and pyrimidine or purine bases. 140 WO 01/90121 PCT/USO1/16671 RIO Base X

OR

2

R

7 (XI) wherein: Rl R 2 R7 R X Base H H H CH 3 0 2,4-0-Diacetyluracil H H H CH 3 0 Hypoxanthine H H H CH 3 0 2,4-0-Diacetylthymine H H H CH3 0 Thymine H H H CH3 0 Cytosine H H H CH 3 0 4-(N-mono acetyl)cytosine H H H CH 3 0 4-(N,N-diacetyl)cytosine H H H CH 3 0 Uracil H H H CH 3 0 5-Fluoiouracil H H H CH3 S 2,4-0-Diacetyluracil H H H CH 3 S Hypoxanthine H H H CH3 S 2,4-0-Diacetylthymine H H H CH 3 S Thymine H H H CH 3 S Cytosine H H H CH3 S 4-(N-mono-acetyl)cytosin H H H CH 3 S 4-(NN-diacetyl)cytosine H H H CH 3 S Uracil H H H CH 3 S 5-Fluorouracil

CH

3 monophosphate H H CH3 2,4-O-Diacetyluracil monophosphate H H CH 3 0 Hypoxanthine monophosphate H H CH-3 0 2,4-0-Diacetylthymine 141 WO 01/90121 PCTIUSG1/16671 R' RR *X Base monophosphate H H CH 3 0 Thymine monophosphate H H CH 3 0 Cytosine monophosphate H H CH 3 0 4-(N-mono acetyl)cytosine monophosphate H H CH 3 0 4-(NN-diacety1)cytosine monophosphate H H CH 3 0 Uracil monophosphate H H CH3 0 5-Fluorouracil monophosphate H H CH 3 S 2,4-0-Diacetyluracil monophosphate H H CH3 S Hypoxanthine monophosphate H H CH 3 S 2,4-0-Diacetylthymine monophosphate H H CH 3 S Thymine monophosphate H H CH 3 S Cytosine monophosphate H H CH3 S 4-(N-mono acetyl)cytosine monophosphate H H CH 3 S 4-(N,N-diacetyl)cytosine monophosphate H H CH3 S Uracil monophosphate H H CH 3 S 5-Fluorouracil diphosphate H H CH3 0 2,4-0-Diacetylurac diphosphate H H CH 3 0 Hypoxanthine diphosphate H H CH 3 0 2,4-0-Diacetylthymine diphosphate H H CH3 0 Thymine diphosphate H H CH3 0 Cytosine diphosphate H H CH 3 0 4-(N-mono acetyl)cytosine diphosphate H H CH3 0 4-(N,N-diacetyl)cytosine diphosphate H H CH 3 0 Uracl diphosphate H H CH3 0 5-Fluorouracil diphosphate H H CH3 S 2,4-0-Diacetyluracil diphosphate H H CH 3 8 Hypoxanthine diphosphate H H CH3 S 2,4-0-Diacetylthym diphosphate H H CH3 S Thymine 142 WO 01/90121 PCT/USO1/16671 RR2 R R*X Base diphosphate H H CH 3 S Cytosine triphosphate H H CH 3 0 2,4-0-Diacetyluracil triphosphate H H CH 3 0 Hypoxanthine triphosphate H H CH 3 0 2,4-0-Diacetylthymine triphosphate H H CH 3 0 Thymine triphosphate H H CH 3 0 Cytosine triphosphate H H CH 3 0 4-(N-mono acetyl)cytosine triphosphate H H CH 3 0 4-(NN-diacetyl)cytos triphosphate H H CH 3 0 Uracil triphosphate H H CH 3 0 5-Fluorouracil triphosphate H H CH 3 S 2,4-O-Diacetyluracil triphosphate H H CH 3 S Hypoxanthine triphosphate H H CH3 S 2,4-0-Diacetylthym triphosphate HA H CH3 S Thymine tiphosphate H H CH 3 S Cytosine monophosphate monophosphate Br CF 3 0 2,4-0-Diacetyluracil monophosphate monophosphate Br CF 3 0 Hypoxanthine monophosphate monophosphate Br CF 3 0 2,4-0-Diacetylthymine monophosphate monophosphate Br CF 3 0 Thymine monophosphate monophosphate Br CF 3 0 Cytosine monophosphate monophosphate Br CF 3 0 4-(N-mono acetyl)cytosine monophosphate monophosphate Br CF 3 0 4-(NN-diacetyl)cytosine monophosphate monophosphate Br CF 3 0 Uracil monophosphate monophosphate Br CF 3 0 5-Fluorouracil. monophosphate monophosphate Br CF 3 S 2,4-0-Diacetyluracil monophosphate monophosphate Br CF 3 S Hypoxanthine nonophosphate monophosphate Br CF 3 S 2,4-0-Diacetylthymine monophosphate monophosphate Br CF 3 S Thymine monophosphate monophosphate Br CF 3 S Cytosine 143 WO 01/90121 PCT/USO1/16671 R R R7 R X Base monophosphate monophosphate Br CF 3 S 4-(N-mono acetyl)cytosine monophosphate monophosphate Br CF 3 S 4-(NN-diacetyl)cytos monophosphate monophosphate Br CF 3 S Uracil monophosphate monophosphate Br CF 3 S 5-Fluorouracil acetyl acetyl N02 CF 3 0 4-(NN-diacetyl)cytosine acetyl acetyl N02 CF 3 S 4-(N,N-diacetyl)cytosine acetyl acetyl N02 CF 3 0 4-(NN-diacety)cytosine acetyl acetyl N02 2-bromo- S 4-(NN-diacetyl)cytosine vinyl Alternatively, the following nucleosides of Formula XII are prepared, using the appropriate sugar and pyrimidine or purine bases. RIO Base x R6 5 (XII) wherein: RJR X Base U CH3 0 2,4-0-Diacetyluracil H CH 3 0 Hypoxanthine H CH 3 0 2,4-0-Diacetythymine H CH3 0 Thymine H CH 3 0 Cytosine H CH 3 0 4-(N-mono-acetyl)cytosine H CT 3 0 4-(NN-diacetyl)cytosine H CH 3 0 Uracil H CH 3 0 5-Fluorouracil 144 WO 01/90121 PCT'USO1/16671 R Ra XBase H CH S 2,4-0-Diacetyluracil H CH 3 S Hypoxanthine H CH 3 S 2,4-0-Diacetylthymine H CH3 s Thymine H CH 3 S Cytosine H CH 3 S 4-(N-mono-acetyl)cytosine H CH 3 S 4-(NN-diacetyl)cytosine H CH3 8 Uracil H CH 3 S 5-Fluorouracil monophosphate CH 3 0 2,4-0-Diacetyluracil monophosphate CH 3 0 Hypoxanthine monophosphate CH 3 0 2,4-0-Diacetythymine monophosphate CH 3 0 Thymine monophosphate CH 3 0 Cytosine monophosphate CH 3 0 4-(N-mono-acetyl)cytosine monophosphate CH 3 0 4-(NN-diacetyl)cytosine monophosphate CH 3 0 Uracil monophosphate CH 3 0 5-Fluorouracil monophosphate CH 3 S 2,4-0-Diacetyluracil monophosphate CH 3 S Hypoxanthine monophosphate CH 3 S 2,4-0-Diacetythymine monophosphate CH 3 S Thymine monophosphate CH 3 S Cytosine inonophosphate CH 3 S 4-(N-mono-acetyl)cytosine monophosphate CH 3 S 4-(N,N-diacetyl)cytosine monophosphate CH 3 S Uracil monophosphate CH 3 S 5-Fluorouracil diphosphate CH 3 0 2,4-0-Diacetyluracil diphosphate CH 3 0 Hypoxanthine diphosphate CH 3 0 2,4-0-Diacetylthymine diphosphate CI 3 0 Thymine 145 WO 01/90121 PCTUSO1/16671 RR X Base diphosphate CH 3 0 Cytosine diphosphate CH 3 0 4-(N-mono-acetyl)cytosine diphosphate CU 3 0 4-(NN-diacetyl)cytosine diphosphate CH 3 0 Uracil diphosphate CH 3 0 5-Fluorouracil diphosphate CH3 S 2,4-0-Diacetyluxacil diphosphate CH 3 S Hypoxanthine diphosphate CH 3 S 2,4-0-Diacetylthymine diphosphate CH 3 S Thymine diphosphate CH 3 S Cytosine triphosphate CI 3 0 2,4-O-Diacetyluracil triphosphate CH 3 0 Hypoxanthine triphosphate CH 3 0 2,4-0-Diacetylthymine triphosphate CH 3 0 Thymine triphosphate CH 3 0 Cytosine triphosphate CH3 0 4-(N-mono-acetyl)cytosine triphosphate CH 3 0 4-(NN-diacetyl)cytosine triphosphate CH 3 0 Uracil triphosphate CH3 0 5-Fluorouracil triphosphate CH 3 S 2,4-O-Diacetyluracil triphosphate CH 3 S Hypoxanthine triphosphate CH 3 S 2,4-ODiacetylthymine triphosphate CH3 S Thymine triphosphate CH 3 S Cytosine monophosphate CF 3 0 2,4-0-Diacetyluracil monophosphate CF 3 0 Hypoxanthine monophosphate CF 3 0 2,4-0-Diacetylthymine monophosphate CF 3 0 Thymine monophosphate CF 3 0 Cytosine monophosphate CF 3 0 4-(N-mono-acetyl)cytosine monophosphate CF 3 0 4-(NN-diacetyl)cytosine 146 WO 01/90121 PCTUS01/16671 RI R*X Base monophosphate CF 3 0 Uracil monophosphate CF 3 0 5-Fluorouracil monophosphate CF 3 S 2,4-0-Diacetyluracil monophosphate CF 3 S Hypoxanthine monophosphate CF 3 S 2,4-0-Diacetylthyrine monophosphate CF 3 S Thymine monophosphate CF 3 S Cytosine monophosphate CF 3 S 4-(N-mono-acetyl)cytosine monophosphate CF 3 S 4-(NN-diaoety1)cytosine monophosphate CF 3 S Uracil monophosphate CF 3 S 5-Fluorouracil acetyl CF 3 0 4-(NN-diacetyl)cytosine acetyl CF 3 S 4-(NN-diacetyl)cytosine acetyl 2-brono-vinyl 0 4-(NN-diacetyl)cytosine acetyl 2-bromo-vinyl S 4-(NN-diacety1)cytosine Alternatively, the following nucleosides of Formula XVII are prepared, using the appropriate sugar and pyrimidine or purine bases. RIO Base 10 6 R x 0R

R

9

R

7 5 (XVII) wherein: RiRT X Base R! R H CH3 H 0 2,4-0-Diacetyluracil NHAc Me H CH 3 H 0 Hypoxanthine NH2 Me H CH 3 H 0 2,4-0-Diacetylthymine NHAc Me H CH 3 H 0 Thyrnine NH2 Me 147 WO 01/90121 PCTrUS01/16671 RIT' X Base R R H CH3 H 0 Cytosine NH2 Me H CH3 H 0 4-(N-mono-acetyl)cytosine NHAc Me H CH 3 H 0 4-(N,N-diacetyl)cytosine NHAc Me H CH 3 H 0 Uracil NI2 Me H CH3 H 0 5-Fluorouracil NH2 Me H CH 3 H S 2,4-0-Diacetyluracil NHAc Me H CH 3 H 'S Hypoxanthine NH2 Me H CH3 H S 2,4-0-Diacetylthyniine NHAc Me H CH 3 H S Thymine NH2 Me H CH 3 H S Cytosine NH2 Me H CH 3 H S 4-(N-mono-acetyl)cytosine NHAc Me H CH 3 H S 4-(N,N-diacetyl)cytosine NHAc Me H CH 3 H S Uracil NH2 Me H CH 3 H S 5-Fluorouracil NH2 Me monophosphate C13 H 0 2,4-0-Diacetyluracil NHAc Me monophosphate CH 3 H 0 Hypoxanthine NH2 Me monophosphate CH 3 H 0 2,4-0-Diacetythymine NHAc Me monophosphate CH 3 H 0 Thymine NH2 Me monophosphate CH 3 H 0 Cytosine NH2 Me monophosphate CH 3 H 0 4-(N-mono-acetyl)cytosine NHAC Me monophosphate CH 3 H 0 4-(NN-diacetyl)cytosine NHAc Me monophosphate CH 3 H 0 Uracil NH12 Me monophosphate CH3 H 0 5-Fluorouracil NH2 , Me monophosphate CH 3 H S 2,4-0-Diacetyluracil NHAc Me monophosphato CH 3 H S Hypoxanthine NH2 Me monophosphate CH3 H S 2,4-0-Diacetylthymine NHAc Me monophosphate CH 3 H S Thymine NH2 Me monophosphate CH3 H S Cytosine NH2 Me ionophosphate CH3 H S 4-(N-mono-acetyl)cytosine NHAc Me monophosphate CH3 H S 4-(NN-diacetyl)cytosine NHAc Me monophosphate CH3 H S Uracil NH2 Me 148 WO 01/90121 PCTfUSO1/16671 RI RV R X Base Rj RW monophosphate CH 3 H S 5-Fluorouracil NH2 Me diphosphate CH H 0 2,4-0-Diacetyluracil NHAc Me diphosphate CH3 H 0 Hypoxanthine NH2 Me diphosphate CH3 H 0 2,4-0-Diacetylihymine NH2 Me diphosphate CH 3 H 0 Thymine NH2 Me diphosphate CH 3 H 0 Cytosine NH12 Me diphosphate CH 3 H 0 4-(N-mono-acetyl)cytosine NHAc Me diphosphate CH 3 H 0 4-(N,N-diacetyl)cytos NHAc Me diphosphate CH 3 H 0 Uracil NH2 Me diphosphate CH 3 H 0 5-Fluorouracil NH2 Me diphosphate CH 3 H S 2,4-0-Diacetyluracil NH2 Me diphosphate CH 3 H S Hypoxanthine NH2 Me diphosphate CH 3 H S 2,4-0-Diacetylthymine NHAc Me diphosphate CH 3 H S Thymine NH2 Me diphosphate CH3 H S Cytosine NH2 Me triphosphate CH3 H 0 2,4-0-Diacetyluracil NHAc Me triphosphate CH 3 H 0 Hypoxanthine NHAc Me triphosphate CH 3 H 0 2,4-0-Diacetylthymnde NHAc Me triphosphate CH 3 H 0 Thymine NH2 Me triphosphate Cn 3 H 0 Cytosine NH2 Me triphosphate CH 3 H 0 4-(N-mono-acetyl)cytosine NHAc Me triphosphate CH 3 H 0 4-(N,N-diacetyl)cytosine N112 Me triphosphate CH 3 H 0 Uracil NH2 Me triphosphate CH 3 H 0 5-Fluorouracil NH2 Me triphosphate CH3 H S 2,4-0-Diacetyluracil NH2 Me triphosphate CH 3 H S Hypoxanthine NH2 Me triphosphate CH 3 H S 2,4-0-Diacetylthyniine NH2 Me triphosphate CH3 H S Thymine NH2 Me triphosphate CH 3 H S Cytosine NH2 Me monophosphate CF 3 H 0 2,4-0-Diacetyluracil NH2 Me monophosphate CF 3 H 0 Hypoxantlhine NH2 Me 149 WO 01/90121 PCTUSOI/16671 R Rel X Base R monophosphate CF 3 H 0 2,4-0-Diacetylthynine NH2 Me monophosphate CF 3 H 0 Thymine NH2 Me monophosphate CF 3 H 0 Cytosine NH2 Me monophosphate CF 3 H 0 4-(N-mono-acetyl)cytosine NH2 Me monophosphate CF 3 H 0 4-(N,N-diacetyl)cytosine NH2 Me monophosphate CF 3 11 0 Uracil NH2 Me monophosphate CF 3 H 0 5-Fluorouracil NH2 Me monophosphate CF3 H S 2,4-0-Diacetyluracil NH2 Me monophosphate CF 3 H S Hypoxantbine NH2 Me monophosphate CF 3 H S 2,4-0-Diacetylthymine NH2 Me monophosphate CF 3 H S Thymine NH2 Me monuophosphate CF 3 H S Cytosine N112 Me monophosphate CF 3 H S 4-(N-mono-acetyl)cytosine NH2 Me monophosphate CF 3 H S 4-(N,N-diacetyl)cytosine NH2 Me monophosphate CF 3 H S Uracil N12 Me monophosphate CF 3 H S 5-Fluorouracil NH2 Me acetyl CH 3 H 0 4-(NN-diacetyl)cytosine H Br acetyl CH 3 H S 4-(NN-diacetyl)cytosine H Br acetyl CH 3 OH 0 4-(NN-diacetyl)cytosine H Br acetyl CH 3 OH S 4-(NN-diacetyl)cytosine H Br Example 3: Preparation of 3'-C-methylriboadenine The title compound can be prepared according to a published procedure (RY. Nutt, M.J. Dickinson, F.W. Holly, and E. Walton, "Branched-chain sugar nucleosides. II. 3'-C 5 methyladenine ", J. Org. Chem 1968, 33, 1789-1795) (Scheme 9). 150 WO 01/90121 PCT/USO1/16671 Scheme 9 BzO O BzO BzO OCH 0 0 O OH OH R =NHBz N HO Bzo N 0 , BzO $Z OCH3 OH OH BzO BzO OBz OBz (a) RuO 2 / NaIO 4 ; (b) MeMgI / TiC1 4 ; (c) HCi / MeOH / H20; (d) BzC1 I pyridine; (e) AcBr, HBr / AcOH; (f) chloromercuri-6-benzamidopurine; (g) NJ1 / MeOH. 5 In a similar manner, but using the appropriate sugar and pyrimidine or purine bases, the following nucleosides of Formula I are prepared. y N X2 R'O O ~-0

OR

2

OR

5 (IT') wherein: RIR aX1 X2 y H H H H H H H H H H H NH 2 H H H H H NH-cyclopropyl H H H H H NH-methyl H H H H H NH-ethyl H H H H H NH-acetyl H H H H H OH 151 WO 01/90121 PCT/US01/16671 RH R 2 R X2 y H H H H H OMe H H H H H OEt H H H H H 0-cyclopropyl H H H H H O-acetyl H H H H H SH H H H H H SMe H H H H H SEt H H H H H S-cyclopropyl H H H H H F H H H H H Cl H H H H H Br H H H H H I monophosphate H H H H NHt monophosphate H H H H NH-acetyl monophosphate H H H H NH-cyclopropyl naonophosphate H H H H NH-methyl monophosphate H H H H NH-ethyl monophosphate H H H H OH monophosphate H H H H O-acetyl monophosphate H H H H OMe monophosphate H H H H OEt monophosphate H H H H 0-cylopropy monophosphate H H H H SH monophosphate H H H H SMe monophosphate H H H H SEt monophosphate H H H H F monophosphate H H H H F monophosphate H H H H cl monophosphate H H H H Br ionophosphate H H H H I diphosphate H H H H NH 2 152 WO 01/90121 PCTUS01/16671 RI RR X1 X2 y diphosphate H H H H NH-acetyl diphosphate H H H H NH-cyclopropyl diphosphate H H H H NH-methyl diphosphate H H H H NH-ethyl diphosphate H H H H OH diphosphate H H H H 0-acetyl diphosphate H H H H OMe diphosphate H H H H OEt diphosphate H H H H O-cyclopropyl diphosphate H H H H SH diphosphate H H H H SMe diphosphate -H H H H SEt diphosphate H H H H S-cyclopropyl diphosphate H H H H F diphosphate H H H- H Cl diphosphate H H H H Br diphosphate H H H H I triphosphate H H H H NH 2 triphosphate H H H H NH-acetyl triphosphate H H H H NH-cyclopropyl triphosphate H H H H NH-methyl triphosphate H H H H NH-ethyl triphosphate H H H H OH triphosphate H H H H OMe triphosphate H H H H OEt triphospbate H H H H 0-cyclopropyl triphosphate H H H H O-acetyl triphosphate H H H H SH triphosphate H H H H SMe triphosphate H H H H SEt triphosphate H H H H S-cyclopropyl 153 WO 01/90121 PCT/US01/16671 triphosphate H H H H F triphosphate H H H Cl triphosphate H H H H Br triphosphate H H H H I monophosphate monophosphate monophosphate H H NH 2 monophosphate monophosphate monophosphate H H NH-cyclopropyl monophosphate monophosphate monophosphate H H OH monophosphate monophosphate monophosphate H H F monophosphate monophosphate monophosphate H H Cl diphosphate diphosphate diphosphate H H NH2 diphosphate diphosphate diphosphate H H NH4-cyclopropyl diphosphate diphosphate diphosphate H H OH diphosphate diphosphate diphosphate H H F diphosphate diphosphate diphosphate H H Cl triphosphate triphosphate triphosphate H H NH 2 triphosphate triphosphate triphosphate H H NH-cyclopropyl triphosphate triphosphate triphosphate H H OH triphosphate triphosphate triphosphate H H F triphosphate triphosphate triphosphate H H Cl H H H F H NH2 ~ H H H F H NI-cyclopropyl H H H F H OH H H H F H F H H H F H CI H H H Cl H NH 2 H H H CI H NH-cyclopropyl H H H Cl H OH H H H Cl H F H H H C1 H Cl H H H Br H NH 2 H H H Br H NH-cyclopropyl 154 WO 01/90121 PCTUS01/16671 R y H H H Br H OH H H H Br H F H H H Br H Cl H H H NH 2 H NH 2 H H H NH2 H NH-cyclopropyl H H H NH 2 H OH H H H NH 2 H F H H H NH2 H Cl H H H SH H NH2 H H H SH H NH-cyclopropyl H H H SH H OH H H H SH H F H H H SH H Cl acetyl H H H H NH2 acetyl H H H H NH-cyclopropyl acotyl H H H H OH acetyl H H H H F acetyl H H H H Cl acetyl H H F H Ni2 acetyl H H F H NH-cyclopropyl acetyl H H F H OH acetyl H H F H F acetyl H H F H Cl H acetyl acetyl H H NH 2 H acetyl acetyl H H NI--cyclopropyl H acetyl acetyl H H OH H acetyl acetyl H H F H acetyl acetyl H H Cl acetyl acetyl acetyl H H NH 2 acetyl acetyl acetyl H H NH-cyclopropyl acetyl acetyl acetyl H H OH 155 WO 01/90121 PCT/US01/16671 RX X y acetyl acetyl acetyl H H F acetyl acetyl acetyl H H C1 monophosphate acetyl acetyl H H NH 2 monophosphate acetyl acetyl H H NH-cyclopropyl monophosphate acetyl acetyl H H OH monophosphate acetyl acetyl H H F monophosphate acetyl acetyl H H Cl diphosphate acetyl acetyl H H NH 2 diphosphate acetyl acetyl H H NH-cyclopropyl diphosphate acetyl acetyl H H OH diphosphate acetyl acetyl H H F diphosphate acetyl acetyl H H Cl triphosphate acetyl acetyl H H NH 2 triphosphate acetyl acetyl H H NH-cyclopropyl triphosphate acetyl acetyl H H OH triphosphate acetyl acetyl H H F triphosphate acetyl acetyl H H Cl H H H H NH 2 H H H H H NH2 NH2 H H H H NH2 NH-cyclopropyl H H H H NH 2 NH-methyl H H H H NH 2 NH-ethyl H H H H NH2 NH-acetyl H H H H NH2 OH H H H H NH 2 OMe H H H H NH 2 OEt H H H H NH 2 0-cyclopropyl H H H H NH 2 0-acetyl H H H H NH 2 SH H H H H NH 2 SMe H H H H NH2 SEt 156 WO 01/90121 PCT/US01/16671 Rl -R2 X3 X2 y H H H H NH2 S-cyclopiopyl H H H H NH 2 F H H H NH 2 C l H H H H NH2 Br H H H NH2 I monophosphate H H H NH2 NH2 monophosphate H H H NH2 NH-acetyl monophosphate H H H NH2 NH-cyclopropyl monophosphate H H H NH2 NH-methy1 monophosphate H H H NH2 NH-ethyl monophosphate H H H NH2 OH monophosphate H H H NH2 0-acetyl monophosphate H H H NH2 OMe monophosphate H H H NH2 OEt monophosphate H H H NH2 O-cyclopropyl monophosphate H H H NH2 SH monophosphate H H H NH2 SMe monophosphate H H H NH2 SEt monophosphate H H H NH2 S-cyclopropyl monophosphate H H H NH2 F monophosphate H H H NH2 C1 mo-nopfiosphate H H H NH2 .Br monophosphate H H H NH2 I diphosphate H H H NH2 NH2 diphosphate H H H NH2 NH-acetyl diphosphate H H H NH2 NH-cyclopropy1 diphosphate H H H NH2 NH-mnethyl diphosphate H H H NH2 NH-ethyl diphosphate H H H H OH diphosphate H H0-acetyl diphosphate H H H NH2 OMe 157 WO 01/90121 PCT/US0I/16671 e R 2

R

3 X X Y diphosphate H H H NH2 OEt diphosphate H H H NH 2 0-cyclopropyl diphosphate H H H NH2 SH diphosphate H H H NH 2 SMe diphosphate H H H NH 2 SEt diphosphate H H H NH2 S-cyclopropyl diphosphate H H H NH2 F diphosphate H H H NH 2 Cl diphosphate H H H NH2 Br diphosphate H H H Ni2 I triphosphate H H H NH 2 NH2 triphosphate H H H NH 2 NH-acetyl triphosphate H H H NH 2 NH-Cyclopropy1 triphosphate H H H NH2 NH-methyl triphosphate H H H NH 2 NH-ethyl triphosphate H H4 H NH2 OH triphosphate H H H NH2 OMe triphosphate H H H NH 2 OEt triphosphate H H H NH 2 0-cyclopropyl triphosphate H H H NH 2 0-acetyl triphosphate H H H NH 2 SH triphosphate H H H NH 2 SMe triphosphate H H H NH 2 SEt triphosphate H H H NH 2 S-cyclopropyl triphosphate H H H Ni2 F triphosphate H H H NH 2 Cl triphosphate H H H NH2 Br triphosphate H H H NH2 I monophosphate monophosphate monophosphate H NH2 NH2 monophosphate maonophosphate monophosphate H NH 2 NH-cyclopropyl monophosphate monophosphate monophosphate H NH 2 OH 158 WO 01/90121 PCTIUS01/16671 RW R R X-w XwV = y monophosphate monophosphate monophosphate H NH 2 F monophosphate monophosphate monophosphate H NH2 Cl diphosphate diphosphate diphosphate H NH 2

NH

2 diphosphate diphosphate diphosphate H NH2 NH-cyclopropyl diphosphate diphosphate diphosphate H NH 2 OH diphosphate diphosphate diphosphate H NH2 F diphosphate diphosphate diphosphate H NH2 Cl triphosphate triphosphate triphosphate H NH2 NH 2 triphosphate triphosphate triphosphate H NH2 NH-cyclopropyl triphosphate triphosphate triphosphate H NH2 OH triphosphate triphosphate triphosphate H NH 2 F triphosphate triphosphate triphosphate H NH 2 Cl H H H P NH 2

NH

2 H H H F Ni2 NH-cyclopropyl H H H F NH 2 OH H H H F NH2 F H H H F NH2 Cl H H H Cl NH2 NH2 H H H Cl NH 2 NH-cyclopropyl H H H Cl NH2 OH H H H Cl NH2 F H H H Cl NH2 Cl H H H Br NH2 NH2 H H H Br NH 2 NH-cyclopropyl H H H Br NH 2 OH H H H Br NH 2 F H H H Br NH2 CI H H H NH 2 NH2 Ni2 H H H NH 2

NH

2 NH-cyclopropyl H H H NH2 NH2 OH H H [ NH 2

NH

2 F 159 WO 01/90121 PT/Us01/16671 Rx x y H H H NH 2

NH

2 Cl H H H SH NH 2 NH2 HSH NH 2 NH-cyclopropyl SH NH2 OH H H H SH Ni2 F H HSH NH2 C1 H 1 14SI Nil 2 Cl acetyl H H H NH 2

N

2 acetyl H H H NH2 NH-cyclopropyl acetyl H H H NH 2 OH acetyl H H H Nil 2 F acetyl H H H NH2 Cl acetyl H H F Ni2 NH2 acetyl H H F NH2 NH-cyclopropyl acetyl H H F NH2 OH acetyl H H F NH 2 F acetyl H H F NH 2 C H acetyl acetyl H NiH 2

NH

2 H acetyl acetyl H NH 2 NH-cyclopropyl H acetyl acetyl H NH 2 OH H acetyl acetyl H NH 2 F H acetyl acetyl H NH2 Cl acetyl acetyl acetyl H NH 2 NH2 acetyl acetyl acetyl H NH 2 NH-cyclopropyl acetyl acetyl acetyl H NH 2 OH acetyl acetyl acetyl H NH 2 F acetyl acetyl acetyl H NH2 Cl monophosphate acetyl acetyl H NH 2

NH

2 monophosphate acetyl acetyl H NH 2 NH-cyclopropyl monophosphate acetyl acetyl H NH 2 OH monophosphate acetyl acetyl H NH 2 F nonophosphate acetyl acetyl H NH2 C1 160 . WO 01/90121 PCT/USOI/16671 diphosphate acetyl acetyl H NH 2

NH

2 diphosphate acetyl acetyl H NH 2 NH-cyclopropyl diphosphate acetyl acetyl H NH 2 OH diphosphate acetyl acetyl H NH 2 F diphosphate acetyl acetyl H NH2 Cl triphosphate acetyl acetyl H NH2 NH2 triphosphate acetyl acetyl H NH 2 NH-cyclopropyl triphosphate acetyl acetyl H NH 2 OH triphosphate acetyl acetyl Hl NH 2 F triphosphate acetyl acetyl H NH 2 Cl H H H H Cl H H H H H Cl H H H H H Cl NH 2 H H H H C NH-cyclopropyl H H H H Cl NH-methyl H H H H Cl NH-ethyl H H H H Cl NH-acetyl H H H H Cl OH H H H H Cl OMe H H H H Cl OEt H H H H Cl 0-cyclopropyl H H H H Cl 0-acetyl H H H H C1 SH H H H H Cl SMe H H H H Cl SEt H H H H Cl S-cyclopropyl monophosphate H H H Cl NH2 monophosphate H H H Cl NH-acetyl monophosphate H H H Cl NH-cyclopropyl monophosphate H H H Cl NH-methyl monophosphate H H H C1 NH-ethyl 161 WO 01/90121 PCTUSQ1/16671 monophosphate H H H C1 OH monophosphate H H H C1 0-acetyl monophosphate H H H Cl OMe monophosphate H H H Cl OEt monophosphate H H H Cl O-cyclopropyl monophosphate H H H Cl SH monophosphate H H H Cl SMe monophosphate H H H Cl SEt monophosphate H H H Cl S-cyclopropyl diphosphate H H H Cl NH 2 diphosphate H H H Cl NH-acetyl diphosphate H H H Cl NH-cyclopropyl diphosphate H H H Cl NH-methyl diphosphate H H H Cl NH-ethyl diphosphate H H H Cl OH diphosphato H H H Cl 0-acetyl diphosphate H H H Cl OMe diphosphate H H H Cl OEt diphosphate H H H Cl 0-cyclopropyl diphosphate H H H Cl SH diphosphate H H H Cl SMe diphosphate H H H Cl SEt diphosphate H H H Cl S-cyclopropyl triphosphate H H H Cl NH 2 triphosphate H H H Cl NH-acetyl triphosphate H H H Cl NH-cyclopropyl triphosphate H H H C1 NH-methyl triphosphate H H H Cl NH-ethyl triphosphate H H H Cl OH triphosphate H H H Cl OMe triphosphate H H H Cl OEt 162 WO 01/90121 PCTUSO1/16671

R

3 Y triphosphate H H H Cl 0-cyclopropy1 triphosphate H H H C1 0-acetyl triphosphate H H H CI SH triphosphate H H H Cl SMe triphosphate H H H Cl SEt triphosphate H H H Cl S-cyclopropy1 monopliosphate monophosphate monophosphate H Cl NH 2 monophosphate monophosphate monophosphate H Cl NH-cyclopropyl monophosphate monophosphate monophosphate H C1 OH diphosphate diphosphate diphosphate H Cl NH 2 diphosphate diphosphate diphosphate H Cl NH-cyclopropyl diphosphate diphosphate diphosphate H CI OH triphosphate triphosphate triphosphate H Cl NH2 triphosphate triphosphate triphosphate H Cl NH-cyclopropyl triphosphate triphosphate triphosphate H Cl OH H H H F Cl NH2 H H H F Cl NH-cyclopropyl H H H F Cl OH H H H Cl Cl NH2 H H H Cl Cl NH-cyclopropyl H H H Cl Cl OH H H H Br Cl NH 2 H H H Br Cl NH-cyclopropyl H H H Br Cl OH H H H NH 2 Cl NH2 H H H NH 2 CJ NH-cyclopropyl H H H NH 2 Cl OH H H H SH C1 NH2 H H H SH Cl NH-cyclopropyl H H H SIT Cl OH acetyl H H H Cl NH2 163 WO 01/90121 .

.PCT/USO1/16671 acetyl H H H Cl NH-cyclopropyl acetyl H H H C1 OH acetyl H H F C1 NH 2 acetyl H H F Cl NH-cyclopropyl acetyl H H F Cl OH H acetyl acetyl H Cl NH 2 H acetyl acetyl H C1 NH-cyclopropyl H acetyl acetyl H C1 OH acetyl acetyl acetyl H Cl NH 2 acetyl acetyl acetyl H Cl NH-cyclopropyl acetyl acetyl acetyl H1 Cl OH monophosphate acetyl acetyl H1 CI NH 2 monophosphate acetyl acetyl H C1 NH-cyclopropyl monophosphate acetyl acetyl H Cl OH diphosphate acetyl acetyl H Cl NH 2 diphosphate acetyl acetyl H Cl NH-cyclopropyl diphosphate acetyl acetyl H Cl OH triphosphate acetyl acetyl H Cl NH 2 triphosphate acetyl acetyl H C1 NH-cyclopropyl triphosphate acetyl acetyl H Cl OH H H H H C1 NH2 H H H H Cl NH-cyclopropyl H H H H Cl OH H H H H Br NH 2 H H H H Br NH-cyclopropyl H H H H Br OH Alternatively, the following nucleosides of Formula VI are prepared, using the appropriate sugar and pyrimidine or purine bases. 164 WO 01/90121 PCT/USO1/16671 y

R

1 0 CH, .!O

-

a O, o

OR

2 OR (VI) wherein: R R2 R3 y H H H H H H H H H NH2 H H H H NH-cyclopropyl H H H H NH-methyl H H H H NH-ethyl H H H H NH-acetyl H H H H OH H H H H OMe H H H H OEt H H H H 0-cyclopropyl H H H H 0-acetyl H H H H SH H H H H SMe H H H H SEt H H H H S-cyclopropyl monophosphate H H H NH 2 monophosphate H H H NH-acetyl monophosphate H H H NH-cyclopropyl monophosphate H H H NH-methyl monophosphate H H H NH-ethyl monophosphate H H H OH monophosphate H H H 0-acetyl 165 WO 01/90121 PCT/US01/16671 monophosphate H H H OMe monophosphate H H H OEt monophosphate H H H 0-cyclopropyl monophosphate H H H SH monophosphate H H H SMe monophosphate H H H SEt monophosphate H H H S-cyclopropyl diphosphate H H H NH 2 diphosphate H H H NH-acetyl diphosphate H H H NH-cyclopropyl diphosphate H H H NH-methyl diphosphate H H H NE-ethyl diphosphate H H H OH diphosphate H H H 0-acetyl diphosphate H H H OMe diphosphate IT H H OEt diphosphate H H H O-cyclopropyl diphosphate H H H SIT diphosphate H H H SMe diphosphate H H H SEt diphosphate H H H S-cyclopropyl triphosphate H H H NH2 triphosphate H H H NH-acetyl triphosphate H H H NH-cyclopropyl triphosphate H H H NH-methyl triphosphate H H H NH-ethyl triphosphate H H H OH triphosphate H H H OMe triphosphate H H H OEt triphosphate H H H O-cyclopropyl triphosphate H H H 0-acetyl 166 WO 01/90121 PCT/USU1/16671 tiohe HH triphosphate H H H SIe triphosphate H H H SME triphosphate H- H H- SEt triphosphate H H H S-cyclopropyl monophosphate monophosphate monophosphate H NH2 monophosphate monophosphate monophosphate H NH-cyclopTopyl monophosphate monophosphate monophosphate H OH diphosphate diphosphate diphosphate H NH2 diphosphate diphosphate diphosphate H NH-cyclopropyl diphosphate diphosphate diphosphate H OH triphosphate triphosphate triphosphate H Ni2 triphosphate triphosphate triphosphate H NH-rcyclopropyl triphosphate triphosphate triphosphate H OH H H H F NH2 H H H F NH-cyclopropyl H H H F OH H H H Cl NH2 H H H Cl NH-cyclopropyl H H H Cl OH H H H Br Ni2 H H H Br NH-cyclopropyl H H H Br OH H H H NH 2

NH

2 H H H NH 2 NH-cyclopropyl H H H NH 2 OH H H H SH NH 2 H H H SH NH-cyclopropyl H H H SH OH acetyl H H H NH 2 acetyl H H H NH-cyclopropyl acetyl H H H OH 167 WO 01/90121 PCTUS01/16671 R R R'Xi Y acetyl H H F NI2 acetyl H H F NH-cyclopropyl acetyl H H F OH H acetyl acetyl H 1H 2 H acetyl acetyl H NH-cyclopropyl H acetyl acetyl H OH acetyl acetyl acetyl H NH2 acetyl acetyl acetyl H NH-cyclopropy1 acetyl acetyl acetyl H OH monophosphate acetyl acetyl H NH2 monophosphate acetyl acetyl H NH-cyclopropyl monophosphate acetyl acetyl H OH diphosphate acetyl acetyl H NEz diphosphate acetyl acetyl H NH-cyclopropyl diphosphate acetyl acetyl H OH triphosphate acetyl acetyl H NH2 triphosphate acetyl acetyl H NH-cyclopropyl triphosphate acetyl acetyl H OH Alternatively, the following nucleosides of Formula XIf are prepared, using the appropriate sugar and pyrimidine or purine bases. RO Base R' x

OR

2

OR

3 5 (XHI) wherein: R' R2 R X Base H H H CH 3 0 2,4-0 Diacetyluracil H H H CH3 O Hypoxanthine 168 WO 01/90121 PCT/US01/16671 R" R 2 RlR X Base H H H CH 3 0 2,4-0 Diacetyithymine H H H CH 3 O Thymine H H H CH3 0 Cytosine H H H CH4 3 0 4-(N-mono acetyl)cytosine H H H CH 3 0 4-(NN diacetyl)cytosine H H H CH 3 0 Uracil H H H CH 3 0 5-Fluorouracil H H H CH 3 S 2,4-0 Diacetyluraci H H H CH 3 S Hypoxanthine H H H CH 3 S 2,4-0 Diacetylthymiine H H H CH 3 S Thymine H H H CH 3 S Cytosine H H H CH3 S 4-(N-mono acetyl)cytosine H H H CH3 S 4-(NN diacetyl)cytosine H H U Ci3 S Uracil H H H CH 3 S 5-Fluorouracil monophosphate H H CH 3 0 2,4-0 Diacetyluracil monophosphate H H CH 3 O Hypoxanthine monophosphate H H CH3 0 2,4-0 Diacetylthym monophosphate H H CH 3 0 Thymine monophosphate H H CH3 0 Cytosine monophosphate H H CH 3 0 4-(N-mono acetyl)cytosine 169 WO 01/90121 PCTIUS0I/16671 2 R X Base monophosphate H H CH3 0 4-(NN diacetyl)cytosine monophosphate H H CH 3 0 Uracil monophosphate H H CH 3 0 5-Fluorouracil monophosphate H H CH3 S 2,4-0 Diacetyluracil monophosphate H H CH S Hypoxanthine monophosphate H H CH 3 S 2,4-0 Diacetylthyma nonophosphate H H CH 3 S Thymine monophosphate H H CH 3 S Cytosine monophosphate H H CH3 S 4-(N-mono acetyl)cytosine monophosphate H H CH 3 S 4-(NN diacetyl)cytosine monophosphate H H CH 3 S Uracil monophosphate H H CH 3 S 5-Fluorouracil diphosphate H H CH3 0 2,4-0 Diacetyluracil diphosphate H H CH 3 ) Hypoxanthine diphosphate H H CH 3 0 2,4-0 Diacetylthymine diphosphate H H CH3 0 Thymine diphosphate H H CH 3 0 Cytosine diphosphate H H CH 3 0 4-(N-mono acetyl)cytosine diphosphate H H CH 3 0 4-(N,N diacetyl)cytosine diphosphate H H CH 3 0 Uracil diphosphate H H CH3 0 5-Fluoronracil diphosphate H H CH 3 S 2,4-0 Diacetyluracil 170 WO 01/90121 PCT/US01/16671 Ri 2 R X Base diphosphate H H CH 3 S Hypoxanthine diphosphate H H CH 3 S 2,4-0 Diacetylthym diphosphate H H CH 3 S Thymine diphosphate H H CH 3 S Cytosine triphosphate H H CH 3 0 2,4-0 Diacetyluracil triphosphate H H CI 3 0 Hypoxanthine triphosphate H H CH 3 0 2,4-0 Diacetylthymine triphosphate H H CH 3 0 Thynine triphosphate H H CH 3 0 Cytosine triphosphate H H CH 3 0 4-(N-mono acetyl)cytosine triphosphate H H CH 3 0 4-(NN diacetyl)cytosine triphosphate H H CH 3 0 Uracil triphosphate H H CH 3 0 5-Fluorouracil triphosphate H H CH 3 S 2,4-0 Diacetyluracil triphosphate H H CH 3 S Hypoxanthine trphosphate H H CH 3 S 2,4-0 Diacetylthymine triphosphate H H CH 3 S Thymine triphosphate H H CH 3 S Cytosine monophosphate monophosphate monophosphate CF 3 0 2,4-0 Diacetyluracil monophosphate monophosphate monophosphate CF 3 0 Hypoxanthine monophosphate monophosphate monophosphate CF 3 0 2,4-0 Diacetylthymine manophosphate monophosphate monophosphate CF 3 0 Thymine monophosphate monophosphate monophosphate CF 3 0 Cytosine 171 WO 01/90121 PCT/USO1/16671 Ri R2 - X Base monophosphate monophosphate monophosphate CF 3 0 4-(N-mono acetyl)cytosine monophosphate monophosphate monophosphate CF 3 0 4-(NN diacetyl)cytosine monophosphate monophosphate monophosphate CF 3 0 Uracil monophosphate monophosphate monophosphate CF 3 0 5-Fluorouracil monophosphate inonophosphate monophosphate CF 3 S 2,4-0 Diacetyluracil monophosphate monophosphate monophosphato CF 3 S Hypoxanthine monophosphate monophosphate monophosphate CF 3 S 2,4-0 Diacetyithymine monophosphate monophosphate monophosphate CF 3 S Thymine monophosphate monophosphate monophosphate CF 3 S Cytosine monophosphate monophosphate monophosphate CF 3 S 4-(N-mono acetyl)cytosine monophosphate monophosphate monophosphate CF 3 S 4-(NN diacetyl)cytosine monophosphate monophosphate monophosphate CF 3 S Uracil monophosphate monophosphate monophosphate CF 3 S 5-Fluorouracil acetyl acetyl acetyl CF 3 0 4-(N,N diacetyl)cytosine acetyl acetyl acetyl CF 3 S 4-(N,N diacetyl)cytosine acetyl acetyl acetyl 2-bromo- 0 4-(N,N vinyl diacetyl)cytosine acetyl acetyl acetyl 2-bromo- S 4-(NN vinyl diacetyl)cytosine H H H CH 3 0 2-(NN-diacetyl) guanine H H H CH 3 0 6-0-acetyl guamno H H H CH 3 0 8-fhuoroguanine 172 WO 01/90121 PCT/US01/16671

RR

2 Rt R X Base H H H CH 3 0 guanine H H H CH 3 0 6-(N,N-diacetyl) adenine H H H CH3 0 2-fluoroadenine H H H CH 3 0 8-fluoroadenine H H H CH 3 0 2,8-difluoro adenine H H H CH 3 0 adenine H H H CH 3 S 2-(NN-diaoetyl) guanine H H H CH 3 S 6-0-acetyl guanine H H H CH 3 S 8-fluoroguanine H H H CH 3 S guanine H H H CH 3 S 6-(NN-diacetyl) adenine H H H CH3 S 2-fluoroadenine H H H CH 3 S 8-fluoroadenine H H H CH3 S 2,8-difluoro adenine H H H CH 3 S adenine monophosphate H H CH 3 0 2-(N,N-diacetyl) guanine monophosphate H H CH 3 0 6-0-acetyl guanine monophospliate H H CH 3 0 8-fluoroguanine monophosphate H H CH 3 0 guanine monophosphate H H CH3 0 6-(NN-diacetyl) adenine nsonophosphate H H CH3 0 2-fluoroadenine monophosphate H H CH3 0 8-fluoroadenine 173 WO 01/90121 PCT/US0I/16671 R R'R X Base monophosphate H H CH 3 0 2,8-difluoro adenine monophosphate H H CH 3 0 adenine monophosphate H H CH3 S 2-(NN-diacetyl) guanine monophosphate H H CH3 S 6-0-acetyl guanine monophosphate H H CH3 S 8-fluoroguanine monophosphate H H CH3 S guanine monophosphate H H CH3 S 6-(NN-diacetyl) adenine monophosphate H H CH3 S 2-fluoroadenine monophosphate H H CH3 S 8-fluoroadenine monophosphate H H CH3 S 2,8-difluoro adenine monophosphate H H CH 3 S adenine diphosphate H H C113 0 2-(NN-diacetyl) guanine diphosphate H H CH 3 0 6-0-acetyl guanine diphosphate H H CH 3 0 8-fluoroguanine diphosphate H H CH3 0 guanine diphosphate H H CH 3 0 6-(NN-diacetyl) adenine diphosphate H H CH 3 0 2-fluoroadenine diphosphate H H CH 3 0 8-fluoroadenine diphosphate H H Ci3 0 2,8-difluoro adenine diphosphate H H CR 3 0 adenine diphosphate H H CH 3 S 2-(N,N-diacetyl) guanine 174 WO 01/90121 PCTfUS01/16671 Re RaR * X Base diphosphate H H CH3 S 6-0-acetyl guanine diphosphate H H CH3 S 8-fluoroguanine diphosphate H H CH3 S guanine diphosphate H H CH3 S 6-(NN-diacetyl) adenine diphosphate H H CH3 S 2-fluoroadenine diphosphate H H CH3 S 8-fluoroadenine diphosphate H H CH 3 S 2,8-difluoro adenine diphosphate H H CI3 S adenine triphosphate H H CH3 0 2-(NN-diacetyl) guanine triphosphate H H CH3 0 6-0-acetyl guanine triphosphate H H CH3 0 8-fluoroguanine triphosphate H H CH3 0 guanine triphosphate H H CH3 0 6-(NN-diacetyl) adenine triphosphate H H CH3 0 2-fluoroadenine triphosphate H H CH 3 0 8-fluoroadenine triphosphate H H CH 3 0 2,8-difluoro adenine triphosphate H H CH3 0 2-(NN-diacetyl) guanine triphosphate H H CH3 S 6-0-acetyl guanine triphosphate H H CH3 S 8-fluoroguanine triphosphate H H CH, S guanine triphosphate H H CH, S 6-(NN-diacetyl) adenine triphosphate H H CH3 S 2-fluoroadenine 175 WO 01/90121 PCT/USO1/16671 R R 2 - R w X Base triphosphate H H CH3 S 8-fluoroadenine triphosphate H H CH3 S 2,8-difluoro adenine triphosphate H H CH 3 S adenine monophosphate monophosphate monophosphate CF 3 0 2-(N,N-diacetyl) guanine monophosphate monophosphate monophosphato CF 3 0 6-0-acetyl guanine monophosphate monophosphate monophosphate CF 3 0 8-fluoroguanine monophosphate monophosphate monophosphate CF 3 0 guanine monophosphate monophosphate monophosphate CF 3 0 6-(N,N-diacetyl) adenine monophosphate monophosphate monophosphate CF 3 0 2-fluoroadenine monophosphate monophosphate monophosphate CF 3 0 8-fluoroadenine monophosphate monophosphate monophosphate CF3 0 2,8-difluoro adenine monophosphate monophosphate monophosphate CF 3 0 adenine monophosphate monophosphate monophosphate CF 3 S 2-(NN-diacetyl) guanine monophosphate monophosphate inonophosphate CF 3 S 6-0-acetyl guanine monophosphate monophosphate monophosphate CF 3 S 8-fluoroguanine monophosphato monophosphate monophosphate CF 3 S guanine monophosphate inonophosphate monophosphate CF 3 S 6-(NN-diacetyl) adenine monophosphate monophosphate monophosphate CF 3 S 2-fluoroadenine monophosphate monophosphate monophosphate CF 3 S 8-fluoroadenine monophosphate monophosphate monophosphate CF 3 S 2,8-difluoro adenine monophosphate monophosphate monophosphate CF 3 S adenine acetyl acetyl acetyl CF 3 0 guanine acetyl acetyl acetyl CF 3 S guanine 176 WO 01/90121 PCT/USO1/16671 R1 R2 - R R Base acetyl acetyl acetyl 2-bromo- 0 guanine vinyl acetyl acetyl acetyl 2-bromo- S guanine vinyl Alternatively, the following nucleosides of Formula XIV are prepared, using the appropriate sugar and pyrimidine or purine bases. RIO Base -x -OR2 5 (XI wherein: R,' R2 XX Base H H CH3 0 2,4-0-Diacetyluracil H H CH 3 0 Hypoxanthine H H CH3 0 2,4-0-Diacetylthymine H H CH 3 0 Thymnine H H CH 3 0 Cytosine H H CH 3 0 4-(N-mono-acetyl)cytosine H H CH3 0 4-(NN-diacetyl)cytosine H H CH 3 0 Uracil H H CH 3 0 5-Fluorouracil H H CH 3 S 2,4-0-Diacetyluracil H H CH 3 S Hypoxanthine H H CH 3 S 2,4-0-Diacetylthymine H H CH 3 S Thymine H H CI 3 S Cytosine H H CH 3 S 4-(N-mono-acetyl)cytosin 177 WO 01/90121 PCT/US01/16671 X Base H H OH3 S 4-(N,N-diacetyl)cytosine

H-H

H H CH3 S Uracil H H OH 3 S 5-Fluorouracil monophosphate H CH 3 0 2,4-0-Diacetyluracil monophosphate H CH 3 0 Hypoxanthine monophosphate H C113 0 2,4-0-Diacetylthyiu monophosphate H CH 3 0 Thymine monophosphate H C113 0 Cytosine monophosphate H- CH3 0 4-(N-mono-acetyl)cytosine monophosphate H CH3 0 4-(NN-diacetyl)cytos monophosphate H CH 3 0 Uracil monophosphate H CH 3 0 5-Fluorouracil monophosphate H CH 3 S 2,4-0-Diacetyluracil monophosphate H CH3 S Hypoxanthine monophosphate H CH3 S 2,4-0-Diacetylthym monophosphate H CH 3 S Thymine monophosphate H CH 3 S Cytosine monophosphate H CH3 S 4-(N-mono-acetyl)cytosine monophosphate H CH 3 S 4-(NN-diacetyl)cytosine monophosphate H Ci3 S Uracil monophosphate H 1CH3 S 5-Fluorouracil diphosphate H CH 3 0 2,4-0-Diacetyluracil diphosphate H CH 3 0 Hypoxanthine diphosphate H CH3 0 2,4-0-Diacetylthymine diphosphate H CH3 0 Thymine diphosphate H CH 3 0 Cytosine diphosphate H CH 3 0 4-(N-mono-acetyl)cytosine diphosphate H CH3 0 4-(NN-diacetyl)cytosine diphosphate H CH 3 0 Uracil diphosphate H CH 3 0 5-Fluorouracil diphosphate H CHt S 2,4-0-Diacetyluracil 178 WO 01/90121 . PCT/US01/16671 R R RX Base diphosphate H CH3 S Hypoxanthine diphosphate i CH3 S 2,4-0-Diacetythymine diphosphate H CH3 S Thymine diphosphate H CH 3 S Cytosine triphosphate H CH 3 0 2,4-0-Diacetyluracil triphosphate H CHI 0 Hypoxanthine triphosphate H CH3 0 2,4-0-Diacetylthymine triphosphate H CH3 0 Thymine triphosphate H CH 3 0 Cytosine triphosphate H CH3 0 4-(N-mono-aoetyl)cytosine triphosphate H CH 3 0 4-(NN-diaoetyl)cytosine triphosphate H CH3 0 Uracil triphosphate H CH 3 0 5-Fluorouracil triphosphate H CH 3 S 2,4-0-Diacetyluracil triphosphate H CH 3 S Hypoxanthine triphosphate H CH 3 S 2,4-O-Diaoetylthymine triphosphate H CH 3 S Thymine triphosphate H CH 3 S Cytosine monophosphate monophosphate CF 3 0 2,4-0-Diacetyluracil monophosphate monophosphate CF 3 0 Hypoxanthine monophosphate monophosphate CF 3 0 2,4-0-Diaoetylthymine monophosphate monophosphate CF 3 0 Thymine monophosphate monophosphate CF 3 0 Cytosine monophosphate monophosphate CF 3 0 4-(N-mono-acetyl)oytosine monophosphate monophosphate CF 3 0 4-(NN-diaoetyl)cytosine monophosphate monophosphate CF 3 0 Uracil monophosphate monophosphate CF 3 0 5-Fluarouracil monophosphate monophosphate CF 3 S 2,4-0-Diacetyluracil monophosphate monophosphate CF 3 S Hypoxanthine monophosphate monophosphate CF 3 S 2,4-0-Diacetylthyniine monophosphate monophosphate CF 3 S Thymine 179 WO 01/90121 PCTfUS01/16671 R RX Base monophosphate monophosphate CF 3 8 Cytosine monophosphate monophosphate CF 3 S 4-(N-mono-acetyl)cytosine monophosphate monophosphate CF 3 S 4-(NN-diacetyl)cytosine monophosphate monophosphate CF 3 S Uracil monophosphate monophosphate CF 3 S 5-Fluorouracil acetyl acetyl CF 3 0 4-(NN-diacetyl)cytosine acetyl acetyl CF 3 S 4-(NN-diacetyl)cytosine acetyl acetyl 2-bromo- 0 4-(NN-diacetyl)cytosine vinyl acetyl acetyl 2-bromo- S 4-(NN-diacetyl)cytosine vinyl Alternatively, the following nucleosides of Formula XV are prepared, using the appropriate sugar and pyrimidine or purine bases, RIO Base x 5 (XV) wherein: Ri R 6 X Base H CH 3 0 2,4-0-Diacetyluracil H CH3 0 Hypoxanthine H CH3 0 2,4-0-Diacetylthymine H CH 3 0 Thymine H CHT 3 0 Cytosine H CH 3 0 4-(N-mono-acetyl)cytosine H CH 3 0 4-(N,N-diacety1)cytosine H CH3 0 Uracil 180 WO 01/90121 PCT/US01/16671 i X Base H CH3 0 5-Fluorouracil H CH 3 S 2,4-0-Diacetyluracil H Ci S Hypoxanthine H CH 3 S 2,4-0-Diacetylthymine HCH3 S Thymine H CH 3 S Cytosine H CH S 4-(N-mono-acetyl)cytosine H CH 3 S 4-(N,N-diacetyl)cytosine H CH3 S Uracil H CH S 5-Fluorouracil monophosphate CH 3 0 2,4-0-Diacetylutacil monophosphate CH 3 0 Hypoxanthine monophosphate CR 3 0 2,4-0-Diacetylthyrnine monophosphate CH 3 0 Thymine monophosphate CH 3 0 Cytosine monophosphate CH 3 ) 4-(N-mono-acetyl)cytosine monophosphate CH 3 0 4-(NN-diacetyl)cytosine monophosphate CH 3 0 Uracil monophosphate CH 3 0 5-Fluorouracil monophosphate CH3 S 2,4-0-Diacetyluracil monophosphate CH 3 S Hypoxanthine monophosphate CH 3 S 2,4-0-Diacetylthymine monophosphate CH 3 S Thymine monophosphate CH 3 S Cytosine monophosphate CH 3 S 4-(N-mono-acetyl)cytosine monophosphate CH 3 S 4-(N,N-diacetyl)cyto sine monophosphate CH 3 S Uracil monophosphate CH3 S 5-Fluorouracil diphosphate CH 3 0 2,4-0-Diacetyluracil diphosphate CH 3 0 Hypoxanthine diphosphate CH 3 0 2,4-0-Diacetylthymaine 181 WO 01/90121 PCT.[USO1/16671 Rl R16X Base diphosphate CH 3 0 Thymine diphosphate CH 3 0 Cytosine diphosphate CH 3 0 4-(N-mono-acetyl)cytosiue diphosphate OH 3 0 4-(NN-diacetyl)cytosine diphosphate CH 3 0 Uracil diphosphate CH 3 0 5-Fluorouracil diphosphate CH 3 S 2,4-0-Diacetyluracil diphosphate CH 3 S Hypoxanthine diphosphate CH3 S 2,4-0-Diacetylthymine diphosphate CH 3 S Thynine diphosphate CH3 S Cytosine triphosphate CH 3 0 2,4-0-Diacetyluracil triphosphate CH 3 0 Hypoxanthine triphosphate CH 3 0 2,4-0-Diacetylthymine triphosphate CH 3 0 Thymine triphosphate CH 3 0 Cytosine triphosphate CH 3 0 4-(N-mono-acetyl)cytosine triphosphate CH 3 0 4-(NN-diacetyl)cytosine triphosphate CH 3 0 Uracil triphosphate CH 3 0 5-Fluorouracil triphosphate CH 3 S 2,4-0-Diacetyluracil triphosphate CH 3 S Hypoxanthine triphosphate CH3 S 2,4-0-Diacetylthymine triphosphate CH3 S Thymine triphosphate CH3 S Cytosine monophosphate CF 3 0 2,4-0-Diacetyluracil monophosphate CF 3 0 Hypoxanthine monophosphate CF 3 0 2,4-0-Diacetylthymnine monophosphate CF 3 0 Thymine monophosphate CF 3 0 Cytosine monophosphate CF 3 0 4-(N-mono-acetyl)cytosine 182 WO 01/90121 PCTUS01/16671 R R X Base monophosphate CF 3 0 4-(,N-diacetyl)cytosine monophosphate CF 3 0 Uracil monophosphate CF 3 0 5-Fluorouracil monophosphate CF 3 S 2,4-0-Diacetyluracil monophosphate CF 3 S Hypoxanthine monophosphate CF 3 S 2,4-O-Diacetylthymine monophosphate CF 3 S Thymine monophosphate CF 3 S Cytosine monophosphate CF 3 S 4-(N-mono-acetyl)cytosine monophosphate CF 3 S 4-(NN-diacetyl)cytosine monophosphate CF 3 S Uracil monophosphate CF 3 S 5-Fluorouracil acetyl CF 3 0 4-(NN-diacetyl)cytosine acetyl CF 3 S 4-(NN-diacetyl)cytosine acetyl 2-bromo-vinyl 0 4-(N,N-diacetyl)cytosine acetyl 2-bromo-vinyl S 4-(NN-diacetyl)cytosine Alternatively, the following nucleosides of Formula XVIII are prepared, using the appropriate sugar and pyrimidine or purine bases. RIO Base Rt 6 xR 5 (XVIHI) wherein: R' R' R X Base R" Re H CH 3 OH 0 2,4-0-Diacetyluracil H Me H CH 3 OH 0 Hypoxanthine H Me H CH 3 OH 0 2,4-O-Diacetylthymine H Me 183 WO 01/90121 PCTfUS01/16671 RR X Base H CH 3 OH 0 Thymine H Me H CH 3 OH 0 Cytosine H Me H CH 3 OH 0 4-(N-mono-acetyl)cytosine H Me H CI3 OH 0 4-(NN-diacetyl)cytosine H Me H CH 3 OH 0 Uracil H Me H CH 3 OH o 5-Fluorouracil H Me H CH 3 OH S 2,4-0-Diacetyluracil H Me H CH 3 OH S Hypoxantbine H Me H CH 3 OH S 2,4-0-Diacetylthymine H Me H CH 3 OH S Thymine H Me H CH 3 OH S Cytosine H Me H CH 3 OH S 4-(N-mono-acetyl)cytosine H Me H CH 3 OH S 4-(NN-diacetyl)cytosine H Me H CH 3 OH S Uracil H Me H CH3 OH S 5-Fluorouracil H Me monophosphate CH 3 OH 0 2,4-0-Diacetyluracil H Me monophosphate CH3 OH 0 Hypoxanthine H Me monophosphate CH 3 OH o 2,4-0-Diacetylthynine H Me monophosphate CH 3 OH 0 Thymine H Me monophosphate CH3 OH 0 Cytosine H Me monophosphate C3 OH 0 4-(N-mono-acetyl)cytosine H Me monophosphate CH 3 OH 0 4-(N,N-diacetyl)cytosine H Me monophosphate CH 3 OH 0 Uracil H Me monophosphate CH3 OH 0 5-Fluorouracil H Me monophosphate CH3 OH S 2,4-0-Diacetyluracil H Me monophosphate C3 OH S Hypoxanthine H Me monophosphate CH3 OH S 2,4-0-Diacetylthymine H Me monophosphate CH 3 OH S Thymine H Me monophosphate CH 3 OH S Cytosine H Me monophosphate CH 3 OH S 4-(N-mono-acetyl)cytosine H Me monophosphate CH3 OH S 4-(NN-diacetyl)cytosine H Me 184 WO 01/90121 PCTIUS01/16671 RiR* R7 X Base RY Rt monophosphate CH 3 OH S Uracil H Me monophosphate CH3 QH S 5-Fluorouracil H Me diphosphate CH 3 OH 0 2,4-O-Diacetyluracil H Me diphosphate CH3 OH1 0 Hypoxanthine H Me diphosphate CH 3 OH 0 2,4-0-Diacetylthymine H Me diphosphate CH 3 OH 0 Thymine H Me diphosphate CH 3 OH 0 Cytosine H Me diphosphate CH 3 OH 0 4-(N-mono-acetyl)cytosine H Me diphosphate CI 3 OH 0 4-(NN-diacetyl)cytosine H Me diphosphate CH 3 OH 0 Uracil H Me diphosphate CH 3 OH 0 5-Fluorouracil H Me diphosphate CH 3 OH S 2,4-0-Diacetyluracil H Me diphosphate CH 3 OH S Hypoxanthine H Me diphosphate CH 3 OH S 2,4-O-Diacetylthymine H Me diphosphate CH 3 OH, S Thymine H Me diphosphate CH 3 OH S Cytosine H Me triphosphate CH 3 OH 0 2,4-0-Diacetyluracil H Me triphosphate CH 3 OH 0 Hypoxanthine H Me triphosphate CH 3 OH 0 2,4-0-Diacetylthymine H Me triphosphate CH3 OH 0 Thymine H Me triphosphate CH 3 OH 0 Cytosmie H Me triphosphate Ci1 3 OH 0 4-(N-mono-acetyl)cytosine H Mo triphosphate CH 3 OH 0 4-(N,N-diacetyl)cytosine H Me triphosphate CH 3 OH 0 Uracil H Me triphosphate CH 3 OH 0 5-Fluorouracil H Me triphosphate CH 3 Oil S 2,4-0-Diacetyluracil H Me triphosphate CH 3 OH 8 Hypoxanthine H Me triphosphate CH 3 OH S 2,4-0-Diacetylthymine H Me triphosphate CH3 OH S Thymine H Me triphosphate CH OH S Cytosine H Me Inonophosphate CF 3 OH 0 2,4-0-Diacetyluracil H Me 185 WO 01/90121 PCTUSO1/16671 RI R7 R X Base R9 monophosphate CF 3 OH 0 Hypoxanthine H Me monophosphate CF 3 OH 0 2,4-0-Diacetylthymine H Me monophosphate CF 3 OH 0 Thymine H Me monophosphate CF 3 OH 0 Cytosine Hf Me monophosphate CF 3 OH 0 4-(N-mono-acetyl)cytosine H Me monophosphate CF 3 OH 0 4-(NN-diacetyl)cytosine H Me monophosphate CF 3 OH 0 Uracil H Me monophosphate CF 3 OH 0 5-Fluorouracil H Me monophospbate CF 3 OH S 2,4-0-Diacetyluracil H Me monophosphate CF 3 OH S Hypoxanthine H Me monophosphate CF 3 OH S 2,4-0-Diacetyithymine H Me monophosphate CF 3 OH S Thyine H Me monophosphate CF 3 OH S Cytosine H Me monophosphate CF 3 OH S 4-(N-mono-acetyl)cytosine H Me monophosphate CF 3 OH S 4-(N,N-diacetyl)cytosine H Me monophosphate CF 3 OH S Uracil H Me monophosphate CF 3 OH S 5-Fluorouracil H Me acetyl Ci 3 OH 0 4-(NN-diacetyl)cytosine H Br acetyl CH 3 OH S 4-(NN-diacetyl)cytosine H Br VIE Anti-Hepatitis C Activity Compounds can exhibit anti-hepatitis C activity by inhibiting HCV polymerase, by inhibiting other enzymes needed in the replication cycle, or by other pathways. A number 5 of assays have been published to assess these activities. A general method that assesses the gross increase of HCV virus in culture is disclosed in U.S. Patent No. 5,738,985 to Miles et al. In vitro assays have been reported in Ferrari et al., JnL of Vir., 73:1649-1654, 1999; Ishii et al., Hepatology, 29:1227-1235,1999; Lobmann et al., nl. ofBio. Chen., 274:10807 10815, 1999; and Yamashita et al, ln. ofBio. Chem., 273:15479-15486, 1998. 10 WO 97/12033, filed on September 27, 1996, by Emory University, listing C. Hagedorn and A. Reinoldus as inventors, and which claims priority to U.S.S.N. 60/004,383, 186 WO 01/90121 PCT/USO1/16671 filed on September 1995, describes an HCV polymerase assay that can be used to evaluate the activity of the compounds described herein. Another HICV polymerase assay has been reported by Bartholomeusz, et al., Hepatitis C virus (HCV) RNA polymerase assay using cloned HCV non-structural proteins; Antiviral Therapy 1996:1(Supp 4) 18-24. 5 Screens that measure reductions in kinase activity from HCV drugs are disclosed in U.S. Patent No. 6,030,785, to Katze et al., U.S. Patent No. 6,010,848 to Delvecchio et al, and U.S. Patent No. 5,759,795 to Jubin et al. Screens that measure the protease inhibiting activity of proposed HCV drugs are disclosed in U.S. Patent No. 5,861,267 to Su et al, U.S. Patent No. 5,739,002 to De Francesco et al, and U.S. Patent No. 5,597,691 to Houghton et 10 al Example 4: Phosphorylation Assay of Nucleoside to Active Triphosphate To determine the cellular metabolism of the compounds, HepG2 cells were obtained from the Anexican Type Culture Collection (Rockville, MD), and were grown in 225 cmz tissue culture flasks in minimal essential medium supplemented with non-essential amino 15 acids, 1% penicillin-streptomycin. The medium was renewed every three days, and the cells were 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 medium, confluent HepG2 cells were seeded at a density of 2.5 x 106 cells per well in a 6-well plate and exposed to 10 pM of [ 3 H] labeled active compound (500 dpm/pmol) for the specified 20 time periods. The cells were maintained at 37 0 C under a 5% CO 2 atmosphere. At the selected time points, the cells were washed three times with ice-cold phosphate-buffered saline (PBS). Intracellular active compound and its respective metabolites were extracted by incubating the cell pellet overnight at -20*C with 60% methanol followed by extraction with an additional 20 AL of cold methanol for one hour in an ice bath. The extracts were 25 then combined, dried under gentle filtered air flow and stored at -20*C until HPLC analysis. The preliminary results of the HPLC analysis are tabulated in Table 1. 187 WO 01/90121 PCT/US01/16671 Table 1 [pmolmillion cells] p-D-2'-CH 3 - -D-2'-CH 3 - pfI-D-2'-CHr Time (h) riboA-TP riboU-TP riboC-TP riboG-TP 2 33.1 0.40 2.24 ND 4 67.7 1.21 3.99 ND 8 147 1.57 9.76 2.85 24 427 6.39 34.9 0.91 30 456 7.18 36.2 3.22 48 288 9.42 56.4 6.26 Example 5: Bioavailability Assay in Cynomolgus Monkeys Within 1 week prior to the study initiation, the cynomolgus monkey was surgically 5 implanted with a chronic venous catheter and subcutaneous venous access port (VAP) to facilitate blood collection and underwent a physical examination including hematology and serum chemistry evaluations and the body weight was recorded. Each monkey (six total), received approximately 250 uCi of 3 iH activity with each dose of active compound, namely p-D-2'-CH 3 -riboG at a dose level of 10 mg/kg at a dose concentration of 5 mg/mL, either 10 via an intravenous bolus (3 monkeys, IV), or via oral gavage (3 monkeys, PO). Each dosing syringe was weighed before dosing to gravimetrically determine the quantity of formulation administered. Urine samples were collected via pan catch at the designated intervals (approximately 18-0 hours pre-dose, 0-4, 4-8 and 8-.12 hours post-dosage) and processed. Blood samples were collected as well (pre-dose, 0.25, 0.5, 1, 2, 3, 6, 8, 12 and 24 hours 15 post-dosage) via the chronic venous catheter and VAP or from a peripheral vessel if the chronic venous catheter procedure should not be possible. The blood and urine samples were analyzed for the maximum concentration (C.,), time when the maximum concentration was achieved (Tm), area under the curve (AUC), half life of the dosage concentration (TV,), clearance (CL), steady state volume and distribution (V,,) and 20 bioavailability (F), which are tabulated in Tables 2 and 3, and graphically illustrated in Figures 2 and 3, respectively. 188 WO 01/90121 PCT[US01/16671 Table 2: Oral Bioavailability in Monkeys Dose AUC Norm AUC Mean Norm AUC F (%) (mg) (ng/mL x h) (ng/aL x h/mg) (ng/mL x h/mg) IV Monkey 1 46.44 13614 293.2 IV Monkey 2 24.53 6581 268.3 IV Monkey 3 20.72 6079 293.4 284.9 PO Monkey 1 29.04 758 26.1 PO Monkey 2 30.93 898 29.0 PO Monkey 3 30.04 1842 61.3 38.8 13.6 Table 3: Experimental Pharmacokinetics of f-D-2'-CH 3 -riboG in Cynomolgus Monkeys IV PO Dose/Route (mg/kg) 10 10 CQ= (ng/mL) 6945.6 1886.0 217.7± 132.1 T. (hr) 0.25 ± 0.00 2.00 1 1.00 AUC (ng/mL x br) 8758.0 +4212.9 1166.0 ± 589.6 TA (hr) 7.9*+5.4 10.3 ±4.1 CL (L/hr/kg) 1.28 ± 0.48 V. (L/kg) 2.09 ±0.54 F (%) 13.8 5 Example 6: Bone Marrow Toxicity Assa Human bone marrow cells were collected from normal healthy volunteers and the mononuclear population was separated by Ficoll-Hypaque gradient centrifugation as described previously by Sommadossi J-P, Carlisle R. "Toxicity of 3'-azido.3' deoxythymidine and 9-(1,3-dihydroxy-2-propoxymethyl)guaniue for normal human 10 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 2',3'-dideoxy-3'-thiacytidine in normal human bone marrow progenitor cells" Biochemical Phannacology 1992; 44:1921-1925. The culture assays for CFU-GM and BFU-E were performed using a bilayer soft agar or 15 methylcellulose method. Drugs were diluted in tissue culture medium and filtered. After 14 to 18 days at 37CC in a humidified atmosphere of 5% CO 2 in air, colonies of greater than 50 cells were counted using an inverted microscope. The results in Table 4 are presented as the percent inhibition of colony formation in the presence of drug compared to solvent control cultures. 189 WO 01/90121 PCT/US01/16671 Table 4: Human Bone Marrow Toxicity CFU-GM and BFU-E Clonogenic Assays Treatment CFU-GM BFU-E ribavirin ~ 5 1 p.-D-2-CH3-riboA > 100 > 100 p-D-2'-CHrriboU > 100 > 100 p-D-2'-CH 3 -riboC >10 > 10 p-D-2'-CH-riboG > 10 > 100 Example 7: Mitoehondria Toxicity Assay HepG2 cells were cultured in 12-well plates as described above and exposed to 5 various concentrations of drugs as taught by Pan-Zhou X-R, Cui L, Zhou X-J, Sommadossi J-P, Darley-Usmer VM. "Differential effects of antiretroviral nucleoside analogs on mitochondrial function in HepG2 cells" Antimicrob Agents Chemother 2000; 44:496-503. Lactic acid levels in the culture medium after 4 day drug exposure was measured using a Boehringer lactic acid assay kit. Lactic acid levels were normalized by cell number as 10 measured by hemocytometer count. The preliminary results from this assay are tabulated in Table 5. Table 5: Mitochondrial Toxicity Study (L-lactic acid assay) Conc. (pM) lactate (mg/10 6 cell) % of Control Control 2.18 NIAU 10 3.73 170.4 p-D-2'-C~riboC 1 2.52 115.3 10 2.36 107.9 50 2.26 103.4 100 2.21 101.2 0

NH

2 HO F HO H 3 C OH OH OH 15 FIAU p-D-2'-CHa-riboC 190 - 191 This invention has been described with reference to its preferred embodiments. Variations and modifications of the invention, will be obvious to those skilled in the art from the foregoing detailed description of the invention. The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates. Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

Claims (20)

1. A method for the treatment of a hepatitis C virus infection in a host, comprising administering to the host an antivirally effective amount of a deoxynucleoside, wherein the deoxynucleoside is a P-D-2'-C-methyl-"up" pyrimidine 5 nucleoside, or pharmaceutically acceptable salt or a phosphate thereof.

2. The method of claim 1, wherein the deoxynucleoside is a P-D-2'-C-methyl "up" uracil nucleoside, or pharmaceutically acceptable salt or a phosphate thereof.

3. The method of claim 1, wherein the deoxynucleoside is a P-D-2'-C-methyl 'up" cytosine nucleoside, or pharmaceutically acceptable salt or a phosphate thereof. 10

4. The method of claim 1, wherein the host is a human.

5. The method of claim 28, wherein the antivirally effective amount is ranging from 0.1 to 100 mg/kg/day.

6. The method of claim 5, wherein the antivirally effective amount is ranging from 1 to 50 mg/kg/day. 15

7. The method of claim 5, wherein the antivirally effective amount is ranging from 1 to 20 mg/kg/day.

8. The method of claim 1, wherein the deoxynucleoside is administered in combination or alternation with a second anti-hepatitis C agent.

9. The method of claim 8, wherein the second agent is an interferon, ribavirin, a 20 protease inhibitor, a thiazolidine derivative, a polymerase inhibitor, or a helicase inhibitor.

10. The method of claim 8, wherein the second agent is an interferon.

11. The method of claim 8, wherein the second agent is ribavirin.

12. A method for inhibiting replication of a hepatitis C virus in a host, comprising contacting the host with an antivirally effective amount of a deoxynucleoside, wherein the 25 deoxynucleoside is a P-D-2'-C-methyl- "up" pyrimidine nucleoside, or pharmaceutically acceptable salt or a phosphate thereof.

13. The method of claim 12, wherein the deoxynucleoside is a P-D-2'-C-methyl "up" uracil nucleoside, or pharmaceutically acceptable salt or a phosphate thereof.

14. The method of claim 12, wherein the deoxynucleoside is a -D-2'-C-methyl 30 "up" cytosine nucleoside, or pharmaceutically acceptable salt or a phosphate thereof.

15. The method of claim 12, wherein the host is a human cell.

16. The method of claim 12, wherein the antivirally effective amount is ranging from 0.1 to 100 mg/kg/day. 193

17. The method of claim 16, wherein the antivirally effective amount is ranging from 1 to about 50 mg/kg/day.

18. The method of claim 16, wherein the antivirally effective amount is ranging from 1 to about 20 mg/kg/day. 5

19. The method of claim 12, wherein the deoxynucleoside is administered in combination or alternation with a second anti-hepatitis C agent.

20. The method of claim 16, wherein the second agent is an interferon, ribavirin, a protease inhibitor, a thiazolidine derivative, a polymerase inhibitor, or a helicase inhibitor. 10 Idenix Pharmaceuticals, Inc. Univesita Degli Studi Di Cagliari Patent Attorneys for the Applicant/Nominated Person SPRUSON & FERGUSON