(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY(PCT)
`
`(19) World Intellectual Property Organization KFAIPO:
`International Bureau
`
`(43) International Publication Date
`9 October 2008 (09.10.2008)
`
` (10) International Publication Nuniber
`
`WO 2008/121634 A2
`
`(51) International Patent Classification:
`
`Notclassified
`
`(21) International Application Number:
`PCT/US2008/058183
`
`(22) International Filing Date:
`
`26 March 2008 (26.03.2008)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/909,315
`60/982,309
`12/053,015
`
`30 March 2007 (30.03.2007)
`24 October 2007 (24.10.2007)
`21 March 2008 (21.03.2008)
`
`US
`US
`US
`
`(71) Applicant (for all designated States except US): PHAR-
`MASSET,INC. [US/US]; 303a College Road East, Prince-
`ton, NJ 08540 (US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): SOFIA, Michael,J.
`[US/US]; 3066 Antler Drive, Doylestown, PA 18902 (US).
`DU, Jinfa [US/US]; 1206 Reins Circle, New Hope, PA
`18938 (US). WANG,Peiyuan [CN/US]; 20 Radburn Road,
`Glen Rock, NJ 07452 (US). NAGARATHNAM,Dhana-
`palan [US/US]; 52 Virginia Rail Drive, Bethany, CT 06524
`(US).
`
`(74) Agent: KOWALCHYK,Katlierine, M.; Merchant &
`Gould P.c., P.O. Box 2903, Minneapolis, MA 55402-0903
`(US).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO,AT, AU, AZ, BA, BB, BG, BH, BR, BW,BY, BZ, CA,
`CH, CN, CO, CR, CU, CZ, DE, DK, DM,DO,DZ, EC, EE,
`EG,ES, FI, GB, GD, GE, GH, GM,GT, HN, HR, HU,ID,
`IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC,
`LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN,
`MW, MX, MY, MZ, NA, NG,NI, NO, NZ, OM, PG, PH,
`PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV,
`SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN,
`ZA, ZM, ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM,KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU,TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE,ES, FI,
`FR, GB, GR, HR, HU,IE,IS, IT, LT, LU, LV, MC, MT, NL,
`NO,PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG,
`CI, CM,GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`
`without international search report and to be republished
`upon receipt of that report
`
`(54) Title: NUCLEOSIDE PHOSPHORAMIDATE PRODRUGS
`
`R
`|
`
`3b
`
`R
`
`R3a
`
`Co,R4
`
`N---P——_O
`
`1
`||
`|
`OR!
`
`O
`
`o
`
`5
`
`R
`
`Base
`
`R
`
`Y
`
`Xx
`
`(I)
`
`AQIMUMMATAURIAAAA
`
`+ (57) Abstract: Disclosed herein are phosphoramidate prodrugs of nucleoside derivatives for the treatment of viral infections in
`cr) mammals, which is a compound,its stereoisomer, salt (acid or basic addition salt), hydrate, solvate, or crystalline form thereof,
`\& represented by the following structure: Also disclosed are methods of treatment, uses, and processes for preparing each of which
`
`=WO2008/12 utilize the compoundrepresented by formula(1).
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`WO2008/121634
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`NUCLEOSIDE PHOSPHORAMIDATE PRODRUGS
`
`This application is being filed on March 25, 2008, as a PCT International
`
`Patent application in the name of Pharmasset, Inc., a U.S. national corporation,
`
`5
`
`applicant for the designation ofall countries except the US, and Michael Joseph
`
`Sofia, a citizen ofthe U.S.; Jinfa Du, a citizen of the U.S.; Peiyuan Wang, a
`
`citizen of the People’s Republic of China; and Dhanapalan Nagarathnam, a
`
`citizen of the U.S.; applicants for the designation of the US only, and claims
`
`priority to U.S. Provisional Application Nos. 60/909,315, filed March 30, 2007;
`
`10
`
`60/982,309, filed October 24, 2007; and U.S. Non-Provisional Application No.
`
`12/053,015, filed March 21, 2008. The contents of each of the above-noted
`
`applications is hereby incorporated by reference in its entirety.
`
`Field of Invention
`
`15
`
`The present invention pertains to nucleoside phosphoramidates andtheir
`
`use as agents for treating viral diseases. These compoundsare inhibitors of
`
`RNA-dependent 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 invention provides novel chemical
`
`20
`
`compounds,andthe use of these compoundsaloneor in combination with other
`
`antiviral agents for treating HCV infection.
`
`Background
`
`Hepatitis C virus (HCV)infection is a major health problem that leadsto
`
`chronic liver disease, such as cirrhosis and hepatocellular carcinoma,in a
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`substantial numberofinfected 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 than 200 million infected individuals
`
`5
`
`worldwide, with at least 3 to 4 million people being infected each year. Once
`
`infected, about 20% of people clear the virus, but the rest can harbor HCV the
`
`rest of their lives. Ten to twenty percent of chronically infected individuals
`
`eventually develop liver-destroying cirrhosis or cancer. Theviral diseaseis
`
`transmitted parenterally by contaminated blood and blood products,
`
`10
`
`contaminated needles, or sexually and vertically from infected mothers or carrier
`
`mothersto their offspring. Current treatments for HCV infection, which are
`
`restricted to immunotherapy with recombinant interferon-a aloneorin
`
`combination with the nucleoside analogribavirin, are of limited clinical benefit.
`
`Moreover, there is no established vaccine for HCV. Consequently, there is an
`
`15—_urgent need for improved therapeutic agents that effectively combat chronic
`
`HCVinfection.
`
`The HCV virion is an enveloped positive-strand RNAvirus with a single
`
`oligoribonucleotide genomic sequence of about 9600 bases which encodes a
`
`polyprotein of about 3,010 amino acids. The protein products of the HCV gene
`
`20
`
`consist ofthe structural proteins C, El, and E2, andthe non-structural proteins
`
`NS2, NS3, NS4A and NS4B, and NSSA and NSSB. The nonstructural (NS)
`
`proteinsare believed to provide the catalytic machinery forviral replication.
`
`The NS3 protease releases NS5B, the RNA-dependent RNApolymerase from
`
`the polyprotein chain. HCV NSSBpolymeraseis required for the synthesis of a
`
`25.
`
`double-stranded RNA from a single-stranded viral RNA that serves as a template
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`in the replication cycle of HCV. Therefore, NS5B polymerase is considered to
`
`be an essential componentin the HCVreplication complex (K.Ishi, et al,
`
`Heptology, 1999, 29: 1227-1235; V. Lohmann,etal., Virology, 1998, 249: 108-
`
`118). Inhibition of HCV NS5B polymerase prevents formation of the double-
`
`5
`
`stranded HCV RNAandtherefore constitutes an attractive approach to the
`
`development of HCV-specific antiviral therapies.
`
`HCVbelongs to a muchlarger family of viruses that share many
`
`common features.
`
`Flaviviridae Viruses
`
`10
`
`The Flaviviridae family of viruses comprisesat least three distinct
`
`genera: pestiviruses, which cause disease in cattle and pigs; flavivruses, which
`
`are the primary cause of diseases such as dengue fever and yellow fever; and
`
`hepaciviruses, whose sole member is HCV. Theflavivirus genus includes more
`
`than 68 membersseparated into groups onthe basis of serological relatedness
`
`15
`
`(Calisheret 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
`
`20
`
`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, 64 1-
`
`643).
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`The pestivirus genus includes bovineviral diarrhea virus (BVDV),
`
`classical swine fever virus (CSFV,also called hog cholera virus) and border
`
`disease virus (BDV)of sheep (Moennig, V. et al. Adv. Vir. Res. 1992, 41, 53-
`
`98). Pestivirus infections of domesticated livestock (cattle, pigs and sheep) cause
`
`5_significant economic losses worldwide. BVDV causes mucosaldisease in cattle
`
`andis of significant economic importanceto 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
`
`10
`
`surveys indicate considerable pestivirus exposure in humans.
`
`Pestiviruses and hepacivirusesare 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 GBvirus-C (also called
`
`hepatitis G virus, HGV). The hepacivirus group (hepatitis C virus; HCV)
`
`15
`
`consists of a numberof closely related but genotypically distinguishable viruses
`
`that infect humans. There are at least 6 HCV genotypes and more than 50
`
`subtypes. Dueto the similarities between pestiviruses and hepaciviruses,
`
`combined with the poorability of hepaciviruses to grow efficiently in cell
`
`culture, bovine viral diarrhea virus (BVDV)is often used as a surrogate to study
`
`20
`
`the HCV virus.
`
`The genetic organization of pestiviruses and hepacivirusesis very
`
`similar. These positive stranded RNAvirusespossessa single large open reading
`
`frame (ORF) encodingall the viral proteins necessary for virus replication.
`
`These proteins are expressed as a polyprotein that is co- and post-translationally
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`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 RNAare located within approximately the carboxy-terminal. Two-
`
`thirds of the ORF are termed nonstructural (NS) proteins. The genetic
`
`5
`
`organization and polyprotein processing of the nonstructural protein portion of
`
`the ORF for pestiviruses and hepacivirusesis very similar. For both the
`
`pestiviruses and hepaciviruses, the mature nonstructural (NS) proteins, in
`
`sequential order from the amino-terminusof the nonstructural protein coding
`
`region to the carboxy-terminus of the ORF, consist of p7, NS2, NS3, NS4A,
`
`10
`
` NS4B, NSSA, and NSSB.
`
`The NS proteins of pestiviruses and hepaciviruses share sequence
`
`domainsthat are characteristic of specific protein functions. For example, the
`
`NS3 proteins of viruses in both groups possess amino acid sequence motifs
`
`characteristic of serine proteinases and of helicases (Gorbalenyaet al., Nature,
`
`‘15
`
`1988, 333, 22; Bazan and Fletterick Virology , 1989,171,637-639; Gorbalenyaet
`
`al., Nucleic Acid Res.,1989, 17, 3889-3897). Similarly, the NS5B proteins of
`
`pestiviruses and hepaciviruses have the motifs characteristic of RNA-directed
`
`RNApolymerases (Koonin, E.V. and Dolja, V.V., Crir. Rev. Biochem. Molec.
`
`Biol. 1993, 28, 375-430).
`
`20
`
`The actual roles and functions of the NS proteins of pestiviruses and
`
`hepacivirusesin the lifecycle ofthe viruses are directly analogous. In both cases,
`
`the NS3 serine proteinase is responsible forall proteolytic processing of
`
`polyprotein precursors downstream ofits position in the ORF (Wiskerchen and
`
`Collett, Virology, 1991, 184, 341-350; Bartenschlageret al., J. Virol. 1993, 67,
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`3835-3844; Eckart et al. Biochem. Biophys. Res. Comm. 1993,192, 399-406;
`
`Grakoui et al., J. Virol. 1993, 67, 2832-2843; Grakouiet al., Proc. Natl. Acad
`
`Sci. USA 1993, 90, 10583-10587; Hijikata et al., J. Virol. 1993, 67, 4665-4675;
`
`Tomeet al., J. Virol., 1993, 67, 4017-4026). The NS4Aprotein, in both cases,
`
`5
`
`acts as a cofactor with the NS3 serine protease (Bartenschlageret al., J. Virol.
`
`1994, 68, 5045-5055; Failla et al., J. Virol. 1994, 68, 3753-3760; Xu et al., J.
`
`Virol., 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. Biochem. Biophys., 1995, 323, 47-53; Warrener and Collett,
`
`10.
`
`J. Virol. 1995, 69,1720-1726). Finally, the NSSB proteins of pestiviruses and
`
`hepaciviruses have the predicted RNA-directed RNA polymerasesactivity
`
`(Behrenset al., EMBO, 1996, 15, 12-22; Lechmannet al., J Virol., 1997, 71,
`
`8416-8428; Yuanet al., Biochem. Biophys. Res. Comm. 1997, 232, 231-235;
`
`Hagedorn, PCT WO 97/12033; Zhonget al, J. Virol., 1998, 72, 9365-9369).
`
`15
`
`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-o alone or in combination with the
`
`nucleoside analog ribavirin. This therapyis limitedin its clinical effectiveness
`
`and only 50% oftreated patients respond to therapy. Therefore, there is
`
`20_significant need for more effective and novel therapies to address the unmet
`
`medical need posed by HCV infection.
`
`A numberofpotential molecular targets for drug developmentofdirect
`
`acting antivirals as anti -HCV therapeutics have now beenidentified including,
`
`but not limited to, the NS2-NS3 autoprotease, the N3 protease, the N3 helicase
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`and the NS5B polymerase. The RNA-dependent RNA polymeraseis absolutely
`
`essential for replication of the single-stranded, positive sense, RNA genome and
`
`this enzymehaselicited significant interest among medicinal chemists.
`
`Inhibitors of HCV NSSBaspotential therapies for HCV infection have
`
`5
`
`been reviewed: Tan,S.-L., et al., Nature Rev. Drug Discov., 2002, 1, 867-881;
`
`Walker, M.-P. et al., Exp. Opin. Investigational Drugs, 2003, 12, 1269-1280; Ni,
`
`Z-J., et al., Current Opinion in Drug Discovery and Development, 2004, 7, 446-
`
`459; Beaulieu, P. L., et al., Current Opinion in Investigational Drugs, 2004, 5,
`
`838-850; Wu,J., et al., Current Drug Targets-Infectious Disorders, 2003, 3,
`
`10
`
`207-219; Griffith, R.C., et al, Annual Reports in Medicinal Chemistry, 2004, 39,
`
`223-237; Carrol, S., et al., Infectious Disorders-Drug Targets, 2006, 6, 17-29.
`
`The potential for the emergence of resistant HCVstrains and the needto identify
`
`agents with broad genotype coverage supports the need for continuing efforts to
`
`identify novel and more effective nucleosides as HCV NSSBinhibitors.
`
`15
`
`Nucleoside inhibitors of NSSB polymerase can act either as a non-natural
`
`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 nucleoside analog must be taken upbythe cell and converted in
`
`vivo to a triphosphate to compete for the polymerase nucleotide bindingsite.
`
`20
`
`This conversionto the triphosphate is commonly mediated by cellular kinases
`
`which imparts additional structural requirements on a potential nucleoside
`
`polymerase inhibitor. Unfortunately,this limits the direct evaluation of
`
`nucleosides as inhibitors of HCVreplication to cell-based assays capable of in
`
`situ phosphorylation.
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`In somecases, the biological activity of a nucleoside is hamperedby its
`
`poor substrate characteristics for one or more of the kinases needed to convert it
`
`to the active triphosphate form. Formation of the monophosphate by a
`
`nucleoside kinase is generally viewed asthe rate limiting step of the three
`
`5
`
`phosphorylation events. To circumvent the need forthe initial phosphorylation
`
`step in the metabolism of a nucleoside to the active triphosphate analog, the
`
`preparation of stable phosphate prodrugs has been reported. Nucleoside
`
`phosphoramidate prodrugs have been shownto be precursors of the active
`
`nucleoside triphosphate andto inhibit viral replication when administered to
`
`10
`
`viral infected whole cells (McGuigan,C., et al., J. Med. Chem., 1996, 39, 1748-
`
`1753; Valette, G., et al., J. Med. Chem., 1996, 39, 1981-1990; Balzarini,J., et al.,
`
`Proc. National Acad Sci USA, 1996, 93, 7295-7299; Siddiqui, A. Q., et al., J.
`
`Med. Chem., 1999, 42, 4122-4128; Eisenberg,E.J., et al., Nucleosides,
`
`Nucleotides and Nucleic Acids, 2001, 20, 1091-1098; Lee, W.A.,et al.,
`
`15
`
`Antimicrobial Agents and Chemotherapy, 2005, 49, 1898); US 2006/0241064;
`
`and WO 2007/095269.
`
`Also limiting the utility of nucleosides as viable therapeutic agentsis
`
`their sometimes poor physicochemical and pharmacokinetic properties. These
`
`poor properties can limit the intestinal absorption of an agent and limit uptake
`
`20_into the target tissue or cell. To improve on their properties prodrugs of
`
`nucleosides have been employed. It has been demonstrated that preparation of
`
`nucleoside phosphoramidates improves the systemic absorption of a nucleoside
`
`and furthermore, the phosphoramidate moiety of these "pronucleotides”is
`
`masked with neutral lipophilic groups to obtain a suitable partition coefficient to
`
`25
`
`optimize uptake and transport into the cell dramatically enhancing the
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`intracellular concentration of the nucleoside monophosphate analogrelative to
`
`administering the parent nucleoside alone. Enzyme-mediated hydrolysis of the
`
`phosphate ester moiety produces a nucleoside monophosphate wherein the rate
`
`limiting initial phosphorylation is unnecessary.
`
`5
`
`SUMMARYOF THE INVENTION
`
`The present invention is directed toward novel phosphoramidate
`
`prodrugs of nucleoside derivatives for the treatmentofviral infections in
`
`mammals, which is a compound,its stereoisomers, salts (acid or basic addition
`
`salts), hydrates, solvates, or crystalline forms thereof, represented by the
`
`10—following structure:
`
`RY
`1
`R
`|
`|| *
`ms—P
`|
`OR
`
`3b
`
`CO,R4
`
`
`
`1
`
`O
`
`Base
`
`RS
`
`Y
`
`x
`
`Oo
`
`RS
`
`I
`
`wherein
`
`(a)
`
`R!is hydrogen, n-alkyl; branched alkyl; cycloalkyl; or aryl, which
`
`15
`
`includes, butis not limited to, phenyl or naphthyl, where pheny! or naphthyl are
`
`optionally substituted with at least one of Cy.alkyl, C2.¢ alkenyl, C26 alkynyl,
`C;-6 alkoxy, F, Cl, Br,I, nitro, cyano, C;¢ haloalkyl, -N(R")s, Cy,acylamino,-
`NHSO,C;.¢ alkyl, -SO,N(R")2, COR", and -SO,C}.¢ alkyl; (R" is independently
`
`hydrogen or alkyl, which includes, but is not limited to, Cj-29 alkyl, C1-10 alkyl,
`or Cy.¢ alkyl, R'is —OR' or -N(R'),);
`
`20
`
`R’is hydrogen, C 1-10 alkyl, R*or R®? and R? together are (CH),
`(b)
`so as to form a cyclic ring that includes the adjoining N and C atoms,
`C(O)CR*R*°NHR’, where n is 2 to 4 and R', R®, and R®;
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`R*and R®are (i) independently selected from hydrogen, C).19
`(c)
`alkyl, cycloalkyl, -(CH2),(NR”)2, Cis hydroxyalkyl, -CH2SH, -(CH2)2S(O)aMe,-
`(CH2)3NHC(NH)Nh), (1 H-indol-3-yl)methyl, (1 H-imidazol-4-yl)methyl,-
`(CH2)¢COR®, aryl and aryl C;.3 alkyl, said aryl groups optionally substituted
`| with a group selected from hydroxyl, Cj-19 alkyl, Cialkoxy, halogen, nitro and
`cyano;(ii) R™* and R®both are C}.¢ alkyl; (iii) R®* and R*® together are(CH2)r so
`as to formaspiro ring;(iv) R*is hydrogen and R* and R? together are (CH2)n
`so as to form a cyclic ring that includes the adjoining N and C atoms(v) R®is
`hydrogen and R™ and R? together are (CH), so as to form a cyclic ring that
`includes the adjoining N and C atoms, wherec is | to 6, d is 0 to 2, e is 0 to 3, f
`10
`is 2 to 5,nis 2 to 4, and where R°is independently hydrogen or Cy.. alkyl and
`R®is -OR' or -N(R*),); (vi) R® is H and R”is H, CH3, CHyCH3, CH(CHs3)2,
`
`CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH-indol-3-yl, -CH2CH2SCHs,
`
`CH2CO2H, CH2C(O)NH2, CH2CH2zCOOH, CH2CH2C(O)NH2,
`
`15
`
`CH»CH2CH2CH2NH)p, -CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl,
`
`CH2OH, CH(OH)CH3, CH2((4'-OH)-Ph), CH2SH,or lower cycloalkyl; or (viii)
`R™is CH3, -CHyCH3, CH(CH3)2, CH2»CH(CHs3)2, CH(CH3)CH2CH3, CH2Ph,
`
`CH,-indol-3-yl, -CH2CH2SCH3, CH2CO.H, CH2C(O)NH2, CH2CH2COOH,
`
`CH2CH2C(O)NH2, CH2CH2CH2CH2NHz2, -CH2CH2CH2NHC(NH)NHb, CH2-
`
`20
`
`imidazol-4-yl, CHyOH, CH(OH)CH3, CH2((4'-OH)-Ph), CH2SH,or lower
`cycloalkyl and R®is H, where R?is independently hydrogenor alkyl, which
`includes, but is not limited to, C)-29 alkyl, C1.19 alkyl, or Ci¢ alkyl, R®is -OR'or
`-N(R’)2);
`
`R‘ is hydrogen, C1-19 alkyl, C1-10 alkyl optionally substituted with
`(d)
`a loweralkyl, alkoxy, di(lower alkyl)-amino, or halogen, C)-19 haloalkyl, C3-10
`
`25
`
`cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, aryl, such as phenyl,
`
`heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl;
`
`(c)
`R?is H,a loweralkyl, CN, vinyl, O-(loweralkyl), hydroxy! lower
`alkyl, i.e., -(CH2),»OH, wherepis 1 -6, including hydroxyl methyl (CH2OH),
`CHF, N3, CH2CN, CH2NH2, CH2NHCH3, CH2N(CH3)2, alkyne (optionally
`30
`
`substituted), or halogen, including F, Cl, Br, or I, with the provisos that when X
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`is OH,base is cytosine and R°is H, R° cannot be N3 and whenXis OH,R°is
`CHor CHF andB is a purine base, R° cannot be H;
`
`(f)
`
`R° is H, CH3, CH>F, CHF», CFs, F, or CN;
`
`(g)
`
`X is H, OH, F, OMe, halogen, NH, or N3;
`
`5
`
`Y is OH, H, Cjalkyl, C24 alkenyl, C24 alkynyl, vinyl, N3, CN,
`(h)
`Cl, Br, F, I, NO2, OC(O)O(Ci4 alkyl), OC(O)O(C, 4 alkyl), OC(O)O(C24
`alkynyl), OC(O)O(Cz4 alkenyl), OC}-19 haloalkyl, O(aminoacyl), O(C}.19 acyl),
`
`O(C)4 alkyl), O(C24 alkenyl), S(C1-4 acyl), S(Cj-4 alkyl), S(C2.4 alkynyl), S(C24
`
`alkenyl), SO(C;4 acyl), SO(C,4 alkyl), SO(C24 alkynyl), SO(C24 alkenyl),
`
`10 SOC, acyl), SO2(C)4 alkyl), SO2(C24 alkynyl), SO2(C24 alkenyl), OS(O)2(C)-
`
`4 acyl), OS(O)2(C14 alkyl), OS(O)2(C24 alkenyl), NH2, NH(C).4 alkyl), NH(C2-4
`alkenyl), NH(C24 alkynyl), NH(Ci4 acyl), N(C)4 alkyl)2, N(Cj-13 acyl)2,
`
`wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N3, CN,
`one to three halogen (Cl, Br, F, 1), NO2, C(O)O(C)4 alkyl), C(O)O(C}.4 alkyl),
` C(O)O(Cz4 alkynyl), C(O)O(C24 alkenyl), O(Ci-4 acyl), O(C)4 alkyl), O(C24
`alkenyl), S(C4 acyl), S(Ci4 alkyl), S(C24 alkynyl), S(Co4 alkenyl), SO(Ci4
`
`15
`
`acyl), SO(C)4 alkyl), SO(C2-4 alkynyl), SO(C24 alkenyl), SO2(C,4 acyl),
`
`$O2(C;4 alkyl), SO2(C24 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C)4 acyl),
`
`OS(O)2(Ci4 alkyl), OS(O)2(Co-4 alkenyl), NH2, NH(Ci-4 alkyl), NH(C24
`alkenyl), NH(C24 alkynyl), NH(Ci4 acyl), N(Cy4 alkyl)2, N(C1.4 acyl)2;
`
`20
`
`the base is a naturally occurring or modified purine or pyrimidine base
`
`represented by the following structures:
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`R8
`
`R?
`
`R9
`
`SS
`
`N
`
`}
`
`wy
`
`a
`
`RS
`
`O R’
`
`O
`
`)
`
`wy
`
`b
`
`NH
`
`Z
`
`0 }
`
`ww
`
`R10
`
`NN
`
`N
`
`4
`
`N
`
`c
`
`Oo
`
`N
`
`NH
`
`RU }
`
`uy
`
`aA
`
`N
`
`NH,
`
`d
`
`wherein
`
`Z is N or CR”;
`
`R’, R°.R’, R’°, and R'are independently H, F, Cl, Br, I, OH, OR’, SH,
`SR', NH2, NHR’, NR"2, lower alkyl of C)-C¢, halogenated (F, Cl, Br, I) lower
`
`alkyl of C\-Cg, lower alkenyl of C2-C¢, halogenated (F, Cl, Br, I) lower alkenyl
`
`of C2-C¢, lower alkynyl of C2-Cg such as C=CH,halogenated (F, Cl, Br, I) lower
`
`alkynyl of C2-C¢, lower alkoxy of C)-C6, halogenated (F, Cl, Br, I) lower alkoxy
`
`10
`
`of C)-Ce, CO2H, CO2R', CONH2, CONHR', CONR",, CH=CHCO2H,or
`
`CH=CHCO2R',
`
`wherein R' is an optionally substituted alkyl , which includes, butis not
`
`limited to, an optionally substituted Cj.29 alkyl, an optionally substituted C,_;9
`
`alkyl, an optionally substituted lower alkyl]; an optionally substituted cycloalkyl;
`
`15
`
`an optionally substituted alkynyl of C2-C¢, an optionally substituted lower
`
`alkenyl of C2-C,, or optionally substituted acyl, which includes but is not limited
`
`to C(O) alkyl, C(O)(C}-20 alkyl), C(O)(C1-40 alkyl), or C(O)(lower alkyl) or
`
`alternatively, in the instance of NR'2, each R' compriseat least one C atom that
`
`are joined to form a heterocycle comprising at least two carbon atoms; and
`
`20
`
`R”is H, halogen (including F, Cl, Br, J), OH, OR’, SH, SR', NH>, NHR',
`NR"2, NO2 loweralkyl of C,-C¢, halogenated (F, Cl, Br, I) lower alkyl of C,-Ce,
`
`lower alkenyl of C2-C¢, halogenated (F, Cl, Br, I) lower alkenyl of C2-C¢ , lower
`
`alkynyl of C2-C,, halogenated (F, Cl, Br, I) lower alkynyl of C2-C¢, lower alkoxy
`
`of C,-C¢, halogenated (F, Cl, Br, J) lower alkoxy of C)-Cg, CO2H, CO2R',
`
`25
`
`CONH2, CONHR', CONR'2, CH=CHCO2H, or CH=CHCO,R’; with the proviso
`
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`that whenbaseis represented bythe structure c with R'! being hydrogen, R’”is
`not a: (i) -C=C-H,(ii) -C=CHh,or(iii) -NO}.
`
`DEFINITIONS
`
`5
`
`The phrase "a" or "an" entity as used herein refers to one or more ofthat
`
`entity; for example, a compoundrefers to one or more compoundsorat 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
`
`10
`
`provided in the Summary ofthe 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 mayor maynotbepresent, and that the description includes single, double,
`ortriple 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 compoundin 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 othernitrogen.
`
`15
`
`20
`
`The term "alkenyl" refers to an unsubstituted hydrocarbon chain radical
`
`having from 2 to 10 carbon atoms having one or twoolefinic double bonds,
`
`25
`
`preferably one olefinic double bond. The term "Czy 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 "C>.4 alkenyl" refers to an
`alkenyl comprising 2 to 4 carbon atoms. Examples include, but are not limited
`
`30
`
`to, vinyl, 1-propenyl, 2-propeny!(allyl) or 2-butenyl (crotyl).
`
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`The term "halogenated alkenyl" refers to an alkenyl comprising at least
`
`one of F, Cl, Br, and I.
`
`The term "alkyl" refers to an unbranched or branched chain, saturated,
`monovalent hydrocarbon residue containing 1! to 30 carbon atoms. The term "Cj.
`yw alkyl" refers to an alkyl comprising 1 to M carbon atoms, where M is an
`
`5
`
`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 "Cj-4 alkyl"
`
`refers to an alkyl containing |
`
`to 4 carbon atoms. The term "lower alkyl"
`
`denotes a straight or branched chain hydrocarbon residue comprising |
`
`to 6
`
`10
`
`carbon atoms.
`
`"C;-29 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, t-butyl or pentyl,
`
`isopentyl, neopentyl, hexyl, heptyl, and octyl.
`
`The term (arjalkyl or
`
`15
`
`(heteroaryl)alkyl indicate the alkyl group is optionally substituted by an aryl or a
`
`heteroaryl group respectively.
`
`The term "cycloalkyl"
`
`refers
`
`to an unsubstituted or
`
`substituted
`
`carbocycle, in which the carbocycle contains 3 to 10 carbon atoms; preferably 3
`
`to 8 carbon atoms; more preferably 3 to 6 carbon atoms(i.e., lower cycloalkyls).
`
`20
`
`Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, 2-
`
`methyl-cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
`
`The term "cycloalkyl alkyl" refers to an additionally unsubstituted or
`
`substituted alkyl substituted by a lower cycloalkyl. Examples of cycloalkyl
`
`alkyls include, but are not limited to, any one of methyl, ethyl, propyl, i-propyl,
`
`25
`
`n-butyl, i-butyl, t-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl
`
`that
`
`is
`
`substituted with
`
`cyclopropyl,
`
`2-methyl-cyclopropyl,
`
`cyclobutyl,
`
`cyclopentyl, and cyclohexyl.
`
`The term "cycloheteroalkyl" refers to an unsubstituted or substituted
`
`heterocycle, in which the heterocycle contains 2 to 9 carbon atoms; preferably 2
`
`30
`
`to 7 carbon atoms; more preferably 2 to 5 carbon atoms.
`
`Examples of
`
`cycloheteroalkyls include, but are not
`
`limited to, aziridin-2-yl, N-C,.3-alkyl-
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`aziridin-2-yl, azetidinyl, N-C,.3-alkyl-azetidin-m'-yl, pyrrolidin-m'-yl, N-C,.3-
`
`alkyl-pyrrolidin-m'-yl, piperidin-m'-yl, and N-C;.3-alkyl-piperidin-m'-yl, where
`
`m' is 2, 3, or 4 depending on the cycloheteroalkyl. Specific examples of N-C;.3-
`
`alkyl-cycloheteroalkyls include, but are not limited to, N-methyl-aziridin-2-yl,
`
`5
`
`N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-
`
`In
`methyl-piperidin-2-yl, N-methy]-piperidin-3-yl, and N-methyl-piperidin-4-yl.
`the instance of R*, the point of attachment between the cycloheteroalkyl ring
`carbon and the oxygen occurs at any one of m'
`
`The term "heterocycle"
`
`refers
`
`to an unsubstituted or
`
`substituted
`
`10
`
`heterocycle containing carbon, hydrogen, and at least one of N, O, and S, where
`the C and N canbetrivalentortetravalent, i.e., sp’- or sp’-hybridized. Examples
`of heterocycles include, but are not limited to, aziridine, azetidine, pyrrolidine,
`
`In the instance of piperazine, as
`piperidine, imidazole, oxazole, piperazine, etc.
`related to R'° for NR‘,
`the corresponding opposite nitrogen atom of the
`
`15
`
`piperazinyl is substituted by a lower alkyl represented by the following structure:
`
`lowermS
`
`Preferably, the opposite nitrogen of the piperazinyl is substituted by a methyl
`
`group.
`
`The term "halogenated alkyl" (or "haloalkyl") refers to an unbranched or
`
`20
`
`branched chain alkyl comprising at least one of F, Cl, Br, and I. The term "Cj.
`
`haloalkyl”refers to an alky] comprising 1 to M carbon atoms that comprises at
`
`least one of F, Cl, Br, and J, 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.
`
`"Cj-3 haloalkyl" refers to a haloalkyl comprising 1 to 3
`
`25
`
`carbonsandatleast one of F, Cl, Br, and J. The term "halogenated loweralkyl"
`
`(or "lower haloalkyl") 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,
`
`fluoromethyl,
`
`chloromethyl,
`
`bromomethyl,
`
`iodomethyl,
`
`difluoromethy],
`
`dichloromethyl, dibromomethyl, diiodomethyl, trifluoromethyl, trichloromethyl,
`
`30
`
`tribromomethy],
`
`triiod