AU2013200925B2 - Compounds and pharmaceutical compositions for the treatment of viral infections - Google Patents

Abstract

Provided herein are compounds, compositions and methods for the treatment of liver disorder, including HCV and/or HBV infections. Specifically, compound and compositions of 5 nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-viral agents.

Description

AUSTRALIA Patents Act COMPLETE SPECIFICATION (ORIGINAL) Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art: Name of Applicant: Idenix Pharmaceuticals, Inc. and Centre National de la Recherche Scientifique and L'Universite Montpellier II Actual Inventor(s): Jean-Pierre Sommadossi, Gilles Gosselin, Claire Pierra, Christian Perigaud, Suzanne Peyrottes Address for Service and Correspondence: PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Invention Title: COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF VIRAL INFECTIONS Our Ref: 963387 POF Code: 125692/477387, 481579, 493911 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): 6000 COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF VIRAL INFECTIONS The present application is a divisional from Australian Patent Application 5 No. 2007339226, the entire disclosure of which is incorporated herein by reference. CROSS REFERENCE TO RELATED APPLICATIONS This patent applications claims the benefit of priority to 1) U.S. Provisional Apple. No. 60/877,944, filed December 28, 2006; 2) U.S Provisional Appl. No. 60/936,290, filed June 18, 2007; and 3) U.S. Provisional Application No. 60/985,891, filed November 6, 2007. The disclosures of the above referenced applications are incorporated by reference in their entirety herein. FIELD 100011 Provided herein are compounds, methods and pharmaceutical compositions, for use in treatment of viral infections, including hepatitis C virus infection, and hepatitis B virus infection in a host in need thereof. In a particular embodiment, phosphoroamidate or phosphonoamidate nucleoside compounds are provided which allow concentration of the drug in the liver. BACKGROUND Flaviviridae Viruses 100021 The Flaviviridae family of viruses comprises at least three distinct genera: pestiviruses, which cause disease in cattle and pigs;flaviviruses, which are the primary cause of diseases such as dengue fever and yellow fever; and hepaciviruses, whose sole member is HCV. The flavivirus genus includes more than 68 members separated into groups on the basis of serological relatedness (Calisher et al., J. Gen. Virol, 1993, 70, 37-43). Clinical symptoms vary and include fever, encephalitis and hemorrhagic fever (Fields Virology, Editors: Fields, B. N., Knipe, D. M., and Howley, P. M., Lippincott-Raven Publishers, Philadelphia, PA, 1996, Chapter 31, 931-959). Flaviviruses of global concern that are associated with human disease include the dengue hemorrhagic fever viruses (DHF), yellow fever virus, shock syndrome and Japanese encephalitis virus (Halstead, S. B., Rev. Infect. Dis., 1984, 6, 251-264; Halstead, S. B., Science, 239:476-481, 1988; Monath, T. P., New Eng. J. Med., 1988, 319, 641-643). 100031 The pestivirus genus includes bovine viral diarrhea virus (BVDV), classical swine fever virus (CSFV, also called hog cholera virus) and border disease Ia WO 2008/082601 PCT/US2007/026408 virus (BDV) of sheep (Moennig, V. el al. Adv. Vir Res. 1992, 41, 53-98). Pestivirus infections of domesticated livestock (cattle, pigs and sheep) cause significant economic losses worldwide. BVDV causes mucosal disease in cattle and is of significant economic importance to the livestock industry (Meyers, G. and Thiel, H.

J., Advances in Virus Research, 1996, 47, 53-118; Moennig V., et al, Adv. Vir. Res. 1992, 41, 53-98). Human pestiviruses have not been as extensively characterized as the animal pestiviruses. However, serological surveys indicate considerable pestivirus exposure in humans. 10004] Pestiviruses and hepaciviruses are closely related virus groups within the Flaviviridae family. Other closely related viruses in this family include the GB virus A, GB virus A-like agents, GB virus-B and GB virus-C (also called hepatitis G virus, HGV). The hepacivirus group (hepatitis C virus; HCV) consists of a number of closely related but genotypically distinguishable viruses that infect humans. There are approximately 6 HCV genotypes and more than 50 subtypes. Due to the similarities between pestiviruses and hepaciviruses, combined with the poor ability of hepaciviruses to grow efficiently in cell culture, bovine viral diarrhea virus (BVDV) is often used as a surrogate to study the HCV virus. [00051 The genetic organization of pestiviruses and hepaciviruses is very similar. These positive stranded RNA viruses possess a single large open reading frame (ORF) encoding all the viral proteins necessary for virus replication. These proteins are expressed as a polyprotein that is co- and post-translationally processed by both cellular and virus-encoded proteinases to yield the mature viral proteins, The viral proteins responsible for the replication of the viral genome RNA are located within approximately the carboxy-terminal. Two-thirds of the ORF are termed nonstructural (NS) proteins. The genetic organization and polyprotein processing of the nonstructural protein portion of the ORF for pestiviruses and hepaciviruses is very similar. For both the pestiviruses and hepaciviruses, the mature nonstructural (NS) proteins, in sequential order from the amino-terminus of the nonstructural protein coding region to the carboxy-terminus of the ORF, consist of p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B. 100061 The NS proteins of pestiviruses and hepaciviruses share sequence domains that are characteristic of specific protein functions. For example, the NS3 proteins of viruses in both groups possess amino acid sequence motifs characteristic of serine 2 WO 2008/082601 PCT/US2007/026408 proteinases and of helicases (Gorbalenya et aL. (1988) Nature 333:22; Bazan and Fletterick (1989) Virology 171:637-639; Gorbalenya et al. (1989) Nucleic Acid Res. 17.3889-3897). Similarly, the NS5B proteins of pestiviruses and hepaciviruses have the motifs characteristic of RNA-directed RNA polymerases (Koonin, E.V. and Dolja, V.V. (1993) Crit. Rev. Biochem. Molec. Biol. 28:375-430). [0007] The actual roles and functions of the NS proteins of pestiviruses and hepaciviruses in the lifecycle of the viruses are directly analogous. In both cases, the NS3 serine proteinase is responsible for all proteolytic processing of polyprotein precursors downstream of its position in the ORF (Wiskerchen and Collett (1991) Virology 184:341-350; Bartenschlager et al. (1993) J Virol. 67:3835-3844; Eckart et al. (1993) Biochem. Biophys. Res. Comm. 192:399-406; Grakoui et al. (1993) J. Virol. 67:2832-2843; Grakoui et al. (1993) Proc. Natil. Acad. Sci. USA 90:10583-10587; Hijikata et al. (1993) J. Virol. 67:4665-4675; Tome et al. (1993) J. Virol. 67:4017 4026). The NS4A protein, in both cases, acts as a cofactor with the NS3 serine protease (Bartenschlager et al. (1994) J Virol. 68:5045-5055; Failla et al. (1994) J Virol. 68: 3753-3760; Lin et al. (1994) 68:8147-8157; Xu et al. (1997) J Virol. 71:5312-5322). The NS3 protein of both viruses also functions as a helicase (Kim et al. (1995) Biochem. Biophys. Res. Comm. 215: 160-166; Jin and Peterson (1995) Arch. Biochem. Biophys., 323:47-53; Warrener and Collett (1995) J Virol. 69:1720 1726). Finally, the NSSB proteins of pestiviruses and hepaciviruses have the predicted RNA-directed RNA polymerases activity (Behrens et al.(1996) EMBO J 15:12-22; Lchmann et al.(1997) J Virol. 71:8416-8428; Yuan et al.(1997) Biochem. Biophys. Res. Comm. 232:231-235; Hagedorn, PCT WO 97/12033; US patent nos. 5,981,247; 6,248,589 and 6,461,845 Zhong et al.(1998) J Virol. 72.9365-9369). Hepatitis C Virus [00081 The hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide. (Boyer, N. et al. J. Hepatol. 32:98-112, 2000). HCV causes a slow growing viral infection and is the major cause of cirrhosis and hepatocellular carcinoma (Di Besceglie, A. M. and Bacon, B. R., Scientific 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 3 WO 2008/082601 PCT/US2007/026408 deaths per year in the United States, and HCV infection is the leading indication for liver transplantation. 100091 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)). [00101 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 internal ribosome entry. This mechanism involves the binding of ribosomes 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 NS3 region. These proteinases are required for cleavage of specific regions of the precursor polyprotein into mature peptides. The carboxyl half of nonstructural protein 5, NS5B, contains the RNA dependent RNA polymerase. The function of the remaining nonstructural proteins, NS4A and NS4B, and that of NS5A (the amino-terminal half of nonstructural protein 5) remain unknown. [00111 A significant focus of current antiviral research is directed to 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)). 4 WO 2008/082601 PCT/US2007/026408 [00121 In light of the fact that HCV infection has reached epidemic levels worldwide, and has tragic effects on the infected patient, there remains a strong need to provide new effective pharmaceutical agents to treat hepatitis C that have low toxicity to the host. [00131 Further, given the rising threat of other flaviviridae infections, there remains a strong need to provide new effective pharmaceutical agents that have low toxicity to the host. Hepatitis B 100141 Hepatitis B virus has reached epidemic levels worldwide. After a two to six month incubation period in which the host is unaware of the infection, HBV infection can lead to acute hepatitis and liver damage, that causes abdominal pain, jaundice, and elevated blood levels of certain enzymes. HBV can cause fulminant hepatitis, a rapidly progressive, often fatal form of the disease in which massive sections of the liver are destroyed. Patients typically recover from acute viral hepatitis. In some patients, however, high levels of viral antigen persist in the blood for an extended, or indefinite, period, causing a chronic infection. Chronic infections can lead to chronic persistent hepatitis. Patients infected with chronic persistent HBV are most common in developing countries. Chronic persistent hepatitis can cause fatigue, cirrhosis of the liver and hepatocellular carcinoma, a primary liver cancer. In western industrialized countries, high risk groups for HBV infection include those in contact with HBV carriers or their blood samples. The epidemiology of HBV is in fact very similar to that of acquired immunodeficiency syndrome, which accounts for why HBV infection is common among patients with AIDS or HIV-associated infections. However, HBV is more contagious than HIV, 100151 Daily treatments with a-interferon, a genetically engineered protein, have shown promise. A human serum-derived vaccine has also been developed to immunize patients against IBV. Vaccines have been produced through genetic engineering. While the vaccine has been found effective, production of the vaccine is troublesome because the supply of human serum from chronic carriers is limited, and the purification procedure is long and expensive. Further, each batch of vaccine prepared from different serum must be tested in chimpanzees to ensure safety. In addition, the vaccine does not help the patients already infected with the virus. 5 [0016] An essential step in the mode of action of purine and pyrimidine nucleosides against viral diseases, and in particular, HBV and HCV is their metabolic activation by cellular kinases, to yield the mono-, di- and triphosphate derivatives. The biologically active species of many nucleosides is the triphosphate form, which inhibits viral DNA polymerase, 5 RNA polymerase, or reverse transcriptase, or causes chain termination. [0017] In light of the fact that hepatitis B and C viruses have reached epidemic levels worldwide, and has severe and often tragic effects on the infected patient, there remains a strong need to provide new effective pharmaceutical agents to treat humans infected with the virus that have low toxicity to the host. 10 [0018] Therefore, there is a continuing need for effective treatments of HCV and HBV infections. [0018A] Where the terms "comprise", "comprises", "comprised" or "comprising" are used in this specification (including the claims) they are to be interpreted as specifying the presence of the stated features, integers, steps or components, but not precluding the presence of one or 15 more other features, integers, steps or components, or group thereof. [0018B] The discussion of documents, acts, materials, devices, articles and the like is included in this specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters formed part of the prior art base or were common general knowledge in the field relevant to the present invention 20 as it existed before the priority date of each claim of this application. SUMMARY [0019] Phosphoramidate and phosphonoamidate compounds of a variety of therapeutic agents are provided, as well as methods for their manufacture and use in the treatment of a 25 variety of disorders including liver disorders. Such compounds can be used in some embodiments to permit concentration of the therapeutic agent in the liver. In one embodiment, the compound is a S-pivaloyl-2-thioethyl phosphoramidate, S-pivaloyl-2-thioethyl phosphonoamidate, S-hydroxypivaloyl-2-thioethyl phosphoramidate or S-hydroxypivaloyl-2 thioethyl phosphonoamidate. 30 [0019A] In one aspect the present invention provides a compound of formula: 6 OO ~ R RY )"S - Oj RP N Ra Rb or a pharmaceutically acceptable salt, a tautomeric or polymorphic form thereof, wherein; 5 RI is optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, hydroxyalkyl, amino, heterocyclyl or heteroaryl; Ra and Rb are selected as follows: i) Ra and Rb are each independently hydrogen or optionally substituted alkyl, carboxyalkyl, hydroxyalkyl, hydroxyarylalkyl, acyloxyalkyl, aminocarbonylalkyl, 10 alkoxycarbonylalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heterocyclyl; or ii) Ra and Rb together with the nitrogen atom on which they are substituted form a 3-7 membered heterocyclic or heteroaryl ring; and

R

1 is a moiety derivable by removal of a hydrogen from a hydroxy group of an anti viral drug, 15 and wherein when RI is tert-butyl or hydroxy-tert-butyl, then R 1 is not 3'-azido-2',3' dideoxythymidine. [0020] Phosphoramidate or phosphonoamidate compounds of a variety of therapeutic agents are provided. As used herein, a "phosphoramidate or phosphonoamidate compound of a therapeutic agent" includes a therapeutic agent derivatized to include a phosphoramidate or 20 phosphonoamidate group. The therapeutic agent is, for example, an anti-viral agent that includes, or has been derivatized to include, a reactive group, such as a hydroxyl, for attachment of the phosphoramidate or phosphonoamidate moiety. Such therapeutic agents include, but are not limited to nucleosides and nucleoside analogs including acyclic nucleosides. In some embodiments, phosphoramidates of nucleotides and nucleotide analogs 25 are also provided, such as phosphoramidates of 1', 2', 3'-branched and 4'-branched nucleosides. Such compounds can be administered in an effective amount for the 6a WO 2008/082601 PCT/US2007/026408 treatment of liver disorders, including infectious diseases, such as hepatitis B and hepatitis C infection, including resistant strains thereof. [0021] In certain embodiments, while not being limited to any theory, it is possible that the parent drug is obtained from selective metabolism of the phosphoramidate or phosphonoamidate compound in the liver, and thus the parent drug is capable of accumulating in the liver of a host. By selectively targeting and activating compounds in the liver, potentially undesired distribution of active compound in the gastrointestinal tract can be reduced. Moreover, therapeutic amounts of active compound at the site of infection in the liver can be increased. [00221 In certain embodiments, a 5'-monophosphate or phosphonate of a parent nucleoside (or nucleoside derivative) drug is formed from metabolism of the phosphoramidate or phosphonoamidate compound in the liver, allowing the monophosphate or phosphonate to form and accumulate in the liver of a host. Thus, in certain embodiments, the phosphoramidate in effect provides a stabilized phosphate on the nucleoside or nucleoside analogue. In certain embodiments, where the compound needs to be triphosphorylated to be active, this advantageously can eliminate the requirement for the initial phosphorylation step, and promote more ready formation of the active triphosphate, which inhibits the target enzyme, and can enhance the overall activity of the nucleoside or nucleoside analog. 100231 Without being limited to any theory, in one embodiment, a phosphoramidate of a nucleoside, such as a 2'-C-methyl-ribonucleoside, is provided, that is selectively concentrated in the liver after oral administration, and metabolized in the liver cell to yield a 5'-monophosphate that can be enzymatically converted to the active form of the 5'-triphosphate, which inhibits the HCV polymerase. Thus potentially therapeutic doses can be reduced in comparison to administering the nucleoside parent molecule. 100241 Thus, in some embodiments, after oral administration of the phosphoramidate and phosphonamidate compounds described herein, the compounds can advantageously concentrate in the liver cells at the site of infection and convert to the phosphate or phosphonate in the liver cell, which then is optionally further phosphorylated to implement its therapeutic effect. 7 WO 2008/082601 PCT/US2007/026408 100251 Since these methods allow accumulation of the phosphoramidate or phosphonoamidate compounds disclosed herein in the liver of a host, the methods described herein can be useful, for example, for the treatment and/or prophylaxis of diseases or disorders of the liver, such as hepatitis B or C. [00261 In certain embodiments, the compounds provided herein are useful in the prevention and treatment of Flaviviridae infections and other related conditions such as anti-Flaviviridae antibody positive and Flaviviridae-positive conditions, chronic liver inflammation caused by HCV, cirrhosis, fibrosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis, and fatigue. These compounds or formulations can also be used prophylactically to prevent or retard the progression of clinical illness in individuals who are anti-Flaviviridae antibody or Flaviviridae-antigen positive or who have been exposed to a Flaviviridae. In one specific embodiment, the Flaviviridae is hepatitis C. In certain embodiments, the compound is used to treat any virus that replicates through an RNA-dependent RNA polymerase. [00271 A method for the treatment of a Flaviviridae infection in a host, including a human, is also provided that includes administering an effective amount of a compound provided herein, administered either alone or in combination or alternation with another anti-Flaviviridae agent, optionally in a pharmaceutically acceptable carrier. 100281 In certain embodiments, a method for treatment and/or prophylaxis of hepatitis B infections and other related conditions such as anti-HBV antibody positive and HBV-positive conditions, chronic liver inflammation caused by HBV, fibrosis, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis, and fatigue are provided herein. 100291 In certain embodiments, phosphoramidate or phosphonoamidate compounds of a variety of pharmaceutical agents can be made and used therapeutically as described herein, to enhance delivery of the drug to the liver. In one embodiment, the compound is an S-acyl-2-thioethyl phosphoramidate or an S acyl-2-thioethyl phosphonoamidate derivative, e.g., a S-pivaloyl-2-thioethyl phosphoramidate or a S-hydroxypivaloyl-2-thioethyl phosphonoamidate derivative. 10030] The phosphoramidate or phosphonoamidate compounds, as well as salts thereof, and compositions comprising the compounds, provided herein are useful for 8 WO 2008/082601 PCT/US2007/026408 treatment of disorders of the liver, such as HBV and/or HCV infections. In one embodiment, the compound provided herein is a compound of Formula 1: xa 11 W WI I l R1 N R" N Rb I or a pharmaceutically acceptable salt, solvate, a stereoisomeric, tautomeric or polymorphic form thereof, wherein X, is -C-RY Z or ~S-Ru Z is O or S; each W is independently 0 or S; RY and R" each independently represent alkyl, alkenyl, alkynyl, aryl, aryl alkyl, cycloalkyl, cycloalkenyl, amino, aminoalkyl, hydroxyalkyl, alkoxy, heterocyclyl, or heteroaryl, all optionally substituted; R" and Rb are selected as follows; i) R' and Rb are each independently hydrogen, alkyl, carboxyalkyl, hydroxyalkyl, hydroxyarylalkyl, acyloxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, aryl, aryl alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, all optionally substituted; or ii) R' and Rb together with the nitrogen atom on which they are substituted form a 3-7 membered heterocyclic or heteroaryl ring; n is 0-3; n 2 is 1-4; and R' is a moiety derivable by removal of a hydrogen from a hydroxy group of an anti-viral drug. 10031] In another embodiment, X is -C-RY Z or -S-Re Z is 0, S, NH or NRw, where RW is, e.g., alkyl, alkyl, alkenyl, alkynyl, aryl, aryl alkyl, cycloalkyl, cycloalkenyl, amino, aminoalkyl, alkoxy, heterocyclyl, or heteroaryl, all optionally substituted; 9 WO 2008/082601 PCT/US2007/026408 each W is 0, S, NH or NRw, where RW is, e.g., alkyl, alkyl, alkenyl, alkynyl, aryl, aryl alkyl, cycloalkyl, cycloalkenyl, amino, aminoalkyl, alkoxy, heterocyclyl, or heteroaryl, all optionally substituted; RY and R" each independently represent alkyl, alkenyl, alkynyl, aryl, aryl alkyl, cycloalkyl, cycloalkenyl, amino, aminoalkyl, alkoxy, heterocyclyl, or heteroaryl, all optionally substituted; R' and Rb are selected as follows: i) R' and Rb are each independently hydrogen, alkyl, carboxyalkyl, hydroxyalkyl, hydroxyarylalkyl, acyloxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, aryl, aryl alkyl, cycloalkyl, heteroaryl or heterocyclyl, all optionally substituted; or ii) R' and Rb together with the nitrogen atom on which they are substituted form a 3-7 membered heterocyclic or heteroaryl ring; n is 0-3; n2 is 1-4; and R' is as decribed herein. [00321 Those of skill in the art will recognize that compounds of Formula I can be designed or prepared by reaction, e.g., at a hydroxy group of said anti-viral drug, for example, via condensation or dehydration. For convenience, in the description herein when substituents, such as exemplary R' groups are identified as a drug, those of skill in the art will recognize that the compound e.g. of Formula I comprises a derivative, e.g. a radical of the anti-viral drug. Those derivatives can for example be prepared by elimination of a hydrogen radical from a hydroxy group of the drug, for instance in a dehydration reaction. Where appropriate, certain derivatives can be prepared by modification of a phosphate or phosphonate of an anti-viral drug to yield a compound of formula I. 100331 In certain embodiments of Formula I, R' is a nucleoside comprising a cyclic or acyclic sugar or an analog thereof. 100341 In certain embodiments, R' is an anti-viral nucleoside analog useful for treatment of HCV virus infection selected from ribavirin, viramidine, 2'-C methylcytidine, 2'-C-methylguanosine, valopicitabine (NM 283), MK-0608 and PSI 6130. 100351 In certain embodiments, R' is an anti-viral nucleoside analog useful for treatment of HBV virus infection selected from lamivudine (Epivir-HBV, Zeffix, or 10 WO 2008/082601 PCT/US2007/026408 Heptodin), adefovir, entecavir (Baraclude), telbivudine (Tyzeka, Sebivo), emtricitabine (FTC), clevudine (L-FMAU), viread (Tenofovir), torcitabine, valtorcitabine (monoval LdC), amdoxovir (DAPD) and RCV (Racivir). 100361 In certain embodiments, R' is a non-nucleoside anti-viral useful for treatment of HBV virus infection selected from resiquimod or celgosivir. 100371 In certain embodiments according to Formula 1, RY is substituted alkyl, e.g. hydroxyalkyl or aminoalkyl; and Re and Rb are each independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino substituted alkyl or benzyl. In another embodiment, RY is -OR', -C(R4) 3 or -NHR4 where each RC is independently alkyl, substituted alkyl, aryl or substituted aryl, for instance hydroxy- or amino-substituted alkyl or aryl; and R" and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy or amino-substituted alkyl or benzyl. In a further embodiment, Re and W are independently benzyl or substituted alkyl. In a further embodiment, RY is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, RY is C(CH 3

)

2

CH

2 OH. [00381 In certain embodiments, the compounds provided herein are selected such that R' is not 3'-azido-2',3'-dideoxythymidine. [00391 In another embodiment, the compound provided herein is a compound of Formula Ila or Ilb: 0 0 0O Ry S P R RyS O P RN Rb Ila or RB Rb lIb or a pharmaceutically acceptable salt, solvate, a stereoisomeric, tautomeric or polymorphic form thereof, wherein RY is alkyl, alkenyl, alkynyl, aryl, aryl alkyl, cycloalkyl, cycloalkenyl, amino, aminoalkyl, hydroxyalkyl, heterocyclyl or heteroaryl, all optionally substituted; R and Rb are selected as follows: i) R and Rb are each independently hydrogen, alkyl, carboxyalkyl, hydroxyalkyl, hydroxyarylalkyl, acyloxyalkyl, aminocarbonylalkyl, I 1 WO 2008/082601 PCT/US2007/026408 alkoxycarbonylalkyl, aryl, aryl alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, all optionally substituted; or ii) R' and Rb together with the nitrogen atom on which they are substituted form a 3-7 membered heterocyclic or heteroaryl ring; and R' is an antiviral drug (as used herein where R' is an antiviral drug, that embodiment includes a moiety derivable by removal of a hydrogen from a hydroxy group of an anti-viral drug), such as a nucleoside or nucleoside analog. [00401 In certain embodiments according to Formula Ila or Ilb, RY is substituted alkyl, e.g. hydroxyalkyl or aminoalkyl; and Ra and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino substituted alkyl or benzyl. In another embodiment, RY is -ORC, -C(C)3 or -NHRc where each R' is independently alkyl, substituted alkyl, aryl or substituted aryl, for instance hydroxy- or amino-substituted alkyl or aryl; and R* and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy or amino-substituted alkyl or benzyl. In a further embodiment, R' and Rb are independently benzyl or substituted alkyl. In a further embodiment, RY is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, RY is C(CH 3

)

2 CH2OH. 100411 In another embodiment, the compound provided herein is a compound of Formula: 12 WO 2008/082601 PCT/US2007/026408 HW N H

H

3 H

R

2

R

3 R, R bD 2 3 R3R N H NHR or

H

3 wherein R", R and RT are as described in Formula I and wherein R 2 and R 3 are each independently H, straight chained, branched or cyclic alkyl; acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO aryloxyalkyl, CO-substituted aryl, sulfonate ester such as alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted; alkylsulfonyl, arylsulfonyl, aryl alkylsulfonyl, a lipid, such as a phospholipid; an amino acid; and amino acid residue, a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group which is capable of providing a compound wherein R 2 and/or R 3 is independently H, for example when administered in vivo; or R 2 and R are linked to form a cyclic group by an alkyl, ester or carbamate linkage; and wherein each RL is independently H, carbamyl, straight chained, branched or cyclic alkyl; acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonate ester such as alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted; alkylsulfonyl, arylsulfonyl, aryl alkylsulfonyl, a lipid, such as a phospholipid; an amino acid; an amino acid residue; or a carbohydrate. In certain embodiments according to this paragraph, R 2 and R 3 are each H; R is substituted alkyl, e.g. hydroxyalkyl or aminoalkyl; and Ra and Rb are independently hydrogen, 13 WO 2008/082601 PCT/US2007/026408 alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino substituted alkyl or benzyl. In another embodiment, R 2 and R 3 are each H; Ry is ORC, -C(RC) 3 or -NHRc where each RC is independently alkyl, substituted alkyl, aryl or substituted aryl, for instance hydroxy- or amino-substituted alkyl or aryl; and R' and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In a further embodiment, R 2 and R 3 are each H; Ra and Rb are independently benzyl or substituted alkyl. In a further embodiment, R 2 and R 3 are each H; RY is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, R 2 and R 3 are each H; RY is -C(CH 3

)

2

CH

2 0H. In certain embodiments according to this paragraph, R 2 and

R

3 are each hydrogen, Ra is hydrogen, R is -CH 2

-CH

5 and Ry is -C(CH 3

)

2 CH20H. [00421 In another embodiment, the compound provided herein is a compound of formula: H2 NH 2 N F No Ra/" Rb R/\ Rb R H2N NH2 R R N Rb Re Rb NH /N N R H or R* N R wherein R", Rb and Ry are as described in Formula 1. Rd is selected from the group consisting of hydrogen, alkyl and alkoxy. In certain embodiments, Rd is hydrogen, methyl or methoxy. In certain embodiments according to this paragraph, Ry is substituted alkyl, e.g. hydroxyalkyl or aminoalkyl; and R' and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy or amino-substituted alkyl or benzyl. In another embodiment, Ry is -ORC, -C(R) 3 or 14 WO 2008/082601 PCTIUS2007/026408 -NHRC where each Rc is independently alkyl, substituted alkyl, aryl or substituted aryl, for instance hydroxy- or amino-substituted alkyl or aryl; and R' and Rb a independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In a further embodiment, Ra and Rb are independently benzyl or substituted alkyl. In a further embodiment, RY is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, RY is -C(CH 3

)

2

CH

2 OH. In certain embodiments according to this paragraph, R 2 and R 3 are each hydrogen, R' is hydrogen, Rb is -CH 2

-C

6 H5 and RY is C(CH 3

)

2

CH

2 OH In certain embodiments according to this paragraph, R' is hydrogen, Rb is -CH 2

-C

6

H

5 and RY is -C(CH 3 )2CH 2 OH. 100431 In one embodiment, the nucleosides that can be derivatized to include a phosphoramidate or phosphonoamidate, e.g. at the 5' position include: 0

NH

2 r NH N2N fN H HO O HO NH HO N H N HO~,NN 0~y N HO OH H6 OH OH :CH 3 HO ORM3 100441 Examples of phosphoramidate or phosphonoamidate nucleoside compounds include: 0 HC S O- NH HO 0 H CHN OH OH Md 15 WO 2008/082601 PCT/US2007/026408

NH

2 H2 O -O N ONHCH <OH OH and 0 HO H3ON - N NH2 0 NH HO UCH3 HS d OH [0045] In one embodiment, the nucleosides that can be derivatized to include a phosphoramidate or phosphonoamidate, e.g. at the 5' position include: NH2 NH2 NH2 HO H HO)an HO- 'H [00461 In one embodiment, phosphoramidate or phosphonoamnidate nucleoside compounds include:

NH

2 HO4S4N NH 6 16 WO 2008/082601 PCT/US2007/026408

NH

2 OH N ~ H3 N-kO and

NH

2 0 0 HO>$ S^NO NO

N

3 0H H 100471 In one embodiment, the nucleosides that can be derivatized to include a phosphoramidate or phosphonoamidate, e.g. at the 5' position include: 0 NH2 0, HN)%CH3 N OH N O OH OH OH

NH

2

NH

2 N 0 N 1N 11 HO-P-. -O HO-P O N OH and CH 3 100481 In one embodiment, phosphoramidate or phosphonoamidate nucleoside compounds include: 17 WO 2008/082601 PCT/US2007/026408 0 NH 2 HN I CH3 HO O- HO * HNJ OHN O OH OH

NH

2 HO O N N

M

3 and

NH

2 HO [00491 In one aspect, the compounds described herein are provided or administered in combination with a second therapeutic agent, such as one useful for the treatment or prevention of HBV and/or HCV infections. Exemplary therapeutic agents are described in detail in the sections below. [0050] In another aspect, provided are pharmaceutical compositions, single unit dosage forms, and kits suitable for use in treating or preventing disorders such as HBV and/or HCV infections which comprise a therapeutically or prophylactically effective amount of a compound described herein, e.g. of Formula I, Ila or Ilb, and a therapeutically or prophylactically effective amount of a second therapeutic such as one useful for the treatment or prevention of HBV and/or HCV infections. 100511 In certain embodiments, a method of treatment of a liver disorder is provided comprising administering to an individual in need thereof a treatment 18 WO 2008/082601 PCT/US2007/026408 effective amount of a phosphoramidate or phosphonoamidate derivative of a nucleoside or nucleoside analogue, wherein optionally the derivative is a S-pivaloyl 2-thioethyl phosphoramidate or S-pivaloyl-2-thioethyl phosphonoamidate derivative. The derivative is optionally selected from the compounds disclosed herein. [00521 In some embodiments, provided herein are: (a) compounds as described herein, e.g. of Formula I, Ila or Ilb, and pharmaceutically acceptable salts and compositions thereof; (b) compounds as described herein, e.g. of Formula I, Ila or lIb, and pharmaceutically acceptable salts and compositions thereof for use in the treatment and/or prophylaxis of a liver disorder including Flaviviridae infection, especially in individuals diagnosed as having a Flaviviridae infection or being at risk of becoming infected by hepatitis C; (c) processes for the preparation of compounds as described herein, e.g. of Formula 1, Ila or ib, as described in more detail below; (d) pharmaceutical formulations comprising a compound as described herein, e.g. of Formula I, Ila or Ilb, or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent; (e) pharmaceutical formulations comprising a compound as described herein, e.g. of Formula 1, Ila or Ilb, or a pharmaceutically acceptable salt thereof together with one or more other effective anti-HCV agents, optionally in a pharmaceutically acceptable carrier or diluent; (f) a method for the treatment and/or prophylaxis of a host infected with Flaviviridae that includes the administration of an effective amount of a compound as described herein, e.g. of Formula I, Ila or lIb, its pharmaceutically acceptable salt or composition; (g) a method for the treatment and/or prophylaxis of a host infected with Flaviviridae that includes the administration of an effective amount of a compounds as described herein, e.g. of Formula 1, Ila or Ilb, its pharmaceutically acceptable salt or composition in combination and/or alternation with one or more effective anti-HCV agent; 19 WO 2008/082601 PCT/US2007/026408 (h) compounds as described herein, e.g. of Formula I, Ila or Ilb, and pharmaceutically acceptable salts and compositions thereof for use in the treatment and/or prophylaxis of a HBV infection, especially in individuals diagnosed as having an HBV infection or being at risk of becoming infected by hepatitis B; (i) pharmaceutical formulations comprising a compound as described herein, e.g. of Formula I, Ila or Ilb, or a pharmaceutically acceptable salt thereof together with one or more other effective anti-HBV agents, optionally in a pharmaceutically acceptable carrier or diluent; (j) a method for the treatment and/or prophylaxis of hepatitis B infections and other related conditions such as anti-HBV antibody positive and HBV-positive conditions, chronic liver inflammation caused by HBV, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis, and fatigue that includes administering an effective amount of a compound as described herein, e.g. of Formula I, Ila or IHb, or its pharmaceutically acceptable salt or composition. (k) a prophylactic method to prevent or retard the progression of clinical illness in individuals who are anti-HBV antibody or HBV-antigen positive or who have been exposed to HBV. 100531 Flaviviridae which can be treated are, e.g., discussed generally in Fields Virology, Editors: Fields, B. N., Knipe, D. M., and Howley, P. M., Lippincott-Raven Publishers, Philadelphia, PA, Chapter 31, 1996. In a particular embodiment of the invention, the Flaviviridae is HCV. In an alternate embodiment, the Flaviviridae is a flavivirus or pestivirus. Specific flaviviruses include, without limitation: Absettarov, Alfuy, Apoi, Aroa, Bagaza, Banzi, Bouboui, Bussuquara, Cacipacore, Carey Island, Dakar bat, Dengue 1, Dengue 2, Dengue 3, Dengue 4, Edge Hill, Entebbe bat, Gadgets Gully, Hanzalova, Hypr, Ilheus, Israel turkey meningoencephalitis, Japanese encephalitis, Jugra, Jutiapa, Kadam, Karshi, Kedougou, Kokobera, Koutango, Kumlinge, Kunjin, Kyasanur Forest disease, Langat, Louping ill, Meaban, Modoc, Montana myotis leukoencephalitis, Murray valley encephalitis, Naranjal, Negishi, Ntaya, Omsk hemorrhagic fever, Phnom-Penh bat, Powassan, Rio Bravo, Rocio, Royal Farm, Russian spring-summer encephalitis, Saboya, St. Louis encephalitis, Sal 20 WO 2008/082601 PCT/US2007/026408 Vieja, San Perlita, Saumarez Reef, Sepik, Sokuluk, Spondweni, Stratford, Tembusu, Tyuleniy, Uganda S, Usutu, Wesselsbron, West Nile, Yaounde, Yellow fever, and Zika. 100541 Pestiviruses which can be treated are discussed generally in Fields Virology, Editors: Fields, B. N., Knipe, D. M., and Howley, P. M., Lippincott-Raven Publishers, Philadelphia, PA, Chapter 33, 1996. Specific pestiviruses include, without limitation: bovine viral diarrhea virus ("BVDV"), classical swine fever virus ("CSFV," also called hog cholera virus), and border disease virus ("BDV"). BRIEF DESCRIPTION OF DRAWINGS [00551 Figure 1 depicts depletion of NM108 hydroxySATE phosphoramidate (B299) after incubation with and without NADPH in monkey liver S9. [00561 Figure 2 depicts depletion of NMI07 hydroxySATE phosphoramidate (B 102) after incubation with and without NADPH in monkey liver S9. DESCRIPTION OF EXEMPLARY EMBODIMENTS 100571 Provided herein are compounds, compositions and methods useful for treating liver disorders such as HBV and/or HCV infection in a subject. Further provided are dosage forms useful for such methods. Definitions [00581 When referring to the compounds provided herein, the following terms have the following meanings unless indicated otherwise. [00591 The term "alkyl", as used herein, unless otherwise specified, includes a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbon of typically Ci to CIO, and specifically includes methyl, CF 3 , CC1 3 , CFCl 2 , CF 2 CI, ethyl,

CH

2

CF

3 , CF2CF 3 , propyl, isopropyl, cyclopropyl, butyl, isobutyl, secbutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. The term includes both substituted and unsubstituted alkyl groups, and particularly includes halogenated alkyl groups, and even more particularly fluorinated alkyl groups. Non-limiting examples of moieties with which the alkyl group can be substituted are selected from the group consisting of halogen (fluoro, chloro, bromo or iodo), hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or 21 WO 2008/082601 PCT/US2007/026408 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. [00601 The term "lower alkyl", as used herein, and unless otherwise specified, includes a C 1 to C 4 saturated straight, branched, or if appropriate, a cyclic (for example, cyclopropyl) alkyl group, including both substituted and unsubstituted moieties. [00611 "Alkylene" includes divalent saturated aliphatic hydrocarbon groups particularly having up to about I I carbon atoms and more particularly 1 to 6 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH 2

CH

2 -), the propylene isomers (e.g., CH 2

CH

2 CH2- and -CH(CH 3 )CHz-) and the like. 100621 "Alkenyl" includes monovalent olefinically unsaturated hydrocarbon groups, in certain embodiment, having up to about 11 carbon atoms, from 2 to 8 carbon atoms, or from 2 to 6 carbon atoms, which can be straight-chained or branched and having at least I or from I to 2 sites of olefinic unsaturation. Exemplary alkenyl groups include ethenyl (-CH=CH 2 ), n-propenyl (-CH 2 CH=CH2), isopropenyl (

C(CH

3

)=CH

2 ), vinyl and substituted vinyl, and the like. 100631 "Alkenylene" includes divalent olefinically unsaturated hydrocarbon groups, in certain embodiments, having up to about 11 carbon atoms or from 2 to 6 carbon atoms which can be straight-chained or branched and having at least 1 or from I to 2 sites of olefinic unsaturation. This term is exemplified by groups such as ethenylene (-CH=CH-), the propenylene isomers (e.g., -CH=CHCH 2 - and C(CH 3 )=CH- and -CH=C(CH 3 )-) and the like. [00641 "Alkynyl" includes acetylenically unsaturated hydrocarbon groups, in certain embodiments, having up to about I1 carbon atoms or from 2 to 6 carbon atoms which can be straight-chained or branched and having at least I or from I to 2 sites of alkynyl unsaturation. Non-limiting examples of alkynyl groups include acetylenic, ethynyl (-CECH), propargyl (-CH 2 C=CH), and the like. [00651 The term "aryl", as used herein, and unless otherwise specified, includes phenyl, biphenyl, or naphthyl, and preferably phenyl. The term includes both substituted and unsubstituted moieties. The aryl group can be substituted with any 22 WO 2008/082601 PCTIUS2007/026408 described moiety, including, but not limited to, one or more moieties selected from the group consisting of halogen (fluoro, chloro, bromo or iodo), alkyl, haloalkyl, hydroxyl, amino, alkylamino, arylamino, alkoxy, 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. [00661 "Alkoxy" includes the group -OR where R is alkyl. Particular alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like. [0067] "Alkoxycarbonyl" includes a radical -C(O)-alkoxy where alkoxy is as defined herein. 100681 "Amino" includes the radical -NH 2 . 10069] "Carboxyl" includes the radical -C(O)OH. 100701 The term "alkylamino" or "arylamino" includes an amino group that has one or two alkyl or aryl substituents, respectively. 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. 100711 "Halogen" or "halo" includes chloro, bromo, fluoro or iodo. 100721 "Monoalkylamino" includes the group alkyl-NR'-, wherein R' is selected from hydrogen and alkyl. 10073] "Thioalkoxy" includes the group -SR where R is alkyl. 10074] 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 those skilled in the art of organic synthesis. 100751 "Pharmaceutically acceptable salt" includes any salt of a compound provided herein which retains its biological properties and which is not toxic or otherwise undesirable for pharmaceutical use. Such salts may be derived from a 23 WO 2008/082601 PCT/US2007/026408 variety of organic and inorganic counter-ions well known in the art. Such salts include: (1) acid addition salts formed with organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, trifluoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic, lauric, methanesulfonic, ethanesulfonic, 1,2-ethane-disulfonic, 2 hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 2 naphthalenesulfonic, 4-toluenesulfonic, camphoric, camphorsulfonic, 4 methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic, glucoheptonic, 3-phenylpropionic, trimethylacetic, tert-butylacetic, lauryl sulfuric, gluconic, benzoic, glutamic, hydroxynaphthoic, salicylic, stearic, cyclohexylsulfamic, quinic, muconic acid and the like acids; or (2) salts formed when an acidic proton present in the parent compound either (a) is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion or an aluminum ion, or alkali metal or alkaline earth metal hydroxides, such as sodium, potassium, calcium, magnesium, aluminum, lithium, zinc, and barium hydroxide, ammonia or (b) coordinates with an organic base, such as aliphatic, alicyclic, or aromatic organic amines, such as ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, omithine, choline, N,N'-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N methylglucamine piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like. 100761 Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like, and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrohalides, e.g. hydrochloride and hydrobromide, sulfate, phosphate, sulfamate, nitrate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate, tartarate, citrate, benzoate, 3-(4 hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethane-disulfonate, 2 hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2 24 WO 2008/082601 PCT/US2007/026408 naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4 methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate and the like. 10077] The term "alkaryl" or "alkylaryl" includes an aryl group with an alkyl substituent. The term aralkyl or arylalkyl includes an alkyl group with an aryl substituent. [0078] The term "purine" or "pyrimidine" base includes, but is not limited to, adenine, N 6 -alkylpurines, N'-acylpurines (wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl), N 6 -benzylpurine, N 6 -halopurine, N 6 -vinylpurine, N 6 -acetylenic purine,

N

6 -acyl purine, N 6 -hydroxyalkyl purine, N 6 -alkylaminopurine, N 6 -thioalkyl purine,

N

2 -alkylpurines, N 2 -alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine, 5 methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2- and/or 4 mercaptopyrmidine, uracil, 5-halouracil, including 5-fluorouracil, C' alkylpyrimidines, C 5 -benzylpyrimidines, C 5 -halopyrimidines, C'-vinylpyrimidine, C5 acetylenic pyrimidine, C5-acyl pyrimidine, C'-hydroxyalkyl purine, C' amidopyrimidine, C'-cyanopyrimidine, C'-iodopyrimidine, C 6 -iodo-pyrimidine, C' Br-vinyl pyrimidine, C 6 -Br-vinyl pyrimidine, C'-nitropyrimidine, C5-amino pyrimidine, N 2 -alkylpurines, N 2 -alkyl-6-thiopurines, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, and pyrazolopyrimidinyl. Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 7 deazaguanine, 7-deazaadenine, 2,6-diaminopurine, and 6-chloropurine. Functional oxygen and nitrogen groups on the base can be protected as necessary or desired. Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl, alkyl groups, and acyl groups such as acetyl and propionyl, methanesulfonyl, and p toluenesulfonyl. [00791 The term "acyl" or "O-linked ester" includes a group of the formula C(0)R', wherein R' is an straight, branched, or cyclic alkyl (including lower alkyl), carboxylate reside of amino acid, aryl including phenyl, alkaryl, arylalkyl including benzyl, alkoxyalkyl including methoxymethyl, aryloxyalkyl such as phenoxymethyl; or substituted alkyl (including lower alkyl), aryl including phenyl optionally 25 WO 2008/082601 PCT/US2007/026408 substituted with chloro, bromo, fluoro, iodo, C, to C 4 alkyl or Ci to C 4 alkoxy, sulfonate esters such as alkyl or arylalkyl sulphonyl including methanesulfonyl, the mono, di or triphosphate ester, trityl or monomethoxy-trityl, substituted benzyl, alkaryl, arylalkyl including benzyl, alkoxyalkyl including methoxymethyl, aryloxyalkyl such as phenoxymethyl. Aryl groups in the esters optimally comprise a phenyl group. In particular, acyl groups include acetyl, trifluoroacetyl, methylacetyl, cyclpropylacetyl, propionyl, butyryl, hexanoyl, heptanoyl, octanoyl, neo-heptanoyl, phenylacetyl, 2-acetoxy-2-phenylacetyl, diphenylacetyl, a-methoxy-a trifluoromethyl-phenylacetyl, bromoacetyl, 2-nitro-benzeneacetyl, 4-chloro benzeneacetyl, 2-chloro-2,2-diphenylacetyl, 2-chloro-2-phenylacetyl, trimethylacetyl, chlorodifluoroacetyl, perfluoroacetyl, fluoroacetyl, bromodifluoroacetyl, methoxyacetyl, 2-thiopheneacetyl, chlorosulfonylacetyl, 3-methoxyphenylacetyl, phenoxyacetyl, tert-butylacetyl, trichloroacetyl, monochloro-acetyl, dichloroacetyl, 7H-dodecafluoro-heptanoyl, perfluoro-heptanoyl, 7H-dodeca-fluoroheptanoyl, 7 chlorododecafluoro-heptanoyl, 7-chloro-dodecafluoro-heptanoyl, 7H dodecafluoroheptanoyl, 7H-dodeca-fluoroheptanoyl, nona-fluoro-3,6-dioxa heptanoyl, nonafluoro-3,6-dioxaheptanoyl, perfluoroheptanoyl, methoxybenzoyl, methyl 3-amino-5-phenylthiophene-2-carboxyl, 3,6-dichloro-2-methoxy-benzoyl, 4 (1,1,2,2-tetrafluoro-ethoxy)-benzoyl, 2-bromo-propionyl, omega-aminocapryl, decanoyl, n-pentadecanoyl, stearyl, 3-cyclopentyl-propionyl, I -benzene-carboxyl, 0 acetylmandelyl, pivaloyl acetyl, I -adanantane-carboxyl, cyclohexane-carboxyl, 2,6 pyridinedicarboxyl, cyclopropane-carboxyl, cyclobutane-carboxyl, perfluorocyclohexyl carboxyl, 4-methylbenzoyl, chloromethyl isoxazolyl carbonyl, perfluorocyclohexyl carboxyl, crotonyl, 1-methyl-i H-indazole-3-carbonyl, 2 propenyl, isovaleryl, 1 -pyrrolidinecarbonyl, 4-phenylbenzoyl. [00801 The term "amino acid" includes naturally occurring and synthetic a,, p y or 8 amino acids, and includes but is not limited to, amino acids found in proteins, i.e. glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine. In a preferred embodiment, the amino acid is in the L-configuration. Alternatively, the amino acid can be a derivative of alanyl, valinyl, leucinyl, isoleuccinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, 26 WO 2008/082601 PCT/US2007/026408 glutaroyl, lysinyl, argininyl, histidinyl, p-alanyl, p-valinyl, P-leucinyl, p-isoleuccinyl, p-prolinyl, p-phenylalaninyl, p-tryptophanyl, p-methioninyl, p-glycinyl, p-serinyl, p threoninyl, p-cysteinyl, P-tyrosinyl, p-asparaginyl, p-glutaminyl, p-aspartoyl, p glutaroyl, p-lysinyl, P-argininyl or p-histidinyl. 100811 As used herein, the term "substantially free of' or "substantially in the absence-of" with respect to a nucleoside composition includes a nucleoside composition that includes at least 85 or 90% by weight, preferably 95%, 98 %, 99% or 100% by weight, of the designated enantiomer of that nucleoside. In a preferred embodiment, in the methods and compounds of this invention, the compounds are substantially free of enantiomers. [00821 Similarly, the term "isolated" with respect to a nucleoside composition includes a nucleoside composition that includes at least 85, 90%, 95%, 98%, 99% to 100% by weight, of the nucleoside, the remainder comprising other chemical species or enantiomers. [00831 "Solvate" includes a compound provided herein or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate. 100841 The term "host", as used herein, includes any unicellular or multicellular organism in which the virus can replicate, including cell lines and animals, and preferably a human. Alternatively, the host can be carrying a part of the Flaviviridae viral genome, whose replication or function can be altered by the compounds of the present invention. The term host specifically includes infected cells, cells transfected with all or part of the Flaviviridae genome and animals, in particular, primates (including chimpanzees) and humans. In most 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). 100851 As used herein, the terms "subject" and "patient" are used interchangeably herein. The terms "subject" and "subjects" refer to an animal, such as a mammal including a non-primate (e.g., a cow, pig, horse, cat, dog, rat, and mouse) and a primate (e.g., a monkey such as a cynomolgous monkey, a chimpanzee and a human), and for example, a human. In one embodiment, the subject is refractory or non 27 WO 2008/082601 PCT/US2007/026408 responsive to current treatments for hepatitis C infection. In another embodiment, the subject is a farm animal (e.g., a horse, a cow, a pig, etc.) or a pet (e.g., a dog or a cat). In one embodiment, the subject is a human. 100861 As used herein, the terms "therapeutic agent" and "therapeutic agents" refer to any agent(s) which can be used in the treatment or prevention of a disorder or one or more symptoms thereof. In certain embodiments, the term "therapeutic agent" includes a compound provided herein. In one embodiment, a therapeutic agent is an agent which is known to be useful for, or has been or is currently being used for the treatment or prevention of a disorder or one or more symptoms thereof. 100871 "Therapeutically effective amount" includes an amount of a compound or composition that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. A "therapeutically effective amount" can vary depending on, inter alia, the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated. 100881 "Treating" or "treatment" of any disease or disorder refers, in one embodiment, to ameliorating a disease or disorder that exists in a subject. In another embodiment, "treating" or "treatment" includes ameliorating at least one physical parameter, which may be indiscernible by the subject. In yet another embodiment, "treating" or "treatment" includes modulating the disease or disorder, either physically (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physical parameter) or both. In yet another embodiment, "treating" or "treatment" includes delaying the onset of the disease or disorder. 100891 As used herein, the terms "prophylactic agent" and "prophylactic agents" as used refer to any agent(s) which can be used in the prevention of a disorder or one or more symptoms thereof. In certain embodiments, the term "prophylactic agent" includes a compound provided herein. In certain other embodiments, the term "prophylactic agent" does not refer a compound provided herein. For example, a prophylactic agent is an agent which is known to be useful for, or has been or is currently being used to the prevent or impede the onset, development, progression and/or severity of a disorder. 100901 As used herein, the phrase "prophylactically effective amount" includes the amount of a therapy (e.g., prophylactic agent) which is sufficient to result in the 28 WO 2008/082601 PCTIUS2007/026408 prevention or reduction of the development, recurrence or onset of one or more symptoms associated with a disorder (, or to enhance or improve the prophylactic effect(s) of another therapy (e.g., another prophylactic agent). Compounds 100911 Phosphoramidate and phosphonoamidate compounds of a variety of therapeutic agents can be formed using methods available in the art and those disclosed herein. Such compounds can be used in some embodiments to enhance delivery of the drug to the liver. In one embodiment, the compound is an S-acyl-2 thioethyl phosphoramidate or an S-acyl-2-thioethyl phosphonoamidate derivative, e.g., an S-pivaloyl-2-thioethyl phosphoroamidate, an S-hydroxypivaloyl-2-thioethyl phosphoroamidate, an S-pivaloyl-2-thioethyl phosphonoamidate or an S hydroxypivaloyl-2-thioethyl phosphonoamidate. Therapeutic agents that can be derivatized to compound form include an anti-viral agent that includes, or has been derivatized to include a reactive group for attachment of the phosphoramidate or phosphonoamidate moiety, including but not limited to nucleosides and nucleoside analogues including acyclic nucleosides. Therapeutic agents that can be derivatized to compound form also include an anti-viral agent that includes, or has been derivatized to include a phosphate or phorphonate group that can be derivatized to form a phosphoramidate or phosphonoamidate moiety, including but not limited to nucleosides and nucleoside analogues including acyclic nucleosides. [00921 Nucleosides that can be derivatized include any R' as disclosed herein. Examples of nucleosides that can be derivatized to include a phosphoramidate or phosphonoamidate, e.g. at the 5', 3' or 2' position include: 0 NH 2 HO ( NH HNN NH O N4 HO Ho Ho 9 NH 2 HO N N HO OH 3H OH O CHOH- HO OPH, Examples of phosphoramidate or phosphonoamidate nucleoside compounds include: 29 WO 2008/082601 PCTUS2007/026408 0 H, j S NH HO N NH C H 3 C- O N HH O N H 3 C'~t P-0 N N Oz -r CH 3 OHOH HO OHCH3 NH HO S O-O

H

3 C S NHNO

H

3 I1 O-P-O NH> 4 b HOH HCH3 and 0 HOH3CD HPO- -O N NH 2 o NH HO oCH 3 100931 Phosphoramidate or phosphonoamidate compounds of other nucleosides and nucleoside analogues described herein and known in the art can be formed as described herein and used for the treatment of liver disorders. The phosphoramidate or phosphonoamidate moiety can be e.g., at the 5' position. 100941 In one embodiment, provided herein are compounds, as well as salts thereof, and compositions comprising the compounds, that are useful for treatment of disorders of the liver, including HBV and/or HCV infections. In one embodiment, the phosphoramidate or phosphonoamidate compound provided herein is a compound of Formula Ila or Ilb: Ry S P Ri Ry S R I I /N N Re Rb Ila or Re Rb lb, or a pharmaceutically acceptable salt, solvate, a stereoisomeric, tautomeric or polymorphic form thereof, wherein; 30 WO 2008/082601 PCT/US2007/026408 RY is alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, amino, heterocyclyl or heteroaryl, all optionally substituted; R' and Rb are selected as follows: i) R" and Rb are each independently hydrogen, alkyl, carboxyalkyl, hydroxyalkyl, hydroxyarylalkyl, acyloxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heterocyclyl, all optionally substituted; or ii) R" and Rb together with the nitrogen atom on which they are substituted form a 3-7 membered heterocyclic or heteroaryl ring; and R' is an anti-viral drug (which includes a moiety derivable by removal of a hydrogen from a hydroxy group of an anti-viral drug). In certain embodiments, the compound of Formula Ila or IIb is selected with a proviso that when RY is tert-butyl or hydroxy-tert-butyl, then R' is not 3'-azido-2',3' dideoxythymidine. 100951 In certain embodiments, R', R", Rb and RY are optionally substituted with one or more substituents as defined in the definitions. 10096] In certain embodiments, the compounds are of Formula Ila or Ilb, wherein RY is alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, amino, heterocyclyl or heteroaryl; R and Rb are each independently hydrogen, alkyl, carboxyalkyl, hydroxyalkyl, hydroxyarylalkyl, acyloxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heterocyclyl, all optionally substituted; and R' is an anti-viral drug (which is meant to include a moiety derivable by removal of a hydrogen from a hydroxy group of an anti-viral drug). 100971 In one embodiment, R' is a nucleoside comprising a cyclic or acyclic sugar or analog thereof, including any any nucleoside or analogue thereof described herein or known in the art. 100981 Exemplary nucleoside drugs useful in the treatment of hepatitis C infection that can be derivatized as described herein are: Name Structure 31 WO 2008/082601 PCT/US2007/026408 Name Structure Ribavirin 0

H

2 N- $"N N HO,4 OH OH Viranidine NH

H

2 N-, N N H O -, OH OH Valopicitabine (NM283) NH 2 N HO H N 0 O OH

H

2 N CH

CH

3 2'-C-methylcytidine NH 2 (NMI07) N HO, H N O OH OH 32 WO 2008/082601 PCT/US2007/026408 Name Structure PSI-6130

NH

2 N NO HO- H OH F MK-0608

NH

2 HO 7-Fluoro-MK-0608 F NH 2 N N N HOH NMI08 N NH N N;-' NH 2 HO H OH OH 100991 Exemplary non-nucleoside drugs that can be derivatized as described herein are: 33 WO 2008/082601 PCT/US2007/026408 Name Structure Resiquinod NH 2 N N O N OH Celgosivir 0 W HO9 OH OH 'H Gliotoxin "N5-9 N-CH3 OH( o CH 2 OH [00100] Exemplary nucleoside drugs useful in the treatment of hepatitis B infection that can be derivatized as described herein are: Name Structure Lamivudine or 3TC or NH 2 Epivir N HO S N Entecavir 0 HO-N :Jt NH2 HO Telbivudine or L-dT 0 HN CH 0O NT OH OH 34 WO 2008/082601 PCT/US2007/026408 Name Structure Racivir NH 2 N F HO N Emtricitabine or (-)FTC NH 2 N F HO s N Clevudine or L-FMAU HN CH3 __ N OH OH Amdoxovir NH 2 H2N- % HO N Valtorcitabine NH 2 N OH _ NH 2 LIO 0 O 0 Torcitabine (L-dC) NH 2 __N N O OH OH 35 WO 2008/082601 PCT/US2007/026408 Name Structure Tenofovir or PMPA NH 2 O N HO-P--O OH Adefovir or PMEA NH 2 OI N HO- O OH L-cytidine NH2 OH N 0 OH HO OH 1001011 A phosphoramidate or phosphonoamidate compound of acyclovir, L-ddA or D-ddA can be administered for treatment of Hepatitis B, an example of which is shown below: HO - -O 0' N oH Y N NH N$NH2, Nox NH 2 HO -O\ N N N Acyclovir L-ddA Phosphoroamidate of Acyclovir 100102] Where the nucleoside analog already includes a phosphonate, that phosphonate group can be in corporated in the phosphonoamidate moiety shown in the formulas herein, as shown by way of example in the phosphonoamidate of adefovir: 36 WO 2008/082601 PCT/US2007/026408

NH

2 NN HO ON Nx 0 NH t00103] Thus, in certain embodiments of the compounds of Formula Ila below: 0 0 R S P Ri Ra Rb Ila P R' the moiety: is derived from a drug that is an acyclic nucleoside phosphonate, i.e.: 0 HO R OH which is e.g. PMEA (9-[2-(phosphonomethoxy)ethyl~adenine (adefovir). [001041 In certain embodiments according to Formula Ila or Ilb, RY is substituted alkyl, e.g. hydroxyalkyl or aminoalkyl; and R" and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino substituted alkyl or benzyl. In another embodiment, RY is -OR*, -C(R) 3 or -NHRc where each RC is independently alkyl, substituted alkyl, aryl or substituted aryl, for instance hydroxy- or amino-substituted alkyl or aryl; and R' and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy or amino-substituted alkyl or benzyl. 1001051 In a further embodiment, R' and Rb are independently benzyl or substituted alkyl. In a further embodiment, RY is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, RY is -C(CH 3

)

2 CH2OH. In certain 37 WO 2008/082601 PCT/US2007/026408 embodiments according to this paragraph, R 2 and R 3 are each hydrogen, R is hydrogen, Rb is -CH 2

-C

6

H

5 and RY is -C(CH 3 )2CH 2 OH. [001061 In one embodiment, RY is alkyl or hydroxyalkyl. In one embodiment, RY is methyl, tert-butyl, hydroxy-tert-butyl or hydroxyethyl. In certain embodiments, RY is

-C(CH

3

)

2

CH

2 OH. [001071 In one embodiment, R' and Rb are each independently hydrogen, alkyl, carboxyalkyl, hydroxyalkyl, hydroxyarylalkyl, acyloxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, aryl or arylalkyl, wherein the alkyl groups can be further substituted with one or more substitutents. In one embodiment, at least one of R or Rb is other than hydrogen. In one embodiment, R' and Rb are each independently hydrogen, methyl or benzyl. [001081 In certain embodiments, RY is -C(CH 3

)

2

CH

2 OH and R' and Rb are each independently hydrogen, methyl or benzyl. In certain embodiments, RI is C(CH 3

)

2

CH

2 OH and R' is hydrogen and Rb is benzyl. 1001091 In another embodiment, the compound provided herein is a compound of formula: 0' 0 R0 0 RY P R RY S R HN HN IIla, Illb,

NH

2

NH

2 00 N N N N Ry AS O O RyS O O RfN 'Rb or Ra' Rb IIlIc Id wherein R' and RY are as defined in Formula la or Ilb. In certain embodiments of Formula lla, b, c or d: RY is substituted alkyl, e.g., hydroxyalkyl or aminoalkyl; and In another embodiment, RY is -OR, -C(Rc) 3 or -NHRC where each R' is independently alkyl, substituted alkyl, aryl or substituted aryl, for instance hydroxy 38 WO 2008/082601 PCT/US2007/026408 or amino-substituted alkyl or aryl; and R' and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino substituted alkyl or hydroxy-, amino-, alkyl-,haloalkyl- or trifluoromethyl- subtistuted benzyl. In certain embodiments, R" and R together with the nitrogen atom on which they are substituted form a 3-7 membered heterocyclic or heteroaryl ring. In one embodiment, RY is alkyl or hydroxyalkyl. In one embodiment, RY is methyl, tert-butyl, hydroxy-tert-butyl or hydroxyethyl. In one embodiment, RY is C(CH 3

)

2

CH

2 OH. 1001101 In certain embodiments according to Formula Illa or IlIb, RY is substituted alkyl, e.g. hydroxyalkyl or aminoalkyl. In another embodiment, RY is -ORc, -C(RC) 3 or -NHR where each R' is independently alkyl, substituted alkyl, aryl or substituted aryl, for instance hydroxy- or amino-substituted alkyl or aryl. In a further embodiment, RY is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, RY is -C(CH 3

)

2

CH

2 OH. 1001111 In another embodiment, the compound provided herein is a compound of formula: HO"' P R' HOS /N N R* Rb [Va or RS Rb IVb, wherein R', R' and Rb are e.g. as defined in Formula Ila or Ilb. 1001121 In certain embodiments of Formula [Va or IVb: R' is an antiviral drug, such as a nucleoside or nucleoside derivative; and Ra and Rb are each independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or hydroxy-, amino-, alkyl-,haloalkyl- or trifluoromethyl- subtistuted benzyl. In a further embodiment, RS and Rb are independently H, benzyl or substituted alkyl. In certain embodiments, R" and Rb together with the nitrogen atom on which they are substituted form a 3-7 membered heterocyclic or heteroaryl ring. 1001131 In certain embodiments of Formula IVa or IVb: R' is an antiviral drug, such as a nucleoside or nucleoside derivative; and 39 WO 2008/082601 PCT/US2007/026408 R and Rb are each independently hydrogen, alkyl, carboxyalkyl, hydroxyalkyl, hydroxyarylalkyl, acyloxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, or heterocyclyl, all optionally substituted; and wherein, in one embodiment, one of R and Rb is H and the other is alkyl optionally substituted with aryl, benzyl, or heteroaryl, each optinally substituted. [001141 In another embodiment, the compound provided herein is a compound of formula: 0 0 0 0 HO" S" O'p" R1 HO'^< S'O^ O R' HN HN Va or wherein R' is as defined in Formula Ila or lib. 100115] In certain embodiments, R' is an anti-viral nucleoside analog useful for treatment of HCV virus infection selected from ribavirin, viramidine, 2'-C methylcytidine, 2'-C-methylguanosine, valopicitabine (NM 283), MK-0608 and PSI 6130. As used herein, where R' is an analogue of a nucleoside, such as acyclovir, that itself includes a phosphonate group, that phosphonate can be in the form of the phosphonoamidate in the formulas disclosed herein. Thus, e.g., in formula Va or Vb, the R'P(O)O- fragment is derived from the nucleoside analog that includes a phosphonate. 1001161 In certain embodiments, R' is an anti-viral nucleoside analog useful for treatment of HBV virus infection selected from lamivudine (Epivir-HBV, Zeffix, or Heptodin), adefovir, entecavir (Baraclude), telbivudine (Tyzeka, Sebivo), emtricitabine (FTC), clevudine (L-FMAU), viread (Tenofovir), torcitabine, valtorcitabine (monoval LdC), amdoxovir (DAPD) and RCV (Racivir). 1001171 Further exemplary anti-viral nucleoside analogs that can be used as R' are disclosed in International Publication Nos. W02005021568; W02006094347 and W02006093987 and US Patent Publication No. US20050215510. 1001181 In certain embodiments, R' is a non-nucleoside anti-viral useful for treatment of HBV virus infection selected from resiquimod or celgosivir. 40 WO 2008/082601 PCT/US2007/026408 1001191 In one embodiment, R' is an immunosuppressant, such as combretastatin A-4, mycophenolic acid, pentostatin, nelarabine or mitoxantrone. 100120] In one embodiment, R' is an interfering RNA (iRNA) based antivirals, including short interfering RNA (siRNA) based antivirals. Such compounds are described in International Patent Publication Nos. WO/03/070750 and WO 2005/012525, US patent Nos. 7,176,304; 7,109,165; 7,041,817; 7,034,009; 7,022,828; 6,852,535 and 6,849,726 and US Patent Publication No. US 2004/0209831. 1001211 In another embodiment, the compound provided herein is a compound of formula: HN R' R2 S NHH R

H

3 R N O S RL R3 RNHor RN H wherein Re, R and R are as defined in Formula 3a or lIb and R 2 and R? are each independently H; straight chained, branched or cyclic alkyl; acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonate ester such as alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted; alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, a lipid, such as a phospholipid; an amino acid; and amino acid residue, a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group which is capable of providing a compound wherein R2 and/or R is 41 WO 2008/082601 PCT/US2007/026408 independently H or phosphate (including mono-, di- or triphosphate), for example when administered in vivo; or R 2 and R 3 are linked to form a cyclic group by an alkyl, ester or carbamate linkage. Each RL is independently H, carbaryl, straight chained, branched or cyclic alkyl; acyl (including lower acyl); CO-alkyl, CO-aryl, CO alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonate ester such as alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted; alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, a lipid, such as a phospholipid; an amino acid; an amino acid residue; or a carbohydrate. In certain embodiments, R 2 and R 3 are each hydrogen, R' is hydrogen, R is -CH 2

-C

6 Hs and RI is -C(CH 3

)

2

CH

2 0H. In certain embodiments according to this paragraph, R 2 and R 3 are each H; Ry is substituted alkyl, e.g. hydroxyalkyl or aminoalkyl; and Ra and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In another embodiment, R 2 and R 3 are each H; Ry is -OR', -C(R")3 or -NHR" where each R' is independently alkyl, substituted alkyl, aryl or substituted aryl, for instance hydroxy- or amino substituted alkyl or aryl; and R' and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In a further embodiment, R2 and R 3 are each H; R' and R b are independently benzyl or substituted alkyl. In a further embodiment, R2 and R3 are each H; RY is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, R 2 and R3 are each H; Ry is -C(CH 3

)

2

CH

2 OH. [001221 In another embodiment, the compound provided herein is a compound of formula: 42 WO 2008/082601 PCT/US2007/026408 HN ' OR N _ Ro bS O N 0 RY I R _ RY S , -- NX O 0 NH RY S 0 RR S R N 0 R'R' N-0 0 RH N R'e NR N AN N H R - N R _PNH 00 INR 0 R,,N'R b or 0 R NR Re Re wherein R", Rb and RI are as defined in Formula Ila or Ilb and Re is hydrogen or alkyl. Each RL is independently H, carbaryl, straight chained, branched or cyclic alkyl; acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO aryloxyalkyl, CO-substituted aryl, sulfonate ester such as alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted; alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, a lipid, such as a phospholipid; an amino acid; an amino acid residue; or a carbohydrate. In certain embodiments, R' is methyl, ethyl or propyl, R' is hydrogen, Rb is -CH 2

-C

6

H

5 and Ry is -C(CH 3

)

2 CH2OH. In certain embodiments according to this paragraph, R 2 and R 3 are each H; Ry is substituted alkyl, e.g. hydroxyalkyl or aminoalkyl; and R' and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In another embodiment, R is methyl, ethyl or propyl; R 2 and R 3 are each H; Ry is -OR', -C(Rc) 3 or -NHRC where each RC is independently alkyl, substituted alkyl, aryl or substituted aryl, for instance hydroxy- or amino-substituted alkyl or aryl; and R' and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy or amino-substituted alkyl or benzyl. In a further embodiment, R* is methyl, ethyl or 43 WO 2008/082601 PCT/US2007/026408 propyl; R 2 and R3 are each H; R! and Rb are independently benzyl or substituted alkyl. In a further embodiment, R2 and R3 are each H; RY is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, Re is methyl, ethyl or propyl; R 2 and R 3 are each H; R1 is -C(CH 3 )zCH 2 OH. In certain embodiments according to this paragraph, R' is chosen from nucleosides desribed in U.S. Patent Application Publication No. US 2006/0111324 Al, the content of which is hereby incorporated by reference in its entirety. 1001231 In another embodiment, the compound provided herein is a compound of formula: HN,.RL I NH RtH RV%'

H

3 N K R SD ReN RD O H R S, RRRD H.RL or 0 wherein R 8 , Rb and RY are as defined in Formula Ila or lib. Each R' is independently H, carbamyl, straight chained, branched or cyclic alkyl; acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonate ester such as alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted; alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, a lipid, such as a phospholipid; an amino acid; an amino acid residue; or a carbohydrate. In certain embodiments according to this paragraph, each RL is hydrogen, RY is substituted alkyl, e.g. hydroxyalkyl or aminoalkyl; and R and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, 44 WO 2008/082601 PCT/US2007/026408 for instance hydroxy- or amino-substituted alkyl or benzyl. In another embodiment, each RL' is hydrogen, R1 is -OR*, -C(Rc) 3 or -NHRc where each Rc is independently alkyl, substituted alkyl, aryl or substituted aryl, for instance hydroxy- or amino substituted alkyl or aryl; and Ra and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In a further embodiment, each RL is hydrogen, R' and Rb are independently benzyl or substituted alkyl. In a further embodiment, Ry is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, each RL is hydrogen and RY is -C(CH 3

)

2

CH

2 OH. 100124] In another embodiment, the compound provided herein is a compound of formula: HN RL NNH R NNrR, REN~I~j2Re RD H 3 C H H 1015 rei' " aadRaea eie nFruaIao IVS b. Eh R'i HNNN N H H )HO independently H, carbamyl, straight chained, branched or cyclic alkyl; acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonate ester such as alkyl or arylalkyl sulfonyl including mnethanesulfonyl and benzyl, wherein the phenyl group is optionally substituted; alkylsulfonyl, arylsulfonyl, 45 WO 2008/082601 PCT/US2007/026408 arylalkylsulfonyl, a lipid, such as a phospholipid; an amino acid; an amino acid residue; or a carbohydrate. In certain embodiments according to this paragraph, each RL is hydrogen, RY is substituted alkyl, e.g. hydroxyalkyl or aminoalkyl; and R' and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In another embodiment, each RL is hydrogen, RY is -ORC, -- C(RC) 3 or -NHRC where each R' is independently alkyl, substituted alkyl, aryl or substituted aryl, for instance hydroxy- or amino substituted alkyl or aryl; and R" and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In a further embodiment, each RL is hydrogen, R" and Rb are independently benzyl or substituted alkyl. In a further embodiment, Ry is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, each R' is hydrogen and RY is -C(CH 3 )2CH 2 OH. In another embodiment, the compound provided herein is a compound of formula: HN'R' HNH R S%~ R% NHO R e . R b 2 LH HR , R 2 X NH NH CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyakyl, CO-substituted aryl, sulfonate ester such as alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, 46 WO 2008/082601 PCT/US2007/026408 wherein the phenyl group is optionally substituted; alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, a lipid, such as a phospholipid; an amino acid; an amino acid residue; or a carbohydrate. In certain embodiments according to this paragraph, each RL is hydrogen, Ry is substituted alkyl, e.g. hydroxyalkyl or aminoalkyl; and Ra and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In another embodiment, each RL is hydrogen, Ry is -ORc, -C(RC) 3 or -NHR4 where each R is independently alkyl, substituted alkyl, aryl or substituted aryl, for instance hydroxy- or amino substituted alkyl or aryl; and R' and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In a further embodiment, each RL is hydrogen, R' and Rb are independently benzyl or substituted alkyl. In a further embodiment, Ry is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, each RL is hydrogen and Ry is -C(CH 3 hCH2OH. 1001261 in another embodiment, the compound provided herein is a compound of formula: HH H NH '_N R RH Re R H - Rb H NH NH HN RY H

-

N N-H R Re Rb H H HN H~ NN HH H H 1001271 wherein R", Rb and Ry are as defined in Formula Ila or l1b. Each RL is independently H, carbamyl, straight chained, branched or cyclic alkyl; acyl (including 47 WO 2008/082601 PCT/US2007/026408 lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonate ester such as alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted; alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, a lipid, such as a phospholipid; an amino acid; an amino acid residue; or a carbohydrate. In certain embodiments according to this paragraph, each RL is hydrogen, RY is substituted alkyl, e.g. hydroxyalkyl or aminoalkyl; and R' and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In another embodiment, each RL is hydrogen, RY is -OR*, -C(R*) 3 or -NHRC where each Rc is independently alkyl, substituted alkyl, aryl or substituted aryl, for instance hydroxy- or amino substituted alkyl or aryl; and R' and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In a further embodiment, each RL is hydrogen, R' and Rb are independently benzyl or substituted alkyl. In a further embodiment, RY is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, each RL is hydrogen and RY is -C(CH 3 )2CH20H. 1001281 In another embodiment, the compound provided herein is a compound of formula: HN N H3 RY H3 NH H R 00 i 7__ 0~H R'oRL 48 WO 2008/082601 PCT/US2007/026408 [001291 wherein R", Rb and RY are as defined in Formula Ila or I1b. Each RL is independently H, carbamyl, straight chained, branched or cyclic alkyl; acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonate ester such as alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted; alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, a lipid, such as a phospholipid; an amino acid; an amino acid residue; or a carbohydrate. In certain embodiments according to this paragraph, each RL is hydrogen, RY is substituted alkyl, e.g. hydroxyalkyl or aminoalkyl; and Ra and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In another embodiment, each RL is hydrogen, RY is -ORC, -C(R*) 3 or -NHRc where each R is independently alkyl, substituted alkyl, aryl or substituted aryl, for instance hydroxy- or amino substituted alkyl or aryl; and Ra and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In a further embodiment, each RL is hydrogen, R and Rb are independently benzyl or substituted alkyl. In a further embodiment, RY is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, each R' is hydrogen and RY is -C(CH3)2CH 2 OH. 1001301 In another embodiment, the compound provided herein is a compound of formula: 0o N N NH2 RY S -l--o4 NHNN RNRH6 6H R S .R R S RRY S,,o 0 R3 NH2 ~HOI~O Re Rb IN b 00 NLN RY RK N NH S M3 N NH 2 Ns b -ooNY Rb R'SH N or RR H H 49 WO 2008/082601 PCT/US2007/026408 [00131] wherein R", Rb and RY are as defined in Formula Ila or lIb. Each RL is independently H, carbamyl, straight chained, branched or cyclic alkyl; acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonate ester such as alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted; alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, a lipid, such as a phospholipid; an amino acid; an amino acid residue; or a carbohydrate. In certain embodiments according to this paragraph, each RL is hydrogen, RY is substituted alkyl, e.g. hydroxyalkyl or aminoalkyl; and Re and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In another embodiment, each RL is hydrogen, RY is -ORC, -C(RC) 3 or -NHR' where each R* is independently alkyl, substituted alkyl, aryl or substituted aryl, for instance hydroxy- or amino substituted alkyl or aryl; and Ra and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In a further embodiment, each RL is hydrogen, Ra and R are independently benzyl or substituted alkyl. In a further embodiment, Ry is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, each RL is hydrogen and R1 is -C(CH 3

)

2 CH2OH. 1001321 In another embodiment, the compound provided herein is a compound of formula: 00 NH NH N N R S N R S N o O- O/OHR R Hd aH NN NH 2 R R H H O RYS$O.~O ,N ~ R tO~\ NHZ o~\ NN..- 0~~H N R' IH or 0 "\ 1001331 wherein Re, Rb and RY are as defined in Formula hla or IIb. Each RL is independently H, carbamyl, straight chained, branched or cyclic alkyl; acyl (including 50 WO 2008/082601 PCT/US2007/026408 lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonate ester such as alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted; alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, a lipid, such as a phospholipid; an amino acid; an amino acid residue; or a carbohydrate. In certain embodiments according to this paragraph, each RL is hydrogen, RY is substituted alkyl, e.g. hydroxyalkyl or aminoalkyl; and R' and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In another embodiment, each RL is hydrogen, RY is -OR", -C(RC) or -NHRC where each R is independently alkyl, substituted alkyl, aryl or substituted aryl, for instance hydroxy- or amino substituted alkyl or aryl; and R" and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In a further embodiment, each RL is hydrogen, R' and Rb are independently benzyl or substituted alkyl. In a further embodiment, Rr is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, each RL is hydrogen and RY is -C(CH 3 hCH 2 0H. 1001341 In certain embodiments, 2-deoxy-2-fluoro-2-C-ethynyl-p-D-nucleosides can be formed and derived into phosphoramidate compounds to potentiate delivery of an active monophosphate to the liver of an individual inflicted with HCV, such as the compounds described herein by way of example. In certain embodiments, a compound of the following formula is provided: R T BASE RTN BASE W W z x -.

A y A or y CA wherein: T = 0, S, CH 2 , CH(hal) or CH(hal) 2 , S(O)n; n= 1, 2; hal = halogen; R = H, acyl (with lower linear and non linear alkyl -Cl to 6-, aminoacid), monophosphate, diphosphate, triphosphate, monophosphate prodrug such as (alkyl 51 WO 2008/082601 PCT/US2007/026408

O)

2 PO, (tBuSate-0) 2 PO, cyclic monophosphate prodrug, phosphoramidate prodrug (aromatic amine, aminoacid); X and Y are independently H, OH, 0-alkyl (lower), 0-acyl, F, NH 2 , NH-alkyl, N-dialkyl, NH-acyl, N-diacyl, or azido; Z is H, alkyl, alkenyl, alkynyl, hydroxymethyl, fluoromethyl, or azido; W is H, alkyl, alkenyl, alkynyl, hydroxymethyl, fluoromethyl, azido, carboxylic acid, CO2-alkyl, cyano, or carboxamide; A is H, alkyl, alkenyl, alkynyl, hydroxymethyl, fluoromethyl, azido, carboxylic acid, CO 2 -alkyl, cyano, or carboxamide; and Base is a natural or modified base. Optionally the compounds include a chlorine atom at the 2'-position. [001351 In another embodiment, the compound provided herein is a compound of formula: R SNR N/~ NH N I 0 AHOO 0 SNH NH o~~ ~~ N~o*o2 oil RL 0l wherein Ra, Rb and RY are as defined in Formula fla or lib; A is H, alkyl, alkenyl, alkynyl, hydroxymethyl, fluoromethyl, azido, carboxylic acid, C0 2 -alkyl, cyano, or carboxamide; and Rbl is halo, alkoxy or haloalkyl. Each RL is independently H, carbamyl, straight chained, branched or cyclic alkyl; acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonate ester such as alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted; alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, a lipid, such as a phospholipid; an amino acid; an amino acid residue; or a carbohydrate. In certain embodiments according to this paragraph, each 52 WO 2008/082601 PCT/US2007/026408 RL is hydrogen, RY is substituted alkyl, e.g. hydroxyalkyl or aminoalkyl; and R' and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In another embodiment, each RL is hydrogen, RY is -OR', -C(I) 3 or -NHR' where each R' is independently alkyl, substituted alkyl, aryl or substituted aryl, for instance hydroxy- or amino substituted alkyl or aryl; and R' and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In a further embodiment, each R' is hydrogen, R' and Rb are independently benzyl or substituted alkyl. In a further embodiment, RY is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, each RL is hydrogen and RY is -C(CH 3

)

2

CH

2 0H. 1001361 In another embodiment, the compound provided herein is a compound of formula:

NH

2 Y Y 0 0 NHl 2 RR H'3 H 3 . Rb ORfR RW ARb wherein R 8 , Rb and RF are as defined in Formula Iha or IIb. In certain embodiments, Ra is hydrogen, Rb is -CHr-C 6 HS and RF is -C(CH 3 )2CH2OH. In certain embodiments according to this paragraph, RT is substituted alkyl, e.g. hydroxyalkyl or aminoalkyl; and R' and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In 53 WO 2008/082601 PCT/US2007/026408 another embodiment, RI is -OR, -C(R*) 3 or -NHRC where each R' is independently alkyl, substituted alkyl, aryl or substituted aryl, for instance hydroxy- or amino substituted alkyl or aryl; and R" and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In a further embodiment, R and Rb are independently benzyl or substituted alkyl. In a further embodiment, RY is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, RY is -C(CH 3 )2CH 2 OH. 1001371 In another embodiment, the compound provided herein is a compound of formula: x HN R' x RY S Ro3 O N OR2 OR3, wherein X is halogen, Ra, Rb and RY are as defined in Formula Ia or Ilb and R 2 and

R

3 are each independently H, straight chained, branched or cyclic alkyl; acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO substituted aryl, sulfonate ester such as alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted; alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, a lipid, such as a phospholipid; an amino acid; and amino acid residue, a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group which is capable of providing a compound wherein R 2 and/or R 3 is independently H or phosphate (including mono-, di- or triphosphate), for example when administered in vivo; or R 2 and R 3 are linked to form a cyclic group by an alkyl, ester or carbamate linkage. RL is hydrogen or any lipophillic group known to those of skill in the art. In certain embodiments, R 2 and R 3 are each hydrogen, R' is hydrogen, Rb is -CH 2

-C

6

H

5 and RY is -C(CH 3

)

2

CH

2 OH. In certain embodiments said lipophilic group is selected from alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroaryl-alkyl. In certain embodiments according to this paragraph, X is fluoro, RL is hydrogen, R 2 and R 3 are each H, RY is substituted alkyl, e.g. hydroxyalkyl or aminoalkyl; and Ra and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino 54 WO 2008/082601 PCT/US2007/026408 substituted alkyl or benzyl. In another embodiment, X is fluoro, RL is hydrogen, R 2 and R 3 are each H, RY is -OR', -C() 3 or -NHRC where each R' is independently alkyl, substituted alkyl, aryl or substituted aryl, for instance hydroxy- or amino substituted alkyl or aryl; and R' and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In a further embodiment, X is fluoro, RL is hydrogen, R 2 and R 3 are each H, R and Rb are independently benzyl or substituted alkyl. In a further embodiment, X is fluoro, RL is hydrogen, R 2 and R 3 are each H, RY is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, X is fluoro, RL is hydrogen, R 2 and R 3 are each H, RY is -C(CH 3

)

2

CH

2 OH. [001381 In another embodiment, the compound provided herein is a compound of formula: C1 0 N N O ( N O' R.'Rb :.,CH3 wherein R", Rb and RY are as defined in Formula Ila or Ilb. In certain embodiments, RY is substituted alkyl, e.g. hydroxyalkyl or aminoalkyl; and R* and R ar independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In another embodiment, RY is -ORC, -C(RC)3 or -NHR* where each R' is independently alkyl, substituted alkyl, aryl or substituted aryl, for instance hydroxy- or amino-substituted alkyl or aryl; and Ra and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In a further embodiment, R" and R b are independently benzyl or substituted alkyl. In a further embodiment, RY is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, R' is hydrogen, R b is -CH2-C6H5 and RY is -C(CH3)2CH2OH. [001391 In another embodiment, the compound provided herein is a compound of formula: 55 WO 2008/082601 PCT/US2007/026408 0 NH R"

N

R SR R N NH2E OH OH [001401 wherein R', Rb and RY are as defined in Formula Ila or lib. In certain embodiments, RY is substituted alkyl, e.g. hydroxyalkyl or aminoalkyl; and R' and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In another embodiment, RY is -ORc, -C(RC) 3 or -NHRc where each RC is independently alkyl, substituted alkyl, aryl or substituted aryl, for instance hydroxy- or amino-substituted alkyl or aryl; and R" and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In a further embodiment, Ra and Rb are independently benzyl or substituted alkyl. In a further embodiment, RY is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, R' is hydrogen, Rb is -CH 2

-C

6 Hs and RY is -C(CH 3 )2CH 2 OH. 1001411 In another embodiment, the compound provided herein is a compound of formula: 0 RY S HO O N N NH 2 O Re- R _ HOH 1001421 wherein R', Rb and RY are as defined in Formula Ila or lIb. In certain embodiments, RY is substituted alkyl, e.g. hydroxyalkyl or aminoalkyl; and Ra and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In another embodiment, RY is -ORC, -C(RC) 3 or -NHRc where each RC is independently alkyl, substituted alkyl, aryl or substituted aryl, for instance hydroxy- or amino-substituted alkyl or aryl; and R' and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In a further embodiment, Ra and Rb are independently benzyl or substituted alkyl. In a further 56 WO 2008/082601 PCTIUS2007/026408 embodiment, RY is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, Ra is hydrogen, Rb is -CH 2

-C

6

H

5 and RY is -C(CH 3

)

2 CH2OH. 1001431 In another embodiment, the compound provided herein is a compound of formula: 0F-0 RY S R R N RaN Rb Im.7 OH OH 1001441 wherein R, Rb and RY are as defined in Formula Ila or Ilb. In certain embodiments, RY is substituted alkyl, e.g. hydroxyalkyl or aninoalkyl; and Ra and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In another embodiment, RY is -ORc, -C(RC) 3 or -NHRC where each RC is independently alkyl, substituted alkyl, aryl or substituted aryl, for instance hydroxy- or amino-substituted alkyl or aryl; and R* and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In a further embodiment, R' and Rb are independently benzyl or substituted alkyl. In a further embodiment, RY is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, Ra is hydrogen, Rb is -CH 2

-C

6 HS and RY is -C(CH 3

)

2

CH

2 OH. 1001451 1001461 In another embodiment, the compound provided herein is a compound of formula: 57 WO 2008/082601 PCT/US2007/026408 HW-RL HWR HN Ry S OR S OF R Nb R RL H RH\H2$ NH H, NH R S RRNRb H s 4L HN"R whrenRe~ \Rb wherein wherein R', Rb and RY are as defined in Formula Ila or IIb. R' is hydrogen or any lipophillic group known to those of skill in the art. In certain embodiments, R" is hydrogen, Rb is -CH 2

-C

6

H

5 and RY is -C(CH 3

)

2

CH

2 OH. In certain embodiments said lipophilic group is selected from alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroaryl-alkyl. In certain embodiments according to this paragraph, RY is substituted alkyl, e.g. hydroxyalkyl or aminoalkyl; and Ra and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy or amino-substituted alkyl or benzyl. In another embodiment, RY is -C(RC) 3 or -NHRc where each Rc is independently alkyl, substituted alkyl, aryl or substituted aryl, for instance hydroxy- or amino-substituted alkyl or aryl; and Re and Rb are independently hydrogen, alkyl, substituted alkyl, benzyL or substituted benzyl, for instance hydroxy or amino-substituted alkyl or benzyl. In a further embodiment, Re and R are independently benzyl or substituted alkyl. In a further embodiment, RY is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, RY is C(CH3) 2

CH

2 OH. (001471 In another embodiment, the compound provided herein is a compound of formula: 58 WO 2008/082601 PCT/US2007/026408

NH

2 000 0NO CH 2 LY N NH RyRa RbR 0 N N -1 NH2 N 0 ~ R SP Ra Rb\ N Ra\ RO Hd

NH

2

H

3 C N F 0 0 OO'R 00 0 HC,

H

2 N N R SRy SbO HORb, 0 Ra Rb Ry SPP01 0

NH

2

NH

2 0 ('Z 0 N Ry P N N Ry S O O Ra Rb Ra Rb H HO wherein the variables are as described above. [00149] In onote embodiment, isnthcoulnuclrosidedI oerembmntis acompondo NH2 N2 S O (N N Ry 0 Ry S P R(NRb N or Ra' NRb H wherein the variables are as described above. [00149] In aoe embodiment, h isoamnaul nucloside. hnoerembdietR is acopudf 2'- or 3'- prodrug of biologically active 1', 2', 3' or 4'C-branched p-D or p3-L 59 WO 2008/082601 PCT/US2007/026408 nucleoside. The term 1', 2', 3' or 4'C-branched, as used in this specification, includes a nucleoside that has an additional non-natural substituent in the 1', 2', 3' or 4' position (i.e., carbon is bound to four nonhydrogen substituents). The term 2' prodrug, as used herein, includes a ', 2', 3' or 4' C-branched-p-D or p-L nucleoside that has a biologically cleavable moiety at the 2'-position, including, but not limited to acyl, and in one embodiment, a natural or synthetic D or L amino acid, in one embodiment, an L-amino acid. The term 3'-prodrug, as used herein, includes a ', 2', 3' or 4' C-branched-p-D or O-L nucleoside that has a biologically cleavable moiety at the 3'-position, including, but not limited to acyl, and in one embodiment, a natural or synthetic D or L amino acid, in one embodiment, an L-amino acid. In one embodiment, the amino acid is valine. [001501 Examples of prodrugs (that can be further derivatized as described herein to include a phosphoramidate or phosphonoamidate moiety, for example, at the 5' position) include 2'-L-valine ester of p-D-2'-C-methyl-cytidine; 2'-L-valine ester of p-D-2'-C-methyl-thymidine; 2'-L-valine ester of p-D-2'-C-methyl-adenosine; 2'-L valine ester of p-D-2'-C-methyl-guanosine; 2'-L-valine ester of p-D-2'-C-methyl-5 fluorocytidine; 2'-L-valine ester of p-D-2'-C-methyl-uridine; 2'-acetyl ester of -D 2'-C-methyl-cytidine; 2'-acetyl ester of p-D-2'-C-methyl-thymidine; 2'-acetyl ester of p-D-2'-C-methyl-adenosine; 2'-acetyl ester of p-D-2'-C-methyl-guanosine; 2'-acetyl ester of p-D-2'-C-methyl-5-fluoro-cytidine; and 2'-esters of p-D-2'-C-methyl (cytidine, 5-fluorocytidine, guanosine, uridine, adenosine, or thymidine) wherein (i) the 2' ester is an amino acid ester; or (ii) the 2' ester is an alkyl or aryl ester. [00151] Further examples of prodrugs are 3'-L-valine ester of P-D-2'-C-methyl cytidine; 3'-L-valine ester of p-D-2'-C-methyl-thymidine; 3'-L-valine ester of p-D 2'-C-methyl-adenosine; 3'-L-valine ester of p-D-2'-C-methyl-guanosine; 3'-L-valine ester of 0-D-2'-C-methyl-5-fluorocytidine; 3'-L-valine ester of p-D-2'-C-methyl uridine; 3'-acetyl ester of p-D-2'-C-methyl-cytidine; 3'-acetyl ester of P-D-2'-C methyl-thymidine; 3'-acetyl ester of p-D-2'-C-methyl-adenosine; 3'-acetyl ester of P D-2'-C-methyl-guanosine; 3'-acetyl ester of p-D-2'-C-methyl-5-fluoro-cytidine; and 3'-esters of p-D-2'-C-methyl-(cytidine, 5-fluorocytidine, guanosine, uridine, adenosine, or thymidine) wherein (i) the 3' ester is an amino acid ester; or (ii) the 3' ester is an alkyl or aryl ester. 60 WO 2008/082601 PCT/US2007/026408 1001521 Additional examples of prodrugs include 2',3'-L-divaline ester of p-D-2' C-methyl-cytidine (dival-2'-Me-L-dC); 2',3'-L-divaline ester of p-D.2'-C-methyl thymidine; 2',3'-L-divaline ester of p-D-2'-C-methyl-adenosine; 2',3'-L-divaline ester of P-D-2'-C-methyl-guanosine; 2',3'-L-divaline ester of p-D-2'-C-methyl-5 fluoro-cytidine; 2',3'-L-divaline ester of $-D-2'-C-methyl-uridine; 2',3'-diacetyl ester of p-D-2'-C-methyl-cytidine; 2',3'-diacetyl ester of p-D-2'-C-methyl-thymidine; 2',3'-diacetyl ester of P-D-2'-C-methyl-adenosine; 2',3'-diacetyl ester of p-D-2'-C methyl-guanosine; 2',3'-diacetyl ester of p-D-2'-C-methyl-5-fluoro-cytidine; and 2',3'-diesters of p-D-2'-C-methyl-(cytidine, 5-fluorocytidine, guanosine, uridine, adenosine, or thynidine) wherein (i) the 2' ester is an amino acid ester and the 3' ester is an alkyl or aryl ester; (ii) both esters are amino acid esters; (iii) both esters are independently alkyl or aryl esters; or (iv) the 2' ester is an alkyl or aryl ester and the 3'-ester is an amino acid ester. 100153] In one embodiment, R' is: .0 RIO Re Base -1-0 R10 Re Base -O Re R 8 Base 1 Re orx

R

9 R ' R 9

R

7 Re R 7 x XI XII wherein Base is a natural or non-natural purine or pyrimidine base as defined herein;

R

6 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, azido, cyano, Br-vinyl, alkoxy, acyloxy, alkoxycarbonyl, alkenyloxy, halo, NO 2 or NRaob Ra 6 a and R 6 b are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, aryl, heteroaryl or heterocyclyl; R', R!, R' and R'O are selected as follows: i) R 7 and R 9 are each independently hydrogen, OR 7 ", hydroxy, alkyl, alkenyl, alkynyl, azido, cyano, Br-vinyl, alkyloxycarbonyl, acyloxy, halo, NO 2 or NReaR*b; ii) Re and R' are each independently H, alkyl or halo; or iii) each R 7 and R, R' and R'", R! and R 9 or R' and R' 0 together form a double bond; R " is H; straight chained, branched or cyclic alkyl (including lower alkyl); acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, 61 WO 2008/082601 PCT/US2007/026408 CO-substituted aryl, 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; alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, a lipid, including a phospholipid; an amino acid; and amino acid residue, a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group which is capable of providing a compound wherein R 7 , is H or phosphate (including mono-, di- or triphosphate), for example, when administered in vivo; wherein in one embodiment R 7 ,is not phosphate (including mono-, di- or triphosphate or a stabilized phosphate prodrug), or two R 7 ' groups are linked to form a cyclic group by an alkyl, ester or carbamate linkage; and X is 0, S, SO 2 or CH 2 . [001541 In one embodiment, R' has formula: N XX N N X 2 V R R3 XIll [001551 wherein and R 2 and R 3 are each independently H; straight chained, branched or cyclic alkyl; acyl (including lower acyl); CO-alkyl, CO-aryl, CO alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonate ester such as alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted; alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, a lipid, such as a phospholipid; an amino acid; and amino acid residue, a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group which is capable of providing a compound wherein R 2 and/or R 3 is independently H or phosphate (including mono-, di- or triphosphate), for example when administered in vivo; or R 2 and R 3 are linked to form a cyclic group by an alkyl, ester or carbamate linkage; 1001561 wherein Y' is hydrogen, bromo, chloro, fluoro, iodo, CN, OH, OR 4 , NH 2 ,

NHR

4 , NR 4

R

3 , SH or SR; [00157] X 1 is a straight chained, branched or cyclic optionally substituted alkyl,

CH

3 , CF 3 , C(Y 3

)

3 , 2-Br-ethyl, CH 2 F, CH 2 CI, CH 2

CF

3 , CF 2

CF

3 , C(Y 3

)

2

C(Y

3 )3,

CH

2 OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH, 62 WO 2008/082601 PCT/US2007/026408

COOR

4 , COO-alkyl, COO-aryl, CO-Oalkoxyalkyl, CONH 2 , CONHR 4 , CON(R 4

)

2 , chloro, bromo, fluoro, iodo, CN, N 3 , OH, OR 4 , NH 2 , NHR 4 , NR 4

R

5 , SH or SR 5 ; and 1001581 X 2 is H, straight chained, branched or cyclic optionally substituted alkyl,

CH

3 , CF 3 , C(Y 3

)

3 , 2-Br-ethyl, CH 2 F, CH 2 CI, CH 2

CF

3 , CF 2 CF3, C(Y 3

)

2

C(Y

3

)

3 ,

CH

2 OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH,

COOR

4 , COO-alkyl, COO-aryl, CO-Oalkoxyalkyl, CONH 2 , CONHR 4 , CON(R4)2, chloro, bromo, fluoro, iodo, CN, N 3 , OH, OR 4 , NH 2 , NHR 4 , NR 4

R

5 , SH or SR 5 ; and 100159] wherein each Y 3 is independently H, F, Cl, Br or I; 1001601 each R 4 and R5 is independently hydrogen, acyl (including lower acyl), alkyl (including but not limited to methyl, ethyl, propyl and cyclopropyl), lower alkyl, alkenyl, alkynyl or cycloalkyl. 1001611 In the embodiments described herein, R 2 and/or R 3 may be a pharmaceutically acceptable leaving group which is capable of providing a compound wherein R 2 and/or R 3 is independently H or phosphate (including mono-, di- or triphosphate), for example when administered in vivo. 1001621 In another embodiment, each R 2 and R 3 is independently hydrogen or acyl. In another embodiment, R2 and R3 are linked to form a cyclic group by an alkyl, ester or carbanate linkage. 1001631 In another embodiment, R' is: x2 N O (Y 3 C R2 OR 3 XIV [001641 wherein R 2 , R 3 , Y', Y 3 , X' and X 2 are as defined in Formula XIII. 1001651 In one embodiment, R' is: JR ase ase X,1 XX R OR 2

R

7 or R 2 0 R 7 XX XXI XXII wherein Base is selected from the group consisting of 63 WO 2008/082601 PCT[US2007/026408 Y Y W2 W2 N w3 x2N w3j" x (A) (B) Y1 Y1

Y

1 x 3 A Y2 X 3 0 W__ 4 '1O I II I (C) (D)(E(F W400NW! W4 0 W I (G) (H) 64 WO 2008/082601 PC1'/US2007/026408 NR'R' NR 4 Rs NR 4

R

5 x3 N y 2 x - Y I II NR5 x 2 w (I) VJ)()()

NR

4

R

5

NR

4 R' x 3 1 N--Y2 x 3 )N-'0 (M) (N) N R 4RK NR'R' NR 4 R 11 3 N Y 2 x 3 N 0 N V2 NR 4 R 3 x 2 N (0) (P)(Q() 65 WO 2008/082601 PCT[US2007/026408 NR4R 5 NRS Ni 9 No ' I I (S) (T) OH OH OH x 3 N -, Y2 X 3 N- , Y rI IV OH

X

2 N 0 (U) (V) (W)(X OH OH (Y) (Z) 66 WO 2008/082601 PCTIUS2007/026408 0 00 3 N y 2 X 3 D N) 0 N N"I III 0 X2 -)A NH N 0 (AA) (AB) (AC) (AD) o 0 N)'NH N >NH (AE) (AF) o 0 0 0 R SR4N R5R4N NR"R' NR 4R 5 N N N N (AG) (AH) (AM) (AJ) Y Y we ws W3::K X 2 w- X (BA) (BB) 67.

WO 2008/082601 PCTIUS2007/026408 x2 2 x 2 Y' ) 3 Y1x3Dy 2 Y1 (BC) (BD) (BE) x 2 (BF)

W

2 W 1 W2 3w 2 (BG) (BH) 68 WO 2008/082601 PCT11JS2007/026408

NR

4 R' NR R 5

NR

4

R

5 x2X 2 x2 SWI WV W) 3 V (BI) (13J) (BK) x 2 W* (BL) NR 4 R NR 4 R5 w2J~w w 2j , w I (BM4) (BN)

NR

4

R

5

NR

4 R' X2

X

2 N NH INN x 3 yl x~3 NR 4 R NR 4 R 5 x 2 N X2 l N NN (BO) (BP) (BQ) (BR) 69 WO 2008/082601 PCT/US2007/02641)8 NR'R' NR 4 R' 'reN NNH NN x ,- yI x3 N (BS) (BT) OH OH OH O x 2'X OH 2 OHx2 wJ (BU) (BV) (BW) (BX) OH OH (BY) (BZ) 76 WO 2008/082601 PCTIS2007/026408 H 0 x 2 x2 N NH x Y X OH: OH OH N N N N Y' OH (BAA) (BAB) (BAC) (BAD) 0 0 HN NH HN NH X3 Y2 x3 0 (BAE) and (BAF) 1001661 wherein each W', W 2 , W 3 and W4 s independently N, CH, CF, CI, CBr, CCI, CCN, CCH 3 , CCF 3 , CCH2CH 3 , CC(0)NH 2 , CC(O)NHR 4 , CC(O)N(R 4 )2, CC(O)OH, CC(O)OR 4 or CX 3 ; [001671 each W* is independently 0, S, NR or NR 4 ; [001681 X is 0, S, SO 2 , CH 2 , CH 2 OH, CHF, CF 2 , C(Y 3

)

2 , CHCN, C(CN) 2 , CHR 4 or C(R 4

)

2 ; [001691 X* is CH, CF, CY 3 or CR 4 ; 1001701 X 2 is H, straight chained, branche or cyclic optionally substituted alkyl,

CH

3 , CF 3 , C(Y 3 )3, 2-Br-ethyl, CH 2 F, CH 2 CI, CH 2 CF3, CF 2

CF

3 , C(Y 3

)

2

C(Y

3

)

3 ,

CH

2 OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH,

COOR

4 , COO-alkyl, COO-aryl, CO-Oalkoxyalkyl, CONH 2 , CONHR 4 , CON(R 4 )2, chloro, bromo, fluoro, iodo, CN, N 3 , OH, o4, NH 2 , NHR', NR 4

R

5 , SH or SW; [001711 each X 3 is independently a straight chained, branched or cyclic optionally substituted alkyl (including lower alkyl), CHb, CH2CN, CH 2

N

3 , CH 2

NH

2 , 71 WO 2008/082601 PCT/US2007/026408

CH

2

NHCH

3 , CH 2

N(CH

3

)

2 , CH 2 OH, halogenateki alkyl (including halogenated lower alkyl), CF 3 , C(Y 3

)

3 , 2-Br-ethyl, CH 2 F, CH 2 Cl, CH 2

CF

3 , CF 2

CF

3 , C(Y 3 )2C(Y 3 )3, optionally substituted alkenyl, haloalkenyl, Br-Vinyl, optionally substituted alkynyl, haloalkynyl, N 3 , CN, -C(O)OH, -C(0)OR 4 , -C(P)O(lower alkyl), -C(O)NH 2 ,

-C(O)NHR

4 , -C(O)NH(lower alkyl), -C(O)N(R) 2 , -C(O)N(lower alkyl) 2 , OH, OR4, -O(acyl), -O(lower acyl), -O(alkyl), -O(lower alkyl), -O(alkenyl), -O(alkynyl), -O(arylalkyl), -O(cycloalkyl), -S(acyl), -S(lower acyl), -S(R 4 ), -S(lower alkyl), -S(alkenyl), -S(alkynyl), -S(arylalkyl), -S(cyclOalkyl), chloro, bromo, fluoro, iodo,

NH

2 , -NH(lower alkyl), -NHR 4 , -NR 4

R

5 , -NH(4cyl), -N(lower alkyl)2, -NH(alkenyl), -NH(alkynyl), -NH(arylalkyl), -NH(cycloalkyl), -N(acyl)2; 1001721 each Y is independently selected from the group consisting of H, optionally substituted lower alkyl, cycloalkyl, ilkenyl, alkynyl, CH 2 OH, CH2NH 2 ,

CH

2

NHCH

3 , CH 2

N(CH

3 )2, CH 2 F, CH 2 CI, C1 2

N

3 , CH 2 CN, CH2CF 3 , CF 3 , CF 2

CF

3 ,

CH

2

CO

2 R, (CH 2 )mCOOH, (CH 2 )mCOOR, (CH2)mCONH 2 , (CH 2 )mCONR 2 , and

(CH

2 )mCONHR; [001731 wherein R is H, alkyl or acyl; 1001741 Y' is hydrogen, bromo, chloro, fludro, iodo, CN, OH, OR 4 , NH 2 , NHR 4 ,

NR

4

R

5 , SH or SR 4 ; 1001751 each Y 2 is independently 0, S, NH !or NR 4 ; 1001761 each Y 3 is independently H, F, Cl, Br or I; [001771 each R 4 and R is independently hydrogen, acyl (including lower acyl), alkyl (including but not limited to methyl, ethfl, propyl and cyclopropyl), lower alkyl, alkenyl, alkynyl or cycloalkyl; 1001781 each R 6 is independently an optionally substituted alkyl (including lower alkyl), CH 3 , CH 2 CN, CH 2

N

3 , CH 2

NH

2 , CH 2

NHICH

3 , CH2N(CH3)2, CH 2 OH, halogenated alkyl (including halogenated lower alkyl), CF 3 , C(Y 3

)

3 , 2-Br-ethyl, CH 2 F,

CH

2 Cl, CH 2

CF

3 , CF 2

CF

3 , C(Y 3

)

2

C(Y

3

)

3 , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, -CH 2 C(O)OH, -CH 2 C(0)OR 4 ,

-CH

2 C(O)O(lower alkyl), -CH 2

C(O)NH

2 , -CH 2

C(O)NHR

4 , -CH 2 C(O)NH(lower alkyl), -CH 2

C(O)N(R

4

)

2 , -CH 2 C(O)N(lower alkyl)2, -(CH 2 )mC(O)OH,

-(CH

2 ).C(0)OR 4 , -(CH 2 )mC(O)O(lower alkyl), -(CH 2 ).C(O)NH2,

-(CH

2 )mC(O)NHR 4 , -(CH2)mC(O)NH(lower alkyl), -(CH 2 )mC(O)N(R 4

)

2 , 72 WO 2008/082601 PCT/US2007/026408

-(CH

2 )mC(O)N(lower alkyl) 2 , -C(O)OH, -C(O)OR4, -C(0)O(lower alkyl), -C(O)NH 2 ,

-C(O)NHR

4 , -C(O)NH(lower alkyl), -C(O)N(R 4 )2, -C(O)N(lower alkyl)2 or cyano; 1001791 each R 7 is independently H, OH, 012, optionally substituted alkyl (including lower alkyl), CH 3 , CH2CN, CH 2

N

3 , CH2NH2, CH 2

NHCH

3 , CH2N(CH 3 )2,

CH

2 OH, halogenated alkyl (including halogenated lower alkyl), CF 3 , C(Y 3

)

3 , 2-Br ethyl, CH 2 F, CH 2 Cl, CH2CF 3 , CF2CF 3 , C(Y 3 )2C(Y 3

)

3 , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alltynyl, haloalkynyl, optionally substituted carbocycle (for example, a 3-7 menbered carbocyclic ring), optionally substituted heterocycle (for example, a 3-7 mersbered heterocyclic ring having one or more 0, S and/or N), optionally substituted heteroaryl (for example, a 3-7 membered heteroaromatic ring having one or more 0, S and/or N), -CH 2 C(O)OH,

-CH

2 C(O)OR', -CH 2 C(O)O(lower alkyl), -CH 4 C(O)SH, -CH 2

C(O)SR

4 ,

-CH

2 C(O)S(lower alkyl), -CH 2 C(O)NH2, -CH C(O)NHR 4 , -CH 2 C(O)NH(lower alkyl), -CH 2

C(O)N(R

4 )2, -CH 2 C(O)N(lower alkyl)2, -(CH 2 )mC(O)OH,

-(CH

2 )mC(O)OR 4 , -(CH 2 )mC(0)O(lower alkyl) -(CH 2 )mC(O)SH, -(CH 2 )mC(O)SR 4 , -(CH2)mC(0)S(lower alkyl), -(CH 2 )mC(O)NH -(CH 2 )mC(O)NHR 4 ,

-(CH

2 )mC(O)NH(lower alkyl), -(CH 2 )mC(O)N(R 4 )2, -(CH2)mC(O)N(lower alkyl) 2 , -C(O)OH, -C(O)OR 4 , -C(0)O(lower alkyl), -Q(0)SH, -C(O)SR 4 , -C(O)S(lower alkyl), -C(O)NH 2 , -C(O)NHR 4 , -C(O)NH(lower alkyl), -C(O)N(R 4

)

2 , -C(O)N(lower alkyl)2, -O(acyI), -O(lower acyl), -O(RW), -O(alkyl), -O(lower alkyl), -O(alkenyl), -O(alkynyl), -O(arylalkyl), -O(cycloalkyl), -S acyl), -S(lower acyl), -S(R 4 ), -S(lower alkyl), -S(alkenyl), -S(alkynyl), -S(arylalkyl), S(cycloalkyl), NO 2 , NH 2 , -NH(lower alkyl), -NHR 4 , -NR 4 R, -NH(acyl), -N(lower elkyl) 2 , -NH(alkenyl), -NH(alkynyl), -NH(arylalkyl), -NH(cycloalkyl), -N(acyl)2, a*do, cyano, SCN, OCN, NCO or halo (fluoro, chloro, bromo, iodo); [001801 alternatively, R 6 and R 7 can come together to form a spiro compound selected from the group consisting of optionally substituted carbocycle (for example, a 3-7 membered carbocyclic ring) or optionally substituted heterocycle (for example, a 3-7 membered heterocyclic ring having one or more 0, S and/or N); 1001811 each m is independently 0, 1 or 2. [001821 In one embodiment, the base is 73 WO 2008/082601 PCT/US2007/026408

NH

2 / N or N NH 2 {001831 In one embodiment, the base is

NH

2 N NNN or N NH 2 1001841 In another embodiment, R' is +0 ase 40 ase ase

R'

0

R

8

R

10

R

8

R

1 0

R

6 s RI' R8 R8 rR

R

9

R

7

R

9

R

7

R

9

R

7 XXX XXXI XXXII 1001851 wherein each R 6 and R 7 is as defined in Formulae XX, XXI or XXII above; 1001861 wherein each R 8 and R' 1 is independently hydrogen, an optionally substituted alkyl (including lower alkyl), CHj, CH 2 CN, CHzN 3 , CH 2

NH

2 ,

CH

2

NHCH

3 , CH 2

N(CH

3 )2, CH 2 OH, halogen ted alkyl (including halogenated lower alkyl), CF 3 , C(Y3) 3 , 2-Br-ethyl, CH 2 F, CH 2 CI, CH 2

CF

3 , CF2CF 3 , C(Y 3

)

2

C(Y

3 )3, optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, -CH 2 C(0)OH, -CH 2 C(O)OR, -CH 2 C(O)O(lower alkyl), -CH2C(O)NH2,

-CH

2 C(0)NHR 4 , -CH 2 C(O)NH(lower alkyl)i -CH2C(O)N(R 4 )2, -CH 2 C(O)N(lower alkyl) 2 , -(CH 2 )mC(O)OH, -(CH 2 )mC(0)OR 4 , L(CH 2 )mC(0)O(lower alkyl),

-(CH

2 )mC(0)NH 2 , -(CH2)mC(O)NHR 4 , -(CH )mC(O)NH(lower alkyl),

(CH

2 )mC(O)N(R 4

)

2 , -(CH2)mC(0)N(lower alkyl)2, -C(O)OH, -C(O)OR 4 , -C(0)O(lower alkyl), -C(0)NH2, -C(0)NHW, -C(O)NH(lower alkyl), -C(0)N(R4)2, -C(0)N(lower alkyl)2, cyano, azido, NH-acyl or N(acyl)2; 74 WO 2008/082601 PCT/US2007/026408 (001871 each R 9 and R' 0 are independently Ijydrogen, OH, OR 2 , optionally substituted alkyl (including lower alkyl), CH 3 , tH 2 CN, CH 2 N, CH 2

NH

2 ,

CH

2

NHCH

3 , CH2N(CH 3 )2, CH 2 OH, halogenated alkyl (including halogenated lower alkyl), CF 3 , C(Y 3

)

3 , 2-Br-ethyl, CH 2 F, CH 2 Cl, CH 2

CF

3 , CF 2

CF

3 , C(Y 3

)

2

C(Y

3

)

3 , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted carbocycle (for example, a 3-7 membered carbocyclic ring), optionally substituted heterocycle (for example, a 3-7 membered heterocyclic ring having one or more 0, S andor N), optionally substituted heteroaryl (for example, a 3-7 membered heteroaromatic ping having one or more 0, S and/or N), -CH 2 C(O)OH, -CH2C(O)OR 4 , -CH 2 C(O)O(lower alkyl), -CH 2 C(O)SH,

-CH

2

C(O)SR

4 , -CH 2 C(O)S(lower alkyl), -CH 2 C(O)NIH2, -CH 2

C(O)NHIR

4 ,

-CH

2 C(O)NH4(lower alkyl), -CH 2

C(O)N(R

4 )2, .CH 2 C(O)N(lower alkyl)2,

-(CH

2 )mC(O)OH, -(CH 2 )mC(0)OR 4 , -(CH2)m (O)O(lower alkyl), -(CH 2 )mC(O)SH,

-(CH

2 )mC(O)SR 4 , -(CH 2 )mC(O)S(lower alkyl) -(CH 2

).C(O)NH

2 , -(CH 2 )mC(O)NHR 4 ,

-(CH

2 )mC(O)NH(lower alkyl), -(CH 2 )mC(O)N(R 4

)

2 , -(CH 2 ).C(O)N(lower alkyl) 2 , -C(O)OH, -C(O)OR 4 , -C(O)O(lower alkyl), -C(O)SH, -C(0)SR 4 , -C(O)S(lower alkyl), -C(O)NH 2 , -C(O)NHR 4 , -C(O)NH(lower alkyl), -C(O)N(R 4

)

2 , -C(O)N(lower alkyl)2, -O(acyl), -O(lower acyl), -O(R4), -O(alkyl), -O(lower alkyl), -O(alkenyl), -O(alkynyl), -O(arylalkyl), -O(cycloalkyl), -S(acyl), -S(lower acyl), -S(R 4 ), -S(lower alkyl), -S(alkenyl), -S(alkynyl), -S(arylalkyl), -S(cycloalkyl), NO2, NH2, -NH(lower alkyl), -NHRW, -NR4R', -NH(acyl), -N(lower 41kyl)2, -NH(alkenyl), -NH4(alkynyl), -NH(arylalkyl), -NH(cycloalkyl), -N(acyl)2, azido, cyano, SCN, OCN, NCO or halo (fluoro, chloro, bromo, iodo); [001881 each m is independently 0, 1 or 2; [001891 alternatively,

R

6 and R' 0 , R 7 and 19, R' and R 7 or R 9 and R" can come together to form a bridged compound selected from the group consisting of optionally substituted carbocycle (for example, a 3-7 m mbered carbocyclic ring) or optionally substituted heterocycle (for example, a 3-7 mymbered heterocyclic ring having one or more 0, S and/or N); or 1001901 alternatively, R6 and R7 or R9 and IR' can come together to form a spiro compound selected from the group consisting of optionally substituted carbocycle (for example, a 3-7 membered carbocyclic ring) or optionally substituted heterocycle (for example, a 3-7 membered heterocyclic ring l aving one or more 0, S and/or N). 75: WO 2008/082601 PCT/US2007/026408 [00191] In another embodiment, R' is: ase* - ase* ase*

R

12

R

12 12 XR Xl X

R

2

R

3 R2R or R 2 0 R 13 XL XLI XLII wherein Base* is a purine or pyrimidine base as defined herein; 1001921 each R1 2 is independently a substituted alkyl (including lower alkyl),

CH

2 CN, CH 2

N

3 , CH 2

NH

2 , CH 2

NHCH

3 , CH2N(CH 3 )2, CH 2 OH, halogenated alkyl (including halogenated lower alkyl), CF 3 , C(Y) 3 , 2-Br-ethyl, CH 2 F, CH 2 Cl, CHzCF 3 ,

CF

2

CF

3 , C(Y 3

)C(Y

3

)

3 , substituted alkenyl, ha oalkenyl (but not Br-vinyl), substituted alkynyl, haloalkynyl, -CH 2 C(O)OH, -CH 2 C(O OR 4 , -CH 2 C(O)O(lower alkyl),

-CH

2 C(O)NH-2, -CH 2

C(O)NHR

4 , -CH 2 C(O)NH(lower alkyl), -CH 2

C(O)N(R

4

)

2 ,

-CH

2 C(O)N(lower alkyl) 2 , -(CH 2 )mC(O)OH, -(CH 2 )mC(O)OR 4 , -(CH 2 )mC(O)O(lower alkyl), -(CH 2 )mC(O)NH 2 , -(CH 2 )mC(O)NHR 4 , 1-(CH 2 )mC(O)NH(lower alkyl),

-(CH

2 )mC(O)N(R 4

)

2 , -(CH 2 )mC(O)N(lower alkyl)2, -C(O)OH, -C(O)OR 4 , -C(O)NH 2 ,

-C(O)NHR

4 , -C(O)NH(lower alkyl), -C(O)N(R 4 )2, -C(O)N(lower alkyl)2; [00193] each R1 3 is independently substituted alkyl (including lower alkyl),

CH

2 CN, CH 2

N

3 , CH 2

NH

2 , CH2NHCH 3 , CH 2

A(CH

3

)

2 , CH 2 OH, halogenated alkyl (including halogenated lower alkyl), CF 3 , C(Y 3

)

3 , 2-Br-ethyl, CH 2 F, CH 2 CI, CH 2

CF

3 ,

CF

2

CF

3 , C(Y 3 )2C(Y 3

)

3 , substituted alkenyl, haloalkenyl (but not Br-vinyl), substituted alkynyl, haloalkynyl, optionally substituted carbocycle (for example, a 3-7 membered carbocyclic ring), optionally substituted heter6cycle (for example, a 3-7 membered heterocyclic ring having one or more 0, S and/or N), optionally substituted heteroaryl (for example, a 3-7 membered heteroaromatic ring having one or more 0, S and/or N), -CH 2 C(O)OH, -CH 2

C(O)OR

4 , -CH 2 C(O)O(lower alkyl), -CH 2 C(O)SH,

-CH

2

C(O)SR

4 , -CH 2 C(0)S(lower alkyl), -CH C(O)NH 2 , -CH 2

C(O)NHR

4 ,

-CH

2 C(O)NH(lower alkyl), -CH 2

C(O)N(R

4 )2 -CH 2 C(O)N(lower alkyl)2,

-(CH

2 )mC(O)OH, -(CH 2 ).C(O)OR*, -(CH 2 )m(0)O(lower alkyl), -(CH 2 )mC(O)SH,

-(CH

2 ).C(0)SR 4 , -(CH2)mC(0)S(lower alkyl), -(CH 2 ).C(0)NH 2 , -(CH 2 )mC(O)NHR 4 ,

-(CH

2 ).C(O)NH(lower alkyl), -(CH 2 ).C(0)N(R 4

)

2 , -(CH 2 )mC(O)N(lower alkyl)2, 76 WO 2008/082601 PCTIUS2007/026408 -C(0)OH, -C(0)OR 4 , -C(0)SH, -C(0)SR 4 , -C(0)S(lower alkyl), -C(O)NH 2 ,

-C(O)NHR

4 , -C(O)NH(lower alkyl), -C(0)N(Rf) 2 , -C(O)N(lower alkyl) 2 , -O(R 4 ), -O(alkynyl), -O(arylalkyl), -O(cycloalkyl), -S( cyl), -S(lower acyl), -S(R 4 ), -S(lower alkyl), -S(alkenyl), -S(alkynyl), -S(arylalkyl), -S(cycloalkyl), -NHR 4 , -NR 4

R

3 , NH(alkenyl), -NH(alkynyl), -NH(arylalkyl), -NH(cycloalkyl), SCN, OCN, NCO or fluoro; 1001941 alternatively, R 2 and R 3 can come together to form a spiro compound selected from the group consisting of optionally substituted carbocycle (for example, a 3-7 membered carbocyclic ring) or optionally substituted heterocycle (for example, a 3-7 membered heterocyclic ring having one or more 0, S and/or N); [001951 R 2 and R 3 are according to Formula XII; and 1001961 each m is independently 0, 1 or 2. 1001971 In another embodiment, R is: ase* ase*

R

10

R

1 2 R 0 R1 2 R11 Ra or R1 R8

R

9 R13

R

9 R13 L LI wherein Base* is a purine or pyrimidine base as described herein; and 100198] each R and R" is independently hydrogen, an optionally substituted alkyl (including lower alkyl), CH 3 , CH2CN, CH 2

N

3 , CH 2

NH

2 , CH 2

NHCH

3 , CH2N(CH3)2,

CH

2 OH, halogenated alkyl (including halogenated lower alkyl), CF 3 , C(Y 3

)

3 , 2-Br ethyl, CH 2 F, CH 2 C, CH 2

CF

3 , CF 2

CF

3 , C(Y 3

)

2

C(Y

3

)

3 , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, -CH 2 C(0)OH,

-CH

2

C(O)OR

4 , -CH 2 C(0)0(lower alkyl), -CH 2 C(O)NH2, -CH 2

C(O)NHR

4 ,

-CH

2 C(O)NH(lower alkyl), -CH2C(0)N(R 4 )2, -CH 2 C(O)N(lower alkyl)2,

-(CH

2 )mC(O)OH, -(CH 2

).C(O)OR

4 , -(CH 2 )mC(O)O(lower alkyl), -(CH2)mC(O)NH2,

-(CH

2

).C(O)NHR

4 , -(CH2)mC(O)NH(lower alkyl), -(CH 2 )mC(O)N(R 4 )2, -(CH2)mC(0)N(lower alkyl)2, -C(0)OH, -C(O)OR 4 , -C(0)0(lower alkyl), -C(O)NH 2 ,

-C(O)NHR

4 , -C(0)NH(lower alkyl), -C(0)N(R 4 )2, -C(O)N(lower alkyl)2, cyano, NH acyl or N(acyl)2; 77 WO 2008/082601 PCT/US2007/026408 1001991 each R' and R' 0 are independently hydrogen, OH, OR 2 , optionally substituted alkyl (including lower alkyl), CH 3 , CH 2 CN, CH 2

N

3 , CH 2 NH2,

CH

2

NHCH

3 , CH 2

N(CH

3

)

2 , CH 2 OH, halogenated alkyl (including halogenated lower alkyl), CF 3 , C(Y 3

)

3 , 2-Br-ethyl, CH 2 F, CH 2 C1, CH 2 CF3, CF 2

CF

3 , C(Y 3

)

2

C(Y

3

)

3 , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted carbocycle (for example, a 3-7 membered carbocyclic ring), optionally substituted heterocycle (for example, a 3-7 membered heterocyclic ring having one or more 0, S and/or N), optionally substituted heteroaryl (for example, a 3-7 membered heteroaromatic ring having one or more 0, S and/or N), -CH 2 C(0)OH, -CH 2

C(O)OR

4 , -CH 2 C(0)0(lower alkyl), -CH 2 C(O)SH,

-CH

2

C(O)SR

4 . -CH 2 C(O)S(lower alkyl), -CH 2 C(0)NH 2 , -CH 2

C(O)NHR

4 ,

-CH

2 C(O)NH(lower alkyl), -CH 2

C(O)N(R

4

)

2 , -CH 2 C(O)N(lower alkyl)2,

-(CH

2 )mC(O)OH, -(CH 2 )mC(O)OR 4 , -(CH 2 )mC(O)O(lower alkyl), -(CH 2 )mC(O)SH,

-(CH

2 ).C(0)SR 4 , -(CH2)mC(O)S(lower alkyl), -(CH 2 )mC(O)NH2, -(CH 2 )mC(O)NHR 4 , -(CH2)mC(0)NH(lower alkyl), -(CH 2 )mC(O)N(R 4 )2, -(CH 2 )mC(O)N(lower alkyl)2, -C(0)OH, -C(O)OR 4 , -C(O)0(lower alkyl), -C(O)SH, -C(O)SR 4 , -C(O)S(lower alkyl), -C(O)NH 2 , -C(O)NHR 4 , -C(O)NH(lower alkyl), -C(O)N(R 4 )2, -C(O)N(lower alkyl)2, -O(acyl), -O(lower acyl), -O(R 4 ), -O(alkyl), -O(lower alkyl), -O(alkenyl), -O(alkynyl), -O(arylalkyl), -O(cycloalkyl), -S(acyl), -S(lower acyl), -S(R 4 ), -S(lower alkyl), -S(alkenyl), -S(alkynyl), -S(arylalkyl), -S(cycloalkyl), NO 2 , NH 2 , -NH(lower alkyl), -NHR 4 , -NR 4 R', -NH(acyl), -N(lower alkyl)2, -NH(alkenyl), -NH(alkynyl), -NH(arylalkyl), -NH(cycloalkyl), -N(acyl)2, azido, cyano, SCN, OCN, NCO or halo (fluoro, chloro, bromo, iodo); [002001 each R 2 is independently a substituted alkyl (including lower alkyl),

CH

2 CN, CH 2

N

3 , CH 2

NH

2 , CH 2 NHCH3, CH 2

N(CH

3 )2, CH 2 OH, halogenated alkyl (including halogenated lower alkyl), CF3, C(Y 3

)

3 , 2-Br-ethyl, CH 2 F, CH 2 CI, CH 2

CF

3 ,

CF

2 CF3, C(Y 3

)

2

C(Y

3

)

3 , substituted alkenyl, haloalkenyl (but not Br-vinyl), substituted alkynyl, haloalkynyl, -CH 2 C(O)OH, -CH 2 C(0)OR 4 , -CH 2 C(O)O(lower alkyl),

-CH

2 C(O)NH2, -CH 2 C(O)NHR, -CH 2 C(O)NH(lower alkyl), -CH2C(O)N(R 4 )2,

-CH

2 C(O)N(lower alkyl)2, -(CH 2 )mC(O)OH, -(CH 2 )mC(0)OR 4 , -(CH2)mC(0)O(lower alkyl), -(CH 2 )mC(O)NH2, -(CH 2 )mC(O)NHR 4 , -(CH 2 )mC(0)NH(lower alkyl),

-(CH

2 )mC(O)N(R 4

)

2 , -(CHz)mC(O)N(lower alkyl)2, -C(O)OH, -C(0)OR 4 , -C(O)NH 2 ,

-C(O)NHR

4 , -C(O)NH(lower alkyl), -C(O)N(R 4 )2, -C(O)N(lower alkylh; 78 WO 2008/082601 PCT/US2007/026408 [00201] each m is independently 0, 1 or 2; 1002021 alternatively, R' and R", R 9 and R", R! and R" or R' 0 and R1 2 can come together to form a bridged compound selected from the group consisting of optionally substituted carbocycle (for example, a 3-7 membered carbocyclic ring) or optionally substituted heterocycle (for example, a 3-7 membered heterocyclic ring having one or more 0, S and/or N); or 100203) alternatively, R1 2 and R1 3 or R 9 and R' 0 can come together to form a spiro compound selected from the group consisting of optionally substituted carbocycle (for example, a 3-7 membered carbocyclic ring) or optionally substituted heterocycle (for example, a 3-7 membered heterocyclic ring having one or more 0, S and/or N). 1002041 In one aspect, R' is: +0 ase Base 0 0 B or B H H LX LXI 1002051 B indicates a spiro compound selected from the group consisting of optionally substituted carbocycle (for example, a 3-7 membered carbocyclic ring) or optionally substituted heterocycle (for example, a 3-7 membered heterocyclic ring having one or more 0, S and/or N); [002061 Base is selected from the group consisting of: 79 WO 2008/082601 PCT[US20071026408 RORR' R' O R' R" R ' R" R"N R' N N N, N, N , 1 N 0 N R, R'N O N N R' (a) (b) (C) (d) (e) R'0 0 R H 2 N 7

NH

2 R-R' N NH 2 (9) (h) (i) and R" N' 4. R 0) [002071 wherein each R', R", R"' and R"" are independently selected from the group consisting of H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -0 alkyl, 0-alkenyl, 0-alkynyl, 0-aryl, 0-arylalkyl, -0-acyl, 0-cycloalkyl, NH1 2 , NH alkyl, N-dialkyl, NH-acyl, N-aryl, N-arylalkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S aryl, S-cycloalkyl, S-arylalkyl, F, Cl, Br, I, CN, COOH, CONH 2 , C0 2 -alkyl, CONH alkyl, CON-dialkyl, OH, CF 3 , CH 2 OH, (CH 2 )mOH, (CH 2 )mNH 2 , (CH 2 ).COOH,

(CH

2 )mCN, (CH 2

).NO

2 and (CH 2 )mCONH2; [002081 m is 0 or 1; [002091 each W is independently C-R" or N; [002101 T and V independently are CH or N; [002111 Q is CH, -CCI, -CBr, -CF, -CI, -CCN, -C-COOH, -C-CONH 2 , or N; 1002121 Q, and Q2 independently are N or C-R; 1002131 Q3, Q4, Q5 and Q6 independently are N or CH; and [00214] tautomeric forms thereof. 1002151 In another aspect, R' is: 80 WO 2008/082601 PCT/US2007/026408 ase +O B ase * Base Me E E H H H H H H or 1002161 G and E independently are selected from the group consisting of CH3,

CH

2 OH, CH 2 F, CHzN 3 , CH 2 CN, (CH 2 )mCOOH, (CH 2 )mCOOR, (CH2)mCONH2,

(CH

2 )mCONR 2 , (CH 2 )mCONHR, N 3 and N-acyl; 1002171 mis0or1; [002181 R is H, alkyl or acyl; and [002191 Base is as defined for Formula (XIII). 1002201 In one embodiment, at most one of G and E can further be hydrogen. 1002211 In another embodiment, R' is: -0*O M ase Me H H 100222] wherein M is selected from the group consisting of 0, S, SO, and SO 2 ; and Base is as defined for Formula (XIII). [002231 In certain embodiments, R' is: 088 ase Base 0Base tO Base Ma Me M Me A H X X OH , HO OH HO H +o-Lo ase A or H H [002241 wherein A is selected from the group consisting of optionally substituted lower alkyl, cycloalkyl, alkenyl, alkynyl, CH 2 OH, CH 2

NH

2 , CH 2

NHCH

3 , 81 WO 2008/082601 PCT/US2007/026408

CH

2

N(CH

3

)

2 , CH 2 F, CH 2 CI, CH 2

N

3 , CH 2 CN, CH 2

CF

3 , CF 3 , CF2CF 3 , CH 2

CO

2 R, (CH2)mCOOH, (CH 2 )mCOOR, (CHZ)mCONH 2 , (CH 2 )mCONR 2 , and (CH 2 ).CONHR; (002251 Y is selected from the group consisting of H, optionally substituted lower alkyl, cycloalkyl, alkenyl, alkynyl, CH 2 OH, CH 2

NH

2 , CH2NHCH 3 , CH 2

N(CH

3 )2,

CH

2 F, CH 2 Cl, CH 2 N3, CH 2 CN, CH 2

CF

3 , CF 3 , CF 2

CF

3 , CH 2

CO

2 R, (CH 2 )mCOOH,

(CH

2 ).COOR, (CH 2 )mCONH 2 , (CH 2

).CONR

2 , and (CH2)mCONHR; 1002261 X is selected from the group consisting of H, -OH, optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, -0-alkyl, -0-alkenyl, -0-alkynyl, -0-aryl, -0 arylalkyl, -0-cycloalkyl-, 0-acyl, F, Cl, Br, 1, CN, NC, SCN, OCN, NCO, NO 2 , NH 2 ,

N

3 , NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aryl, NH-arylalkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aryl, S-arylalkyl, S-acyl, S cycloalkyl, C0 2 -alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-alkynyl, CONH-arylalkyl, CONH-cycloalkyl, CH 2 OH, CH2NH 2 , CH 2

NHCH

3 , CH 2

N(CH

3

)

2 ,

CH

2 F, CH 2 CI, CH 2

N

3 , CH 2 CN, CH 2

CF

3 , CF 3 , CF 2

CF

3 , CH 2

CO

2 R, (CH 2 ),COOH,

(CH

2 )mCOOR, (CH 2 )mCONH 2 , (CH 2 )mCONR 2 , (CH 2 )mCONHR, an optionally substituted 3-7 membered carbocyclic, and an optionally substituted 3-7 membered heterocyclic ring having 0, S and/or N independently as a heteroatom taken alone or in combination; 1002271 m is 0 or 1; 1002281 R is H, alkyl or acyl; and Base is a non-natural base selected from the group of: R" R O R R' RO" R" R R R R'C OR" NR R.)NN% 0 NAR 0,~N (a) (b) (C) (d)(e) R'

H

2 N R-R' NNQ R'"' (g) (h) and 82 WO 2008/082601 PCT/US2007/026408 1002291 wherein each R', R", R"' and R'"' is independently selected from the group consisting of H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -0 alkyl, 0-alkenyl, 0-alkynyl, 0-aryl, 0-arylalkyl, -0-acyl, 0-cycloalkyl, NH 2 , NH alkyl, N-dialkyl, NH-acyl, N-aryl, N-arylalkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S aryl, S-cycloalkyl, S-arylalkyl, F, Cl, Br, I, CN, COOH, CONI-1 2 , C0 2 -alkyl, CONH alkyl, CON-dialkyl, OH, CF 3 , CH 2 OH, (CH 2 )mOH, (CH 2

).NH

2 , (CH 2 )mCOOH,

(CH

2 )mCN, (CH 2 )mNO 2 and (CH2).CONH 2 ; 1002301 m is 0 or 1; 1002311 each W is independently C-R" or N; 1002321 T and V independently are CH or N; 1002331 Q is CH, -CCI, -CBr, -CF, -Cl, -CCN, -C-COOH, -C-CONH2, or N; [002341 Q1 and Q2 independently are N or C-R""; and 1002351 Q3, Q4, Q5 and Q6 independently are N or CH; [002361 with the proviso that in bases (g) and (i), R', R"" are not H, OH, or NH 2 ; and Q, T, V, Q2, Qs and Q6 are not N. 1002371 In one embodiment, R' is a 2'-(alkyl or aryl) ester or 3'-(alkyl or aryl) ester of 1', 2', 3' or 4'C-branched-p-D or p-L nucleoside with any natural or non natural purine or pyrimidine base. In one embodiment, R' is a 2' or 3'-(D or L) amino acid ester of ', 2', 3' or 4' C-branched -p-D or p-L nucleoside, wherein the amino acid is a natural or synthetic amino acid. In another embodiment, R' is a 3'-D or L-amino acid ester of ', 2', 3' or 4' C-branched-l-D or p-L nucleoside, wherein the amino acid is a natural or synthetic amino acid. In one embodiment, the amino acid is an L-amino acid. 1002381 In one embodiment, the amino acid residue is of the formula C(O)C(R' )(R1 2

)(NR

3

R'

4 ), 1002391 wherein R" is the side chain of an amino acid and wherein, R" can optionally be attached to R to form a ring structure; or alternatively, R" is an alkyl, aryl, heteroaryl or heterocyclic moiety; 1002401 R1 2 is hydrogen, alkyl (including lower alkyl) or aryl; and 83 WO 2008/082601 PCT/US2007/026408 1002411 R'" and R' 4 are independently hydrogen, acyl (including an acyl derivative attached to R") or alkyl (including but not limited to methyl, ethyl, propyl, and cyclopropyl). [00242) In another embodiment, at least one of R 2 and R 3 is an amino acid residue. In one embodiment, at least one of R 2 and R 3 is L-valinyl. 1002431 In one embodiment, R' is: .0 R1 * RBase* 1- 0 R1 Re Base* Base*

R

10 1-0 xI Base1 K4 Re or

R

9

R

7

R

9

R

7 R' R 7 wherein R 6 , R 7 , R 8 , R, R' 0 and Base* are as defined in Formula XXX, XXXI, XL, XLI or XLII. 1002441 In one embodiment, R' is: -- Base* R* -10 Base* ~)OBase*

OR

3

R

2 0 R o wherein R 2 , R 3 , Re and Base* are as defined in Formula XXX, XXXI, XL, XLI or XLII. 1002451 In one embodiment, R' is: Y Y Y Rio NX2 X N 2 X N X 2 - 0 R 7 -1.0 X2 -- R1 o N X 2 -- e RR0 N X2 1- I 1X S, or x

OR

3 wherein X' and X 2 are each independently hydrogen, alkyl, halo or amino; Y is hydrogen, amino, aminoalkyl, aminocycloalkyl, alkyl, cycloalkyl, hydroxy, alkoxy, 84 WO 20081082601 PCT/US2007/026408 cycloalkoxy, SH or thioalkyl; X is 0 or S; and wherein R 6 , R 7 , R 8 , R! are as defined in Formula XXX, XXXI, XL, XLI or XLII. [00246] In one embodiment, R' is: Y Y

R

6 1 0N 0 xx _X R R 7 R R7 R' RT wherein X' is hydrogen, alkyl, halo or amino; Y is hydrogen, amino, aminoalkyl, aminocycloalkyl, alkyl, cycloalkyl, hydroxy, alkoxy, cycloalkoxy, SH or thioalkyl; X is 0 or S; and wherein R, R7, R 8 , R 9 are as defined in Formula XXX, XXXI, XL, XLI or XLII. [002471 In one embodiment, R' is:

R

2 0 OR0 R 2 O OR 3 CH3 Base*

R

2 0 OR 3

R

2 0 OR 3 wherein R 2 , R 3 , and Base* are as defined in Formula XIII, XXX, XXXI, XL, XLI or XLII. 1002481 In one embodiment, R' is: 85 WO 2008/082601 PCT/US2007/026408 Y X X -1N N3 X'_X - 0O N N X - 0-O

R

2 0 OR9H3

R

2 0 OR 3 Y Y C H X1 - 0 -O Ox2 or H C

R

2 0 R 3

R

2 0 OR 3 wherein R 2 , R 3 , Y', Y 3 , X', and X 2 are as defined in Formula XIII. 1002491 In one embodiment, R' is: Y y X1 0 NX -- -- N-O N"O HH3H

R

2 0 OR R 2 0 OR 3 Y -1-o CHa N or

H

3 C

R

2 0 OR 3 R 2 0 OR wherein R 2 , R 3 , Y', Y3, X1, and X 2 are as defined in Formula XIII. 100250] In one embodiment, R' is: V --- I-0 or

R

2 0 OR 3

R

2 R wherein R 2 , R 3 , R 6 , Y, and X' are as defined in Formula XIII, XX, XXI or XXII. [002511 In one embodiment, R' is: 86 WO 2008/082601 PCT/US2007/026408 -1-0 Re Base' Base*

OR

3

R

2 0 R 7 -' -- Base* R 2 -O a sRr 3 O a e

R

2 e wherein R 2 , R 3 , R 6 , R 7 , X and Base* are as defined in Formula XIII, XX, XXI, XXII, XL, XLI or XLII. 1002521 In one embodiment, R' is -0 -e RsBase* RI RR wherein R 8 is alkyl, alkenyl or alkynyl; R is OR 7 ; R' is OR 7 ';

R

7 ' is H or Rm, N-Ra RP R' is a side chain of any natural or non-natural amino acid; and R' is hydrogen, hydroxy, alkyl or alkoxy; and Base* is as defined in Formula XL, XLI or XLII In one embodiment, Ra is methyl, ethyl, vinyl or ethynyl; R 7 is hydroxy or fluoro; R 9 is hydroxy and other variables are as described herein. 1002531 In one embodiment, R' is -1-0

H

3 C Base HO OH [00254] In one embodiment, R8 is methyl or ethyl. In one embodiment, R 7 is H or 87 WO 2008/082601 PCT/US2007/026408 H3C NH2 H3C0 1002551 In one embodiment, the phosphoramidate compound provided herein is:

NM

2 NH 2 6S Oor SNNH o3 s __, N N) N N 6 OH OH or a pharmaceutically acceptable salt, solvate or hydrate thereof. 1002561 In one embodiment, the phosphoram'idate compound provided herein is:

NH

2 0 9N O N Ra' 'Rb 1002571 In one embodiment, the phosphoramidate compound provided herein is:

NH

2 CH t NHN HO S O 0-O a NH RYO H / H 2 N CH

H

3 88 WO 2008/082601 PCT/US2007/026408 1002581 In one embodiment, the phosphoramidate compound provided herein is:

NH

2 RyN'Rb H H, [002591 In one embodiment, the phosphoramidate compound provided herein is:

NH

2 N HOe xt S,-"O , H3 N O NH 6 H 1002601 In one embodiment, the phosphoramidate compound provided herein is:

NH

2 N Ry S H2N CH3 1002611 In one embodiment, the phosphoramidate compound provided herein is:

NH

2 N NH

H

2 N CH 3

H

3 89 WO 2008/082601 PCT/US2007/026408 1002621 In one embodiment, the phosphoramidate compound provided herein is: NH2 N H S' O-J 0 6H 1002631 In one embodiment, the phosphoramidate compound provided herein is: H3 C NH 0 RA S R'NRb HO [002641 In one embodiment, the phosphoramidate compound provided herein is: 0 0 H 3 C '-INH OO HNHN HO 1002651 In one embodiment, the phosphoramidate compound provided herein is:

NH

2 -- N RV S-Os H R ? N N 1002661 In one embodiment, the phosphoramidate compound provided herein is: 90 WO 2008/082601 PCT/US2007/026408

NH

2 0 N OS 'O- O

H

3 C N NH H H 1002671 In one embodiment, the phosphoramidate compound provided herein is:

NH

2 0 > Y RaN, R H H 1002681 In one embodiment, the phosphoramidate compound provided herein is:

NH

2 HOS O

H

3 C N!,H 6 HH 1002691 In one embodiment, the phosphoramidate compound provided herein is:

NH

2 Ry OjRa, '- 3 H H, 1002701 In one embodiment, the phosphonoamidate compound provided herein is a phosphonoamidate form of PMPA or PMEA such as: 91 WO 2008/082601 PCT/US2007/026408

NH

2 N HON S O NH Optically Active Compounds 1002711 It is appreciated that compounds provided herein have several chiral centers and may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that any racemic, optically-active, diastereomeric, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound provided herein, which possess the useful properties described herein is within the scope of the invention. It being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase). 1002721 In particular, since the ' and 4' carbons of a nucleoside are chiral, their nonhydrogen substituents (the base and the CHOR groups, respectively) can be either cis (on the same side) or trans (on opposite sides) with respect to the sugar ring system. The four optical isomers therefore are represented by the following configurations (when orienting the sugar moiety in a horizontal plane such that the oxygen atom is in the back): cis (with both groups "up", which corresponds to the configuration of naturally occurring B-D nucleosides), cis (with both groups "down", which is a nonnaturally occurring -L configuration), trans (with the C2' substituent "up" and the C4' substituent "down"), and trans (with the C2' substituent "down" and the C4' substituent "up"). The "D-nucleosides" are cis nucleosides in a natural configuration and the "L-nucleosides" are cis nucleosides in the non-naturally occurring configuration. 1002731 Likewise, most amino acids are chiral (designated as L or D, wherein the L enantiomer is the naturally occurring configuration) and can exist as separate enantiomers. 92 WO 2008/082601 PCT/US2007/026408 [002741 Examples of methods to obtain optically active materials are known in the art, and include at least the following. i) physical separation of crystals - a technique whereby macroscopic crystals of the individual enantiomers are manually separated. This technique can be used if crystals of the separate enantiomers exist, i.e., the material is a conglomerate, and the crystals are visually distinct; ii) simultaneous crystallization - a technique whereby the individual enantiomers are separately crystallized from a solution of the racemate, possible only if the latter is a conglomerate in the solid state; iii) enzymatic resolutions - a technique whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the enantiomers with an enzyme; iv) enzymatic asymmetric synthesis - a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer; v) chemical asymmetric synthesis - a synthetic technique whereby the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which may be achieved using chiral catalysts or chiral auxiliaries; vi) diastereomer separations - a technique whereby a racemic compound is reacted with an enantiomerically pure reagent (the chiral auxiliary) that converts the individual enantiomers to diastereomers. The resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences and the chiral auxiliary later removed to obtain the desired enantiomer; vii) first- and second-order asymmetric transformations - a technique whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from 93 WO 2008/082601 PCT/US2007/026408 the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer. The desired enantiomer is then released from the diastereonier; viii) kinetic resolutions - this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non racemic reagent or catalyst under kinetic conditions; ix) enantiospecific synthesis from non-racemic precursors - a synthetic technique whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x) chiral liquid chromatography - a technique whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase. The stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions; xi) chiral gas chromatography - a technique whereby the racemate is volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase; xii) extraction with chiral solvents - a technique whereby the enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent; xiii) transport across chiral membranes - a technique whereby a racemate is placed in contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential 94 WO 2008/082601 PCT/US2007/026408 transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane which allows only one enantiomer of the racemate to pass through. [002751 In some embodiments, compositions of phosphonoamidate or phosphoramidate compounds are provided that are substantially free of a designated enantiomer of that nucleoside. In a preferred embodiment, in the methods and compounds of this invention, the compounds are substantially free of enantiomers. In some embodiiments, the composition includes that includes a compound that is at least 85, 90%, 95%, 98%, 99% to 100% by weight, of the compound, the remainder comprising other chemical species or enantiomers. Preparation of Compounds 1002761 The compounds provided herein can be prepared, isolated or obtained by any method apparent to those of skill in the art. Exemplary methods of preparation are described in detail in the examples below. 1002771 In certain embodiments, compounds provided herein can be prepared by coupling alcohols and H-phosphonate monoesters as illustrated in the reaction scheme below: Scheme A R -111H + RO R RS R R" 1' N RA any reactive function on RY, R' R', R', R'O or on the base may be protected during the coupling reaction. A variety of coupling agents known to one of skill in the art can be used. Exemplary coupling agents for use in the reaction include, but are not limited to HOBt (N-Hydroxybenzotriazole), HBTU (2-(1 H-Benzotriazole- -yl)-1,1,3,3 tetramethylaminium hexafluorophosphate), DCC (N,N'-dicyclohexytcarbodiimide), BOP (Benzotriazole-1-yl-oxy-tris-(dimethylamino) phosphoniumhexafluorophosphate), PyBOP (oH-benzotriazol- 95 WO 2008/082601 PCT/US2007/026408 yloxytripyrrolidinophosphonium hexafluorophosphate) and others known to one of skill in the art. 1002781 A general scheme for the synthesis of hydroxytBuSATE N benzylphosphoramidate nucleoside derivatives represented by B is provided in Schemes BI -B3 below. HO NHR S R., OSQp 04 R 2 BASE 0 NH R R

OR

5

OR

3 B [002791 where R = H, Tr, MMTr or DMTr in case of reactive amine; R', R 2 , R 4 , R = H, alkyl or halo and R 3 / R 5 are both H or isopropylidene. 1002801 Scheme Bi: Synthesis of the H-phosphonate monoester reagent Tff. MeTaaq3% TrT! , Ta0 TftCI, DMAP NaOHaq 30%, 1) CDI, DMFlWiuene or CH 2 C DCM, NEt dioxan 2) HS(CH 2 )ZOH 1H9 3 * pyrM~n* 2)TEAB1M -HNEt, H 1002811 Scheme B2: Synthesis of the protected nucleosides (R= DMTr and/or

R

3

/R

5 = isopropylidene) H2 NH 2 HDMTr H R 4

R

2 BASE H H R 2 A 1)TMSpydieR2 BASE aoeton 3I P ) THAO , 25% I e H Zan R, pTSA R, 2) DMTfC f DMAP R, q H H 3) NHOM 28% 1dioxan or TBAF IMin THF H2.

HD

M T r

R

4

R

2 BASE R R, SE Re R, 2) DMTrCI I DMAP R, H H 3) NH 4 0H 28% 1oxen H H or TOAF 1 Min THF 1002821 Scheme B3: Coupling of (non)protected nucleosides with reagent 5, oxidative amination and deprotection step 96 WO 2008/082601 PCT/US2007/026408 HR poHR TrO .HNEta + Ho~ ne 5 Rt (aq)TFAOO% H (g)4 2R3S 1002831 In addition, certain nucleosides and analogs thereof and prodrugs thereof can be prepared according to methods described in U.S. Patent Nos. 6,812,219; 7,105,493; 7,101,861; 6,914,054; 6,555,676; 7,202,224; 7,105,499; 6,777,395; 6,914,054; 7,192,936; US publication Nos. 2005203243; 2007087960; 2007060541; 2007060505; 2007060504; 2007060503; 2007060498; 2007042991; 2007042990; 2007042940; 2007042939 and 2007037735; International Publication Nos. WO 04/003000; WO 04/022999; WO 04/002422; WO 01/90121 and WO 01/92282. Other patents/patent applications disclosing nucleoside analogs to treat hepatitis C virus that can be derivatized as described herein include: PCT/CAOO/01316 (WO 01/32153; filed November 3, 2000) and PCT/CA01/00197 (WO 01/60315; filed February 19, 2001) filed by BioChem Pharma, Inc. (now Shire Biochem, Inc.); PCT/USO2/01531 (WO 02/057425; filed January 18, 2002); PCT/US02/03086 (WO 02/057287; filed January 18, 2002); US 7,202,224; 7,125,855; 7,105,499 and 6,777,395 by Merck & Co., Inc.; PCT/EP01/09633 (WO 02/18404; published August 21, 2001); US 2006/0040890; 2005/0038240; 2004/0121980; 6,846,810; 6,784,166 and 6,660,721 by Roche; PCT Publication Nos. WO 01/79246 (filed April 13, 2001), WO 02/32920 (filed October 18, 2001) and WO 02/48165; US 2005/0009737 and US 2005/0009737; 7,094,770 and 6,927,291 by Pharmasset, Ltd. Contents of these references are hereby incorporated by reference in their entireties. Assay Methods 1002841 Compounds can be assayed for HBV activity according to any assay known to those of skill in the art. Compounds can be assayed for HCV activity according to any assay known to those of skill in the art. 1002851 Further, compounds can be assayed for accumulation in liver cells of a subject according to any assay known to those of skill in the art. In certain embodiments, a compound can be administered to the subject, and a liver cell of the 97 WO 2008/082601 PCT/US2007/026408 subject can be assayed for the compound or a derivative thereof, e.g. a nucleoside, nucleoside phosphate or nucleoside triphosphate derivative thereof. 1002861 In one embodiment, a phosphoramidate or phosphonoamidate nucleoside compound is administered to cells, such as liver cells, in vivo or in vitro, and the nucleoside triphosphate levels delivered intracellularly are measured, to indicate delivery of the compound and triphosphorylation in the cell. The levels of intracellular nucleoside triphosphate can be measured using analytical techniques known in the art. Methods of detecting ddATP are described herein below by way of example, but other nucleoside triphosphates can be readily detected using the appropriate controls, calibration samples and assay techniques. 1002871 In one embodiment, ddATP concentrations are measured in a sample by comparison to calibration standards made from control samples. The ddATP concentrations in a sample can be measured using an analytical method such as HPLC LC MS. In one embodiment, a test sample is compared to a calibration curve created with known concentrations of ddATP to thereby obtain the concentration of that sample. 1002881 In one embodiment, the samples are manipulated to remove impurities such as salts (Na*, K 4 , etc.) before analysis. In one embodiment, the lower limit of quantitation is about - 0.2 pmol / mL for hepatocyte cellular extracts particularly where reduced salt is present. 1002891 In one embodiment, the method allows successfully measuring triphosphate nucleotides formed at levels of I - 10,000 pmol per million cells in e.g. cultured hepatocytes and HepG2 cells. Methods of Use 100290) The phosphoramidate and phosphonoamidate compounds of a variety of therapeutic agents can be formed using methods available in the art and those disclosed herein. Such compounds can be used in some embodiments to enhance delivery of the drug to the liver. 1002911 In one embodiment, the compound comprises a S-acyl-2-thioethyl phosphoramidate or S-acyl-2-thioethyl phosphonoamidate, e.g., a S-pivaloyl-2 thioethyl phosphoramidate or S-hydroxypivaloyl-2-thioethyl phosphonoamidate derivative. Therapeutic agents that can be derivatized to phosphoramidate or 98 WO 2008/082601 PCTfUS2007/026408 phosphonoamidate compound form include any anti-viral agent that includes, or has been derivatized to include a reactive group for attachment of the phosphoramidate or phosphonoamidate moiety, including but not limited to nucleosides and nucleoside analogues including acyclic nucleosides. 1002921 Advantageously, such phosphoramidate and phosphonamidate compounds advantageously can have enhanced delivery to the liver. In some embodiments, the compounds permit delivery of an active 5'-monophosphate of a nucleoside to the liver, which can enhance the formation of active triphosphorylated compound. 1002931 In one embodiment, provided herein are methods for the treatment and/or prophylaxis of a host infected with Flaviviridae that includes the administration of an effective amount of a compounds provided herein, or a pharmaceutically acceptable salt thereof. In one embodiment, provided herein are methods for treating an HCV infection in a subject. In certain embodiments, the methods encompass the step of administering to the subject in need thereof an amount of a compound effective for the treatment or prevention of an HCV infection in combination with a second agent effective for the treatment or prevention of the infection. The compound can be any compound as described herein, and the second agent can be any second agent described in the art or herein. In certain embodiments, the compound is in the form of a pharmaceutical composition or dosage form, as described in the sections above. 1002941 Flaviviridae that can be treated are discussed generally in Fields Virology, Editors: Fields, B. N., Knipe, D. M., and Howley, P. M., Lippincott-Raven Publishers, Philadelphia, PA, Chapter 31, 1996. In a particular embodiment of the invention, the Flaviviridae is HCV. In an alternate embodiment of the invention, the Flaviviridae is a flavivirus or pestivirus. Specific flaviviruses include, without limitation: Absettarov, Alfuy, Apoi, Aroa, Bagaza, Banzi, Bouboui, Bussuquara, Cacipacore, Carey Island, Dakar bat, Dengue 1, Dengue 2, Dengue 3, Dengue 4, Edge Hill, Entebbe bat, Gadgets Gully, Hanzalova, Hypr, llheus, Israel turkey meningoencephalitis, Japanese encephalitis, Jugra, Jutiapa, Kadam, Karshi, Kedougou, Kokobera, Koutango, Kumlinge, Kunjin, Kyasanur Forest disease, Langat, Louping ill, Meaban, Modoc, Montana myotis leukoencephalitis, Murray valley encephalitis, Naranjal, Negishi, Ntaya, Omsk hemorrhagic fever, Phnom-Penh bat, Powassan, Rio Bravo, Rocio, Royal Farm, Russian spring-summer encephalitis, Saboya, St. Louis encephalitis, Sal Vieja, San Perlita, Saumarez Reef, Sepik, Sokuluk, 99 WO 2008/082601 PCT/US2007/026408 Spondweni, Stratford, Tembusu, Tyuleniy, Uganda S, Usutu, Wesselsbron, West Nile, Yaounde, Yellow fever, and Zika. [002951 Pestiviruses that can be treated are discussed generally in Fields Virology, Editors: Fields, B. N., Knipe, D. M., and Howley, P. M., Lippincott-Raven Publishers, Philadelphia, PA, Chapter 33, 1996. Specific pestiviruses include, without limitation: bovine viral diarrhea virus ("BVDV"), classical swine fever virus ("CSFV," also called hog cholera virus), and border disease virus ("BDV"). [002961 In certain embodiments, provided herein are methods for the treatment and/or prophylaxis of hepatitis B infections that includes administering an effective amount of a compound as described herein, e.g. of Formula I, Ila or Ilb, its pharmaceutically acceptable salt or composition. In another embodiment, provided herein are methods of treatment and/prophylaxis of conditions related to hepatitis B infections, such as anti-HBV antibody positive and HBV-positive conditions, chronic liver inflammation caused by HBV, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis, and fatigue. In certain embodiments, provided herein are prophylactic methods to prevent or retard the progression of clinical illness in individuals who are anti-HBV antibody or HBV-antigen positive or who have been exposed to HBV. 1002971 In certain embodiments, the subject can be any subject infected with, or at risk for infection with, HCV and/or HBV. Infection or risk for infection can be determined according to any technique deemed suitable by the practitioner of skill in the art. In one embodiment, subjects are humans infected with HCV and/or HBV. 1002981 In certain embodiments, the subject has never received therapy or prophylaxis for an HCV and/or HBV infection. In further embodiments, the subject has previously received therapy or prophylaxis for an HCV and/or HBV infection. For instance, in certain embodiments, the subject has not responded to an HCV and/or HBV therapy. For example, under current interferon therapy, up to 50% or more HCV subjects do not respond to therapy. In certain embodiments, the subject can be a subject that received therapy but continued to suffer from viral infection or one or more symptoms thereof. In certain embodiments, the subject can be a subject that received therapy but failed to achieve a sustained virologic response. In certain embodiments, the subject has received therapy for an HCV and/or HBV infection but 100 WO 2008/082601 PCTUS2007/026408 has failed to show, for example, a 2 logo decline in HCV RNA levels after 12 weeks of therapy. It is believed that subjects who have not shown more than 2 logwo reduction in serum HCV RNA after 12 weeks of therapy have a 97-100% chance of not responding. 100299) In certain embodiments, the subject is a subject that discontinued an HCV and/or HBV therapy because of one or more adverse events associated with the therapy. In certain embodiments, the subject is a subject where current therapy is not indicated. For instance, certain therapies for HCV are associated with neuropsychiatric events. Interferon (IFN)-alfa plus ribavirin is associated with a high rate of depression. Depressive symptoms have been linked to a worse outcome in a number of medical disorders. Life-threatening or fatal neuropsychiatric events, including suicide, suicidal and homicidal ideation, depression, relapse of drug addiction/overdose, and aggressive behavior have occurred in subjects with and without a previous psychiatric disorder during HCV therapy. Interferon-induced depression is a limitation for the treatment of chronic hepatitis C, especially for subjects with psychiatric disorders. Psychiatric side effects are common with interferon therapy and responsible for about 10% to 20% of discontinuations of current therapy for HCV infection. [003001 Accordingly, provided are methods of treating or preventing an HCV infection in subjects where the risk of neuropsychiatric events, such as depression, contraindicates treatment with current HCV therapy. In one embodiment, provided are methods of treating or preventing HCV infection in subjects where a neuropsychiatric event, such as depression, or risk of such indicates discontinuation of treatment with current HCV therapy. Further provided are methods of treating or preventing HCV infection in subjects where a neuropsychiatric event, such as depression, or risk of such indicates dose reduction of current HCV therapy. [003011 Current therapy is also contraindicated in subjects that are hypersensitive to interferon or ribavirin, or both, or any other component of a pharmaceutical product for administration of interferon or ribavirin. Current therapy is not indicated in subjects with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia) and other subjects at risk from the hematologic side effects of current therapy. Common hematologic side effects include bone marrow suppression, neutropenia and thrombocytopenia. Furthermore, ribavirin is toxic to red blood cells and is associated 101 WO 2008/082601 PCT/US2007/026408 with hemolysis. Accordingly, in one embodiment, provided are methods of treating or preventing HCV infection in subjects hypersensitive to interferon or ribavirin, or both, subjects with a hemoglobinopathy, for instance thalassemia major subjects and sickle-cell anemia subjects, and other subjects at risk from the hematologic side effects of current therapy. 1003021 In certain embodiments, the subject has received an HCV and/or HBV therapy and discontinued that therapy prior to administration of a method provided herein. In further embodiments, the subject has received therapy and continues to receive that therapy along with administration of a method provided herein. The methods can be co-administered with-other therapy for HBC and/or HCV according to the judgment of one of skill in the art. In certain embodiments, the methods or compositions provided herein can be co-administered with a reduced dose of the other therapy for HBC and/or HCV. [003031 In certain embodiments, provided are methods of treating a subject that is refractory to treatment with interferon. For instance, in some embodiments, the subject can be a subject that has failed to respond to treatment with one or more agents selected from the group consisting of interferon, interferon a, pegylated interferon a, interferon plus ribavirin, interferon a plus ribavirin and pegylated interferon a plus ribavirin. In some embodiments, the subject can be a subject that has responded poorly to treatment with one or more agents selected from the group consisting of interferon, interferon a, pegylated interferon a, interferon plus ribavirin, interferon a plus ribavirin and pegylated interferon a plus ribavirin. A pro-drug form of ribavirin, such as taribavirin, may also be used. [003041 In certain embodiments, the subject has, or is at risk for, co-infection of HCV with HIV. For instance, in the United States, 30% of HIV subjects are co infected with HCV and evidence indicates that people infected with HIV have a much more rapid course of their hepatitis C infection. Maier and Wu, 2002, World J Gastroenterol 8:577-57. The methods provided herein can be used to treat or prevent HCV infection in such subjects. It is believed that elimination of HCV in these subjects will lower mortality due to end-stage liver disease. Indeed, the risk of progressive liver disease is higher in subjects with severe AIDS-defining immunodeficiency than in those without. See, e.g., Lesens et al., 1999, J Infect Dis 179:1254-1258. In one embodiment, compounds provided herein have been shown to 102 WO 2008/082601 PCT/US2007/026408 suppress HIV in HIV subjects. Thus, in certain embodiments, provided are methods of treating or preventing HIV infection and HCV infection in subjects in need thereof. [003051 In certain embodiments, the compounds or compositions are administered to a subject following liver transplant. Hepatitis C is a leading cause of liver transplantation in the U.S, and many subjects that undergo liver transplantation remain HCV positive following transplantation. In one embodiment, provided are methods of treating such recurrent HCV subjects with a compound or composition provided herein. In certain embodiments, provided are methods of treating a subject before, during or following liver transplant to prevent recurrent HCV infection. [003061 In certain embodiments, provided herein are methods for the treatment and/or prophylaxis of hepatitis B infections and other related conditions such as anti HBV antibody positive and HBV-positive conditions, chronic liver inflammation caused by HBV, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis, and fatigue that includes administering an effective amount of a compound or composition provided herein. 1003071 In one embodiment, provided herein are methods for treatment and/or prophylaxis of hepatitis B infections and other related conditions such as anti-HBV antibody positive and HBV-positive conditions, chronic liver inflammation caused by HBV, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis, and fatigue that includes administering an effective amount of a compound or composition provided herein. Second Therapeutic Agents [003081 In certain embodiments, the compounds and compositions provided herein are useful in methods of treatment of a liver disorder, that comprises further administration of a second agent effective for the treatment of the disorder, such as HCV and/or HBV infection in a subject in need thereof. The second agent can be any agent known to those of skill in the art to be effective for the treatment of the disorder, including those currently approved by the FDA. 1003091 In certain embodiments, a compound provided herein is administered in combination with one second agent. In further embodiments, a second agent is administered in combination with two second agents. In still further embodiments, a second agent is administered in combination with two or more second agents. 103 WO 2008/082601 PCTIUS2007/026408 1003101 As used herein, the term "in combination" includes the use of more than one therapy (e.g, one or more prophylactic and/or therapeutic agents). The use of the term "in combination" does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject with a disorder. A first therapy (e.g., a prophylactic or therapeutic agent such as a compound provided herein) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, I hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, I week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, I hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, I week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent) to a subject with a disorder. [003111 As used herein, the term "synergistic" includes a combination of a compound provided herein and another therapy (e.g., a prophylactic or therapeutic agent) which has been or is currently being used to prevent, manage or treat a disorder, which is more effective than the additive effects of the therapies. A synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) permits the use of lower dosages of one or more of the therapies and/or less frequent administration of said therapies to a subject with a disorder. The ability to utilize lower dosages of a therapy (e.g., a prophylactic or therapeutic agent) and/or to administer said therapy less frequently reduces the toxicity associated with the administration of said therapy to a subject without reducing the efficacy of said therapy in the prevention or treatment of a disorder). In addition, a synergistic effect can result in improved efficacy of agents in the prevention or treatment of a disorder. Finally, a synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) may avoid or reduce adverse or unwanted side effects associated with the use of either therapy alone. 1003121 The active compounds provided herein can be administered in combination or alternation with another therapeutic agent, in particular an anti-HCV or hepatitis B agent. In combination therapy, effective dosages of two or more agents are administered together, whereas in alternation or sequential-step therapy, an effective dosage of each agent is administered serially or sequentially. The dosages 104 WO 2008/082601 PCT/US2007/026408 given 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 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. In certain embodiments, an anti-HCV (or anti-pestivirus or anti flavivirus) compound that exhibits an EC5 0 of 10-15 tM, or preferably less than 1-5 gM, is desirable. 1003131 It has been recognized that drug-resistant variants of flaviviruses, pestiviruses or HCV can emerge after prolonged treatment with an antiviral agent. Drug resistance most typically occurs by mutation of a gene that encodes for an enzyme used in viral replication. The efficacy of a drug against the viral 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. Alternatively, the pharmacokinetics, biodistribution or other parameter of the drug can be altered by such combination or alternation therapy. In general, combination therapy is typically preferred over alternation therapy because it induces multiple simultaneous stresses on the virus. [003141 Any of the viral treatments described in the Background of the Invention can be used in combination or alternation with the compounds described in this specification. Nonlimiting examples of second agents include: 1003151 HCV Protease inhibitors: Examples include Medivir HCV Protease Inhibitor (Medivir/Tobotec); ITMN-191 (InterMune), SCH 503034 (Schering) and VX950 (Vertex). Further examples of protease inhibitors include substrate-based NS3 protease inhibitors (Attwood et al., Antiviral peptide derivatives, PCT WO 98/22496, 1998; Attwood et al., Antiviral Chemistry and Chemotherapy 1999, 10, 259-273; Attwood et al., Preparation and use of amino acid derivatives as anti-viral agents, German Patent Pub. DE 19914474; Tung et al. Inhibitors of serine proteases, particularly hepatitis C virus NS3 protease, PCT WO 98/17679), including alphaketoamides and hydrazinoureas, and inhibitors that terminate in an electrophile such as a boronic acid or phosphonate (Llinas-Brunet et al, Hepatitis C inhibitor 105 WO 2008/082601 PCT/US2007/026408 peptide analogues, PCT WO 99/07734); Non-substrate-based NS3 protease inhibitors such as 2,4,6-trihydroxy-3-nitro-benzanide derivatives (Sudo K. et al., Biochemical and Biophysical Research Communications, 1997, 238, 643-647; Sudo K. et al. Antiviral Chemistry and Chemotherapy, 1998, 9, 186), including RD3-4082 and RD3 4078, the former substituted on the amide with a 14 carbon chain and the latter processing a para-phenoxyphenyl group; and Sch 68631, a phenanthrenequinone, an HCV protease inhibitor (Chu M. et al., Tetrahedron Letters 37:7229-7232, 1996). [003161 SCH 351633, isolated from the fungus Penicillium griseofulvum, was identified as a protease inhibitor (Chu M. et al., Bioorganic and Medicinal Chemistry Letters 9:1949-1952). Eglin c, isolated from leech, is a potent inhibitor of several serine proteases such as S. griseus proteases A and B, o.-chymotrypsin, chymase and subtilisin. Qasim M.A. et al., Biochemistry 36:1598-1607, 1997. 1003171 U.S. patents disclosing protease inhibitors for the treatment of HCV include, for example, U.S. Patent No. 6,004,933 to Spruce et al. which discloses a class of cysteine protease inhibitors for inhibiting HCV endopeptidase 2; U.S. Patent No. 5,990,276 to Zhang et al. which discloses synthetic inhibitors of hepatitis C virus NS3 protease; U.S. Patent No. 5,538,865 to Reyes et a; WO 02/008251 to Corvas International, Inc, and US7,169,760, US2005/176648, WO 02/08187 and WO 02/008256 to Schering Corporation. HCV inhibitor tripeptides are disclosed in US Patent Nos. 6,534,523, 6,410,531, and 6,420,380 to Boehringer Ingelheim and WO 02/060926 to Bristol Myers Squibb. Diaryl peptides as NS3 serine protease inhibitors of HCV are disclosed in WO 02/48172 and US 6,911,428 to Schering Corporation. Imidazoleidinones as NS3 serine protease inhibitors of HCV are disclosed in WO 02/08198 and US 6,838,475 to Schering Corporation and WO 02/48157 and US 6,727,366 to Bristol Myers Squibb. WO 98/17679 and US 6,265,380 to Vertex Pharmaceuticals and WO 02/48116 and US 6,653,295 to Bristol Myers Squibb also disclose HCV protease inhibitors. Further examples of HCV serine protease inhibitors are provided in US 6,872,805 (Bristol-Myers Squibb); WO 2006000085 (Boehringer Ingelheim); US 7,208,600 (Vertex); US 2006/0046956 (Schering Plough); WO 2007/001406 (Chiron); US 2005/0153877; WO 2006/119061 (Merck); WO 00/09543 (Boehringer Ingelheim), US 6,323,180 (Boehringer Ingelheim) WO 03/064456 (Boehringer Ingelheim), US 6,642,204(Boehringer Ingelheim), WO 03/064416 (Boehringer Ingelheim), US 7,091,184 (Boehringer Ingelheim), WO 106 WO 2008/082601 PCT/US2007/026408 03/053349 (Bristol-Myers Squibb), US 6,867,185, WO 03/099316 (Bristol-Myers Squibb), US 6,869,964, WO 03/099274 (Bristol-Myers Squibb), US 6,995,174, WO 2004/032827 (Bristol-Myers Squibb), US 7,041,698, WO 2004/043339 and US 6,878,722 (Bristol-Myers Squibb). [003181 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, 1996, 32, 9-18), especially compound RD-1 -6250, possessing a fused cinnamoyl moiety substituted with a long alkyl chain, RD4 6205 and RD4 6193; 1003191 Thiazolidines and benzanilides identified in Kakiuchi N. et al. J. EBS Letters 421, 217-220; Takeshita N. et al. Analytical Biochemistry, 1997, 247, 242 246; [003201 A phenanthrenequinone possessing activity against 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, 1996, 37, 7229 7232), and SCH 351633, isolated from the fungus Penicillium griseofulvum, which demonstrates activity in a scintillation proximity assay (Chu M. et al., Bloorganic and Medicinal Chemistry Letters 9, 1949-1952); 1003211 Helicase inhibitors (Diana G.D. et al., Compounds, compositions and methods for treatment of hepatitis C, U.S. Pat. No. 5,633,358; Diana G.D. et al., Piperidine derivatives, pharmaceutical compositions thereof and their use in the treatment of hepatitis C, PCT WO 97/36554); [003221 Nucleotide polymerase inhibitors and gliotoxin (Ferrari R. et al. Journal of Virology, 1999, 73, 1649-1654), and the natural product cerulenin (Lohmann V. et al., Virology, 1998, 249, 108-118); [003231 Interfering RNA (iRNA) based antivirals, including short interfering RNA (siRNA) based antivirals, such as Sirna-034 and others described in International Patent Publication Nos. WO/03/070750 and WO 2005/012525, and US Patent Publication No. US 2004/0209831. 1003241 Antisense phosphorothioate oligodeoxynucleotides (S-ODN) complementary to sequence stretches in the 5' non-coding region (NCR) of the virus (Alt M. et al., Hepatology, 1995, 22, 707-717), or nucleotides 326-348 comprising the 107 WO 2008/082601 PCT/US2007/026408 3' end of the NCR and nucleotides 371-388 located in the core coding region of the HCV RNA (Alt M. et al., Archives of Virology, 1997, 142, 589-599; Galderisi U. et al., Journal of Cellular Physiology, 1999, 181, 251-257); 1003251 Inhibitors of IRES-dependent translation (Ikeda N el al., Agent for the prevention and treatment of hepatitis C, Japanese Patent Pub. JP-08268890; Kai Y. et al. Prevention and treatment of viral diseases, Japanese Patent Pub. JP-10101591); 1003261 Ribozymes, such as nuclease-resistant ribozymes (Maccjak, D. J. et al., Hepatology 1999, 30, abstract 995) and those disclosed in U.S. Patent No. 6,043,077 to Barber et al., and U.S. Patent Nos. 5,869,253 and 5,610,054 to Draper et al.; and [003271 Nucleoside analogs have also been developed for the treatment of Flaviviridae infections. 1003281 In certain embodiments, the compounds provided herein can be administered in combination with any of the compounds described by Idenix Pharmaceuticals in International Publication Nos. WO 01/9012 1, WO 01/92282, WO 2004/003000, 2004/002422 and WO 2004/002999. [003291 Other patent applications disclosing the use of certain nucleoside analogs that can be used as second agents to treat hepatitis C virus include: PCT/CAOO/0 1316 (WO 01/32153; filed November 3, 2000) and PCT/CA01/00197 (WO 01/60315; filed February 19, 2001) filed by BioChem Pharma, Inc. (now Shire Biochem, Inc.); PCT/US02/01531 (WO 02/057425; filed January 18, 2002); PCT/US02/03086 (WO 02/057287; filed January 18, 2002); US 7,202,224; 7,125,855; 7,105,499 and 6,777,395 by Merck & Co., Inc.; PCT/EP01/09633 (WO 02/18404; published August 21, 2001); US 2006/0040890; 2005/0038240; 2004/0121980; 6,846,810; 6,784,166 and 6,660,721 by Roche; PCT Publication Nos. WO 01/79246 (filed April 13, 2001), WO 02/32920 (filed October 18, 2001) and WO 02/48165; US 2005/0009737; US 2005/0009737; 7,094,770 and 6,927,291 by Pharmasset, Ltd. [003301 Further compounds that can be used as second agents to treat hepatitis C virus are disclosed in PCT Publication No. WO 99143691 to Emory University, entitled "2'-Fluoronucleosides". The use of certain 2'-fluoronucleosides to treat HCV is disclosed. 1003311 Other miscellaneous compounds that can be used as second agents include 1-amino-alkylcyclohexanes (U.S. Patent No. 6,034,134 to Gold et al.), alkyl lipids 108 WO 2008/082601 PCT/US2007/026408 (U.S. Pat. No. 5,922,757 to Chojkier et al.), vitamin E and other antioxidants (U.S. Pat. No. 5,922,757 to Chojkier et al.), squalene, amantadine, bile acids (U.S. Pat. No. 5,846,964 to Ozeki et al.), N-(phosphonoacetyl)-L-aspartic acid, (U.S. Pat. No. 5,830,905 to Diana et al.), benzenedicarboxamides (U.S. Pat. No. 5,633,388 to Diana et al.), polyadenylic acid derivatives (U.S. Pat. No. 5,496,546 to Wang et al.), 2',3' dideoxyinosine (U.S. Pat. No. 5,026,687 to Yarchoan et al.), benzimidazoles (U.S. Pat. No. 5,891,874 to Colacino et al.), 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. 6,056,961), and piperidenes (U.S. Patent No. 5,830,905 to Diana et al.). Exemplary Second Agents for Treatment of HCV 1003321 In one embodiment, one or more compounds provided herein can be administered in combination or alternation with an anti-hepatitis C virus interferon, such as Intron A (interferon alfa-2b) and Pegasys (Peginterferon alfa-2a); Roferon A (Recombinant interferon alfa-2a), Infergen (consensus interferon;interferon alfacon-1), PEG-Intron (pegylated interferon alfa-2b) and Pegasys* (pegylated interferon alfa-2a). 1003331 In one embodiment, the anti-hepatitis C virus interferon is infergen, IL-29 (PEG-Interferon lambda), R7025 (Maxy-alpha), Belerofon, Oral Interferon alpha, BLX-883 (Locteron), omega interferon, multiferon, medusa interferon, Albuferon or REBIF*. 1003341 In one embodiment, one or more compounds provided herein can be administered in combination or alternation with an anti-hepatitis C virus polymerase inhibitor, such as ribavirin, viramidine, NM 283 (valopicitabine), PSI-6130, R1626, HCV-796 or R7128. 1003351 In certain embodiments, the one or more compounds provided herein can be administered in combination with ribavarin and an anti-hepatitis C virus interferon, such as Intron A (interferon alfa-2b) and Pegasys (Peginterferon alfa-2a); Roferon A* (Recombinant interferon alfa-2a), Infergen (consensus interferon;interferon alfacon-1), PEG-Intron* (pegylated interferon alfa-2b) and Pegasys* (pegylated interferon alfa-2a). [003361 In one embodiment, one or more compounds provided herein can be administered in combination or alternation with an anti-hepatitis C virus protease 109 WO 2008/082601 PCT/US2007/026408 inhibitor such as ITMN-191, SCH 503034, VX950 (telaprevir) or Medivir HCV Protease Inhibitor. (003371 In one embodiment, one or more compounds provided herein can be administered in combination or alternation with an anti-hepatitis C virus vaccine, such as TG4040, PeviPROTM, CGI-5005, HCV/MF59, GVOOI, IC41 or INNO0101 (El). 1003381 In one embodiment, one or more compounds provided herein can be administered in combination or alternation with an anti-hepatitis C virus monoclonal antibody, such as AB68 or XTL-6865 (formerly HepX-C); or an anti-hepatitis C virus polyclonal antibody, such as cicavir. (00339] In one embodiment, one or more compounds provided herein can be administered in combination or alternation with an anti-hepatitis C virus immunomodulator, such as Zadaxin* (thymalfasin), NOV-205 or Oglufanide. 1003401 In one embodiment, one or more compounds provided herein can be administered in combination or alternation with Nexavar, doxorubicin, PI-88, amantadine, JBK-122, VGX-410C, MX-3253 (Ceglosivir), Suvus (BIVN-401 or virostat), PF-03491390 (formerly IDN-6556), G126270, UT-231B, DEBIO-025, EMZ702, ACH-0137171, MitoQ, ANA975, AVI-4065, Bavituxinab (Tarvacin), Alinia (nitrazoxanide) or PYN17. Exemplary Second Agents for Treatment of HBV [003411 It has been recognized that drug-resistant variants of HBV can emerge after prolonged treatment with an antiviral agent. Drug resistance most typically occurs by mutation of a gene that encodes for an enzyme used in the viral life cycle, and most typically in the case of HBV, DNA polymerase. The efficacy of a drug against HBV 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. Alternatively, the pharmacokinetics, biodistribution, or other parameter of the drug can be altered by such combination or alternation therapy. In general, combination therapy is typically preferred over alternation therapy because it induces multiple simultaneous stresses on the virus. [003421 The anti-hepatitis B viral activity of compounds provided herein can be enhanced by administering one or more of these further agents in combination or 110 WO 2008/082601 PCT[US2007/026408 alternation. Alternatively, for example, one or more compounds provided herein can be administered in combination or alternation with any other known anti-hepatitis B virus agent. Such agents include anti-hepatitis B virus interferons, such as Intron A* (interferon alfa-2b) and Pegasys* (Peginterferon alfa-2a); polymerase inhibitors, such as Epivir-HBV (lamivudine), Hepsera (adefovir dipivoxil), baraclude (entecavir), Tyzeka (telbivudine), Emtricitabine (FTC), Clevudine (L-FMAU), Viread (tenofovir), Valtorcitabine, Amdoxovir, ANA 380, Pradefovir (remofovir) and RCV (racivir); vaccines, such as Hi-8 HBV, HepaVaxx B and HBV Core Antigen vaccine; and other agents, such as HepX, SpecifEx-HepB, Zadaxin, EHT899, Bay 41-4109, UT 231-B, HepeX-B and NOV-205 or any other compound that exhibits an ECso of less than 15 micromolar in 2.2.15 cells; or their prodrugs or pharmaceutically acceptable salts. Several other examples of anti-HBV agents are provided in U.S. Application Publication No. 20050080034 and international publication no. WO 2004/096286, which are incorporated by reference in their entireties. 1003431 In one embodiment, one or more compounds provided herein can be administered in combination or alternation with anti-hepatitis B virus agent such as interferon a-2b, peginterferon a-2a, lamivudine, hepsera, baraclude, telbivudine, emtricitabine, clevudine, tenofovir, valtorcitabine, amdoxovir, ANA 380, remofovir, racivir, alinia, Hi-8 HBV and HepaVaxx B. 1003441 In another embodiment, a compound provided herein is administered in combination or alternation with an immune modulator or other pharmaceutically active modifer of viral replication, including a biological material such as a protein, peptide, oligonucleotide, or gamma globulin, including but not limited to interfereon, interleukin, or an antisense oligonucleotides to genes which express or regulate hepatitis B replication. [003451 Any method of alternation can be used that provides treatment to the patient. Nonlimiting examples of alternation patterns include 1-6 weeks of administration of an effective amount of one agent followed by 1-6 weeks of administration of an effective amount of a second anti-HBV agent. The alternation schedule can include periods of no treatment. Combination therapy generally includes the simultaneous administration of an effective ratio of dosages of two or more anti-HBV agents. 111 WO 2008/082601 PCT/US2007/026408 [003461 In light of the fact that HBV is often found in patients who are also anti HIV antibody or HIV-antigen positive or who have been exposed to HIV, the active anti-HBV compounds disclosed herein or their derivatives or prodrugs can be administered in the appropriate circumstance in combination or alternation with anti HIV medications. [003471 The compounds provided herein can also be administered in combination with antibiotics, other antiviral compounds, antifungal agents or other pharmaceutical agents administered for the treatment of secondary infections. Pharmaceutical Compositions and Methods of Administration 1003481 Phosphoramidate and phosphonoamidate compounds of a variety of therapeutic agents can be formulated into pharmaceutical compositions using methods available in the art and those disclosed herein. Such compounds can be used in some embodiments to enhance delivery of the drug to the liver. In one embodiment, the compound comprises a S-acyl-2-thioethyl phosphoramidate or S-acyl-2-thioethyl phosphonoamidate, e.g., a S-pivaloyl-2-thioethyl phosphoramidate or S hydroxypivaloyl-2-thioethyl phosphonoamidate derivative. Therapeutic agents that can be derivatized to phosphoramidate or phosphonoamidate compound form include any anti-viral agent that includes, or has been derivatized to include a reactive group for attachment of the phosphoramidate or phosphonoamidate moiety, including but not limited to nucleosides and nucleoside analogues including acyclic nucleosides. Any of the phosphoramidate or phosphonoamidate compounds disclosed herein can be provided in the appropriate pharmaceutical composition and be administered by a suitable route of administration. 1003491 The methods provided herein encompass administering pharmaceutical compositions containing at least one compound as described herein, including a compound of general Formula I, Ila or Ilb, if appropriate in the salt form, either used alone or in the form of a combination with one or more compatible and pharmaceutically acceptable carriers, such as diluents or adjuvants, or with another anti-HCV or anti-HBV agent. [003501 In certain embodiments, the second agent can be formulated or packaged with the compound provided herein. Of course, the second agent will only be formulated with the compound provided herein when, according to the judgment of 112 WO 2008/082601 PCT/US2007/026408 those of skill in the art, such co-formulation should not interfere with the activity of either agent or the method of administration. In certain embodiments, the compound provided herein and the second agent are formulated separately. They can be packaged together, or packaged separately, for the convenience of the practitioner of skill in the art. 1003511 In clinical practice the active agents provided herein may be administered by any conventional route, in particular orally, parenterally, rectally or by inhalation (e.g. in the form of aerosols). In certain embodiments, the compound provided herein is administered orally. 1003521 Use may be made, as solid compositions for oral administration, of tablets, pills, hard gelatin capsules, powders or granules. In these compositions, the active product is mixed with one or more inert diluents or adjuvants, such as sucrose, lactose or starch. [003531 These compositions can comprise substances other than diluents, for example a lubricant, such as magnesium stearate, or a coating intended for controlled release. [003541 Use may be made, as liquid compositions for oral administration, of solutions which are pharmaceutically acceptable, suspensions, emulsions, syrups and elixirs containing inert diluents, such as water or liquid paraffin. These compositions can also comprise substances other than diluents, for example wetting, sweetening or flavoring products. [003551 The compositions for parenteral administration can be emulsions or sterile solutions. Use may be made, as solvent or vehicle, of propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, or injectable organic esters, for example ethyl oleate. These compositions can also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization can be carried out in several ways, for example using a bacteriological filter, by radiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other injectable sterile medium. 113 WO 2008/082601 PCT/US2007/026408 1003561 The compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active principle, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols. 1003571 The compositions can also be aerosols. For use in the form of liquid aerosols, the compositions can be stable sterile solutions or solid compositions dissolved at the time of use in apyrogenic sterile water, in saline or any other pharmaceutically acceptable vehicle. For use in the form of dry aerosols intended to be directly inhaled, the active principle is finely divided and combined with a water soluble solid diluent or vehicle, for example dextran, mannitol or lactose. 100358] In one embodiment, a composition provided herein is a pharmaceutical composition or a single unit dosage form. Pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., a compound provided herein, or other prophylactic or therapeutic agent), and a typically one or more pharmaceutically acceptable carriers or excipients. In a specific embodiment and in this context, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term "carrier" includes a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water can be used as a carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin. 1003591 Typical pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are well-known to those skilled in the art of pharmacy, and non limiting examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, 114 WO 2008/082601 PCT/US2007/026408 water, ethanol and the like. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a subject and the specific active ingredients in the dosage form. The composition or single unit dosage form, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. 1003601 Lactose free compositions provided herein can comprise excipients that are well known in the art and are listed, for example, in the U.S. Pharmocopia (USP) SP (XXI)/NF (XVI). In general, lactose free compositions comprise an active ingredient, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. Exemplary lactose free dosage forms comprise an active ingredient, microcrystalline cellulose, pre gelatinized starch, and magnesium stearate. 1003611 Further encompassed herein are anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical arts as a means of simulating long term storage in order to determine characteristics such as shelf life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379 80. In effect, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations. [003621 Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine can be anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected. 1003631 An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions 115 WO 2008/082601 PCT/US2007/026408 can be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs. 1003641 Further provided are pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose. Such compounds, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers. 100365] The pharmaceutical compositions and single unit dosage forms can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Such compositions and dosage forms will contain a prophylactically or therapeutically effective amount of a prophylactic or therapeutic agent, in certain embodiments, in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the subject. The formulation should suit the mode of administration. In a certain embodiment, the pharmaceutical compositions or single unit dosage forms are sterile and in suitable form for administration to a subject, for example, an animal subject, such as a mammalian subject, for example, a human subject. 1003661 A pharmaceutical composition is formulated to be compatible with its intended route of administration. Examples of routes of administration include, but are not limited to, parenteral, e.g., intravenous, intradermal, subcutaneous, intramuscular, subcutaneous, oral, buccal, sublingual, inhalation, intranasal, transdermal, topical, transmucosal, intra-tumoral, intra-synovial and rectal administration. In a specific embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to human beings. In an embodiment, a pharmaceutical composition is formulated in accordance with routine procedures for subcutaneous administration to human beings. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing 116 WO 2008/082601 PCT/US2007/026408 agent and a local anesthetic such as lignocamne to ease pain at the site of the injection. [003671 Examples of dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a subject, including suspensions (e.g., aqueous or non aqueous liquid suspensions, oil in water emulsions, or a water in oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a subject; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a subject. 1003681 The composition, shape, and type of dosage forms provided herein will typically vary depending on their use. For example, a dosage form used in the initial treatment of viral infection may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the maintenance treatment of the same infection. Similarly, a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease or disorder. These and other ways in which specific dosage forms encompassed herein will vary from one another will be readily apparent to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing, Easton PA (2000). 1003691 Generally, the ingredients of compositions are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration. 1003701 Typical dosage forms comprise a compound provided herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof lie within the range of 117 WO 2008/082601 PCT[US2007/026408 from about 0.1 mg to about 1000 mg per day, given as a single once-a-day dose in the morning or as divided doses throughout the day taken with food. Particular dosage forms can have about 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 100, 200, 250, 500 or 1000 mg of the active compound. Oral Dosage Forms 1003711 Pharmaceutical compositions that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing, Easton PA (2000). 1003721 In certain embodiments, the oral dosage forms are solid and prepared under anhydrous conditions with anhydrous ingredients, as described in detail in the sections above. However, the scope of the compositions provided herein extends beyond anhydrous, solid oral dosage forms. As such, further forms are described herein. 1003731 Typical oral dosage forms are prepared by combining the active ingredient(s) in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration. For example, recipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, micro crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents. [003741 Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided 118 WO 2008/082601 PCTfUS2007/026408 solid carriers, or both, and then shaping the product into the desired presentation if necessary. [003751 For example, a tablet can be prepared by compression or molding. Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free flowing form such as powder or granules, optionally mixed with an excipient. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. 1003761 Examples of excipients that can be used in oral dosage forms include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof. 1003771 Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre gelatinized starch, and mixtures thereof. The binder or filler in pharmaceutical compositions is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form. 1003781 Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL PH 101, AVICEL PH 103 AVICEL RC 581, AVICEL PH 105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof. An specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC 581. Suitable anhydrous or low moisture excipients or additives include AVICEL PH 103TM and Starch 1500 LM. 1003791 Disintegrants are used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much 119 WO 2008/082601 PCT/US2007/026408 disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art. Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, specifically from about I to about 5 weight percent of disintegrant. [003801 Disintegrants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, agar agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof. 1003811 Lubricants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, for example, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Piano, TX), CAB 0 SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than about I weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated. Delayed Release Dosage Forms 1003821 Active ingredients such as the compounds provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 120 WO 2008/082601 PCT/US2007/026408 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; 6,699,500 each of which is incorporated herein by reference. Such dosage forms can be used to provide slow or controlled release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein. Thus encompasseed herein are single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled release. [003831 All controlled release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non controlled counterparts. Ideally, the use of an optimally designed controlled release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled release formulations include extended activity of the drug, reduced dosage frequency, and increased subject compliance. In addition, controlled release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects. 1003841 Most controlled release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds. 100385] In certain embodiments, the drug may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In one embodiment, a pump may be used (see, Sefton, CRC Crit. Ref Biomed Eng. 14:201 (1987); Buchwald et aL., Surgery 88:507 (1980); 121 WO 2008/082601 PCTIUS2007/026408 Saudek et al., N. Engl. J. Med. 321:574 (1989)). In another embodiment, polymeric materials can be used. In yet another embodiment, a controlled release system can be placed in a subject at an appropriate site determined by a practitioner of skill, i.e., thus requiring only a fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984)). Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990)). The active ingredient can be dispersed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer, that is insoluble in body fluids. The active ingredient then diffuses through the outer polymeric membrane in a release rate controlling step. The percentage of active ingredient in such parenteral compositions is highly dependent on the specific nature thereof, as well as the needs of the subject. Parenteral Dosage Forms 1003861 In one embodiment, provided are parenteral dosage forms. Parenteral dosage forms can be administered to subjects by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration typically bypasses subjects' natural defenses against contaminants, parenteral dosage forms are typically, sterile or capable of being sterilized prior to administration to a subject. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry 122 WO 2008/082601 PCT/US2007/026408 products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions. 1003871 Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. [003881 Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into the parenteral dosage forms. Transdermal, Topical & Mucosal Dosage Forms [003891 Also provided are transdermal, topical, and mucosal dosage forms. Transdermal, topical, and mucosal dosage forms include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16*, 18th and 20 h eds., Mack Publishing, Easton PA (1980,1990 & 2000); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels. Further, transdermal dosage forms include "reservoir type" or "matrix type" patches, which can be applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredients. [00390] Suitable excipients (e.g., carriers and diluents) and other materials that can be used to provide transdermal, topical, and mucosal dosage forms encompassed herein are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied. With that fact in mind, typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane 1,3 diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form lotions, tinctures, creams, emulsions, gels or ointments, which are non toxic and 123 WO 2008/082601 PCT/US2007/026408 pharmaceutically acceptable. Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, e.g., Remington's Pharmaceutical Sciences, 16 *, 18th and 20 e eds., Mack Publishing, Easton PA (1980, 1990 & 2000). [003911 Depending on the specific tissue to be treated, additional components may be used prior to, in conjunction with, or subsequent to treatment with active ingredients provided. For example, penetration enhancers can be used to assist in delivering the active ingredients to the tissue. Suitable penetration enhancers include, but are not limited to: acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and various water soluble or insoluble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate). 1003921 The pH of a pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied, may also be adjusted to improve delivery of one or more active ingredients. Similarly, the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery. Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery. In this regard, stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery enhancing or penetration enhancing agent. Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition. Dosage and Unit Dosage Forms 1003931 In human therapeutics, the doctor will determine the posology which he considers most appropriate according to a preventive or curative treatment and according to the age, weight, stage of the infection and other factors specific to the subject to be treated. In certain embodiments, doses are from about I to about 1000 mg per day for an adult, or from about 5 to about 250 mg per day or from about 10 to 50 mg per day for an adult. In certain embodiments, doses are from about 5 to about 124 WO 2008/082601 PCT/US2007/026408 400 mg per day or 25 to 200 mg per day per adult. In certain embodiments, dose rates of from about 50 to about 500 mg per day are also contemplated. [00394] In further aspects, provided are methods of treating or preventing an HCV and/or HBV infection in a subject by administering, to a subject in need thereof, an effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. The amount of the compound or composition which will be effective in the prevention or treatment of a disorder or one or more symptoms thereof will vary with the nature and severity of the disease or condition, and the route by which the active ingredient is administered. The frequency and dosage will also vary according to factors specific for each subject depending on the specific therapy (e.g., therapeutic or prophylactic agents) administered, the severity of the disorder, disease, or condition, the route of administration, as well as age, body, weight, response, and the past medical history of the subject. Effective doses may be extrapolated from dose response curves derived from in vitro or animal model test systems. 1003951 In certain embodiments, exemplary doses of a composition include milligram or microgram amounts of the active compound per kilogram of subject or sample weight (e.g., about 10 micrograms per kilogram to about 50 milligrams per kilogram, about 100 micrograms per kilogram to about 25 milligrams per kilogram, or about 100 microgram per kilogram to about 10 milligrams per kilogram). For compositions provided herein, in certain embodiments, the dosage administered to a subject is 0.140 mg/kg to 3 mg/kg of the subject's body weight, based on weight of the active compound. In certain embodiments, the dosage administered to a subject is between 0.20 mg/kg and 2.00 mg/kg, or between 0.30 mg/kg and 1.50 mg/kg of the subject's body weight. 1003961 In certain embodiments, the recommended daily dose range of a composition provided herein for the conditions described herein lie within the range of from about 0.1 mg to about 1000 mg per day, given as a single once-a-day dose or as divided doses throughout a day. In one embodiment, the daily dose is administered twice daily in equally divided doses. In certain embodiments, a daily dose range should be from about 10 mg to about 200 mg per day, in other embodiments, between about 10 mg and about 150 mg per day, in further embodiments, between about 25 and about 100 mg per day. It may be necessary to use dosages of the active ingredient outside the ranges disclosed herein in some cases, as will be apparent to those of 125 WO 2008/082601 PCT/US2007/026408 ordinary skill in the art. Furthermore, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with subject response. [003971 Different therapeutically effective amounts may be applicable for different diseases and conditions, as will be readily known by those of ordinary skill in the art. Similarly, amounts sufficient to prevent, manage, treat or ameliorate such disorders, but insufficient to cause, or sufficient to reduce, adverse effects associated with the composition provided herein are also encompassed by the above described dosage amounts and dose frequency schedules. Further, when a subject is administered multiple dosages of a composition provided herein, not all of the dosages need be the same. For example, the dosage administered to the subject may be increased to improve the prophylactic or therapeutic effect of the composition or it may be decreased to reduce one or more side effects that a particular subject is experiencing. 100398) In certain embodiment, the dosage of the composition provided herein, based on weight of the active compound, administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof in a subject is 0.1 mg/kg, I mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 10 mg/kg, or 15 mg/kg or more of a subject's body weight. In another embodiment, the dosage of the composition or a composition provided herein administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof in a subject is a unit dose of 0.1 mg to 200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 7.5 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 mg to 7.5 mg, 0.25 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, I mg to 15 mg, 1 mg to 12 mg, I mg to 10 mg, 1 mg to 7.5 mg,1 mg to 5 mg, or I mg to 2.5 mg. 1003991 In certain embodiments, treatment or prevention can be initiated with one or more loading doses of a compound or composition provided herein followed by one or more maintenance doses. In such embodiments, the loading dose can be, for instance, about 60 to about 400 mg per day, or about 100 to about 200 mg per day for one day to five weeks. The loading dose can be followed by one or more maintenance doses. In certain embodiments, each maintenance does is, independently, about from about 10 mg to about 200 mg per day, between about 25 mg and about 150 mg per day, or between about 25 and about 80 mg per day. 126 WO 2008/082601 PCT/US2007/026408 Maintenance doses can be administered daily and can be administered as single doses, or as divided doses. [004001 In certain embodiments, a dose of a compound or composition provided herein can be administered to achieve a steady-state concentration of the active ingredient in blood or serum of the subject. The steady-state concentration can be determined by measurement according to techniques available to those of skill or can be based on the physical characteristics of the subject such as height, weight and age. In certain embodiments, a sufficient amount of a compound or composition provided herein is administered to achieve a steady-state concentration in blood or serum of the subject of from about 300 to about 4000 ng/mL, from about 400 to about 1600 ng/mL, or from about 600 to about 1200 ng/mL. In some embodiments, loading doses can be administered to achieve steady-state blood or serum concentrations of about 1200 to about 8000 ng/mL, or about 2000 to about 4000 ng/mL for one to five days. In certain embodiments, maintenance doses can be administered to achieve a steady state concentration in blood or serum of the subject of from about 300 to about 4000 ng/mL, from about 400 to about 1600 ng/mL, or from about 600 to about 1200 ng/mL. 100401] In certain embodiments, administration of the same composition may be repeated and the administrations may be separated by at least I day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In other embodiments, administration of the same prophylactic or therapeutic agent may be repeated and the administration may be separated by at least at least I day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. [004021 In certain aspects, provided herein are unit dosages comprising a compound, or a pharmaceutically acceptable salt thereof, in a form suitable for administration. Such forms are described in detail above. In certain embodiments, the unit dosage comprises 1 to 1000 mg, 5 to 250 mg or 10 to 50 mg active ingredient. In particular embodiments, the unit dosages comprise about 1, 5, 10, 25, 50, 100, 125, 250, 500 or 1000 mg active ingredient. Such unit dosages can be prepared according to techniques familiar to those of skill in the art. 127 WO 2008/082601 PCTIUS2007/026408 100403] The dosages of the second agents are to be used in the combination therapies provided herein. In certain embodiments, dosages lower than those which have been or are currently being used to prevent or treat HCV and/or HBV infection are used in the combination therapies provided herein. The recommended dosages of second agents can be obtained from the knowledge of those of skill. For those second agents that are approved for clinical use, recommended dosages are described in, for example, Hardman et al., eds., 1996, Goodman & Gilman's The Pharmacological Basis Of Basis Of Therapeutics 9 'h Ed, Mc-Graw-Hill, New York; Physician's Desk Reference (PDR) 5 7 'h Ed., 2003, Medical Economics Co., Inc., Montvale, NJ, which are incorporated herein by reference in its entirety. 1004041 In various embodiments, the therapies (e.g., a compound provided herein and the second agent) are administered less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, at about I hour apart, at about I to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about I I hours apart, at about I I hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours part. In various embodiments, the therapies are administered no more than 24 hours apart or no more than 48 hours apart. In certain embodiments, two or more therapies are administered within the same patient visit. In other embodiments, the compound provided herein and the second agent are administered concurrently. 1004051 In other embodiments, the compound provided herein and the second agent are administered at about 2 to 4 days apart, at about 4 to 6 days apart, at about I week part, at about I to 2 weeks apart, or more than 2 weeks apart. 1004061 In certain embodiments, administration of the same agent may be repeated and the administrations may be separated by at least I day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In other embodiments, administration of the same agent may be repeated and the 128 WO 2008/082601 PCT/US2007/026408 administration may be separated by at least at least I day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. 1004071 In certain embodiments, a compound provided herein and a second agent are administered to a patient, for example, a mammal, such as a human, in a sequence and within a time interval such that the compound provided herein can act together with the other agent to provide an increased benefit than if they were administered otherwise. For example, the second active agent can be administered at the same time or sequentially in any order at different points in time; however, if not administered at the same time, they should be administered sufficiently close in time so as to provide the desired therapeutic or prophylactic effect. In one embodiment, the compound provided herein and the second active agent exert their effect at times which overlap. Each second active agent can be administered separately, in any appropriate form and by any suitable route. In other embodiments, the compound provided herein is administered before, concurrently or afler administration of the second active agent. 1004081 In certain embodiments, the compound provided herein and the second agent are cyclically administered to a patient. Cycling therapy involves the administration of a first agent (e.g., a first prophylactic or therapeutic agents) for a period of time, followed by the administration of a second agent and/or third agent (e.g., a second and/or third prophylactic or therapeutic agents) for a period of time and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improve the efficacy of the treatment. 1004091 In certain embodiments, the compound provided herein and the second active agent are administered in a cycle of less than about 3 weeks, about once every two weeks, about once every 10 days or about once every week. One cycle can comprise the administration of a compound provided herein and the second agent by infusion over about 90 minutes every cycle, about I hour every cycle, about 45 minutes every cycle. Each cycle can comprise at least I week of rest, at least 2 weeks of rest, at least 3 weeks of rest. The number of cycles administered is from about I to about 12 cycles, more typically from about 2 to about 10 cycles, and more typically from about 2 to about 8 cycles. 129 WO 2008/082601 PCT/US2007/026408 1004101 In other embodiments, courses of treatment are administered concurrently to a patient, i.e., individual doses of the second agent are administered separately yet within a time interval such that the compound provided herein can work together with the second active agent. For example, one component can be administered once per week in combination with the other components that can be administered once every two weeks or once every three weeks. In other words, the dosing regimens are carried out concurrently even if the therapeutics are not administered simultaneously or during the same day. 1004111 The second agent can act additively or synergistically with the compound provided herein. In one embodiment, the compound provided herein is administered concurrently with one or more second agents in the same pharmaceutical composition. In another embodiment, a compound provided herein is administered concurrently with one or more second agents in separate pharmaceutical compositions. In still another embodiment, a compound provided herein is administered prior to or subsequent to administration of a second agent. Also contemplated are administration of a compound provided herein and a second agent by the same or different routes of administration, e.g., oral and parenteral. In certain embodiments, when the compound provided herein is administered concurrently with a second agent that potentially produces adverse side effects including, but not limited to, toxicity, the second active agent can advantageously be administered at a dose that falls below the threshold that the adverse side effect is elicited. Kits [004121 Also provided are kits for use in methods of treatment of a liver disorder such as HCV and/or HBV infections. The kits can include a compound or composition provided herein, a second agent or composition, and instructions providing information to a health care provider regarding usage for treating the disorder. Instructions may be provided in printed form or in the form of an electronic medium such as a floppy disc, CD, or DVD, or in the form of a website address where such instructions may be obtained. A unit dose of a compound or composition provided herein, or a second agent or composition, can include a dosage such that when administered to a subject, a therapeutically or prophylactically effective plasma level of the compound or composition can be maintained in the subject for at least 1 130 WO 2008/082601 PCTIUS2007/026408 days. In some embodiments, a compound or composition can be included as a sterile aqueous pharmaceutical composition or dry powder (e.g., lyophilized) composition. 1004131 In some embodiments, suitable packaging is provided. As used herein, "packaging" includes a solid matrix or material customarily used in a system and capable of holding within fixed limits a compound provided herein and/or a second agent suitable for administration to a subject. Such materials include glass and plastic (e.g., polyethylene, polypropylene, and polycarbonate) bottles, vials, paper, plastic, and plastic-foil laminated envelopes and the like. If e-beam sterilization techniques are employed, the packaging should have sufficiently low density to permit sterilization of the contents. 1004141 The following Examples illustrate the synthesis of representative compounds provided herein. These examples are not intended, nor are they to be construed, as limiting the scope of the claimed subject matter. It will be clear that the scope of claimed subject matter may be practiced otherwise than as particularly described herein. Numerous modifications and variations of the subject matter are possible in view of the teachings herein and, therefore, are within the scope the claimed subject matter. 131 WO 2008/082601 PCT/US2007/026408 EXAMPLES Preparation of A550 (NM204), the Hydroxy-tBuSATE N benzylphosphoramidate derivative of L-2',3'-dideoxyadenosine L-ddA HO 24S OLH d NM204, A550 SYNTHETIC SCHEME: NHz I) (PhO) 2 p(0)1--H yO H O H H.NEt 3 3 H uneIH S/AcH pyDiMT bLddA 2) FIiN I H20 rt. 15 ndnl ,.L. 10ni 10% 00C4,UanNR, H daoIM0IAO :'1DMT HA d<uuH 3 IH0 3 mlap, 35% 1. Synthesis of carboxylic acid 2: OM 0 0 H MTtci NaOHO liome ON5%7 OH 1 2 1004151 2,2-Dimethyl-3-hydroxypropanoic acid methyl ester (965 pL, 7.57 mmol) was added dropwise to a stirring solution of 4,4'-dimethoxytrityl chloride (2.82 g, 8.33 mmol) in anhydrous pyridine (7.6 mL) at room temperature. The reaction 132 WO 2008/082601 PCT/US2007/026408 mixture turned to a red solution quickly, then to an orange suspension (ca. 30 min), and this was left stirring overnight. The mixture was poured carefully over saturated aqueous NaHCO 3 solution (30 mL) and the product was extracted with Et 2 0 (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried (Na 2 SO4) and the volatiles were removed under reduced pressure. The resulting oil was co evaporated with toluene and the residue was quickly purified by flash column chromatography (SiO 2 , 0 = 4 cm, H =20 cm) eluting with 5 -+ 10 - 20 -+ 30% Et20 in petroleum ether (40-60). Evaporation of the fractions (Rf =0.25, 30% Et 2 0 in petroleum ether (40-60)) afforded ether 1 as a yellow oil (3.11 g, 95%). This compound (3.00 g, 6.91 mmol) was dissolved in THF (35 mL) and an aqueous solution of NaOH (10%, 3.5 g in 35 mL H 2 0) was then added at room temperature. The solution turned instantly dark orange and this was stirred for 2 days. The medium was then carefully neutralized by dropwise addition of HCI (1 M). The product was extracted with Et 2 O (4 x 50 mL) and the combined organic extracts were washed with brine (50 mL), dried (Na 2

SO

4 ) and the volatiles were removed under reduced pressure. The crude yellow oil was quickly purified by flash column chromatography (SiO2, 0 = 2 cm, H = 10 cm) eluting with 50% Et2O in petroleum ether (40-60). Evaporation of the fractions afforded carboxylic acid 2 as a white foam (2.23 g, 77%). Rf= 0.50 (50% Et 2 0 in petroleum ether (40-60)); 'H-NMR (300 MHz, CDC 3 ) 1.10 (s, 6H, 2 x CH 3 ), 3.06 (s, 2H, CH 2 O), 3.65 (s, 6H, 2 x OCH 3 ), 6.62-6.79 (m, 4H, PhCH), 7.02-7.46 (stack, 8H, PhCH); 3 C-NMR (75 MHz, CDCl 3 ) 22.6 (2 x CH3), 43.5 (C(CH 3

)

2 ), 55.1 (2 x OCH 3 ), 85.9 (CPh3), [125.3, 126.7, 127.7, 128.2, 129.1, 130.0, 136.0, 144.9, 158.4 (Ph), some overlap], 182.2 (C=0). Synthesis of thioester 3: OMe OMe /\/ CDI / O HO SHOH Meo O 92% MeO 2 3 1004161 1,1'-carbonyldiimidazole (830 mg, 5.12 mmol) was added to a stirring solution of carboxylic acid 2 in anhydrous PhMe/DMF (2/1, v/v, 2.7 mL) at room 133 WO 2008/082601 PCT/US2007/026408 temperature and the reaction mixture turned turbid instantly. After 30 min, the medium was diluted by adding anhydrous PhMe/DMF (93/7, v/v, 17 mL) and cooled to -10 *C. 2-Mercaptoethanol (359 piL, 5.12 mmol) was then added dropwise and the solution was stirred for I h at this temperature. The reaction mixture was diluted with

H

2 0 (60 mL) and the product was extracted with Et 2 0 (3 x 15 mL). The combined organic extracts were washed with brine (15 mL), dried (Na2SO 4 ) and the volatiles were removed under reduced pressure (bath temperature not exceeding 20 *C). The residue was purified by flash column chromatography (SiO2, 0 = 4 cm, H = 15 cm, 1% Et 3 N) eluting with 60 -4 70% Et 2 0 in petroleum ether (40-60). Evaporation of the fractions afforded thioester 3 as a white syrup (1.74 g, 92%) that solidified upon storage at 4 *C. Rf= 0.35 (70% Et 2 O in petroleum ether (40-60)); 'H-NMR (300 MHz, CDCl 3 ) 1.16 (s, 6H, 2 x CH 3 ), 3.02 (t,J 6.0, 2H, CH 2 S), 3.09 (s, 2H, CH 2 O), 3.66 (t, J6.0, 2H, CH 2 OH), 3.72 (s, 6H, 2 x OCH 3 ), 6.74-6.78.(m, 4H, PhCH), 7.09 7.36 (stack, 8H, PhCH); 3 C-NMR (75 MHz, CDCl 3 ) 22.9 (CH 3 , 2 x CH 3 ), 31.7 (CH 2 ,

CH

2 S), 51.0 (quat. C, C(CH;) 2 ), 55.2 (CH 3 , 2 x OCH 3 ), 61.9 (CH2, CH 2 OH), 70.0 (CH2, CH20), 85.8 (quat. C., CPh 3 ), [113.0 (CH, Ph), 126.7 (CH, Ph), 127.7 (CH, Ph), 128,2 (CH, Ph), 130.1 (CH, Ph), some overlap], [135.9 (quat. C, Ph), 144,8 (quat. C, Ph), 158.4 (quat. C, Ph), some overlap], 205.0 (quat. C, C=0). Synthesis of H-phosphonate monoester 4:

NH

2 0NH PhO-P-OPh N N O OH H N N 0-P-OH - Et 3 N H20H 80% 4 [004171 p-L-ddA (1.00 g, 4.25 mmol) was co-evaporated with anhydrous pyridine (3 x 10 mL) and then dissolved in anhydrous pyridine/DMF (1/1, v/v, 21 mL). Diphenyl phosphite (5.76 mL, 29.8 mmol) was then added dropwise to this solution at room temperature. The reaction mixture was stirred for 20 min upon which a mixture of Et3N/H 2 0 (1/1, v/v, 8.5 mL) was added dropwise, and stirring was pursued for an additional 20 min. The reaction mixture was concentrated under reduced pressure to approximately 15-20 mL and this residue was directly purified by flash column chromatography (SiO 2 , 0 = 4 cm, H = 15 cm, 1% Et 3 N) eluting slowly with CHzCl2 134 WO 2008/082601 PCT/US2007/026408 (150 mL) then 5% (200 mL) -+ 10% (200 mL) -> 15% (300 mL) MeOH in CH 2

CI

2 . Evaporation of the fractions afforded H-phosphonate monoester 4 as a white foam (1.36 g, 80%) that could be kept for several weeks at 4 *C. Rf= 0.10 (Et 3 N/MeOH/CH2CI2, 1/10/89); 'H-NMR (300 MHz, CDCI 3 ) 1.21 (t, J 7.4, 9H, 3 x

NCH

2

CH

3 ), 1.92-2.50 (stack, 4H, 2 x 2'-H, 2 x 3'-H), 3.02 (q, J 7.4, 6H, 3 x

NCH

2 CH3), [3.96-4.03 and 4.18-4.30 (stacks, 3H, 4'-H, 2 x 5'-H), 6.28 (m, l'-H), 6.91 (d, J623, 1H, P-H), 7.05 (br s, 2H, NH 2 ), 8.21 (s, IH), 8.54 (br s, IH, OH), 8.57 (s, I H). Synthesis of phosphoramidate diester 5 MeO

NH

2 N

NH

2 / N OH*EtN1. 3, PyBOP N, COT H 2. CC 4 , BnNH 2 N N O p- O e 4 5. used as a crude [004181 H-Phosphonate monoester 4 (1.03 g, 2.57 mmol) and alcohol 3 (1.66 g, 3.45 mmol ) were co-evaporated with anhydrous pyridine (3 x 5 mL) and then dissolved in anhydrous pyridine (5 mL). PyBOP (I H-benzotriazol-1 yloxytripyrrolidinophosphonium hexafluorophosphate, 1.60 g, 3.08 mmol) was then added in one portion and the reaction mixture was stirred for 15 min at room temperature. The solution was poured over saturated aqueous NaHCO3 solution (30 mL) and the product was extracted with CH 2 C1 2 (4 x 15 mL). The combined organic extracts were washed with brine (10 mL), dried (Na 2

SO

4 ) and concentrated under reduced pressure to leave the corresponding H-phosphonate diester as a slightly yellow oil (1.84 g, assuming 2.41 mmol). This was co-evaporated with anhydrous pyridine (3 x 5 mL; note: do not evaporate to dryness in order to help further solubilization), and the residue was dissolved in anhydrous CCL4 (24 mL). Benzylamine (791 tL, 7.23 mmol) was added dropwise and the reaction mixture turned cloudy instantly (slight heat development was observed). The milky solution was stirred for I h at room temperature and poured over saturated aqueous NaHCO 3 solution (30 mL) and the product was extracted with CH 2

C

2 (4 x 15 mL). The combined organic extracts were washed with brine (15 mL), dried (Na 2

SO

4 ) and concentrated under reduced pressure to afford phosphoramidate diester 5 as a yellow 135 WO 2008/082601 PCT/US2007/026408 oil (2.00 g, assuming 2.31 mmol). This was used in the next step without any further purification. Rf = 0.29 (4% MeOH in CH 2

CI

2 ); 1 H-NMR (300 MI-z, CDCI,) 1.11 (s, 6H, 2 x CH 3 ), 1.91-2.05 (m, 2H), 2.31-2.59 (m, 2H), 3.06 (m, 2H, CH 2 S), 3.08 (s, 2H,

CH

2 0DMTr), 3.69 (s, 6H, 2 x OCH), 3.83-4.28 (stacks, 7H, CH 2 0, NCH 2 Ph, 4'-H, 2 x 5'-H), 5.71 (br s, 1H, NH), 6.18 (in, IH, l'-H), 6.69-6.80 (in, 4H, PhCH), 7.02-7.31 (stack, 13H, PhCH), 7.90 (s, 1H), 8.01 (s, IH), 8.23 (s, 2H, NH 2 ); "P-NMR (61 MHz, CDCl 3 ) 8.82, 8.99. Synthesis of NM204 (A550), the Hydroxy-iBuSATE N-benzylphosphoramidate derivative of L-ddA: NH2 dioxanel NH 2 "> 0 H 2 00 0 H N Me 35 eps o HN6 5 (Crude) NM 204 (purifned and iyophixed) 100419] Crude phosphoramidate diester 5 (2.00 g, assuming 2.31 mmol) was dissolved in dioxane/AcOH/H 2 0 (25/17/25, v/v/v, 462 mL) and the solution was stirred for 3 d at room temperature. Evaporation of the volatiles under reduced pressure left a residue that was purified by flash column chromatography (SiO2, 0 3 cm, H = 15 cm) eluting with CH 2 C1 2 (100 mL) then 2% (100 mL) -+ 4% (100 mL) -+ 6% (100 mL) -+ 8% (150 mL) MeOH in CH 2 C1 2 . Evaporation of the fractions left NM 204 as a white foam that was dissolved in MeCN (5 mL). Upon addition of H20 (5 mL), the solution turned turbid and required sonication before lyophilization. The resulting white powder was dried at room temperature (using P 2 0 5 as a desiccant) under vacuum for I d. The title compound was obtained as a highly hygroscopic white powder (1:1 mixture of diastereoisomers as judged by " P-NMR; 499 mg, 35% over 3 steps). (a]20= + 4.20 (c 1.0, CHC1 3 ) ; Rf= 0.29 (4% MeOH in CH 2 CI2); 'H NMR (300 MHz, DMSO-d6) 1.10 (s, 6H, 2 x CH), 2.02-2.14 (m, 2H, 2 x 3'-H), 2.41-2.55 (m, 2H, 2 x 2'-H), 3.01 (t, J6.4, 2H, CH 2 S), 3.43 (d,J 5.0, 2H, CH 2 OH), 3.75-4.07 and 4.18-4.29 (stacks, 7H, CH 2 0, NCH 2 Ph, 4'-H, 2 x 5'-H), 5.02 (t, J 5.0, 1H, O), 5.62 (m, I H, NH), 6.25 (t, J5.1, 1 H, l'-H), 7.16-7.36 (stack, 7H, PhH,

NH

2 ), 8.14 (s, I H), 8.26 (s, IH); "C-NMR (75 MHz, DMSO-d6)21.8 (2 x CH 3 ), 25.9 and 26.0 (CH 2 , 3'-C), 28.2 and 28.3 (CH 2 , CH 2 S), 30.9 and 31.0 (CH 2 , 2'-C), 44.2 136 WO 2008/082601 PCT/US2007/026408

(CH

2 , NCH 2 Ph), 51.7 (quat. C, C(CH 3

)

2 ), 63.7 and 63.8 (CH2, CH 2 0), 66.8 (CH 2 , m, 5'-C), 68.3 (CH 2 , CH20H), 78.9 (CH, m, 4'-C), 84.2 (CH, l'-C), 118.9 (quat. C), [126.5 (CH, Ph), 127.2 (CH, Ph), 128.1 (CH, Ph), some overlap], 138.8 and 138.9 (CH), 140.5 and 140.6 (quat. C), 148.9 (quat. C), 152.3 (CH), 155.0 (quat. C), 204.0 (quat. C, C=0); "P-NMR (61 MHz, DMSO-d6) 9.86, 9.95; m/z (FAB') 563 (2), 306 (76), 153 (100); HRMS 565.2034 ([M+H]*. C 24

H

3 4 0 6

N

6 PS requires 565.1998); HPLC t R = 3.52 min (20% TEAC 20 mM in MeCN); UV (EtOH 95%) mx = 259 (ema 15900), Xmin = 224 (cmin 7200). Preparation of B102, the Hydroxy-IBuSATE N-benzylphosphoramidate derivative of 2'-C-methylcytidine:

NH

2 HO N 0 NH H H B102 PROCEDURE A: Synthesis of H-phosphonate monoester 5 H TrT T TrT Tnc..,f4 NaCHEq 30%. M ) CD 001. Mtoune 0CM. NEI, lon2) MS(CHalOM 2 9 At 1) HPO, pyrdIn 2) TEAB IM Synthesis of carboxylic acid 3: 1004201 To a stirred solution of 2,2-dimethyl-3-hydroxypropanoic acid methyl ester (_, 15 ml, 117.6 mmol) in a mixture of anhydrous methylene chloride (590 ml) and triethylamine (23 ml), were added triphenylmethylene chloride (1.2 eq, 39.3 g) and 4-dimethylaminopyridine (0.1 eq, 1.44 g). The reaction mixture was left refluxing 137 WO 2008/082601 PCrfUS2007/026408 overnight. The mixture was poured carefully over a saturated aqueous NaHCO 3 solution and the product was extracted with methylene chloride and washed with water. The combined organic extracts were evaporated under reduced pressure to give crude compound 2 which will be used for the next step without further purification. The resulting oil was dissolved in a mixture of dioxan (350 ml) and an aqueous solution of NaOH (30%, 350 ml). The heterogene mixture was refluxed for 16 hours. The reaction mixture was allowed to cool down to room temperature, the two phases were separated, and the organic phase carefully neutralized by dropwise addition of HCI (1 M). The product was extracted with methylene chloride and the organic phases were evaporated under reduced pressure. The crude orange oil was recrystallized from methylene chloride to afford carboxylic acid 3 as white crystals (92%). R 1 = 0.50 (70% diethyl ether in petroleum ether); 'H-NMR (400 MHz, CDC 3 ) 1.24 (s, 6H, 2 x CHi), 3.19 (s, 2H, CH 2 0), 7.2-7.5 (m, 15H, C 6

H

5 ). Synthesis of H-phosphonate monoester 5: 1004211 1,1'-carbonyldiimidazole (1.3 eq, 1.17 g) was added to a stirring solution of carboxylic acid 3 (2 g, 5.56 mmol) in an anhydrous mixture of toluene and dimethylformamide (2/1, v/v, 4.5 ml) at room temperature, and the reaction mixture turned turbid instantly. After 30 min, the reaction mixture was diluted with a mixture of toluene and dimethylformamide (93/7, v/v, 28 ml), cooled to -10 *C, and 2 mercaptoethanol (1.3 eq, 500 pL) was added. The solution was stirred for 3 h at this temperature. The volatiles were removed under reduced pressure (bath temperature not exceeding 25 *C). The residue was dissolved in methylene chloride and washed with water. The organic phases were combined, dried over sodium sulphate (Na2SO4), filtered and evaporated to dryness to give compound 4 as a yellow oil. This compound will be coevaporated with anhydrous pyridine and used for the next step without further purification. Rf= 0.71 (70% Et 2 0 in petroleum ether); 'H-NMR (400 MHz,

CDC

3 ) 1.20 (s, 6H, 2 x CH 3 ), 3.05 (t, J= 6.4 Hz, 2H, CH 2 S), 3.15 (s, 2H, CH 2 OTr), 3.69 (t, J =6.4 Hz, 2H, CH 2 0H), 7.3-7.9 (m, 15H, C 6 HS). [004221 Phosphorus acid (10 eq, 4.1 g) was coevaporated two times with anhydrous pyridine, dissolved in that solvent (25 ml) and added to crude 4. The reaction mixture was stirred at room temperature and a white precipitate appeared after few minutes. The reaction mixture was cooled down to 0 *C and pivaloyl chloride (5.5 eq, 3.4 ml) was added. The reaction mixture was allowed to warm to 138 WO 2008/082601 PCT/US2007/026408 room temperature and stirred for 3h. The reaction was stopped by addition of a solution of triethylammonium bicarbonate (TEAB I M, 10 ml) and diluted with ethyl acetate (EtOAc). After extraction with EtOAc and TEAB 0.5M, the organic phases were combined, dried over sodium sulphate, filtered and evaporated to dryness (bath temperature not exceeding 30 *C). The residue was purified by flash column chromatography eluting with 10% of methanol in methylene chloride + 1% triethylamine. Evaporation of the fractions afforded the H-phosphonate monoester 5 as a white syrup (90%). Rf= 0.25 (70% Et 2 O in petroleum ether); 'H-NMR (400 MHz, CDC 3 ) 1.17 (in, 2 x CH 3 + excess (CH 3

CH

2

)

3 N), 2.9 (m, excess (CH 3

CH

2

)

3 N), 3.12 (t, J= 6.8 Hz, 2H, CH 2 S), 3.37 (s, 2H, CH 2 OTr), 3.90 (m, 2H, CH 2 OP), 7.2-7.6 (in, 15H, C 6 Hs), 9.9 (m, excess (CH 3

CH

2

)

3 NH); 3 P-NMR (161 MHz, CDC 3 ) 3.85 (s). Synthesis of B102, the Hydroxy-IBuSATE N-benzylphosphoramidate derivative of 2'-C-methylcytidine: The following two strategies were used: Strategy a Synthesis of the protected nucleoside 7 N4 N NH H 1) TMSCt, pyidne pT5A 2) OmTtC I OMAP rO 3 NH40H 29% 1 MOMu [004231 A mixture of 2'C-methylcytidine (NMI07) (10 g, 39.0 mmol), triethyl orthoformate (8.3 eq, 54 ml) and p-toluenesulfonic acid monohydrate (1 eq, 7.4 g) in anhydrous acetone (650 ml), was refluxed overnight under nitrogen atmosphere. The reaction mixture was neutralized with an aqueous ammonia solution (26%) and the precipitate filtered. The filtrate was evaporated under reduced pressure and coevaporated with ethanol. Purification of the crude mixture on silica gel column chromatography (eluant: stepwise gradient [0-10%] of methanol in methylene chloride) led to compound 6 as a pale-yellow solid (86%). R 1 = 0.30 (20% MeOH in methylene chloride), 'H-NMR (400 MHz, DMSO-d 6 ) 1.06 (s, 3H, CH 3 ), 1.33 (s, 3H,

CH

3 ), 1.47 (s, 3H, CH 3 ), 3.6 (m, 2H, H-5', H-5"), 4.1 (m, IH, H-4'), 4.41 (d, IH, H 3', J= 3.2 Hz), 5.16 (t, I H, OH-5', J = 4.0 Hz, D 2 0 exchangeable), 5.69 (d, IH, H-5, 139 WO 2008/082601 PCT/US2007/026408 J= 8.0Hz), 6.04 (s, IH, H-i'), 7.14-7.19 (bd, 2H, NH 2 , D 2 0 exchangeable), 7.74 (d, I H, H-6, J = 8.0 Hz); LC/MS Scan ES- 296 (M-H)', Scan ES+ 298 (M+H)*, m." 280.7 nm. 1004241 Compound 6 (4.4 g, 14.8 mmol) was dissolved in anhydrous pyridine (74 ml) and chlorotrimethylsilane (3 eq, 5.4 ml) was added. The reaction mixture was stirred at room temperature under nitrogen atmosphere for 2h, then 4,4' dimethoxytrityl chloride (1.5 eq, 7.5 g) and 4-dimethylaminopyridine (0.5 eq, 900 mg) were successively added. The reaction mixture was stirred overnight at room temperature, then quenched with a saturated aqueous NaHCO 3 solution. The crude product was extracted with methylene chloride, washed with saturated aq NaHCO 3 solution, and water. The combined organic phases were concentrated under reduced pressure, then dissolved in a mixture of dioxan (160 ml) and aqueous ammonia (28%, 29 ml). The solution was heated at 70*C for 3h and evaporated to dryness. The crude mixture was purified on silica gel column chromatography (eluant: stepwise gradient of methanol [1-5%] in methylene chloride) to give protected nucleoside 7 as a yellow solid (81%). Rf =0.16 (30% EtOAc in CH2CI 2 ) 'H-NMR (400 MHz, DMSO-do) 1.03 (s, 3H, CH 3 ), 1.30 (s, 3H, CH 3 ), 1.42 (s, 3H, CH), 3.5 (m, 2H, H-5', H-5"), 3.71 (s, 6H, 2 x OCH 3 ), 4.0 (d, I H, H-4', J= 3.2 Hz), 4.36 (d, 1 H, H-3', J= 2.8 Hz), 5.1 (m, IH, OH-5', D 2 0 exchangeable), 5.90 (s, IH, H-i'), 6.2 (m, 1H, H-5), 6.8-7.2 (m, 13H, DMTr), 7.6 (m, IlH, H-6), 8.32 (s, IH, NH, D 2 0 exchangeable) ; LC/MS Scan ES- 598 (M-H)', XmaI= 231.7 nm, %m2 283.7 nm. Synthesis B102 (compound 10) NHVUr TfT N .HNEt3 r HDMTr H TN eq TFA0% Ha H H 140 WO 2008/082601 PCT/US2007/026408 100425] Compounds 7 (2.0 g, 3.34 mmol) and 5 (2.2 eq, 4.3 g) were coevaporated together with anhydrous pyridine and dissolved in this solvent (50 ml). Pivaloyl chloride (2.5 eq, I ml) was added dropwise and the solution stirred at room temperature for 2h30. The reaction mixture was diluted with methylene chloride and neutralized with an aqueous solution of ammonium chloride (Ni 4 C1 0.5M). After extraction with methylene chloride / aq NH 4 CI 0.5M, the organic phases were combined, evaporated under reduced pressure (bath temperature not exceeding 30 *C) and coevaporated with toluene. The crude mixture was purified on silica gel column chromatography (eluant: stepwise gradient [0-5%] of methanol in methylene chloride + 2*/.. acetic acid) to afford the desired product 8 which was coevaporated with toluene to give a beige foam (94%). Rf= 0.63 (5% MeOH in CH 2

C

2 ); 'H-NMR (400 MHz, CDCl 3 ) 1.21 (m, 9H, 3 CH 3 ), 1.42 (s, 3H, CH3), 1.60 (s, 3H, CH 3 ), 3.13 (in, 2H,

CH

2 S), 3.17 (m, 2H, CH 2 OTr), 3.79 (s, 6H, 2 x OCH 3 ), 4.1 (m, 2H, CH 2 OP), 4.2-4.3 (m, 3H, H-5', H-5", H-4'), 5.09 (d, I H, H-3', J= 7.6 Hz), 5.89 (d, IH, H-5, J 5.6 Hz), 6.0 (m, IH, H-I'), 6.8-7.7 (in, 29 H, Tr, DMTr, H-6); 3 P-NMR (161 MHz,

CDCI

3 ) 7.92, 8.55; LC/MS Scan ES+ 1066 (M+H)*, Scan ES- 1064 (M-H)'. 1004261 a solution of compound 8 (3.4 g, 3.15 mmol) in anhydrous carbon tetrachloride (30 ml) was added dropwise benzylamine (10 eq, 3.4 ml). The reaction mixture was stirred at room temperature for Ih30. A white precipitate appeared. The solution was diluted with methylene chloride and neutralized with an aqueous solution of hydrogen chloride (HCI I M). After successive extractions with CH 2

CI

2 / HCI 1 M and CH 2

CI

2 / aq NaHC0 3 , the organic phases were combined, dried over Na 2

SO

4 , filtered and evaporated to dryness. The crude mixture was purified on silica gel column chromatography (eluant: stepwise gradient [0-5%] of methanol in methylene chloride) to give 2 as a yellow foam (87%). Rf = 0.35 (5% MeOH in methylene chloride); 'H-NMR (400 MHz, CDCI 3 ) 1.1-1.2 (m, 9H, 3 CH 3 ), 1.40 (s, 3H, CH 3 ), 1.59 (s, 3H, CH 3 ), 2.9-3.2 (m, 4H, CH 2 OTr, CH 2 OS), 3.76 (s, 6H, 2 x

OCH

3 ), 3.9-4.4 (m, 8H, CH 2 OP, CH 2 N, H-3', H-4', H-5', H-5"), 5.0 (in, IH, H-5), 6.0 (2s, IH, H-I'), 6.7-7.7 (m, 34 H, Tr, DMTr, C 6 H5CH 2 , H-6); "P-NMR (161 MHz, CDCl 3 ) 8.40, 8.8.68; LC/MS Scan ES+ 1171 (M+H)*. 1004271 Finally, compound 9 (2.39g, 2.04 mmol) was dissolved in a mixture of methylene chloride (10 ml) and an aqueous solution of trifluoroacetic acid (90%, 10 ml). The reaction mixture was stirred at 35-40*C for 2h, then diluted with ethanol 141 WO 2008/082601 PCT/US2007/026408 (140 ml). The volatiles were evaporated under reduced pressure and coevaporated with ethanol. The crude mixture was purified by silica gel column chromatography (eluant: stepwise gradient of methanol [0-30%] in methylene chloride), followed by a purification on reverse phase chromatography (eluant: stepwise gradient of acetonitrile [0-50%] in water), to give the desired product 10 (B102) (1:1 mixture of diastereoisomers as judged by 31 P-NMR, 36%) which was lyophilized from a mixture of dioxan / water. Rf= 0.34 (15% MeOH in methylene chloride); 'H-NMR (400 MHz, DMSO-d6) 0.92 (s, 3H, CH 3 ), 1.10 (s, 6H, 2 x CH), 3.0 (m, 2H, CH 2 S), 3.33 (in, IH, H-3'), 3.56 (s, 2H, CH 2 OH), 3.8-4.0 and 4.05-4.25 (stacks, 7H, CH 2 OP,

NCH

2 Ph, H-4', H-5' and H-5"), 4.9 (m, I H, OH-3', J= 5.4 Hz, D 2 0 exchangeable), 5.07 (s, I H, OH-2', D 2 0 exchangeable), 5.3 (m, IH, CH 2 OH, D 2 0 exchangeable ), 5.6-5.7 (m, 2H, H-5 and NH, D 2 0 exchangeable), 5.91 (s, IH, H-i'), 7.3-7.4 (stack, 7H, PhH, NH. D 2 0 exchangeable), 7.6 (in, 1H, H-6); "P-NMR (161 MHz, DMSO d6) 9.71, 9.91; HPLC tR = 4.67 min (0-100% acetonitrile over a period of 8 min), Xm, 274.9; LC/MS Scan ES+ 587 (M+H)*. Strategy b: Synthesis of protected nucleoside 11 NH2 NHDMTr N N Ho o1) TMScI, pytdne H 2) DMTrC I D MAP H H 3) TAF IMIF H H NM107 U 93% 1004281 NM107 (10 g, 38.87 mmol) was dissolved in anhydrous pyridine (194 ml) and chlorotrimethylsilane (4.5 eq, 21.6 ml) was added. The reaction mixture was stirred at room temperature under nitrogen atmosphere for 2h30, then 4,4' dimethoxytrityl chloride (1.5 eq, 19.8 g) and 4-dimethylaminopyridine (0.5 eq, 2.37 g) were successively added. The reaction mixture was stirred overnight at room temperature, then quenched with a saturated aqueous NaHC03 solution. The crude product was extracted with methylene chloride, washed with saturated aq NaHCO 3 solution, and water. The combined organic phases were concentrated under reduced pressure, then dissolved in tetrahydrofuran (110 ml). To that solution was added tetrabutylammonium fluoride IM in THF (1 eq, 38.87 ml) and the reaction mixture was stirred for 30 min at room temperature. After extraction with EtOAc and water, 142 WO 2008/082601 PCT/US2007/026408 the organic phases were collected and evaporated to dryness. The crude mixture was purified on silica gel column chromatography (eluant: stepwise gradient of methanol [0-10%] in methylene chloride) to give protected nucleoside LI as a yellow solid (93%). Rf= 0.32 (10% MeOH in CH 2

CI

2 ) 'H-NMR (400 MHz, DMSO-d) 0.79 (s, 3H, CH 3 ), 3.56 (m, 2H, H-5', H-5"), 3.71 (s, 7H, 2 x OCH 3 , H-4'), 5.0 (m, 4H, H-3', OH-2',, OH-3', OH-5', D 2 0 exchangeable), 5.72 (s, IH, H-I'), 6.16 (m, IH, H-5), 6.8-7.2 (m, 13H, DMTr), 7.82 (m, 1 H, H-6), 8.24 (m, 1 H, NH D 2 0 exchangeable); LC/MS Scan ES- 560 (M+H)*, ES- 558 (M-H)', , = 284.7 nn. Synthesis of protected phosphoramidate pronucleotide L3, precursor of 10 DMT HOMTr H N Et 2 + H HW H HH 11 1k 37% CW. HDMTr a O TFAcHT2N 1004291 Compound 11 (7 g, 12.5 mmol) and _ (1.5 eq, 11.0 g) were coevaporated together with anhydrous pyridine and dissolved in this solvent (187 ml). Pivaloyl chloride (2.0 eq, 3.08 ml) was added dropwise at -I 5C and the solution stirred at this temperature for I h30. The reaction mixture was diluted with methylene chloride and neutralized with an aqueous solution of ammonium chloride (NH4CI 0.5M). After extraction with methylene chloride / aq NH 4 CI 0.5M, the organic phases were combined, evaporated under reduced pressure (bath temperature not exceeding 30 *C) and coevaporated with toluene. The crude mixture was purified on silica gel column chromatography (eluant: stepwise gradient [0-5%) of methanol in methylene chloride + 0.2% acetic acid) to afford the desired product 12 which was coevaporated with toluene to give a white foam (3.5 g, 27%). Rf= 0.44 (5% MeOH in CH 2 C1 2 ); 'H-NMR (400 MHz, DMSO) 0.8 (m, 3H, CH 3 ), 1.14 and 1.06 (2s, 6H, 2 CH), 3.06 (m, 2H, CH2S), 3.16 (m, 2H, CH 2 OTr), 3.5 (m, IH, H-3'), 3.70 (m, 6H, 2 OCH 3 ), 3.90 (m,, I H, H-4'), 4.03 (m, 2H, CH 2 0P), 4.24 (m, 2H, H-5', H-5"), 5.30 and 5.04 (2ms, 2H, OH-2' and OH-3', D 2 0 exchangeable), 5.78 (m, IH, H- '), 5.98 (m, 1H, P-H), 6.22 143 WO 2008/082601 PCT/US2007/026408 (I, IH, H-5), 7.0-7.5 (m, 16 H, Tr), 8.32 (m, 1H, H-6); "P-NMR (161 MHz, DMSO) 9.17, 9.65; LC/MS Scan ES+ 1026 (M+H)*, max= 282.7 n. 1004301 To a solution of compound 2 (500 mg, 0.49 mmol) in anhydrous carbon tetrachloride (4.9 ml) was added dropwise benzylamine (5 eq, 0.266 ml). The reaction mixture was stirred at room temperature for 3h and the solvent removed under reduced pressure. The crude mixture was purified on silica gel column chromatography (eluant: stepwise gradient [0-5%) of methanol in methylene chloride) to afford compound 13 as a foam (75%). Rf = 0.25 (3% MeOH in methylene chloride); 'H-NMR (400 MHz, DMSO) 0.79 (s, 3H, CH 3 ),1.13 and 1.06 (2s, 6H, 2

CH

3 ), 3.05 (m, 4H, CH 2 OTr, CH 2 OS), 3.51 (m, 1H, H-3'), 3.69 (s, 6H, 2 x OCH 3 ), 3.87 (m, 3H, CH 2 OP, CH 2 N, H-3'), 4.08 (m, 2H, H-5', H-5"), 5.19 and 5.0 (2m, 2H, OH-2' and OH-3', D 2 0 exchangeable), 5.67 (m, IH, NH, D20 exchangeable), 5.75 (2s, 1 H, H-i'), 6.21 (m, IH, H-5), 6.7-7.5 (m, 34 H, Tr, DMTr, C4 5

CH

2 , H-6); I 3

P

NMR (161 MHz, DMSO) 9.84, 9.69; LC/MS Scan ES+ 1132 (M+H)*. 100431] Compound 13 can be converted into the phosphoramidate prodrug 2 (B 102) following experimental conditions described for the last step in Examples 3 (Procedure A) and in Example 4. PROCEDURE B: NH, Phi8(oH)z NMfi 2.hTE~ distil azeotfopo HO -95% 14 I PhB(OH) 2 MMD Na 2

SO

4 2 82*C, 3h 2 1. EOC1. MeCN 40*C. 1.5h 2. BnNH2. CC4 -W0% rorn 3 RT, 1h 3. Citric Acid work up NHaI EtOH 0 8 "c. 25-30min N 4ys 1 NH -65% 6102 SYNTHETIC SCHEME: 144 WO 2008/082601 PCT/US2007/026408 1004321 B 102 is synthesized as a mixture of phosphorous diastereomers in 1:1 ratio. Isolated overall yield from NMI07 to B102 was 31%, as not all the coupled material produced was used for deprotection. Step 1.1: NH 2 NH2 IN NH n ~o o, o HO OH NM107 2 Material Grade .e Quantity nsity Amount Eq NM107 99% 257.2 150g - 0.583 1 PhB(OH)2 98% 122.1 78g - 0.639 1.10 Pyridine anhydrous 98% 79.1 2.51 0.978 - 1004331 NM107 was dissolved in pyridine under argon and benzeneboronic acid was added. The stirred mixture was heated at reflux for 3h under argon. Distillation of the azeotrope was then performed, removing 1.2L (pyridine/water). T head: 103*C + 113 0 C T mixture : 112*C + 116 0 C The mixture was cooled to room temperature and the pyridine was evaporated under vacuum to get golden oil. The product was stored under vacuum overnight to be used for the next step. A ratio of 97:3 product:starting material was observed by I H-NMR (d6-DMSO). Prior to Step 1.2, the crude was dissolved in 250mL anhydrous pyridine. Alternatively the following conditions may be used: - eq benzeneboronic acid - 5 eq pyridine - 1.5 eq Na2SO4 - 5mL CH 3 CN for Ig of NM107 - Heat at reflux for lh-1h30. Cool to RT. Used for next reaction. - 98-99% of conversion by proton NMR Step 1.2: 145 WO 2008/082601 PCTIUS2007/026408

NH

2 Hoo E -g TrtoN HO 0N0T o t H NNXLO 0 3S,-0 P o --. S ", NH* 2 4Hd 6H FW Density Amount Material Grade Quantity Eq gmor' gmr mol 2,3-PhB-NM107 343.1 Solution -0.583 1 Phosphonate 3 - 585.7 615g - 1.049 1.8 EDCI.HCI 98% 191.7 570g - 2.973 5.1 Acetonitrile anhydrous 98% - 3L Benzylamine 98% 107.2 445mL 0.98 4.0 Carbon tetrachloride 98% 153.8 260mL 1.59 2.6 4* *Extra equivalents of these reagents may be added (e.g. l5eq) if required (if P-OH visible by HPLC) 1004341 Phosphonate 3 was dissolved in 3L of acetonitrile under argon. A solution of 2,3-PhB-NMI07 from Step 1.1 was added followed by EDCI.HCI. The mixture was stirred under argon at 41-46 C for 4h after which time HPLC analysis indicated -7:1 ratio of P-H product to NMI07. The mixture was cooled to 18 *C and benzylamine was added dropwise followed by carbon tetrachloride. The reaction was slightly exothermic. Analysis by HPLC indicated complete conversion of P-H to phosphoramidate product. Ethyl acetate (I L) was added to the mixture which was then acidified to pH 4 with 3L of 20% citric acid. The aqueous phase was extracted with 2.5L of ethyl acetate. The organic phases were combined and washed with 3L of 10% citric acid. The organic phase was basified to pH 8 with 5L of aqueous sodium bicarbonate (saturated) and washed a second time with 2L of aqueous sodium bicarbonate (saturated). The organic phase was dried over sodium sulfate, filtered under vacuum and evaporated to give a yellow foam, 712g. [00435] The crude residue was dissolved in dichloromethane (IL) and purified on silica plug (2.3Kg of silica). Eluted with: 5L 4% Methanol / DCM, 2*1 L4%, 3*1L 5%, 8*250mL 6%, 4250mL 7%, 9*1L 7%. Evaporation of the relevant fractions gave 25 4 g (HPLC purity: 98.5%, yield: 52%) and 73 g (HPLC purity: 87.6%, yield: 13%) of phosphoramidate 4. 146 WO 2008/082601 PCT/US2007/026408 Step 2:

NH

2

NH

2 TNo HO 0 a0 6, 0OON N 0 s H ,P-s N 4 o H bH 5 H OH Material Grade ot Quantity mount Eq Igmr Mel Phosphoramidate 4 828.9 246g - 0.291 1 AcCI 99% 78.5 62.6mL 1.105 1.049 3.0* EtOH anhydrous 98% - 3.5L* *Subsequently 2.0eq AcCI and 1:10 w/v 4:EtOH ratio were used. 1004361 Phosphoramidate 4 was dissolved in anhydrous ethanol and acetyl chloride was added (exothermic: 18*C to 27*C) to the reaction mixture, under argon. The mixture was stirred at 60*C under argon. After 30min, HPLC analysis indicated complete conversion of the phosphoramidate 4 to deprotected product 5. The mixture was cooled to 25*C and solid sodium bicarbonate (1.04Kg) was added in several portions (foaming, pH -5.5-6). The mixture was filtered through Celite and washed with two volumes of ethanol. The filtrate was evaporated under vacuum at 35*C. The residue was triturated with TBME (3L) for lh and then filtered to remove the trityl by-product. The solid obtained was dried under vacuum to give 185g with 93% purity at 254nm by HPLC. If required, any residual benzeneboronic acid may be removed from the product by dissolution in water and treatment with Amberlite IRA-743 resin. The following alternative reaction conditions (to avoid the possibility of acylating 4) are possible: - 2.Oeq AcCl in EtOH 1:10 v:v to generate HCI and consume all AcCl (exothermic) - Phosphoramidate 4 in EtOH (to make 1:10 w:v total volume EtOH) - Add HCI/EtOH solution to reaction mixture at 20 0 C - 60 0 C under argon, 30-45min 147 WO 2008/082601 PCT/US2007/026408 The crude was purified by reverse-phase chromatography (1.5Kg of prepared Bakerbond 40pm C-18 RP-silica - washed with 100% acetonitrile gradient to 100%

H

2 0). The crude was dissolved in acetonitrile (58mL), H 2 0 (I64mL) and saturated aqueous sodium bicarbonate solution (1 70mL). Elution under gentle vacuum with a stepwise gradient of 3% MeCN / H20, 10%, 15%, 25% (pure product eluted) and evaporation of the relevant fractions gave 106g B102 (62% yield) with 98.6% purity at 254nm by HPLC. Typical analytical data is shown below: B102: C 24

H

35

N

4 0 9 PS 586.59gmol~ HPLC AUC (Method Test 20): 98.9% @ 254nm, Rt 3.34min m/z (ESI +): 587.12 [M+H]* 100%; 1173.62 [2M+H]* 80% VmIX (KBr disc) (cm'): 3343.1 br (0-H, N-H); 1647.2 br (C=0 base, thioester) KF: 2.02% H20 content Specific Rotation: [a]oD 20 +55.011 (c. 10.492mg cm-3 in DMSO) Elemental analysis: Calculated: C 49.14%; H 6.01%; N 9.55%; S 5.47%; P 5.28%; Found: C 48.74%; H 5.83%; N 9.41%; S 5.81%; P 5.33% NMR: Analyzed using 'H, 1 3 C, 3 1 P, COSY, DEPT, HSQC and HMBC experiments. 'H NMR 8H (400 MHz, d6-DMSO): 0.94 (3H, d, J 1.8Hz, CH 3 ), 1.11 (6H, s,

(CH

3 )2C), 3.04 (2H, m,'J 6.4Hz, CH 2 S), 3.44 (2H, d, J 5.0Hz, CH 2 OH), 3.60 (lH, br-m, H-3'), 3.82-4.01 (5H, m, H-4', CH 2 0, CH 2 Ph), 4.07-4.12 (IH, m, H-5'), 4.13-4.24 (11H, m, H-5"), 4.94 (1 H, t, J 5.0Hz, CH 2 OH), 5.07 (1H, d, J 1.8Hz, OH-2'), 5.26 (1H, t, J6.8Hz, OH-3'), 5.64-5.76 (1H, m, P-N-H), 5.69, 5.70 (1 H, 2 x d, 2 x J7.6Hz, H-5), 5.93 (1 H, br-s, H-l'), 7.13-7.20 (2H, 2 x br-s, NH 2 ), 7.20-7.25 (1H, m, Ar-H), 7.28-7.35 (4H, m, 4 x Ar-H), 7.53, 7.57 (1H, 2 x d, J7.6Hz, H-6) 3 C NMR Sc (100 MHz, d6-DMSO): 19.81 (CH3), 21.79 (C(CH3)2), 28.17, 28.24 (CH 2 S), 44.18 (PhCH 2 ), 51.62 (C(CH 3 )2), 63.74, 63.79 (CH 2 0), 64.21, 64.51 (C-5'), 68.29 (CH 2 OH), 72.41, 72.57 (C-3'), 77.80, 77.85 (C-2'), 79,47, (C-4'), 91.66, (C-I'), 93.82 (C-5), 126.68, 127.09, 128.08, 128.09 (5 x Ar-C), 148 WO 2008/082601 PCT/US2007/026408 140.34, 140.38, 140.40 (Ar-Cio 0 , C-6), 155.12, 165.21 (C-2, C-4), 203.85 (C=OS) " P NMR 8p (162 MHz, d6-DMSO): 9.71, 9.91 (iP, 2 x s, ratio 1.00:1.07) 100437] Synthetic Procedure A can be used for synthesizing nucleoside prodrugs such as B 102. Protection of the 2' and 3' hydroxyl groups as well as the amino group that may be present on the nucleoside base is preferred. In Strategy A, the 2' and 3' hydroxyl groups are protected, e.g., as the acetonide derivative and the amino group is protected, e.g., as the di-methoxytrityl derivative. Hydrolysis of the acteonide after the coupling of the nucleoside with the SATE intermediate is carried out using an acid such as TFA. This hydrolysis procedure can potentially produce by-products and give low yields, and the di-methoxytrityl chloride is disadvantageously expensive. Synthetic Procedure B, below, can overcome the such difficulties. An acid, such as a boronic acid, such as phenyl boronic acid is used to protect the 2' and 3' hydroxyl groups on the sugar moiety. Coupling the nucleoside phenyl boronate derivative with the SATE intermediate can give good yield, and the phenyl boronate deprotection conveniently takes place during the work-up of the reaction mixture, on washing with an acid such as an aqueous citric acid solution. The final removal of a protecting group such as a trityl group (on the Sate moiety) is mildly carried out using an organic solvent system, such as an acetyl chloride/ethanol mixture. This deprotection reaction can be consistently reproducible, scalable and gave significantly high yield. Preparation of B299, the Hydroxy-tBuSATE N-benzylphosphoramidate derivative of 2'-C-methylguanosine HNO 0 JK ~ ~ 1 sCH 0 0 .. j N A S NH NH 2 OH OH B299 PROCEDURE A: SYNTHETIC SCHEME: 149 WO 2008/082601 PCT/US2007/026408 ?N TrO Bertzy mrIns. HOO Ho HA c Tc2 ~NH HO N 0 .4H OH2 100438] 2'-C-methylguanosine (NM108) (3 g, 10.10 mmol) and compound 5 [for the synthesis of5, See Example 2] (6.48 g, 11.10 mmol) were coevaporated together with anhydrous pyridine and dissolved in this solvent (152 mL). Pivaloyl chloride (2.48 mL, 20.18 mmol) was added dropwise at -15*C and the solution was stirred at the same temperature for 2h. The reaction mixture was diluted with methylene chloride and neutralized with an aqueous solution of ammonium chloride (NH4CI 0.5M). After extraction with methylene chloride / aq NH 4 CI 0.5M, the organic phases were combined, dried over Na 2

SO

4 evaporated under reduce pressure (bath temperature not exceeding 30*C) and coevaporated twice with toluene. The crude mixture was purified on silica gel flash column chromatography (eluant : stepwise gradient [0-10%] of methanol in methylene chloride + 0.2% acetic acid) to afford the desired product 6 (2.5 g, 32%). Rf =0.34 (15% MeOH in CH 2 C1 2 ); 'H-NMR (400 MHz, DMSO-d 6 0.80 (s, 3H, CH 3 ), 1.13 (s, 6H, 2 x CH 3 ), 3.04 (m, 2H, CH 2 OTr), 3.14 (m, 2H, CH2S), 3.97-4.08 (m, 4H, H-3', H-4', CH 2 0P), 4.28-4.38 (m, 2H, H-5', H 5"), 5.10-5.35 (m, 2H, OH-2', OH-3', D20 exchangeable), 5.77 (s, I H, H-I'), 6.52 (bs, 2H, NH 2 , D 2 0 exchangeable), 7.11-7.42 (m, 15H, Tr), 7.75 (s, IH, H-8), 10.67 (bs, IH, NH, D 2 0 exchangeable); 1 3 P-NMR (161 MHz, DMSO-d 6 ) 9.47, 9.20; LC/MS Scan ES+ 764 (M+H)*, Scan ES- 762 (M-H)'. [004391 To a solution of compound 6 (2.5 g, 3.27 mmol) in anhydrous carbon tetrachloride (33 mL) was added dropwise benzylamine (5 eq, 1.79 mL). The reaction mixture was stirred at room temperature for I h and evaporated under reduced pressure (bath temperature not exceeding 30*C). The crude mixture was purified on silica gel flash column chromatography (eluant: stepwise gradient [0-10%] of methanol in methylene chloride) to give compound 7 as a white foam (2.9 g, quantitative yield). 150 WO 2008/082601 PCT/US2007/026408 Rf = 0.27 (10% MeOH in methylene chloride); 'H-NMR (400 MHz, DMSO-d 6 ) 0.81 (s, 3H, CH 3 ), 1.10 (s, 6H, 2 x CH 3 ), 2.99-3.08 (m, 4H, CH 2 OTr, CH 2 S), 3.87-4.30 (m, 8H, H-3', H-4', H-5', H-5 " CH 2 OP, NCH 2 Ph), 5.66 (m, I H, NH, D 2 0 exchangeable), 5.76 (s, I H, H-I'), 6.60 (bs, 2H, NH 2 , D 2 0 exchangeable), 7.17-7.39 (m, 20H, Tr,

C

6

H

3

CH

2 ), 7.77 (s, IH, H-8); "P-NMR (161 MHz, DMSO-d 6 ) 9.93, 9.78; LC/MS Scan ES+ 869 (M+H)*, Scan ES- 867 (M-H)~. 1004401 Compound 7 (2.84 g, 3.27 mmol) was dissolved in a mixture of trifluoroacetic acid (1.1 mL) and methylene chloride (11.4 mL). The reaction mixture was stirred 0.5h at room temperature. The solution was diluted with ethanol, evaporated under reduce pressure (bath temperature not exceeding 30*C) and coevaporated twice with toluene. The crude mixture was purified on silica gel flash column chromatography (eluant : stepwise gradient [0-30%] of methanol in methylene chloride) and then, on reverse phase column chromatography (eluant: stepwise gradient [0-100%] of acetonitrile in water) to give the desired product 8 (B299) (1:1 mixture of diastereoisomers according to "P-NMR, 800 mg, 39%) which was lyophilized from a mixture of dioxan / water. Rf = 0.57 (20% MeOH in methylene chloride); 'H-NMR (400 MHz, DMSO-d6) 0.82 (s, 3H, CH 3 ), 1.09 (s, 6H, 2 x CH), 3.01 (m, 2H, CH 2 S), 3.42 (d, 2H, CH2OH, J= 8.0 Hz), 3.81-4.00 (m, 6H, H-3', H-4' CH 2 OP, NCH 2 Ph), 4.11-4.27 (m, 2H, H-5', H-5"), 4.92 (t, 1H, CH 2 OH, J = 8.0 Hz, D 2 0 exchangeable), 5.16 (s, IH, OH-2', D 2 0 exchangeable), 5.40 (m, I H, OH-3', D 2 0 exchangeable), 5.64 (m, IH, NH, D 2 0 exchangeable), 5.75 (s, IH, H 1'), 6.50 (bs, 2H, NH 2

D

2 0 exchangeable), 7.19-7.32 (m, 5H, PhH), 7.77 (s, IH, H 8), 10.61 (bs, IH, NH, D 2 0 exchangeable); "P-NMR (161 MHz, DMSO-d6) 9.91, 9.78; HPLC tR = 3.67 min (0-100% acetonitrile over a period of 8 min), X,,,,= 251.3; LC/MS Scan ES+ 627 (M+H)*, Scan ES- 625 (M-H)'. 151 WO 2008/082601 PCT/US2007/026408 Preparation of B208, the Hydroxy-tBuSATE N-benzylphosphoramidate derivative of 2'-C-methylthymidine HO N NH S vN 0 OH OH B208 SYNTHETIC SCHEME: TrTO NH o-- -- - o'HN'Et, TrTO H HO 0 HH 0 H pyr, PI Benzylamine, H O O TF A T rTO N H 0 N H9 6NHN0 H34/- OH OH H OH 1004411 2'-C-Methylthymidine (NM105) (700 mg, 2.57 mmol) and 5 [for the synthesis of 5, See Example 2] (1.1 eq, 1.6 g) were coevaporated together with anhydrous pyridine and dissolved in this solvent (40 ml). Pivaloyl chloride (2.0 eq, 0.63 3 ml) was added dropwise at -I 5*C and the solution stirred at this temperature for Ih30. The reaction mixture was diluted with methylene chloride and neutralized with an aqueous solution of ammonium chloride (N-l 4 Cl 05M). After extraction with methylene chloride / aq N-4Cl 0.5M, the organic phases were combined, evaporated under reduced pressure (bath temperature not exceeding 30 *C) and coevaporated with toluene. The crude mixture was purified on silica gel column chromatography (eluant: stepwise gradient [0- 10%] of methanol in methylene chloride + 0.2% acetic 152 WO 2008/082601 PCT/US2007/026408 acid) to afford the desired product 6 which was coevaporated with toluene to give a white foam (942 mg, 50%). Rf= 0.56 (15% MeOH in CH 2

CI

2 ); 'H-NMR (400 MHz, DMSO) 1.00 (s, 3H, CH 3 ), 1.13 (s, 6H, 2 CH 3 ), 1.77 (s, 3H, CH 3 ), 3.16 (in, 2H,

CH

2 S), 3.32 (m, 2H, CH 2 OTr), 3.6 (in, 1H, H-3'), 3.9 (in, IH, H-4'), 4.0 (in, 2H,

CH

2 0P), 4.2-4.3 (in, 2H, H-5', H-5"), 5.21 (s, 1H, OH-2', D 2 0 exchangeable), 5.40 (t, 1H, OH-3', D 2 0 exchangeable), 5.83 (s, 1 H, H-I'), 6.0 (s, I H, P-H), 7.0-7.5 (m, 16 H, Tr, H-6); 3 P-NMR (161 MHz, DMSO) 9.29, 9.68; LCIMS Scan ES+ 761 (M+Na)*. 1004421 To a solution of compound 6 (920 mg, 1.25 mmol) in anhydrous carbon tetrachloride (13 ml) was added dropwise benzylamine (10 eq, 1.4 ml). The reaction mixture was stirred at room temperature for 2h. A white precipitate appeared. The solution was diluted with methylene chloride and neutralized with an aqueous solution of hydrogen chloride (HCl IM). After successive extractions with CH 2

CI

2 / HCI IM and CH 2

CI

2 / aq NaHCO 3 , the organic phases were combined, dried over Na 2 SO4, filtered and evaporated to dryness. The crude mixture was purified on silica gel column chromatography (eluant: stepwise gradient [0-10%] of methanol in methylene chloride) to give 7 as a white foam (875 mg, 83%). Rf= 0.56 (15% MeOH in CH 2 CIZ); 'H-NMR (400 MHz, DMSO) 0.99 (s, 3H, CH3), 1.12 (s, 6H, 2 CH 3 ), 1.75 (s, 3H, CH 3 ), 3.04 (in, 4H, CH 2 OTr, CH 2 S), 3.69 (i, IH, H-3'), 3.8-4.0 (in, 5H,

CH

2 OP, CH 2 N, H-4'), 4.0-4.2 (n, 2H, H-5', H-5"), 5.17 (s, I H, OH-2', D 2 0 exchangeable), 5.3 (m, I H, OH-3', D 2 0 exchangeable), 5.7 (in, 1 H, NH, D 2 0 exchangeable), 5.82 (s, 1H, H-I'), 7.1-7.5 (m, 21 H, Tr, CHsCH2, H-6); 1 3 P-NMR (161 MHz, DMSO) 9.95, 9.86; HPLC tR = 7.91 min (0-100% acetonitrile over a period of 8 min), X.. = 266.7 nm; LC/MS Scan ES+ 866 (M+Na)*. 1004431 Finally, compound 7 (860 mg, 1.02 mmol) was dissolved in a mixture of methylene chloride (15 ml) and trifluoroacetic acid (0.51 ml). The reaction mixture was stirred at room temperature for 2h, then diluted with toluene. The volatiles were evaporated under reduced pressure and coevaporated with ethanol. The crude mixture was purified by silica gel column chromatography (eluant: stepwise gradient of methanol [0-10%] in methylene chloride), followed by a purification on reverse phase chromatography (eluant: stepwise gradient of acetonitrile [0-50%] in water), to give the desired product 8 (B208) (257 mg, 42%). Rf= 0.31 (10% MeOH in methylene chloride); 'H-NMR (400 MHz, DMSO-d6) 0.99 (s, 3H, CH3), 1.10 (s, 6H, 2 x CH 3 ), 153 WO 2008/082601 PCT/US2007/026408 1.75 (s, 3H, CH 3 ), 3.0 (m, 2H, CH2S), 3.42 (d, 2H, CH 2 OH), 3.7 (m, IH, H-3'), 3.8 4.0 (stack, 5H, CH 2 OP, NCH 2 Ph, H-4'), 4.0-4.3 (m, 2H, H-5' and H-5"), 4.9 (m, I H,

CH

2 OH, D 2 0 exchangeable), 5.17 (s, IH, OH-2', D 2 0 exchangeable), 5.3 (m, I H, OH-3', D 2 0 exchangeable ), 5.7 (m, IH, NH, D 2 0 exchangeable), 5.81 (s, I H, H- '), 7.2-7.4 (stack, 6H, PhH, H-6); 1 3 P-NMR (161 MHz, DMSO-d6) 9.84, 9.90; HPLC tR = 4.98 min (0-100% acetonitrile over a period of 8 min), ,= 269.0 nm; LC/MS Scan ES+ 602 (M+H)*. Kr ' "it W1A1

VV

Preparation of B261, the Hydroxy-tBuSATE N-benzylphosphonamidate derivative of PMEA N *N O., ,%, B261 PROCEDURE A: Synthesis of intermediate 4:

NH

2 N N> NH2 1. (COC) 2 , DMF, CH 2

C

2 N N N| 2. Pyridine, CH2Cl2 HN O O -- OH HO--S OH 3 0 OOMTr 4. BnNH 2 4, ca. 8% MeO 1004441 A 500 mL triple-neck flask fitted with a condenser was charged with PMEA (2.00 g, 7.25 mmol), CH2CI2 (121 mL) and DMF (617 pL, 7.98 mmol). The resulting slurry was vigorously stirred and oxalyl chloride (2.21 mL, 25.4 mmol) was added dropwise at 0*C over 10 min (gas evolution). The slurry turned to a yellow solution (10 min) before turning turbid (10 min). This was further stirred for 3 h under 154 WO 2008/082601 PCT/US2007/026408 reflux and turned to a white, thick slurry. The products were schlenk-dried I h in situ by evaporation of all volatiles under reduced pressure, at room temperature. The resulting yellow solid could then be partially dissolved in CH2CI2 (121 mL), and pyridine (1.17 mL, 14.5 mmol) was added dropwise at 0*C over 10 min. The white suspension turned to a blue solution, which was cooled to - 78*C. A solution of alcohol 3 [for the synthesis of 3, See Example 13 (3.480 g, 7.25 mmol) and triethylamine (6.37 mL, 45.7 mmol) in CH2C2 (72 mL) was then added slowly (ca. 45 min), dropwise along the internal wall, and the reaction was stirred 10 h at - 78*C. Benzylamine (2.37 mL, 21.7 mmol) was then added dropwise at - 78*C and the solution was left stirring warming to r.t. over 1 h. NaHCO3 (aq. sat., 200 mL) was poured over the reaction and the layers separated. The aqueous phase was extracted with CH2CI2 (2 x 100 mL) and the combined organic extracts were dried with brine (50 mL) and Na2SO4. The solution was filtered and concentrated to afford ca. 6.5 g of crude yellow syrup. Purification by flash column chromatography (SiO2, 0 = 3.5 cm, H = 11 cm) eluting with 4 -+ - 12% MeOH in CH2CI2 (1% Et3N) afforded 3.70 g of a yellow foam (0.15 < Rf < 0.30, 10% MeOH in CH2CI2) that were submitted to a second purification by flash column chromatography (SiO2, 0 = 3.5 cm, H = 12 cm) eluting with 4 -+6% MeOH in CH2CI2 (1% Et3N) to afford 2.67 g of a yellow foam (0.16 < Rf < 0.25, 10% MeOH in CH2C12). This was submitted to a third purification by flash column chromatography (SiO2, 0 = 3.5 cm, H = 12 cm) eluting with 4 -+6% MeOH in CH2C12 (1% Et3N) to produce 165 mg of phosphonamidate 4 (ca. 2.7 %) as a white foam and 1.75 g of mixed compounds. These were submitted to a last purification by flash column chromatography (SiO2, 0 = 3.5 cm, H = 12 cm) eluting with 4 -.+6% MeOH in CH2Cl2 (1% Et3N) afforded 353 mg of phosphonamidate 4 (ca. 5.9 %) as a white foam. Total yield: 8.6%. Rf 0.21 (6% MeOH in CH2Cl2); IH-NMR (300 MHz, CDCI3) 1.13 (s, 6H, 2 CH3), 3.02-3.10 (m, 2H, CH2S), 3.59 (t, J 7.5, 2H, CH2), 3.58 (s, 6H, 2 x OCH3), 3.73 (t, J 7.1, 21J,CH2), 3.88-4.09 (stacks, 4H, 2 , CH2), 4.21 (t, J 7.0, 2H, CH20), 5.50 (br s, 2H, NH2), 6.67-6.78 (in, 4H, PhH), 7.04-7.38 (stack, 9H, PhH), 7.72 (s, IH), 8.22 (s, IH); 31P-NMR (121 MHz, CDCI3) 25.0; m/z (FAB+) 825 (1), 303 (100); HRMS 825.3171 ([M+H]+. C43H5007N6PS requires 825.3199). 155 WO 2008/082601 PCTIUS2007/026408 Synthesis of compound 5 (B261): MeO

NH

2

NH

2 N N \h / N N, Cq(HICO 2 H/ 'N N CH2C , N N0 O 0*~C, 55 min OsO HN OMe H N6 04 5,58% 1004451 Dichloroacetic acid (20% solution in CH2CI2, ca. 140 drops) was added dropwise to a solution of ether 4 (353 mg, 0.43 mmol) in CH2Cl2 (4.3 mL) at 0 *C and this was stirred for 55 min. Solid NaHCO3 (ca. 1.5 g) was then added and the slurry was stirred for 10 min before filtration and evaporation. Purification by flash column chromatography (SiO2, 0 = 1.5 cm, H = 10 cm) eluting with 4% -+ 10% MeOH in CH2C12 afforded pure phosphonamidate 5 (130 mg after lyophilization in THF/H20 and 3 day-stay in P205 desiccator, 58%). This reaction was also performed on 165 mg of ether 4 to produce 51 mg of phosphonamidate 5 (B261, 49%). Rf= 0.20 (10% MeOH in CH2CI2); 1H-NMR (300 MHz, DMSO-d6) 1.10 (s, 6H, 2 x CH3), 2.80 (t, J 7.0, 2H, CH2S), 3.43 (d, J 5.5, 2H, CH2OH), 3.69 (A of AB, J 4.8, 1H, I x . CH2P), 3.71 (B of AB, J 4.8, IH, I ); CH2P), 3.75-3.88 (stacks, 4H, CH20, NCH2), 3.88-4.07 (m, 2H, NCH2Ph), 4.30 (t, J 7.0, 2H, CH20), 4.97 (t, J 6.1, 1H, OH), 5.31 5.42 (m, i H, NH), 7.16-7.32 (stack, 7H, PhH, NH2), 8.09 (s, 1H), 8.13 (s, 1H); 13C NMR (75 MHz, DMSO-d6) 21.8 (2 x CH3), 28.4 and 28.5 (CH2, CH2S), 42.4 (CH2, NCH2), 43.3 (CH2, NCH2), 51.7 (quat. C, C(CH3)2), 61.7 and 61.8 (CH2, CH2O), 64.6 (CH2, CH20), 68.4 (CH2, CH20), 118.5 (quat. C), [126.5 (CH, Ph), 127.0 (CH, Ph), 128.0 (CH, Ph), some overlap], 140.5 and 140.6 (quat. C), 141.0 (CH), 149.4 (quat. C), 152.3 (CH), 155.9 (quat. C), 203.9 (quat. C, C=0); 31P-NMR (121 MHz, DMSO-d6) 25.9; m/z (FAB+) 161 (32), 256 (42), 523 (100); HRMS 523.1899 ([M+H]+. C22H3205N6PS requires 523.1892); HPLC (CI8, flow: 0.5 mUmin, solution A = TEAC 20 mM, solution B = 20% TEAC 20 mM): tR = 5.04 min (60% A in B), tR = 27.24 min (t= 9-4 10 min: 100% A; t = 19--+ 30 min: 0 -+50% B in A; t = 156 WO 2008/082601 PCT/US2007/026408 39-+ 35 min: 50 -+100% B in A); UV (EtOH 95%) kmax = 205 (emax 23900), )min = 228 (emin 5400). PROCEDURE B: [improved preparation of the Hydroxy-tBuSATE N-benzylphosphoramidate derivative (13261, Compound A) of PMEAI SYNTHETIC SCHEME: H 7r NH, N) N N Hi (COc, DMF N H KXS Oi cA2 H 1 N NHN PMEStep Stp H B NHz HNN s Step 1: Synthesis of intermediate A 1004461 To the suspension of PMEA (2 g, 7.3 mmol) in 120 mL of DCM (anhydrous) was added DMF (640 mg, 1.2 eq), followed with oxalyl chloride (2.3 mL, 3.5eg) at room temperature. The mixture was heated to reflux for 1.5 hrs to give a thick yellow suspension. The mixture was concentrated to dryness through rotarvap to give the crude intermediate a as pale yellow solid. LCMS analysis of the aliquot of intermediate a in methanolic solution confirmed the structure of the product in good purity. 157 WO 2008/082601 PCT/US2007/026408 Step 2: Synthesis of intermediate U: 1004471 The crude intermediate , (7.33 mmol) was suspended into 100 mL of anhydrous DCM. The suspension was cooled to 0 *C. To this was added pyridine (1.2 mL, 14.6 mmol, 2 eq) at 0 *C. After the addition, the pale yellow suspension turned to a golden colored clear solution. This solution was cooled to -32 *C with ACN/dry ice bath. To this was added a solution of 1 (3.52 g, 7.33 mmol, leq) in 70 mL of anhydrous DCM that contained triethylamine (6.3 mL, 44 mmol, 6eq) drop-wise. The internal reaction temperature was maintained between -35*C - -30 *C during the addition. The bright golden colored solution turned to a green colored solution with some precipitate crashing out from the solution during the addition. The precipitate was presumably the triethylamine HCI salt. It took 20 minutes to complete the addition. After the addition, the mixture was stirred at -30*C -10*C for Ihr. The reaction mixture was cooled back to -20*C. To this was added benzylamine (2.4 mL, 22 mmol, 3eq). The mixture was stirred at -20*C for 10 minutes. To the reaction mixture was added saturated NaHl-COVH2O and the mixture was stirred for 2 minutes. The DCM layer was separated, dried with Na 2

SO

4 and concentrated to dryness to give the crude intermediate 1 as yellow viscous oil. HPLC analysis of the crude intermediate gave 62% purity at 272 nrm. Step 3: Synthesis of intermediate 1: [004481 The crude intermediate U (7.33 mmol) as viscous pale yellow oil was dissolved into 200 mL of MeOH. The reaction mixture was refluxed overnight. HPLC analysis of the reaction mixture indicated the complete conversion of the amidine to amine. [The retention time of amidine (RT=5.92 min) is very close to the amine (RT=5.98 min) by the current in-house HPLC method!) The mixture was cooled to RT and filtered. The filtrate was concentrated to dryness by rotar-vap. The obtained crude product was purified through silica gel column chromatography (120g silica gel combiflash column was used, 3-8% of MeOH in DCM as the eluent) to give 3.1 g pure product i as white foam in 51% isolated yield from 2g of PMEA. lH-NMR of the obtained & was consistent with the desired structure. HPLC analysis of the obtained A gave 96% purity (AUC). 158 WO 2008/082601 PCT/US20071026408 Step 4: Synthesis of B261 (Compound ) 1004491 Intermediate 1 (300 mg, 0.36 mmol) was dissolved into EtOH (anhydrous, 5 mL). To this was added acetyl chloride (43 mg, 1.5 eq) in one portion at room temperature. The reaction should be operated in a closed reaction flask to avoid the loss of HCI gas. The reaction mixture was stirred at RT for 30 min. To this was added solid NaHC0 3 and the mixture was stirred for 15 min. pH of the reaction mixture was found to be around 7-8. The mixture was filtered and the filtrate was concentrated to dryness. The crude product was purified through silica gel column chromatography (5-10% MeOH in DCM as the eluent) to give 163 mg of I as clear viscous oil in 86% yield. 1 H-NMR of the obtained product was consistent with the desired structure. HPLC analysis of the obtained product gave 97.4% purity (AUC). Preparation of B263, the Hydroxy-IBuSATE N-benzylphosphoramidate derivative of 2'-C-methyladenosine

NH

2 B263 SYNTHETIC SCHEME: NHDMTr NHDMTr HNEt 3 + H HO Benztmne. CC NHDMTr M N T N NHq TFAI CM;C-h 4H 159 WO 2008/082601 PCT/US2007/026408 1004501 The pronucleotide B263 (94 mg, 6% overall yield) has been synthesized from its parent nucleoside 2'-C-methyl-6-NH-dimethoxytrityl-adenosine (1.59 g, 2.73 mmol) following a similar procedure than the one described for the synthesis of the pronucleotide prepared in the Example 2 (Procedure A, Strategy b), and isolated as a white lyophilized powder. 'H NMR (DMSO-d, 400 MHz) S (ppm) 0.80 (s, 3H), 0.97 0.98 (d, J= 4.26 Hz, 6H), 3.02 (m, 2H), 3.34-3.35 (m, 2H), 3.76-3.96 (m, 4H), 4.03 4.05 (m, 2H), 4.154.17 (m, 2H), 4.76-4.79 (m, 1H), 5.32 (s, IH), 5.34-5.36 (m, IH), 5.45-5.55 (m, 1H), 5.93 (s, IH), 7.1-7.4 (m, 7H), 8.14 (s, IH), 8.21 (1H); "P NMR (DMSO-d 6 , 162 MHz) 8 (ppm) 9.75 and 9.86 (2s); Scan ES+ 611 (M+H)*, Xmax =258 nm; HPLC (0-100% ACN over a period of 8 min) tR= 4

.

79 min Xna = 260.8 run. Preparation of B229, the Hydroxy-tBuSATE N-benzylphosphoramidate derivative of 2'-C-methyluridine OChiral o o B229 N 0 A I5 % P, ~ I -0Tr% 1 2IH 82%. NH NH 0 NIIv I~O U\L28% me0 Reagents and Conditions: (i) pTsOH.H 2 0, CH(OEth, acetone, r.t.; (ii) PivCl, pyr, r.t; (iii) Benzylamnine, CCL 4 , rt; (iv) aq. 90% TFA, DCM. r.t. 160 WO 2008/082601 PCT/US2007/026408 1004511 The pronucleotide 6 (446 mg, 0.76 mmol, overall yield 9% over 4 steps) has been synthesized from its nucleoside parent .I following a similar procedure described for the synthesis of the pronucleotide prepared in Example 2, Strategy A. B229 6. 1004521 'H NMR (400 MHz, DMSO-d 6 ): 8 0.98 (s, 3H, CH 3 ); 1.10 (s, 6H, 2 x

CH

3 ); 3.03 (m, 2H, CH2S); 3.41 (m, 2H, CH2OH, J 5.6 Hz); 3.61 (m, IH, H-3'); 3.8 4.0 and 4.05-4.25 (stacks, 5H, NCH Ph, H-4', H-5' and H-5"); 4.05-4.25 (2 x IH, 2 x mn, CH2OP); 4.91 (t, IH, 3'-OH, D 2 0 exchangeable, J= 5.62 Hz); 5.20 (br-s, lH, 2' OHD20 exchangeable); 5.39 (a-t, IH, CH 2 OH, D 2 0 exchangeable, J= 7.32 Hz); 5.52 (m, 1H, H-5); 5.65 (m, I H, PhNH.D 2 0 exchangeable); 5.8 (br-s, 1H, H-l'); 7.2 7.32 (m, 5H, ArH); 7.55 (a-dd, 1H, H-6); 11.37 (br-s, lH, NH, D 2 0 exchangeable). "P NMR (161.8 MHz, DMSO-d6): 8 9.73 and 9.98 (ratio of signals by integration of 52:48) m/z (ES+) 588.11 (M+H)*. HPLC (Method 20): chemical purity 99.2%, 3.48 mins. CHN analysis:- Found: C, 49.29, H, 5.95, N, 6.88, P, 5.16; C 24

H

34

N

3 01oPS requires C, 49.06, H, 5.83, N, 7.15, P, 5.46. [a)D 2+26.3 (c, 0.571 in H 2 0). v,,, (KBr): 3373 (br, NH and OH), 1682 (C=0). Preparation of B186, the Hydroxy-tBuSATE N-benzylphosphoramidate derivative of 2'-C-methylinosine HO NH B186 SYNTHETIC SCHEME: 161 WO 2008/082601 PCT/US2007/026408 8 NtaPO ~d eTr NH P60. in.. cc N NH aqTFAICKZar H0% H0% 1004531 The pronucleotide B186 (314 mg, 8% overall yield) has been synthesized from its parent nucleoside 2',3'-0-isopropylidene-2'-C-methyl-inosine (2.0 g, 6.26 mmol) following a similar procedure than the one described for the synthesis of the pronucleotide prepared in the Example 2 (Procedure A, Strategy a), and isolated as a white lyophilized powder. 'H NMR (DMSO-d 6 , 400 MHz) 8 (ppm) 0.79 (s, 3H), 1.09 (s, 6H), 3.01-3.04 (t,fJ=6.53 Hz, 2H), 3.42 (s, 2H), 3.84-3.91 (m, 2H), 3.94-4.03 (m, 3H), 4.05-4.09 (m, I H), 4.15-4.26 (m, 21), 4.92 (s, 1H), 5.36 (s, IH), 5.43 (t, J= 6.54 Hz, I H), 5.62-5.71 (m, 1H), 5.94 (s, IH), 7.18-7.22 (m, I H), 7.25-7.30 (m, 4H), 8.08 (s, I H), 8.10 (s, 1H), 12.15 (brs, IH); "P NMR (DMSO-d6, 162 MHz) S (ppm) 9.76 9.90 (2s); Scan ES* 612(M+H)*, X = 240.7 nm; HPLC (0-100% ACN over a period of 8 min) tR=4.72 min X '=243.1 im. Preparation of B396, the Hydroxy-IBuSATE N-benzylpbosphoramidate derivative of 9-[2-C-methyl-p-ribofuranosyll-6-chloropurine T N NH B396 SYNTHETIC SCHEME: 162 WO 2008/082601 PCT/US2007/026408 N T N T,11aq TFA, C6CH2 2 H H H, H Br,2aw* CC~o aq FA I CHAN4 1004541 The pronucleotide B396 (75 mg, 10% overall yield) has been synthesized from its parent nucleoside 9-[2-C-methyl-p-ribofuranosyl]-6-chloropurine (571 mg, 1.90 mmol) following a similar procedure than the one described for the synthesis of the pronucleotide prepared in the Example 4 and isolated as a white lyophilized powder. 'H NMR (DMSO-d 6 , 400 MHz) 8 (ppm) 0.82 (d, J =2.63 Hz, 3H), 1.07 (s, 6H), 3.02 (m, 2H), 3.40-3.41 (q, J= 3.36 Hz and J= 1.89 Hz, 2H), 3.85-3.98 (m, 4H), 4.12 (s, 2H), 4.25 (m, 2H), 4.89-4.90 (m, 1H), 5.47 (s, 1H), 5.50 (s, 1H), 5.62-5.70 (m, I H), 6.10 (d, J= 1.23 Hz, I H), 7.17-7.29 (m, 5H), 8.76 (s, IH), 8.82 (s, IH); 31 P NMR (DMSO-d 6 , 162 MHz) 8 (ppm) 9.91 and 9.79 (2s); Scan ES 630 (M+H)*, K max = 260 nm; HPLC (0-100% ACN over a period of 8 min) tR- 4

.

4 2 min a= 265 inn. ~a I Preparation of B307, the Hydroxy-tBuSATE N-benzylphosphoramidate derivative of 2',3'-0-carbonate-2'-C-methylguanosine HO N- -O NH3 P0 0 H CH 3 0 B307 SYNTHETIC SCHEME: 163 WO 2008/082601 PCT/US2007/026408 0 N O- 0 N N HO OH DMF 00 yled - 26 % TFA 0CM OM cH, 00 yield - 72 % N-Benzylaminyl-2',3'-0-carbonate-2'-C-methylguanosin-S'-yI-O (triphenylmethyloxy-tert-butyl-S-acyl-2-thioethyl) phosphate (CI): 1004551 Compound B2 [See, Compound 7, Example 3, Procedure A] (250 mg, 0.288 mmol) was dissolved in dimethylformamide (3.5 mL) and treated with 1,1 carbonyldiiniidazole (186.60 mg, 1.15 mmol). The mixture was stirred at room temperature for 4 h 30 and concentrated under reduced pressure (bath temperature not exceeding 30 *C). The crude residue was subjected to silica gel chromatography, eluting with a gradient 0-10 % methanol in dichloromethane, to give Q as a colorless oil. (68 mg, 26%). Compound Cl: 'H NMR (400 MHz, DMSO-dd 8 10.80 (Is, IH, NH), 7.80 (s, I H, H-8), 7.33-7.18 (m, 20H, 4 C 6 H), 6.66 (sl, 2H, NH 2 ), 6.30 (s, 1IH, H-l'), 5.78 (m, I H, PNH), 5.22 (m, IH, H-3'), 4.47-4.30 (m, 2H, H-4' and H-5'a), 4.20-4.05 (m, I H, H-5'b), 3.99-3.87 (m, 4H, CH 2 0 and CH 2 N), 3.10-3.03 (m, 4H,

CH

2 S and CH 2 OTr), 1.27 (s, 3H, CH 3 ), 1.11 (s, 6H, 2 CH 3 ). "P NMR (162 MHz, DMSO-dd 8 10.42 (s), 10.18 (s). LR LC/MS (M+H*) 895.4 (5.57 min). UV: X,.= 253 nm. 164 WO 2008/082601 PCT/US2007/026408 N-Benzylaminyl-O-(hydroxy-tert-butyl-S-acyl-2-thioethyl)-2',3'-0-carbonate-2' C-meth-ylguanosin-5'-yl phosphate B307 (Compound ): 1004561 Compound C1 (65 mg, 0.073 mmol) was dissolved in dichloromethane (260 pL) and treated with TFA (26 pL). The mixture was stirred at room temperature for 15 min, then diluted with ethanol, evaporated to dryness (bath temperature not exceeding 30 *C) and coevaporated with toluene. The resulting residue was purified by reverse phase (C 18) silica gel column chromatography eluting with a gradient 0 100% acetonitrile in water and lyophilised from a mixture of water/dioxane to give B307 (Compound QL) (34 mg, 72%, white lyophilised powder). B307 (Compound C2)::'H NMR (400 MHz, DMSO-d6) 510.84 (Is, I H, NH), 7.80 (s, IH, H-8), 7.32 7.20 (m, 5H, C6Hs), 6.69 (Is, 2H, NH 2 ), 6.30 (s, IH, H-i'), 5.77 (m, IH, PNH), 5.25 (d, IH, H-3', J.

4 ' = 20.0 Hz), 4.92 (Is, IH, OH), 4.50-4.41 (s, 2H, CH 2 OH), 3.03 (t, 2H, CH 2 S, Jcm.s-cmo = 8.0 Hz), 1.30 (s, 3H, CH), 1.10 (s, 3H, CH 3 ), 1.08 (s, 3H, CH,). "C NMR (100 MHz, DMSO-d 6 ): 8 204.4 (C=0), 154.5 (C-4), 153.1 (C-2), 150.7 (C-6), 140.9 (C 6 HS), 135.6 (C-8), 128.7-127.3 (5C, C 6 HS), 117.0 (C-5), 89.7 (C l'), 83.7 and 83.6 (2C, C-2' and C-3'), 81.8 (C-4'), 68.8 (CH 2 OH), 65.1 (CH 2 0), 64.5 (C-5'), 52.2 (C(CH 3

)

2 CH2OH), 44.7 (CH 2 N), 28.7 (CH 2 S), 22.3 (2C, 2 CH 3 ), 18.3

(CH

3 ). 3 'P NMR (162 MHz, DMSO-d6) 5 10.39 (s), 10.15 (s). LR LC/MS (2M+H*) 1305.4 (M+H*) 653.2 (2M-H')1303.8 (M-H) 651.4 (5.57 min). HRFAB-MS

C

26

H

34 0joN 6 PS (M+H*) calculated 653.1795, found 653.1819. UV: X, = 251 nm. Rf 0.67 (MeOH/CH 2 Cl, 20/80, v/v). Preparation of B242, the Hydroxy-tBuSATE N-(4 trifluoromethyl)benzylphosphoramidate derivative of 2'-C-methylguanosine Ho > S.. N ;/ NH, I 0 0 NH '4CH 3 HO OH CF, B242 SYNTHETIC SCHEME: 165 WO 2008/082601 PCT/US2007/026408 TrO -s NNH, S O- O

N

9 o H CH 3 4-T'efluormethyl - 0 cc , D21 CF, yied 6% TFA /DCM 0 ~ 1CH3 HO OH CF3 2& yleW - 30 % 2'-C-Methylguanosin-5'-yl-N-(4-trifluoromethyl)-benzylaminyl-O (triphenylmethyloxy-tert-butyl-S-acyl-2-thioethyl) phosphate (Q&): 1004571 To a solution of compound B1 [See, Compound 7, Example 3, Procedure A] (355 mg, 0.465 mmol) in anhydrous carbon tetrachloride (4.65 mL) 4 trifluoromethylbenzylamine (331 sL, 2.324 mmol) was added. The reaction mixture was stirred at room temperature for 1 h 30 and concentrated under reduced pressure (bath temperature not exceeding 30 *C). The resulting residue was subjected to silica gel chromatography, eluting with a gradient 0-10 % methanol in dichloromethane, to give D1 as a white solid. (420 mg, 96%). Compound DI: 'H NMR (400 MHz, DMSO-d 6 ) 8 7.77-7.20 (m, 20H, 3 C6H5, C 6

H

4

CF

3 and H-8), 6.57 (Is, 2H, NHI), 5.84 5.75 (m, 2H, H-i' and PNH), 5.50 (m, 1H, OH-3'), 4.26-3.86 (m, 8H, H-3', H-4', H 5', CH20 and CH2N), 3.10 (t, 2H, CH2S, JcH2s-cmo = 4.0 Hz), 3.03 (m, 2H, CH2OTr), 1,11 (s, 6H, 2 CH 3 ), 0,82 (s, 3H, CH 3 ). "C NMR (100 MHz, DMSO-d 6 ): 8 204.0 (C=0), 157.2 (C-4), 154.2 (C-2), 151.3 (C-6), 145.8-143.9 (4C, 3 C 6 H5 and

C

6

H

4

CF

3 ), 135.6 (C-8), 129.0-120.0 (20C, 3 C 6 s5 and C 6

H

4

CF

3 ), 117.0 (C-5), 91.0 (C- 1'), 86.1 (C(C 6 H,)), 80.7 (C-3'), 78.7 (C-2'), 73.3 (C-4'), 70.0 (CH 2 OTr), 65.9

(CH

2 O), 64.4 (C-5'), 50.8 (C(CH3)2CH 2 OTr), 44.2 (CH2N), 28.8 (CH 2 S), 22.7 (2C, 2 166 WO 2008/082601 PCT/US2007/026408

CH

3 ), 20.4 (CH 3 ). "P NMR (162 MHz, DMSO-dd: S 9.80 (s), 9.64 (s). ' 9 F NMR (376 MHz, DMSO-d): S - 60.8 (s). LR LC/MS (M+H*) 937.3 (M-H') 935.4 (5.47 min). UXV X, = 254 nm. Rf0.61 (MeOH/CH2Cl, 15/85, v/v). O-(Hydroxy-tert-butyl-S-acyl-2-thioethyl)-2'-C-methylguanosin-5'-yl-N-( 4 trifluorome-thyl)-benzylaminyl phosphate B242 (Compound D2: [004581 Compound D1 (400 mg, 0.427 mmol) was dissolved in dichloromethane (1.6 mL) and treated with TFA (160 pL). The mixture was stirred at room temperature for 15 mn, then diluted with ethanol, evaporated to dryness (bath temperature not exceeding 30 *C) and coevaporated with toluene. The resulting residue was subjected to silica gel chromatography, eluting with a gradient 0-15 % methanol in dichloromethane and then purified by reverse phase (C 18) silica gel column chromatography eluting with a gradient 0-100% acetonitrile in water and lyophilised from a mixture of water/dioxan to give compound B2742 (Compound D2 (90 mg, 30%, white lyophilised powder). B242 (Compound 2): 'H NMR (400 MHz, DMSO-d 6 ) 8 10.54 (Is, 1H, NH), 7.75 (s, 1H, H-8), 7.75-7.52 (m, 4H, C 6

H

4

CF

3 ), 6.50 (sl, 2H, NH 2 ), 5.82-5.74 (m, 2H, H-I' and PNH), 5.40 (m, 1H, OH-3'), 5.17 (s, IH, OH-2'), 4.92 (t, 1H, OH, Jo-"c2 = 4.0 Hz), 4.26-3.84 (m, 8H, H-3', H-4', H-5', CH20 and CH 2 N), 3.41 (d, 2H, CH 2 OH, JCH2-OH = 4.0 Hz), 3.03 (t, 2H,CH 2 S, JcH2S CH20 = 8.0 Hz), 1.07 (s, 6H, 2 CH), 0.82 (s, 3H, CHi). ' 3 C NMR (100 MHz, DMSO d: 8 204.4 (C=0), 157.2 (C-4), 154.1 (C-2), 151.2 (C-6), 145.9 (C 6

H

4

CF

3 ), 135.8 (C-8), 128.3-125.4 (6C, C 6

H

4

CF

3 ), 117.0 (C-5), 90.9 (C-i'), 80.5 (C-3'), 78.7 (C-2'), 73.2 (C4'), 68.8 (CH2OH), 66.0 (CH 2 0), 64.4 (C-5'), 52.2 (C(CH 3

)

2

CH

2 OH), 44.3

(CH

2 N), 28.7 (CH 2 S), 22.3 (2C, 2 CH 3 ), 20.4 (CH 3 )."P NMR (162 MHz, DMSO-dj: 6 9.62 (s), 9.77 (s). ' 9 F NMR (376 MHz, DMSO-d): 8 - 60.8 (s). LR LC/MS (M+H*) 695.2 (M-H-) 693.4 (4.25 min). HRFAB-MS C 2 6

H

35 0 9

N

6

F

3 PS (M+H*) calculated 695.1876, found 695.1874. MV Xm. = 253 nim. Rf 0.43 (MeOH/CH 2 CI, 20/80, v/v). - Exa mpf'e12 i Preparation of B503, the Hydroxy-tBuSATE N-benzylphosphoramidate derivative of 9-[(2R)2-deoxy-2-Huoro-2-C-ethynyl-p-D-erythro-furanosyl] guanine 167 WO 2008/082601 PCT/US2007/026408 HO -,-/ NHI 0 NH HO F B503 SYNTHETIC SCHEME: NH7 N Na s N-,- NH2 HO 0N N S_.o-P-O01 ---- o H Tr- SII_, -- EINWH HO F - HO F .1 H yield =28% nc Benzamine 0 - HNH TFA N Od.26% 6 HO F >MY quantitative yield {9-[(2R)2-Deoxy-2-fluoro-2-C-ethynyl- D-erythro-furanosyl]-guanin)-S'-yI-O (tripbe-nylmethyloxy-tert-butyl-S-acyl-2-thioethyl) H-phosphonate (Q1.): 1004591 Compound B5 [Unpublished results] (100 mg, 0.32 mmol) and compound . [See Compound 5 of Example 2] (246 mg, 0.42 mmol) were coevaporated together with anhydrous pyridine and dissolved in this solvent (4.8 mL). Pivaloyl chloride (80 pL, 0.64 mmol) was added dropwise at - 15 *C and the solution was stirred at the same temperature for 2 h. The reaction mixture was diluted with dichloromethane and neutralised with an aqueous solution of Ni4C1 0.5M. The mixture was partitioned between dichloromethane and aqueous NH 4 CI 0.5M, the organic phases were combined, dried over Na 2 SO4 evaporated under reduced pressure (bath temperature not exceeding 30 "C) and coevaporated twice with toluene. The crude mixture was purified by flash column chromatography eluting with a gradient 168 WO 2008/082601 PCT/US2007/026408 0-10 % methanol in dichloromethane + 0.2 % acetic acid) to afford the desired product GI as a colorless oil (68 mg, 28%).Compound Gi: 'H NMR (400 MHz, DMSO-d 6 ): 8 10.72 (Is, IH, NH), 7.83 (s, I H, H-8), 7.35-7.11 (m 15H, 3 CdHs), 6.59 (m, 2H, NH 2 ), 6.36 (d, IH, OH-3', J OH.3'= 7.6 Hz), 6.14 (d, I H, H-l', JI'.F = 18.0 Hz), 4.65 (m, 1H, H-3'), 4.40-4.33 (in, 2H, H-5'), 4.10-4.01 (m, 3H, H-4' and CH 2 0), 3.93 (d, 1H, CCH, 4 JH-F = 5.6 Hz), 3.15-3.12 (m, 2H, CH 2 S), 3.04 (s, 2H, CH 2 OTr). "P NMR (162 MHz, DMSO-d 6 ): 8 9.50 (s), 9.22 (s). ' 9 F NMR (376 MHz, DMSO d: 8 -156.5 (in). LR LC/MS (B) (M+Na') 798.2 (M-H') 774.2 (4.93 min). 13:. Xm = 254 nm. Rf0.48 (MeOHICH2Cl, 15/85, v/v). 1004601 N-Benzylaminyl-{9-[(2R)2-deoxy-2-fluoro-2-C-ethynyl-p-D-erythro furanosyl]-guanin}-5'-yl-O-(triphenylmethyloxy-tert-butyl-S-acyl-2-thioethyl) phosphate (G2) [00461] To a solution of compound G1 (68 mg, 0.088 mmol) in anhydrous carbon tetrachloride (880 pL), benzylamine (48 jiL, 0.44 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 h and evaporated to dryness (bath temperature not exceeding 30 *C). The crude mixture was filtered on a silica gel plug, eluting with a gradient 0-10 % methanol in dichloromethane to give compound G2 as a white solid (80 mg, quantitative yield). Compound G2: "P NMR (162 MHz, DMSO-d 6 ): S 9.95 (s) 9.80 (s). ' 9 F NMR (376 MHz, DMSO-d 6 ): 8 -157.5 (m). LR LC/MS (B) (M+H*) 881.3 (M-H-) 879.4 (5.18 min). UV:. = 254 nm. Rf 0.31 (MeOI/CH 2 C1, 15/85, v/v). N-Benzylaminyl-{9-[(2R)2-deoxy-2-fluoro-2-C-ethynyl-p-D-erythro-furanosyll guanin)-5'-yl-O-(hydroxy-tert-butyl-S-acyl-2-thioethyl) phosphate B503 (Compound G3): 1004621 Compound 2 (80 mg, 0.09 mmol) was dissolved in dichloromethane (320 pL) and treated with TFA (32 ptL). The mixture was stirred at room temperature for 10 min, filtered through a solid phase extraction column eluting with a gradient 0 30 % methanol in dichloromethane, then purified by reverse phase (C 18) silica gel column chromatography eluting with a gradient 0-100 % acetonitrile in water and lyophilised from a mixture of water/dioxan to give compound B503 (Compound 2) 169 WO 2008/082601 PCT/US2007/026408 (15 mg, 26%, white lyophilised powder). B503 (Compound G3): 'H NMR (400 MHz, DMSO-d 6 ): & 10.61 (is, IH, NH), 7.83 (s, I H, H-8), 7.30-7.18 (m, 5H, C1H), 6.60 (Is, 2H, NH 2 ), 6.32 (m, IH, OH-3'), 6.11 and 6.12 (2 d, 2 x 1H, 2 H-l', JI'-F = 18.0 Hz), 5.68 (m, IH, PNH), 4.93 (t, 1H, OH, JOH-CH2 = 5.5 Hz), 4.61 (m, 1H, H-3'), 4.26-4.18 (m, 2H, H-5'), 4.08 (m, 1H, HA'), 3.98-3.82 (m, 5H, CH 2 0, CH 2 N and CC), 3.42 (d, 2H, CH 2 OH, JcH2-OH = 5.0 Hz), 3.01 (m, 2H, CH 2 S), 1.09 (s, 6H, 2 CHJ). "P NMR (162 MHz, DMSO-do): 8 9.92 (s), 9.79(s). "F NMR (376 MHz, DMSO-d 6 ): 8 -156.8 (m). LR LC/MS (B) (M+H*) 639.2 (M-H') 637.3 (3.85 min). HRFAB-MS C 26

H

3 3 0sN 6 FPS (M+H*) calculated 639.1802, found 639.1816. ULV:. Xm = 253 nm. Rf 0.46 (MeOH/CH 2 CI, 20/80, v/v). The starting nucleoside was synthesized as follows: (004631 Synthesis of 9-[(2R)-2-deoxy-2-C-ethynyl-2-fluoro-p-D-erythro furanosyl]-guanine (D961, starting nucleoside of EXAMPLE 12), and synthesis of its triphosphate derivative B427) NH HO IN NH 2 HO F D961 SYNTHETIC SCHEME: 170 WO 2008/082601 PCT/US2007/026408 NJNH (NH MH 0 N 0 N S0N OMO NH3MOH4

C,.L

4 N N, 0 N ', HO F I1O ywd.8rieyW 48% 9-[3,5-O-(1,3-Diyl-1,1,3,3-tetraisopropydisiloxane)-ribo-furanosyl1-N' isobutyryl-guanine (B): Hirao, I.; Ishikawa, M.; Miura, K. Chem. Lett. 1986, 11, 1929-1932. 1004641 9-[3,5-0-(1,3-diyl- 1,13,3-tetraisopropyldisiloxane)- 2

-C

trimethylsilyethynyl-p-D-arabino-furanosyl]-

N

2 -isobutyryl-guanine (B2): To a suspension of Cr0 3 (11.07 g, 110.76 mmol) in dichloromethane (220 mL) at 0 *C, acetic anhydride (10.4 mL, 110.76 mmol) and anhydrous pyridine (17.82 mL, 221.52 mmol) were added. Compound B1 (22 g, 36.92 mmol) in solution in dichloromethane (110 mL) was added dropwise. The cooling bath was removed and the resulting solution stirred at room temperature for 5 h. The reactionmixture was poured into cold ethyl acetate, filtered through a silica and celite gel plug, concentrated to dryness and coevaporated twice with toluene. The residue obtained was dissolved in dichloromethane and stirred with an excess of MgSO4 ovemight, filtered and evaporated to get the ketone. The trimethylsilylacetylene (12.5 mL, 88.60 mmol) was dissolved in anhydrous THF (98 mL) under argon. Butyllithium (55.4 mL, 1.6 M in hexanes) was added dropwise at - 78 *C. The reaction mixture was stirred for 30 min at - 78 *C and then allowed to warm up to - 55 *C. The ketone in solution in THF (49 mL) was added dropwise at - 78 *C. The reaction mixture was stirred for 1 h at - 78 *C and then allowed to warm up to - 30 *C and stirred for 3 h. The reaction was quenched by careful addition of aqueous saturated NH4CI (72 mL) at - 78 *C. After warming to room temperature, the mixture was diluted with ethyl acetate, washed twice with saturated brine, dried (Na 2

SO

4 ) and concentrated to dryness. The crude material was purified using column chromatography eluting with 1.5 % MeOH in 171 WO 2008/082601 PCT/US2007/026408 dichloromethane to give compound B2 (8.59 g, 34 %, 2 steps) as a pale yellow foam. Compound B2: NMR 'H (250 MHz. DMSO-dd): 8 12.10 (Is, 1H, NH), 11.69 (Is, IH, NH), 7.91 (s, IH, H-8), 6.69 (s, 1H, OH), 5.94 (s, I H, H-1'), 4.29 (d, 1H, H-3', J 3 '.4' = 5.5 Hz), 3.85-3.95 (in, 3H, H-4', H-5' and H-5"), 2.46 (m, 1H, CH(CH 3 )2), 0.90-1.08 (m, 30H, iPr and CH(CH 3

)

3 ), 0.00 (s, 9H, Si(CH) 2 ). LC/MS (A): (M+H 4 ) 692.4 (24.96 min). UV;:X,, = 254 nm, X,2 = 281 nm. Rf 0.34 (MeOH/CH2CI, 15/85, v/v). 9-[(2R)-2-Deoxy-2-fluoro-3,5-O(1,3-diyl-1,1,3,3-tetraisopropydisioxane)- 2

-C

trimethyl-silylethynyl-p-D-erythro-furanosyl]-N2-isobutyryl-guanine (L): [004651 Compound B2 (2.00 g, 2.89 mmol) was dissolved in dried DCM (60 mL) under argon and pyridine (1.45 mL, 18.06 mmol) was added. The reaction mixture was cooled to -20 *C and DAST (4.11 mL, 31.35 mmol) was added dropwise. The cooling bath was removed after completion of the addition. Stirring was continued for 1 h 15 and the mixture was dissolved with ethyl acetate and poured into saturated NaHC03 and stirred for 5 min. The organic layer was washed with saturated brine, dried (Na2SO 4 ), concentrated, and purified by silica gel chromatography eluting with ethyl acetate in DCM (2 %) to give the desired compound B (1.41 g, 70 %) as a yellow oil. Compound B3: NMR 'H (250 MHz, DMSO-d : 8 12.22 (s, IH, NH), 8.09 (s, IH, H-8), 6.21 (d, IH, H-I', J'-F = 15.6 Hz), 4.54 (dd, IH, H-3', Jy-F = 23.6 Hz, Jr-4.= 9.8 Hz), 4.33 (m, IH, H-5', 2jr.s., = 13.1 Hz), 4.16 (m, IH, H-5"), 2.81 (m, I H, CH(CH 3

)

2 ), 1.13-1.03 (m, 34 H, iPr and CH(CH 3

)

2 ), 0.08 (s, 9H, Si(CH3) 3 , 3 JH-H 6.9 Hz). NMR ' 9 F (235 MHz. DMSO-d 8 - 160.26 (dd, JF-' = 16.1 Hz, JF-3' = 23.3 Hz). LC/MS (A): (M+H*) 694.7 (24.02 min). LRFAB-MS (GT): 694 (M+H)*, 692 (M-H)'. UV: Xma = 256 n. Rf 0.46 (MeOHICH 2 CI, 05/95, v/v). 9-[(2R)-2-Deoxy-2-C-ethynyl-2-fluoro-p-D-erythro-furanosyl]-N2-isobutyryl guanine (B4): [004661 Compound B3 (1.31 g, 1.89 mmol) was dissolved in methanol (13.8 mL) and ammonium fluoride (908.9 mg, 24.54 mmol) was added. The resulting solution was stirred at reflux for I h and evaporated to dryness. The crude material was purified on silica gel chromatography eluting with a stepwise gradient 6-10 % of 172 WO 2008/082601 PCTIUS2007/026408 methanol in dichloromethane to yield compound B4 (344 mg, 48 %) as a pale yellow oil. Compound 1B4: NMR 'H (400 MHz. DMS0-d: 8 12.18 (Is, IH, NH), 11.77(ls, IH, NH), 8.34 (s, IH, H-8), 6.29 (d, IH, OH-3', JOH.3' = 7.5 Hz), 6.20 (d, IH, H-', JI'.F = 16.2 Hz), 5.39 (t, IH, OH-5', JOH.s' = 5.1 Hz), 4.52 (dt, IH, H-3', J3'-F = 22.9 Hz), 3.98 (m, IH, H-4'), 3.90-3.85 (m, 2H, H-5' and ethynyl), 3.72 (m, IH, H-5"), 2.52 (m, IH, CH(CH 3

)

2 ), 1.14 (d, 6 H, CH(CH 3

)

2 , 3JH-H = 6.9 Hz). NMR 3 C (100 MHz. DMSO-d): 5 180.7 (C-6), 155.3 (C-2), 148.9 (C4), 137.3 (C-8), 120.4(C-5), 95.8 (d, C-2', 'J2'-F = 182.1 Hz), 87.7 (d, C-I', 2 J,,.F = 39.2 Hz), 83.4 (d, CCH, 3 JC-F 9.1 Hz), 82.6 (C4'), 75.9 (d, CCH, 2 JC-F = 31.2 Hz), 72.9 (d, C-3', 2 J3'.F 19.1 Hz), 59.3 (C-5'). NMR "F (235 MHz, DMSO-d6) 8 - 158.9 (m). LC/MS (A): (M+H*) 380.3 (8.34 min). UV:m = 260 nm, a = 277 nm. R/0.40 (MeOH/CH 2 CI, 15/85, v/v). 9-[(2R)-2-Deoxy-2-C-ethynyl-2-fluoro-0-D-erythro-furanosyl-guanine D961 (Compound BS: 1004671 Compound B4 (0.78 g, 1.33 mmol) was dissolved in saturated methanolic ammonia (62 nL) and stirred at room temperature for 20 h. The reaction mixture was then evaporated to dryness under reduced pressure. The residue was dissolved in water and washed twice with ethyl acetate. The aqueous layer was evaporated and purified on reverse phase column chromatography (C 18) eluting with a gradient 2-15 % of acetonitrile in water. The residue obtained was then dissolved in hot ethyl acetate, filtered and dried to give D961 (Compound B5 (134 mg, 33 %) as a yellow solid. NMR 1 H (400 MHz. DMSO-d6): 8 10.70 (Is, IH, NH), 7.98 (s, IH, H-8), 6.60 (Is, 2H, NH 2 ), 6.21 (d, IH, OH-3', JOH.3' = 7.6 Hz), 5.83 (d, IH, H-I', Ji.-F = 16.9 Hz), 5.29 (t, I H, OH-5', JoH45 = 5.2 Hz), 4.50 (td, IH, H-3', J 3 '.F = 22.8 Hz, J3.4t 9.2 Hz), 3.93-3.81 (in, 3H, H-4', H-5' and ethynyl), 3.70 (m, IH, H-5"). NMR "C (100 MHz. DMSO-d6): S 157.2 (C-6), 154.3 (C-2), 151.05 (C4), 135.1 (C-8), 116.7 (C-5), 96.4 (d, C-2', 'Jc.F = 182.1 Hz), 87.4 (d, C-', 2 3C.F 39.2 Hz), 83.1 (d, CCH, JC.F = 9.1 Hz), 82.4 (C-4'), 76.2 (d, CCH, 2 JC-F = 31.2 Hz), 73.2 (d, C-3', 2 Jc-F = 20.1 Hz), 59.5 (C-5'). NMR "F (235 MHz, DMSO-d ); S-158.5 (m). LC/MS (A): (M+H*) 310.1 (5.55 min). LRFAB-MS (GT): 619 (2M+H)*, 310 (M+H)*, 152 (B+H)*, 617 (2M-H), 308 (M-H)'. UV X. = 254 nm. 173 WO 2008/082601 PCT/US2007/026408 O0 0 0 1i II 1 1 HO-P-0-P-0-P-0 OH OH OH N --

NH

2 OHF B427 SYNTHETIC SCHEME: HO B 1) POC1 3 o--4 Po(OEt)b . . . HO 2)nBu 3 N, DMF H

(BU

3

NH)

2

H

2

P

2 0 7 HO F 3)EtN 3 M*, HCo0' D961 B427 Standard procedure for preparation of nucleoside 5'-triphosphate: (Ludwig, J. Aca Biochim. Biophys. Acad. Sci. Hung. 1981, 16, 131-133.) 1004681 To a solution of nucleoside (0.286 mmol) in triethylphosphate (750 PL), phosphoryle chloride (75 siL, 0.807 mmol) was added at 0 *C. This reaction mixture A was stirred overnight at 5 *C. Tributylammonium pyrophosphate (PPi/Bu 3 N 1/1,5, Ig, 2.19 mmol) was dissolved in anhydrous DMF (2 mL). Tributylamine (420 tL, 1.76 mmol) was added to the PPi and the resulting mixture was stirred for 15 min at 0 *C. 2.4 mL of this solution were added to the section mixture A. The reaction mixture was stirred at 0 *C for I min. The reaction was carefully quenched with TEAB 1 M (pH = 7,5, 10 mL), stirred 20 min at 0 *C, then diluted with water and ethyl acetate. The aqueous phase was concentrated under reduced pressure. The crude material was subjected to DEAE-Sephadex chromatography eluting with a gradient 10'3-1 M of TEAB). The desired fractions were combined, concentrated under reduced pressure and coevaporated with a mixture of water/methanol, and finally coevaporated with water. The resulting residue was purified on semipreparative HPLC. Fractions containing the expected product were concentrated under reduced pressure, coevaporated wiht a mixture of water/methanol and lyophilised from water. The 174 WO 2008/082601 PCT/US2007/026408 triethylammonium salt triphosphate was eluted three times with water on a Dowex Na' resin column to yield after lyophilisation from water to the sodium salt. (004691 9-[(2R)2-deoxy-2-C-ethynyl-2-fluoro-p-D-erythro-furanosyl]-guanine 5'-triphospbate sodium salt (B427): 'H NMR (400 MHz. D0): 8 7.97 (s, IH, H-8), 6.19 (d, IH, H-I', 3JI'-F = 16.0 Hz), 4.70 (m, IH under H 2 0, H-3'), 4.39 (m, IH, H 5'), 4.29-4.22 (m, 2H, H-4' and H-5"), 2.98 (d, 1H, ethynyl, 4 JH-F = 5.0 Hz). P NMR (162 MHz. D2O): -10.50 (d, IP, Py, Jpy-pp = 19.4 Hz), -11.03 (d, iP, P., Jpe.p = 19.4 Hz), -22.38 (t, IP, Ps, Jpppy= Jpp 0 = 19.4 Hz). NMR "F (376 MHz. DMSO-#4): 8 - 159,1 (m). LRFAB-MS (GT): 638 (M+Na)*, 616 (M+H)*, 594 (M-Na+2H)*, 572 (M-2Na+3H)*, 550 (M-3Na+4H)*, 592 (M-Na)', 570 (M-2Na+H)-, 548 (M-3Na+2H)'. Preparation of B306, the Hydroxy-tBuSATE N-benzylphosphoramidate derivative of 2'-C-methyl-5-aza-7-deaza-guanosime H3 NH2 H H B306 SYNTHETIC SCHEME: 175 WO 2008/082601 PCT/US2007/026408 HH Bt1irOWbO CC1 4 j NH2 aq TFA I CHI 2 Ch NH H , NHZ [004701 The pronucleotide B306 (25 mg, 6% overall yield) has been synthesized from its parent nucleoside 2'-C-methyl-5-aza-7-deaza-guanosine (200 mg, 0.67 mmol) following a similar procedure than the one described for the synthesis of the pronucleotide prepared in the Example 4 and isolated as a white lyophilized powder. 'H NMR (DMSO-d 6 , 400 MHz) 8 (ppm) 0.90-0.91 (d, J= 2.56 Hz, 3H), 1.09 (d, J= 4.26 Hz, 6H), 3.07-3.10 (t, J= 6.66 Hz, 2H), 3.42 (d, J= 5.64 Hz, 2H), 3.86-3.99 (m, 6H), 4.10-4.15 (m, IH), 4.15-4.20 (m, IH), 4.90-4.93 (t, J= 5.64 Hz, I H), 5.28 (s, 1 H), 5.46-5.50 (m, 1H) 5.62-5.69 (m, IH), 5.80 (s, 1H), 7.00 (s, 2H), 7.18-7.21 (m, 2H), 7.26-7.33 (m, 5H); "P NMR (DMSO-d 6 , 162 MHz) 8 (ppm) 9.80-9.95 (2s); Scan ES* 627 (M+H)*, % m=261.7 nm; HPLC (0-100% ACN over a period of 8 min) tR=3.18 min ,ma 258.4 nm. Preparation of B389, the Hydroxy-tBuSATE N-benzylphosphoramidate derivative of 2'-C-methyl-7-deaza-guanosine H H H H B389 SYNTHETIC SCHEME: 176 WO 2008/082601 PCT/US2007/026408 s HNE t 3 4 H H NH2 _ T I ~~H 2 Benzytamine, CC4 H NH H H, H2 s H, NH 3 AHaq TFA/CHO2 N TH H HHH 1004711 The pronucleotide B389 (80 mg, 21% overall yield) has been synthesized from its parent nucleoside 2'-C-methyl-7-deaza-guanosine (200 mg, 0.67 mmol) following a similar procedure than the one described for the synthesis of the pronucleotide prepared in the Example 4 and isolated as a white lyophilized powder. 'H NMR (DMSO-d 6 , 400 MHz) 8 (ppm) 0.74 (s, 3H), 1.09 (s, 6H), 3.0 (t, J=6.10 Hz, 2H), 3.42 (d, J= 5.49 Hz, 2H), 3.8-4.0 (2m, 6H), 4.04-4.11 (in, lIH), 4.24-4.17 (in, I H), 4.90-4.93 (t, J=5.36 Hz I H), 4.96-4.98 (d, J= 4.76 Hz, I H), 5.31-5.36 (mn, I H), 5.57.5.67 (in, 1H), 5.93 (s, IH), 6.21-6.26 (mn, 3H), 6.76 (d, J= 22Hz, I H), 7.19-7.23 (in, lH), 7.27-7.32 (mn, 4H), 10.34 (brs, IH); 3 P NMR (DMSO-d 6 , 162 MHz) (ppm) 9.77 and 9.90 (2s); Scan ES* 626 (M+H)*, x~ = 258.7 nmn; HPLC (0-100% ACN over a period of 8 min) ta =3.84 min X max= 259.6 nm. Preparation of B288, the Hydroxy-:BuSATE N-benzylphosphoramidate derivative of 3'-C-methyluridine H HOM B288 SYNTHETIC SCHEME: 177 WO 2008/082601 PCT/US2007/026408 TrTO s PlucQ pyrminI H H NH To BeaVyren . cc$, N Ha NH aQ TFA I CH2Cl H H H H 34% &44% 1004721 The pronucleotide B288 (34 mg, 3% overall yield) was synthesized from its parent nucleoside 3'-C-methyl-uridine (513 mg, 1.99 mmol) following a similar procedure than the one described for the synthesis of the pronucleotide prepared in the Example 4 and isolated as a white lyophilized powder. 'H NMR (DMSO-d, 400 MHz) 6 (ppm) 1.09 (s, 6H), 1.15 (s, 3H), 3.00-3.05 (m, 2H), 3.30 (s, IH), 3.42 (d, J= 6.13Hz, 2H), 3.76-3.79 (m, I H), 3.86-3.99 (m, 6H), 4.92-4.94 (t, J= 5.40 Hz, IH), 4.97 (s, I H), 5.47 (m, 1H), 5.59-5.62 (m, IH), 5.67-5.78 (m, I H), 5.83-5.87 (m, IH), 7.20-7.24 (m, I H), 7.30 (m, 4H),7.66-7.71 (m, IH), 11.32 (brs, Ii); " P NMR (DMSO-d 6 , 162 MHz) S (ppm) 9.66 and 9.95 (2s); Scan ES* 588 (M+H)*, Xma = 261.7 nm. Preparation of B350, the Hydroxy-tBuSATE N-benzylphosphoramidate derivative of 3'-C-methylguanosine O0 HO HO OH B350 SYNTHETIC SCHEME: 178 WO 2008/082601 PCT/US2007/026408 0 HN N HO H 4 H H NM7 ~Benzytamine cI, H-o -O N N NH, HN HC TA C Ho DC - HO OH 3'-C-Methylguanosin-S'-yl-O-(triphenylmethyloxy-tert-butyl-S-acyl-2-thioethyl) H-phos-pbonate (EJ): 1004731 3'-C-Methylguanosine (NM76) (233.7 mg, 0.79 mmol) and compound A3 [See Compound 5 of Example 2] (504.9 mg, 0.87 mmol) were coevaporated together with anhydrous pyridine and dissolved in this solvent (11.8 mL). Pivaloyl chloride (193.7 piL, 1.57 mmol) was added dropwise at - 15*C and the solution was stirred at the same temperature for 2 h. The reaction mixture was diluted with dichloromethane and neutralized with an aqueous solution of NH 4 Cl 0.5M. The mixture was partitioned between dichloromethane and aqueous NH 4 CI 0.5M, the organic phases were combined, dried over Na 2

SO

4 evaporated under reduced pressure (bath temperature not exceeding 30 *C) and coevaporated twice with toluene. The crude mixture was filtered on a silica gel plug eluting with a gradient 0-10% methanol in dichloromethane + 0.2% acetic acid) to afford the desired product E (250 mg, 42%).Compound El: "P NMR (162 MHz, DMSO-d6): 8 9.93 (s), 9.13(s). LR LC/MS (M+H*) 521.1 (5.88 min). V: Ame = 262 nm. Rf0.21 (MeOH/CH 2 CI, 15/85, v/v). N-Benzylaminyl-3'-C-methylguanosin-5'-yl-O-(triphenylmethyloxy-tert-butyl-S acyl-2-thioethyl) phosphate (E2): 1004741 To a solution of compound El (250 mg, 0.33 mmol) in anhydrous carbon tetrachloride (3.3 mL), benzylamine (178 pL, 1.637 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 h 30 and evaporated to dryness (bath temperature not exceeding 30 *C). The crude mixture was filtered on a silica gel plug eluting with a gradient 0-30 % methanol in dichloromethane) to give compound 179 WO 2008/082601 PCT/US20071026408 E2 as a white solid (290 mg, quantitative yield).Compound E: "P NMR (162 MHz, DMSO-de) 8 9.91 (s), 9.74 (s). LR LC/MS (M+H*) 869.3 (M-H-) 867.7 (5.20 min). UV:. X. = 253 nm. Rf 0.13 (MeOH/CH 2 CI, 10/90, v/v). N-Benzylaminyl-O-(hydroxyl-tert-butyl-S-acyl-2-thioethyl)-3'-C-methylguanosin 5 '-yI phosphate B350 (Compound ): [00475] Compound E (290 mg, 0.33 mmol) was dissolved in dichloromethane (1.16 mL) and treated with TFA (113 L). The mixture was stirred at room temperature for 10 min, then diluted with ethanol, evaporated to dryness (bath temperature not exceeding 30 *C) and coevaporated with toluene. The resulting residue was subjected to silica gel chromatography, eluting with a gradient 0-30 % methanol in dichloromethane, then purified by reverse phase (C 18) silica gel column chromatography eluting with a gradient 0-100% acetonitrile in water and lyophilised from a mixture of water/dioxan to give B350 (Compound K3) (15 mg, 7%, white lyophilised powder). B350 (Compound E3): 'H NMR (400 MHz, DMSO-do) 8 10.60 (m, I H, NH), 7.90 (s, 1 H, H-8), 7.30-7.19 (m, 5H, C 6 Hj), 6.47 (Is, 2H, NH 2 ), 5.72 5.59 (m, 2H, H-I' and PNH), 5.51 (d, IH, OH-2', JOH2'.I' = 8.0 Hz), 4.94-4.92 (2H, OH-3' and OH), 4.28 (m, 1H, H-2'), 4.01-3.83 (m, 7H, H4', H-5', CH 2 0 and CH 2 N), 3.41 (m, 2H, CH2OH), 3.02 (t, 2H, CH2S, Jcwscxo = 6.0 Hz), 1.20 (s, 3H, CH 3 ), 1.09 (s, 6H, 2 CH 3 ). "P NMR (162 MHz, DMSO-d6) 8 9,86 (s), 9,72 (s). LR LC/MS (M+H*) 627.2 (M-H-) 625.5 (3.87 min). HRFAB-MS C 25

H

36

O

9

N

6 PS (M+H 4 ) calculated 627.2002, found 627.2014.UV: X = 251 fin. Preparation of B305, the Hydroxy-tBuSATE N-benzylphosphoramidate derivative of 1-[2-C-methyl-p-ribofuranosyl]-3-carboxamido-4-fluoro-pyrazole NH2 B305 180 WO 2008/082601 PCT/US2007/026408 SYNTHETIC SCHEME: -- HNEt, +T> Benzybmnbe. CC 4 as TFA I CH2Ch 4 [004761 The pronucleotide B305 (28.3 mg, 8% overall yield) has been synthesized from its parent nucleoside 1-[2-C-methyl-p-ribofuranosyl]-pyrazolo-3-carboxamide 4-fluoro (180 mg, 0.65 mmol) following a similar procedure than the one described for the synthesis of the pronucleotide prepared in the Example 4 and isolated as a white lyophilized powder. 'H NMR (DMSO-d 6 , 400 MHz) 8 (ppm) 0.75 (s, 3H), 1.08 1.09 (d, J= 3.35 Hz, 6H), 2.98-3.02 (m, 2H), 3.40-3.42 (m, 2H), 3.85-4.03 (m, 5H), 4.16-4.19 (m, 2H), 4.89-4.92 (m, IH), 5.25-5.29 (m, 2H), 5.55 (s, 1H), 5.56-5.64 (m, 1H), 7.19-7.22 (m, 1H), 7.26-7.50 (m, 7H), 8.05 (d, J= 4.32 Hz, IH); "P NMR (DMSO-d 6 , 162 MHz) 8 (ppm) 9.75 and 9.90 (2s); ' 9 F NMR (d 6 -DMSO, 235 MHz) 5 (ppm) -170.70 (d, J=61.74 Hz, IF); Scan ES* 605 (M+H)*, X = 233.7 run; HPLC (0-100% ACN over a period of 10 min) tR= 4.56 min Xma = 235.2 rnm. Preparation of B436, the Hydroxy-tBuSATE N-benzylphosphoramidate derivative of 2'-C-methyl-7-deaza-7-fluoro-adenosine HOH B436 181 WO 2008/082601 PCT/US2007/026408 SYNTHETIC SCHEME: NHDMTf NHDMTr .HNEt 3 + H3 H, HH M H H NH2 Btnzy mrnn, CC- NHDMT N TKH, N NH aq TFA I CH2Ci H-6 H H H 1004771 The pronucleotide B436 (30 mg, 9% overall yield) has been synthesized from its parent nucleoside 2'-C-methyl-7-deaza-6-NH-dimethoxytrityl-adenosine (320 mg, 0.53 mmol) following a similar procedure than the one described for the synthesis of the pronucleotide prepared in the Example 2 (Procedure A, Strategy b), and isolated as a white lyophilized powder. 'H NMR (DMSO-d, 400 MHz) 8 (ppm) 0.66 (s, 3H), 1.02 (s, 6H), 2.95-2.98 (t, J= 6.10 Hz, 2H), 3.35 (d, J= 5.49 Hz, 2H), 3.77 3.85 (m, 3H), 3.88-3.95 (m, 3H), 4.03-4.18 (m, 2H), 4.83-4.86 (t, J= 5.44 Hz, 1H), 5.14 (s, IH), 5.21-5.25 (t, J= 7.40 Hz, I H), 5.55-5.66 (m, I H), 6.14 (s, IH), 6.9-7.3 (m, 8H), 8.01 (s, I H); "P NMR (DMSO-d 6 , 162 MHz) 8 (ppm) 9.77 and 9.89 (2s); 19 F NMR (d 6 -DMSO, 235 MHz) 8 (ppm) -166.85 (d, J=l 4.16 Hz, IF); Scan ES + 628(M+H)*, Xmax = 280.7 nm; HPLC (0-100% ACN over a period of 10 min) t= 4.78 min %m.x = 280.8 n. Preparation of B589, the Hydroxy-tBuSATE N-benzylpbosphoramidate derivative of 4'-C-metbyluridine HO 0 H NH HC Hd OH B589 182 WO 2008/082601 PCTiUS2007/026408 SYNTHETIC SCHEME: N rNH HOpd 5, PvCI N nNHH -: .H cct 4 J CC10 MOOHOH OHH He OH ama &QZElHO H 0P s - TFA I CHZC1 2 HN CH H3 H 1004781 Following the procedures described for Example 4, and starting from 4'-C methyluridine (A437) (200 mg, 0.77 mmol), intermediate P3 was first produced (62 mg, 11%. "P NMR (DMSO- d 6 , 162 MHz) 8 (ppm) 9.15, 9.56 (2s); Scan ES" 747 (M+Na)*, Xm, =259.7nm), then compound P4 during the second step (28 mg, 39%. Scan ES* 852 (M+Na)*), and finally the desired prodrug B589 was obtained as a white powder after lyophilization from dioxane (21 mg, 58%). 'H NMR (DMSO- d, 400 MHz) S (ppm) 1.10 (s, 6H), 1.13 (s, 3H), 3.03 (t, J= 6.42 Hz, 2H), 3.15 (d, J= 5.29 Hz, 1H), 3.42 (d, J= 5.67 Hz, 211), 3.72-4.16 (m, 7H), 4.06-4.15 (m, I H), 4.92 (t, J= 5.29 Hz, IH), 5.22 (d, J= 5.29 Hz, I H), 5.36-5.38 (2d, I H), 5.57-5.60 (2d, IH), 5.64-5.70 (m, I H), 5.78-5.80 (2d, 1 H), 7.20-7.31 (m, 5H), 7.60-7.64 (2d, I H); 3 1 P NMR (DMSO- d 6 , 162 MHz) 8 (ppm) 9.58, 9.77 (2s); Scan ES* 610 (M+Na)*, X max =260.7 nm. Preparation of B678, the Hydroxy-tBuSATE N-benzylphosphoramidate derivative of 4'-C-fluoromethylguanosine 183 WO 2008/082601 PCT/US2007/026408 MOj~r: HO NH N N. N N F 5oH B678 SYNTHETIC SCHEME: 0 N H HO N NH 2 Cpd S. PieYSH BnNH 2 V pyidie 0 N NH 2 F H HCCa, HO OH F HO OH H0 N H 0 ~~N'H mnftmnlionho K10 40o -o N NH N NH2 HHN F HO OH W1 1004791 Following the procedures of the Procedure A described in Example 3, and starting from 4'-C-fluoromethylguanosine (A402) (69.4mg, 0.22 mmol), compound Lj (67.5 mg, 39%) was obtained as intermediate after the first step. Scan ES' 780 (M-H)-. Second step led to the formation of intermediate P (57.5 mg; 76%). Compound 2 (26.3 mg, 0.03 mmol) was dissolved in dichloromethane (1 ml) and treated with montmorillonite K10 (150 mg) and stirred at room temperature for I h. The reaction mixture was directly deposited on silica SPE tube and extracted with a gradient 0-100% MeOH in dichloromethane to give after lyophilization from dioxane/water B678 as a white powder (7.7 mg, 40%). 'H NMR (DMSO- d 6 , 400 184 WO 2008/082601 PCTUS2007/026408 MHz) S (ppm) 1.09 (2 Is, 6H), 3.03-3.05 (m, 2H), 3.42 (m, 2H), 3.87-4.00 (m, 6H), 4.15-4.24 (m, 2H), 4.43-4.66 (m, 2H), 4.74 (m, I H), 4.93 (m, IH), 5.52 (d, J= 4.36 Hz, IH), 5.58 (m, 1H), 5.70-5.73 (m, IH), 5.75-5.77 (d, J= 8.05 Hz, 1H), 6.52 (Is, 2H), 7.24-7.35 (m, 5H), 7.92 (2s, IH); "P NMR (DMSO- d 6 , 162 MHz) S (ppm) 9.70, 9.83 (2s); "F NMR (d 6 -DMSO, 235 MHz) 8 (ppm) -235.92, -236.25 (2s); Scan ES' 645 (M+H)*, X. = 250.7 nm HPLC (0-100% ACN over a period of 8 min) t R= 3

.

9 1 min X = 251.1 nn. Preparation of B704, the Hydroxy-tBuSATE N-benzylphosphoramidate derivative of acyclovir

H

0 Th0,N 0 NNNH 6 B704 SYNTHETIC SCHEME: H NH, gO O -O I NH HOO- -NNN~ OF 0- O N N acyclovir El pyidine IBenzylamine cc", I-I 62 TFAo 185 WO 2008/082601 PCT/US2007/026408 Scheme I 9-(2-Hydroxy-ethoxymethyl)-guanin-5'-yl-O-(triphenylmethyloxy-tert-butyl-S acyl-2-thioethyl) H-phosphonate (FU): 1004801 Acyclovir (200 mg, 0.89 mmol) and compound A (See Compound A of Example 2] (674.2 mg, 1.15 mmol) were coevaporated together with anhydrous pyridine and dissolved in this solvent (13.3 mL). Pivaloyl chloride (162 pL, 1.15 mmol) was added dropwise at - 15*C and the solution was stirred at room temperature for 2 h. The reaction mixture was diluted with dichloromethane and neutralized with an aqueous solution of NH 4 CI 0.5M. The mixture was partitioned between dichloromethane and aqueous NH 4 CI 0.5M, the organic phases were combined, dried over Na 2

SO

4 evaporated under reduced pressure (bath temperature not exceeding 30 *C) and coevaporated twice with toluene. The crude mixture was filtered on a silica gel plug eluting with a gradient 0-15% methanol in dichloromethane + 0.2% acetic acid) to afford the desired product F1 (602 mg, 98%).Compound Fl:LR LC/MS (M+H*) 691.9 (M-H-) 690.0 (4.82 min). UV. X.x = 254 nm. N-Benzylaminyl-9-(2-hydroxy-ethoxymethyl)-guanin-5'-yl-O (triphenylmethyloxy-tert-butyl-S-acyl-2-thioethyl) phosphate (s): 1004811 To a solution of compound F1 (602 mg, 0.87 mmol) in anhydrous carbon tetrachloride (8.7 mL), benzylamine (475 pL, 4.35 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 h 30 and evaporated to dryness (bath temperature not exceeding 30 *C). The crude mixture was subjected to to silica gel chromatography, eluting with a gradient 0-10% methanol in dichloromethane to give compound F2 as a white solid (550 mg, 79%).Compound F2: 'H NMR (400 MHz, DMSO-d) 8 7.77 (s, I H, H-8), 7.58-7.17 (m, 20H, 4 C 6 H), 6.68 (Is, 2H, NH 2 ), 5.59 (m, I H, PNH), 5.32 (s, 2H, OCH 2 N), 3.92-3.78 (m, 6H, CH 2

SCH

2 0, CHzN,

POCHCH

2 O), 3.51 (t, 2H, POCH 2

CH

2 0, JCH2.CH2 = 5.2 Hz), 3.16 (s, 2H, CH2OTr), 3.00 (t, 2H, CHS, JCH2S-CH20 = 5.6 Hz), 1.12 (s, 6H, 2 CH). "C NMR (100 MHz, DMSO-d 6 ): 8 204.0 (C=0), 157.2 (C4), 154.6 (C-2), 151.8 (C-6), 143.9 (4 C, 4

C

6

H

5 ), 136.9 (C-8), 128.9-127.2 ( 20C, 4 C 6

H

5 ), 117.0 (C-5), 86.3 (IC, C(CH)), 72.3 (OCH 2 N), 70.0 (CH2OTr), 68.2 (POCH 2

CH

2 0), 64.8 (POCH 2

CH

2 0), 64.2

(CH

2

SCH

2 0), 50.8 (C(CH 3 )2), 44.7 (CH 2 N), 28.8 (CH 2 S), 22.,8 (2C, C(CH 3

)

2 ). 31 P 186 WO 2008/082601 PCT/US2007/026408 NMR (162 MHz, DMSO-d) 8 9,79 (s). LR LC/MS (M+H*) 797.2 (5.15 min)..UV Am. = 254 run. Rf 0.57 (MeOH/CH 2 CI, 15/85, v/v). N-Benzylaminyl-9-(2-hydroxy-ethoxymethyl)-guanin-5'-yl-O-(hydroxy-tert butyl-S-acyl-2-thioethyl) phosphate B704 (Compound 3): 1004821 Compound 2 (550 mg, 0.69 mmol) was dissolved in dichloromethane (2.2 mL) and treated with TFA (220 pL). The mixture was stirred at room temperature for 15 min, filtered through a solid phase extraction column eluting with a gradient 0 15 % methanol in dichloromethane, then purified by reverse phase (C 18) silica gel column chromatography eluting with a gradient 0-100% acetonitrile in water and lyophilised from a mixture of water/dioxan to give B704 (Compound 3), (103 mg, 27%, white lyophilised powder). B704 (Compound E3): 'H NMR (400 MHz, DMSO-d): 6 10.57 (s, 1H, NH), 7.79 (s, I H, H-8), 7.29-7.18 (m, 5H, CH 5 ), 6,49 (Is, 2H, NH 2 ), 5.55 (m, IH, PNH), 5.33 (s, 2H, OCH 2 N), 4.92 (t, I H, OH, JOH-CH2 = 5.2 Hz), 3.94-3.73 (m, 6H, CH 2

SCH

2 0, CH 2 N, POCH 2 CH20), 3.60 (t, 2H, POCH 2

CH

2 0, Jc2-.cH2 = 4.2 Hz), 3,42 (d, 2H, CH 2 OH, JCK2-OH = 4.4 Hz), 3.00 (t, 2H, CH 2 S, JCH2S cH2o = 6.4 Hz), 1.10 (s, 6H, 2 CH 3 ). 1 3 C NMR (100 MHz, DMSO-d): 8 204.4 (C=0), 157.2 (C-4), 154.4 (C-2), 151.9 (C-6), 141.0 (IC, C 6 Hs), 138.1 (C-8), 128.6-127.2 (5C, C 6 Hs), 117.0 (C-5), 72.3 (OCH 2 N), 68.8 (CH 2 OH), 68.2 (POCH 2

CH

2 0), 64.7

(POCH

2

CH

2 0), 64.2 (CH 2

SCH

2 0), 52.2 (C(CH 3

)

2 ), 44.7 (CH2N), 28.7 (CH 2 S), 22.3 (2C, C(CH 3

)

2 ). 3'P NMR (162 MHz, DMSO-d): 8 9.76 (s). LR LC/MS (M+H) 555.9 (M-H-) 553.9 (3.77 min). HRFAB-MS C 2 2

H

3 2 0 7

N

6 PS (M+H*) calculated 555.1791, found 555.1795. UV . = 250 nm. Preparation of B390, the Hydroxy-tBuSATE N-benzylphosphoramidate derivative of 2'-C-methyl-2',3'-di-O-acetyl-cytidine Nil 2 HN A. A B390 187 WO 2008/082601 PCT/US2007/026408 SYNTHETIC SCHEME: NHDMTr NHDMTr TNO N UT N TAI TH Nrr aq TFA I CH 2 C NHZ [004831 To a solution of pronucleotide 13 (See Example 2, Procedure A, Strategy b) (300 mg, 0.27 mmol) in anhydrous acetonitrile were successively added triethylamine (92 l), acetic anhydride (2.2 eq, 54 pl) and 4-dimethylaminopyridine (0.1 eq, 4 mg). The reaction mixture was stirred at room temperature for 2h and triethylamine (92 pl), acetic anhydride (2.2 eq, 54 p4l) and 4-dinethylaminopyridine (0.1 eq, 4 mg) were added again. After removal of the solvents under reduced pressure, the crude mixture was purified on silica gel column chromatography (eluant: stepwise gradient of methanol [0-5%] in methylene chloride) to give the fully protected pronucleotide (329 mg, quantitative yield). This compound was finally treated with a mixture of trifluoroacetic acid (132 pl) and methylene chloride (3.9 ml). After 1 h30 stirring at room temperature trifluoroacetic acid (132 pl) were added again and the mixture stirred I h more. The solvents were evaporated under reduced pressure and coevaporated with toluene. The crude mixture was purified on silica gel column chromatography (eluant: stepwise gradient of methanol [0-10%] in methylene chloride) to give B390 (36.4 mg, 21%) lyophilized as a white powder. 'H NMR (DMSO-d 6 , 400 MHz) 8 (ppm) 1.10 (s, 6H), 1.33 (d, J= 2.60 Hz, 3H), 2.05 (s, 6H), 3.01-3.04 (t, .= 6.54 Hz, 2H), 3.31 (d, J= 5.45 H, 2H), 3.85-3.90 (m, 2H), 3.94-3.99 (m, 2H), 4.09-4.11 (m, 2H), 4.21-4.23 (m, 1H), 4.90-4.93 (t,.J= 5.71 Hz, 1H), 5.22 (m, I H), 5.67-5.73 (m, 2H), 6.20(m, I H),7.21-7.27 (m, 7H), 7.54 (m, I H); "P NMR (DMSO-d 6 , 162 MHz) 8 (ppm) 9.69 and 9.86 (2s); Scan ES * 671 (M+H)*, X,, = 188 WO 2008/082601 PCT/US2007/026408 273.7 nm; HPLC (0-100% ACN over a period of 10 min) tR=5.0 4 min X.=233.7 nm and 271.4 rnm. Preparation of B302 NchIral o1 0 B302 Synthesis of Hydroxy-tBuSATE N-benzylphosphoramidate 2', 3'-cyclic carbonate derivative of 2'-C-methylcytidine B302 The following strategy was used for the synthesis: NHDMTr NHDMTr CDI Trt:O, N~ 9'Mo Tt TWA 0 0 N NH 13 14 92%

NH

2 HO 0 0 & 6 0 15 B302 71% [00484) Protected phosphoramidate 13 (1.72 g, 1.52 mmol) was dissolved in anhydrous dichloromethane (1 7ml) under argon. 1,1 '-Carbonyldiimidazole (251 mg, 1.55 mmol) was added and the reaction mixture was stirred at room temperature under argon for 1 h. [004851 Analysis by TLC (8% MeOH in DCM) indicated incomplete conversion of starting material (Rf 0.35) to product (Rf 0.56). HPLC analysis (method Test20, 272 189 WO 2008/082601 PCT/US2007/026408 nm) confirmed the profile: 9% starting material (Rt 7.30 min) and 91% product (Rt 7.97 min). Further portions of CDI (final total 299 mg, 1.84 mmol) were added and the reaction mixture was left to stir for an additional 24 h at room temperature after which time analysis by HPLC indicated 1.5% SM and 97.5% P. [004861 The reaction mixture was evaporated in vacuo to give an off-white foam (1.97 g). Purification by silica gel plug column, eluting with ethyl acetate, and evaporation of the appropriate fractions gave the protected cyclic carbonate 14

(C

6 5

H

65

N

4 0 12 PS 1157.27 gmol') as a white foam (1.62 g, 92% yield). TLC (8% MeOH in DCM): Rf 0.56; HPLC Test2O AUC: 99.5% @ 254 nm, Rt 7.97 min; m/z (ESI-): 1155.9 [M-H]- 100%; m/z (ESI+): 1157.5 [M+H]* 100%, 1179.5 [M+Na]* 20%. 100487] Protected cyclic carbonate 14 (1.50 g, 1.30 mmol) was dissolved in anhydrous dichloromethane (1 5ml) at room temperature under argon. Neat trifluoroacetic acid (1.77 g, 15.5 mmol) was added dropwise to the reaction mixture which was then stirred for 45 min at room temperature. Analysis by HPLC (method Test20, 272nm) indicated disappearance of starting material (Rt 7.97 min) and formation of product (Rt 3.80 min). 100488] Anhydrous methanol (5 ml) was added to the reaction mixture and solvents (10 ml) were partially removed in vacuo at 25*C. Further methanol (7 ml) was added to the mixture which was then evaporated to give an orange residue. Trituration with hexane/TBME 3:2 (12 ml) for 20 min yielded a sticky residue plus an opaque supernatant which was decanted. Retrituration with hexane/TBME 3:2 (5 ml) for 1 h and removal of the second supernatant gave, after coevaporation with methanol (3 ml), a pale foam (1.18 g). [00489] The crude foam was purified by reverse phase chromatography (loaded in 1 ml acetonitrile and eluted with 0%, 10%, 15%, 20%, 25%, 30% acetonitrile in water). Combination of the relevant fractions, evaporation of the solvents at 25"C and chasing with ethanol (I ml) gave cyclic carbonate 15, B302, as a white foamy solid (560 mg, 71% yield). 190 WO 2008/082601 PCTIUS2007/026408 B302: C 2 5H 33

N

4 01OPS 612.59gmol HPLC AUC (Method Test20): 99% @ 254nm, Rt 3.83min n/z (ESI+): 613.1 [M+H}* 100%; 1225.5 [2M+H] 100%; 453.1 [N+H]* 95% m/z (ESI -): 611.4 [M-H] 80%; 1223.9 [2M-H- 50%; 451.3 [N-H]- 100%

NH

2 Fragment N = Exactly similar fragmentation is observed for B 102 and B234. Chrncal Formula: OtH N 4 OsP Exact Mass: 452.1097

V.A

1 (KBr disc) (cm'): 3346.4, 3206.5 0-H, intermolecular H-bond; 1815.3 C=0 cyclic 5-ring carbonate; 1650.9 br C=0 base, thioester KF: 1.54% H 2 0 content Specific Rotation: [t]D 24 +9.289 (c 10.104mg cm 3 in DMSO) m.p.: 100-102*C contracts and softens, 104-106*C phase transition 1, 127-135 0 C phase transition II to a sticky glass, 140-150*C partial melting to sticky residue, 200 21 0C decomposes to a brown sticky material Elemental Analysis: Calculated: C 49.02%; H 5.43%; N 9.15% Found: C 49.30%; H 5.26%; N 9.30% - passed with 0.26% F present (from TFA) NMR: Assigned using 'H, "C, "P, COSY, TOCSY, DEPT, HSQC and HMBC [004901 H NMR 8 H (400 MHz, d6-DMSO): 1.11 (6H, s, (CH 3

)

2 C), 1.30 (3H, br-s,

CH

3 ), 3.04 (2H, m, CH2S), 3.44 (2H, d, J4Hz, CH 2 OH), 3.87-3.92 (2H, m, CH 2 0), 3.94-4.01 (2H, m, CH 2 Ph), 4.15-4.25 (2H, m, H-5', H-5"), 4.37 (1H, br-s, H-4'), 4.95 (2H, br-s, H-3', CH 2 OH), 5.75-5.77 (2H, 2 x d, J7Hz, H-5, P-N-H), 6.07 (1H, br-s, H-1'), 7.22-7.25 (1 H, m, Ar-H), 7.29-7.33 (4H, m, 4 x Ar-H), 7.39, 7.44 (2H, 2 x br-s,

NH

2 ), 7.62 (1 H, br-d, J 7Hz, H-6) 1004911 "C NMR 8 c (100 MHz, d6-DMSO): 17.72 (CH 3 ), 21.78 (C(CH 3 )2), 28.13, 28.21 (CH 2 S), 44.17 (PhCH 2 ), 51.62 (C(CH 3

)

2 ), 63.84, 63.89 (CH 2 0), 64.55 (C-5'), 68.29 (CH 2 OH), 94.23 (C-5), 126.70 (Ar-Cpm), 127.08, 128.11 (2 x Ar-Cmta, 2 x Ar-Conme), 140.35, 140.38 (Ar-Cip,), 152.73, 154.45 (C-2, C4), 165.69 (C-6), 203.87 (C=OS). C-i', C-2', C-3', C-4' and C=0 broadened into baseline and were not observed. 191 WO 2008/082601 PCT/US2007/026408 "P NMR Sp (162 MHz, d6-DMSO): 9.80, 9.94 (1P, 2 x s, ratio 1.15:1.00) Preparation of B234, the Hydroxy-tBuSATE N-benzylphosphoramidate derivative of 3'-O-L-valinyl-2'-C-methylcytidine N~tial S"09 CIIN 0 N NH 0 O 0 B234 The following strategy was used for the synthesis: BocVaI NHDMTr NHDMTr CDi AN DCM Trt:,y s ,40 0 C -os -o N0 WA 0C 0 NH H 0O I NHBoc 13 16 88% NH2 HO N see, N 0 HO );yH NH2 B'34 48% 1004921 Boc protected valine (6.72 g, 30.94 mmol) was dissolved in anhydrous DCM (50 ml) and 1,1 '-carbonyldiimidazole (4.87 g, 30.01 mmol) was added at room temperature under argon. Vigorous evolution of gas was observed initially during the activation step and the mixture was stirred at room temperature for 30 min. 192 WO 2008/082601 PCT/US2007/026408 [004931 Protected phosphoramidate 13 (10.0 g, 8.84 mmol) was dissolved in anhydrous dichloromethane (50 ml) in a separate vessel under argon.The activated Boc-Val solution was added dropwise to the phosphoramidate solution and the resulting mixture was heated to 40*C under argon for 24 h. [004941 Analysis by TLC (8% MeOH in DCM) indicated complete conversion of starting material 13 (Rf 0.35) to product (Rf 0.50). HPLC analysis (method Test2O, 272 nm) confirmed the profile: starting material (Rt 7.30 min) and product (Rt 9.46 min). 1004951 The reaction mixture was evaporated in vacuo to give an off-white foam. Purification by silica gel column chromatography, loaded from DCM, eluting with ethyl acetate/hexane 1:1 then 100% ethyl acetate, and evaporation of the appropriate fractions gave the protected valine ester 16 (C 7 Hs4N50s 14 PS 1330.52 gmol') as a white foam (10.3 g, 88% yield). TLC (ethyl acetate): Rf 0.24; HPLC Test20 AUC: 97% @ 272 nm, Rt 9.46 min; m/r (ESI-): 1329.29 (M-H]' 100%; m/z (ESI+): 1331.68 [M+H]* 25%, 303.16 [DMTr]* 100%. [00496] Protected valine ester 16 (3.0 g, 2.25 mmol) was dissolved in anhydrous dichloromethane (22.5ml) at room temperature under argon. Neat trifluoroacetic acid (4.5 ml, 58.4 mmol) was added dropwise to the reaction mixture over 3 min which was then stirred for I h at room temperature. Analysis by HPLC (method Test20, 272nm) indicated disappearance of starting material (Rt 9.46 min) and formation of product (Rt 3.33 min) along with significant Boc intermediate (Rt 4.60 min). 100497] Additional neat trifluoroacetic acid (1.0 ml, 13.0 mmol) was added dropwise to the reaction mixture which was then stirred for a further 1 h at room temperature. Analysis by HPLC (method Test2O, 272nm) indicated disappearance of Boc intermediate (Rt 4.60 min) and formation of product (Rt 3.33 min). 1004981 The reaction mixture was cooled to 5*C and anhydrous methanol (50 ml) was added, stirring for 30 min. Solvents were removed in vacuo at 25*C. The residue was treated with TBME (50 ml x 3) and triturated, decanting the three TBME liquors. 1004991 The residual material was dissolved in anhydrous methanol (5 ml) and anhydrous DCM (10 ml) and solid sodium bicarbonate (5 g) was added, stirring for 30 min, to give pH 6. The clear liquid was passed through a syringe filter. The residual solid bicarbonate was washed with 25% methanol in DCM (anhydrous, 10 ml) and the 193 WO 2008/082601 PCT/US2007/026408 solution was again filtered. The combined filtrates were concentrated in vacuo to give crude 17 (2.15 g), [005001 The crude material was purified by reverse phase chromatography (loaded in 15 ml water and 3 ml acetonitrile and eluted with 0%, 5%, 20%, 30% acetonitrile in water). Combination of the relevant fractions and evaporation of the solvents at 25*C gave valine ester 17, B234, as a white foamy solid (737 mg, 48% yield). B234: C 29 H4N 5 0 1 oPS 685.73gmol' HPLC AUC (Method Test20): 99% @ 254nm, Rt 3.33min m/t (ESI+): 686.3 [M+H]* 100%; 1371.6 [2M+H]* 20%; 526.1 [N+H]* 20% m/z (ESI -): 744.4 [M+OAc]' 35%; 1369.8 [2M-H]- 35%; 1430.2 [2M+OAc]- 15%; 524.5 [N-H]' 100% N H 2 Fragment N 0 Exactly similar fragmentation : N . is observed for B 102 0 d 6H and B302. NH, chemical Formula: C22H32N 5 0oP Exact Mass: 525.1988 V.. (KBr disc) (cm-'): 3350.7, 3211.9 O-H, N-H; 1757.8 C=O ester; 1673.9, 1652.0 C=O thioester, base KF: 1.94% H 2 0 content Specific Rotation: [a]Do +44.370 (c 10.033mg cm' 3 in DMSO) NMR: Assigned using 'H, "C, " P, COSY, TOCSY, DEPT, HSQC and HMBC 1005011 H NMR 8 H (400 MHz, d6-DMSO): 0.96, 0.98 (2 x 3H, 2 x s, (CH 3 )2CH), 1.03 (3H, br-s, CH 3 ), 1.11 (6H, s, (CH 3

)

2 C), 2.15 (1 H, m, (CH 3

)

2 CH), 3.03 (2H, m,

CH

2 S), 3.44 (2H, a-s, CH 2 OH), 3.85 (IH, a-d, J4.8Hz, CHNH 2 ), 3.85-3.92 (2H, m, CH20), 3.92-4.00 (2H, m, CH2Ph), 4.06-4.11 (1H, br-m, H-5'), 4.17-4.20 (1H, br-m, H-5"), 4.27-4.29 (1 H, br-m, H-4'), 5.08 (1 H, br-s, H-3'), 5.73 (1 H, a-t, J7.3Hz, H-5), 5.74-5.82 (I H, in, P-N-H), 5.92 (I H, br-s, H-1'), 7.22-7.25 (1H, m, Ar-H), 7.28-7.32 (4H, m, 4 x Ar-H), 7.60, 7.63 (2 x 0.58, 2 x d, J7.3Hz, H-6). 2 x 0-H and 2 x NH 2 not observed. 194 WO 2008/082601 PCT/US2007/026408 1005021 "C NMR 8 c (100 MHz, d6-DMSO): 17.84, 17.96 (CH(CH3) 2 ), 20.42, 20.48 (CH13), 21.78, (C(CH) 2 ), 28.09, 28.16 (CH 2 S), 29.72 (CH(CH3) 2 ), 44.16 (PhCH 2 ), 51.62 (C(CH3) 2 ), 57.84 (CHNH 2 ), 63.77, 63.81 (CH 2 0, C-5'), 68.26

(CH

2 OH), 74.67 (C-3'), 77.28 (C-4'), 78.09 (C-2'), 91.32 (C-l'), 94.22 (C-5), 126.71 (Ar-Cpmi), 127.04, 127.08, 128.11 (2 x Ar-Cmeta, 2 x Ar-Cortho), 140.23, 140.27, 140.32 (Ar-Cips, C-6), 155.06 (C-2), 165.32 (C4), 169.65, 169.72 (CO 2 R), 203.84 (C=OS). C-1', C-3', C-4' broadened into baseline but observable. 1005031 'P NMR Se (162 MHz, d6-DMSO): 9.63, 9.96 (1P, 2 x s, ratio 1.02:1.00) Preparation of B183, the Hydroxy-tBuSATE N-benzylphosphoramidate derivative of 2'-C-methyl-NH-4-acetyl-cytidine NHAc HH JH H H B183 SYNTHETIC SCHEME:

NH

2 NHAC AcO H H H DMF H 1005041 To a solution of B102 (See Example 2) (compound ,0., 200 mg, 0.34 mmol) in anhydrous dimethylformamide (3.4 ml) was added dropwise acetic anhydride (1.1 eq, 34 pl). The reaction mixture was stirred at room temperature for 4h and 10 s] of acetic anhydride were added again. The reaction mixture was stirred overnight and the solvent evaporated under reduced pressure. The crude mixture was purified on silica gel column chromatography (eluant: stepwise gradient of methanol [0-10%] in methylene chloride) to give the desired acetylated pronucleotide B183 195 WO 2008/082601 PCT/US2007/026408 (169 mg, 79%) isolated as a white lyophilized powder. 'H NMR (DMSO-d, 400 MHz) 5 (ppm) 0.93 (s, 3H), 1.09 (s, 6H), 2.09 (s, 3H), 3.01-3.04 (t, J= 6.54 Hz, 2H), 3.40-3.42 (d, J= 5.10 Hz, IH), 3.53-3.62 (m, 2H), 3.83-3.91 (m, IH), 3.94-4.01 (m, 4H), 4.10-4.15 (m, 1H), 4.20-4.25 (m, 1H), 4.88-4.91 (t,J= 5.20 Hz, 1H), 5.23 (s, 1 H), 5.33-5.37 (t, J= 7.19 Hz, 1H), 5.67-5.78 (m, IH), 5.93 (s, I H), 7.18-7.21 (m, IH), 7.27-7.32 (m, 5H), 7.96 and 8.03 (2d, J=7.59 Hz, I H), 10.87 (s, 1H); "P NMR (DMSO-d 6 , 162 MHz) S (ppm) 9.74 and 9.98 (2s); Scan ES* 629(M+H)+, Xma = 300.7 nm; HPLC (0-100% ACN over a period of 8 min) tR= 4

.

8 9 min m = 302.1 nm Preparation of B187, the Hydroxy-tBuSATE N-(2 (trifluoromethyl)benzyl)phosphosphoramidate derivative of 2'-C-methylcytidine

NH

2 HH B187 SYNTHETIC SCHEME: NHDMTr NHDMTr H H HO2 196 WO 2008/082601 PCT/US2007/026408 [005051 To a solution of compound 8 (See Example 2, Procedure A, Strategy a) (1.4 g, 1.3 mmol) in anhydrous carbon tetrachloride (13 ml) was added dropwise N-2 (trifluoromethyl)benzylamine (10 eq, 2.3 g). The reaction mixture was stirred at room temperature for 3h and the solvent removed under reduced pressure. The crude mixture was purified on silica gel column chromatography (eluant: stepwise gradient [0-3%) of methanol in methylene chloride) to afford the desired protected nucleoside as a foam (60%). This compound was converted into the phosphoramidate prodrug B187 (245 mg, 35%) following experimental conditions described in the Example 2 Strategy A and isolated as a white lyophilized powder. 'H NMR (DMSO-d, 400 MHz) S (ppm) 0.92 (s, 3H), 1.09 (s, 6H), 3.05 (t,J= 6.45 Hz, 2H), 3.29 (s, 1H), 3.41 (d, J= 5.60 Hz, 2H), 3.91-3.93 (m, 3H), 4.17-4.21 (m, 4H), 4.91 (t, J= 5.59 Hz, 1H), 5.06 (d, J= 4.25 Hz, 1H), 5.23 (t, J= 7.50 Hz, 1H), 5.65-5.67 (m, 1H), 5.76-5.83 (m, I H), 5.91 (s, IH), 7.08 and 7.16 (2s, 2H), 7.45-7.79 (m, 5H); "P NMR (DMSO-d 6 , 162 MHz) S (ppm) 9.57-9.78 (2s, IP); ' 9 F NMR (d 6 -DMSO, 235 MHz) S (ppm) 60.79 (s, 3F); Scan ES+ 655 (M+H)*, X = 280.73 nm; HPLC (0-100% ACN over a period of 10 min) tp =5.08 min X=271.4 nm. Preparation of B399, the Hydroxy-tBuSATE N-(4 (trifluoromethyl)benzyl)phosphosphoramidate derivative of 2'-C-methylcytidine

NH

2 NH H H F B399 SYNTHETIC SCHEME: 197 WO 2008/082601 PCT/US2007/026408 NHOMTr NHDMTr NH* H2 I f 54% F aq TFA Ic 2 Cla NH 2 H2 F 1005061 To a solution of compound 8 (See Example 2, Procedure A, Strategy a) (1.0 g, 0.94 mmol) in anhydrous carbon tetrachloride (10 ml) was added dropwise N 4-trifluoromethylbenzylamine (5 eq, 670 pl). The reaction mixture was stirred at room temperature for 3h and the solvent removed under reduced pressure. The crude mixture was purified on silica gel column chromatography (eluant: stepwise gradient [0-5%] of methanol in methylene chloride) to afford the desired protected nucleoside as a foam (84%). This compound was converted into the phosphoramidate prodrug B399 (204 mg, 40%) following experimental conditions described in the Example 2 Strategy A and isolated as a white lyophilized powder. 'H NMR (DMSO-d, 400 MHz) S (ppm) 0.91-0.92 (d, J= 2.09 Hz, 3H), 1.09 (s, 6H), 3.02-3.06 (m, 2H), 3.41(d, J= 6.17 Hz, 2H), 3.53-3.57 (m, IH), 3.84-3.94 (m, 3H), 4.03-4.13 (m, 3H), 4.18-4.23 (m, I H), 4.91-4.94 (t,J 5.48 Hz, IH), 5.06 (s, IH), 5.23-5.27 (t, J= 6.82 Hz, I H), 5.65-5.67 (m, IH), 5.79-5.87 (m, IH), 5.90 (s, IH), 7.09 and 7.16 (2s, 2H), 7.48-7.55 (m, 3H), 7.64-7.67 (m, 2H); ' F NMR (d 6 -DMSO, 235 MHz) S (ppm) -60.79 (s, 3F); "P NMR (DMSO-d 6 , 162 MHz) 8 (ppm) 9.55 arid 9.76 (2s); Scan ES 655 (M+H)*, X ma = 270 nm; HPLC (0-100% ACN over a period of 10 min) t R =5.03 min x = 271 nn. E9ampl28 198 WO 2008/082601 PCT/US2007/026408 Preparation of B204, the Hydroxy-tBuSATE N-(n-methyl-n-octyl amine)phosphosphoramidate derivative of 2'-C-methylcytidine NH2 H N H H 0 B204 SYNTHETIC SCHEME: NHDMTr NHDMTr T N ccid HH aq TFA ICHAci NH, HOH 1005071 To a solution of compound 8 (See Example 2, Procedure A, Strategy a) (950 mg, 0.89 mmol) in anhydrous carbon tetrachloride (9 ml) was added dropwise n methyl-n-octylamine (10 eq, 1.28 g). The reaction mixture was stirred at room temperature for 3h and the solvent removed under reduced pressure. The crude mixture was purified on silica gel column chromatography (eluant: stepwise gradient [0-3%] of methanol in methylene chloride) to afford the desired protected nucleoside as a foam (88%). This compound was converted into the phosphoramidate prodrug B204 (52 mg, 7%) following experimental conditions described in the Example 2 Strategy A and isolated as a white lyophilized powder. 'H NMR (DMSO-d6, 400 MHz) 8 (ppm) 0.83 (m, 3H), 0.93-0.94 (d, J= 3.75 Hz, 3H), 1.10 (s, 6H), 1.22 (s, IOH), 1.44 (m, 2H), 2.56 (d, J= 8.2 Hz, 3H), 2.88-2.93 (m, 2H), 3.31 (m, 2H), 3.43 (d, J= 5.60 Hz, 2H), 3.50-3.53 (m, 1H), 3.91-3.93 (m, 3H), 4.04-4.07 (m,I H), 4.134.16 199 WO 2008/082601 PCT/US2007/026408 (m, IH), 4.91 (t, J= 5.59 Hz, I H), 5.06 (s, IH), 5.23 (m, 1 H), 5.65-5.67 (m, 1H), 5.91 (s, 1H), 7.08-7.16 (m, 2H), 7.50-7.57 (m, IH); 31 P NMR (DMSO-d 6 , 162 MHz) 8 (ppm) 10.52 and 10.66 (2s); Scan ES 623 (M+H)*, X.,, = 280.73 nm; HPLC (0 100% ACN over a period of 8 min) tR =6.07 min X 274.9 run. Preparation of B244, the Hydroxy-tBuSATE N,N (dibutylamine)phosphoramidate derivative of 2'-C-methylcytidine NH2 H5 B244 SYNTHETIC SCHEME: NHDMTr NHOMTr Nq T7>/C 2

C

2 61% 1005081 To a solution of compound 12 (See Example 2, Procedure A, Strategy b) (1.5 g, 1.46 mmol) in anhydrous carbon tetrachloride (15 ml) was added dropwise dibutylamine (10 eq, 2.5 ml). The reaction mixture was stirred at room temperature for 3h and the solvent removed under reduced pressure. The crude mixture was purified on silica gel column chromatography (eluant: stepwise gradient [0-5%) of methanol in methylene chloride) to afford the desired protected nucleoside as a foam (61%). This compound was converted into the phosphoramidate prodrug B244 (21 200 WO 2008/082601 PCT/US2007/026408 mg, 4%) following experimental conditions described in the Example 2 Strategy B and isolated as a white lyophilized powder. 'H NMR (DMSO-d 6 , 400 MHz) 6 (ppm) 0.76-0.81 (td, J= 2.40 Hz andtj= 7.43 Hz, 6 H), 0.86-0.87 (d, J= 5.51Hz, 3H), 1.05 (s, 6H), 1.11-1.19 (m, 4H), 1.33-1.39 (m, 4H), 2.80-2.87 (q, J= 9.50 Hz, J= 8.67 Hz, 4H), 3.01-3.04 (t, J= 6.23 Hz, 2H), 3.42-3.43 (m, 2H), 3.50-3.60 (m, IH), 3.81-3.88 (m, 3H), 3.974.01 (m, 1H4), 4.07-4.10 (m, 1H), 4.84-4.87 (m, I H), 5.06 (s, 1H), 5.23 and 5.29 (2d, J= 8.0 Hz,I H), 5.70 (s, 1H), 5.91 (brs, IH), 7.10 and 7.17 (2s, 2H), 7.49 and 7.55 (2d, J= 8.0 Hz,IH); 31 P NMR (DMSO-d, 162 MHz) 6 (ppm) 10.44 and 10.56 (2s); Scan ES+ 609 (M+H)*, X.m, = 279.7 nm; HPLC (0-100% ACN over a period of 8 min) tR =5.59 min X= 274.9 nm. Preparation of B308, the Hydroxy-IBuSATE N methylbenzylphosphosphoramidate derivative of 2'-C-methyl-cytidine

NH

2 Ha N B308 SYNTHETIC SCHEME: NHDMTr NHDMTr Tr N el H H H H H 6 66 aq TFA /CH 2 Cl 2 NH 2 HO H 201 WO 2008/082601 PCT/US2007/026408 1005091 To a solution of compound 12 (See Example 2, Procedure A, Strategy b) (2.7 g, 2.6 mmol) in anhydrous carbon tetrachloride (26 ml) was added dropwise N benzylmethylamine (5 eq, 1.67 ml). The reaction mixture was stirred at room temperature for 3h and the solvent removed under reduced pressure. The crude mixture was purified on silica gel column chromatography (eluant: stepwise gradient [0-5%] of methanol in methylene chloride) to afford the desired protected nucleoside as a foam (44%). This compound was converted into the.phosphoramidate prodrug B308 (43 mg, 2%) following experimental conditions described in the Example 2 Strategy B and isolated as a white lyophilized powder. 'H NMR (DMSO-d 6 , 400 MHz) 5 (ppm) 0.93-0.94 (s, 3 H), 1.10 (s, 6H), 2.43-2.45(d, J= 4.26 Hz, 3H), 3.13 (t, J 6.23 Hz, 2H), 3.36-3.37 (d, J= 5.24 Hz, 2H), 3.56-3.60 (m, 2H), 3.97-4.01 (m, 3H), 4.07-4.21 (m, 3H), 4.92-4.94 (m,IH),5.08 (s, 1H), 5.30-5.32 (m, 1H), 5.59-5.67 (2d J= 8.0 Hz, I H), 5.91 (s, I H), 7.13 (m, 2H), 7.42-7.50 (m, 5H), 7.45-7.54 (2d J= 8.0 Hz, IH); " 3 P NMR (DMSO-d 6 , 162 MHz) S (ppm) 10.53 and 10.34 (2s); Scan ES + 601 (M+H)*, A..,= 268.7; HPLC (0-100% ACN over a period of 8 min) tR =3.37 min = 274.9 rnm. Preparation of B353, the Hydroxy-tBuSATE N-piperidinephosphosphoramidate derivative of 2'-C-methyl-cytidine

NH

2 B353 SYNTHETIC SCHEME: 202 WO 2008/082601 PCT/US2007/026408 NKDMTr NO4O'r as TFA /C0aCh T N

H

3 H H OH% 100510] To a solution of compound .2 (See Example 2, Procedure A, Strategy b) (300 mg, 0.29 mmol) in anhydrous carbon tetrachloride (3 ml) was added dropwise piperidine (5 eq, 145 pl). The reaction mixture was stirred at room temperature for 3h and the solvent removed under reduced pressure. The crude mixture was purified on silica gel column chromatography (eluant: stepwise gradient [0-5%] of methanol in methylene chloride) to afford the desired protected nucleoside as a foam (55%). This compound was converted into the phosphoramidate prodrug B353 (19 mg, 22%) following experimental conditions described in the Example 2 Strategy B and isolated as a white lyophilized powder. 'H NMR (DMSO-d 6 , 400 MHz) 8 (ppm) 0.92 (d, .J=2.56, 3H), 1.10 (s, 6H), 1.44-1.43 (m, 4H), 1.50-1.53 (m, 2H), 2.97-3.02 (m, 4H), 3.07-3.10 (t, J= 6.66 Hz, 2H), 3.42 (d, J= 5.64 Hz, 2H), 3.56-3.60 (m, 1 H), 3.89-3.94 (m, 3H), 4.04-4.10 (m, I H), 4.13-4.20 (m, 1H), 4.91-4.93 (t, J= 5.64 Hz, I H), 5.06 (s, IH), 5.25-5.31 (2d,. = 9.31 Hz, IH), 5.68 (m, I H), 5.90 (s, IH), 7.17 and 7.10 (2s, 2H), 7.50-7.55 (2d, J= 9.01 Hz, IH); " P NMR (DMSO-d 6 , 162 MHz) S (ppm) 8.75 and 8.59 (2s); Scan ES * 565 (M+H)*, X, = 275.7 nm; HPLC (0-100% ACN over a period of 6 min) tR= 3

.

08 min X = 273.7 nn. Preparation of B354, the Hydroxy-tBuSATE N cyclohexylaminephosphosphoramidate derivative of 2'-C-methyl-cytidine 203 WO 2008/082601 PCT/US2007/026408

NH

2 H! (N H, B354 SYNTHETIC SCHEME: NHDMTr NHOMTr T H CC4 Ho H H N2H H aq TFA I CH2Cb H N(H H, 1005111 To a solution of compound 12 (See Example 2, Procedure A, Strategy b) (300 mg, 0.29 mmol) in anhydrous carbon tetrachloride (3 ml) was added dropwise cyclohexylamine (5 eq, 170 ptl). The reaction mixture was stirred at room temperature for 3h and the solvent removed under reduced pressure. The crude mixture was purified on silica gel column chromatography (eluant: stepwise gradient [0-5%] of methanol in methylene chloride) to afford the desired protected nucleoside as a foam (55%). This compound was converted into the phosphoramidate prodrug B354 (44 mg, 50%) following experimental conditions described in the Example 2 Strategy B and isolated as a white lyophilized powder. 'H NMR (DMSO-d, 400 MHz) 8 (ppm) 0.92 (d, J=2.56, 3H), 1.10 (s, 6H), 1.13 (m, 5H), 1.46-1.47 (m, I H), 1.62 (m, 2H), 1.76-1.78 (m, 2H),2.80 (m, I H), 3.07-3.10 (t, J= 6.66 Hz, 2H), 3.42 (d, J= 5.64 Hz, 2H), 3.56-3.60 (m, 1H), 3.89-3.94 (m, 3H), 4.04-4.10 (m, IH), 4.13-4.20 (m, IH), 4.91-4.93 (t, J= 5.64 Hz, 1H), 5.06 (m, 2H), 5.25 and 5.31 (2d, J= 7.2 Hz, IH), 5.68 5.71 (m, IH), 5.90 (s, I H), 7.19 and 7.09 (2s, 2H), 7.50 and 7.55 (2d, J= 7.2 Hz, I H); 3 'P NMR (DMSO-d, 162 MHz) S (ppm) 9.05 and 8.91 (2s) Scan ES+ 579 (M+H)*, X 204 WO 2008/082601 PCT/US2007/026408 ,= 280.7 nm; HPLC (0-100% ACN over a period of 6 min) tR= 3

.

2 3 min = 274.9 run. Preparation of B391, the Hydroxy-tBuSATE N morpholinophosphosphoramidate derivative of 2'-C-methyleytidine

NH

2

H

3 B391 SYNTHETIC SCHEME: NHDMTr NHDMTr H1 3 0 HH H HH Ho H( H 49% 1005121 To a solution of compound 12 (See Example 2, Procedure A, Strategy b) (350 mg, 0.34 mmol) in anhydrous carbon tetrachloride (3.4 ml) was added dropwise morpholine (10 eq, 300 pl). The reaction mixture was stirred at room temperature for 3h and the solvent removed under reduced pressure. The crude mixture was purified on silica gel column chromatography (eluant: stepwise gradient [0-5%] of methanol in methylene chloride) to afford the desired protected nucleoside as a foam (70%). This compound was converted into the phosphoramidate prodrug B391 (53 mg, 49%) following experimental conditions described in the Example 2 Strategy B and isolated 205 WO 2008/082601 PCT/US2007/026408 as a white lyophilized powder. 'H NMR (DMSO-d, 400 MHz) 8 (ppm) 0.92 (d, J=-2.56, 3H), 1.10 (s, 6H), 3.0 (m, 4H), 3.07-3.10 (t, 1-= 6.66 Hz, 2H), 3.31 (s, 2H), 3.42 (d, J= 5.64 Hz, 2H), 3.56-3.60 (m, 3H), 3.89-3.94 (m, 3H), 4.04-4.10 (m, IH), 4.13-4.20 (m, 1H), 4.91-4.93 (t, J= 5.64 Hz, 1H), 5.08 (s, 1H), 5.25-5.31 (m, I H), 5.68-5.71 (d, J= 7.2 Hz, 1H), 5.90 (s, I H), 7.18 and 7.12 (2s, 2H), 7.52 and 7.50 (2d, J= 7.6 Hz, IH); " P NMR (DMSO-d6, 162 MHz) 8 (ppm) 7.76 and 7.61 (2s); Scan ES + 567(M+H)*, X. = 279.7 nm; HPLC (0-100% ACN over a period of 10 min) tR =3.42 min max = 273.7 nm. Preparation of B395, the Hydroxy-:BuSATE N-pyrrolidinephosphosphoramidate derivative of 2'-C-methyleytidine

NH

2 H4 H NO SYNTHETIC SCHEME: NHDMW NHDMr aq TFA J CH 2 C NH 2 HH3 'o-1% [005131 To a solution of compound .12(See Example 2, Procedure A, Strategy b) (500 mg, 0.49 mnmol) in anhydrous carbon tetrachloride (5 ml) was added dropwise 206 WO 2008/082601 PCT/US2007/026408 pyrrolidine (5 eq, 200 ld). The reaction mixture was stirred at room temperature for 3h and the solvent removed under reduced pressure. The crude mixture was purified on silica gel column chromatography (eluant: stepwise gradient [0-5%] of methanol in methylene chloride) to afford the desired protected nucleoside as a foam (87%). This compound was converted into the phosphoramidate prodrug B395 (48 mg, 21%) following experimental conditions described in the Example 2 Strategy B and isolated as a white lyophilized powder. 'H NMR (DMSO- 6 , 400 MHz) & (ppm) 0.93-0.94 (d, J= 3.75 Hz, 3H), 1.10 (s, 6H), 1.78-1.79 (q,J= 5.80 Hz, 4H), 3.09-3.09 (m, 6H), 3.42 (s, 2H), 3.57-3.59 (m, IH), 3.92-3.93 (in, 3H), 4.09-4.11 (m, lH), 4.16-4.18 (m, IH), 4.93 (brs, 1H), 5.10 (s, IH), 5.28-5.32 (t, J= 8.00 Hz, IH), 5.70 (d,J=8.0 Hz, 1H), 5.89 (s, 1H), 7.27 and 7.40 (2s, 2H), 7.55 and 7.61 (2d, f= 8.0 Hz, 1H); 31 P NMR (DMSO-d 6 , 162 MHz) S (ppm) 7.56 and 7.69 (2s); Scan ES + 551 (M+H)*, X ma = 275.7 nm; HPLC (0-100% ACN over a period of 10 min) tR =3.88 min ax 273.7 nm. Example 35 Anti-HBV Activity 1005141 The compound of Example I (NM 204) (Hydroxy-:BuSATE N benzylphosphoramidate derivative of L-ddA) (A550) was contacted with HBV infected HepG2 cells. EC 5 0 values were measured according to standard techniques. As shown in the table below, the compound of Example I showed significant activity compared to parent molecule LddA. HBV wt (HepG2) Drug N __________ __ ECso (pLM) LddA 3 >10 Ex I (A550) 3 0.062 0.018 LdT 3 0.26 0.048 Lamivudine 3 0.022 * 0.007 Example 36 Preparation of Calibration Curve for measurement of ddATP 207 WO 2008/082601 PCT/US2007/026408 1005151 Measurements of the concentration of 2'-3'-dideoxyadenosine-5' triphosphate (ddATP) (the triphosphate nucleotide of 2'-3'-dideoxyadenosine (ddA) are performed by liquid chromatography tandem mass spectrometry (LC/MS/MS), e.g., of methanolic extracts of hepatocytes. [005161 The concentration of ddATP is measured by comparison to a standard curve. [005171 Working stock solutions of TP-ddA are prepared from a 100 pmol / ld stock solution in de-ionized water of ddATP (tetrasodium salt of > 91% purity) purchased from Sigma Chemical Co as follows: ddATP working stock solutions and Preparation of Standard Curve for ddATP. 1. Working stock#1 Test compound Stock conc Vol taken DIH 2 0 vol Total vol Conc pmol/ul pL pL pL 2Mn0igL/p TP-ddA 100 2000 2000 4000 50.0 500 2. Working stock#2 Test article Stock conc Vol taken DIH20 vol Total vol Conc omol/ul pL pL pL 2ingjI TP-ddA 100 1000 3000 4000 25.0 250 3. Working stock#4(prepared from stock#1) Test article Stock conc Vol taken DIH20 vol Total vol Conc Dmollul pl pL pL gjngjpI TP-ddA 100 500 3500 4000 12.5 125 4. Working stock#5 (prepared from stock#1) Test article Stock conc Vol taken DIH20 vol Total vol Conc Dmol/ul pL pL pl Rgtgj/pl TP-ddA 100 200 3800 4000 5.0 50 5. Working stock#6 (prepared from stock#1) Test article Stock conc Vol taken DIH20 vol Total vol Conc omol/ul pl pL pL g!2gVpl TP-ddA 100 100 3900 4000 2.5 25 6. Working stock#7 (prepared from stock#1) Test article Stock conc Vol taken DIH20 vol Total vol Conc Dmovul pL pL pL Mj/ TP-ddA 100 40 3960 4000 1.0 10 1005181 Internal standard (ISTD) working stock are prepared from a 0.50 mg /mL stock solution of 2-deoxyadenosine 5-triphosphate purchased from Sigma Chemical Co. 208 WO 2008/082601 PCT/US2007O26408 ISTD Stock conc Vol taken MeOH vol Total vol Conc Conc pg/mL pt pL pL pg/mL pmol / mL dATP 500 200 9800 10000 10 500 1005191 In some embodiments, calibration standards are prepared as follows using Preparation of cal stds: Gsjlt s td conc ljvju Wt wofn working stock con workina stock vol ISTD Vol MeOH Vol total vol Dmonlf Q Mmol/lL Mk L uL 81k 0 0.1 0 50 940 990 #1 50 0.1 #5 5.0 10 50 940 1000 #2 125 0.1 #4 12.5 10 50 940 1000 #3 250 0.1 #3 25.0 10 50 940 1000 #4 500 0.1 #2 50.0 10 50 940 1000 #5 1000 0.1 #1 100.0 10 50 940 1000 liver samples: 1005201 In some embodiments the following HPLC conditions are used for the HPLC MS, e.g. HPLC Tandem MS analysis instrument method: 209 WO 2008/082601 PCT/US2007/026408 [005211 HPLC is conducted on Phenomenex Luna Amino 3jpm 100A, 30x2mm column, with a mobile phase: A: 70% 10mM NH40Ac 30% ACN pH 6.0;and B: 70% ImM NH40Ac 30% ACN pH 10.5 as follows: Gradient elution program: Flow Step Time(min) (pl/min) A (%) B (%) 0 0 400 60 40 1 1.1 400 60 40 2 1.11 400 40 60 3 2.11 400 30 70 4 2.6 400 20 80 5 3.1 400 0 100 6 5.5 400 0 100 7 5.51 400 60 40 8 10 400 60 40 Injection volume: 50 ul Flow rate to MS: 0.400 mUmin, no splitting of flow Multiple Reaction Monitoring (MRM) conditions: (AP13000) Ionization Mode: Positive Ion Electrospray (ESI+) lonSpray Voltage (IS): 5000 V Temperature (TEM): 550 0 C Turbo IS gas 8 Umin Nebulizer (NEB): 14 CAD Gas Setting (CAD): 6 Declustering potential (DP) 68 V Collision energy (CE) 27 eV Entrance/ Exit potentials (EP/CXP) -OV / I IV Compound Precursor ion => Product Ion ddA triphosphate 476.2 -> 135.9 ddA diphosphate 396.2 => 135.9 dA triphosphate (ISTD) 460.2 => 135.9 *Luna Amino column is directly connected on the inlet end to a "Security Guard" cartridge holder suitable for 2.1 mm Phenomenex columns, containing a C 18 cartridge. 210 WO 2008/082601 PCT/US2007/026408 Example 37 In vitro Phosphorylation in Hepatocytes 1005221 Primary hepatocytes (Rat, Cynomolgus Monkey or human) were seeded at 0.8x 106 in a collagen-coated 12-well plate and allowed to attach 4-6 hours after which time the seeding medium was replaced with serum-free culture medium and cells allowed to acclimatize to the new medium overnight. On the next day, cells were exposed for 1, 4, 8 and 24 hours to test article (NM204) (A5 50) at 10 and 5OpM prepared in fresh culture medium from stock solution in DMSO (final DMSO concentration was 0.1%). At each time point, an aliquot (500pl) was collected and immediately added to 500 1 pl of acetonitrile and stored at -20*C until analysis. The remaining exposure medium was removed and the cell monolayer (stuck to dish) washed 2 times with ice-cold PBS. Any remaining PBS was carefully removed by aspiration and cells were harvested by scraping in I mL 70% ice-cold methanol. Cell samples were placed overnight at -20*C and cellular debris removed by centrifugation on the next day. The supernatants were removed and filtered prior to analysis by LC/MS. A standard curve was prepared by using untreated cells processed similarly except that prior to harvesting in 70% methanol, 1Opl of LddATP standard solutions prepared in methanol were added to the washed monolayers. These control samples were then processed and analyzed as described for test samples. 100523] The results are shown below: LddA-TP formation in hepatocytes Ex I (A550) IOpM LddA TP Levels (pmol/million cells) Time (hour) Rat Monkey Human 1 159.5 287.5 161.5 4 388.0 978.0 312.5 8 468.5 1230.0 352.5 24 422.0 344.0 366.0 Ex I (ASSO) 50pM LddATP Levels (pmol/million cells) Time (hour) Rat Monkey Human 393.0 2085.0 682.5 4 1212.0 5690.0 1480.0 8 1590.0 6030.0 1930.0 211 WO 2008/082601 PCT/US2007/026408 24 1505.0 3030.0 2062.5 1005241 As indicated from the data, significant levels of L-ddATP were detected in the hepatocytes. In monkey hepatocytes, the levels appear to reach a maximum level at 8 hours followed by a rapid decline. In contrast, levels in both rat and human hepatocyte appear to level off after 8 hours. Example 38 In vivo Studies in Rat 1005251 Distribution of NM-204 (the compound of Example 1 (Hydroxy-IBuSATE N-benzylphosphoramidate derivative of L-ddA) (A550) in the rat liver was evaluated following a single intravenous (1.V.) or oral administration of A550 (NM-204) at a dose of 20 (oral) or 10 (I.V.) mg/Kg body weight. The dose solutions were prepared on the same day prior to dose administration. 1005261 At the specified time point (I and 3 hours for IV animals or 1, 3 and 8 hours for oral animals), each animal was euthanized by CO 2 gas followed by exsanguination via the abdominal vein. Livers were collected immediately after sacrifice, flash frozen in liquid nitrogen, placed on dry ice, and later stored at -70*C, before being analyzed. Preparation of calibration standards from control liver extracts: 1005271 Control rat liver samples were taken from whole frozen livers (Bioreclamation, Inc. Hicksville, NY) with the aid of a tissue coring utensil (Harris Unicore, 8.0mm, VWR, ). Each - 0.1 g sample was placed in individual 2 mL poly vials with 0.940 mL of 80% MeOH / 20% DIH 2 0 and homogenates were prepared using a mechanical tissue disruptor (Tissue Master, Omni-International, Inc, Marietta GA). The vials received a 10 gl aliquot of a working stock solution and a 50 pl aliquot of the ISTD before vortexing for -30 sec. The mixtures were stored overnight at -20 0 C and the next day were removed for 10min of centrifugation in a benchtop centrifuge. Each supernatant was transferred to individual centrifugation filtration units (0.45 pm) and the resulting filtrates were transferred to HPLC vials for the LC/MS/MS analysis.The final concentrations of ddATP in the calibration standards was 1000, 500, 250, 125, 50, and 0 pmol / ml. Each calibration standard was directly 212 WO 2008/082601 PCT/US2007/026408 injected in a 50 pL volume onto the ion-exchange column for analysis. Standard curve analysis of calibration standards from control liver extracts was conducted. [005281 Analysis of ddATP was done by an ion-exchange chromatography method with on-line positive ionization ESI-MSIMS detection in multiple reaction monitoring (MRM) detection mode. The peak areas obtained for 4 of the 5 calibrants allowed for construction of a standard curve that demonstrated good linearity (R 2 = 0.9996) over a 50 - 1000 pmol / ml concentration range. This is equivalent to a range of 5 - 100 pmol per gram liver by the sample preparation employed. The HPLC MS MS conditions described in Example 5 were utilized. The lower limit of quantitation demonstrated by the LC/MS/MS method is e.g., - 0.2 pmol / mL for hepatocyte cellular extracts which contain much less salt. 1005291 The results showing intracellular levels of A550 (NM204) (showing the compound entered the liver cells) and LddATP (showing cleaving of the phosphoramidate moiety and triphosphorylation of the ddA to the active triphosphate in the liver) are shown below: A550 (Ex 1) and LddATP measured in livers of male rats dosed IV or 0 with A550 (Ex 1) Concentration Compound (A550) (Ex 1) Timepoint Concentration. ddA-TP Animal Number (pmol / g liver) (hrs) (pmol / g liver) (pmol / 10' cells)* IV dose (10 mg/kg) IMI 65.8 1 2025 17.8 1M2 89.1 1 1930 16.9 1M3 85.1 1 1355 11.9 Mean 80.0 1770 15.5 IV dose (10 mg/kg) 2M1 28.3 3 1345 11.8 2M2 26.0 3 1940 17.0 2M3 29.3 3 2990 26.2 Mean 27.9 2092 18.3 Oral dose (20 mg/kg) 3M1 411 1 210 1.8 3M2 272 1 575 5.0 3M3 70.2 1 400 3.5 Mean 251 395 3.5 Oral dose (20 mg/kg) 4M1 360 3 200 1.8 4M2 92.1 3 330 2.9 4M3 161 3 405 3.6 Mean 204 312 2.7 213 WO 2008/082601 PCT/US2007/026408 Oral dose (20 mg/kg) 5MI 16.4 8 280 2.5 5M2 28 8 805 5.2 5M3 16.2 8 275 2.4 Mean 20.1 382 3.3 *Hepatocellularity number for rat was 114 x 106 cells per gram liver (Toxicology in Vitro 20 (2005) 1582-1586. 1005301 Thus, these results show that the compound can be used to enhance concentration of the drug in the liver. These results also show the enhanced concentration of the active triphosphate which is formed in the liver cells. Example 39 HCV Replicon Assay [005311 Huh-7 cells containing HCV Coni subgenomic replicon (GS4.1 cells), (C. Seeger; Fox Chase University, Philadelphia, PA, USA), are grown in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 2 mM L-glutamine, 110 mg/L sodium pyruvate, IX non-essential amino acids, 100 U/mL penicillin- streptomycin and 0.5 mg/mL G418 (Invitrogen). For dose-response testing, the cells are seeded in 96-well plates at 7.5x10 3 cells/well in a volume of 50 iL and incubated at 37*C/5% CO 2 . Three hours after plating, 50 pL of ten 2-fold serial dilutions of compounds (highest concentration, 75 pM) are added and cell cultures were incubated at 37 0 C/5% CO 2 in the presence of 0.5% DMSO. Alternatively, compounds are tested at a single concentration of 15 PM. In all cases, Huh-7 cells lacking the HCV replicon served as negative control. The cells are incubated in the presence of compounds for 72 hours after which they were monitored for expression of the NS4A protein by enzyme-linked immunosorbent assay (ELISA). For this, the plates were then fixed for I min with 1: 1 acetone:methanol, washed twice with phosphate-buffered saline (PBS), 0.1% Tween 20, blocked for I hour at room temperature with TNE buffer containing 10% FBS and then incubated for 2 h at 37

*

C with the anti-NS4A mouse monoclonal antibody A-236 (ViroGen) diluted in the same buffer. After washing three times with PBS, 0.1% Tween 20, the cells are incubated I hour at 37*C with anti-mouse immunoglobulin G- peroxidase conjugate in TNE, 10% FBS. After washing as described above, the reaction is developed with 0 phenylenediamine (Zymed). The reaction is stopped after 30 minutes with 2 N H 2 S0 4 and the absorbance is read at 492 rim using a Sunrise Tecan spectrophotometer. ECs" values are determined from the % inhibition versus concentration data using a 214 WO 2008/082601 PCT/US2007/026408 sigmoidal non-linear regression analysis based on four parameters with Tecan Magellan software. When screening at a single concentration, the results are expressed as % inhibition at 15 pM. For cytotoxicity evaluation, GS4.1 cells are treated with compounds as described above and cellular viability was monitored using a Cell Titer 96 AQu.., One Solution Cell Proliferation Assay (Promega). CC 5 0 values are determined from the % cytotoxicity versus concentration data with Tecan Magellan software as described above. Results 1005321 Compounds presented in the table below were assayed according to the replicon assay described above. 215 WO 2008/082601 PCT/US2007/026408 Compound Reference StruteHCELA2 EC50 (pM CC5 0 (;AM) NUCLEOSIDE PARENT: CI A634 H (NMI07) ++ EXAMPLE 2: HI>o0 B 102 1 C EXAMPLE 26: H B 187 0t EXAMPLE 27: Ho s" B399 l NNO, EXAMPLE 28: B204 EXAMPLE 29: HOs~~ 4 B244 N'4M B35 N) ~OH H' + 2166 WO 2008/082601 PCT/US2007/026408 Compound Reference Structure HCV ELISA 2 ECso (pM) CC 0 (pM) EXAMPLE 32: HIc s N B354 N 0 80H 6H HO iicrid EXAMPLE 33: H 1 C . B391 N C~ ~ 6H N oCH, 0' OH OH + + ................................................................................. ............... EXAMPLE 34:

N

4 B395 0 N H................................. H. EXAMPLE 24: B234 ;x:%++ +9 ................................................................................. ............... EXAMPLE 23: - -4 N B302 cl% 0+ + ......................................................................................... ...... ............... EXAMPLE 22: B390 NH B83 NUCLEOSIDE PARENT:N H A844 (NM 108) CH N OH .. H 4 EXAMPLE 3: B299 6H 27 OH +++ 217 WO 2008/082601 PCT/US2007/026408 Compound Reference SrcueHCV ELISA 2 __________________ _ ___ ___ __ ___ ___ ___ ___ __ ECso (i cc" (M) EXAMPLE 11:N B242 . +4+* EXAMPLE 10: c ~ e.( B307 NH2CJ NNCV1r NUCLEOSIDE PARENT: j A374 (NM8O) C4 H, EXAMPLE 6: s I o B263 \ c 1 xrJ HN ++ + 0 Mal NUCLEOSIDE PARENT: FNH C809 (NMIO6) ~o .4 0 C".g EXAMPLE 7: t~ P ~N B229 NM+lbCP NUCLEOSIDE PARENT: MO ~ H A608 HdbR + 4+ EXAMPLE 8: + B 186 C NUCLEOSIDE PARENT: ~ChIrai A849 '*LCH) .................. L............................................. ...... . ........ ....... ........ 218 WO 2008/082601 PCT/US2007/026408 Compound Reference Structure HCV ELISA 2 _ __ ECso (pM) CC(piM) EXAMPLE 9: s N B396 iv . -zCH, 01 H0 OH NUCLEOSIDE PARENT: Ho o ' N -NH, D961 .. . . . . . .. .. . . .O.. . .. .. . . . . . o + + EXAMPLE 12: J B503 & O F NUCLEOSIDE PARENT: E310 o.cH, HOOH .4.. + EXAMPLE 18: Ys .P.o B436 ECo in ELISA 2 assay is provided as follows: +++ 5 1 jpm, ++ > 1-10 pm and + > 10 pm CCso is provided as follows: ++ 5 75 jpm, + > 75 jm Example 40 HBV Drug susceptibility assay a) Collagen-I coated cell culture plates were seeded with cells at a density of 0.25-0.5x 106 cells per well in 2 ml of growth/selection media. b) Drug stock solutions were made up freshly in 100% DMSO as 200x stocks. Seven 4-fold dilutions of test compound were prepared ranging from 2.5 pM to 0.0006 pM (final). Master drug dilutions were divided into 4 aliquots, and then stored at -20'C until used. c) One day after cells were seeded, drug treatments were initiated by adding 10 pl of drug dilution along with 2 ml of fresh growth/selection media. 219 WO 2008/082601 PCT/US2007/026408 Thus, the final DMSO concentration did not exceed 0.5%. The no-drug control wells received 10 pl of DMSO in fresh media. d) Cells were treated every-other-day with 2 ml of fresh drug combinations/medium for a total of 8 days. Cell lysates were then collected on day 10 as described below and endogenous polymerase assay were performed. Preparation of nucleocapsid-containing lysates for EPA analysis a) Two days after the final drug treatment, cells were harvested. b) Media was carefully aspirated and the cell monolayers were rinsed once with I ml of PBS. c) I ml of lysis buffer (50 mM Tris-HCI pH 7.5/150 mM NaCI/5 mM MgC2/0.2% NP-40) was added to each well. The detergent is required to strip the outer envelope from virions and to allow capture of the inner nucleocapsids. Plates were kept on ice for >30 min. d) Lysed cells were transferred to 1.5 ml-microfuge tubes. e) Lysates were clarified by spinning at room temperature for 5 min at 14,000 rpm. f) Clarified lysates were transferred to fresh tubes and immediately frozen on dry-ice, then stored at -80*C until endogenous polymerase assays can be performed as described below. Endogenous polymerase assay (EPA) of cell lysates a) EPAs were performed essentially as described in Seifer, et al (1998). J. Virol. 72: 2765-2776. Clarified lysates were thawed at room temperature. b) Intracellular HBV nucleocapsids were immunoprecipitated from the cytoplasmic lysates overnight at 4*C with a polyclonal rabbit anti-HBcAg antibody and immobilized on protein A sepharose CL-4B beads. c) After 2 washes of the immobilized capsids with I ml of EPA wash buffer (75 mM NH 4 CI, 50 mM Tris-HCl pH 7.4, 1 mM EDTA), endogenous polymerase reactions were initiated by adding 50 p of detergent-containing EPA cocktail (50 mM Tris-HCI pH7.4, 75 mM NH 4 CI, 1 mM EDTA, 20 mM MgCl2, 0.1 mM P-ME, 0.5% NP-40, 100 gM cold dGTP, TTP, dCTP, and 50 nM 3 3 P-dATP) and incubated overnight at 37 0 C. The detergent is required to enhance permeability of the nucleocapsids. 220 WO 2008/082601 PCT/US2007/026408 d) Following digestion with I mg/ml of Proteinase K for 1 hour at 37*C, endogenously "P-labeled HBV DNA was liberated via phenol/chloroform extraction. e) The nucleic acids were then precipitated with one volume of 5 M NH 4 acetate and 2.5 volumes 100% EtOH, and separated on a 1% native agarose gel in Tris-borate buffer. 0 Gels were blotted onto positively charged nylon membrane overnight at room temperature via capillary transfer in 0.4 N NaOH. g) Dried membranes were exposed to a phosphoimager screen (GE Healthcare) overnight at room temperature, then scanned (Storm 860, GE Healthcare) and quantitated with ImageQuant software (GE Healthcare). h) Dose-response curves were generated using XLfit 4.1 software. The mean effective drug concentrations that inhibit endogenous HBV polymerase activity by 50% were calculated from several independent experiments. Cytotoxicity determination A standard in vitro cytotoxicity assay was performed in HepG2 cells. Cells were exposed to drug for 9 days. Cell viability was determined via MTS staining using a CellTiter 96 Aqueous One Solution cell proliferation assay according to the manufacturer's instructions. a) HepG2 cells were seeded in 96-well tissue culture plates in 100 sl fresh growth media at 7x103 cells per well. b) Drug stock solutions were made up in 100% DMSO as 400x stock solutions and stored at -20*C until used. c) Four hours after cells were plated the drug dilutions were prepared and then added to the cells. Cells received up to 100 pM of drug in a total of 200 pl of fresh growth media containing 0.25% DMSO. Control wells received growth media with 0.25% DMSO growth media. Plates were incubated at 37 0 C, 5% CO 2 . d) Cells were treated every-other-day with fresh growth media and fresh drug dilutions for a total of 8 days as described above. e) On day 9, cell viability of HepG2 cells was determined by adding 20 pl of MTS CellTiter 96 Aqueous One Solution. Following 4 hours of incubation at 37*C, absorbance was measured at A4o nm in a Victor V plate reader (Perkin Elmer). 221 WO 2008/082601 PCT/US2007/026408 f The CC 5 o concentrations were determined using XLfit 4.1 software. 1005331 The antiviral in vitro activity of PMEA, B261 (hydroxy-tBuSATE N benzylphosphoramidate derivative of PMEA as shown in Example 10 Table) along with LdT as control was tested in a total of 4 HBV drug susceptibility assays. The table below provides the results: HBV Cell Assay (EPA Read-out) Cytotoxicity Antiviral Activity* Drug (CC 50 in pM) (EC 50 in pM) SI PMEA >100 0.328 10.082 >310 B261 19.6 0.016 ± 0.004 1,225 LdT >100 0.366 t 0.056 >273 Cytoxicity and efficacy was determined on collagen plates. Example 41 Determination of total metabolism in liver subcellular fractions (depletion of parent) 1005341 NADPH Incubations. Microsomal or S9 incubations were conducted in a final volume of 0.5 mL. Pooled liver microsomal or S9 protein (1.0 mg/mL), suspended in incubation buffer (100mM potassium phosphate, pH 7.4, 5 mM MgC 2 , and 0.1 mM EDTA) was preincubated for 5 min at 37*C with 10-50 pM OHSATE phosphoramidate compound from a stock solution in DMSO (final DMSO concentration was 0.1%); the reaction was initiated by the addition of NADPH (3 mM final concentration). Incubations with no NADPH served as controls. At specific times (0-120 min), 0.1 mL samples were taken and the reaction terminated by the addition of I volume of stop solution (acetonitrile). The samples were vortex for 30 sec and then centrifuged at 1500g for 10 min. The supernatant was transferred to HPLC glass vials and analyzed without further processing by HPLC. Figures 1 and 2 depict depletion of NM108 SATE phosphoroamidate (B299) and NM 107 SATE phosphoroamidate (B 102), respectively, after incubation with NADPH in monkey liver S9. HPLC system for medium samples-unchanged prodrug HPLC: Agilent 1100 Column: Phenomenex Luna C18(2), 20x2mm, Mobile phases (MP): MP(A) 10mM K 2 HPO4 pH5, MP(B) ACN Gradient elution: 20 to 63% MP(B) run from 0 to 30 min 222 WO 2008/082601 PCT/US2007/026408 Runtime: 20 min Flow rate: 1 mL/min Injection volume: 10-20 pL UV: 252 nm-NM I 08SATE deriv (B299) 272 nm-NM 107SATE deriv (B 102) 1005351 Thus, without being limited to any theory, since the metabolism is NADPH dependent, it is possible that the phosphoroamidate compound is preferentially activated by Cytochrome P450 in the liver. Example 42 Determination of Triphosphate Levels in Cells Preparation of primary hepatocyte cultures 1005361 Freshly isolated cells from animal and human liver were obtained in suspension on ice. Following receipt, cells were pelleted by centrifugation at 500 rpm (rat) or 700 rpm (monkey and human) and resuspended at 0.8 million cells per mL of platting medium (HPM). Multi-well collagen-coated plates (12-well) were then seeded by addition of 1 mL of cell suspention (0.8 million cells/ mL). The plates were gently shaken to evenly distribute the cells and placed in an incubator at 37*C for approximately 4 to 6 hours to allow cells to attach. Once cells have attached, the platting medium was removed and replaced with hepatocyte culture medium (HCM). Cells were left overnight in an incubator at 37"C to acclimatize to culture and the medium. Incubations with test article [00537] Hepatocyte incubations were conducted in a final volume of 1.0 mL HCM/well (0.8 million cells/ mL). HCM from overnight incubation of cells was removed and replaced with fresh HCM, pre-warmed to 37*C, containing 10 IM test article from a stock solution in DMSO (final DMSO concentration was 0.1 %). At specific times (up to 24 hrs), incubation medium was discarded and the cell monolayers were carefully washed two times with ice-cold PBS. Following the last wash, all PBS was carefully removed and 1 mL of extraction buffer (ice-cold 70% methanol) was added. Each well was sealed with parafilm immediately following addition of methanol. Once the entire plate was processed, additional parafilm was placed on entire plate forming a double seal to prevent evaporation during the extraction process. The cover lid was then placed on the plate and sealed with tape. 223 WO 2008/082601 PCTIUS2007/026408 The plates were then stored at -20 0 C for a minimum of 24 hrs to allow for extraction of intracellular contents. Preparation of Huh7 or HepG2 cultures 1005381 HepG2s or Huh7 cells were plated at 0.4 X 106 cells/well in collagen coated 12-well plates. Cells were allowed to attach overnight. Culture medium from overnight incubation of cells was removed and replaced with fresh culture medium, pre-warmed to 37 0 C, containing 10 piM test article from a stock solution in DMSO (final DMSO concentration was 0.1%). After 24-72 hours, incubation medium was discarded and the cell monolayers were carefully washed two times with ice-cold PBS. Following the last wash, all PBS was carefully removed and I mL of extraction buffer (ice-cold 70% methanol) was added. Each well was sealed with parafilm immediately following addition of methanol. Once the entire plate was processed, additional parafilm was placed on entire plate forming a double seal to prevent evaporation during the extraction process. The cover lid was then placed on the plate and sealed with tape. The plates were then stored at -20*C for a minimum of 24 hrs to allow for extraction of intracellular contents. Sample preparation for analysis [005391 Cellular extracts were prepared by transferring 0.9 mL of extract into 2 mL microfuge tubes followed by centrifugation for 5 min at 14,000 rpm. Approximately I 00pL of the supernatant was transferred to HPLC vials and triphosphate levels determined by LCMS/MS as described below. 1005401 HPLC conditions: NM107-triphosphate HPLC: Column: Phenomenex Luna Amino 3 m I OOA, 30x2mm, Mobile phases (MP): (A) 70% 10mM NH4OAc 30% ACN pH 6.0 (B) 70% ImM NH 4 OAc 30% ACN pH 10.5 224 WO 2008/082601 PCT/US2007/026408 Gradient elution: Step Time Flow A B 0 0.00 400 80 20 1 0.10 400 80 20 2 0.11 400 40 60 3 0.21 400 40 60 4 2.60 400 10 90 5 2.61 400 0 100 6 5.60 400 0 100 7 5.61 400 80 20 8 9.00 400 80 20 Flow rate to MS: 0.400 mL/min, no split Injection volume: 10 4L Compound Precursor ion Product ion NM107 triphosphate 498.0 112.0 [005411 Exemplary HPLC conditions: NM108-triphosphate HPLC: Column: Phenomenex Luna Amino 3 pm 1OA, 30x2mm, Mobile phases (MP): (A) 70% 10mM NH40Ac 30% ACN pH 6.0 (B) 70% 1mM NH4OAc 30% ACN pH 10.5 Gradient elution: Step Time Flow A B 0 0.00 400 60 40 1 0.10 400 60 40 2 0.11 400 40 60 3 0.21 400 40 60 4 2.60 400 10 90 5 2.61 400 0 100 6 5.61 400 0 100 7 5.61 400 60 40 8 9.00 400 60 40 Flow rate to MS: 0.400 m~lmin, no split Injection volume: 10 pL Compound Precursor ion Product ion NMI08 triphosphate 538.0 152.0 225 WO 2008/082601 PCT/US2007/026408

NH

2 NNH2 HO 14 0 NMI07 and B102 1005421 NM 107 triphosphate and B 102 triphosphate levels in cell extracts were observed as follows: Intracellular Triphosphate (pmol/million cells) drug in culture Human Monkey HepG2* Huh7* B102 991 1838 1.5 9.2 NM107 19 10 17 37 24 hr incubation In 10 PM drug *72 hr incubation In 10 PM drug 1005431 As seen from the data levels of intracellular triphosphate for B102 were higher compared to those for NMI07. Example 43 Demonstration of Potent Antiviral Activity of Second Generation Nucleoside Inhibitors, B102, in HCV-Infected Chimpanzees 1005441 Nucleoside analogs such as NMI 07 (2'methyl cytidine, valopicitabine nucleoside component) have shown efficacy against HCV in the clinical setting and their 5'-triphosphates (TP) can be potent inhibitors of HCV NS5B polymerase. However, their wide systemic distribution and inefficient hepatic conversion to TP may lead to reduced safety and antiviral activity. The in vivo preclinical safety and antiviral activity of the nucleotide prodrugs, B102 were assessed. 1005451 Methods: For pharmacokinetic (PK) and toxicology studies, B102 were orally administered to rats or monkeys at doses from 20 to 300 mg/kg/day up to 14 days. Hepatic nucleoside TP levels were determined by LC-MS/MS. Compounds (10 mg/kg/day) were administered once daily by oral gavage for 4 days in chimpanzees chronically infected with HCV genotype 1. HCV viral loads were monitored before, during and after treatment by quantitative RT-PCR. 226 WO 2008/082601 PCT/US2007/026408 100546) Results: PK studies in rat and monkey revealed that B102 and has a first pass hepatic extraction of >95% with low systemic exposure (<1%). Hepatic TP levels were 10-50-fold higher with nucleotide prodrugs versus a nucleoside counterpart. No toxicity was observed after administration of 50 mg/kg/day of A2 to monkeys for 14 days. No initial emesis or GI toxicity was observed. In HCV infected chimpanzees, B 102 produced a rapid and potent antiviral effect followed by a rebound to baseline after drug discontinuation. Mean viral load reductions ranged from 1.5 log10 with B102 to over 4 days of drug exposure. An equivalent dose of valopicitabine led to a 0.7 logl0 viral reduction. No lab abnormalities or evidence of toxicities were observed in chimpanzees. 1005471 Thus, when orally administered, B102 generates high hepatic levels of triphosphates coupled with low systemic exposure, leading to rapid and potent inhibition of HCV replication in chimpanzees, thus demonstrating a promising in vivo preclinical safety profile and antiviral activity. Example 44 100548] Compounds were tested in an anti-HBV assay. Determination of anti-HBV activity in HBV virions and nucleocapsids via endoenous polymerase assays (EPA) Drug susceptibility assay using a wild-type HBV producer cell line 1. 12-well collagen-I coated plates were seeded with producer cells expressing wild type HBV at a density of 0.5-1x10 6 cells per well in 2 ml growth/selection media. 2. Drug stock solutions were made up freshly in 100% DMSO as 200x stocks. Five additional 4-fold dilutions were prepared from these 200x stock in 100% DMSO. For each experiment, 4 aliquots of each drug dilution series were stored at -20'C until used. 3. Once cells reached confluency (1 day after cells were seeded), drug treatment was initiated by adding 10 pl of drug dilution into 2 ml of fresh growth/selection media. Thus, the final DMSO concentration did not exceed 0.5%. The no-drug control wells received only 10 pl of DMSO in fresh media. 4. Cells were treated every-other-day with 2 ml of fresh drug/medium for a total of 8 days. Cell lysates were then collected on day 10 and subjected to EPA analysis as described below. Preparation of nucleocapsid-containing lysates for EPA analysis 227 WO 2008/082601 PCT/US2007/026408 1. Cells were grown for 3 to 4 days in 12-well collagen-I coated plates until confluent. 2. Media was carefully aspirated and the cell monolayers were rinsed once with 1 ml of PBS. 3. One ml of lysis buffer (50 mM Tris-HCI pH 7.5/150 mM NaCl/5 mM MgCl 2 /0.2% NP-40) was added to each well. Plates were stored on ice for 30 min to 4 h. 4. Lysed cells were transferred to 1.5 ml-microfuge tubes. 5. Lysates were clarified by spinning at 14,000 rpm for 5 min at room temperature. 6. Clarified lysates were transferred to fresh tubes and immediately frozen on dry ice, then stored at -80 0 C until endogenous polymerase assays were performed as described below. Preparation of secreted virions from supernatant for EPA analysis 1. Cells were grown for 3 to 4 days in 12-well collagen-I coated plates until confluent. 2. Media was carefully aspirated and transferred to 1.5 ml-microfuge tubes. 3. Supernatants were clarified by spinning at 14,000 rpm for 5 min at room temperature. 4. Clarified supernatants were transferred to fresh tubes and immediately frozen on dry-ice, then stored at -80 0 C until endogenous polymerase assays were performed essentially as described below. Endogenous polymerase assay (EPA) of cell lysates and supernatants 1. EPAs were performed essentially as desribed by Seifer et al (1998). Intracellular HBV nucleocapsids were immunoprecipitated from the cytoplasmic lysates overnight at 4"C with a polyclonal rabbit anti-HBcAg antibody and immobilized on protein A sepharose CL-4B beads. Secreted virions were immunoprecipitated from clarified cell supernatants overnight at 4*C with a monoclonal mouse anti-LS antibody (MAI8/7) in the absence of detergent. 2. Following 3 washes of the immobilized capsids or virions with 1 ml of EPA wash buffer (75 mM NH4C1, 50 mM Tris-HCI pH 7.4, 1 mM EDTA), endogenous polymerase reactions were initiated by adding 50 pl of detergent-containing EPA cocktail (50 mM Tris-HCI pH7.4, 75 mM NH4CI, 1 mM EDTA, 20 mM MgC 2 , 0.1 mM P-ME, 0.5% NP-40, 100 pM cold dGTP, TTP, dCTP, and 50 nM "P-dATP) and 228 WO 2008/082601 PCT/US2007/026408 incubated overnight at 37oC. The detergent is required to strip the outer envelope from immunoprecipitated virions as well as to enhance permeability of the nucleocapsids. 3. Following digestion with 1 mg/mI of proteinase K for lh at 37*C, endogenously "P-labeled HBV DNA was liberated via phenol/chloroform extraction. 4. The nucleic acids were precipitated with 1 volume of SM NH-acetate and 2.5 volumes of 100% EtOH, and then separated on a 1% native agarose gel in Tris borate-EDTA buffer. 5. Gels were blotted onto positively charged nylon membrane overnight at room temperature via capillary transfer in 0.4 N NaOH. 6. Dried membranes were exposed to a Phosphorlmager screen (GE Healthcare) overnight at room temperature, then scanned (Storm 860, GE Healthcare) and quantitated with ImageQuant software (GE Healthcare). 7. The 50% effective concentration (EC50) values were calculated from the resulting best-fit equations determined by Xlfit, version 4.1 (IDBS). 1005491 The following results were obtained. Compound Ref. No. Virion RI Structure EC 5 o(pM) EC 5 o(pM) A348 - N (NM 48) A362 - N (NM 77) ++ ++ N MW A616 o- N (NM 128) ++ N CAI C819 o a O- -o (NM 177) N++ ++ 229 WO 2008/082601 PCT/US2007/026408 A361 N (NM 55) 0 .. .. NN A550 0 (NM 204) B261 N N-O O^, .. + PMEA NH 2 N HO- O N L-dT +++

EC

3 o in HBV virion and RI is provided as follows: +++S 1 m, ++ >1-10 pm and +>10 pm Example 45: Ethynyl nucleosides for the Treatment of HCV Exemplary compound syntheses are described below: 230 WO 2008/082601 PCT/US2007/026408 HO 0 N B O- -O HO F 7 HO F CC,' HOF !%",0F. MO4 F. 31S*:: X=CF CC .C -Scheme 6 0-(triphenylmethyloxy-tert-butyl-S-acyl-2-thioethyl) H-phosphonate (00550] To a stirred solution of 7j (0.32mmol) and S-(2-Phosphite-ethyl) 2,2 dimethyl-3-triphenylmethyloxy-thiopropionate (0.42 mmnol) in pyridine (5mil) at -15 *Cwas added dropwise pivaloyl chloride (0.64 mmol) under nitrogen.The reaction mixture was stirred at -1 5*C for 2 hours. Dichloromethane and NH4LCI solution were added. Organic phase was separated washed with NI-lCl solution, dried over Na 2

SO

4 , filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (DCM/MeOH) to yield the title compound Brown powder. Molecular Formula Ca 8

H

3

,FN

5 0 8 PS 'H NMR (DMSO-do, 400 MHz) 5 (ppm) 1.12 (s, 6H),1.84 (im, 4H) 3.04 (s, 2H), 3.92 (d, J= 5.60 Hz, I H), 4.01-4.10 (mn, 3H), 4.33-4.39 (in, 2H), 4.60-4.66 (in, 1H), 6.13 (d, J= 18.00 Hz, I H), 6.67 (s, 2H), 7.21-7.35 (mn, 5H), 7.81 (s, lH), 10.86 (brs, 1 H) 3jL:.N-(4-fluoro-benzylaminyl)-9-[(2R)2-deoxy-2-fluoro2-C-ethynyl-p-D thioethyl) phosphate 1005511 To a stirred solution of 29(0.088 mmiol) in anhydrous carbon tetrachloride (880 p~L), 4-fluoro-benzylamine (0.44 mnmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 h and evaporated to dryness (bath temperature not exceeding 30 *C). The crude mixture was filtered on a silica gel plug, eluting with a gradient 0-10 % methanol in dichloromethane to yield the title 231 WO 2008/082601 PCT/US2007/026408 compound. White solid. Molecular Formula C4sH 4 sF 2N 6 0PS 'H NMR (DMSO d 6 , 400 MHz) 8 (ppm) 1.09 (s, 6H), 3.03 (s, 2H), 3.39-3.41 (m, 2H), 3.90-3.93 (m,51-), 4.05-4.08 (m, 1H), 4.20-4.23 (m, 2H), 4.62-4.65(m, 1H), 5.74 (m, I H), 6.08 6.14 (dd, J= 17.94 Hz and .= 4.22 Hz, I H), 6.32 (m, I H), 6.67 (s, 2H), 7.21-7.35 (m, 19H), 7.81 (s, I H), 10.86 (brs, IH) " P NMR (DMSO-d 6 , 162 MHz) 8 (ppm) 9.83 (s, IP) "F NMR (DMSO- d 6 , 235 MHz) 5 (ppm) -116.24 (s, IF), -158-.2 (s, IF) Scan ES* 899 (M-H)*, UV %.. 255 nm 31a: N-(4-fluoro-benzylaminyl)-(9-[(2R)2-deoxy-2-fluoro-2-C-ethynyl-p-D erythro-furanosyl]-guanin)-5'-yl-O-(bydroxy-tert-butyl-S-acyl-2-thioethyl) phosphate 1005521 30a (0.09 mmol) was dissolved in dichloromethane (320 pL) and treated with formic acid (32 gL). The mixture was stirred at room temperature for 10 min, filtered through a solid phase extraction column eluting with a gradient 0-30 % methanol in dichloromethane, then purified by reverse phase (C 18) silica gel column chromatography eluting with a gradient 0-100 % acetonitrile in water and lyophilised from a mixture of water/dioxan to yield the title compound. White solid. Molecular Formula C 2 6

H

3

IF

2

N

6 OPS 'H NMR (d 6 -DMSO, 400 MHz) 8 (ppm) 1.09 (s, 6H), 3.03 (s, 2H), 3.39-3.41 (m, 2H), 3.90-3.93 (m,5H), 4.05-4.08 (m, IH), 4.20-4.23 (m, 2H), 4.62-4.65(m, I H), 4.92( m, lI H), 5.74 (m, 1H), 6.08-6.14 (dd, J= 17.94 Hz and = 4.22 Hz, I H), 6.32 (m, 1 H), 6.67 (s, 2H), 7.21-7.35 (m, 4H), 7.81 (s, I H), 10.86 (brs, 11H) " P NMR (DMSO-d, 162 MHz) & (ppm) 9.66 (s, IP) "F NMR (DMSO d 6 , 235 MHz) 8 (ppm) -116.24 (s, IF), -158.44 (s, IF) Scan ES* 657 (M-H)*, UV X ma 254nm 30b: N-(4-methoxy-benzylaminyl)-(9-[(2R)2-deoxy-2-fluoro-2-C-ethynyl-p-D erythro-furanosyl]-guanin)-5'-yl-O-(triphenylmethyloxy-tert-butyl-S-acyl-2 thioethyl) phosphate (005531 30b was synthesized from 29 and 4-methoxy-benzylamine as described for 30a. White solid. Molecular Formula C 46

H

4 8FN 6 0,PS 'H NMR (DMSO- d 6 , 400 MHz) 8 (ppm) 1.09 (s, 6H), 3.03 (m, 2H),3.42 (d, .=5.02 Hz, 2H),3.71 (d, J= 3.60 Hz, 3!:H), 3.85-3.90 (m, 5H), 4.06-4.10 (m, IH), 4.23-4.29 (m, 2H), 4.604.66 (m, IH), 5.54-5.57 (m, 1H), 6.08-6.14 (dd, J= 17.94 Hz and J= 4.22 Hz, IH), 6.28-6.33 (m, I H), 6.60 (s, 2H), 6.80-6.85 (m, 2H), 7.18-7.20 (m, 2H), 7.23-7.25 (m, 15H), 7.82 (s, I H), 10.56 (brs, 1 H) )" P NMR (DMSO-d, 162 MHz) 8 (ppm) 9.83 (s, I P) "F 232 WO 2008/082601 PCT/US2007/026408 NMR (DMSO- d 6 , 235 MHz) 8(ppm) -116.24 (s, IF), -158.2 (s, IF) Scan ES* 911 (M-H)*, UV ;., 255 nm 31b: N-(4-methoxy-benzylaminyl)-{9-[(2R)2-deoxy-2-fluoro-2-C-ethynyl-A-D erythro-furanosyl]-guanin}-5'-yl-O-(hydroxy-tert-butyl-S-acyl-2-thioethyl) phosphate [005541 L.p was synthesized from 30b as described for 31a. White solid. Molecular Formula C27H34FN 6 OPS 'H NMR (d 6 -DMSO, 400 MHz) 8 (ppm) 1.09 (s, 6H), 3.03 (m, 2H),3.42 (d, .J=5.02 Hz, 2H),3.71 (d, .1= 3.60 Hz, 3H), 3.85-3.90 (m, 5H), 4.06-4.10 (m, IH), 4.23-4.29 (m, 2H), 4.60-4.66 (m, IH), 4.92 (t, J=5.50 Hz, I H), 5.54-5.57 (m, 1H), 6.08-6.14 (dd, J= 17.94 Hz and J= 4.22 Hz, IH), 6.28-6.33 (m, IH), 6.60 (s, 2H), 6.80-6.85 (m, 2H), 7.18-7.20 (m, 2H), 7.82 (s, IH), 10.56 (brs, IH) ,'' P NMR (DMSO-d 6 , 162 MHz) S (ppm) 9.86 (s, IP) 'F NMR (DMSO- d 6 , 235 MHz) 8 (ppm) -158.24 (s, IF) Scan ES+ 669 (M-H)*, UV Xn 254nm 30c: N-(4-trifluoro-benzylaminyl)-(9-[(2R)2-deoxy-2-fluoro-2-C-ethynyl-p-D erythro-furanosyl]-guanin)-5'-yl-O-(triphenylmethyloxy-tert-buty-S-acyl-2 thioethyl) phosphate [00555] 1c was synthesized from 29 and 4-trifluoromethyl-benzylamine as described for 30. White solid. Molecular Formula C 4 H.sF 4

N

6 08PS 'H NMR (d 6 -DMSO, 400 MHz) 8 (ppm) 1.09 (s, 6H), 3.03 (t, J= 6.44 Hz, 2H),3.42 (s, 2H), 3.87 3.92 (m, SH), 4.03-4.08 (m, IH), 4.24-4.29 (m, 2H), 4.60-4.64 (m, 1 H), 5.79-5.82 (m, 1 H), 6.08-6.14 (dd, J= 17.94 Hz and J= 4.22 Hz, I H), 6.28-6.33 (m, I H), 6.60 (s, 2H), 7.23-7.25 (m, 15H), 7.50-7.70 (m, 4H), 8.25 (brs, 1 H), 10.76 (brs, 1H),'' P NMR (DMSO-d, 162 MHz) S (ppm) 9.86 (s, IP) " F NMR (DMSO- d 6 , 235 MHz) S (ppm) -158.20 (s, IF) Scan ES 4 949 (M-H)*, UV %a 254nm 31c: N-(4-trifluoromethyl-benzylaminyl)-(9-[(2R)2-deoxy-2-fluoro-2-C-ethynyl p-D-erythro-furanosyl-guanin)-5'-yl-O-(hydroxy-tert-butyl-S-acyl-2-thioethyl) phosphate [005561 3c was synthesized from 30c as described for 31a. White solid. Molecular Formula C 27 HJiF 4

N

6 OsPS 'H NMR (d 6 -DMSO, 400 MHz) 6 (ppm) 1.09 (s, 6H), 3.03 (t,J= 6.44 Hz, 2H),3.42 (s, 2H), 3.87-3.92 (m, 5H), 4.03-4.08 (m, I H), 4.24-4.29 (m, 2H), 4.60-4.64 (m, IH), 4.91 (brs, I H), 5.79-5.82 (m, IH), 6.08 6.14 (dd, J= 17.94 Hz and = 4.22 Hz, 1 H), 6.28-6.33 (m, I H), 6.60 (s, 2H), 7.50-7.70 (m, 4H), 8.25 (brs, I H), 10.64 (brs, IH) ,' P NMR (DMSO-d, 162 MHz) 8 (ppm) 233 WO 2008/082601 PCT/US2007/026408 9.86 (s, IP) "F NMR (DMSO- d 6 , 235 MHz) 6 (ppm) -158.24 (s, IF) Scan ES* 669 (M-H)*, UV X m 254nm [00557] Further exemplary compounds synthesized using procedures similar to those described herein are listed below. Note the following names for the compounds synthesized in the examples. 6a: 6-Chloro-9-((2R)-2-deoxy-2-C-ethynyl-2-fluoro-p-D-erythro pentofuranosyl]purine 6b:N2-Isobutyryl-9-[(2R)-2-deoxy-2-C-ethynyl-2-fluoro-p-D-erythro pentofuranosyl]guanine 6c: 1-[(2R)2-Deoxy-2-C-ethynyl-2-fluoro-p-D-erythro-pentofuranosyl]uracile 6d: 1-[( 2 R)-2-Deoxy-2-C-ethynyl-2-fluoro-p-D-erythro-pentofuranosyl]thymine 6e: N4-Benzoyl-1-[(2R)-2-deoxy-2-C-ethynyl-2-fluoro-p-D-erythro pentofuranosyl]cytosine 6f: 5-Fluoro- 1-[(2R)2-deoxy-2-C-ethynyl-2-fluoro-p-D-erythro pentofuranosyl]uracile 6g: 4-Chloro-7-((2R)2-deoxy-2-C-ethynyl- -2-fluoro-p-D-erythro pentofuranosyl]pyrrolo[2,3-d]pyrimidine 7i: 9-[(2R)2-Deoxy-2-C-ethynyl-2-fluoro-o-D-erythro-pentofuranosylladenine 7j: 9 -[(2R)-2-Deoxy-2-C-ethynyI-2-fluoro-p-D-erythro-pentofuranosyl]guanine 7k: 1-[(2R)-2-Deoxy-2-C-ethynyl-2-fluoro-p-D-erythro-pentofuranosyl]cytosine 71: 4-Amino-7-[(2R)2-deoxy-2-C-ethynyl-2-fluoro-p-D-erythro pentofuranosyl]pyrrolo[2,3-d]pyrimidine I lc: 1-[(2R)-2-Deoxy-2-C-ethynyl-2-fluoro-p-D-erythro-pentofuranosyl]-uracil-5'-yl bis(S-pivaloyl-2-thioethylphosphate I If: 1-[(2R)-2-Deoxy-2-C-ethynyl-2-fluoro-p-D-erythro-pentofuranosyl]-5 fluorouracil-5'-yl-bis(S-pivaloyl-2-thioethylphosphate) Ilk: 1-[( 2 R)-2-Deoxy-2-C-ethynyl-2-fluoro-p-D-erythro-pentofuranosyl]-cytosin-5' yl-bis(S-pivaloyl-2-thioethylphosphate) I11 : 1-[( 2 R)-2-Deoxy-2-C-ethynyl-2-fluoro-p-D-erythro-pentofuranosyl]-4 aminopyrrolo(2,3-d]pyrimidin-5'-yl-bis(S-pivaloyl-2-thioethylphosphate) 16: 9

-[(

2

R)-

2 ,3-Dideoxy-2-C-ethynyl-2-fluoro-p-D-glycero-pentofuranosyl]guanine 234 WO 2008/082601 PCTIUS2007/026408 17: 9-[(2R)-2,3-Dideoxy-2-C-ethynyl-2-fluoro-3-D-glycero-pentofuanosyljguanin S '-yl-bis(S-pivaloyl.2-thioethylphosphate) 20: 9-[(2R)-2-Deoxy-2-C-ethynyl-2-fluoro-J3-D-erythro-pentofuranosyijguanin-5'-y bis(S-pivaloyl-2-thioethylphosphate 23: 9- [(2R)2-Deoxy-3,5-di-O-isobutyry1-2-C-ethynyl-2-fluoro-o3-D-erythro pentoftuwaosyl]guanine 24: N2-Isobutyryl-9-[(2R)2-Deoxy.3 ,5-di-O-isobutyryI-2-C-ethyny1-2-fluoro-o-D erythro-pentofuranosyl] guanine 27i: 9-[(2R)-2-Deoxy-2-C-ethynyl-2-fluoro-o3-D-erythro-pentofuranosyl]adenine 5' triphosphate sodium salt 27j: 9- [(2R)-2-Deoxy-2-C-ethynyI-2-fluoro- P-D-erythro-pentofuranosyll guanine 5' triphosphate sodium salt 28: 9-[(2R)-2,3-dideoxy-2-C-ethynyl-2-fluoro-p3-D-glycero-pentofuranosyl]guanine 5'-triphosphate sodium salt 235 WO 2008/082601 PCT/US2007/026408 Po~in. TIPOSC1, AciO. CN,0 fl0vUThF NN. TTmHa I :8 vwb r* Tluerw DASi Id:O - Mymin.otmn It! -5-fluaorcmruft NHUS *04o-P MOONr Z3dNHdn HF TI : Or adenie 7: Er - cytoolne MWcweV9 71: W - 4-lnoproWo(.3d"pflno 4Schwn I. or Tw. AT 0~'~ ?.T RI. 10%.D(T4eo" l4m Th)~An PAN T 3 ) M ~ . 4I R T _ _ _ 4Pcbwbn s.T7 It ac 0 N F C~N% 0 N )mur 4.MO 23236 WO 2008/082601 PCT/US2007/026408 P L........P N NW 0 00 TMP t0 RM. THP > swA a san AP~Tr.T:P 4 o N NMnTrMFtS(M tO O N NIusTr N NtHWm1r +k13I 17 N N .+ \ N m rN 2 -scheme 30. f)uranos yl0puri I L _0 0 -T, "" N OMF XF 18 X) CHOVrs H -Scheme 3b 1005581 6-Chloro-[3 ,5-0-( I,3-diyl-l, 1,3,3-tetraisopropyldisiloxane)-p-.D-ribo furanosyl]purine (18.84 mmol) was coevaporated twice with TI-F then dissolved in anhydrous Ti-F (50 mL). Anhydrous DMSO (1 19.82 mmol) was added and the resulting solution was cooled down to between -40 *C and -30 *C. Trifluoroacetic anhydride (36.17 mmol) was added dropwise and the solution was stirred between -40 *C and -30 *C for 2 h after which EtN 3 (97.52 mmol) was added. The resulting solution was allowed to warm UP to room temperature over 30 min while stirring, then diluted with diethyl ether and washed with H 2 O, dried (Na2SO 4 ) and evaporated to 237 WO 2008/082601 PCT/US2007/026408 dryness. The crude material was purified by column chromatography eluting with I % ethyl acetate in dichloromethane. The yellow oil obtained was dissolved in DCM and stirred with an excess of MgSO 4 at room temperature for 36 h, filtered and concentrated under reduced pressure to give the title compound. Pale yellow foam. Molecular Formula C 22

H

35

CIN

4 0s Si 2 .'H NMR (DMSO-d 6 , 250 MHz) 8 (ppm) 9.01 (s, 1H, H-8), 8.61 (s, IH, H-2), 6.35 (s, 1H, H-I'), 5.35 (d, 1H, H-3', J3-4'= 9.7 Hz), 4.31 (m, I H, H-4'), 4.12-4.09 (m, 2H, H-5', H-5"), 1.22-0.94 (m, 28H, iPr). LRFAB-MS (GT): 527 (M+H)*, 525 (M-H)'. UV Xmx 263 nim. Rf 0.17 (ethyl acetate/CH 2 CI, 10/90, v/v). 4a and 4'a: 6-Chloro-9-[3,5-0-(1,3-diyl-1,1,3,3-tetraisopropyldisiloxane)-2-C trimethysilylethynyl-p-D-arabino-furanosylpurine (1a) and 6-chloro-9-13,5-0 (1,3-diyl-1,1,3,3-tetralsopropyl-disiloxane)-2-C-trimethylsilylethyny-p-D-ribo furanosyllpurine (4'a) 1005591 Trimethylsilylacetylene (59.20 mmol) was dissolved in anhydrous THF (70 mL). n-Butyllithium (37 mL, 1.6 M in hexanes) was added dropwise at - 78 *C. The reaction mixture was stirred for 30 min at - 78 "C and then allowed to warm up to - 55 *C. 3a (11.84 mmol) in solution in THF (34 mL) was added dropwise at - 78 *C. The reaction mixture was stirred for 1 h at - 78 "C and then allowed to warm up to 30 *C. The reaction was quenched by careful addition of aqueous saturated NH4C1 (45 mL) at -78 *C. After warming to room temperature, the mixture was diluted with diethyl ether, washed with saturated brine, dried (Na 2

SO

4 ) and concentrated to dryness. The crude material was purified by silica gel chromatography eluting with 20 % Et 2 O in petroleum ether to yield two compounds: 4a (4.62 g, 62 %). Pale yellow foam. Molecular Formula C 27 H4sC1N 4 0 5 Si 'H NMR (DMSO-d 6 , 200 MHz) 5 (ppm) 8.81 (s, I H, H-8), 8.64 (s, 1H, H-2), 6.64 (s, IH, OH-2'), 6.33 (s, I H, H-I'), 4.57 (d, I H, H-3', J 3

.

4 .= 6.6 Hz), 4.20-3.97 (m, 3H, H-4', H-5' and H-5"), 1.20-1.00 (m, 28H, iPr), 0.14 (s, 9H, Si(CH 3

)

3 ). LRFAB-MS (GT): 625 (M+H)*. R 1 0.72 (ethyl acetate/CH 2 C1, 10/90, v/v); and E' (0.75 g, 10 %). Yellow oil. Molecular Formula C 2 7

H

45

CIN

4 03 Sij 'H NMR (DMSO-d, 200 MHz) 8 (ppm) 8.80 (s, 1H, H-8), 8.73 (s, I H, H-2), 6.64 (s, I H, OH 2'), 6.55 (s, 1 H, H-i'), 4.62 (d, 1H, H-3', 3 J3.

4 .= 9.1 Hz), 4.39 (in, IH, H-4'), 4.13 (dd, IH, H-5', J' 4 = 3.4 Hz, 2 j5.., = 13.2 Hz), 3.90 (dd, 1H, H-5", J..4. = 2.6 Hz, 238 WO 2008/082601 PCT/US2007/026408 2Js,..- = 13.2 Hz), 1.15-1.00 (m, 28H, iPr), 0.10 (s, 9H, Si(CHJ) 3 ). LRFAB-MS (GT): 625 (M+H)*. RJ 0.64 (ethyl acetate/CH 2 CI, 10/90, v/v). 5a: 6-Chloro-9-[(2R)2-deoxy-2-fluoro-3,5-0-(1,3-diyl-1,1,3,3 tetraisopropyldisiloxane)-2-C-trimethylsilyletbynyl-p.-D-erythro pentofuranosylipurine [005601 4a.(6.78 mmol) was dissolved in dried toluene (31.8 mL) under argon and cooled to -20*C. DAST (40.68 mmol) was added dropwise and the cooling bath was removed after the addition was complete. Stirring was continued for 1.5 hour and the mixture was dissolved with ethyl acetate and poured into saturated NaHCO 3 and stirred for 5 min. The organic layer was washed with saturated brine, dried (Na 2

SO

4 ), concentrated, and purified by silica gel chromatography eluting with 20 % Et 2 0 in petroleum ether to give the title compound (1.11 g, 26 %). Yellow oil. Molecular Formula C 27

H

4 4

CIN

4 0 4 Si. 'H NMR (CDCl 3 -d.200 MHz,) S(ppm) 8.79 (s, 1H, H 8), 8.48 (s, IH, H-2), 6.48 (d, IH, H-1', JI'.-F = 16.0 Hz), 4.74 (dd, I H, H-3', J 3

'-

4 '= 9.4 Hz, J3'-F = 22.4 Hz), 4.36 (d, 1H, H.5', 2

J

5 ..5,. = 13.4 Hz ), 4.20 (m, 1H, H-4'), 4.10 (dd, I H, H-5", 2

J

5 .s' = 13.4 Hz, J 5

-.

4 = 2.6 Hz ), 1.30-1. 10 (m, 28H, iPr), 0.00 (s, 9H, Si(CH) 3 ). LRFAB-MS (GT): 627 (M+H)*. UV ?a. 263 rim. Rf 0.24 (diethyl ether/petroleum ether, 30/70, v/v). 6a: 6-Chloro-9-[(2R)-2-deoxy-2-C-ethynyl-2-fluoro-p-D-erythro pentofuranosyll purine [005611 A mixture of 5a (3.65 mmol) and ammonium fluoride (47.45 mmol) in methanol (12.5 mL) was heated at reflux for 2 h. After cooling down to room temperature, the mixture was concentrated to dryness and purified on silica gel chromatography eluting with a stepwise gradient 2-4 % of methanol in DCM to provide the title compound (0.89 g, 78 %). Yellow solid. Molecular Formula

C,

2 HiCIFN 4 0 3 . 'H NMR (DMSO-d, 200 MHz) S(ppm) 9.02 (s, 1H, H-8), 8.89 (s, I H, H-2), 6.55 (d, 1H, H-i', JI'-F = 16.1 Hz), 6.34 (ld, I H, OH-3'), 5.38 (It, 1H, OH 5'), 4.64 (dt, I H, H-3', J 3 .. 4.= 9.3 Hz, J3'.F = 22.5 Hz), 4.07 (m, I H, H-4'), 3.83 (m, 2H, H-5', H-5"), 3.76 (d, IH, ethynyl, 4 JH-F = 5.3 Hz). 1 3 C NMR (DMSO-d, 75 MHz,) S(ppm) 152.0 (C-2), 151.2 (CA), 149.5 (C-6), 144.7 (C-8), 130.9 (C-5), 95.1 (d, C-2', 'J2'-F 1 82.3 Hz), 88.0 (d, C-l', 2 j 1 '-F = 39.8 Hz), 82.9 (d, CCH, JC-F " 8.2 Hz), 82.5 (C-4'), 75.3 (d, CCH, JC-F = 31.5 Hz), 72.7 (d, C-3', 2J 3 '-F = 19.5 Hz), 59.0 239 WO 2008/082601 PCT[US2007/026408 (C-5'). '"F NMR (DMSO-d6. 235 MHz) 8(ppm) -159.0 (in). LC/MS: (M+H*) 313.1 (8.29 min). UV Amu 262 nm. Rf 0.21 (MeOH/CH2CI, 7/93, v/v). 2: 9-[(2R)2-Deoxy-2-C-ethyny-2-fluoro-p-D-erythro-pentofuranosyl]adenine 1005621 6a (2.24 mmol) was dissolved in saturated ammoniacal methanol (80 mL) and heated for 4 h in a steel bomb at 90 *C. After cooling down to room temperature the mixture was coevaporated to dryness and purified by silica gel chromatography eluting with a gradient 5-8 % of methanol in DCM to yield the title compound (305 mg, 46 %). Yellow solid. Molecular Formula C, 2

H,

2 FNsO 3 'H NMR (DMSO-d 6 . 200 MHz) 8(ppm) 8.40 (s, IH, H-8), 8.17 (s, IH, H-2), 7.38 (Is, 2H, NH2) 6.35 (d, 1H, H-l ', 3 Ji..F = 17.1 Hz), 6.25 (m, I H, OH-3'), 5,33 (It, I H, OH-S'), 4.68 (m, IH, H-3'), 4.00-3.69 (m, 3 H, H4', H-5', H-5"), 3.77 (d, 1 H, ethynyl, 4 JH-F = 5.4 Hz). 1 1C NMR ( DMSO-d 6 , 75 MHz) S(ppm) 155.8 (C-4),152. (C-2), 149.0 (C-6), 138.7 (C-8), 118.5 (C-5), 95.4 (d, C-2', IJ 2 '-F " 180.8 Hz), 87.6 (d, C-', 2 Ji.F= 40.5 Hz), 82.5 (d, CCH, 3 JC-F = 8.0 Hz), 82.0 (C4'), 74.5 (d, CCH, 2 JC-F = 3 1.0 Hz), 72.8 (d, C-3', 2 J3'.F = 19.5 Hz), 59.2 (C-5'). "F NMR (DMSO-d 6 , 235 MHz) 8(ppm) -158.0 (t). LC/MS: (M+H*) 294.1 (5.74 min). UV Ama 258 n. Rf 0.33 (MeOH/CH 2 CI, 15/85, v/v). 4b: N'-Isobutyryl-9-3,5-0-(1,3-diyl-1,1,3,3-tetraisopropyldisiloxane)-2-C trimethylsilylethynyl-p-D-arabino-furanosylguanine [00563] To a suspension of Cr0 3 (110.76 mmol) in DCM (220 mL) at 0 *C, acetic anhydride (110.76 mmol) and anhydrous pyridine (221.52 mmol) were added. 9-[3,5 0-(1,3-Diyl- 1,1,3,3-tetraisopropyldisiloxane)-ribo-furanosyl]-N2-isobutyrylguanine (36.92 mmol) in solution in DCM (110 mL) was added dropwise. The cooling bath was removed and the resulting solution stirred at room temperature for 5 h. The reaction mixture was poured into cold ethyl acetate, filtered through a silica and celite gel plug, concentrated to dryness and coevaporated twice with toluene. The residue obtained was dissolved in DCM and stirred with an excess of MgSO 4 overnight, filtered and evaporated to get the ketone. The trimethylsilylacetylene (88.60 mmol) was dissolved in anhydrous THF (98 mL) under argon. n-Butyllithium (55.4 mL, 1.6 M in hexanes) was added dropwise at - 78 *C. The reaction mixture was stirred for 30 min at - 78 *C and then allowed to warm up to - 55 *C. The ketone in solution in THF (49 ml) was added dropwise at - 78 *C. The reaction mixture was stirred for 1 h at 240 WO 2008/082601 PCT/US2007/026408 78 *C and then allowed to warm up to - 30 *C and stirred for 3 h. The reaction was quenched by careful addition of aqueous saturated NH 4 C1 (72 mL) at - 78 *C. After warming to room temperature, the mixture was diluted with ethyl acetate, washed twice with saturated brine, dried (Na2SO 4 ) and concentrated to dryness. The crude material was purified using column chromatography eluting with 1.5 % MeOH in dichloromethane to give the title compound (8.59 g, 34 %, 2 steps). Pale yellow foam. Molecular Formula C 3

IH

5 sNsO 6 Si 3 . 'HNMR (DMSO-d.250 MiHz) S(ppm) 12.10 (Is, I H, NH), 11.69 (Is, I H, NH), 7.91 (s, IH, H-8), 6.69 (s, 1H, OH), 5.94 (s, I H, H 1'), 4.29 (d, I H, H-3', J 3 .. 4.= 5.5 Hz), 3.85-3.95 (in, 31H, H-4', H-5' and H-5"), 2.46 (in, IH, CH(CH 3

)

2 ), 0.90-1.08 (in, 30H, iPr and CH(CH 3

)

3 ), 0.00 (s, 9H, Si(CH 3 )2). LC/MS: (M+H*) 692.4 (24.96 min). UV Xm 1 254 im, X.m2 281 nmi. Rf 0.34 (MeOH/CH 2 C], 15/85, v/v). 5b: NY-Isobutyryl-9-[(2R)-2-deoxy-2-fluoro-3,5-0-(1,3-diyl-1,1,3,3 tetralsopropyldisiloxane)-2-C-trimethyl-silyethymyl-p.-D-erythro pentofuranosyljguanine [005641 4b (2.89 mmol) was dissolved in dried DCM (60 mL) under argon and pyridine (18.06 mmol) was added. The reaction mixture was cooled to -20 *C and DAST (31.35 mmol) was added dropwise. The cooling bath was removed after completion of the addition. Stirring was continued for 1 h 15 and the mixture was dissolved with ethyl acetate and poured into saturated NaHCO 3 and stirred for 5 min. The organic layer was washed with saturated brine, dried (Na2SO 4 ), concentrated, and purified by silica gel chromatography eluting with ethyl acetate in DCM (2 %) to give the title compund (1.41 g, 70 %). Yellow oil. Molecular Formula C 3 :Hs4 FNsOs Si 3 . 'H NMR (DMSO-d 6 250 MHz) 8(ppm) 12.22 (s, I H, NH), 8.09 (s, 1H, H-8), 6.21 (d, I H, H-i', JI'-F = 15.6 Hz), 4.54 (dd, I H, H-3', J3'-F = 23.6 Hz, 33'.4.= 9.8 Hz), 4.33 (m, IH, H-5', 2

J

5 -.-. = 13.1 Hz), 4.16 (in, 1 H, H-5"), 2.81 (in, 1H, CH(CH 3

)

2 ), 1.13-1.03 (m, 34 H, iPr and CH(CH 3

)

2 ), 0.08 (s, 9H, Si(CH) 3 , 3 JH.K = 6.9 Hz). "F NMR (DMSO-d, 235 MHz) 8(ppm) - 160.26 (dd, JF-1- = 16.1 Hz, JF.3- = 23.3 Hz). LCIMS: (M+H*) 694.7 (24.02 min). LRFAB-MS (GT): 694 (M+H)*, 692 (M-H)-. UV m.a 256 nm. Rf0.46 (MeOH/CH 2 CI, 05/95, v/v). 6b: N-Isobutyryl-9-[(2R)-2-deoxy-2-C-ethynyl-2-fluoro-0-D-erythro pentofuranosyljguanine. 241 WO 2008/082601 PCT/US20071026408 [00565] b (1.89 mmol) was dissolved in methanol (13.8 mL) and ammonium fluoride (24.54 mnol) was added. The resulting solution was stirred at reflux for I h and evaporated to dryness. The crude material was purified on silica gel chromatography eluting with a stepwise gradient 6-10 % of methanol in DCM to yield the title compound (344 mg, 48 %). Pale yellow oil. Molecular Formula C1 6

H

2 e FNsO 4 Si 3 . 'H NMR (DMSO-d, 400 MHz) S(ppm) 12.18 (Is, lH, NH), I l.77(ls, IH, NH), 8.34 (s, IH, H-8), 6.29 (d, IH, OH-3', JOH.

3 = 7.5 Hz), 6.20 (d, 1H, H-l', JI'F = 16.2 Hz), 5.39 (t, IH, OH-5', JoH.' = 5.1 Hz), 4.52 (dt, 1H, H-3', J3'-F = 22.9 Hz), 3.98 (in, IH, H-4'), 3.90-3.85 (in, 2H, H-5' and ethynyl), 3.72 (m, IH, H-5"), 2.52 (m, I H, CH(CH 3

)

2 ), 1.14 (d, 6 H, CH(CH 3 )2, 3 JH-H = 6.9 Hz). 1 3 C NMR (DMSO-d6, 100 MHz) S(ppm) 180.7 (C-6), 155.3 (C-2), 148.9 (C4), 137.3 (C-8), 120.4(C-5), 95.8 (d, C-2', 'J2'.F = 182.1 Hz), 87.7 (d, C-I', 2

J

1 '-F = 39.2 Hz), 83.4 (d, CCH, 3 JC-F = 9.1 Hz), 82.6 (C4'), 75.9 (d, CCH, 2JC-F = 31.2 Hz), 72.9 (d, C-3 , 2 J3,-F = 19.1 Hz), 59.3 (C-5'). 'F NMR (DMSO-d 6 , 235 MHz) S(ppm) - 158.9 (m). LC/MS: (M+H*) 380.3 (8.34 min). UV %m,a 256 nm, Ry0.40 (MeOH/CH 2 Cl, 15/85, v/v). 71: 9- [( 2 R)-2-Deoxy-2-C-ethynyl-2-fluoro-p-D-erythro-peutofuranosyl]guanine 1005661 b (1.33 mmol) was dissolved in saturated methanolic ammonia (62 mL) and stirred at room temperature for 20 h. The reaction mixture was then evaporated to dryness under reduced pressure. The residue was dissolved in water and washed twice with ethyl acetate. The aqueous layer was evaporated and purified on reverse phase column chromatography (C 18) eluding with a gradient 2-15 % of acetonitrile in water. The residue obtained was then dissolved in hot ethyl acetate, filtered and dried to give the title compound (134 mg, 33 %). Yellow solid. Molecular Formula Cj2Hz 2 FNsO4 'H NMR (DMSO-d, 400 MHz) 8(ppm) 10.70 (Is, I H, NH), 7.98 (s, I H, H-8), 6.60 (Is, 2H, NH 2 ), 6.21 (d, IH, OH-3', JOH-3' = 7.6 Hz), 5.83 (d, I H, H-1', J1'-F = 16.9 Hz), 5.29 (t, 1H, OH-5', JoHs,. = 5.2 Hz), 4.50 (td, IH, H-3', J3'-F = 22.8 Hz, J 3 .. 4.= 9.2 Hz), 3.93-3.81 (in, 3H, H-4', H-5' and ethynyl), 3.70 (m, IH, H-5"). '"C NMR (DMSO-d, 100 MHz) 8(ppm) 157.2 (C-6), 154.3 (C-2), 151.05 (C-4), 135.1 (C-8), 116.7 (C-5), 96.4 (d, C-2', 'Jc-F = 182.1 Hz), 87.4 (d, C- , 2 JC-F = 39.2 Hz), 83.1 (d, CCH, JC-F 9.1 Hz), 82.4 (C-4'), 76.2 (d, CCH, 2 JC-F = 31.2 Hz), 73.2 (d, C-3', 2 JC-F = 20.1 Hz), 59.5 (C-5'). "F NMR (DMSO-d, 235 MHz) 8(ppm) -158.5 (m). LC/MS (A): (M+H*) 310.1 (5.55 min). LRFAB-MS (GT): 619 (2M+H), 310 (M+H)*, 152 (B+H)*, 617 (2M-H)~, 308 (M-H)~. UV "m 253 nm 242 WO 2008/082601 PCT/US2007/026408 3c: 1-1 2 -Oxo- 3 ,5-0-(1, 3 -diyl-1,1,3,3-tetraisopropyldisiloxane)-p-D-ribo furanosyluracile 1005671 3c was synthesized from I-[3,5-0-(1,3-diyl-1,1,3,3 tetraisopropyldisiloxane)-ribo-furanosyl]uracile as described for 3a. Pale yellow foam. Molecular Formula C21HaN 2 0 7 Si 2 'H NMR (DMSO-d, 400 MHz) 8(ppm) 11.58 (is, IH, NH), 7.74 (d, 1H, H-6, J 6

.

5 = 8.0 Hz), 5.68 (d, IH, H-5, J 5

.

6 = 8.0 Hz), 5.45 (s, IH, H-I'), 4.97 (d, IH, H-3', J3-.

4 . = 9.2 Hz), 4.06-3.90 (m, 3H, H-4', H-5'), 1.14-0.87 (m, 28H, iPr). LR LC/MS: (M+H*) 485.1 (M-H-) 483.1 (5.53 min). UV Xm. 262 nm. Rf 0.40 (MeOHICH 2 Cl, 05/95, v/v). 4c: 1-[3,5-O-(1,3-diyl-1,1,3,-tetraisopropyldisiloxane)-2-C-trimethylsilylethynyl P-D-arabino-furanosylluracile Yoshimura, Y.; lino, T.; Matsuda, A. Tetrahedron Lett. 1991, 32, 6003-6006. 100568] Molecular Formula C 26

H

46

N

2 0 7 Si3'H NMR (DMSO-d 6 , 400 MHz) 6(ppm) 11.35 (Is, IH, NH), 7.44 (d, IH, H-6, J 6

.

5 = 8.0 Hz), 6.54 (s, 1H, OH), 6.02 (s, IH, H-I '), 5.54 (d, IH, H-5, J6.5= 8.0 Hz), 4.13-3.93 (m, 3H, H-3', H-5'), 3.75 (m, IH, H-4'), 1.03-0.96 (m, 28H, iPr), 0.00 (s, 9H, Si(CH3)3).. "C NMR (DMSO-d 6 , 100 MHz) S(ppm) 163.4 (C-4), 150.8 (C-2), 141.6 (C-6), 103.6 (CCSi), 101.2 (C-5), 92.5 (CCSi), 87.3 (C-I'), 80.9 (C4'), 77.9 (C-2'), 75.9(C-3'), 61.8 (C-5'), 17.7-17.1 (8C, 4 SiC(CH 3

)

2 ), 13.3-12.6 (4C, 4 SiC(CH 3 )2), 0.2 (3C, Si(CH 3

)

3 ). LR LC/MS: (M+H*) 583.2 (M-H-) 581.2 (6.72 min). UV Xmu 261 nm. Rf 0.27 (Ethyl acetate/CH 2 CI, 10/90, v/v). 2c: 1-1(2R)-2-Deoxy-2-fluoro-3,5-O-(1,3-diyl-1,1,3,3-tetraisopropyldisiloxane)-2 C-trimethylsilyiethynyl-p-D-erythro-pentofuranosylluracile 1005691 L was synthesized from 4c as described for 5a. Yellow oil. Molecular Formula C 27

H

4

FN

2 0Si 3 'H NMR (DMSO-d, 400 MHz) 8(ppm) 11.62 (si, 1 H, NH), 7,43 (dl, IH, H-6, J 6

.

5 = 8.0 Hz), 6.12 (d, 1H, H-I', JI'-F = 16.8 Hz), 5.68 (d, I H, H-5, JS-6 = 8.0 Hz), 4.22-3.85 (m, 4H, H-3', H-4', H-5'), 1.16-1.00 (m, 28H, iPr), 0.00 (s, 9H, Si(CH) 3 ). "F NMR (DMSO-d, 376 MHz) 8(ppm) -159.7. LR LC/MS: (M+H*) 585.2 (M-H') 583.3 (6.47 min). UV X,,. 261 nm. R 1 f 0.52 (Ethyl acetate/CH 2 CI, 15/85, v/v). 6c: 1-1(2R) 2 -Deoxy- 2 -C-ethynyl-2-fluoro-p-D-erythro-pentofuranosyluracile 243 WO 2008/082601 PCT/US2007/026408 100570] A mixture of Sc (0.56 mmol) and ammonium fluoride (7.31 mmol) were dissolved in methanol (IOmL) stirred at reflux for I h and evaporated to dryness. The resulting residue was purified on silica gel flash column chromatography eluting with a gradient 0-20 % methanol in DCM and then, on reverse phase column chromatography eluting with a gradient 0-100 % acetonitrile in water to give the desired product which was lyophilised from water (47 mg, 31 %). White lyophilised powder. Molecular Formula CuIH,, FN 2 0 5 .'H NMR (DMSO-d, 400 MHz) S(ppm) 11.49 (sl, IH, NH), 7.87 (d, IH, H-6, Js5 = 8.0 Hz), 6.18 (d, IH, OH-3', JOH-3' = 7.2 Hz), 6.10 (d, IH, H-i', JI -F = 18.0 Hz), 5.69 (d, 1H, H-5, Js.

6 = 8.0 Hz), 5.32 (m, 1H, OH-5'), 4.19-4.10 (m, 2H, H-3' and ethynyl), 3.85-3.75 (m, 2H, H-4' H-5'), 3.60 (m, 1H, H-5"). "C NMR (DMSO-d, 100 MHz) S(ppm) 163.3 (C-4), 150.6 (C 2), 140.1 (C-6), 102.5 (C-5), 95.5 (d, C-2', J2'-F - 186.1 Hz), 87.1 (d, C-', 2 JI'.F = 40.2 Hz), 83.2 (d, CCH, 2 JC-F =8.0 Hz), 82.1 (C4'), 76.5 (d, CCH, 4 JC-F = 30.1 Hz), 73.3 (d, C-3', 2 JC-F = 19.1 Hz), 58.7 (C-5'). "F NMR (DMSO-d, 376 MHz) 8(ppm) -158,2. LR LC/MS: (M+H) 271.1 (M-H') 269.2 (1.12 min). HRFAB-MS Ct HnO 5

N

2 F. (M+H*) calculated 271.0730, found 271.0739. UV X, 261 nm. Rf 0.33 (MeOH/CH 2 Cl, 20/80, v/v). 2d: 1-[3,5-0-(1,3-diyl-1,1,3,3-tetraisopropyldisiloxane)-p-D-ribo furanosyl]thymine [00571] The 1 -(p-D-ribo-furanosyl)thymine (40.9 mmol) was dissolved in pyridine (435ml) and the mixture was cooled down to 0*C with an ice-bath for 25 minutes. Then, TIPSC1 2 (16.2ml) was added and after complete addition, the mixture was allowed to warm up to room temperature. The reaction mixture was stirred at room temperature for 3hrs, diluted with dichloromethane and water, washed with a saturated aqueous solution of NaHC0 3 . The organic phases were combined, dried over Na 2

SO

4 , filtered and evaporated. The residue was coevaporated with toluene to remove pyridine. The resulting residue was purified by flash column chromatography eluting with a gradient 0-2 % of methanol in dichloromethane to give the title compound . Off-white powder. Molecular Formula C22He NzO, Si 2 . 'H NMR (DMSO-d 6 .400 MHz) S(ppm) 0.94-1.04 (m, 28H), 1.73 (s, 3H), 3.86-3.96 (m, IH), 4.06-4.13 (m, 2H), 4.14-4.20 (m, IH), 5.44-5.48 (m, I H), 5.53 (brs, IH), 5.77 (brs, I H) 7.42 (s, I H), 11.35 (brs, IH). UV %. 212 rn, 266 nm. 244 WO 2008/082601 PCT/US2007/026408 3: 1-[2.Oxo-3,5-0-(1,3-diyl-1,1,3,3-tetraisopropyldsiloxane)-p-D-ribo furanosylithymine [00572] To a suspension of Cr0 3 (60 mmol) in dichloromethane (200 mL) at 0 *C, acetic anhydride (59 mmol) and anhydrous pyridine (120 mmol) were added. 2 (20 mmol) in solution in DCM was added dropwise. The cooling bath was removed and the resulting solution stirred at room temperature for 3 h. The reaction mixture was poured into cold ethyl acetate, filtered through a silica and celite gel plug, concentrated to dryness and coevaporated twice with toluene to give the title compound. Colorless oil. Molecular Formula C22H 3 s N 2 0 7 Si 2 4d: 1-13,5-0-(1,3-diyl-1,1,3,3-tetraisopropyldisiloxane)-2-C-trimethylsilylethynyl P-D-arabino-furanosyllthymine [005731 ! was synthesized from 3d and trimethylacetylene as described for 4a. Brown solid. Molecular Formula C 2 7 H4S N 2 0, Si3. Scan ES + 597 (M+H)*, UV X"m 265 nm. L: 1-[(2R)-2-Deoxy-2-fluoro-3,5-0-(1,3-diyl-1,1,3,3-tetraisopropyldisiloxane)-2 C-trimethyl-silylethynyl-p-D-erythro-pentofuranosyljthymine 1005741 L was synthesized from 4a as described for 5a. Brown solid. Molecular Formula C 2 7

H

4 7

FN

2 0 6 Si 3 'H NMR (CDCI 3 -d 6 ,400 MHz) 8(ppm) 0.1 (s, 9H), 1.05 1.14 (m, 28H), 1.92 (s, 3H), 3.99-4.13 (m, 1H), 4.44-4.9 (m, 3H), 6.35 (d, IH, J= 16.44 Hz), 7.2 (s, IH), 8.86 (s, IH). Scan ES* 599 (M+H)*, 6d: 1-1(2R)-2-Deoxy-2-C-ethynyl-2-fluoro-fp-D-erythro-pentofuranosyl]thymine [005751 d was synthesized from 5d as described for 7i. Molecular Formula C1 2 H1 3

FN

2 0 5 . 'H NMR (CDC 3 -d. 400 MHz) 8(ppm) 1.75 (s, 3H), 3.6-3.65 (m, IH), 3.82-3.84 (m, 2H), 4.07 (d, 1H, J= 5.27 Hz), 4.19 (m, 1M), 5.4 (brs, 1H), 6.08 (d, IH,J= 17.8 Hz), 6.17 (brs, IH), 7.8 (s, IH), 11.46 (brs, IH). Scan ES' 285 (M+H)*, UV Xma, 266 nmn. 4e: N 4 -Benzoyl-1-13,5-O-(1,3-diyl-1,1,3,3-tetraisopropyldisiloxane)-2-C trimethylsilylethynyl-p-D-arabino-furanosylicytosine 1005761 4e was synthesized from 3e and trimethylacetylene as described for 4a. Brown solid. Molecular Formula C 3 3

H

51

N

3 0 7 Sij Scan ES 686 (M+H)*, UV Xm 260 nm, 310 nm. 245 WO 2008/082601 PCT/US2007/026408 :5e N'-benzoyl-1-[(2R)2-Deoxy-2-fluoro-3,5-O-(1,3-diyl-1,1,3,3 tetraisopropyldisiloxane)-2-C-trimethyl-silyethynyl-p-D-erythro pentofuranosyl]cytosine 1005771 Se was synthesized from N 4 -benzoyl-1 -[3,5-O-(1,3-diyl-1,1,3,3 tetraisopropyldisiloxane)-2-C-trimethyl-silylethynyl-D-arabino-furanosyl]cytosine as described for 5a. Yellow solid. Molecular Formula C 3 aH4 FN 3

O

6 Si 2 . Scan ES + 688 (M+H)*, UV Xma 260 run, 310 n. 6e: N'-benzoyl-1-{(2R)-2-Deoxy-2-C-ethynyl-2-fluoro-p-D-erythro pentofuranosyllcytosine 1005781 L was synthesized from 5e as described for 71. White powder. Molecular Formula CisH 6

FN

3 0 5 . 'H NMR (DMSO-d 6 , 400 MHz) 8(ppm) 3.63 3.69 (m, 1H), 3.82-.393 (in, 2H), 4 (d, I H, J= 5.27 Hz), 4.13-4.24 (in, 1H), 5.38 (brs, 11-1), 6.23-6.28 (m, 2H), 7.32-7.36 (in, I H), 7.49-7.53 (in, 2H), 7.6-7.64 (m, I H), 7.99-8.01 (in, 2H), 8.34 (d, I H, J= 7.32 Hz), 11.30 (brs, IH). Scan ES* 374 (M+H)*, UV X. 262 nm, 303 run. 7k: 1-1(2R)-2-Deoxy-2-C-ethynyl-2-fluoro-p-D-erythro-pentofuranosylcytosine 1005791 Molecular Formula CIH1 2

FN

3 0 4 .'H NMR (DMSO-d 6 400 MHz) 8(ppm) 3.57-3.62 (in, 1H), 3.77-3.80 (in, 2H), 3.95 (d, IH, J= 5.53 Hz), 4.03-4.16 (in, IH), 5.2 (brs, 1H), 5.73 (d, I H, J= 7.19 Hz), 6.06 (d, IH, J= 7.19 Hz), 6.14-6.25 (in, 1 H), 7.17-7.3 (2brs, 2H), 7.74 (d, I H, J = 7.74 Hz). Scan ES * 270 (M+H)*, UV Am 271 nm. 8k : N'-dimethoxytrityl-1-[(2R)2-Deoxy-2-C-ethynyl-2-fluoro-p-D-erythro pentofuranosylcytosine 1005801 To a stirred solution of 7k (2.34 mmol) in pyridine (7.2 ml) was added trimethylsilyl chloride (9.36 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. 4-dimethylamino pyridine (1.17 mmol) and dimethoxytrityl chloride (3.51 mmol) were then added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM and sat NaHCO 3 solution. The organic phase was washed twice with sat NaHCO 3 solution, dried over Na 2

SO

4 , filtered and evaporated. The crude material was dissolved in a solution NH40HIdioxin (2:1) and stired for 4hrs. Solvent was evaporated and the residue purified by silica gel chromatography (DCM/EtOH) to yield the title 246 WO 2008/082601 PCT/US2007/026408 compound. White foam. Molecular Formula C 32

H

3 0 FN 3 0 6 . Scan ES - 570 (M+H)', UV %mam 277 nm 9k: 1-1(2R)-2-Deoxy-2-C-ethynyl-2-fluoro-p-D-erythro-pentofuranosyll-4-N dimetboxytrityl-cytosin-5'-yl-bis(S-pivaloyl-2-thioethylphosphate [005811 To a stirred solution of §k(0.35 mmol) in anh THF/tetrazole solution (1.05 mmol) was added bis(S-pivaloyl-2-thioethyl) NN-diisopropylphosphoramidite (0.42 mmol) at 0*C. The reaction mixture was stirred at room temperature for 3hrs. The reaction mixture was cooled down to 0*C and tert-butyl hydroperoxyde (0.7ml/mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with DCM, neutralized with sat Na 2

S

2 0 3 solution. The organic phase was washed twice with H 2 0, extracted, dried over Na 2

SO

4 , filtered and evaporated. The crude material was purified by silica gel chromatography (DCM/EtOH) to yield the title compound. Glassy compound. Molecular Formula

C

47 H, FN3011 PS 2 . Scan ES + 938 (M+H)*, UV % m. 277 nim ilk: 1-1(2R)-2-Deoxy-2-C-ethynyl-2-fluoro-p-D-erythro-pentofuranosyl]-cytosin 5'-yl-bis(S-pivaloyl-2-thloethylphosphate [00582] 9k (34 mmol) was stirred in AcOH/MeOH/H 2 0 (3/6/1) solution for 2hrs and at 50*C for 4 hours. The reaction mixture was then evaporated and purified by silica gel chromatography (DCM/EtOH) to yield the title compound. White lyophilized powder. Molecular Formula C 2 5

H

37

FN

3 O, PS 2 . 'H NMR (DMSO-d 6 , 400 MHz) S (ppm) 1.17 (s, 18H), 3.08-3.11 (t, J= 6.07 Hz, 4H), 3.99-4.08 (m, 7H), 4.22-4.28 (m, 2H), 5.73-5.75 (d, J= 7.30 Hz, 1H), 6.30 (brs, 2H), 7.26-7.31 (d, .1=17.30 Hz, 2H), 7.47-7.48 (d, J= 7.30 Hz, I H) "F NMR (DMSO-d, 376 MHz) S (ppm) -156.48 (s, IF) 'P NMR (DMSO-d, 162 MHz) 8 (ppm) -1.96 (s, lP). Scan ES* 638 (M+H)*, UV %m. 271 nm 12: N 2 -Metboxytrityl-9-[(2R)2-deoxy-2-C-ethynyl-2-fluoro-p-D-erythro pentofuranosyljguanine 1005831 To a stirred solution of 71 (5.18 mmol) in pyridine (7 ml/mmol) was added trimethylsilyl chloride at room temperature. The mixture was stirred at room temperature for 6 hours. Methoxytrityl chloride (6.21 nmol) was then added and the reaction mixture was stirred at room temperature for 16 hours and 2 hours with

NH

4 0H (4ml/mmol). The mixture was diluted with ethyl acetate, washed with H 2 0, sat NaHC0 3 solution and sat NaCl solution, dried over Na 2

SO

4 , filtered and 247 WO 2008/082601 PCT/US2007/026408 evaporated. The crude material was purified by silica gel chromatography (DCM/MeOH) to yield the title comound.Yellowish oil. Molecular Formula

C

32 Hn FNsOs. 13: N2-Methoxytrityl-9-[(2R)-2-deoxy-2-C-ethynyl-2-fluoro-5-0-tert butyldimethylsilyl-p-D-erythro-pentofuranosyllguanine 1005841 To a stirred solution of 2(2.29 mmol) in pyridine (5 ml) at 0*C, was added tert-butyldimethylsilyl chloride (2.75 mmol). The reaction mixture was stirred at room temperature for 24 hours. It was then diluted in DCM and washed twice with

H

2 0. The organic phase was extracted, dried over Na 2

SO

4 , filtered and evaporated. The crude material was purified by silica gel chromatography (DCM/MeOH) to yield the title compound.Yellowisb oil._Molecular Formula C 3 sH44 FN 5

O

5 Si. Scan ES + 696 (M+H)*, Xma 260 nm. Scan ES- 694 (M+H)', UV X ma 260 nim 14: N2-Methoxytrityl-9-[(2R)-2,3-dideoxy-2-C-ethynyl-2-fluoro-5-0-tert butyldimethylsilyl-p-D-glycero-pentofuranosylIguanine 1005851 To a stirred solution of 13 (0.14 mmol) in acetonitrile (47 ml/mmol) was added 4-dimethylamino pyridine (0.56 mmol) and phenyl chlorothionoformate (0.43 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours and was concentrated under reduced pressure. The residue obtained was dissolved in DCM, the organic phase was washed with H 2 0, HCI (IN), dried over Na 2

SO

4 , filtered evaporated and co-evaporated with toluene. [005861 The crude material was dissolved in toluene (12 ml/mmol), azo-bis isobutyronitrile (0.02 mmol) and tributylstannane (0.24 mmol) were added at room temperature. The reaction mixture was stirred at 125*C for 2 hours and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (DMC/MeOH) to yield the title compound. Yellowish oil. Molecular Formula CnH 4 4 FN 5

O

4 SI. Scan ES + 680 (M+H)*, UV % ma 260 nml 15: N2-Methoxytrityl-9-[(2R)-2,3-dideoxy-2-C-ethynyl-2-fluoro-p-D-glycero pentofuranosyljguanine 100587] 14 (0.35 mmol) was dissolved in MeOH (20 ml/mmol). Ammonium fluoride (3.55 mmol) was then added at room temperature and the reaction mixture was stirred at 70*C for 2 hours. After concentration under reduced pressure, the crude material was purified by silica gel chromatography (DCM/MeOH) to yield the title 248 WO 2008/082601 PCT/US2007/026408 compound. Beige foam. Molecular Formula C 32

H

3 o FNsO. 'H NMR (CDCl 3 -d 6 , 400 MHz) 8 (ppm) 2.38-2.45 (m, 2H), 2.75 (brs, 2H), 3.64-3.67 (d, J= 12.20 Hz, 2H), 3.77 (s, 4H), 4.20-4.23 (d, 1= 11.7 Hz, lH), 4.41-4.42 (d, J= 8.4 Hz, IH), 5.83-5.87 (d, J=16.24 Hz, IH), 6.80-6.82 (d,J= 8.12 Hz, 4H), 7.26-7.31 (m, IIH), 7.84 (brs, I H), 9.26 (brs, I H) 16: 9-[(2R)-2,3-Dideoxy-2-C-ethynyl-2-fluoro-0-D-glycero pentofuranosyl]guanine 1005881 15 (0.09 mmol) was stirred in AcOH/THF/H 2 0 (3/6/1) solution at 50*C for 1 day. The reaction mixture was then concentrated under reduced pressure and purified by silica gel chromatography, C18 (H 2 0/ACN) Beige lyophilisated powder. Molecular Formula C1 2 H1 2

FN

5 0s.'H NMR (DMSO-d, 400 MHz) 8 (ppm) 2.57 2.74 (m, 2H), 3.56 (s, 1H), 3.61-3.64 (d, J= 12.10 Hz, I H), 3.79-3.82 (d, J= 12.10 Hz, I H), 3.91-3.93 (d, .1=5.40 Hz, I H), 4.32-4.35 (m, 1H), 5.25 (s, I H), 6.06-6.10 (d, J= 18.20 Hz, IH), 6.64 (s, IH), 8.01 (s, 1H), 10.82 (s, IH) ' 9 F NMR (DMSO-d 6 , 376 MHz) 8 (ppm) -138.4 (s, IF).Scan ES 292 (M+H)', Scan ES* 316 (M+Na)*, UV X mx. 251 nm 17: 9-1(2R)-2,3-Dideoxy-2-C-ethynyl-2-fluoro-p-D-erythro-pentofuranosyl] guanin-5'-yl-bis(S-pivaloyl-2-thioethylphosphate) [00589] 17 was synthesized from 14 (0.35 mmol) as described for 9. The crude material was then stirred in AcOHfIHF/H 2 0 (4/2/1) at 50 0 C, for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (DCM/MeOH) to yield the title compound, Beige solid. Molecular Formula C 26

H

37 FNSOSPSi 2 'H NMR (DMSO-d, 400 MHz) 8 (ppm) 2.48 (s, 18H), 2.65-2.68 (m, 2H), 3.06-3.10 (q, .I= 3.71Hz, and .= 6.02 Hz, 4H), 3.97-4.04 (in, 5H), 4.31-4.35 (m, 2H), 4.50-4.52 (in, IH), 6.13-6.18 (d, J= 17.60 Hz, IH), 6.63 (s, 2H), 7.82 (s, 1H), 10.85 (s, IH). "F NMR (DMSO-d 6 , 376 MHz) 8 (ppm) -139.2 (s, IF). Scan ES + 662 (M+H)*, UV % m. 254 tun. HPLC (0-100% ACN over a period of 8 min) tR=5.

6 5 min. 18: N 2 -Methoxytrityl-9-[(2R)-2-deoxy-2-C-ethymyl-2-fluoro-5-0-tert butyldimethylsilyl-3-O-tetrahydropyrany-p-D-erythro-pentofuranosyllguanine (005901 To a stirred solution of 1 (0.8 mmol), in anh THF (20 ml/mmol), at room temperature, was added p-toluen sulfonic acid (0.12 mmol) and dihydropyran (2 mI/mimol). The reaction mixture was stirred at room temperature for 3 days and 249 WO 2008/082601 PCT/US2007/026408 neutralized with TEA. The mixture was diluted with DCM, washed twice with H 2 0. The organic phase was dried over Na 2

SO

4 , filtered and evaporated. The crude material was purified by silica gel chromatography (DCM/MeOH) to yield the title compound. Molecular Formula C43Hs2 FNsO 6 Si. Scan ES* 780 (M+H)* 19: M-Methoxytrityl-9-[(2R)-2-deoxy-2-C-ethynyl-2-fluoro-3-0 tetrahydropyranyl-P-D-erythro-pentofuranosyl]guanine 1005911 19 was synthesized from 18, as described for 15. Molecular Formula C3 7 H3s FN 5 0 6 . Scan ES + 666 (M+H)*. 21: N2-Tetrahydropyranyl-9-[(2R)-2-deoxy-2-C-etynyl-2-fluoro-5-0-tert butyldimethylsilyl-3-0-tetrahydropyranyl-p-D-erythro-pentofuranosylIguanine [00592] 2 was obtained from the purification of 18. Molecular Formula C 2 5

H

42

FN

5

O

6 SI. Scan ES + 592 (M+H)*, UV ,. 273 nm 22: M-Tetrabydropyranyl-9-[(2R)-2-deoxy-2-C-ethynyl-2-fluoro-3-O tetrahydropyranyl-p-D-erythro-pentofuranosyllguanine 100593] 22 was synthesized from 21(0.46 mmol), as described for 15. Molecular Formula C 2 2 H2s FN 5 0 6 20: 9

-[(

2 R)-2-Deoxy-2-C-ethynyl-2-fluoro-p-D-erythro-pentofuranosyllguanin-5' yl-bis(S-pivaloyl-2-thioethylphosphate [005941 2 was synthesized from 19 (0.09 mmol), as described for 9k. The crude material was then stirred at room temperature in AcOHITHF/H 2 0 (4/2/1) solution overnight. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (DCM/MeOH) to yield the title compound. White lyophilized powder. Molecular Formula C 26 H3 7

FN

5

O,PS

2 'H NMR (DMSO-d 6 , 400 MHz) 8 (ppm) 1.16 (s, 20H), 3.06-3.09 (in, 4H), 3.90-3.91 (d, J= 5.40 Hz, I H), 3.99-4.10 (q, J= 6.70 Hz and J= 7.00 Hz, 4H), 4.32-4.38 (in, 2H), 4.63 (m, 1H), 6.10 6.14 (d, = 16.93 Hz, IH), 6.69 (s, 2H), 7.79 (s, 1H), 10.96 (s, lH) 'P NMR (DMSO d 6 , 162 MHz) 8 (ppm) -1.91 (s, IP) "F NMR (DMSO-d, 376 MHz) 8 (ppm) -156.82 (s, IF) Scan ES* 678 (M+H)*. 25: 1-(2R)-2-Deoxy-2-fluoro-3,5-O-(1,3-diyl-1,1,3,3-tetraisopropyldisioxane)-2 C-trimethylsilylethynyl-p-D-erythro-pentofuranosyl]-4-thiouracile 1005951 c (820 mg, 1.40 mmol) was dissolved in anhydrous 1,2-dichloroethane (35 mL) and treated with Lawesson's reagent (1.13 g, 2.80 mmol). The reaction 250 WO 2008/082601 PCT/US2007/026408 mixture was stirred at reflux overnight and evaporated to dryness. The resulting residue was filtered on a silica gel plug eluting with a gradient 0-5 % of ethyl acetate in dichloromethane to give the title compound. Yellow oil. Molecular Formula

C

26

H

4 s FN 2 0sSSij LR LC/MS: (M+H*) 601.3 (M-H') 599.3 (7.03 min). UV XAm 332 rim. Rf 0.71 (Ethyl acetate/CH 2 CI, 7/93, v/v). 26: 1-[(2R)2-Deoxy-2-fluoro-3,5-0-(1,3-diyl-1,1,3,3-tetraisopropyldisiloxane)-2 C-ethynyl-J-D-erythro-pentofuranosyljcytosine 100596] Crude 25 was dissolved in saturated ammoniacal methanol (9 mL). The resulting solution was heated by micro-waves at 120 *C for 20 min and concentrated under reduced pressure to give the title compound. Oily residue. Molecular Formula

C

26 H FN3O 5 Si 3 LR LC/MS (B): (M+H 4 ) 512.3 (M-H') 510.3 (5.33 min). UV Xm". 242 tm, ma 273 nm. 271: 9 -1( 2 R)-2-Deoxy-2-C-ethynyl-2-fluoro-p-D-erythro-pentofuranosylladenine 5'-triphosphate sodium salt [005971 To a solution of 7i (0.286 mmol) in triethylphosphate (750 pL), phosphoryle chloride (75 IL, 0.807 mmol) was added at 0 "C. This reaction mixture A was stirred overnight at 5 *C. Tributylammoniun pyrophosphate (PPi/Bu 3 N 1/1,5, Ig, 2.19 mmol) was dissolved in anhydrous DMF (2 mL). Tributylamine (420 pL, 1.76 mmol) was added to the PPi and the resulting mixture was stirred for 15 min at 0 *C. 2.4 mL of this solution were added to the rection mixture A. The reaction mixture was stirred at 0 *C for I min. The reaction was carefully quenched with TEAB 1 M (pH = 7,5, 10 mL), stirred 20 min at 0 *C, then diluted with water and ethyl acetate. The aqueous phase was concentrated under reduced pressure. The crude material was subjected to DEAE-Sephadex chromatography eluting with a gradient 10'- 1 M of TEAB). The desired fractions were combined, concentrated under reduced pressure and coevaporated with a mixture of water/methanol, and finally coevaporated with water. The resulting residue was purified on semipreparative HPLC. Fractions containing the expected product were concentrated under reduced pressure, coevaporated wiht a mixture of water/methanol and lyophilised from water. The triethylammonium salt triphosphate was eluted three times with water on a Dowex Na' resin column to yield after lyophilisation from water to the sodium salt. 251 WO 2008/082601 PCT/US2007/026408 [005981 Molecular Formula C1 2 Hu, FN 5

O

2

P

3 3Na. 'H NMR (D 2 0, 300 MHz) &Sppm) 8.31 (s, I H, H-8), 8.14 (s, IH, H-2), 6.28 (d, 1H, H-', 3 Ji--F = 15.6 Hz), 4.64 (m, 1H, H-3'), 4.42 (m, IH, H-5'), 4.35-4.25 (m, 2H, H4' and H-5"), 2.82 (d, 1H, ethynyl, 4 JH-F = 5.5 Hz). 31 P NMR (D 2 0, 121 MHz) S(ppm) -10.27 (d, IP, PI, JP,.PP 19.4 Hz), -11.03 (d, IP, Pa, Jp.pp = 19.4 Hz), -22.38 (t, IP, Pp, Jp.py = Jpp.pI = 19.4 Hz). "F NMR (D 2 0, 282 MHz) 8(ppm) - 160.0 (m). LRFAB-MS (GT): 600 (M+H)*, 578 (M-Na+2H)*, 556 (M-2Na+3H), 598 (M-H)", 576 (M-Na)', 554 (M 2Na+H)", 532 (M-3Na+2H)". 27:. 9-[(2R)-2-Deoxy-2-C-ethynyl-2-fluoro-p-D-erythro-pentofuranosylI guanine 5'-triphosphate sodium salt [00599] 2Tjwas synthesized from j as described for 27. Molecular Formula C1 2 Hu, FNSO 3

P

3 3Na. 'H NMR (D 2 0, 400 MHz) 8(ppm) 7.97 (s, 1H, H-8), 6.19 (d, 1H, H-i', 3 JI'-F = 16.0 Hz), 4.70 (m, 1H under H 2 0, H-3'), 4.39 (m, 1H, H-5'), 4.29 4.22 (m, 2H, H-4' and H-5"), 2.98 (d, 1H, ethynyl,' J.F =5.0 Hz). 31 P NMR (D 2 0, 162 MHz):.-10.50 (d, IP, Py, Jpy-pp = 19.4 Hz), -1 1.03 (d, IP, Pa, Jpa-P = 19.4 Hz), 22.3 8 (t, IP, Pp, Jpppy = Jppp, = 19.4 Hz). "F NMR (DMSO-d 6 , 376 MHz) S(ppm) 159,1 (m). LRFAB-MS (GT): 638 (M+Na)*, 616 (M+H)*, 594 (M-Na+2H)*, 572 (M-2Na+3H)*, 550 (M-3Na+4H)*, 592 (M-Na)', 570 (M-2Na+Hy, 548 (M-3Na+2H)~. .. 4-Chloro-7-(3,5-0-(1,3-diyl-1,1,3,3-tetraisopropyldisiloxane)-p-D-rbo furanosyl]pyrrolo[2,3-djpyrimidine 100600] 2g was synthesized from 9-[pJ-D-ribo-furanosyl]-7-deaza-6-chloropurine, as described for intermediate 12.Yellow oil. Molecular Formula C 23

H

3 8CIN3OSSi 2 . 'H NMR (DMSO-d 6 , 400 MHz) 8 (ppm) 0.96-1.04 (m, 28H), 3.92-3.95 (m, 3H), 4.41-4.58 (m, 2H), 5.65 (s, I H), 6.08 (s, 1H), 6.71 (s, I H), 7.83 (s, 1H), 8.62 (s, 1H) _3- 4 -Chloro-7-[2-oxo-3,5-0-(1,3-diyl-1,1,3,3-tetraisopropyldisiloxane)-p-D erythro-pentofuranosyllpyrrolo[2,3-d]pyrimidine [006011 Ig was synthesized from 2g as described for 3d. Brown solid. Molecular Formula C2aH3 6 ClN 3

O

5 Si 2 . Scan ES+ (M+H)* 528, UV Xma, 271 nm Ig 4-Chloro-[3,5-O-(1,3-diyl-1,1,3,3-tetraisopropyldisiloxane)-2-C trimethylsilylethynyl-P-D-arabino-furanosyl]pyrrolo[2,3-dlpyrimidine [006021 4g was synthesized from 3g as described for 4a. Beige solid. Molecular Formula : C 2 gH 46 ClN 3 0sSia.'H NMR (DMSO-d 6 , 400 MHz) S (ppm), 0.12 (s, 9H), 252 WO 2008/082601 PCT/US2007/026408 0.95-1.09 (m, 28H), 3.90-3.94 (m, 1H), 4.02-4.03 (m, 2H), 4.37-4.39 (d, .1= 6.74 Hz, 1H), 6.43 (s, 1H), 6.44 (s, 1H), 6.68 (d, J= 3.71 Hz, 1H), 7.71-7.72 (d, J=3.84 Hz, 1H), 8.66 (s, 1H) 5a: 4-Chloro-7-[(2R)2-deoxy-2-fluoro-3,5-0-(1,3-diyl-1,1,3,3 tetraisopropydisiloxane)-2-C-trimethylsilylethynyl- P-D-erythro pentofuranosyllpyrrolo[2,3-djpyrimidine [006031 5g was synthesized from 4g as described for 5a. Yellow oil. Molecular formula CzsH4sCIFN3OSSij.'H NMR (DMSO-d, 400 MHz) 8 (ppm) 0.33 (s, 9H), 1.02-1.13 (m, 28H), 4.0.-4.03 (d, J= 13.42 Hz, IH), 4.124.14 (d, J= 9.43 Hz, I H), 4.27-4.31 (d, J= 14.00 Hz, lH), 4.71 (brs, 1H), 6.58-6.62 (d,J= 17.07 Hz, I H), 6.82 6.83 (d, .= 3.80 Hz, I H), 7.72 (d, J= 3.80 Hz, I H), 8.69 (s, IH) "F NMR (DMSO d 6 , 235 MHz) 8 (ppm) -159.6 (s, IF) 6g: 4-Chloro-7-[(2R)2-deoxy-2-C-ethynyl-2-fluoro-p-D-erythro pentofuranosyljpyrrolo[2,3-djpyrimidine [006041 §g was synthesized from fg as described for 6a.Yellow oil. Molecular Formula CI 3 HuICIFN 3 0 3 . 'H NMR (DMSO-d 6 , 400 MHz) S (ppm) 3.60-3.65 (d, J= 5.44 Hz, 1H), 3.68-3.71 (d, J= 12.35 Hz, IH), 3.85-3.88 (d, /= 12.35 Hz, 1H), 3.95 3.97 (d, .J= 8.90 Hz, IH), 4.46-4.54 (dd, J= 23.23 Hz and ./= 9.39 Hz, IH), 5.38 (s, IH), 6.28 (s, IH), 6.57-6.61 (d, J= 16.47 Hz, IH), 6.79 (d, J= 3.82 Hz, IH), 8.04 (d, ..- =3.78 Hz, 1H), 8.70 (s, IH) " F NMR (DMSO-d, 235 MHz) 8 (ppm) -158.30 (s, IF). Scan ES* 312 (M+H)*. Scan ES' 356 (M+HCO 2 ). 71: 4-Amino-7-1(2R)2-deoxy-2-C-ethynyl-2-fluoro-p-D-erythro pentofuranosyljpyrrolo[2,3-dpyrimidine 1006051 71 was synthesized from 6g as described for 6a. White lyophilised powder. Molecular Formula C1 3

H,

3

FN

4 0 3 . 'H NMR (DMSO-d6, 400 MHz) 8 (ppm) 3.61 (d, J= 5.52 Hz, 1H), 3.63-3.67 (m, I H), 3.80-3.83 (d, J= 12.14 Hz, IH), 3.86-3.88 (d, J= 9.38 Hz, 1H), 4.46-4.54 (dd, J= 23.23 Hz and J 9.39 Hz, IH),5.30 (brs, I H), 6.1 (brs, I H), 6.41-6.47 (d, J= 16.47 Hz, IH), 6.57-6.61 (d, J=- 16.47 Hz, IH), 7.04 (s, 2H), 7.37-7.38 (d, J= 3.65 Hz, IH), 8.05 (s, IH) " F NMR (DMSO-d 6 , 235 MHz) 5 (ppm) -157.15 (s, IF) Scan ES+ 293 (M+H)*, UV na. 275 nm 23: 9 -1(2R)2-Deoxy-3,5-di-O-isobutyryl-2-C-ethynyl-2-fluoro-p-D-erythro pentofuranosylj guanine 253 WO 2008/082601 PCT/US2007/026408 [00606] A solution of 9-[(2R)-2-Deoxy-2-C-ethynyl-2-fluoro-p-D-erythro furanosyl]guanine (0.16 mmol), 4-dimethylaminopyridine (0.01 mmol), triethylamine (0.48 mmol) and isobutyric anhydride (0.48 mmol), in acetonitrile (Iml) was stirred at room temperature for 6 hours. The reaction mixture was hydrolysed with a NaHCO 3 saturated solution. Ethyl acetate was added. The organic phase was separated, washed with NaCl saturated solution, dried over Na 2

SO

4 , filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (DCM/EtOH) to yield the title compound White powder. Molecular Formula

CZOH

24

FN

5 0 6 'H NMR (DMSO-d, 400 MHz) 8 (ppm)1.02-1.22 (m, 12H), 2.53-2.59 (m, I H), 2.65-2.70 (m, 1H), 4.04 (d, J= 4.77 Hz, I H), 4.35-4.40 (m, 3H), 5.88-5.94 (dd, J= 9.39 Hz andfJ= 8.21 Hz, 1H), 6.21-6.25 (d, J= 17.28 Hz, 1H), 6.58 (s, 2H), 7.09 (s, I H), 10.82 (s, I H). Scan ES* 450.0 (M+H)*, UV na. 251 num 24: N-2-Isobutyryl-9-[(2R)2-deoxy-3,5-di-O-isobutyryl-2-C-ethynyl-2-fluoro-p-D erythro-pentofuranosyljguanine [00607] L was obtained from the purification of 23. White powder. Molecular Formula C2 4 H3,FN 5 0 'H NMR (DMSO-d, 400 MHz) 6 (ppm) 1.02-1.22 (m, 18H), 2.53-2.59 (m, I H), 2.65-2.70 (m, 1H), 2.74-2.80 (m, IH), 4.04 (d, J= 4.90 Hz, 1H), 4.35-4.40 (in, 3H), 5.73-5.80 (dd, J= 10.14 Hz and J= 7.80 Hz, 1H), 6.29-6.34 (d, J= 17.36 Hz, I H), 8.23 (s, I H), 11.80 (brs, IH), 12.3 (brs, I H). Scan ES* 520 (M+H)*, UV mX. 257 rn 4f.; 5-Fluoro-1-[3,5-O-(1,3-diyl-1,1,3,3-tetraisopropyldisiloxane)-2-C trimethylsilylethynyl-p-D-arabino-furanosylluracile 1006081 4_f was synthesized from 3f as described for 4a. Orange solid. Molecular Formula C 26

H

4 5

FN

2 0 7 Si 3 'H NMR (DMSO-d6, 400 MHz) 8 (ppm) 0.13 (s, 911), 0.94-1.06 (in, 28 H), 3.75 (m, I H), 3.96-4.09 (m, 3H), 5.99 (d, J= 1.53 Hz, 1 H), 6.53 (s, IH),7.58-7.60 (d, J= 6.76 Hz, IH), 11.8 (brs, IH) Scan ES~ 599 (M-H)~, UV Xma' 271 nm 5f. 5-Fluoro-1-1(2R)-2-deoxy-2-fluoro-3,5-O-(1,3-diyl-1,1,3,3 tetraisopropyldisiloxane)-2-C-trimethyl-silylethynyl-p-D-erythro pentofuranosylluracile 1006091 .f was synthesized from 4f as described for 5a. White solid. Molecular Formula C 26

H

44

F

2

N

2 0 6

SI

3 . 'H NMR (DMSO-d6, 400 MHz) 8 (ppm) 0.13 (s, 9H), 254 WO 2008/082601 PCT/US2007/026408 0.94-1.06 (in, 28 H), 3.92-3.95 (d, J= 12.47 Hz, 1H), 3.96-4.09 (in, I H), 4.21 (d, J= 12.22 Hz, IH),5.20(brs, 1H), 6.10-6.15 (d, J= 16.53 Hz, I H),7.56 (s, 1H), 12.23 (brs, IH) "F NMR (DMSO-d 6 , 235 MHz) & (ppm) -160.06 (s, IF), -165.94 (s, IF) Scan ES + 603 (M-H)*, UV X . 272 nm 61: 5-Fluoro-1-[(2R)-2-deoxy-2-C-ethynyl-2-fluoro-p-D-erythro.

pentofuranosyljuracile 1006101 6f was synthesized from 51 as described for 6a. White solid. Molecular Formula C 11

HOF

2

N

2 0 5 . 'H NMR (DMSO-d, 400 MHz) & (ppm) 3.61-3.64 (d, J= 12.55 Hz, IH), 3.81-3.85 (m, 2H), 4.11 (d, J= 4.91 Hz, 1H), 4.14-4.20 (m, 1H), 5.50 (s, I H), 6.04-6.09 (d, J= 16.91 Hz, I H), 6.20 (d, J= 7.64 Hz, I H), 8.29 (d,.J= 7.09 Hz, 1H), 12.05 (s, 1H) "F NMR (DMSO-d, 235 MHz) 8 (ppm) -158.74 (s, IF), -166.27 (s, IF) Scan ES* 289.0 (M-H)*, UV X m. 270 rnm. j11f 1-(2R)-2-deoxy-2-C-ethynyl-2-fluoro-p-D-eryhro-pentofuranosyll-5 fluorouracil-5'-y-bis(S-pivaloyl-2-thioethylpbospbate) [00611 11f was synthesized from 6f as described 9k. White solid. Molecular Formula C 25

H

35

F

2

N

2 0 1

OPS

2 . 'H NMR (DMSO-d6+DO, 400 MHz) 8 (ppm) 1.15-1.17 (m, I8H), 3.10 (t, J= 6.40 Hz, 4H), 4-4.08 (m, 5H), 4.19 (d, J= 5.39 Hz, I H), 4.24 4.39 (m, 3H), 6.12 (d, J= 16.82 Hz, I H), 6.39 (d, J = 6.07 Hz, 1H), 7.86 (brs, IH), 12.12 (brs, 1 H). 28: 9-1(2R)-2,3-dideoxy-2-C-ethynyl-2-fluoro-p-Dycero pentofuranosyliguanine 5'-triphosphate sodium 100612] 28 was synthesized from 16 as described for 27i. White powder. Molecular Formula C 12

H

12 FNSNaO, 2 P,. 'H NMR (D20, 400 MHz) (ppm) 2.61 2.72 (m, 2H), 2.95-2.96 (in, I H), 4.16-4.22 (m, IH), 4.35-4.40 (m, I H), 4.6-4.7 (in, 1 H), 6.17 (d, J= 16 Hz, I H), 8.02 (s, I H). "F NMR (D 2 0, 235 MHz) 8 (ppm) ( 138.95)-(-138.74) (m, IF), "P NMR (D20, 162 MHz) S (ppm) -10.66 (d, J= 19.44 Hz, IP), -11.14 (d, J= 19.44 Hz, IP), -22.82 (t, J= 19.44 Hz, IP). Scan ES* 599.6 (M-3Na) 3 *, UV )mx. 253 nm. [006131 All publications and patent, applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. While the claimed subject matter has been described in terms of various embodiments, the 255 WO 20081082601 PCT/US2007/026408 skilled artisan will appreciate that various modifications, substitutions, omissions, and changes may be made without departing from the spirit thereof. Accordingly, it is intended that the scope of the subject matter limited solely by the scope of the following claims, including equivalents thereof. 256

Claims (27)

1. A compound of formula: R S O Ri N 5 Ra Rb or a pharmaceutically acceptable salt, a tautomeric or polymorphic form thereof, wherein; RI is optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, hydroxyalkyl, amino, heterocyclyl or heteroaryl; 10 Ra and Rb are selected as follows: i) Ra and Rb are each independently hydrogen or optionally substituted alkyl, carboxyalkyl, hydroxyalkyl, hydroxyarylalkyl, acyloxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heterocyclyl; or ii) Ra and Rb together with the nitrogen atom on which they are substituted form a 15 3-7 membered heterocyclic or heteroaryl ring; and R 1 is a moiety derivable by removal of a hydrogen from a hydroxy group of an anti viral drug, and wherein when RI is tert-butyl or hydroxy-tert-butyl, then R 1 is not 3'-azido-2',3' dideoxythymidine. 20

2. The compound of claim 1 having the formula: 0 0 HO HO __AS _Oj PLR1 N Ra Rb 25 or a pharmaceutically acceptable salt, a tautomeric or polymorphic form thereof. 257

3. The compound of claim 1 having the formula: NHON H 3 N' 0 1 SS Rb R S1 C 0 O N - L Y O NH ORaN,'Rb or OaN'R OR 2 OR' Ra- 'Rb7 OR 2 OR 3 0 0 N NH25 R~s 0 Ny N1 C~N ~ H 3 N- 0 Ry1 HN:l "NH 2 Y0-. 0- 0r1 N 0 R~ 'Rb Ra N, R bOR 2 OR 3 O 2 OR 3 NH 2 OH ~N N H Ry O, O1 H R ",O1H 3 N R Rb or 0 Ra 'Rb O 2 OR 3 O 2 OR 3 5 wherein R 2and R 3are each independently H, or R 2and R 3are linked to form a cyclic group by an alkyl, ester or carbamate linkage; or a pharmaceutic ally acceptable salt, a tautomeric or polymorphic form thereof; or a compound of formula: 10 258 N-K RL Nk 0 0 CH2 NH jN 0 0 W" R S N N 'NH HRL N 0 0 R wherein Rd is hydrogen, methyl or methoxy; each RL is independently H, carbamyl, straight chained, branched or cyclic alkyl; acyl; CO 5 alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonate ester, a lipid, an amino acid; an amino acid residue; or a carbohydrate; or a pharmaceutically acceptable salt, a tautomeric or polymorphic form thereof; or a compound of formula: N4He o 0 Ry' S N 0 CH4 NH RY S' ~ NH 2 NN R; /~ ~ ~ \P, c 0 NH 2 NHN 100 10 5 HO 259 NHN 0 N O 0 "NN N N NN or a pharmaceutically acceptable salt, a tautomeric or polymorphic form thereof. 5

4. The compound of any one of the previous claims wherein RI is substituted alkyl and Ra and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl; or wherein RI is hydroxyalkyl or aminoalkyl.

5. The compound of any one of the previous claims wherein RI is -OR', -C(R') 3 or 10 NHR' where each R' is independently alkyl, substituted alkyl, aryl or substituted aryl; and Ra and Rb are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl; or wherein Ra and Rb are independently hydrogen, benzyl or substituted alkyl; or wherein RI is alkyl or hydroxyalkyl; or wherein RI is -C(CH 3 ) 2 CH 2 OH. 15

6. The compound of claim 1, wherein R 1 is selected from ribavirin, viramidine, valopicitabine, PSI-6130, MK-0608, resiquimod, celgosivir, lamivudine, entecavir, telbivudine, racivir, emtricitabine, clevudine, amdoxovir, valtorcitabine, tenofovir and Adefovir. 20

7. A method for the treatment of a host infected with a Flaviviridae virus or hepatitis B virus, comprising administering an effective treatment amount of a compound of any one of claims 1 to 6. 260

8. The method of claim 7, wherein the virus is hepatitis C, and wherein the host is a human.

9. The method of claim 8, wherein said administration directs a substantial amount of 5 said compound or pharmaceutically acceptable salt thereof to the liver of said host, and wherein said compound or pharmaceutically acceptable salt thereof is administered in combination or alternation with a second anti-viral agent selected from an interferon, a ribavirin, an interleukin, a NS3 protease inhibitor, a cysteine protease inhibitor, a phenanthrenequinone, a thiazolidine derivative, a thiazolidine, a benzanilide, a helicase 10 inhibitor, a polymerase inhibitor, a nucleotide analogue, a gliotoxin, a cerulenin, an antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES -dependent translation, or a ribozyme.

10. The method of claim 9, wherein the second agent is selected from pegylated interferon 15 alpha 2a, interferon alphacon- 1, natural interferon, albuferon, interferon beta-i a, omega interferon, interferon alpha, interferon gamma, interferon tau, interferon delta or interferon y lb.

11. The method of claim 9, wherein the host is a human. 20

12. The method of claim 11, wherein said administration directs a substantial amount of said compound or pharmaceutically acceptable salt thereof to the liver of said host.

13. The method of claim 7 comprising treating a human host infected with hepatitis B 25 virus.

14. A method of treatment of a hepatitis C or B infection, comprising administering to an individual in need thereof a treatment effective amount of a phosphoramidate or phosphonoamidate derivative of a nucleoside or nucleoside analogue or a pharmaceutically 30 acceptable salt thereof.

15. A pharmaceutical composition comprising a compound of any one of claims 1 to 6 and a pharmaceutically acceptable excipient, carrier or diluent. 261

16. The composition of claim 16, wherein the composition is an oral formulation.

17. A use of compound of any one of claims 1 to 6 in the manufacture of a medicament for the treatment of a host infected with a Flaviviridae virus, hepatitis B virus, or hepatitis C virus, 5 and wherein the host is a human.

18. The use of claim 17, wherein a substantial amount of said compound or pharmaceutically acceptable salt thereof is directed to the liver of said host, and wherein said compound or pharmaceutically acceptable salt thereof is for administration in combination or 10 alternation with a second anti-viral agent optionally selected from an interferon, a ribavirin, an interleukin, a NS3 protease inhibitor, a cysteine protease inhibitor, a phenanthrenequinone, a thiazolidine derivative, a thiazolidine, a benzanilide, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, a gliotoxin, a cerulenin, an antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependent translation, or a ribozyme. 15

19. The use of claim 18, wherein the second agent is selected from the group consisting of pegylated interferon alpha 2a, interferon alphacon-1, natural interferon, albuferon, interferon beta-ia, omega interferon, interferon alpha, interferon gamma, interferon tau, interferon delta or interferon y- lb. 20

20. The use of claim 18, wherein the host is a human.

21. The use of claim 20, wherein said administration directs a substantial amount of said compound or pharmaceutically acceptable salt thereof to the liver of said host. 25

22. The use of claim 17, for the treatment of a human host infected with hepatitis B virus, and wherein said compound or pharmaceutically acceptable salt thereof is for administration in combination or alternation with a second anti-viral agent optionally selected from interferon alfa-2b, Peginterferon alfa-2a, lamivudine, entecavir, telbivudine, racivir, emtricitabine, 30 clevudine, amdoxovir, valtorcitabine, tenofovir or adefovir, and wherein a substantial amount of said compound or pharmaceutically acceptable salt thereof is directed to the liver of said host. 262

23. A use of the compound of any one of claims 1-6 for manufacturing a medicament for treating of a host infected with a Flaviviridae virus, hepatitis B virus, or hepatitis C virus.

24. A use of a phosphoramidate or phosphonoamidate derivative of a nucleoside or 5 nucleoside analogue of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treatment of a hepatitis C or B infection.

25. The use of claim 24 for the treatment of hepatitis C. 10

26. The use of claim 24 for the treatment of hepatitis B.

27. A compound according to claim 1, substantially as herein described with reference to any of the Examples and/or Figures. 263