Docket No. 60137.0034USP1
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`NUCLEOSIDE PHOSPHORAMIDATE PRODRUGS
`
`Field of Invention
`
`The present invention pertains to nucleoside phosphoramidates andtheir use as
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`agents for treating viral diseases. These compoundsare inhibitors of RNA-dependent
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`RNAviral replication and are useful as inhibitors of HCV NSSB polymerase, as
`
`inhibitors of HCV replication and for treatment of hepatitis C infection in mammals. The
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`invention provides novel chemical compounds, and the use of these compoundsalone or
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`in combination with other antiviral agents for treating HCV infection.
`
`Background
`
`Hepatitis C virus (HCV)infection is a major health problem that leads to chronic
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`liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of
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`infected individuals, estimated to be 2-15% of the world's population. There are an
`
`estimated 4.5 million infected people in the United States alone, according to the U.S.
`
`Center for Disease Control. According to the World Health Organization, there are more
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`than 200 million infected individuals worldwide, with at least 3 to 4 million people being
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`infected each year. Once infected, about 20% of people clear the virus, but the rest can
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`harbor HCVtherest of their lives. Ten to twenty percent of chronically infected
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`individuals eventually develop liver-destroying cirrhosis or cancer. The viral disease is
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`transmitted parenterally by contaminated blood and blood products, contaminated
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`needles, or sexually and vertically from infected mothers or carrier mothers to their
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`offspring. Current treatments for HCV infection, which are restricted to immunotherapy
`
`GIL2013
`I-MAK, INC. V GILEAD PHARMASSET LLC
`IPR2018-00121
`
`GIL2013
`I-MAK, INC. V GILEAD PHARMASSET LLC
`IPR2018-00121
`
`

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`Docket No. 60137.0034USP1
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`with recombinant interferon-a alone or in combination with the nucleoside analog
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`ribavirin, are of limited clinical benefit as resistance develops rapidly. Moreover, there is
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`no established vaccine for HCV. Consequently, there is an urgent need for improved
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`therapeutic agents that effectively combat chronic HCV infection.
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`The HCV virion is an enveloped positive-strand RNA virus with a single
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`oligoribonucleotide genomic sequence of about 9600 bases which encodes a polyprotein
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`of about 3,010 amino acids. The protein products of the HCV gene consist of the
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`structural proteins C, El, and E2, and the non-structural proteins NS2, NS3, NS4A and
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`NS4B, and NSSA and NSSB. The nonstructural (NS) proteins are believed to provide the
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`catalytic machinery for viral replication. The NS3 protease releases NSSB, the RNA-
`
`dependent RNA polymerase from the polyprotein chain. HCV NSSB polymeraseis
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`required for the synthesis of a double-stranded RNA from a single-stranded viral RNA
`
`that serves as a template in the replication cycle of HCV. Therefore, NS5B polymeraseis
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`considered to be an essential componentin the HCV replication complex (K. Ishi, etal,
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`Heptology, 1999, 29: 1227-1235; V. Lohmann,etal., Virology, 1998, 249: 108-118).
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`Inhibition of HCV NSSB polymerase prevents formation of the double-stranded HCV
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`RNAandtherefore constitutes an attractive approach to the development of HCV-
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`specific antiviral therapies.
`
`HCVbelongs to a much larger family of viruses that share many common
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`features.
`
`Flaviviridae Viruses
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`Docket No. 60137.0034USP1
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`The Flaviviridae family of viruses comprisesat least three distinct genera:
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`pestiviruses, which cause disease in cattle and pigs; flavivruses, which are the primary
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`cause of diseases such as dengue fever and yellow fever; and hepaciviruses, whose sole
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`memberis HCV.The flavivirus genus includes more than 68 membersseparated into
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`groups on the basis of serological relatedness (Calisheret al., . Gen. Virol, 1993,70,37-
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`43). Clinical symptoms vary andinclude fever, encephalitis and hemorrhagic fever
`
`(Fields Virology, Editors: Fields, B. N., Knipe, D. M., and Howley, P. M., Lippincott-
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`Raven Publishers, Philadelphia, PA, 1996, Chapter 31, 931-959). Flaviviruses of global
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`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-
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`481, 1988: Monath, T. P., New Eng. J. Med, 1988, 319, 64 1-643).
`
`The pestivirus genus includes bovineviral diarrhea virus (BVDV), classical swine
`
`fever virus (CSFV,also called hog cholera virus) and border disease virus (BDV)of
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`sheep (Moennig, V.et al. Adv. Vir. Res. 1992, 41, 53-98). Pestivirus infections of
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`domesticated livestock (cattle, pigs and sheep) cause significant economic losses
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`worldwide. BVDV causes mucosal disease in cattle and is of significant economic
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`importance to the livestock industry (Meyers, G. and Thiel, H.J., Advances in Virus
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`Research, 1996, 47, 53-118; Moennig V., et al, Adv. Vir. Res. 1992, 41, 53-98). Human
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`pestiviruses have not been as extensively characterized as the animalpestiviruses.
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`However, serological surveys indicate considerable pestivirus exposure in humans.
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`Pestiviruses and hepaciviruses are closely related virus groups within the
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`Flaviviridae family. Other closely related viruses in this family include the GB virus A,
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`-3-
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`Docket No. 60137.0034USP1
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`GB virus A-like agents, GB virus-B and GB virus-C (also called hepatitis G virus, HGV).
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`The hepacivirus group (hepatitis C virus; HCV) consists of a numberofclosely related
`
`but genotypically distinguishable viruses that infect humans. There are at least 6 HCV
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`genotypes and more than 50 subtypes. Dueto the similarities between pestiviruses and
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`hepaciviruses, combined with the poor ability of hepaciviruses to grow efficiently in cell
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`culture, bovine viral diarrhea virus (BVDV)is often used as a surrogate to study the HCV
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`virus.
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`The genetic organization of pestiviruses and hepaciviruses is very similar. These
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`positive stranded RNAvirusespossess a single large open reading frame (ORF) encoding
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`all the viral proteins necessary for virus replication. These proteins are expressed as a
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`polyprotein that is co- and post-translationally processed by both cellular and virus-
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`encoded proteinasesto yield the mature viral proteins. The viral proteins responsible for
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`the replication of the viral genome RNAare located within approximately the carboxy-
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`terminal. Two-thirds of the ORF are termed nonstructural (NS) proteins. The genetic
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`organization and polyprotein processing of the nonstructural protein portion of the ORF
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`for pestiviruses and hepaciviruses is very similar. For both the pestiviruses and
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`hepaciviruses, the mature nonstructural (NS) proteins, in sequential order from the
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`amino-terminus of the nonstructural protein coding region to the carboxy-terminusofthe
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`ORF, consist of p7, NS2, NS3, NS4A, NS4B, NSSA, and NSSB.
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`The NSproteins of pestiviruses and hepaciviruses share sequence domainsthat
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`are characteristic of specific protein functions. For example, the NS3 proteins of viruses
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`in both groups possess amino acid sequence motifs characteristic of serine proteinases
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`and of helicases (Gorbalenyaet al., Nature, 1988, 333, 22; Bazan and Fletterick Virology
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`-4-
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`Docket No. 60137.0034USP1
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`, 1989,171,637-639; Gorbalenyaet al., Nucleic Acid Res., 1989, 17, 3889-3897).
`
`Similarly, the NSSB proteins of pestiviruses and hepaciviruses have the motifs
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`characteristic of RNA-directed RNA polymerases (Koonin, E.V. and Dolja, V.V., Cvir.
`
`Rey. Biochem. Molec. Biol. 1993, 28, 375-430).
`
`The actual roles and functions of the NSproteins of pestiviruses and
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`hepacivirusesin the lifecycle of the viruses are directly analogous. In both cases, the NS3
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`serine proteinase is responsible for all proteolytic processing of polyprotein precursors
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`downstream of its position in the ORF (Wiskerchen and Collett, Virology, 1991, 184,
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`341-350; Bartenschlageret al., J. Virol. 1993, 67, 3835-3844; Eckart et al. Biochem.
`
`Biophys. Res. Comm. 1993,192, 399-406; Grakouiet al., J. Virol. 1993, 67, 2832-2843;
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`Grakouiet al., Proc. Natl. Acad Sci. USA 1993, 90, 10583-10587; Hijikata et al., J. Virol.
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`1993, 67, 4665-4675; Tomeetal., J. Virol., 1993, 67, 4017-4026). The NS4Aprotein, in
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`both cases, acts as a cofactor with the NS3 serine protease (Bartenschlageret al., J. Virol.
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`1994, 68, 5045-5055; Failla et al., 7. Virol. 1994, 68, 3753-3760; Xuet al., J. Virol.,
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`1997, 71:53 12-5322). The NS3 protein of both viruses also functions as a helicase (Kim
`
`et al., Biochem. Biophys. Res. Comm., 1995, 215, 160-166; Jin and Peterson, Arch.
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`Biochem. Biophys., 1995, 323, 47-53; Warrener and Collett, /. Virol. 1995, 69,1720-
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`1726). Finally, the NSSB proteins of pestiviruses and hepaciviruses have the predicted
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`RNA-directed RNA polymerases activity (Behrenset al., EMBO, 1996, 15, 12-22;
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`Lechmannetal., J. Virol., 1997, 71, 8416-8428; Yuanet al., Biochem. Biophys. Res.
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`Comm. 1997, 232, 231-235; Hagedorn, PCT WO 97/12033; Zhonget al, J. Virol., 1998,
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`72, 9365-9369).
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`Docket No. 60137.0034USP1
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`Currently, there are limited treatment options for individuals infected with
`
`hepatitis C virus. The current approved therapeutic option is the use of immunotherapy
`
`with recombinant interferon-a alone or in combination with the nucleoside analog
`
`ribavirin. This therapy is limited in its clinical effectiveness and only 50% oftreated
`
`patients respond to therapy. Therefore, there is significant need for more effective and
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`novel therapies to address the unmet medical need posed by HCV infection.
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`A numberof potential molecular targets for drug developmentof direct acting
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`antivirals as anti -HCV therapeutics have now beenidentified including, but not limited
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`to, the NS2-NS3 autoprotease, the N3 protease, the N3 helicase and the NSSB
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`polymerase. The RNA-dependent RNA polymeraseis absolutely essential for replication
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`of the single-stranded, positive sense, RNA genomeandthis enzyme haselicited
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`significant interest among medicinal chemists.
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`Inhibitors of HCV NSSBaspotential therapies for HCV infection have been
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`reviewed: Tan, S.-L., et al., Nature Rev. Drug Discov., 2002, 1, 867-881; Walker, M.P. et
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`al., Exp. Opin. Investigational Drugs, 2003, 12, 1269-1280; Ni, Z-J., et al., Current
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`Opinion in Drug Discovery and Development, 2004, 7, 446-459; Beaulieu,P. L., et al.,
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`Current Opinion in Investigational Drugs, 2004, 5, 838-850; Wu, J., et al., Current Drug
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`Targets-Infectious Disorders, 2003, 3, 207-219; Griffith, R.C., et al, Annual Reports in
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`Medicinal Chemistry, 2004, 39, 223-237; Carrol, S., et al., Infectious Disorders-Drug
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`Targets, 2006, 6, 17-29. The potential for the emergence of resistant HCV strains and the
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`need to identify agents with broad genotype coverage supports the need for continuing
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`efforts to identify novel and more effective nucleosides as HCV NSSBinhibitors.
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`Docket No. 60137.0034USP1
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`Nucleoside inhibitors of NSSB polymerasecanact either as a non-natural
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`substrate that results in chain termination or as a competitive inhibitor which competes
`
`with nucleotide binding to the polymerase. To function as a chain terminator the
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`nucleoside analog must be taken up by the cell and converted in vivo to a triphosphate to
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`compete for the polymerase nucleotide binding site. This conversion to the triphosphate
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`is commonly mediated by cellular kinases which imparts additional structural
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`requirements on a potential nucleoside polymerase inhibitor. Unfortunately, this limits
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`the direct evaluation of nucleosides as inhibitors of HCV replication to cell-based assays
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`capable of in situ phosphorylation.
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`In somecases, the biological activity of a nucleoside is hamperedby its poor
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`substrate characteristics for one or more of the kinases needed to convert it to the active
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`triphosphate form. Formation of the monophosphate by a nucleoside kinaseis generally
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`viewedasthe rate limiting step of the three phosphorylation events. To circumvent the
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`need for the initial phosphorylation step in the metabolism of a nucleosideto the active
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`triphosphate analog, the preparation of stable phosphate prodrugs hasbeen reported.
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`Nucleoside phosphoramidate prodrugs have been shownto be precursors of the active
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`nucleoside triphosphate and to inhibit viral replication when administered to viral
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`infected whole cells (McGuigan,C., et al., J. Med. Chem., 1996, 39, 1748-1753; Valette,
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`G., et al., J. Med. Chem., 1996, 39, 1981-1990; Balzarini, J., et al., Proc. National Acad
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`Sci USA, 1996, 93, 7295-7299; Siddiqui, A. Q., et al.,J. Med. Chem., 1999, 42, 4122-
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`4128; Eisenberg, E. J., et al., Nucleosides, Nucleotides and Nucleic Acids, 2001, 20,
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`1091-1098; Lee, W.A., et al., Antimicrobial Agents and Chemotheryapy, 2005, 49,
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`1898)
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`Docket No. 60137.0034USP1
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`Also limiting the utility of nucleosides as viable therapeutic agentsis their
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`sometimes poor physicochemical and pharmacokinetic properties. These poor properties
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`can limit the intestinal absorption of an agent and limit uptake into the target tissue or
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`cell. To improve on their properties prodrugs of nucleosides have been employed. It has
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`been demonstrated that preparation of nucleoside phosphoramidates improvesthe
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`systemic absorption of a nucleoside and furthermore, the phosphoramidate moiety of
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`these "pronucleotides" is masked with neutral lipophilic groups to obtain a suitable
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`partition coefficient to optimize uptake and transport into the cell dramatically enhancing
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`the intracellular concentration of the nucleoside monophosphate analogrelative to
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`administering the parent nucleoside alone. Enzyme-mediated hydrolysis of the phosphate
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`ester moiety produces a nucleoside monophosphate wherein the rate limiting initial
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`phosphorylation is unnecessary.
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`SUMMARYOF THE INVENTION
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`The present invention is directed toward novel phosphoramidate prodrugs of
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`nucleoside derivatives for the treatment of viral infections in mammals, which is a
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`compound,its stereoisomers, salts (acid or basic addition salts), hydrates, solvates, or
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`crystalline forms thereof, represented by the following structure:
`
`R
`
`
`
` F i|
`N—P—o
`
`Ra
`
`COR4
`
`1
`
`OR
`
`Base
`
`R®
`
`0
`
`yw"
`
`RS
`
`$
`Y
`
`%
`x
`
`I
`
`wherein
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`Docket No. 60137.0034USP1
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`R' is hydrogen, n-alkyl; branchedalkyl; cycloalkyl; or aryl, which includes, butis
`
`not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted
`
`with at least one of C1.¢ alkyl, C26 alkenyl, C26 alkynyl, C,.6 alkoxy, F, Cl, Br, I, nitro,
`cyano, C,.¢ haloalkyl, -N(R"), Cy.6 acylamino, -NHSO2C;.¢ alkyl, -SO,N(R"),, COR",
`and -SO2C 1.6 alkyl;. (R"is independently hydrogen oralkyl, which includes, but is not
`limited to, C1-29 alkyl, Cy-19 alkyl, or Cy.6 alkyl, R' is -OR' or -N(R")2);
`
`R’is hydrogen, C 1-19 alkyl, R** or R®” and R’ together are (CH2)n so as to form a
`cyclic ring that includes the adjoining N and C atoms, C(O)CR**R*’NHR', wherenis 2 to
`4 and R', R** and R®are as defined herein:
`
`R*and R®are (i) independently selected from hydrogen, C}.10 alkyl, -
`(CH2).(NR®):, C16 hydroxyalkyl, -CH2SH, -(CH2)2S(O)sMe, -(CH2)3NHC(=NH)NHb,
`(1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, -(CH2),COR’, aryl or aryl Cy.3 alkyl,
`
`said aryl groups optionally substituted with a group selected from hydroxyl, C1-10 alkyl,
`C16 alkoxy, halogen, nitro or cyano; (ii) R** and R®” both are C1. alkyl; (iii) R** and R®
`together are(CH>)¢ so as to form a spiroring; (iv) R** is hydrogen and R®and R’together
`are (CH), so as to formacyclic ring that includes the adjoining N and C atoms(v) R®” is
`hydrogen and R™and R’together are (CH2)n so as to form a cyclic ring that includesthe
`
`adjoining N and C atoms, wherecis 1 to 6, dis 0 to 2, eis 0 to 3, fis 3 to 5, nis 2 to 4,
`and where R®is independently hydrogen or C16 alkyl and R®is -OR' or —N(R’)s); (vi)
`R* is H and R®is independently selected from H, CH3, CH(CH3)2, CH2CH(CH3),
`
`CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, -CH2CH2SCH3, CH2CO2H, CH2C(O)NHz,
`
`CH,CH2,COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NHo, -CH2CH2CH2NHC(NH)NH2,
`
`CH)-imidazolimidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4'-OH)-Ph), or CH2SH;or(viii)
`R*is CH3, CH(CH3)2, CH2»CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH>-indol-3-yl,-
`
`CH2CH2CH2CH2NH2, -CH2CH2CH2NHC(NH)NH2, CH2-imidazolimidazol-4-yl,
`CH,OH, CH(OH)CH3, CH2((4'-OH)-Ph), or CH2SH and R®”is H, where R’is
`
`CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2,
`
`independently hydrogenor alkyl, which includes, but is not limited to, Cy-20 alkyl, C1-10
`alkyl, or Cy.6 alkyl, R®is -OR' or -N(R*)s);
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`Docket No. 60137.0034USP1
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`R* is hydrogen, C1-19 alkyl, C1.10 alkyl optionally substituted with a lower alkyl,
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`alkoxy or halogen, C1-19 haloalkyl, aryl or substituted aryl wherein said aryl is phenyl;
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`R°is H, an optionally substituted alkyl (including lower alkyl), cyano (CN), CHs,
`
`vinyl, O-alkyl, O-Coweralkyl), including OCH3, OCH2CHs, hydroxyl alkyl, i-e., -
`
`(CH2),.OH, wherein 0 is 1 — 10, hydroxyl loweralkyl, 1.e., -(CH2),OH, wherepis 1 -6,
`
`including hydroxyl methyl (CH2OH), fluoromethyl (CH2F), azido (N3), CH2CN, CH2N3,
`
`CH2NH2, CH2NHCH3, CH2N(CH3)s, ethynyl alkyne (optionally substituted), or halogen,
`includingF, Cl, Br, or I, with the provisos that when X is OH, baseis cytosine and R°is
`H, R° cannot be N3 and whenX is OH, R° is CH; or CH>F and B isa purine base, R
`
`cannot be H.
`
`R° is H, CHs, CHF, CHF>, CF3, F, or CN;
`
`X 1s H, OH, F, OMe, halogen, NH2, or N3
`
`Y is an OH, H,C1-4 alkyl, Co.4 alkenyl, Co.4 alkynyl, vinyl, N3, CN, Cl, Br, F, I,
`
`NOz, C(O)O(C1-4 alkyl), C(OJO(C1-4 alkyl), C(O)O(C2-4 alkynyl), C(O)O(C2.4 alkenyl),
`
`O(C1.10 acyl), O(C;-4 alkyl), O(C2.4 alkenyl), S(Cy_4 acyl), S(C1.4 alkyl), S(Cz_4 alkynyl),
`
`S(C2.4 alkenyl), SO(Cy.4 acyl), SO(C1-4 alkyl), SO(C2.4 alkynyl), SO(C2.4 alkenyl),
`
`SO2(C1.4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl),
`
`OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2.4 alkenyl), NH(Co.
`
`4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, or N(C1-1 acyl)2,
`
`wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N3, CN,
`
`one to three halogen (Cl, Br, F, I), NOz, C(O)O(C1-4 alkyl), C(O)O(C1-4 alkyl), C(O)O(Co.
`
`4 alkynyl), C(O)O(C2-4 alkenyl), O(Ci-4 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), S(Ci.4 acyl),
`
`S(Cy.4 alkyl), S(Cz4 alkynyl), S(C2.4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2.4
`
`alkynyl), SO(C2.4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2.4
`
`alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4
`
`alkyl), NH(C2.4 alkenyl), NH(C24 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-4 acyl)».
`
`Baseis a naturally occurring or modified purine or pyrimidine base represented
`
`by the following structures:
`
`-10-
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`

`Docket No. 60137.0034USP1
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`R?
`
`O
`
`R10
`
`O
`
`RSCh LEC. arr
`
`RS
`
`R?7
`
`O R’
`
`N
`oe
`
`o N
`N
`yal
`
`n7 Ru
`
`ON
`a
`
`x7 NH,
`
`a
`
`b
`
`c
`
`d
`
`wherein
`
`Zis N or CR”:
`
`R’, R&R’, RR’and R"are independently H, F, Cl, Br, I, OH, OR', SH, SR', NHp,
`
`NHR’, NR's, lower alkyl of Ci-C¢, halogenated (F, Cl, Br, I) lower alkyl of C1-Ce, lower
`
`alkenyl of C2-C¢, halogenated (F, Cl, Br, I) lower alkenyl of C2-C¢, lower alkynyl of C2-
`
`Ce such as C=CH,halogenated(F, Cl, Br, I) lower alkynyl of C2-C¢, lower alkoxy of Ci-
`
`Ce, halogenated (F, Cl, Br, I) lower alkoxy of C,-Cs, CO2H, CO2R', CONH2, CONHR’,
`
`CONR*, CH=CHCO2H, or CH=CHCO)R' wherein R'is an optionally substituted alkyl,
`
`whichincludes, but is not limited to, an optionally substituted Cj-20 alkyl, an optionally
`
`substituted C1-10 alkyl, an optionally substituted lower alkyl; an optionally substituted
`
`cycloalkyl; an optionally substituted alkynyl of C2-C¢, an optionally substituted lower
`
`alkenyl of C2-C¢, or optionally substituted acyl, which includesbutis not limited to C(O)
`
`alkyl, C(O)(C 1-20 alkyl), C(O)(C1-10 alkyl), or C(O)(loweralkyl);
`
`R”isan H,halogen (including F, Cl, Br, I), OH, OR', SH, SR', NH2, NHR', NR",
`
`NOzlower alkyl of Ci-C¢, halogenated (F, Cl, Br, I) lower alkyl of Ci-Ce, lower alkenyl
`
`of C2-C¢, halogenated (F, Cl, Br, I) lower alkenyl of C2-C¢ , lower alkynyl of C2-Ce,
`
`halogenated (F, Cl, Br, I) lower alkynyl of C2-C¢, lower alkoxy of C)-C¢, halogenated(F,
`
`Cl, Br, I) lower alkoxy of C1-C¢, CO2H, CO2R', CONH2, CONHR', CONR’2,
`
`CH=CHCO2H, or CH=CHCO2R’, wherein R'is defined above.
`
`-ll-
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`Docket No. 60137.0034USP1
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`DEFINITIONS
`
`The phrase "a" or "an" entity as used herein refers to one or more of that entity;
`2
`for example, a compoundrefers to one or more compounds orat least one compound. As
`
`such,
`
`the terms "a"
`
`(or "an"),
`
`"one or more", and "at
`
`least one" can be used
`
`interchangeably herein.
`
`The phrase "as defined herein above"refers to the first definition provided in the
`
`Summary of the Invention.
`
`The terms "optional" or "optionally" as used herein means that a subsequently
`
`described event or circumstance may but need not occur, and that the description includes
`
`instances where the event or circumstance occurs and instances in which it does not. For
`
`example, "optional bond" means that the bond may or may not be present, and that the
`
`description includes single, double, or triple bonds.
`
`The term "independently" is used herein to indicate that a variable is applied in
`
`any one instance without regard to the presence or absence of a variable having that same
`
`or a different definition within the same compound. Thus, in a compound in which R
`
`appears twice and is defined as "independently carbon or nitrogen", both R's can be
`
`carbon, both R's can be nitrogen, or one R' can be carbon andthe other nitrogen.
`
`The term "alkenyl" refers to an unsubstituted hydrocarbon chain radical having
`
`from 2 to 10 carbon atoms having one or two olefinic double bonds, preferably one
`
`olefinic double bond. The term "C2.x alkenyl" refers to an alkenyl comprising 2 to N
`
`carbon atoms, where N is an integer having the following values: 3, 4, 5, 6, 7, 8, 9, or 10.
`
`The term "C>-19 alkenyl" refers to an alkenyl comprising 2 to 10 carbon atoms. The term
`
`"C24 alkenyl" refers to an alkenyl comprising 2 to 4 carbon atoms. Examples include,
`
`but are notlimited to, vinyl, 1-propenyl, 2-propenyl(allyl) or 2-butenyl (crotyl).
`
`The term "halogenated alkenyl" refers to an alkenyl comprising at least one of F,
`
`Cl, Br, and I.
`
`-12-
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`

`Docket No. 60137.0034USP1
`
`The term "alkyl"
`
`refers
`
`to an unbranched or branched chain,
`
`saturated,
`
`monovalent hydrocarbon residue containing 1 to 30 carbon atoms. The term "Cj-y alkyl"
`
`refers to an alkyl comprising 2 to M carbon atoms, where M is an integer having the
`
`following values: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,
`
`23, 24, 25, 26, 27, 28, 29, or 30. The term "C,-4 alkyl" refers to an alkyl containing 1 to 4
`
`carbon atoms. The term "lower alkyl" denotes a straight or branched chain hydrocarbon
`
`residue comprising 1 to 6 carbon atoms.
`
`"Cj-20 alkyl" as used herein refers to an alkyl
`
`comprising 1
`
`to 20 carbon atoms.
`
`"Cj-19 alkyl" as used herein refers to an alkyl
`
`comprising 1 to 10 carbons. Examples of alkyl groups include, but are not limited to,
`
`lower alkyl groups include methyl, ethyl, propyl, i-propyl, n-butyl,
`
`i-butyl, butyl or
`
`pentyl,
`
`isopentyl, neopentyl, hexyl, heptyl,
`
`and octyl.
`
`The term (ar)alkyl or
`
`(heteroaryl)alkyl
`
`indicate the alkyl group is optionally substituted by an aryl or a
`
`heteroaryl group respectively.
`
`The term "halogenated alkyl" (or "haloalkyl") refers to an unbranched or branched
`
`chain alkyl comprising at least one of F, Cl, Br, and I. The term "C,-3 haloalkyl" refers to
`
`a haloalkyl comprising 1 to 3 carbons and at least one of F, Cl, Br, and I. The term
`
`"halogenated lower alkyl" refers to a haloalkyl comprising 1 to 6 carbon atoms and at
`
`least one of F, Cl, Br, and I. Examples include, but are not limited to, fluoromethy]l,
`
`chloromethyl,
`
`bromomethy],
`
`iodomethyl,
`
`difluoromethyl,
`
`dichloromethyl,
`
`dibromomethyl,
`
`diiodomethyl,
`
`trifluoromethyl,
`
`trichloromethyl,
`
`tribromomethyl,
`
`triiodomethyl, 1-fluoroethyl, 1-chloroethyl, 1-bromoethyl, 1-iodoethyl, 2-fluoroethyl, 2-
`
`chloroethyl,
`
`2-bromoethyl,
`
`2-iodoethyl,
`
`2,2-difluoroethyl,
`
`2,2-dichloroethyl,
`
`2,2-
`
`dibromomethyl, 2-2-diiodomethyl, 3-fluoropropyl, 3-chloropropyl, 3-bromopropyl, 2,2,2-
`
`trifluoroethyl or 1,1,2,2,2-pentafluoroethyl.
`
`The term "alkynyl" refers to an unbranched or branched hydrocarbon chain
`
`radical having from 2 to 10 carbon atoms, preferably 2 to 5 carbon atoms, and having one
`
`triple bond. The term "C2.alkynyl" refers to an alkynyl comprising 2 to N carbon atoms,
`
`where N is an integer having the following values: 3, 4, 5, 6, 7, 8, 9, or 10. The term "C
`
`C24 alkynyl" refers to an alkynyl comprising 2 to 4 carbon atoms. The term "C2-19
`
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`

`Docket No. 60137.0034USP1
`
`alkynyl" refers to an alkynyl comprising 2 to 10 carbons. Examples include, but are
`
`limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl or 3-butynyl.
`
`The term "halogenated alkynyl" refers to an unbranched or branched hydrocarbon
`
`chain radical having from 2 to 10 carbon atoms, preferably 2 to 5 carbon atoms, and
`
`having onetriple bond andat least one of F, Cl, Br, and I.
`
`The term "cycloalkyl" refers to a saturated carbocyclic ring comprising 3 to 8
`
`carbon atoms, 1.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or
`
`cyclooctyl. The term "C3.7 cycloalkyl" as used herein refers to a cycloalkyl comprising 3
`
`to 7 carbonsin the carbocyclic ring.
`
`The term "alkoxy" refers to an -O-alkyl group, wherein alkyl is as defined above.
`
`Examples include, but are not limited to, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-
`
`butyloxy,
`
`i-butyloxy, +butyloxy.
`
`"Lower alkoxy" as used herein denotes an alkoxy
`
`group with a "lower alkyl" group as previously defined. "Cy-10 alkoxy" refers to an-O-
`
`alkyl wherein alkyl is Cy-10.
`
`The term "halogenated alkoxy" refers to an —O-alkyl group in which the alkyl
`
`group comprisesat least one of F, Cl, Br, and I.
`
`The term "halogenated lower alkoxy" refers to an —O-(lower alkyl) group in
`
`which the lower alkyl group comprisesat least one of F, Cl, Br, and I.
`
`The term "amino acid" includes naturally occurring and synthetic a, B y or 6
`
`amino acids, and includesbutis not limited to, amino acids foundin 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,
`
`isoleucinyl, prolinyl, phenylalaninyl,
`
`tryptophanyl, methioninyl, glycinyl,
`
`serinyl,
`
`threoninyl, cysteinyl,
`
`tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl,
`
`lysinyl, argininyl, histidinyl, B-alanyl, B-valinyl, B-leucinyl, B-isoleucinyl, B-prolinyl, B-
`
`phenylalaninyl, B-tryptophanyl, B-methioninyl, B-glycinyl, B-serinyl, B-threoninyl, B-
`
`-14-
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`

`Docket No. 60137.0034USP1
`
`cysteinyl, B-tyrosinyl, B-asparaginyl, B-glutaminyl, B-aspartoyl, B-glutaroyl, B-lysinyl, B-
`
`argininyl or B-histidinyl. When the term amino acid is used,
`
`it is considered to be a
`
`specific and independent disclosure of each of the esters of a, B y or 6 glycine, alanine,
`
`valine,
`
`leucine,
`
`isoleucine, methionine, phenylalanine,
`
`tryptophan, proline,
`
`serine,
`
`threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine
`
`and histidine in the D and L-configurations.
`
`The terms "alkylamino" or "arylamino" refer to an amino group that has one or
`
`two alkyl or aryl substituents, respectively.
`
`The term "protected," as used herein and unless otherwise defined, refers to a
`
`group that is added to an oxygen, nitrogen, or phosphorus atom to preventits further
`
`reaction or for other purposes. A wide variety of oxygen and nitrogen protecting groups
`
`are knownto those skilled in the art of organic synthesis. Non-limiting examplesinclude:
`
`C(O)-alkyl, C(O)Ph, C(O)aryl, CH3, CH2-alkyl, CH»2-alkenyl, CH2Ph, CH2-aryl, CH20-
`
`alkyl, CH2O-aryl, SO2-alkyl, SO2-aryl, fert-butyldimethylsilyl, tert-butyldiphenylsilyl,
`2739
`9
`and 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene).
`
`The term "aryl," as used herein, and unless otherwise specified, refers to
`
`substituted or unsubstituted phenyl (Ph), biphenyl, or naphthyl, preferably the term aryl
`
`refers to substituted or unsubstituted phenyl. The aryl group can be substituted with one
`
`or more moieties selected from among hydroxyl, F, Cl, Br, I, 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 T.W. Greene and P.G. M. Wuts,
`
`"Protective Groups in Organic Synthesis," 3rd ed., John Wiley & Sons, 1999.
`
`The terms "alkaryl" or "alkylaryl" refer to an alkyl group with an aryl substituent.
`
`The terms "aralkyl" or "arylalkyl" refer to an aryl group with an alkyl substituent.
`
`The term "halo," as used herein, includes chloro, bromo, iodo andfluoro.
`
`The term "acyl" refers to a substituent containing a carbonyl moiety and a non-
`
`carbonyl moiety. The carbonyl moiety contains a double-bond betweenthe carbonyl
`
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`

`Docket No. 60137.0034USP1
`
`carbon and a heteroatom, where the heteroatom is selected from among O, N andS.
`
`Whenthe heteroatom is N, the N is substituted by a lower alkyl. The non-carbonyl
`
`moiety is selected from straight, branched, or cyclic alkyl, which includes, but is not
`
`limited to, a straight, branched, or cyclic C129 alkyl, Cy.19 alkyl, or lower alkyl;
`
`alkoxyalkyl, including methoxymethyl; aralkyl, including benzyl; aryloxyalkyl, such as
`
`phenoxymethy]; or aryl, including phenyl optionally substituted with halogen(F, Cl, Br,
`
`I), hydroxyl, C; to C4 alkyl, or C; to C4 alkoxy, sulfonate esters, such as alkyl or aralkyl
`
`sulphonyl, including methanesulfonyl, the mono,di or triphosphate ester,trityl or
`
`monomethoxytrityl, substituted benzyl, trialkylsilyl (e.g. dimethyl-t-butylsilyl) or
`
`diphenylmethylsilyl. When at least one aryl group is present in the non-carbonyl moiety,
`
`itis preferred that the aryl group comprises a phenyl group.
`
`The term "lower acyl" refers to an acyl group in which the non-carbonyl! moiety is
`
`loweralkyl.
`
`The term "purine" or "pyrimidine" base includes, but is not limited to, adenine,
`N°-alkylpurines, N°-acylpurines (wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl),
`N°-benzylpurine, N°-halopurine, N°-vinylpurine, N°-acetylenic purine, N°-acyl purine,
`N°-hydroxyalkyl purine, N°-allcylaminopurine, N°-thioallcyl purine, N’-alkylpurines, N’-
`
`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°-benzylpyrimidines, C-
`halopyrimidines, C°-vinylpyrimidine, C°-acetylenic pyrimidine, C°-acyl pyrimidine, C°-
`hydroxyalkyl purine, C’-amidopyrimidine, C°-cyanopyrimidine, ,C°-iodopyrimidine, C°-
`lodo-pyrimidine, C°-Br-vinyl pyrimidine, C°-Br-vinyl pyrimidine, C’-nitropyrimidine,
`C°-amino-pyrimidine, N’-alkylpurines, N’-alkyl-6-thiopurines, 5-azacytidinyl, 5-
`
`azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, and
`
`pyrazolopyrimidinyl. Purine bases include, but are not limited to, guanine, adenine,
`
`hypoxanthine, 2,6-diaminopurine, and 6-chloropurine. Functional oxygen and nitrogen
`
`groups on the base can be protected as necessary or desired. Suitable protecting groups
`
`are well knownto those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl,
`
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`

`Docket No. 60137.0034USP1
`
`f-butyldimethylsilyl, and ¢-butyldiphenylsilyl, trityl, alkyl groups, and acyl groups such as
`
`acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl.
`
`The term "tautomerism" and "tautomers" have their accepted plain meanings.
`
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`Docket No. 60137.0034USP1
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`An aspect of the invention is directed to a compound,its salts, hydrates, solvates,
`
`crystalline forms, and the like represented by formula I:
`
`Rx
`i
`|
`|
`ee—o
`|
`OR
`
`CO,R4
`
`O
`
`1
`
`yw
`
`RS
`
`0
`
`Base
`
`R®
`
`Y
`
`x
`
`wherein
`
`(a)
`
`R'is hydrogen,n-alkyl; branched alkyl; cycloalkyl; or aryl, which
`
`includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are
`
`optionally substituted with at least one of C,.6 alkyl, C26 alkenyl, Cz alkynyl, C16
`alkoxy, F, Cl, Br, I, nitro, cyano, C1. haloalkyl, -N(R"), Cy-6 acylamino, -NHSO2C1-¢
`alkyl, -SO.N(R')2, COR", and -SO,C1.6 alkyl;. (R"is independently hydrogen oralkyl,
`which includes, but is not limited to, C1-29 alkyl, C1-10 alkyl, or C16 alkyl, R"is -OR' or-
`NR");
`
`(b)—