AU2012233015B2 - Methods and compositions for treating hepatitis C virus - Google Patents

Abstract

C:\NRPortl M T 6351.. DOC-1/10/2012 The present invention provides a method for the treatment of a hepatitis C virus infection in a host, the method comprising administering to the host an effective amount of a purine or pyrimidine p-D-2'-methyl-ribofuranosyl nucleoside or a stabilized phosphate prodrug thereof.

Description

Australian Patents Act 1990 - Regulation 3.2A ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT Invention Title "Methods and compositions for treating hepatitis C virus" The following statement is a full description of this invention, including the best method of performing it known to us: P/00/001 CANRPonbl\DCC\AMT646351 -1DOC-/1/20L2 METHODS AND COMPOSITIONS FOR TREATING HEPATITIS C VIRUS This is a divisional of Australian patent application No. 2010200077, which in turn is a divisional of 2006203121, 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. er aL J Hepatol. 32:98-112, 2000). HCV causes a slow growing viral infection and is the major cause of cirrhosis and hepatocelular carcinoma (Di Besceglie, 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 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 intemal ribosome entry. This mechanism involves the binding of 5 ibosomes to an RNA sequence known as the internal ribosome entry site (IRES). 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 metalloproteinase 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 precmsor 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 NS5A (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-fl-D-ribofuranosyl-1-1,2,4-triazole-3-carboxamide) 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 118:S104 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 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 seum 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:S104-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-tan. 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 U.S. 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.VL 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 hemolysis, flu-like symptoms, anemia, and fatigue. (Gary L. Davis. Gastroenterology 118:S104-S114, 2000). Additional References Disclosing Methods to Treat HCV Infections A number of HCV treatments are reviewed by Bymock et al. 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, 98/22496; 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. Linas-Brunet et al. (1999) Hepatitis C inhibitor peptide analogues, WO 15 99/07734. Two classes of electrophile-based inhibitors have been described, alphaketoamides and hydrazinoureas. The literature has also described a number of non-substrate-based inhibitors. For example, evaluation of the inhibitory effects of 2,4,6-trlhydroxy-3-nitro-benzamide derivatives against HCV protease and other serine proteases has been reported. Sudo, K. et 20 al., (1997) Biochemical and Biophysical Research Communications, 238:643-647; 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. et 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 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 fennentation 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 griscofiluum, demonstrated micromolar activity in a scintillation proximity assay. Chu M. et al., Bioorganic 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 M.A. 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 al., Journal of Virology 73:1649-1654, 1999; Lohmann V. 25 et al., 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 flcpG2 HCV-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 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 ofKai, Y. et al. Nuclease-resistant ribozymes have been targeted at the IRES and recently reported as inhibitors in an HCV-poliovirus chimera plaque assay. Maccjak DJ. 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-Borna virus and anti-Hepatitis C activities. The disclosed NMDA receptor agonists belong to a family of 1-amino-alkylcyclohexanes. U.S. 25 Patent No. 6,030,960 to Morris-Natschke 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.

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 al.), 2',3'-dideoxyinosine (U.S. Patent No. 5,026,687 to Yarchoan et aL.), 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 f-D- or P-L-nucleoside of the Formulas (I)- (XVIII), or a pharmaceutically 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 XX RIO 20 OR2 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 sulfonate ester including alkyl or arylalkyl sulfonyl including methanesufonyl anid 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 5 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; 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-allcoxyalkyl, chloro, bromo, fluoro, iodo, 10 OR 4 , NR 4

NR

5 or SR ; 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). In a second principal embodiment, a compound of Formula II, or a phamaceutically acceptable salt or prodrug thereof; is provided: Y X1 N1 R'ON-x H C 15

OR

2 O (11) wherein

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 20 (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 25 providing a compound wherein R 1 , 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 SR 4 ; 8 X1 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; and

R

4 and R 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 N X2 ROR ND R'X m11) 10 wherein:

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 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', R 2 or R 3 is independently H or phosphate; and Y is hydrogen, bromo, chloro, fluoro, iodo, OR, R 5 or SR 4 ; 20 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; 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 In a fourth principal embodiment, a compound of Formula IV, or a pharmaceutically acceptable salt or prodrug thereof, is provided: Y OR 1 OR 5 R'O WR2 oR (IV) 5 wherein: R1, 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); 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 R 3 is independently H or phosphate; Y is hydrogen, bromo, chloro, fluoro, iodo, OR 4 , NR 4 Rs 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 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). In a fifth principal embodiment, a compound of Formula V, or a pharmaceutically 20 acceptable salt or prodrug thereof, is provided: 10 Y X1 N RIO OR2 OR' (V) wherein: R1, R 2 and R 3 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 R1, R 2 or R 3 is independently H or phosphate; and Y is hydrogen, bromo, chloro, fluoro, iodo, OR 4 , NRR 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

5 or SR 5 ; and 15 R 4 and Rs 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 X1 NK RIO ~0 OR2 OR' 20 (VI) 11 wherein: R', 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 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 R1, R 2 or R 3 is independently H or phosphate; and 10 Y is hydrogen, bromo, chloro, fluoro, iodo, OR 4 , NR 4

R

5 or SR 4 ; 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 , NR 4 NR 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). 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 Rio R'O RIO X XX i6 R6 R6

OR

2 OR' OR2 (VII) (VIII) (IX) wherein: 20 Base is a purine or pyrimidine 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 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, R 2 or R 3 is independently H or phosphate; 12

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), -O(lower acyl), -O(alkyl), -Olower 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, S, SO2 or CH 2 . In a eighth principal embodiment, a compound of Formulas X, XI and X[E, or a pharmaceutically acceptable salt or prodrug thereof; is provided: R1O Base Rio RaO xR' x O' OR O ' R'R () (XH) 10 wherein: Base is a purine or pyrimidine base as defined herein; R', 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 R1, R 2 or R 3 is independently H or phosphate; 20 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(1ower 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(O)O(lower alkyl), -O(acyl), -O(lower acyl), -O(alkyl), Olower alkyl), -O(alkenyl), chlorine, bromine, iodine, NO 2 , NH 2 , -NH(lower alkyl), NH(acyl), -N(lower alkyl) 2 , -N(acyl) 2 ; and 13 X is 0, S, SO 2 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: RIORI RIO as RoBaseRo Base Reso _NI0S _-' x

OR

2 ORs OR 2 5 (XI (X) (XV) wherein: Base is a purine or pyrimidine base as defined herein; R', R 2 and R 3 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

T

, R 2 or R 3 is independently H or phosphate; R' is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br vinyl, -C(0)O(alkyl), -C(O)O(lower alkyl), -O(acyl), -Olower acyl), -O(alkyl), -O(lower alkyl), -O(alkenyl), chloro, bromo, fluoro, iodo, NO2, NH 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 6 R' R' 14 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 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 10 providing a compound wherein R 1 or R 2 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 alkyl) 2 , -N(acyl) 2 ; 15 R7 and R are independently hydrogen, OR2, 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), -Olower alkyl), -O(alkenyl), chlorine, bromine, iodine, NO 2 , NH 2 , -NHlOower 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 and R 9 , R 7 and R" 0 , R8 and R!, or R! and R1 0 can come together to form a pi bond; and X is 0, S, SO2 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 ~xi 25 RI R' 15 wherein: Base is a purine or pyrimidine base as defined herein;

R

1 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 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 10 providing a compound wherein R1 or R 2 is independently H or phosphate;

R

6 is hydrogen, hydroxy, alkyl (including lower aIkyl), azido, cyano, alkenyl, alkynyl, Br vinyl, -C(0)O(alkyl), -C(0)O(lower alkyl), -O(acyl), -O0ower acyl), -O(alkyl), -Olower alkyl), -O(alkenyl), chloro, bromo, fluoro, iodo, NO 2 , NH 2 , -NH(lower alkyl), -NH(acyl), N(lower alkyl) 2 , -N(acyl) 2 ; 15 R 7 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), -Nlower alkyl) 2 , -N(acyl) 2 ; R1 0 is H, alkyl (including lower alkyl), chlorine, bromine or iodine; 20 alternatively, R 7 and R 9 , or R 7 and R' 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 pharmaceutically acceptable salt or prodrug thereof: R0o Base R' 0R'

R

9 R7 25 (XVII 16 wherein: Base is a purine or pyrimidine base as defined herein; R' and R 2 independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrag); 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 1 or R 2 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 alkyl) 2 , -N(acyl) 2 ; 15 R 7 and R 9 are independently hydrogen, OR2, alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, 0-alkenyl, chlorine, bromine, iodine, NO 2 , amino, loweralkylamino or di(lower alkyl)amino; R' is H, alkyl (including lower alkyl), chlorine, bromine or iodine; alternatively, R 7 and R 9 , or R 8 and R 9 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 ECso). In preferred embodiments the compound exhibits an ECSO 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 further 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. Pharmacother. 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 BPLC assay with an NS3/4A fusion protein and NS5A/5B substrate (Sudo K. et al., 18 Antiviral Research 32:9-18, 1996), especially compound RD-1-6250, possessing a fused cinnamnyl moiety substituted with a long alkyl chain, RD4 6205 and RD4 6193; (5) Thiazolidines and benzanilides identified in Kakiuchi N. et a[. . 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 griscofiduumn, which demonstrates activity in a scintillation proximity assay (Chu M et aL., Bioorganic and Medicinal 10 Chenistry 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 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); 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 (12) Nuclease-resistant ribozymes (Maccjak D.J. et al, Fepatology 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 Cynomolgus Monkeys over time after administration. Figure 3a and 3b are line graphs of the phannacokinetics (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 a-D- or #-L-nucleoside as described herein or a 25 pharmaceutically 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 In summary, the present invention includes the following features: (a) P-D- and #-L-nucleosides, as described herein, and pharmaceutically acceptable salts and prodrugs thereof; (b) #-D- and #-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 fl-D- and fl-L-nucleosides, and pharmaceutically acceptable salts and podrugs thereof in the manufacture of a medicament for treatment of an HCV 10 infection; (d) pharmaceutical formulations comprising the O-D- or g-L-nucleosides or pharmaceutically acceptable salts or prodrugs thereof together with a pharmaceutically acceptable carrier or diluent; (e) #-D- and P-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 P-D- and 6-L-nucleosides, as described in more detail below; and (g) processes for the preparation of#P-D- and #-L-nucleosides substantially in the 20 absence of enantiomers of the described nucleoside, or substantially isolated from other chemical entities. L Active Compound, and Physiologicallv Acceptable Salts and Prodruags Thereof In a first principal embodiment, a compound of Formula I, or a pharmaceutically acceptable salt or prodrug thereof, is provided: 21 Y N N X R'O

OR

2 OR' wherein: R', R 2 and R 3 are independently H, phosphate (including mono-, di- or triphosphate and a 5 stabilized phosphate prodmg); 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 1 , R 2 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 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, 15 OR 4 , NR 4

NR

5 or SRs; and

R

4 and Rs are independently hydrogen, acyl (including lower acyl), or alkyl (including but not limited to methyl, ethyl, propyl and cyclopropyl). In a preferred subembodiment, a compound of Formula I, or a pharmaceutically acceptable salt or prodrug thereof, is provided wherein: 20 R', R 2 and R 3 are independently H or phosphate (preferably H); X' is H;

X

2 is H or NH 2 ; and Y is hydrogen, bromo, chloro, fluoro, iodo, NH 2 or OH. 22 In a second principal embodiment, a compound of Formula I, or a pharmaceutically acceptable salt or prodrug thereof, is provided: Y N N xt OR' OR' 5 wherein: R', 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 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 R1, R 2 or R 3 is independently H or phosphate; and Y is hydrogen, bromo, chloro, fluoro, iodo, OR , NR 4

R

5 or SR 4 ; 15 X1 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

R

4 and R 5 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 H1, or a pharimaceutically acceptable salt or prodrug thereof, is provided wherein:

R

1 , R 2 and R 3 are independently H or phosphate (preferably H); X, is H;

X

2 is H or NH 2 ; and 23 Y is hydrogen, bromo, chloro, fluoro, iodo, NH 2 or OH. In a third principal embodiment, a compound of Formula IlII or a pharmaceutically acceptable salt or prodrug thereof, is provided: Y x X1 I R'O 0340 oR2 3R 5 (IH) wherein: R', R 2 and R 3 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyW (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', R 2 or R 3 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

5 or SRs; and

R

4 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 Formia III, or a pharmaceutically acceptable salt or prodrug thereof, is provided wherein: R', R 2 and R 3 are independently H or phosphate (preferably H); Xi is H; 24

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 prodmug thereof, is provided: Y XNN No R'o CH3 5 OR' OR' (IV) 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 pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R', R 2 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 ; 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 , NR 4

NR

5 or SR 5 ; and

R

4 and R 5 are independently hydrogen, acyl (including lower acyl), or alkyl (including but 20 not limited to methyl, ethyl, propyl and cyclopropyl). In a preferred subemabodiment, a compound of Formula IV, or a pharmaceutically acceptable salt or prodrug thereof, is provided wherein: R', R 2 and R 3 are independently H or phosphate (preferably H);

X

1 is H or CH 3 ; and 25 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 NK RIO 0. , oR 2 OR' 5 (V) wherein: R1, 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 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, R 2 or R 3 is independently H or phosphate; and 15 Y is hydrogen, bromo, chloro, fluoro, iodo, OR4, NR4R 5 or SR 4 ; 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', NR4NR 5 or SRS; and R and R 5 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', R 2 and R 3 are independently H or phosphate (preferably H); X1 is H or CH 3 ; and Y is hydrogen, bromo, chloro, fluoro, iodo, NH 2 or OH. 26 In a sixth principal embodiment, a compound of Formula VI, or a pharmaceutically acceptable salt or prodrug thereof, is provided: Y N 0O RIO ~0

OR

2 OR' (VI) 5 wherein:

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 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 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 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 , NR4NR 5 or SR 5 ; and R4 and R 5 are independently hydrogen, acyl (including lower acyl), or alkyl (including but not limited to methyl, ethyl, propyl and cyclopropyl). In a preferred subembodiment, a compound of Formula VI, or a pharmaceutically 20 acceptable salt or prodrug thereof, is provided wherein:

R

1 , R 2 and R 3 are independently H or phosphate (preferably H);

X

1 is H or CH 3 ; and Y is hydrogen, bromo, chloro, fluoro, iodo, NH 2 or OH. 27 In a seventh principal embodiment, a compound selected from Formulas VII, VHI and IX, or a pharmaceutically acceptable salt or prodrug thereof; is provided: Base Base R'O Rio R 1 o

OR

2 oR 3 R (VII) (V1) (X) 5 wherein: Base is a purine or pyrimidine base as defined herein; R1, 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 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', R 2 or R 3 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(0)O(alkyl), -C(0)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 X is 0, S, SO 2 , or CH 2 . 20 In a first preferred subembodiment, a compound of Formula VI, VIII or DC, or a pharmaceutically acceptable salt or prodrug thereof; is provided wherein: Base is a purine or pyrimidine base as defined herein; R', R 2 and R 3 are independently hydrogen or phosphate; R is alkyl; and 25 X is 0, S, SO 2 or CH 2 . 28 In a second preferred subembodiment, a compound of Formula V, VIII or IX, or a phannaceutically acceptable salt or prodmg thereof, is provided wherein: Base is a purine or pyrimidine base as defined herein; R', R 2 and R 3 are hydrogens; 5 R 6 is alkyl and X is 0, S, SO 2 or CH 2 . In a third 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; 10 R1, R 2 and R 3 are independently hydrogen or phosphate; R 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 prodnig thereof, is provided: RIO Base RO Base R0 Base XR' R6 15

OR

2 OR' OR R 7 (X) (XI) wherein: Base is a purine or pyrimidine base as defined herein; R', R 2 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 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;

R

6 is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br vinyl, -C(0)O(alkyl), -C(0)O(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 alkyl) 2 , -N(acyl) 2 ;

R

7 is hydrogen, OR 3 , 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, NO2, NH 2 , -NH(lower alkyl), 10 NH(acyl), -NloweraIkyl)2, -N(acyl) 2 ; and X is 0, S, SO 2 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 R1, R 2 and R 3 are independently hydrogen or phosphate;

R

6 is alkyl; and X is 0, S, SO2 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; R', R 2 and R 3 are hydrogens; R'is alkyl; and X is 0, S, SO2 or CH 2 . In a third preferred subembodiment, a compound of Formula X, XI or XII, or a 25 pharmaceutically acceptable salt or prodnig thereof is provided wherein: Base is a purine or pyrimidine base as defined herein; R', R 2 and R 3 are independently H or phosphate; 30 R 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: RiO Ban

H

3 C 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 R 1 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' or R 2 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: RIO Base RIO Base RIO Base R X 20 OR 2 oR 3

OR

2 R' (XI) (vXI) (XV) wherein: Base is a purine or pyrimidine base as defined herein; 31

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 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 R', R 2 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)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 alkyl)2, -N(acyl)2; and X is 0, S, SO 2 or CH 2 . 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; R', R 2 and R 3 are independently hydrogen or phosphate; R'is alkyl; and X is 0, S, S02 or CH2. 20 In a second 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;

R

1 , R 2 and R 3 are hydrogens;

R

6 is alkyl; and 25 X is 0, S, SO 2 or CH2. In a third preferred subembodiment, a compound of Formula XI, XIV or XV, or a pharmaceutically acceptable salt or prodnmg thereof, is provided wherein: Base is a purine or pyrimidine base as defined herein; 32 R', 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 XVI, or a pharmaceutically acceptable salt or prodrug thereof: R'O Base R R X 6 wherein: Base is a purine or pyrimidine base as defined herein; 10 R 1 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' and R 2 are 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(lower 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 ;

R

7 and R! are independently hydrogen, OR 2 , hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(O)0(alkyl), -C(O)O(lower alkyl), -O(acyl), -O(lower acyl), -O(alkyl), -O(lower alkyl), -O(alkenyl), chlorine, bromine, iodine, NO2, NH 2 , 25 -NH(lower alkyl), -NH(acyl), -N(lower alkyl) 2 , -N(acyl) 2 ; R' and RtW are independently H, alkyl (including lower alkyl), chlorine, bromine or iodine; 33 alternatively, R 7 and R!, R 7 and R'", R! and R!, or R' and RWO can come together to form a pi bond; and X is 0, S, SO 2 or CH 2 . In a first preferred subembodiment, a compound of Formula XVI, or its 5 pharmaceutically acceptable salt or prodmug, 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 1 is independently H or phosphate; (3)

R

6 is alkyl; (4) R 7 and R! are independently OR 2 , alkyl, alkenyl, alkynyl, Br-vinyl, 0 15 alkenyl, chlorine, bromine, iodine, NO 2 , amino, loweralkylamino or di(loweralkyl)amino; (5) R' 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 . 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 1 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 1 is independently H or phosphate; (3)

R

6 is alkyl, alkenyl, alkynyl, Br-vinyl, hydroxy, 0-alkyl, 0-alkenyl, chloro, bromo, fluoro, iodo, NOz, amino, loweralkylanino, or di(loweralkyl)aminn; (4) R 7 and R 9 are 30 independently OR 2 ; (5) R 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 In a third 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 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 1 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)amino; (4) R and R! are independently OR 2 , alkyl, alkenyl, alkynyl, Br-vinyl, 0-alkenyl, chlorine, bromine, iodine, NO2, amino, loweralkylamino or di(loweralkyl)amino; (5) R and R 1 O 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 1 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 phannaceutically acceptable leaving group which when administered in 25 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, N02, amino, loweralkyinino, or di(loweralkyl)amino; (4) R 7 and R! are independently OR 2 , alkyl, alkenyl, alkynyl, Br-vinyl, 0-alkenyl, chlorine, brornine, iodine,

NO

2 , amino, loweralkylamino, or di(loweralkyl)amino; (5) R' and R 0 are independently H, 30 alkyl (including lower alkyl), chlorine, bromine, or iodine; and (6) X is 0. In a fiti 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 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! are independently OR'; (5) R 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 . 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) R1 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 methanesulfony 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 aminn 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 is independently H or phosphate; (3) 20 R is alkyl; (4) R 7 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 . In 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) R1 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 defmition 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 1 is independently H or phosphate; (3)

R

6 is alkyl; (4) R 7 and R 9 are independently OR 2 , alkyl (including lower alkyl), alkenyl, 36 alkynyl, Br-vinyl, 0-alkenyl, chlorine, bromine, iodine, NO 2 , amino, loweralkylamino or di(loweralkyl)amino; (5) R 8 and R"O are independently H, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is 0. In a eighth 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' is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, 0-alkyl, 0-alkenyl, 15 chloro, bromo, fluoro, iodo, NO 2 , amino, loweralkylamino or di(loweralkyl)amino; (4) R 7 and R 9 are independently OR 2 ; (5) RO and R1 0 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 descned 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 R1 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 diloweralkyl)amino; (4) R 7 and R' are independently OR 2 ; (5) R' and R 1 O 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 produg, is provided in which: (1) Base is a purine or 37 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 arylalky sufonyl 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)

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)mnino; (4) R 7 and R9 are independently OR 2 , alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, 0 alkenyl, chlorine, bromine, iodine, NO2, amino, loweralkylamino, or di(loweralkyl)amino; (5) R' and R'O 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 6 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)aminn; (4) R 7 and R! are independently OR 2 ; (5) R' 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 XVL 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 or phosphate; (3) R 6 is alkyl; (4) R and R! are independently OR 2 ; (5) R' and R' 0 are hydrogen; and (6) X is 0, S, SO 2 , or CH 2 . 25 In a thirteenth preferred subembodiment, a compound of Formula XVL, 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) R 7 and R 9 are independently OR 2 ; (5) RB and R' 0 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) R is alkyl; 38 (4) R 7 and R are independently OR 2 , alkyl (including lower alkyl), alkenyl, alkynyl, Br vinyl, 0-alkenyl, chlorine, bromine, iodine, NO 2 , amin, loweralkylamino or di(loweralkyl)amino; (5) R! and R 1 O are hydrogen; and (6) X is 0. In even more preferred subembodiments, a compound of Formula XVI, or its 5 pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is adenine; (2) R1 is hydrogen; (3) R 6 is methyl; (4) R 7 and R 9 are hydroxyl; (5) R' 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 R' are hydroxyl; (5) R and R 10 are hydrogen; and (6) X is 0; 10 (1) Base is cytosine; (2) R' is hydrogen; (3) R 6 is methyl; (4) R 7 and R? are hydroxyl; (5) R and Rlo are hydrogen; and (6) X is 0; (1) Base is thymine; (2) R is hydrogen; (3) R 6 is methyl; (4) R 7 and R 9 are hydroxyl; (5) R 8 and R' 0 are hydrogen; and (6) X is 0; (1) Base is uracil; (2) R 1 is hydrogen; (3) R 6 is methyl; (4) R 7 and R 9 are hydroxyl; 15 (5) R' and R'O are hydrogen; and (6) X is 0; (1) Base is adenine; (2) R1 is phosphate; (3) R 6 is methyl; (4) R and R! are hydroxyl; (5) R' and R' 0 are hydrogen; and (6) X is 0; (1) Base is adenine; (2) R' is hydrogen; (3) R is ethyl; (4) R 7 and R' are hydroxyl; (5) R 8 and R1 0 are hydrogen; and (6) X is 0; 20 (1) Base is adenine; (2) R1 is hydrogen; (3) R 6 is propyl; (4) R7 and R! are 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 butyl; (4) R' 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 methyl; (4) R7 is hydrogen and R! 25 is hydroxyl; (5) R8 and R1 0 are hydrogen; and (6) X is 0; (1) Base is adenine; (2) R' is hydrogen; (3) R 6 is methyl; (4) R7 and R? are hydroxyl; (5) R' and R 1 0 are hydrogen; and (6) X is S; (1) Base is adenine; (2) R1 is hydrogen; (3) R 6 is methyl; (4) R7 and R 9 are hydroxyl (5) R' and R'o are hydrogen; and (6) X is S02; 39 (1) Base is adenine; (2) R1 is hydrogen; (3) R 6 is methyl; (4) R 7 and R! are hydroxyl; (5) R! 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 R 1 0 R R X,' 5 (XVII) wherein: Base is a purine or pyrimidine base as defined herein; R1 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 R1 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), -Q(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(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 ; 25 R 1 " is H, alkyl (including lower alkyl), chlorine, bromine, or iodine; alternatively, R 7 and R!, or R and R' 0 can come together to form a pi bond; and 40 X is 0, S, SO 2 or CH 2 . In a first preferred subembodiment, a compound of Formula XV, 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 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, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, loweralkylamino, or di(loweralkyl)amino; (4) R 7 and R' 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' 0 is H; and (6) X is 0, S, SO 2 , or CH 2 . In a second 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 1 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 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' is independently H or phosphate; (3) R' is alkyl (including lower aly), alkenyl, alkynyl, Br-vinyl, hydroxy, 0-alkyl, 0-alkenyl, chloro, bromo, fluoro, iodo, NO2, amino, loweralkylamino or di(loweralkyl)amino; (4) R 7 and R 9 are independently OR 2 ; (5) RWO is H, alkyl (including lower alkyl), chlorine, 30 bromine, or iodine; and (6) X is 0, S, SO2 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 pyrimidine base as defined herein; (2) Ri 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) R 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) R 7 and R' are independently hydrogen, OR 2 , alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, 0-alkenyl, chlorine, bromine, iodine, NO 2 , amino, loweralkylamio or di(loweralkyl)-amino; (5) R* 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 XVUI, 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 R is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, 0-alkcenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, loweralkylamino or di(loweralkyl)amino; (4) R 7 and R? are independently OR 2 ; (5) R'" is H; and (6) X is 0, S, SO 2 or CH 2 . In a fifth preferred subembodiment, a compound of. Formula XVH, 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 42 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, 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! are independently OR 2 ; (5) R" 0 is H, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is 0. In a sixth preferred subembodiment, a compound of Formula XVl, or its 10 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 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)

R

6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, 0-alkyl, O-alkenyl, 20 chloro, bromo, fluoro, iodo, NO 2 , amino, loweralkylamino, or di(loweralkyl)amino; (4) R 7 and R are independently hydrogen, OR 2 , alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, 0-alcenyl, chlorine, bromine, iodine, NO 2 , amino, loweralkylamino, or di(loweralkyl)amino; (5) R1 0 is H; and (6) X is 0. In a seventh preferred subembodiment, a compound of Formula XVHI, 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

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) R 7 and R? are independently OR 2 ; (5) R'o is H; and (6) X is O. In an eighth preferred subembodiment, a compound of Formula XVH, or its 5 pharmaceutically acceptable salt or prodmug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H or phosphate; (3) R' is alkyl; (4) R 7 and R? are independently hydrogen, OR 2 , alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, loweralkylamino or di(loweralkyl)-amino; (5) R'o 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 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 1 is independently H or phosphate; (3) R' is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, 0-alkenyl, chloro, 15 bromo, fluoro, iodo, NO 2 , amino, loweralkylamino, or di(loweralkyl)amino; (4) R 7 and R! are independently OR 2 ; (5) R 10 is H; and (6) X is 0, S, SO 2 , or CH 2 . In a tenth 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 or phosphate; (3) R 6 is alkyl; 20 (4) R' and R! are independently OR 2 ; (5) R1 0 is H; and (6) X is 0, S, SO2, or CH 2 . In even more preferred subembodiments, a compound of Formula XVII, or its pharmaceutically acceptable salt or prodmg, is provided in which: (1) Base is adenine; (2) R 1 is hydrogen; (3) R 6 is methyl; (4) R 7 and R 9 are hydroxyl; (5) R1 0 is hydrogen; and (6) X is 0; 25 (1) Base is guanine; (2) R 1 is hydrogen; (3) R 6 is methyl; (4) R 7 and R 9 are hydroxyl; (5) R 10 is hydrogen; and (6) X is 0; (1) Base is cytosine; (2) R 1 is hydrogen; (3) R' is methyl; (4) R 7 and R! are hydroxyl; (5) R' 0 is hydrogen; and (6) X is 0; (1) Base is thymine; (2) R1 is hydrogen; (3) R' is methyl; (4) R 7 and R 9 are 30 hydroxyl; (5) R1 0 is hydrogen; and (6) X is 0; 44 (1) Base is uracil; (2) R' is hydrogen; (3) R is methyl; (4) R 7 and R' are hydroxyl; (5) R'* is hydrogen; and (6) X is 0; (1) Base is adenine; (2) R' is phosphate; (3) R 6 is methyl; (4) R 7 and R? are hydroxyl; (5) R' 0 is hydrogen; and (6) X is 0; 5 (1) Base is adenine; (2) R 1 is hydrogen; (3) R is ethyl; (4) R 7 and R 9 are hydroxyl; (5) R'O is hydrogen; and (6) X is 0; (1) Base is adenine; (2) R' is hydrogen; (3) R 6 is propyl; (4) R and R! are hydroxyl; (5) R1 0 is hydrogen; and (6) X is 0; (1) Base is adenine; (2) R 1 is hydrogen; (3) R 6 is butyl; (4) R 7 and R! are hydroxyl; 10 (5) R" is hydrogen; and (6) X is 0; (1) Base is adenine; (2) R' is hydrogen; (3) R is methyl; (4) R 7 and R! are hydroxyl; (5) R" 0 is hydrogen; and (6) X is S; (1) Base is adenine; (2) R1 is hydrogen; (3) R 6 is methyl; (4) R 7 and R 9 are hydroxyl; (5) R1 0 is hydrogen; and (6) X is SO 2 ; or 15 (1) Base is adenine; (2) R' is hydrogen; (3) R 6 is methyl; (4) R 7 and R 9 are hydroxyl; (5) R'" is hydrogen; and (6) X is CH 2 . In an twelfth principal embodiment the invention provides a compound of Formula XVI, or a pharmaceutically acceptable salt or prodmg thereof: R'O Base R 7 20 (XVI) wherein: Base is a purine or pyrimidine base as defined herein; R' 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 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 is 5 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 alkyl) 2 , -N(acyl)2; 10 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, lower alkylamino, or di(loweralkyl)ninn; R' is H, alkyl (including lower alkyl), chlorine, bromine or iodine; alternatively, R 7 and R!, 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) R1 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 R1 is independently H or phosphate; (3) R' is alkyl; (4) R' 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) R! is H, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is 0, S, S02 or CH 2 . 30 In a second preferred subembodiment, a compound of Formula XVII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or 46 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 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 R1 is independently H or phosphate; (3)

R

6 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) R 7 and R' are independently OR 2 ; (5) R 8 is H, alkyl (including lower alkyl), chlorine, bromine, or iodine; and (6) X is 0, S, S02 or CH 2 . In a third preferred subembodiment, a compound of Formula XVI, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or 15 pyrimidine base as defined herein; (2) R1 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 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 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(lower-alkyl)aminn; (4) R 7 25 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 diloweralkyl)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 optionally substituted with one or more substituents as described in the deiiton 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 is independently H or phosphate; (3) 5 R' is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, 0-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, loweralkylmino, 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 8 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' 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)

R

6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, 0-alkenyl, chloro, bromo, fluoro, iodo, NO2, amino, loweralkylamino, or di(loweralkyl)amino; (4) R 7 and R 9 are independently OR 2 ; (5) R 8 is H; and (6) X is 0, S, SO2, or CH 2 . 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 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 30 optionally substituted with one or more substituents as described in the defmition 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 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 and R! are independently OR 2 ; (5) R! is H, alkyl (including lower alkyl), chlorine, bromine, or iodine; and (6) X is 0. 5 In a seventh preferred subembodiment, a compound of Fornula 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; 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 pharmnacutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R' is independently H or phosphate; (3) 15 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) R 7 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) R8 is H; and (6) X is 0. 20 In an eighth 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 1 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) R 7 and R9 25 are independently OR 2 ; (5) R 8 is H; and (6) X is 0, S, S02 or CH2. 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 1 is independently H or phosphate; (3) R' is alkyl; (4) R 7 and R' are independently OR 2 ; (5) R' is H; and (6) X is 0, S, SO2, or CH2. 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 pyrimidine base as defined herein; (2) R1 is independently H or phosphate; (3) R is alkyl; (4) R 7 and R' are independently OR 2 ; (5) R' is H; and (6) X is O. In even more preferred subembodiments, a compound of Fonnula XVI, or its pharmaceutically acceptable salt or prodmg, is provided in which: 5 (1) Base is adenine; (2) R 1 is hydrogen; (3) R 6 is methyl; (4) R 7 and Re are hydroxyl; (5) R is hydrogen; and (6) X is 0; (1) Base is guanine; (2) R1 is hydrogen; (3) R 6 is methyl; (4) R 7 and R! are hydroxyl; (5) R 8 is hydrogen; and (6) X is 0; (1) Base is cytosine; (2) R' is hydrogen; (3) R 6 is methyl; (4) R 7 and R" are 10 hydroxyl; (5) R 8 is hydrogen; and (6) X is 0; (1) Base is thymine; (2) R1 is hydrogen; (3) R 6 is methyl; (4) R 7 and R! are hydroxyl; (5) R' is hydrogen; and (6) X is 0; (1) Base is uracil; (2) R' is hydrogen; (3) R 6 is methyl; (4) R 7 and R 9 are hydroxyl; (5) R 8 is hydrogen; and (6) X is 0; 15 (1) Base is adenine; (2) R' is phosphate; (3) R 6 is methyl; (4) R 7 and R' are hydroxyl; (5) R is hydrogen; and (6) X is 0; (1) Base is adenine; (2) R' is hydrogen; (3) R is ethyl; (4) R 7 and R 9 are hydroxyl; (5) R 8 is hydrogen; and (6) X is 0; (1) Base is adenine; (2) R1 is hydrogen; (3) R 6 is propyl; (4) RI and R! are hydroxyl; 20 (5) R' is hydrogen; and (6) X is 0; (1) Base is adenine; (2) R 1 is hydrogen; (3) R is butyl; (4) R 7 and R! are hydroxyl; (5) R 8 is hydrogen; and (6) X is 0; (1) Base is adenine; (2) R 1 is hydrogen; (3) R 6 is methyl; (4) R 7 and R 9 are hydroxyl; (5) R is hydrogen; and (6) X is S; 25 (1) Base is adenine; (2) R1 is hydrogen; (3) R 6 is methyl; (4) R 7 and R? are hydroxyl; (5) Re is hydrogen; and (6) X is SO 2 ; or (1) Base is adenine; (2) R 1 is hydrogen; (3) R' is methyl; (4) R 7 and R 9 are hydroxyl; (5) R is hydrogen; and (6) X is CH 2 . 50 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 EC 5 o). In preferred embodiments the compound exhibits an ECsa of less than 15 or 10 micromolar, when measured according to the polymerase assay described in Ferrari et al., Jnl. of Vir., 73:1649-1654, 1999; Ishii et al, Hepatology, 29:1227-1235,1999; Lohmann et al, ln. of Bio. Chem., 274:10807-10815, 1999; or Yamashita et al, ln. 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 I. 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 cyclohexylmethyl, 3-methylpentyl, 2,2-diniethylbutyl, 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 The term purine or pyrimidine base includes, but is not limited to, adenine, N 6 alkylpurmines, N 6 -acylpurines (wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl), N' benzylpurine, N 6 -halopurine, N'-vinylpurine, N'-acetylenic purine, N6-acyl purine, N6-hydroxyalkyl purine, N'-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, C-benzylpyrimidines, Cs-halopyrimidines, C5-vinylpyimidine, C 5 acetylenic pyrimidine, C 5 -acyl pyrimidine, C-hydroxyalkyl purine, Cs-amidopyrimidine,

C

5 -cyanopyrimidine, Cs-nitropyrimidine, Cs-aminopyrimidine, N 2 -alkylpurines, N 2 -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-clininopurine, 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, C 1 to C 4 alkyl or C 1 to C 4 alkoxy, sulfonate esters such as alkyl or aralkyl sulphonyl including methanesulfonyl, the mono, di or triphosphate ester, trityl or monomethoxytrityl, substituted benzyl, trialkylsilyl (e.g. dimethyl-t-butylsilyl) or diphenyhmethylsilyl. Aryl groups in the esters optimally comprise a phenyl group. The term "lower acy]" 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 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 tern 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 form (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. Pharmaceutically 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 compound. The compounds of this invention possess antiviral activity against HCV, or are metabolized to a compound that exhibits such activity. IH. 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 pharmnnaceutically 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, aketoglutarate, and ar-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 acting 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 nucleoside 20 will increase the stability of the nucleotide. Examples of substituent groups that can replace one or more hydrogens on the phosphate moiety are ailcyl, 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: Kucera, 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 Res. Hum. Retro Viruses. 6:491-501; 30 Piantadosi, C., .. Marasco C.J., S.L. Morris-Natschke, K.L. Meyer, F. Gumus, J.R. Surles, 55 K.S. Lshaq, L.S. Kucera, N. Iyer, CA 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, KY., 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." Antimicrob. Agents Chemother. 36:2025.2029; Hosetler, KY., L.M. Stumiller, H.B. Lenting, 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 nucleoside, 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 aL); 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. Drag 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 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. Pharmcother. 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 Chemisty 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 series 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. Linas-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 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; 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 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 griscofuluum, which demonstrates 30 activity in a scintillation proximity assay (Chu M. et al., Bioorganic and Medicinal Chemistry Letters 9:1949-1952); 57 (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., 5 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); 10 (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 15 181:251-257, 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); 20 (12) Nuclease-resistant ribozymes. (Maccjak D.J. et al., Hepatology 30 abstract 995, 1999); and (13) Other miscellaneous compounds including 1-aniino-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 al.). 58 V. Pharmaceutical Compositions 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 pharmnaceutically acceptable prodrug 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 pharmaceutically 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 LM, 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 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 com 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, antifingals, 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 ethylenediaminetetruacetic 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 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 film 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. VI. 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-BranchedNucleosides 1'-C-Branched ribonucleosides of the following structure: 61 BASE R1 8

R

9

R

7 wherein BASE is a purine or pyrimidine base as defined herein;

R

7 and RI 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), -O0ower 5 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 and R1 0 are independently H, alkyl (including lower alkyl), chlorine, bromine or iodine; alternatively, R 7 and R!, R 7 and R' 0 , Rs and R', or R' and R" can come together to form a pi bond; 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 or R 2 is independently H or phosphate; R 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 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, lithium dialkylcopper or R' SiMe 3 in TBAF with the appropriate non-protic solvent at a suitable temperature, to give the I '-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 1'-C-branched ribonucleoside is desired. The synthesis of a ribonucleoside is shown in Scheme 1. Alternatively, deoxyribo-nucleoside is desired. To obtain these nucleosides, the 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' 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. 63 Scheme 1 HO

R

6 -M RO OH OH Protection OR 2

OR

3 2) Optional OR 2 ORs Activation 1) Coupling 2) Optional Deprotection BASE 1) Optional BASE R' 2) Protection HO4 2 Re 2) Optional OR Reduction OH OH Optional Deprotection \ASE OH 2. Alternative method for the preparation of 1 '-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 alkline 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 l'-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 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 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 The 1'-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 organolithium, 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 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. Scheme 2

OR

4 DRteAlkaline tratment . Dpioeprotection R10 O 1) Halogenation D-fructose A neD)-psicose ROH 2) Nucleobase glycosylation

R

2 0 OR 3 H 0 B 1) Barton reduction R 1 B SeO ecHve R 1 B OR

SCH

3 2) Dqproteclion OH D~,, t~ OR 4 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 B. General Synthesis of 2'-C-Branched Nucleosides 2'-C-Branched ribonucleosides of the following structure: BASE RIO N6

R

9

R

7 wherein BASE is a purine or pyrimidine base as defined herein; 5 R 7 and R? 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 , NH 2 , -NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, -N(acyl) 2 ; R'O is H, alkyl (including lower alkyl), chlorine, bromine or iodine; 10 alternatively, R 7 and R 9 , or R 7 and R1O can come together to form a pi bond;

R

1 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 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 1 or R 2 is independently H or phosphate; R is an alkyl, chloro-, bromo-, fluoro-, iodo-alkyl (i.e. CF 3 ), alkenyl, or alkynyl (i.e. allyl); 20 and X is 0, S, SO2 or CH2 can be prepared by one of the following general methods. 1. Glycosylation of the nucleobase with an appropriately modiied 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 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 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, Clr pyridine, H 2 0 2 -ammonium molybdate, NaBrOrCAN, NaOCI in HOAc, copper cbromite, 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, lithiumn 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 Oranic Synthesis. John Wiley and Sons, Second Edition, 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 trimethylsilyltriflate. 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 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 LO Oxidation 01 LG Rio Ho,-OH OH 0 2) Optional OR 2 OR Protection 1) Coupling 2) Optional Deprotection BASE 1) Optional ASE

OR

2 2) Optional OH OH Reduction Optional Deprotection HO~JASE OH 5 2. Modfication 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, MnO2, 68 ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate supported on a polymer, Clrpyridine, H 2 0 2 -ammonium molybdate, NaBrO 2 -CAN, NaOC1 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 aL. Protective Grouns 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 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 15 activated to facilitate reduction; i.e. via the Barton reduction. 69 Scheme 4 VASE BASE VASE HO1) Optional R BA R -Z Protection R0-M 0 OH OH 2) nation OR 2 0 2 OH Optional Deprotection IO BASE 1) Optional BASE

OR

2 2) Optional OH OH Reduction Optional Deprotection HO, S 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, begiming 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

SR

8 10 9 7 10 R9 RI wherein BASE is a purine or pyrimidine base as defined herein;

R

7 and R 9 are independently hydrogen, OR 2 , hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(0)O(alkyl), -C(0)O(lower alkyl), -O(acyl), -O(lower 70 acyl), -O(alkyl), -O(Iower alkyl), -O(alkenyl), chlorine, bromine, iodine, NO 2 , NH 2 , -NH(lower alkyl), -NH(acyl), -NQower alkyl) 2 , -N(acyl)2; R is H, alkyl (including lower alkyl), chlorine, bromine or iodine; alternatively, R 7 and R?, or R! and R? 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 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 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;

R

6 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 CH 2 can be prepared by one of the following general methods. 1. Glycosylation oftthe 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 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 71 pyridine, H 2 Orammonium 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 at. 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 Scheme 5 1) Optional R' Rl Ho < LG Protection ,o> LG 61)R-M . HO OH 2) Oxidation OR' 2) Optional O 2 Protection 1) Coupling 2) Optional Deprotecdon BASE 1) Optional ASE Rio>6 Protection R6 2) Optional OH OH Reduction Optional Deprotection H A r OH 2. Modifcation of a pre-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 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 73 as chronic acid or pennanganate supported on a polymer, C1 2 -pyridine, H202 ammonium molybdate, NaBrO 2 -CAN, NaOC1 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 ASE1) Optional ASE R 6 ASE Protection R -M HO OH 2) Oxidation o OR 3 OH OR 3 Optional Deprotection ASE 1) Optional BASE OR22) Optional OH OH Reduction Optional Deprotection HO NO 6JASE OH 74 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 Isugar or nucleoside L-enantiomer as starting material. 5 Examples Example 1: Preparation of 1'-C-methylriboadenine via 6-amino-941-deoy-s-D psicofuranosyblpurine As another alternative method of preparation, the title compound could also be prepared according to a published procedure (J. Farkas, and F. Sorm, "Nucleic acid 10 components and their analogues. XCIV. Synthesis of 6-amino-9-(1-deoxy-p-D psicofuranosyl)purine", Collect. Czech. Chem Commnw. 1967, 32, 2663-2667. J. Farkas", Collect. Czech. Chem. Commun. 1966, 31, 1535) (Scheme 7). Scheme 7 0 NH- J N N p-Tol Br chloromercmi salt p-Tol Br Br p-TolO Op-Tol p-TolO Op-Tol 1) Bu 3 SnH, AIBN

NH

2 2) (MeO) 2 Ba / MeOH N 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 Y N N X1X RIo CH3

OR

2

OR

3 wherein: R R X 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 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 NH 2 monophosphate H H H H NH-acetyl monophosphate H H H H NH-cyclopropyl 76 . I R 1R X 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-cycopropyl 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 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 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 triphosphate H H H H O-cyclopropyl triphosphate H H H H 0-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 triphosphate H H H H F triphosphate H H H H C 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 C1 diphosphate diphosphate diphosphate H H NH 2 diphosphate diphosphate diphosphate H H NH-cyclopropyl diphosphate diphosphate diphosphate H H OH diphosphate diphosphate diphosphate H H F diphosphate diphosphate diphosphate H H C triphosphate triphosphate triphosphate H H NH 2 78 RR 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 CI 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 H H H Br H NH 2 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 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 H H H SH H NH 2 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 NH 2 acetyl H H H H NH-cyclopropyi 79

R

3 acetyl H H H H OH acetyl H H H H F acetyl H H H H CI acetyl H H F H NH 2 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 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 H OH acetyl acetyl acetyl H H F acetyl acetyl acetyl H H Cl 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-cycloprOpy triphosphate acetyl acetyl H H OH 80 Rl R R|X triphosphate acetyl acetyl H H F triphosphate acetyl acetyl H H Cl H H H H NH 2 H H H H H NH 2

NH

2 H H H H NH 2 NH-cyclopropyl H H H H NH 2 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 NH 2 SEt H H H H NH 2 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 monophosphate H H H NH 2

NH

2 monophosphate H H H NH 2 NH-acetyl monophosphate H H H NH 2 NH-cyclopropyl monophosphate H H H NH 2 NH-methyl monophosphate H H H NH 2 NH-ethyl monophosphate H H H NH 2 OH monophosphate H H H NH 2 0-acetyl monophosphate H H H NH 2 OMe monophosphate H H H NH 2 OEt monophosphate H H H NH 2 0-cyclopropy 81

R

3 Y 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 H NH 2

NH

2 diphosphate H H H NH 2 NH-acetyl diphosphate H H H NH 2 NH-cyclopropyl diphosphate H H H NH 2 NH-methyl diphosphate H H H NH 2 NH-ethyl diphosphate H H H NH 2 OH diphosphate H H H NH 2 O-acetyl diphosphate H H H NH 2 OMe diphosphate H H H NH 2 OEt diphosphate H H H NH 2 0-cyclopropyl diphosphate H H H NH 2 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 NH 2 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 X1 1 triphosphate H H H NH2 OH triphosphate H H H NH2 OMe triphosphate H H H NH2 OBt triphosphate H H H NH2 :-cyclopropyl triphosphate H H H NH2 0-acetyl triphosphate H H H NH2 SH triphosphate H H H NH2 SMe triphosphate H H H NH 2 SO triphosphate H H H NH2 S-CYClopropyl triphosphate H H H NH2 F triphosphate H H H NH2 C1 tiphosphate H H H NH2 Br triphosphate H H H NH 2 I monophosphate monophosphate monophosphate H NH 2 NH2 monophosphate monophosphate monophosphate H NH 2 NH-cyclopropyl monophosphate monophosphate monophosphate H NH 2 OH monophosphate monophosphate monophosphate H NH 2 F monophosphate monophosphate monophosphate H NH 2 C diphosphate diphosphate diphosphate H NH 2 NH2 diphosphate diphosphate diphosphate H NH 2 NH-cyclopropyl diphosphate diphosphate diphosphate H NH 2 OH diphosphate diphosphate diphosphate H NH 2 F diphosphate diphosphate diphosphate H NH 2 C triphosphate triphosphate triphosphate H NH 2 NH2 triphosphate triphosphate triphosphate H NH 2 NH-cyclopropyl triphosphate triphosphate triphosphate H NH 2 OH triphosphate triphosphate triphosphate H NH 2 F triphosphate triphosphate trihosphate H NH2 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 R' Re X1 I Y H H H F NH 2 F H H H F NH 2 Cl H H H Cl NH 2

NH

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

NH

2 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 NH 2 Cl H H H NH 2

NH

2

NH

2 H H H NH 2

NH

2 NH-cyclopropyl H H H NH 2

NH

2 OH H H H NH 2

NH

2 F H H H NH 2

NH

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

NH

2 acetyl H H F NH 2 NH-cyclopropyl acetyl H H F NH 2 OH acetyl H H F NH 2 F 84 R112 RaX X2~Y acetyl H H F NH 2 Cl H acetyl acetyl H NH 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 NH 2 Cl acetyl acetyl acetyl H NH 2

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 NH 2 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 NH 2 Cl 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 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 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 NH2 H H H H Cl NH-cyclopropyl H H H H Cl NH-methyl 85 R R Rr-X XT Y H H H H Cl NH-ethyl H H H H Cl NH-acetyl H H H H Cl OH H H H H C1 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 SHI H H H H Cl SMe H H H H Cl SEt H H H H C 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 CI 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 R X X y diphosphate H H H Cl 0-acetyl diphosphate H H H Cl OMe diphosphate H H H Cl ORt 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 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 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 diphosphate 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 87 'RR R X X H H H F Cl NH 2 H H H F Cl NH-cyclopropyl H H H F Cl OH H H H Cl Cl NH 2 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 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 NH 2 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 acetyl acetyl acetyl H Cl OH monophosphate acety! 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 R R2 R XI XI Y diphosphate acetyl acetyl H Cl NH-cyclopropyl diphosphate acetyl acetyl H C1 OH triphosphate acetyl acetyl H Cl NH2 triphosphate acetyl acetyl H Cl NH-cyclopropyl triphosphate acetyl acetyl H Cl 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 SNO N , o R'o C a OR2 OR 3 5 (V) wherein: H H H H H H H H H NH 2 H H H H NH-cyclopropyl H H H H NH-methyl H H H H NH-ethyl H H H H NH-acetyl 89 .R X, 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 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 O-acetyl 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 NH-ethyl diphosphate H H H OH diphosphate H H H O-acetyl diphosphate H H H OMe 90 X1 ll RI RZ R 3 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 tiphosphate H H H NH 2 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 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 triphosphate triphosphate triphosphate H NH-cyclopropyl triphosphate triphosphate triphosphate H OH H H H F NH 2 H H H F NH-cyclopropyl 91 R R12 'i Ry H H H F OH H H H Cl NH 2 H H H Cl NH-cyclopropyl H H H Cl OH H H H Br NH 2 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 acetyl H H F NH 2 acetyl H H F NH-cyclopropyl acetyl H H F OH H acetyl acetyl H NH 2 H acetyl acetyl H NH-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 NH 2 monophosphate acetyl acetyl H NH-cyclopropyl monophosphate acetyl acetyl H OH diphosphate acetyl acetyl H NH 2 diphosphate acetyl acetyl H NH-cyclopropyl diphosphate acetyl acetyl H OH 92 RR R I y triphosphate acetyl acetyl H NH 2 triphosphate acetyl acetyl H NH-cyclopropyl triphosphate acetyl acetyl H OH Alternatively, the following nucleosides of Formula VII are prepared, using the appropriate sugar and pyrimidine or purine bases. Base R'O x R'O R'

OR

2 OR3 5 (VII) wherein: RR2 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 CE 3 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-(NN diacetyl)cytosine H H H CH 3 O 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 R R R X Base H H H CH 3 S 2,4-0 Diacetylthymine H H H CH 3 S Thymine H H H CH 3 S Cytosine H H H CH 3 S 4-(N-mono acetyi)cytosine 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 monophosphate H H CH 3 0 2,4-0 Diacetyluracil monqphosphate H H CH 3 0 Hypoxanthine monophosphate H H CH 3 0 2,4-0 Diacetylthym 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-(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 H CH 3 S 2,4-0 Diacetylthym monophosphate H H CH 3 S Thymine monophosphate H H CH 3 S Cytosine monophosphate H H CH 3 S 4-(N-mono acetyl)cytosine 94 w w 2 wiw X Base monophosphate H H CH 3 S 4-{NN diacetyl)cytosine monophosphate H H OH 3 S Uracil monophosphate H H OH 3 S 5-Fhwmruracil diphosphate H H C113 0 2,4-0 Diacetyluracil diphosphate H H 0113 10 Hypoxonthine diphosphate H H 0113 0 2,4-0 Diacetylthymine diphosphate H H OH 3 0 Thymine diphosphate H H OH 3 0 Cytosine diphosphat H H CH 3 0 4-(N-mono acetyl)cytosine diphosphate H H 0113 0 4-(NN diacetyl)cytosine diphosphate H H 0113 0 Uracil diphosphate H H CH3 0 5-Fluorouracil diphosphate H H OH 3 S 2,4-0 Diacetyluracil diphosphate H H CH 3 S HypoxmAhiine diphosphate H H 0113 S 2,4-0 Diacetyithym diphosphate H H1 OH 3 S Thyrnine diphosphate H H CH 3 S Cytosine tniphospbate H H1 OH 3 0 2,4-0 Diacetylucil triphosphate H H1 OH 3 0 Hypoxanthine triphosphate H H OH 3 0 2,4-0 triphosphate HH 3 0 Thmn triphosphate HH0 95 R R R X Base 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 CH3 S 2,4-0 Diacetyluracil triphosphate H H CH 3 S Hypoxanthine triphosphate H H CH3 S 2,4-0 Diacetylthymine triphosphate H H CH3 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 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 Diacetylthymine monophosphate monophosphate monophosphate CF 3 S Thymine 96 I ' 2 XBase monophosphate monophosphate inonophosphiate CF 3 S Cytosine monophosphate monophospbate inonophosphate CF 3 S 4-(N-mono acetyl)cytosine monophosphate monophospbate monophosphate CF 3 S 4-{NN diaet34)cytosine monophosphate monophosphate monophosphate CF 3 S Uracil monophosphate monophosphate monophosphate CF 3 S 5-Fluorouracil acetyl acetyl acetyl CF 3 0 4-(NN diacetyl)cytosine acetyl acetyl acetyl CF 3 S 4-(NN dkacety1)c~tosiue acetyl acetyl ac-etyl 2-bromo- 0 4-(NN vinyl diacetyl)cytosine acetyl acetyl acetyl 2-bromo- S 4-(NN vinyl diacetyl)cytosine H H H CR 3 0 2-(NNl-diacetyl) guanine H H H CH 3 0 6-0-acetyl guanine H H H CR 3 0 8-fluoroguaie H H H CR 3 0Oguanine H H H CR 3 0 6-(NN-diacetyl) adenine H H H CH 3 0 2-fluoroadenine H H H CH 3 0 8-fluoroademine H H H CM 3 0 2,8-difluoro adenine H H H CR 3 0 adenine H H H CH 3 S 2-(NN-diacetyl) guanine H H H CR 3 S 6-0-acetyl guanine 97 RR R X 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 CH 3 S adenine monophosphate H H CH 3 0 2-(N,N-diacetyl) guanine monophosphate H H CH 3 0 6-O-acetyl guanine monophosphate H H CH 3 0 8-fluoroguanine monophosphate H H CH 3 0 guanine monophosphate H H CH 3 0 6-(NN-diacetyl) adenine monophosphate H H CH 3 0 2-fluoroadenine monophosphate H H CH 3 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 CH 3 S 8-fluoroguanine monophosphate H H CH 3 S guanine monophosphate H H CH 3 S 6-(NN-diacetyl) adenine monophosphate H H CH 3 S 2-fluoroadenine monophosphate H H CH 3 S 8-fluoroadenine 98 R' R32 X Base monophosphate H H GIE1 3 S 2,8-difluoro adenine monophosphate H H CH 3 S adenine diphosphate H H CH 3 0 T-(NN-iacetyl) &iphosphate H H CH3 0 6-0-acetyl guianine diphosphate H H CH 3 0 8-fluoroguanine diphosphate H H CH 3 0 guanine diphosphate H H CH 3 0 6-(NN-dacetyl) adenine diphosphate H H I H 3 10 2-fluoroadenine dliphosphate -H H CH 3 0 8-fluoroademine diphosphate H H CH 3 0 2,8-difuoro adenine diphosphate H H CH 3 0 adenine diphosphate H H CH 3 S 2-(NN-diacetyl) guanine diphosphate H H CR 3 S 6-0-acetyl guanine diphosphate H H OH 3 S 8-fluoroguanine diphosphate H H CH 3 S guanine diphosphate H H C 3 S 6-(NN-ietyl) adenine diphosphate H H OH 3 S 2-fluoroadenine diphosphate H H OH 3 S 8-fluoroadenine diphosphate H H OH 3 S 2,8-difuoro adenine diphosphate H H CH 3 S adenine triphosphate H H OH 3 0 2-(NN-diacetyl) guanine 99 R R R 3 R X Base triphosphate H H CH 3 0 6-0-acety1 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 S 6-0-acetyl guanine triphosphate H H CH3 S 8-fluoroguanine triphosphate H H CH 3 S guanine triphosphate H H CH3 S 6-(NN-diacetyl) adenine triphosphate H H CH 3 S 2-fluoroadenine triphosphate H H CH 3 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---acetyl guanine monophosphate monophosphate monophosphate CF 3 0 8-fluoroguamne monophosphate monophosphate monophosphate CF 3 0 guailne monophosphate monophosphate monophosphate CF 3 0 6-(NN-diacetyl) adenine monophosphate monophosphate monophosphate CF 3 0 j 2-fluoroadenine 100 R R2 R 3 R* X Base 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-O-acetyl guanine monophosphate monophosphate monophosphate

CF

3 S 8-fluorogaanine monophosphate monophosphate monophosphate

CF

3 S guanine monophosphate monophosphate monophosphate CF3 S 6-(NN-diacety1) 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 RV

OR

2 5 (VIII) 101 wherein R RRX Base H H CH 3 0 2,4-0-Diacetyluracil H H CH 3 0 Hypoxanthine H H CH 3 0 2,4-0-Diacetylthyimine 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 CH3 O 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 CH 3 S Cytosine H H CH 3 S 4-(N-mono-acetyl)cytosine H H CH 3 S 4-(NN-diacetyl)cytosine H H CH 3 S Uradil H H CH 3 S 5-Fluorouracil monophosphate H CH 3 0 2,4-0-Diacetyluracil monophosphate H CH 3 0 Hypoxanthine monophosphate H CH 3 0 2,4-0-Diacetylthymine monophosphate H CH 3 0 Thymine monophosphate H CH 3 0 Cytosine monophosphate H CH 3 0 4-(N-mono-acetyl)cytosine monophosphate H CH 3 0 4-(N,N-diacetyl)cytosine monophosphate H CH 3 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 CH 3 S 2,4-0-Diacetylthynine 102 1e X Base monophosphate H CH 3 S Thymine monophosphate H CH 3 S Cytosine monophosphate H CH 3 S 4-(N-mono-acetyl)cytosme monophosphate H CH 3 S 4 N-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 Hypoxnthine diphosphate H CH 3 0 2,4-0-Diacetylthymine diphosphate H CH 3 0 Thymine diphosphate H CH 3 0 Cytosine diphosphate H CH 3 0 4-(N-mono-acetyl)cytosine diphosphate H CH 3 0 4-(NN-diacetyl)cytosine diphosphate H CH 3 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 CH 3 S Thymine diphosphate H CR 3 S Cytosine diphosphate H CH 3 S 4-(N-mono-acetyl)cytosine diphosphate H CH 3 S 4-(NN-diacetyl)cytosine diphosphate H CH 3 S Uracil diphosphate H CH 3 S 5-Fluorouracil triphosphate H CH 3 0 2,4-0-Diacetyluracil triphosphate H CH3 0 Hypoxanthine triphosphate H CH 3 0 2,4-0-diacethylthymnine triphosphate H CH3 0 Thymine triphosphate H CH 3 0 Cytosine triphosphate H CH 3 0 4-(N-mono-acetyl)cytosine triphosphate H CH 3 0 4-(NN-diacetyl)cytosine 103 RX Base triphosphato H CH 3 0 Umcil triphosphate H CH 3 0 5-Fluorouracil triphosphate H CH 3 S 2,4-0-Diacetyuracil triphosphate H CH 3 S Hypoxanthine triphosphate H CH 3 S 2,4-O-DiacetyIthymine triphosphate H CH 3 S Thymine triphosphate H CH 3 S Cytosine triphosphate H CH 3 S 4-(N-mno-acetyl)cytosine triphosphate H CH 3 S 4-(NN-diacetyl)cytosine triphosphate H CH 3 S Uracil triphosphate H CH 3 S 5-Fluomuracil 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 monophosphate 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 2,4-0-Diacetyluracil monophosphate monophosphate CF 3 S Hypoxanthine 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)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 104 R R ReX Base acetyl acetyl 2-bromo- 0 4-(NN-diacetyl)cytosine vinyl acetyl acetyl 2-bromo- S 4-(N,N-diacetyl)cytosine vinyl H H CH 3 0 2-(N,N-diacetyl)-guanine H H CH 3 0 6-0-acetyl guanine H H CH 3 0 8-fluoroguanine H H CH 3 0 guanine H H CH 3 0 6-(NN-diacetyl)-adenine H H CH 3 0 2-fluoroadenine H H CH 3 0 8-fluoroadenine H H CH 3 0 2,8-difluoro-adenine H H CH 3 0 adenine H H CH 3 S 2-(NN-diacetyl)-guanine H H CH 3 S 6-0-acetyl guanine H H CH 3 S 8-fluoroguanine H H CH 3 'S guanine H H CH 3 S 6-(NN-diacetyl)-adenine H H CH 3 S 2-fluoroadenine H H CH 3 S 8-fluoroadenine H H CH 3 S 2,8-difluoro-adenine H H CH 3 S adenine monophosphate H CH 3 0 2-(N,N-diacetyl)-guanine monophosphate H CH 3 0 6-0-acetyl guanine monophosphate H CH 3 0 8-fluoroguanine monophosphate H CH 3 0 guanine monophosphate H CH 3 0 6-(NN-diacetyl)-adenine monophosphate H CH 3 0 2-fluoroadenine monophosphate H CH 3 0 8-fluoroadenine monophosphate H CH 3 0 2,8-difluoro-adenine monophosphate H CH 3 0 adenine 105 R2 R X Base monophosphate H CH 3 S 2-(NN-diacetyl)-guanine monophosphate H CH 3 S 6-0-acetyl guanine monophosphate H CH 3 S 8-fluorognnnine monophosphate H CH 3 8 guanine monophosphate H CH 3 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 CH 3 0 8-fluoroguanine diphosphate H CH 3 0 guanine diphosphate H CH 3 0 6-(NN-diacetyl)-adenine diphosphate H CH 3 0 2-fluoroadenine diphosphate H CH 3 0 8-fluoradenine diphosphate H CH3 0 2,8-difluoro-adenine diphosphate H CH3 O adei diphosphate H CH 3 S 2-(NN-diacetyl)-guanine diphosphate H CH 3 S 6-0-acetyl guanine diphosphate H CH 3 S 8-fluoroguanine diphosphate H CH 3 S guanine diphosphate H CH 3 S 6-(NN-diacetyl)-adenine diphosphate H CH 3 S 2-fluoroadenine diphosphate H CH 3 S 8-fluoroadenine diphosphate H CH 3 S 2,8-difluoro-adenine diphosphate H CH 3 S adenine triphosphate H CH 3 0 2-(NN-diacetyl)-guanine triphosphate H CH 3 0 6-0-acetyl guanine triphosphate H CH 3 0 8-fluoroguanine triphosphate H CH3 0 guanine 106 S- R2 R X Base triphosphate H CH 3 0 6-(N,-acety)-adenine triphosphate H CH 3 0 2-fluoroadenine triphosphate H CH 3 0 8-fluoradenine triphosphate H CH 3 0 2,8-difuoro-adenine triphosphate H CH 3 0 adenine triphosphate H CH 3 S 2-(NN-dicetyl)-guanine triphosphate H CH 3 S 6-0-acetyl guanine triphosphate H CH 3 S 8-fluoroguanine triphosphate H CH 3 S guanine triphosphate H CH 3 S 6-(N,N-diacetyl)-adenine triphosphate H CH 3 S 2-fluoroadenine triphosphate H CH 3 S 8-fluoroadenine triphosphate H CH 3 S 2,8,-difluoro-adenine triphosphate H CH 3 S adenine monophosphate monophosphate CF 3 0 2-(NN-diacetyl)-guanine monophosphate monophosphate CF 3 0 6-0-acetyl guanine monophosphate monophosphate CF 3 0 8-fluoroguanine monophosphate monophosphate CF 3 0 guanine monophosphate monophosphate CF 3 0 6-(NN-diacetyl)-adenine 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-(NN-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 R e R'X Base monophosphate monophosphate CF 3 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 guanine vinyl Alternatively, the following nucleosides of Formula IX are prepared, using the appropriate sugar and pyrimidine or purine bases. Base R6 R'R. 5 (D) wherein: RR X Base H CH 3 0 2,4-0-Diacetyluracil H CH 3 0 Hypoxanthine H CH 3 0 2,4-0-Diacetylthymine H CH 3 0 Thynine H CH 3 0 Cytosine H CH 3 0 4-(N-mono-acetyl)cytosie H CH3 0 4-(NN-diacetyl)cytosine H CH 3 0 Uracil H CH3 0 5-Fluorouracil H CH 3 S 2,4-0-Diacetyluracil H CH 3 S Hypoxanthine H CH3 S 2,4-0-Diacetylthymine 108 RIR X Base H CH 3 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 CH 3 S Uracil H CH 3 S 5-Fluarouracil monophosphate CH 3 0 2,4-0-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 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-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-(NN-diacetyl)cytos 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 CH 3 0 Thymine diphosphate CH 3 0 Cytosine diphosphate CH 3 0 4-(N-mono-acetyl)cytosine diphosphate CH 3 0 4-(NN-diacetyl)cytosine 109 R RX Base diphosphate CH 3 o Uracil diphosphate CH 3 0 5-Fluorouracil diphosphate CH 3 S 2,4-0-Diacetyluracil diphosphate CH 3 S 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 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 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 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)cytos monophosphate CF 3 0 Uracil monophosphate CF 3 0 5-Fluorouracil monophosphate CF 3 S 2,4-0-Diacetyluracil 110 R 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 Cytosime 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-(N,N-diacetyl)cytosine acetyl CF 3 S 4-(NN-diacctyl)cytosine acetyl 2-bromo-vinyl 0 4-(NN-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 pyrinidine or purine bases. R'O R6 R9 R7 5 (XVI wherein: R R R R X Base R R H CH 3 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 CH 3 H H 0 Cytosine OH Me H CH 3 H H 0 4-(N-mono-acetyl)cytosine OH Me H CH 3 H H 0 4-(NN-diacetyl)cytosine OH Me ill R R7 R! X Base i" R H CH3 H H 0 Uracil OH Me H CH3 H H 0 5-Fluorouracil OH Me H CH3 H H S 2,4-0-Diacetyluracil OH Me H CH3 H H S Hypoxanthine OH Me H CH3 H H S 2,4-0-Diacetylthymine OH Me H CH3 H H S Thymine OH Me H CH 3 H H S Cytosine OH Me H CH3 H H S 4-(N-mono-acetyl)cytosine OH Me H CH3 H H S 4-(NN-diacetyl)cytosine OH Me H CH3 H H S Uracil OH Me H CH3 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 Hypoxmthne OH Me monophosphate CH3 H H 0 2,4-0-Diacetylthymine OH Me monophosphate CH 3 H H 0 Thymine OH Me monophosphate CH3 H H 0 Cytosine OH Me monophosphate CH3 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 CH3 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 CH 3 H H S 2,4-0-Diacetylthymine OH Me monophosphate CH3 H H S Thymine OH Me monophosphate CH3 H H S Cytosine OH Me monophosphate CH3 H H S 4-(N-mono-acetyl)cytosine OH Me monophosphate CH3 H H S 4-(NN-diacetyl)cytosine OH Me monophosphate CH 3 H H S Uracil OH Me monophosphate CH3 H H S 5-Fluorouracil OH Me diphosphate CH3 H H 0 2,4-0-Diacetyluracil OH Me diphosphate CH3 H H 0 Hypoxanthine OH Me 112 RR I R" X Base 'RI" R l diphosphate CH 3 H H 0 2,4-0-Diacetylthymine OH Me diphosphate CH 3 H H 0 Thymine OH Me diphosphate CH 3 H H 0 Cytosine OH Me diphosphate CH 3 H H 0 4-(N-mono-acetyl)cytosine OH Me diphosphate CH 3 H H 0 4-(NN-dacetyl)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 CH 3 H H S Hypoxanthine OH Me diphosphate CH 3 H H S 2,4-0-Diacetylthymine OH Me diphosphate CH 3 H H S Thymine OH Me diphosphate CH 3 H H S Cytosine OH Me triphosphate CH 3 H H 0 2,4-0-Diacetyluracil OH Me triphosphate CH 3 H H 0 Hypoxanthine OH Me triphosphate CH 3 H H 0 2,4-0-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 CE 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 2,4-0-Diacetylthymine OH Me triphosphate CH 3 H H S Thymine OH Me triphosphate CH 3 H H S Cytosine OH Me monophosphate CF 3 H H 0 2,4-0-Diacetyluracil OH 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 R' R R7 X 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 OR 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 3 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-acety)cytosine OH Me monophosphate CF 3 H H S 4-(N,N-diacetyl)cytosine OH Me monophosphate CF 3 H H S Uracil OH Me monophosphate CF 3 H H S 5-Fluorouracil OH Me acetyl CH 3 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-diacetyl)cytosine H Br acetyl CH3 OH H S NN-diacetyl)cytosine H Br Example 2: Preparation of 2'-C-methylriboadenine The title compound was prepared according to a published procedure (R.E. Harry O'kuru, J.M. Smith, and M.S. Wolfe, "A short flexible route toward 2'-C-branched 5 ribonucleosides", .Org. Chem. 1997, 62, 1754-1759) (Scheme 8). Scheme 8 BzO- O~ z a , BzoOz b, c , BzO Ro Bz d Y9OBZ rOBZ i BzO OH BzO 0 BzO OBz

NH

2 NHBz S N </ N R =CH 3 HN HO 0Re BzOZ) OH OH BzO BzO 114 (a) Dess-Martin periodinane; (b) MeMgBr / TiC 4 ; (c) BzCa, DMAP, EtN; (d) bis(trimethylsilyl)acetamide, N 6 -benzoyl adenine, TMSOTf (e) NH 3 /MeOH In a similar mamer, but using the appropriate sugar and pyrimidine or purine bases, the following nucleosides of Formula H are prepared. Y N NNX X4 X R'O HaC 0_ 0-_~ 5 O 2

OR

3 wherein: R R R3 X X 2 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 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 C . 115 l R RR0X X2 y H 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 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 S-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 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 H H O-cyclopropyl diphosphate H H H H SH 116 RRX y diphosphate H H H H SMe diphosphate H H H H SEt diphosphate H H H H S-cycloprpyl 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 triphosphate H H H H O-cyclopropyl triphosphate H H H H O-acetyl triphosphate H H H H SH tiphosphate H H H H SMe triphosphate 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 NH 2 monophosphate monophosphate monophosphate H H NH-cyclopropyl 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 RR Rl X Y 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 NH 2 triphosphate triphosphate tripbosphate 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 H H H Br H NH 2 H H H Br H NH-cyclopropyl H H H Br H OH H H H Br H F H H H Br H C H H H NH 2 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 H H H SH H NH2 H H H SH H NH-cyclopropyl 118 RR RX XX .y 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 acetyl H H H H OH acetyl H H H H F acetyl H H H H Cl acetyl H H F H NH 2 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 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 H OH acetyl acetyl acetyl H H F acetyl acetyl acetyl H H Cl 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 119 R RX 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 H F triphosphate acetyl acetyl H H Cl H H H H NH 2 H H H H H NH 2

NH

2 H H H H NH 2 NH-cyclopropyl H H H H NH 2 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 NH 2 SEt H H H H NH 2 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 monophosphate H H H NH 2

NH

2 monophosphate H H H NH 2 NH-acetyl monophosphate H H H NH 2 NH-cyclopropyl monophosphate H H H NH 2 NH-methyl monophosphate H H H NH 2 NH-ethyl 120 y0 ~R R 2 R3X X2 Y monophosphate H H H NH 2 OH monophosphate H H H NH 2 0-acetyl monophosphate H H H NH 2 OMe monophosphate H H H NH 2 OEt monophosphate H H H NH 2 O-cyclopropyl 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 H NH 2

NH

2 diphosphate H H H NH 2 NH-acetyl diphosphate H H H NH 2 NH-cyclopropyl diphosphate H H H NH 2 NH-methyl diphosphate H H H NH 2 NH-ethyl diphosphate H H H NH 2 OH diphosphate H H H NH 2 0-acetyl diphosphate H H H NH 2 OMe diphosphate H H H NH 2 OEt diphosphate H H H NH 2 0-cyclopropyl diphosphate H H H NH 2 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 NH 2 Br diphosphate H H H NH 2 I 121 R R X i Y tiphosphate H H H NH 2 NH2 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 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 NH 2 0-acetyl triphosphate H H H NH 2 SM 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 triphosphate H H H NH 2 Cl triphosphate H H H NH 2 Br tnophosphate H H H NH 2 N monophosphate monophosphate monophosphate H NH 2

NH

2 monophosphate monophosphate monophosphate H NH 2 NH-cyclopropyl monophosphate monophosphate monophosphate H NH 2 OH monophosphate monophosphate monophosphate H NH 2 C monophosphate monophosphate monophosphate H NH 2 Cl diphosphate diphosphate diphosphate H NH 2

NH

2 diphosphate diphosphate diphosphate H NH 2 NH-cyclopropYl diphosphate diphosphate diphosphate H NH 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-oycloprOpYl triphosphate t1phosphate triphosphate H NH 2 OH 122 R |RXX Y triphosphate - triphosphate triphosphate H NH 2 F triphosphate triphospbate triphosphate H NH 2 Cl H H H F NH 2 NH2 H H H F NH 2 NH-cyclopropyl H H H F NH 2 OH H H H F NH 2 F H H H F NHi Cl H H H Cl NH 2

NH

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

NH

2 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 NH 2 Cl H H H NH 2

NH

2

NH

2 H H H NH 2

NH

2 NH-cyclopropyl H H H NH 2

NH

2 OH H H H NH 2

NH

2 F H H H NH 2

NH

2 Cl H H H SH NH 2

NH

2 H H H SH NH 2 NH-cyclopropyl H H H SH NH 2 OH H H H SH NH 2 F H H H SH NH 2 Cl acetyl H H H NH 2

NH

2 acetyl H H H NH 2 NH-cyclopropyl acetyl H H H NH 2 OH acetyl H H H NH 2 F 123 R R3 X acetyl H H H NH 2 Cl acetyl H H F NH 2

NH

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

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 NH 2 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 NH 2 Cl 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 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 NH 2 F triphosphate acetyl acetyl H NH 2 Cl 124 R R R X X Y H H H H Cl H H H H H Cl H H H H H Cl NH 2 H H Hff H C NH-cyclopmpyl H H H H C NH-Methyl H H H H C, NHethyl H H H H Cl NH-acetyl H H H H C OH H H H H Cl OMe H H H H CI OEt H H H H C 0-cylopropyl H H H H C 0-acetyl H H H H C SH H H H H Cl SMe H H H H CH l - SEt H H H H C S-cyclopropyl monophosphate H H H Cl NH2 monophosphate H H H C NH-acetyl monophosphate H H J.H Cl NH-cyclopropyl monophosphate H H H C NH-methyl monophosphate H H H Cl I NH-ethyl monphosphate H H H C OH m onophosphate IH H IH C1 0-acetyl m;onophosphate H H H Cl OMe monophosphate H H H Cl .Et monophosphate H H H Cl 0-cyclopropyl mionohosphate H H H Cl SH monophosphate H H H C1 SMe monophosphate H H H C1 SEt monophosphate H H H C1 S-cyclopropyl diphosphate H H H Cl NH 2 125 R X X 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 Cl O-Wetyl diphosphate H H H C 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 tiphosphate H H H Cl NH 2 triphosphate H H H Cl NH-acetyl triphosphate H H H Cl NH-cyclopropyl triphosphate H H H C] NH-methyl triphosphate H H H Cl NH-ethyl triphosphate H H H Cl OH tiphosphate 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 | RRX X2 Y diphosphate 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 NH-cyclopropyl H H H F Cl OH H H H Cl Cl NH 2 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 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 NH 2 H acetyl acetyl H Cl NH-cyclopropyl H acetyl acetyl H Cl OH acetyl acetyl acetyl H Cl NH 2 acetyl acetyl acetyl H CI NH-cyclopropyl 127 acetyl acetyl acetyl H C1 OH monophosphate acetyl acetyl H C1 NH 2 monophosphate acetyl acetyl H C1 NH-cyclopropyl monophosphate acetyl acetyl H Cl OH diphosphate acetyl acetyl H C1 NH 2 diphosphate acetyl acetyl H CI 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 C1 OH H H H H C1 NH 2 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 V are prepared, using the appropriate sugar and pyrimidine or purine bases. y NK R'o H3C sIc

OR

2

OR

2 5 whemin: R R R X Y H H H H H H H H H NH 2 128 Rz |V 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 OEt 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-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 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 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 129 diphosphate H H H NH-ethyl diphosphate H H H OH diphosphate H H H 0-acetyl diphosphate H H H OMe 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-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-cyclopmopyl 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 RR X Y triphosphate triphosphate triphosphate H NH-cyclopropyl triphosphate triphosphate triphosphate H OH H H H F NH 2 H H H F NH-cyclopropyl H H H F OH H H H Cl NH 2 H H H Cl NH-cyclopropyl H H H Cl OH H H H Br NH 2 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 acetyl H H F NH 2 acetyl H H F NH-cyclopropyl acetyl H H F OH H acetyl acetyl H NH 2 H acetyl acetyl H NH-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 NH 2 monophosphate acetyl acetyl H NH-cyclopropyl 131 R R' X 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 Bas

R

6

OR

2

OR

3 5 X wherein: R R R 3 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 CH 3 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-(NN diacetyl)cytosine H H H CH 3 O Uracil 132 R R XBase 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 Diacetylthymine H H H CH 3 S Thymine H H H CH3 S Cytosine H H H CH 3 S 4-(N-mono acetyl)cytosine H H H CH 3 S 4-(NN diacetyl)cytosine H H H CH 3 S Uracil H H H CH3 S 5-Fluorouracil monophosphate H H CH 3 0 2,4-0 Diacetyluracil monophosphate H H CH3 0 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-mnono acetyl)cytosine monophosphate H H CH3 0 4-(NN diacetyl)cytosine monophosphate H H CH3 o Uracil monaphosphate 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 Diacetylthym 133 R R R 3 R X Base monophosphate H H CH3 S Thymine monophosphate H H OH 3 S Cytosine monophosphate H H CE 3 S 4-(N-mono acetyl)cytosie 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 CH 3 0 2,4-0 Diacetylthymine diphosphate H H CH 3 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-(NN diacetyl)cytosine diphosphate H H CH 3 0 Uracil diphosphate H H CH 3 0 5-Fluorouracil diphosphate H H CH 3 S 2,4-0 Diacetyluracil 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 CH 3 0 Hypoxanthine 134 R R 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 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 CH3 S 2,4-0 Diacetyluracil triphosphate H H CH3 S Hypoxantbine triphosphate H H CH3 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 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-(N,N 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 135

R

1 R2 R'R|X Base monophosphate monophosphate monophosphate CF 3 IS Hypoxanthine monophosphate monophosphate monophosphate CF 3 S 2,4-0 Diacetylthymne 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-(NN diacetyl)cytosine 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-(N,N vinyl diacetyl)cytosine H H H CH 3 0 2-(N,N-diacetyl) guanine H H H CH 3 0 6-0-acetyl guanine H H H CH 3 0 8-fluoroguanine H H H CH 3 0 guanine H H H CH 3 0 6-(NN-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 136 RR R X Base H H H CH 3 S 2-(N,N-diacetyl) 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-(N,N-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 CH 3 S adenine monophosphate H H CH 3 0 2-(N,N-diacetyl) guanine monophosphate H H CH3 0 6-0-acetyl guanine monophosphate H H CH 3 0 8-fluoroguanine monophosphate H H CH 3 0 guanine monophosphate H H CH3 0 6-(NN-diacetyl) adenine monophosphate H H CH 3 0 2-fluoroadenine monophosphate H H CH3 0 8-fluoroadenine monophosphate H H CH3 0 2,8-difluoro adenine monophosphate H H CH3 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 CH 3 S 8-fluoroguanine monophosphate H H OH 3 S guanine 137 R R X Base monophosphate H H CH 3 S 6-(NN-diacetyl) adenine monophosphate H H CH 3 S 2-fluoroadenine monophosphate H H CH 3 S 8-fluoroadenine monophosphate H H CH 3 S 2,8-difuoro 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-(NN-diacetyl) adenine diphosphate H H CH 3 0 2-fluoroadenine diphosphate H H CH 3 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-diacetyl) guanine diphosphate H H CH 3 S 6-0-acetyl guanine diphosphate H H CH 3 S 8-fluoroguanmne diphosphate H H CH 3 S guanine diphosphate H H CH 3 S 6-(NN-diacety) adenine diphosphate H H CH 3 S 2-fluoroadenine diphosphate H H CH 3 S 8-fluoroadenine diphosphate H H CH 3 S 2,8-difluoro adenine 138 R R R X Base diphosphate H H CH 3 S adenine triphosphate H H CH 3 0 2-(N,N-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-(N,N-diacetyl) adenine triphosphate H H CH 3 0 2-fluoroadenine tiphosphate 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-acety1 guanine triphosphate H H CH 3 S 8-fluoroguanine triphosphate H H CH 3 S guanine triphosphate H H CH 3 S 6-(NN-diacetyl) adenine triphosphate H H CH 3 S 2-fluoroadenine triphosphate H H CH 3 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 139 R Ri R ' R* X Base 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 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 CF3 S 2-fluoroadenine monophosphate monophosphate monophosphate CF 3 S 8-fluoroadenine monophosphate monophosphate monophosphate CF3 S 2,8-fluoro 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 XI are prepared, using the appropriate sugar and pyrimidine or purine bases. 140 R'O Base R6

OR

2

R

7 wherein: R R7 R 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 CH 3 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-(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-Diacetyluracil H H H CH 3 S Hypoxanthine H H H CH 3 S 2,4-0-Diacetylthymine H H H CH3 S Thymine H H H CH3 S Cytosine H H H CH 3 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 CH 3 0 2,4-0-Diacetyluracil monophosphate H H CH 3 0 Hypoxanthine monophosphate H H CH 3 0 2,4-0-Diacetylthymine 141 R Rz R7 R X Base monophosphate H H CH3 0 Thymine monophosphate H H C13 0 Cytosine monophosphate H H CH3 0 4-(N-mono acetyl)cytosine monophosphate H H CH 3 0 4-(N,N-diacetyl)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 CH 3 S 4-(N-mono acetyl)cytosine monophosphate H H CH3 S 4-(NN-diacetyl)cytosine monophosphate H H CH 3 S Uracil monophosphate H H CH3 S 5-Fluorouracil diphosphate H H CH 3 0 2,4-0-Diacetylurac diphosphate H H CH3 0 Hypoxanthine diphosphate H H CH 3 0 2,4-0-Diacetylthymine diphosphate H H CH 3 0 Thymine diphosphate H H CH 3 0 Cytosine diphosphate H H C113 0 4-(N-mono acetyl)cytosine diphosphate H H CH3 0 4-(N,N-diacetyl)cytosine diphosphate H H CH3 0 Uracil diphosphate H H CH3 0 5-Fluorouracil diphosphate H H CH3 S 2,4-0-Diacetyluracil diphosphate H H CH 3 S Hypoxanthine diphosphate H H CH 3 S 2,4-0-Diacetylthym diphosphate H H CH3 S Thymine 142 RR R RX 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 CH3 O Thymine triphosphate H H CH3 0 Cytosine triphosphate H H CH 3 0 4-(N-mono acetyl)cytosine triphosphate H H CH 3 0 4-(N,N-diacetyl)cytos triphosphate H H CH3 O 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 Hypoxaithine triphosphate H H CH 3 S 2,4-0-Diacetylthym triphosphate H H CH 3 S Thymine triphospbate 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 monophosphate monophosphate Br CF 3 S 2,4-0-Diacetylthymine monophosphate monophosphate Br CF 3 S Thymine monophosphate monophosphate Br CF 3 S Cytosine 143

R

1 112 X Base monophosphate monophosphate Br CF 3 S 4-(N-moiio acetyl*ytosine monophosphate monophosphate ]Br CF 3 S 4-(N-diacetyl)cytos monophosphate monophosphate Br CF 3 S Uracil mcmophosphate mnon-phospAtde Br CF 3 S 5-Fluorourcil acetyl acetyl N02 CF 3 0 4-(N-diacetyl)cytosine acetyl acetyl N02 CF 3 S 4-(N-dacty cytosine acetyl acetyl N02 CF 3 0 4NN-diacctyl)cytosine acetyl acetyl N02 2-bromo- S 4-(NN-diacetyl)cytosine vinyl Alternatively, the foMowing nucleosides of Formula, XII are prepared, using the appropriate sugar and pyrimidine or purine bases. Rio Base x wherein: 116 X Base H CH 3 0 2,4-0-Diacetyluracil H CH 3 0 Hypoxanthine H CH 3 0 2,4-0-Diacetyltiyrine H CH 3 0 Thymine H CH 3 0 Cytosine H CH 3 0 4-Nmono-acetyl)cytosine H CH 3 0 4-(N-iacty1)cytosine H CH 3 0 UraCil H ICH 3 10 15-Fluorouracil 144 X Base H CH 3 S 2,4-0-Diacetyhn-acil H CH 3 S Hypoxanthine H CH3 S 2,4-0-Diacetylthymine H CH 3 S Thymine H CH 3 S Cytosine H CH 3 S 4-(N-mono-acetyl)cytosine H CH 3 S 4 N-diacetyl)cytosine H CH3 S 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-Diacetylthymine 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-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)cytosine muonophosphate 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 CH 3 0 Thymine 145 X Base diphosphate CH3 0 Cytosine diphosphate CH3 0 4-(N-mono-acetyl)cytosine diphosphate CH 3 0 4-(N,N-diacetyl)cytosine diphosphate CH3 0 Uracil diphosphate CH 3 0 5-Fluorouracil diphosphate C13 S 2,4-0-Diacetyluracil diphosphate CH 3 S Hypoxanthine diphosphate CH3 S 2,4-0-Diacetylthymine diphosphate CH 3 S Thymine diphosphate CH3 S Cytosine triphosphate CH3 0 2,4-0-Diacetyluracil triphosphate CH3 0 Hypoxanthine triphosphate CH3 0 2,4-0-Diacetylthymine triphosphate CH 3 0 Thymine triphosphate CH3 0 Cytosine triphosphate CH3 0 4-(N-mono-acetyl)cytosine triphosphate C113 0 4-(NN-diacetyl)cytosine triphosphate CH3 0 Uracil triphosphate CH3 0 5-Fluorouracil triphosphate CH3 S 2,4-0-Diacetyluracil triphosphate CH3 S Hypoxanthine triphosphate CH3 S 2,4-0-Diacetylthymine tiphosphate CH 3 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 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-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 CF3 0 4N,N-diacetyl)cytosine acetyl CF 3 S 4-(N,N-diacetyl)cytosine acetyl 2-bromo-vinyl 0 4-(NN-diacetyl)cytosine acetyl 2-bromo-vinyl S 4-(N,N-diacetyl)cytosine Alternatively, the following nucleosides of Formula XVII are prepared, using the appropriate sugar and pyrimidine or purine bases. R'O Base R 10 R

R

9

R

7 5 (XVH)~ wherein: R R* If X Base R R H CH 3 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 Thymine NH2 Me 147 R'RR -X Base R R' H CH3 H 0 Cytosine NH2 Me H CH 3 H o 4-(N-mono-acetyl)cytosine NHAc Me H CH 3 H o 4-(NN-diacetyl)cytosine NHAc Me H CH3 H 0 Uracil NH2 Me H CH 3 H 0 5-Fluorouracil NH2 Me H CH 3 H S 2,4-0-Diacetyluracil NHAc Me H CH 3 H S Hypoxantine NH2 Me H CH 3 H S 2,4-0-Diacetylthymine 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 -diacetyl)cytosine NHAc Me H CH 3 H S Uracil NH2 Me H CH 3 H S 5-Fluorouracil NH2 Me monophosphate CH 3 H 0 2,4-0-Diacetyluracil NHAc Me monophosphate CH 3 H 0 Hypoxanthine NH2 Me monophosphate CH 3 H 0 2,4-0-Diacetylthymine NHAc Me monophosphate CH 3 H 0 Thymine NH12 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 NH2 Me monophosphate CH 3 H 0 5-Fluorouracil NH2 Me monophosphate CH 3 H S 2,4-0-Diacetyluracil NHAc Me monophosphate OH 3 H S Hypoxanthine NH2 Me monophosphate CH 3 H S 2,4-0-Diacetylthymine NHAc Me monophosphate CH 3 H S Thymine NH2 Me monophosphate CH 3 H S Cytosine NH2 Me monophosphate CH 3 H S 4-(N-mono-acetyl)cytosine NHAc Me monophosphate CH 3 H S 4-(NN-diacetyl)cytosine NHAc Me monophosphate CH 3 H S Uracil NH2 Me 148 RIRI' X Base R monophosphate CE 3 H S 5-Fluorouracil NH2 Me diphosphate CE 3 H 0 2,4-0-Diacetyluracil NHAc Me diphosphate CH 3 H 0 Hypoxanthine NH2 Me diphosphate CH 3 H 0 2,4-0-Diacetylthymine NH2 Me diphosphate CH 3 H 0 Thymine NH2 Me diphosphate CH 3 H 0 Cytosine NH2 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 CH 3 H S Cytosine NH2 Me triphosphate CH 3 H 0 2,4-0-Diacetyluracil NHAc Me triphosphate CH 3 H 0 Hypoxanthine NHAc Me triphosphate CH 3 H 0 2,4-0-Diacetylthymine NHAc Me triphosphate CH 3 H 0 Thymine NH2 Me tiphosphate CH 3 H 0 Cytosine NH2 Me tiphosphate CH 3 H 0 4-(N-mono-acetyl)cytosine NHAc Me triphosphate CH 3 H 0 4-(NN-diacetyl)cytosine NH2 Me triphosphate CH 3 H 0 Uracil NH2 Me triphosphate CH 3 H 0 5-Fluorouracil NH2 Me triphosphate CH 3 H S 2,4-0-Diacetyluracil NH2 Me triphosphate CH 3 H S Hypoxanthine NH2 Me triphosphate CH 3 H S 2,4-0-Diacetylthymine NH2 Me triphosphate CH 3 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 Hypoxanthine NH2 Me 149 R R' R X Base monophosphate CF 3 H 0 2,4-0-Diacetylthymine 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-(NN-diacetyl)ytosine NH2 Me monophosphate CF 3 H 0 Uracil NH2 Me monophosphate CF 3 H 0 5-Fluorouracil NH2 Me monophosphate CF 3 H S 2,4--Diacetyluracil NH2 Me monophosphate CF 3 H S Hypoxanthine NH2 Me monophosphate CF 3 H S 2,4-0-Diacetylthymine NH2 Me monophosphate CF 3 H S Thymine NH2 Me monophosphate CF 3 H S Cytosine NH2 Me monophosphate CF 3 H S 4-(N-mono-acetyl)cytosme NH2 Me monophosphate CF 3 H S 4-(NN-diacetyl)cytosine NH2 Me monophosphate CF 3 H S Uracil NH2 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 (R.F. Nutt, M.J. Dickinson, F.W. Holly, and E. Walton, "Branched-chain sugar nucleosides. III. 3'-C 5 methyladenine ", J Org. Chem. 1968, 33, 1789-1795) (Scheme 9). 150 Scheme 9 BZO0 1 O a .. O bc azo OCH - d 00 OH OH

R=CH

3 2 NHBz N N -N HO f zBzO OCH3 HO R~ g B OH OH BzO BzO OBz OBz (a) RuO 2 / NaIO 4 ; (b) MeMgI / TiC1 4 ; (c) HCL / MeOH / H 2 0; (d) BzC1 / pyridine; (e) AcBr, HBr / AcOH; (f) chloromercuri-6-benzamidopurine; (g) NH 3 / 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 0

OR

2 OR' wherein:

RR

3 X 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 R Rz R 3 Xi X 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 SBt 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 NH2 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 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 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 2 152 R RX yI 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 0-cyclopropy 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 tiphosphate 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 O-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 RI R2 Re Xi X Y triphosphateH H F triphosphate H H H H Cl tiphosphate H H Br tiphosphae 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 NH 2 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 tiphosphate 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 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 NH2 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 H H H Br H NH 2 H H H Br H NH-cyclopropyl 154 R R2 R X 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 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 H H H SH H NH 2 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 NH 2 acetyl H H H H NH-cyclopropyl acetyl H H H H OH acetyl H H H H F acetyl H H H H Cl acetyl H H F H NH 2 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 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 H OH 155 R RlX Y acetyl acetyl acetyl H H F acetyl acetyl acetyl H H Cl 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 tiphosphate acetyl acetyl H H C1 H H H H NH 2 H H H H H NH 2

NH

2 H H H H NH 2 NH-cyclopropyl H H H H NH 2 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 NH 2 SEt 156 i lR R| Y H H H H NH 2 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 NH 2

NH

2 monophosphate H H H NH 2 NH-acetyl monophosphate H H H NH 2 NH-cyclopropyl monophosphate H H H NH 2 NH-methyl monophosphate H H H NH 2 NH-ethyl monophosphate H H H NH 2 OH monophosphate H H H NH 2 0-acetyl monophosphate H H H NH 2 OMe monophosphate H H H NH 2 OEt monophosphate H H H NH 2 0-cyclopropyl 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 H NH 2

NH

2 diphosphate H H H NH 2 NH-acetyl diphosphate H H H NH 2 NH-cyclopropyl diphosphate H H H NH 2 NH-methyl diphosphate H H H NH 2 NH-ethyl diphosphate H H H NH 2 OH diphosphate H H H NH 2 0-acetyl diphosphate H H H NH 2 OMe 157 R R X X Y diphosphate H H H NH 2 OEt diphosphate H H H NH 2 0-cyclopropyl diphosphate H H H NH 2 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 NH 2 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 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 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 NH 2 F trphosphate H H H NH 2 Cl triphosphate H H H NH 2 Br triphosphate H H H NH 2 I monophosphate monophosphate monophosphate H NH 2

NH

2 monophosphate monophosphate monophosphate H NH 2 NH-cyclopropyl monophosphate monophosphate monophosphate H NH 2 OH 158 -Ri R 2 R X | X2 Y monophosphate monophosphate monophosphate H NH 2 F monophosphate monophosphate monophosphate H NH 2 Cl diphosphate diphosphate diphosphate H NH 2

NH

2 diphosphate diphosphate diphosphate H NH 2 NH-cyclopropyl diphosphate diphosphate diphosphate H NH 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 H H H F NH 2 F H H H F NH 2 Cl H H H Cl NH 2

NH

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

NH

2 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 NH 2 Cl H H H NH 2

NH

2

NH

2 H H H NH 2

NH

2 NH-cyclopropyl H H H NH 2

NH

2 OH H H H NH 2

NH

2 F 159 Hl H HH N C H H H NH 2

NH

2 C H H H SH NH 2

NH

2 H H H SH NH 2 NH-cyclopropyl H H H SH NH 2 OH H H H SH NH 2 F H H H SH NH 2 Cl acetyl H H H NH 2

NH

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

NH

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

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 NH 2 C 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 NH 2 Cl 160 Rl R2 xs X X Y diphosphate acetyl acetyl H NH 2 NH2 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 H 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 H H H H Cl H H H H H Cl H H H H H Cl NH 2 H H H H Cl NH-cyclopropyl H H H H Cl NH-methyl H H H H Cl NH-ethyl H H H H CI NH-acetyl H H H H Cl OH H H H H Cl OMe H H H H Cl Ot H H H H CI 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 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 161 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 diphosphate 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 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 162 R X . X Y 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 diphosphate diphosphate diphosphate H Cl NH-cyclopropyl diphosphate diphosphate diphosphate H CI OH triphosphate triphosphate triphosphate H Cl NH 2 triphosphate triphosphate triphosphate H Cl NH-cyclopropyl triphosphate triphosphate triphosphate H C1 OH H H H F Cl NH 2 H H H F Cl NH-cyclopropyl H H H F Cl OH H H Cl Cl NH 2 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 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 2 163 RI R R R 3 Xy acetyl H H H Cl NH-cyclopropyl acetyl H H H CI 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 NH 2 H acetyl acetyl H Cl NH-cyclopropyl H acetyl acetyl H CI OH acetyl acetyl acetyl H CI NH 2 acetyl acetyl acetyl H Cl NH-cyclopropyl acetyl acetyl acetyl H Cl OH monophosphate acetyl acetyl H Cl NH 2 monophosphate acetyl acetyl H C1 NH-cyclopropyl monophosphate acetyl acetyl H C1 OH diphosphate acetyl acetyl H Cl NH 2 diphosphate acetyl acetyl H C1 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 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 Y NO x f R~o oR 1 OR' wherein

RR

2 RX y H H H H H H H H H NH 2 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 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-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 O-acetyl 165 RRU 'R 'RX y 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 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 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-cyclopropyl triphosphate H H H NH-methyl triphosphate H H H NH-ethyl triphosphate H H H OH tiphosphate H H H OMe triphosphate H H H OEt triphosphate H H H O-cyclopropyl triphosphate H H H O-acetyl 166 R R X Y triphosphate H H H SH tiphosphate 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 triphosphate triphosphate triphosphate H NH-cyclopropyl triphosphate triphosphate triphosphate H OH H H H F NH 2 H H H F NH-cyclopropyl H H H F OH H H H Cl NH 2 H H H Cl NH-cyclopropyl H H H Cl OH H H H Br NH 2 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 RR X Y acetyl H H F NH 2 acetyl H H F NH-cyclopropyl acetyl H H F OH H acetyl acetyl H NH 2 H acetyl acetyl H NH-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 NH 2 monophosphate acetyl acetyl H NH-cyclopropyl 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 XI are prepared, using the appropriate sugar and pyrimidine or purine bases. RO Base R X

O

2

R

3 5 (XMI wherein: R' R 2 RIS RiX Base H H H CH 3 0 2,4-0 Diacetyluracil H H H CH 3 0 Hypoxanthine 168 ie' XBase H H H H 3 0 2,4 Diacetyithymifle H H H CH 3 0 Thymine HH H CH 3 0 Cytosine H H H CH 3 0 4-(N-mono ac-etyl)cytosmne H H H CH 3 0 4-(NN Idiactyl~cytosine H H H CH 3 0OUracil H H H OH 3 0 15-Fluorouracil H H H OH 3 S 2,4-0 Diacet~maci H H H CH 3 s Hypoxanthine H H H CH 3 S 2,4-0 Diacetyithyzuine H H H 0113 S Thymine H H H CH 3 S Cytosine H H H 0113 S 4-(N-mono acetyl)cytosiae HI H H OH 3 S 4-NN diacetyl)cytosine H H H OH 3 S Uracil H H H OH 3 S 5-Fluorouracil monophosphate H H 0113 0 2,4-0 Diacetyluracl monophosphate H H 0113 0 Hypoxantin monaphosphate H H CH 3 0 2,4-0 Diacetyithym monophosphate H H 0113 0 Thyrnine monophosphate H H CH 3 0 Cytosine monophosphate H H CH 3 0 4-(N-mono acetyl)cytosine 169 R' X Base monophosphate H H CH 3 0 4-(NN 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 H CH 3 S 2,4-0 Diacetylthym 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-(NN diacetyl)cytosine monophosphate H H CH 3 S Unacil 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 CH 3 0 2,4-0 Diactyl4thymine diphosphate H H CH 3 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-(NN diacetyl)cytosine diphosphate H H CH 3 0 Uracil diphosphate H H CH 3 0 5-Fluorouracil diphosphate H H CH 3 S 2,4-0 Diacetyluracil 170 R3 R X Base diphosphate H H CH 3 S Hypoxanthine diphosphate H H CH 3 S 2,4-0 Diacetylthym diphosphate H H CH3 S Thymine diphosphate H H CH 3 S Cytosine triphosphate H H CH 3 0 2,4-0 Diacetyluradil 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 tiphosphate 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 tiphosphate 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 Hypoxantbine monophosphate monophosphate monophosphate CF 3 0 2,4-0 Diacetyithymine monophosphate monophosphate monophosphate CF 3 0 Thymine monophosphate monophosphate monophosphate CF 3 0 Cytosine 171 R2 R1 Re X Base monophosphate monophosphate monophosphate CF 3 0 4-(N-nono 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 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 monophosphate monophosphate monophosphate CF 3 S Uracil monophosphate monophosphate monophosphate CF 3 S 5-Fluorouracil acetyl acetyl acetyl CF 3 0 4-(N diacetyl)cytosine 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 H CH 3 0 2-(NN-diacetyl) guanine H H H CH 3 0 6-0-acetyl guanine H H H CH 3 0 8-fluoroguanine 172 R! I I XBase H H H CH 3 10guaine H H H OH 3 10 6-(NN-diacetyl) adenine H H H 0113 0 2-fluoroadenicie H H H OH 3 0 8-fluoroademine H H H 0113 0 2,8-difuoro adenine H H H OH 3 0Qadenine H H H OH 3 S 2-(NN-diacetyl) guanine H H H OH 3 S 6-0-acetyl guanine H H H CH 3 S 8-fluoroguanine H H H OH 3 S guanine H H H CH 3 S 6-(NN-diacetyl) adenine H H H 0113 S 2-fluor-oadenine H H H 0113 S 8-fluoroadenine H H H OH 3 S 2,8-difuoro adenine H H H OH 3 S adenine monophosphate H H 0113 0 2-(NN-diacety!) guanine monophosphate H H 0113 0 6-0-acetyl guanine monophosphate H H 0113 0 8-fluowoguanine monophosphate H H OH 3 0 guanine monophosphate H H 0113 0 6-(NN-diacetyl) adenine monophosphate H H OH 3 0 2-fluoroadenine monophosphate, H IH 013 10 8-fluoroadene 173 R RR X Base monophosphate H HMaR 0 2,8-difuoro adenine monophosphate H H CH 3 0 adenine monophosphate -H H CH 3 S 2-(N,N-diacetyl) monophosphate H H CH 3 S 6-O-acetyl monophosphate H H CH 3 S 8-fluorgummie monophosphate H H CH 3 S guanine monophosphate H H CH 3 S 6-(NN-diacetyl) adenine monophosphate H H 01 3 S 2-fluoroadenine monophosphate H H CH 3 S 8-fluoroadezzine monophosphate H H CH 3 S 2,8-difluoro adenine monophosphate H H CH 3 S adenine diphosphate H H CH 3 0 2-(N-iacetyl) guanmne diphosphate H H CH 3 0 6-0-acetyl guanine diphosphate H H CR 3 0 8-fluoroguanie diphosphate H H CR 3 0 guanine diphosphate H H CH 3 0 6-(NN-diacetyl) adenine diphosphate H H CII, 0 2-fluoroademine diphosphate H H CR, 0 8-flu~oadene diphosphate H H CH3 0 2,8-difuoro adenine diphosphate H H CR 3 0 adenine diphosphate H H CH 3 S 2-(N-iacetyl) guanine_ 174

R

3 ~ B~X ase diphosphale H H OH 3 S 6-0-acetyl guanine diphosphate, H H OH 3 S 8-fluoaninfle diphosphate H H H 3 S guanie diphosphate H H OH 3 S 6-(N-dicetyl) adenine diphosphate H H OH 3 is 2-fluoroadienine diphosphate H H OH 3 S 8-fluoroadenine diphosphate, H H OH 3 S 2,8-difuoro adenine diphosphate H H OH 3 S adenine tiiphosphate H H OH 3 0 2-(NN-diacty) guanine triphosphate H H OH 3 0 6-0-acetyl guanine triphosphate H H OHE 3 0 8-fluoroguanine triphosphate H H OH 3 0 guanine tiiphosphate H H CH 3 0 6-N-diaetyl) adenine triphosphate H H OH 3 0 2-fluoroadenine triphosphate H H OH 3 0 8-fluoroadenine triphosphate H H OH 3 0 2,8-difhioro aqdenine triphosphate H H OH 3 0 2-(N,-diacetyl) Sguanine triphosphate H H OH 3 S 6-0-acetyl triphosphate H H OH 3 S 8-fluorogummin triphosphate H H OH 3 S guanine triphosphate H H OH 3 S 6-(NN-diacetyl) adenine triphosphate H H IOH 3 IS I2-fluoroadenine 175 R R2R R X Base triphosphate H H CH 3 S 8-fluoroadenine triphosphate H H CH3 S 2,8-difluoro adnine triphosphate H H CH 3 S adenine monophosphate monophosphate monophosphate CF 3 0 2-(NN-diacetyl) guanine monophosphate monophosphate monophosphate CF3 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-fuoroadenine 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 CF3 S 6-0-acetyl guanine monophosphate monophosphate monophosphate CF3 S 8-fluoroguanine monophosphate monophosphate monophosphate CF 3 S guanine monophosphate monophosphate monophosphate CF 3 S 6-(N,N-diacetyl) adenine monophosphate monophosphate monophosphate CF 3 S 2-fluoroadenine monophosphate monophosphate monophosphate CF3 S 8-fluoroadenine monophosphate monophosphate monophosphate CF3 S 2,8-difluoro adenine monophosphate monophosphate monophosphate CF3 S adenine acetyl acetyl acetyl CF3 O guanine acetyl acetyl acetyl CF3 S guanine 176 R R R R X 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. R'O Base R X

OR

2 5 (XIV) wherein: R R X Base H H CH3 0 2,4-0-Diacetyluracil H H CH3 0 Hypoxanthine H H CH3 0 2,4-0-Diacetylthymine H H CH3 0 Thymine H H CH3 0 Cytosine H H CH3 0 4-(N-mono-acetyl)cytosine H H CH3 0 4-(NN-diacetyl)cytosine H H CH3 0 Uracil H H CH3 0 5-Fluorouracil H H CH3 S 2,4-0-Diacetyluracil H H CH3 S Hypoxanthine H H CH3 S 2,4-0-Diacetylthymine H H CH3 S Thymine H H CH 3 S Cytosine H H CH 3 S 4-(N-mono-acetyl)cytosin 177 RR2 iR X Base H H CH 3 S 4-(NN-diacetyl)cytosine H H CH 3 S Uracil H H CH 3 S 5-Fluorouracil monophosphate H CH 3 0 2,4-O-Diacetyluracil monaphosphate H CH 3 0 Hypoxanthine monophosphate H CH 3 0 2,4-0-Diacetylthym monophosphate H CH 3 0 Thymine monophosphate H CH 3 0 Cytosine monophosphate H CH 3 0 4-(N-mono-acetyl)cytosine monophosphate H CH 3 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 CH 3 S Hypoxanthine monophosphate H CH 3 S 2,4-0-Diacetythym 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 CH 3 0 2,4-0-Diacetylthymine diphosphate H CH 3 0 Thymine diphosphate H CH 3 0 Cytosine diphosphate H CR 3 0 4-(N-mono-acetyl)cytosine diphosphate H CH 3 0 4-(N-iacetyl)cytosine diphosphate H CH 3 0 Uracil diphosphate H CH 3 0 5-Fluorouracil diphosphate H CH 3 S 2,4-0-Diacetyluracil 178 R Rz R X Base diphosphate H CH 3 S Hypoxanthine diphosphate H CH 3 S 2,4-0-Diacetylthymine diphosphate H CH 3 S Thymine diphosphato H CH 3 S Cytosine triphosphate H CH 3 0 2,4-0-Diacetyhuaci triphosphate H CH 3 0 Hypoxanthine triphosphate H CH 3 0 2,4-0-Diacetylthymine triphosphate H CH 3 0 Thymine triphosphate H CH 3 0 Cytosine triphosphate H CH 3 0 4-(N-mono-acetyl)cytosine triphosphate H CH 3 0 4-(NN-diacetyl)cytosine triphosphate H CH 3 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 2,4-0-Diacetylthymine 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-Diacetylthymine monophosphate monophosphate CF 3 0 Thymine monophosphate 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 2,4-0-Diacetyluracil monophosphate monophosphate CF 3 S Hypoxanthine monophosphate monophosphate CF 3 S 2,4-0-Diacetylthymine monophosphate monophosphate CF 3 S ThyMine 179

R

2 X Base monophosphate monophosphate CF 3 S 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-(N,N-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. R'O Base x Rd 5 (XV) wherein: RR X Base H CH 3 0 2,4-0-Diacetyluracil H CH 3 0 Hypoxanthine H CH 3 0 2,4-0-Diacetylthynine H CH 3 0 Thymine H CH 3 0 Cytosine H CH 3 0 4-(N-mono-acetyl)cytosine H CH 3 0 4-(NN-diacetyl)cytosine H CH 3 0 Uracil 180 R X Base H CH 3 0 5-Fluorouracil H CH 3 S 2,4-0-Diacetyluracil i CH 3 S Hypoxanthine H CH 3 S 2,4-0-Diacetylthymine H CH 3 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 CH 3 S 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-Diacetylthymine 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-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-(NN-diacetyl)cytosine monophosphate CH 3 S Uracil monophosphate CH 3 S 5-Fluorouracil diphosphate CE 3 0 2,4-0-Diacetyluracil diphosphate CH 3 0 Hypoxanthine diphosphate CH 3 0 2,4-0-Diacetylthymine 181 RR X Base diphosphate CH 3 0 Thymine diphosphate CH 3 0 Cytosine diphosphate CH 3 0 4-(N-mono-acetyl)cytosine diphosphate CH 3 0 4-(NN-diacetyl)cytosine diphosphate CH 3 0 Uracil diphosphate CH 3 0 5-Fluomuracil diphosphate CH 3 S 2,4-0-Diacetyluracil diphosphate CH 3 S 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 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 CH 3 S 2,4-0-Diacetylthymine triphosphate CH 3 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 182 RR ' X Base monophosphate CF 3 0 4-(lN-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 2,4-0-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-dacetyl)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. RIO Base x R' R' 5 (XV1H) wherein: R R! R7 X Base R R! H CH 3 OH 0 2,4-0-Diacetyluracil H Me H CH 3 OH 0 Hypoxanthine H Me H CH 3 OH 0 2,4-0-Diacetylthymine H Me 183 ..- R * RX Base H CH3 OH O Thymine H Me H CH 3 OH 0 Cytosine H Me H CH 3 OH o 4-(N-mano-acetyl)cytosine H Me H CH 3 OH 0 4-(NN-diacetyl)cytosine H Me H CH 3 OH 0 Uracil H Me H CH 3 OH 0 5-Fluorouracil H Me H CH 3 OH S 2,4-0-Diacetyluracil H Me H CH 3 OH S Hypoxanthine 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-monc-acetyl)cytosine H Me H CH 3 OH S 4-(NN-diacetyl)cytosine H Me H CH 3 OH S Uracil H Me H CH 3 OH S 5-Fluorouracil H Me monophosphate CH 3 OH 0 2,4-0-Diacetyluracil H Me monophosphate CH 3 OH 0 Hypoxanthine H Me monophosphate CH 3 OH 0 2,4-0-Diaretylthymine H Me monophosphate CH 3 OH 0 Thymine H me monophosphate CH 3 OH 0 Cytosine H Me monophosphate CH 3 OH 0 4-(N-mono-acetyl)cytosine H Me monophosphate CH 3 OH 0 4-(NN-diacetyl)cytosine H Me monophosphate CH 3 OH 0 Uracil H Me monophosphate CH3 OH 0 5-Fluorouracil H Me monophosphate CH 3 OH S 2,4-0-Diacetyluracil H Me monophosphate CH3 OH S Hypoxanthine H Me monophosphate CH3 OH S 2,4-0-Diacetylthymine H Me monaphosphate CH 3 OH S Thymine H Me monophosphate CH 3 OH S Cytosine H Me monophosphate CH3 OH S 4-(N-mono-acetyl)cytosine H Me monophosphate CH3 OH S 4-(NN-diacetyl)cytosine H Me 184 R R R X Base R R monophosphate CH 3 OH S Uracil H Me monophosphate CH 3 OH S 5-Fluorouracil H Me diphosphate CH 3 OH 0 2,4--Diacetyluracil H Me diphosphate CH 3 OH 0 Hypoxantne 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 CH 3 OH 0 4-(NN-diacetyl)cytosine H Me diphosphate CH 3 OH 0 Uracil H Me diphosphate CH 3 OH 0 5-Fluoroum cil 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 2,4-0-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 CH 3 OH 0 Thymine H Me triphosphate CH 3 OH 0 Cytosine H Me triphosphate CH 3 OH 0 4-(N-mono-acetyl)cytosine H Me triphosphate CH 3 OH 0 4-(NN-diacetyl)cytosine H Me triphosphate CH 3 OH 0 Uracil H Me triphosphate CH 3 OH 0 5-Fluorouracil H Me triphosphate CH 3 OH S 2,4-0-Diacetyluracil H Me triphosphate CH 3 OH S Hypoxanthine H Me triphosphate CH 3 OH S 2,4-0-Diacetylthymine H Me triphosphate CH 3 OH S Thymine H Me triphosphate CH 3 OH S Cytosine H Me monophosphate CF 3 OH 0 2,4-0-Diacetyluracil H Me 185 R RiiR X Base |R R! 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 H 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 monophosphate 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-Diacetythymine H Me monophosphate CF 3 OH S Thymine 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-(NN-diacetyl)cytosine H Me monophosphate CF 3 OH S Uracil H Me monophosphate CF 3 OH S 5-Fluorouracil H Me acetyl CH 3 OH 0 4-(NN-diacetyl)cytosine H Br acetyl CH 3 OH S 4-(N,N-diacetyl)cytosine H Br VH. 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., Ln. of Vir., 73:1649-1654, 1999; Ishii et aL., Hepatology, 29:1227-1235,1999; Lohmann et al., n. ofBio. Chem., 274:10807 10815, 1999; and Yamashita et al, n. ofBio. Chem., 273:15479-15486, 1998. 10 WO 97/12033, filed on September 27, 1996, by Emory University, listing C. Hagedom and A. Reinoldus as inventors, and which claims priority to U.S.S.N. 60/004,383, 186 filed on September 1995, describes an HCV polymerase assay that can be used to evaluate the activity of the compounds described herein. Another HCV 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: l(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 detennine the cellular metabolism of the compounds, HepG2 cells were obtained from the American Type Culture Collection (Rockville, MD), and were grown in 225 cm 2 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 piM of [H) labeled active compound (500 dpm/pmol) for the specified 20 time periods. The cells were maintained at 37"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 0 C with 60% methanol followed by extraction with an additional 20 jLL 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 0 C until HPLC analysis. The preliminary results of the HPLC analysis are tabulated in Table 1. 187 Table 1 [pmol/iiion cells] p-D-2'-CH3- .p-D-2'-CH 3 - p-D-2'-CH 3 - P-D-2'-CH 3 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: Bioavailabilitv 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 H 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 bolas (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 (T.), area under the curve (AUC), half life of the dosage concentration (T-A), 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 Table 2: Oral Bioavallability in Monkeys Dose AUC Norm AUC Mean Norm AUC F (%) (mg) (ng/nL x h) (ng/ImL x h/mg) (ng/mL x h/mg) V Monkey 1 46.44 13614 293.2 N Monkey 2 24.53 6581 268.3 1V 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 p-D-2'-CH 3 -riboG in Cynomolgus Monkeys IV PO Dose/Route (mg/kg) 10 10 C._(ng_mL) 6945.6± 1886.0 217.7± 132.1 T.(br) 0.25 0.00 2.00± 1.00 AUC (ng/mL x hr) 8758.0+ 4212.9 1166.0 589.6 T% (br) 7.9± 5.4 10.3 4.1 CL (L/hr/kg) 1.28 0.48 VS(I'kg) 2.09 0.54 F (%) 13.8 5 Example 6: Bone Marrow Toxicity Assay 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)guanine for nonnal 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 Pharmacology 1992; 44:1921-1925. The culture assays for CFU-GM and BFU-E were performed using a bilayer soft agar or 15 methylcellulose method. Dmgs were diluted in tissue culture medium and filtered. After 14 to 18 days at 37 0 C 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 Table 4: Human Bone Marrow Toxicity CFU-GM and BFU-E Clonogenic Assays ICsO in PM Treatment CFU-GM BFU-E ribavirin -5 ~1 P-D-2'-CH 3 -rboA >100 >100 p-D-2'-CH 3 -riboU > 100 > 100 p-D-2'-CH 3 -rboC >10 >10 p-D-2'-CH 3 -riboG > 10 > 100 Example 7: Mitochondria 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 I-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. (p) lactate (mg/10 6 cell) % of Control Control 2.18 FIAU 10 3.73 170.4 p-D-2'-CH 3 -riboC 1 2.52 115.3 10 2.36 107.9 50 2.26 103.4 100 2.21 101.2 NO OH OHOH 15 FIAU p-D-2'-CHrriboC 190 Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not to the exclusion of any other element, integer or step, or group of elements, integers or steps. It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive. All publications mentioned in this specification are herein incorporated by reference. Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed in Australia before the priority date of each claim of the application. 191

Claims (24)

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'-deoxy-2'-C-methyl-nucleoside, or pharmaceutically acceptable salt or a prodrug thereof.

2. 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 deoxynucleoside is a p-D-2'-deoxy-2'-C-methyl-nucleoside, or pharmaceutically acceptable salt or a prodrug thereof.

3. The method of claim 1 or claim 2, wherein the deoxynucleoside is a P-D-2'-deoxy 2'-halo-2'-C-methyl-nucleoside, or pharmaceutically acceptable salt or a prodrug thereof, wherein the halo is chloro, bromo, or iodo.

4. The method of claim 1 or claim 2, wherein the deoxynucleoside is a P-D-2'-deoxy 2'-C-methyl pyrimidine nucleoside, or pharmaceutically acceptable salt or a prodrug thereof.

5. The method of claim 4, wherein the deoxynucleoside is a P-D-2'-deoxy-2'-halo-2' C-methyl pyrimidine nucleoside, or pharmaceutically acceptable salt or a prodrug thereof, wherein the halo is chloro, bromo, or iodo.

6. The method of claim 4, wherein the deoxynucleoside is a p-D-2'-deoxy-2'-C methyl uracil nucleoside, or pharmaceutically acceptable salt or a prodrug thereof.

7. The method of claim 4, wherein the deoxynucleoside is a p-D-2'-deoxy-2'-halo-2' C-methyl uracil nucleoside, or pharmaceutically acceptable salt or a prodrug thereof, wherein the halo is chloro, bromo, or iodo.

8. The method of claim 4, wherein the deoxynucleoside is a P-D-2'-deoxy-2'-C methyl cytosine nucleoside, or pharmaceutically acceptable salt or a prodrug thereof. 192 Iaamni iovm r'rn U A mna ll_.U L-40.JU 4

9. The method of claim 4, wherein the deoxynucleoside is a p-D-2'-deoxy-2'-halo-2' C-methyl cytosine nucleoside, or pharmaceutically acceptable salt or a prodrug thereof, wherein the halo is chloro, bromo, or iodo.

10. The method of claim 1 or claim 2, wherein the deoxynucleoside is a p-D-2'-deoxy 2'-halo-2'-C-methyl-ribonucleoside, or pharmaceutically acceptable salt or a prodrug thereof, wherein the halo is chloro, bromo, or iodo.

11. The method of claim 10, wherein the deoxynucleoside is a -D-2'-deoxy-2'-halo 2'-C-methyl pyrimidine ribonucleoside, or pharmaceutically acceptable salt or a prodrug thereof, wherein the halo is chloro, bromo, or iodo.

12. The method of claim 11, wherein the deoxynucleoside is a P-D-2'-deoxy-2'-halo 2'-C-methyl uracil ribonucleoside, or pharmaceutically acceptable salt or a prodrug thereof, wherein the halo is chloro, bromo, or iodo.

13. The method of claim 11, wherein the deoxynucleoside is a p-D-2'-deoxy-2'-halo 2'-C-methyl cytosine ribonucleoside, or pharmaceutically acceptable salt or a prodrug thereof, wherein the halo is chloro, bromo, or iodo.

14. The method of any one of claims I to 13, wherein the host is a human.

15. The method of any one of claims 1 to 14, wherein the antivirally effective amount is ranging from about 0.1 to about 100 mg/kg/day.

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

17. The method of claim 15, wherein the antivirally effective amount is ranging from about 1 to about 20 mg/kg/day,

18. The method of any one of claims 1 to 17, wherein the deoxynucleoside is administered in combination or alternation with a second anti-hepatitis C agent.

19. The method of claim 18, wherein the second agent is selected from the group consisting of an interferon, ribavirin, a protease inhibitor, a thiazolidine derivative, a polymerase inhibitor, and a helicase inhibitor. 193 WO IrMIMCnwoveIlNKIclblt U UA Kulli I| IL.DOC-4A/2014

20. The method of claim 18, wherein the second agent is an interferon.

21. The method of claim 18, wherein the second agent is ribavirin.

22. The method of claim 1 or claim 2, substantially as hereinbefore described.

23. Use of a p-D-2'-deoxy-2'-C-methyl-nucleoside, or pharmaceutically acceptable salt or a prodrug thereof in the manufacture of a medicament for the treatment of a hepatitis C virus infection in a host by administering to the host an antivirally effective amount of said deoxynucleoside.

24. Use of a p-D-2'-deoxy-2'-C-methyl-nucleoside, or pharmaceutically acceptable salt or a prodrug thereof in the manufacture of a medicament for inhibiting replication of a hepatitis C virus infection in a host by contacting the host with an antivirally effective amount of said deoxynucleoside. 194