(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`6 October 2011 (06.10.2011)
`
`PCT
`
`11111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111
`
`(10) International Publication Number
`WO 2011/123645 A2
`
`(US). WANG, Peiyuan [CNIUS]; 20 Radburn Road,
`Glen Rock, NJ 07452 (US).
`
`(74) Agents: KOWALCHYK, Katherine, M. et al.; Mer(cid:173)
`chant & Gould P.C., P.O.Box 2903, Minneapolis, MN
`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, CL, 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, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD,
`SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,
`TT, TZ, VA, 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, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG,
`ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU,
`LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK,
`SM, 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 (Rule 48.2(g))
`
`(51)
`
`International Patent Classification:
`C07H 19/06 (2006.01)
`C07F 9/26 (2006.01)
`C07H 19/207 (2006.01)
`A61P 31114 (2006.01)
`A61K 3117072 (2006.01)
`
`(21) International Application Number:
`PCT/US20ll/030725
`
`(22) International Filing Date:
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`31 March 2011 (31.03.2011)
`
`English
`
`English
`
`(30) Priority Data:
`61/319,548
`61/319,513
`12/783,680
`
`31 March 2010 (31.03.2010)
`31 March 2010 (31.03.2010)
`20 May 2010 (20.05.2010)
`
`us
`us
`us
`(71) Applicant (for all designated States except US): PHAR-
`MASSET, INC. [US/US]; 303a College Road East,
`Princeton, NJ 08540 (US).
`
`(72)
`(75)
`
`Inventors; and
`Inventors/Applicants (for US only): ROSS, Bruce, S.
`[US/US]; 8 Keppel Road, Plainsboro, NJ 08536 (US).
`SOFIA, Michael, Joseph [US/US]; 3066 Antler Drive,
`Doylestown, PA 18901 (US). PAMULAPATI, Ganap(cid:173)
`ati, Reddy [IN/US]; 4608 Hunters Glen Drive, Plains(cid:173)
`boro, NJ 08536
`(US). RACHAKONDA, Suguna
`[IN/US]; 1272 Sharonbrook Drive, Twinsburg, OH 44087
`(US). ZHANG, Hai-Ren [US/US]; 8680 Manahan Drive,
`Ellicott City, MD 21043 (US). CHUN, Byoung-Kwon
`[KR/US]; 135 Heritage Street, Robbinsville, NJ 08691
`
`--
`
`----------
`---;;;;;;;;;;;;;;; -
`----;;;;;;;;;;;;;;; -
`
`(54) Title: NUCLEOSIDE PHOSPHORAMIDATES
`
`(57) Abstract: Disclosed herein are nucleoside phosphoramidates and their use as agents for treating viral diseases. These com(cid:173)
`pounds are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as in(cid:173)
`hibitors ofHCV replication and for treatment ofhepatitis C infection in mammals.
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`NUCLEOSIDE PHOSPHORAMIDATES
`
`Priority
`
`This application is claims priority to U.S. Patent Application No.
`
`5
`
`611319,513, filed March 31, 2010, U.S. Patent Application No. 61/319,548, filed
`
`March 31, 2010, and U.S. Patent Application No. 12/783,680, filed May 20, 2010,
`
`the subject matter of which are incorporated by reference in their entirety.
`
`Field of the Invention
`
`Disclosed herein are nucleoside phosphoramidates and their use as agents for
`
`treating viral diseases. These compounds are inhibitors of RNA-dependent RNA
`
`viral replication and are useful as inhibitors ofHCV NS5B polymerase, as inhibitors
`
`ofHCV replication and for treatment of hepatitis C infection in mammals.
`
`10
`
`15
`
`Background
`
`Hepatitis C virus (HCV) infection is a major health problem that leads to
`
`chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial
`
`20
`
`number of infected individuals, estimated to be 2-15% ofthe 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 worldwide, with
`
`at least 3 to 4 million people being infected each year. Once infected, about 20% of
`
`25
`
`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(cid:173)
`
`destroying cirrhosis or cancer. The viral disease is transmitted parenterally by
`
`contaminated blood and blood products, contaminated needles, or sexually and
`
`vertically from infected mothers or carrier mothers to their offspring. Current
`
`30
`
`treatments for HCV infection, which are restricted to immunotherapy with
`
`recombinant interferon-a alone or in combination with the nucleoside analog
`
`ribavirin, are of limited clinical benefit. Moreover, there is no established vaccine
`
`for HCV. Consequently, there is an urgent need for improved therapeutic agents
`
`that effectively combat chronic HCV infection.
`
`1
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`The HCV virion is an enveloped positive-strand RNA virus with a single
`
`oligoribonucleotide genomic sequence of about 9600 bases which encodes a
`
`polyprotein of about 3,010 amino acids. The protein products ofthe HCV gene
`
`consist of the structural proteins C, E1, and E2, and the non-structural proteins NS2,
`
`5 NS3, NS4A and NS4B, and NS5A and NS5B. The nonstructural (NS) proteins are
`
`believed to provide the catalytic machinery for viral replication. The NS3 protease
`
`releases NS5B, the RNA-dependent RNA polymerase from the polyprotein chain.
`
`HCV NS5B polymerase is 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
`
`10 HCV. Therefore, NS5B polymerase is considered to be an essential component in·
`
`the HCV replication complex (K. Ishi, et al, Heptology, 1999,29: 1227-1235; V.
`
`Lohmann, et al., Virology, 1998, 249: 1 08-118). Inhibition of HCV NS5B
`
`polymerase prevents formation of the double-stranded HCV RNA and therefore
`
`constitutes an attractive approach to the development of HCV -specific antiviral
`
`15
`
`therapies.
`
`HCV belongs to a much larger family of viruses that share many common
`
`features.
`
`Flaviviridae Viruses
`
`The Flaviviridae family of viruses comprises at least three distinct genera:
`
`20
`
`pestiviruses, which cause disease in cattle and pigs;jlavivruses, 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.
`
`Viral, 1993,70,37-43). Clinical symptoms vary and include fever, encephalitis and
`
`25
`
`hemorrhagic fever (Fields Virology, Editors: Fields, B. N., Knipe, D. M., and
`
`Howley, P. M., Lippincott-Raven Publishers, Philadelphia, P A, 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,
`
`30
`
`251-264; Halstead, S. B., Science, 239:476-481, 1988; Monath, T. P., New Eng. J
`
`Med, 1988,319,64 1-643).
`
`The pestivirus genus includes bovine viral 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
`2
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`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.
`
`5 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.
`
`Pestiviruses and hepaciviruses are closely related virus groups within the
`
`Flaviviridae family. Other closely related viruses in this family include the GB virus
`
`10 A, GB virus A-like agents, GB virus-Band 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 at least 6 HCV genotypes and more than 50 subtypes. Due to the similarities
`
`between pestiviruses and hepaciviruses, combined with the poor ability of
`
`15
`
`hepaciviruses to grow efficiently in cell culture, bovine viral diarrhea virus (BVDV)
`
`is often used as a surrogate to study the HCV virus.
`
`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
`
`20
`
`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
`
`25
`
`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 ofthe ORF, consist ofp7, NS2, NS3,
`
`NS4A, NS4B, NS5A, and NS5B.
`
`30
`
`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
`
`proteinases and ofhelicases (Gorbalenya et al., Nature, 1988, 333, 22; Bazan and
`
`Fletterick Virology, 1989, 171, 637-639; Gorbalenya et al., Nucleic Acid Res., 1989,
`3
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`17, 3889-3897). Similarly, the NS5B proteins ofpestiviruses and hepaciviruses
`
`have the motifs characteristic of RNA-directed RNA polymerases (Koonin, E.V. and
`
`Dolja, V.V., Crir. Rev. Biochem. MoZee. Bioi. 1993, 28, 375-430).
`
`The actual roles and functions of the NS proteins of pestiviruses and
`
`5
`
`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,
`
`Virology, 1991, 184, 341-350; Bartenschlager et al., J Viral. 1993,67, 3835-3844;
`
`Eckart et al. Biochem. Biophys. Res. Comm. 1993,192, 399-406; Grakoui et al., J
`
`10
`
`Viral. 1993,67, 2832-2843; Grakoui et al., Proc. Nat/. Acad Sci. USA 1993,90,
`
`10583-10587; Hijikata et al., J Viral. 1993,67, 4665-4675; Tome et al., J Viral.,
`
`1993, 67, 4017-4026). The NS4A protein, in both cases, acts as a cofactor with the
`
`NS3 serine protease (Bartenschlager et al., J Viral. 1994, 68, 5045-5055; Failla et
`
`al., J Viral. 1994, 68, 3753-3760; Xu et al., J Viral., 1997, 71:53 12-5322). The
`
`15 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, J Viral. 1995, 69,1720-1726).
`
`Finally, the NS5B proteins ofpestiviruses and hepaciviruses have the predicted
`
`RNA-directed RNA polymerases activity (Behrens et al., EMBO, 1996, 15, 12-22;
`
`20
`
`Lechmann et al., J Viral., 1997,71, 8416-8428; Yuan et al., Biochem. Biophys. Res.
`
`Comm. 1997,232, 231-235; Hagedorn, PCT WO 97/12033; Zhong et al, J Viral.,
`
`1998, 72, 9365-9369).
`
`Currently, there are limited treatment options for individuals infected with
`
`hepatitis C virus. The current approved therapeutic option is the use of
`
`25
`
`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% of treated patients respond to therapy. Therefore, there is significant need
`
`for more effective and novel therapies to address the unmet medical need posed by
`
`HCV infection.
`
`30
`
`A number of potential molecular targets for drug development of direct
`
`acting antivirals as anti -HCV therapeutics have now been identified including, but
`
`not limited to, the NS2-NS3 autoprotease, the N3 protease, the N3 helicase and the
`
`NS5B polymerase. The RNA-dependent RNA polymerase is absolutely essential for
`
`4
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`replication of the single-stranded, positive sense, RNA genome and this enzyme has
`
`elicited significant interest among medicinal chemists.
`
`Inhibitors of HCV NS5B as potential therapies for HCV infection'have been
`
`reviewed: Tan, S.-L., et al., Nature Rev. Drug Discov., 2002, 1, 867-881; Walker,
`
`5 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, 207-219; Griffith, R.C., et
`
`al, Annual Reports in Medicinal Chemistry, 2004, 39, 223-237; Carrol, S., et al.,
`
`10
`
`Irifectious Disorders-Drug Targets, 2006, 6, 17-29. The potential for the emergence
`
`of resistant HCV strains and the need to identify agents with broad genotype
`
`coverage supports the need for continuing efforts to identify novel and more
`
`effective nucleosides as HCV NS5B inhibitors.
`
`Nucleoside inhibitors ofNS5B polymerase can act either as a non-natural
`
`15
`
`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 up by the cell and converted in vivo
`
`to a triphosphate to compete for the polymerase nucleotide binding site. This
`
`conversion to the triphosphate is commonly mediated by cellular kinases which
`
`20
`
`imparts additional structural requirements on a potential nucleoside polymerase
`
`inhibitor. Unfortunately, this limits the direct evaluation ofnucleosides as inhibitors
`
`ofHCV replication to cell-based assays capable of in situ pl!osphorylation.
`
`In some cases, the biological activity of a nucleoside is hampered by its poor
`
`substrate characteristics for one or more of the kinases needed to convert it to the
`
`25
`
`active triphosphate form. Formation of the monophosphate by a nucleoside kinase is
`
`generally viewed as the rate limiting step of the three phosphorylation events. To
`
`circumvent the need for the 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
`
`30
`
`shown to be precursors of the active nucleoside triphosphate and to inhibit viral
`
`replication when administered to 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. 1., et al.,
`5
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`Nucleosides, Nucleotides and Nucleic Acids, 2001,20, 1091-1098; Lee, W.A., et
`
`al., Antimicrobial Agents and Chemotherapy, 2005, 49, 1898); US 2006/0241064;
`
`and WO 2007/095269.
`
`Also limiting the utility of nucleosides as viable therapeutic agents is their
`
`5
`
`sometimes poor physicochemical and pharmacokinetic properties. These poor
`
`properties can limit the intestinal absorption of an agent and limit uptake into the
`
`target tissue or cell. To improve on their properties prodrugs ofnucleosides have
`
`been employed. It has been demonstrated that preparation of nucleoside
`
`phosphoramidates improves the systemic absorption of a nucleoside and
`
`10
`
`furthermore, the phosphorarnidate moiety of these "pronucleotides" is masked with
`
`neutral lipophilic groups to obtain a suitable partition coefficient to optimize uptake
`
`and transport into the cell dramatically enhancing the intracellular concentration of
`
`the nucleoside monophosphate analog relative to administering the parent nucleoside
`
`alone. Enzyme-mediated hydrolysis ofthe phosphate ester moiety produces a
`
`15
`
`nucleoside monophosphate wherein the rate limiting initial phosphorylation is
`
`unnecessary. To this end, U.S. Patent Application 12/053,015, which corresponds to
`
`WO 2008/121634 and US 201 0/0016251, discloses a number of phosphoramidate
`
`nucleoside prodrugs, many of which show activity in an HCV assay. Several
`
`compounds disclosed in US 2010/0016251 were tested as a potential clinical
`
`20
`
`candidate for approval by the FDA.
`
`Summary of the Invention
`Disclosed herein is a compound represented by formula 4 and its respective
`
`phosphorus-based diastereomers represented by formulas Sr-4 and Rr-4.
`
`~
`
`0
`
`0
`
`~NH
`O
`*/) /'y'OyN~O
`H
`HN~P-0 'LJ-,.
`~ OPh
`He{
`·-:.-F
`
`25
`
`4
`
`6
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`Rp-4
`
`Brief Description of the Drawings
`
`5
`
`Figure 1.
`
`High resolution XRD diffractogram of 4.
`
`Figure 2.
`
`High resolution XRD diffractogram of Rp-4.
`
`10
`
`Figure 3.
`
`High resolution XRD diffractogram of Sp-4 (Form 1).
`
`Figure 4.
`
`High resolution XRD diffractogram of Sp-4 (Form 1).
`
`Figure 5.
`
`High resolution XRD diffractogram of Sp-4·CH2Ch (Form 2).
`
`15
`
`Figure 6.
`
`High resolution XRD diffractogram of Sp-4·CHCb (Form 3).
`
`Figure 7.
`
`High resolution XRD diffractogram of Sp-4 (Form 4).
`
`20
`
`Figure 8.
`
`High resolution XRD diffractogram of Sp-4 (Form 5).
`
`Figure 9.
`
`High resolution XRD diffractogram of Sr-4 (amorphous).
`
`Figure 10.
`
`X-Ray Crystal Structure for Sp-4 (Form 1)
`
`25
`
`Figure 11.
`
`X-Ray Crystal (Isotropic) Structure for Sp-4·CH2Ch (Form 2)
`
`Figure 12.
`
`X-Ray Crystal (Anisotropic) Structure for Sp-4·CH2Ch (Form 2)
`
`30
`
`Figure 13.
`
`X-Ray Crystal Structure for Sp-4·CHCb (Form 3)
`
`Figure 14.
`
`FT-IR spectrum of 4.
`
`35
`
`Figure 15.
`
`FT-IR spectrum of Rp-4.
`
`Figure 16.
`
`FT-IR spectrum of Sp-4
`
`7
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`Figure 17.
`
`TGA and DSC analysis of 4.
`
`Figure 18.
`
`TGA and DSC analysis of Rp-4.
`
`5
`
`Figure 19.
`
`TGA and DSC analysis of Sp-4.
`
`Figure 20A. X-Ray Crystal Structure for 8 (Sp-isomer) (molecule no. 1 of the
`asymmetric unit).
`
`10
`
`Figure 20B. X-Ray Crystal Structure for 8 (Sp-isomer) (molecule no. 2 of the
`asymmetric unit).
`
`Figure 21._ High resolution XRD diffractogram of Sr-4 (Form 6).
`
`15
`
`20
`
`Figure 22A. X-Ray Crystal Structure for (S)-isopropyi2-(((S)(cid:173)
`(perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate (molecule no. 1 of
`the asymmetric unit).
`
`Figure 22B. X-Ray Crystal Structure for (S)-isopropyi2-(((S)-
`(perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate (molecule no. 2 of
`the asymmetric unit).
`
`Detailed Description of the Invention
`
`25 Definitions
`
`The phrase "a" or "an" entity as used herein refers to one or more of that
`
`entity; for example, a compound refers to one or more compounds or at least one
`
`compound. As such, the terms "a" (or "an"), "one or more", and "at least one" can
`
`be used interchangeably herein.
`
`30
`
`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.
`
`35
`
`The term "P*" means that the phosphorus atom is chiral and that it has a
`
`corresponding Cahn-Ingold-Prelog designation of "R" or "S" which have their
`
`accepted plain meanings.
`
`The term "purified," as described herein, refers to the purity of a given
`
`compound. For example, a compound is "purified" when the given compound is a
`
`40 major component of the composition, i.e., at least 50% w/w pure. Thus, "purified"
`
`8
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`embraces at least 50% w/w purity, at least 60% w/w purity, at least 70% purity, at
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`least 80% purity, at least 85% purity, at least 90% purity, at least 92% purity, at least
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`94% purity, at least 96% purity, at least 97% purity, at least 98% purity, at least 99%
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`purity, at least 99.5% purity, and at least 99.9% purity, wherein "substantially pure"
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`embraces at least 97% purity, at least 98% purity, at least 99% purity, at least 99.5%
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`purity, and at least 99.9% purity
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`The term "metabolite," as described herein, refers to a compound produced
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`in vivo after administration to a subject in need thereof.
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`The term "about" (also represented by~) means that the recited numerical
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`value is part of a range that varies within standard experimental error.
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`The expression "substantially as shown in ... " a specified XRPD pattern
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`means that the peak positions shown in the XRPD pattern are substantially the same,
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`.
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`within visual inspection or resort to selected peak listings(± 0.2 °29). One of
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`ordinary skill understands that the intensities can vary depending on the sample.
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`The term "substantially anhydrous" means that a substance contains at most
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`10% by weight of water, preferably at most 1% by weight of water, more preferably
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`at most 0.5% by weight of water, and most preferably at most 0.1% by weight of
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`water.
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`A solvent or anti-solvent (as used in reactions, crystallization, etc. or lattice
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`and/or adsorbed solvents) includes at least one of a C1 to Cs alcohol, a C2 to Cs
`ether, a c3 to c7 ketone, a c3 to c7 ester, a cl to c2 chlorocarbon, a c2 to c7 nitrile,
`a miscellaneous solvent, a C5 to C12 saturated hydr~carbon, and a C6 to C12 aromatic
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`hydrocarbon.
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`The C 1 to C8 alcohol refers to a straight/branched and/or cyclic/acyclic
`alcohol having such number of carbons. The C1 to Cs alcohol includes, but is not
`limited to, methanol, ethanol, n-propanol, isopropanol, isobutanol, hexanol, and
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`cyclohexanol.
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`The C2 to C8 ether refers to a straight/branched and/or cyclic/acyclic ether
`having such number of carbons. The C2 to Cs ether includes, but is not limited to,
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`dimethyl ether, diethyl ether, di-isopropyl ether, di-n-butyl ether, methyl-t-butyl
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`ether (MTBE), tetrahydrofuran, and dioxane
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`The C3 to C7 ketone refers to a straight/branched and/or cyclic/acyclic ketone
`having such number of carbons. The C3 to C1 ketone includes, but is not limited to,
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`acetone, methyl ethyl ketone, propanone, butanone, methyl isobutyl ketone, methyl
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`butyl ketone, and cyclohexanone.
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`The C3 to C7 ester refers to a straight/branched and/or cyclic/acyclic ester
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`having such number of carbons. The C3 to C7 ester includes, but is not limited to,
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`ethyl acetate, propyl acetate, n-butyl acetate, etc.
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`The C 1 to C2 chlorocarbon refers to a chlorocarbon having such number of
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`carbons. The C 1 to C2 chlorocarbon includes, but is not limited to, chloroform,
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`methylene chloride (DCM), carbon tetrachloride, 1 ,2-dichloroethane, and
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`tetrachloroethane.
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`A C2 to C7 nitrile refers to a nitrile have such number of carbons. The C2 to
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`C7 nitrile includes, but is not limited to, acetonitrile, propionitrile, etc.
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`A miscellaneous solvent refers to a solvent commonly employed in organic
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`chemistry, which includes, but is not limited to, diethylene glycol, diglyme
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`(diethylene glycol dimethyl ether), 1 ,2-dimethoxy-ethane, dimethylformamide,
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`dimethylsulfoxide, ethylene glycol, glycerin, hexamethylphsphoramide,
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`hexamethylphosphorous triame, N-methyl-2-pyrrolidinone, nitromethane, pyridine,
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`triethyl amine, and acetic acid.
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`The term C5 to C 12 saturated hydrocarbon refers to a straight/branched and/or
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`cyclic/acyclic hydrocarbon. The Cs to C12 saturated hydrocarbon includes, but is not
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`limited to, n-pentane, petroleum ether (ligroine ), n-hexane, n-heptane, cyclohexane,
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`and cycloheptane.
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`The term C6 to C12 aromatic refers to substituted and unsubstituted
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`hydrocarbons having a phenyl group as their backbone. Preferred hydrocarbons
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`include benzene, xylene, toluene, chlorobenzene, o-xylene, m-xylene, p-xylene,
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`xylenes, with toluene being more preferred.
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`The term "halo" or "halogen" as used herein, includes chloro, bromo, iodo
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`and fluoro.
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`The term "blocking group" refers to a chemical group which exhibits the
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`following characteristics. The "group" is derived from a "protecting compound."
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`30 Groups that are selective for primary hydroxyls over secondary hydroxyls that can
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`be put on under conditions consistent with the stability of the phosphoramidate (pH
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`2-8) and impart on the resulting product substantially different physical properties
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`allowing for an easier separation of the 3'-phosphoramidate-5'-new group product
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`from the unreacted desired compound. The group must react selectively in good
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`yield to give a protected substrate that is stable to the projected reactions (see
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`Protective Groups in Organic Synthesis, 3nd ed. T. W. Greene and P. G. M. Wuts,
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`John Wiley & Sons, New York, N.Y., 1999). Examples of groups include, but are
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`not limited to: benzoyl, acetyl, phenyl-substituted benzoyl, tetrahydropyranyl, trityl,
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`5 DMT (4,4'-dimethoxytrityl), MMT (4-monomethoxytrityl), trimethoxytrityl, pixyl
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`(9-phenylxanthen-9-yl) group, thiopixyl (9-phenylthioxanthen-9-yl) or 9-(p(cid:173)
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`methoxyphenyl)xanthine-9-yl (MOX), etc.; C(O)-alkyl, C(O)Ph, C(O)aryl, CH20-
`alkyl, CH20-aryl, S02-alkyl, S02-aryl, tert-butyldimethylsilyl, tert(cid:173)
`butyldiphenylsilyl. Acetals, such as MOM or THP and the like are considered
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`possible groups. Fluorinated compounds are also contemplated in so far that they
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`can be attached to the compound and can be selectively removed by passing through
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`a fluorous solid phase extraction media (FluoroFlash®). A specific example includes
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`a fluorinated trityl analog, trityl analog 1-[ 4-(IH, 1H,2H,2H-perfluorodecyl)phenyl)-
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`1,1-diphenylmethanol. Other fluorinated analogs oftrityl, BOC, FMOC, CBz, etc.
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`are also contemplated. Sulfonyl chlorides like p-toluenesulfonyl chloride can react
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`selectively on the 5' position. Esters could be formed selectively such as acetates
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`and benzoates. Dicarboxylic anhydrides such as succinic anhydride and its
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`derivatives can be used to generate an ester linkage with a free carboxylic acid, such
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`examples include, but are not limited to oxalyl, malonyl, succinyl, glutaryl, adipyl,
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`pimelyl, superyl, azelayl, sebacyl, phthalyl, isophthalyl, terephthalyl, etc. The free
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`carboxylic acid increases the polarity dramatically and can also be used as a handle
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`to extract the reaction product into mildy basic _aqueous phases such as sodium
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`bicarbonate solutions. The phosphoramidate group is relatively stable in acidic
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`media, so groups requiring acidic reaction conditions, such as, tetrahydropyranyl,
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`could also be used.
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`The term "protecting group" which is derived from a "protecting compound,"
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`has its plain and ordinary meaning, i.e., at least one protecting or blocking group is
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`bound to at least one functional group (e.g., -OH, -NH2, etc.) that allows chemical
`modification of at least one other functional group. Examples of protecting groups,
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`.include, but are not limited to, benzoyl, acetyl, phenyl-substituted benzoyl,
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`tetrahydropyranyl, trityl, DMT (4,4'-dimethoxytrityl), MMT (4-monomethoxytrityl),
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`trimethoxytrityl, pixyl (9-phenylxanthen-9-yl) group, thiopixyl (9-
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`phenylthioxanthen-9-yl) or 9-(p-methoxyphenyl)xanthine-9-yl (MOX), etc.; C(O)(cid:173)
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`alkyl, C(O)Ph, C(O)aryl, C(O)O(lower alkyl), C(O)O(lower alkylene)aryl (e.g.,-
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`protecting group comprising at least one silicon atom, such as, tert(cid:173)
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`butyldimethylsilyl, tert-butyldiphenylsilyl, Si(lower alkyl)20Si(lower alkyl)20H
`(such as, -Si(Pr)20Si(Pr)20H.
`The term "protecting compound," as used herein and unless otherwise
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`defined, refers to a compound that contains a "protecting group" and that is capable
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`of reacting with a compound that contains functional groups that are capable of
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`being protected.
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`The term "leaving group", as used herein, has the same meaning to the
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`skilled artisan (Advanced Organic Chemistry: reactions, mechanisms and structure-
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`Fourth Edition by Jerry March, John Wiley and Sons Ed.; 1992 pages 351-357) and
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`represents a group which is part of and attached to a substrate molecule; in a reaction
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`where the substrate molecule undergoes a displacement reaction (with for example a
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`nucleophile ), the leaving group is then displaced. Examples of leaving groups
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`include, but are not limited to: halogen (F, Cl, Br, and I), preferably Cl, Br, or I;
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`tosylate, mesylate, triflate, acetate, camphorsulfonate, aryloxide, and aryloxide
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`substituted with at least one electron withdrawing group (e.g., p-nitrophenoxide, 2-
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`chlorophenoxide, 4-chlorophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide,
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`etc.), etc. The term "electron withdrawing group" is accorded its plain meaning
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`here. Examples of electron withdrawing groups include, but are not limited to, a
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`halogen, -N02, -C(O)(lower alkyl), -C(O)(aryl), -C(O)O(lower alkyl),(cid:173)
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`C(O)O(aryl), etc.
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`The term "basic reagent", as used herein, means a compound that is capable
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`of deprotonating a hydroxyl group. Examples of basic reagents include, but are not
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`limited to, a (lower alk)oxide ((lower alkyl)OM) in combination with an alcoholic
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`solvent, where (lower alk)oxides include, but are not limited to, Meo-, EtO-, npro-,
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`ipro-, 1Buo-, iAmO- (iso-amyloxide), etc., and where M is an alkali metal cation,
`such as Lt, Na+, K+, etc. Alcoholic solvents include (lower alkyl)OH, such as, for
`example, MeOH, EtOH, nPrOH, iPrOH, 1Bu0H, iAmOH, etc. Non-alkoxy bases can
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`also be used such as sodium hydride, sodium hexamethyldisilazane, lithium
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`hexamethyldisilazane, lithium diisopropylamide, calcium hydride, sodium
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`carbonate, potassium carbonate, cesium carbonate, DBU, DBN, Grignard reagents,
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`such as (lower alkyl)Mg(halogen), which include but are not limited to MeMgCl,
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`MeMgBr, 1BuMgCl, 1BuMgBr, etc.
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`The term "base" embraces the term "basic reagent" and is meant to be a
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`compound that is capable of deprotonating a proton containing compound, i.e., a
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`Bronsted base. In addition to the examples recited above, further examples of a base
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`include, but are not limited to pyridine, collidine, 2,6-(loweralkyl)-pyridine,
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`dimethyl-aniline, imidazole, N-methyl-imidazole, pyrazole, N-methyl-pyrazole,
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`triethylamine, di-isopropylethylamine, etc.
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`The term "non-nucleophilic base" means a compound that is capable of
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`acting as a Bmnsted base, but has low nucleophilicity. Examples of non(cid:173)