WO2012075140A1 - Compounds - Google Patents

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Publication number
WO2012075140A1
WO2012075140A1 PCT/US2011/062643 US2011062643W WO2012075140A1 WO 2012075140 A1 WO2012075140 A1 WO 2012075140A1 US 2011062643 W US2011062643 W US 2011062643W WO 2012075140 A1 WO2012075140 A1 WO 2012075140A1
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WIPO (PCT)
Prior art keywords
alkyl
hydrogen
acyl
iii
alkaryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/US2011/062643
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English (en)
French (fr)
Inventor
Jinfa Du
Michael Joseph Sofia
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gilead Pharmasset LLC
Original Assignee
Pharmasset Inc
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Filing date
Publication date
Application filed by Pharmasset Inc filed Critical Pharmasset Inc
Priority to JP2013542138A priority Critical patent/JP6069215B2/ja
Priority to EP16152130.7A priority patent/EP3042910B1/en
Priority to CA2818853A priority patent/CA2818853A1/en
Priority to AU2011336632A priority patent/AU2011336632B2/en
Priority to EP11794350.6A priority patent/EP2646453A1/en
Publication of WO2012075140A1 publication Critical patent/WO2012075140A1/en
Anticipated expiration legal-status Critical
Priority to AU2015252113A priority patent/AU2015252113B2/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C07H19/207—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H23/00—Compounds containing boron, silicon or a metal, e.g. chelates or vitamin B12
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • HCV Hepatitis C virus
  • 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 of the HCV gene consist of the structural proteins C, El, and E2, and the non- structural proteins NS2, 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 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: 108-118). 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 therapies.
  • HCV belongs to a much larger family of viruses that share many common features. Dengue viral infections are problematic in the tropical and subtropical regions of the word. Shi et al. Top. Med. Chem. (2001) 7: 243-276. The dengue virus (DENV) is transmitted to humans by certain mosquitos, and it is has been estimated that up to about 50 million infections occur each year. Parkinson et al. Future Med. Chem. (2010) 2(7): 1181-1203. At the present, there are no specific treatments for dengue viral infections. Fagundes et al. Drug Development Research (2011) 72: 480-500.
  • DENV is comprised of ten proteins that includes three structural proteins (C, prM, and E) and seven non-structural proteins (NS 1 , NS2A, NS2B, NS3, NS4A, NS4B, and NS5). Of these ten proteins, only NS3 and NS5 are known to possess enzymatic activity. A desirable drug substance is one that interferes with the action or function of any one of these ten viral proteins. Flaviviridae Viruses
  • the Flaviviridae family of viruses comprises at 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.
  • the flavivirus genus includes more than 68 members separated into groups on the basis of serological relatedness (Calisher et al., J. Gen. Virol, 1993,70,37-43). Clinical symptoms vary and include fever, encephalitis and hemorrhagic fever ⁇ Fields Virology, Editors: Fields, B. N., Knipe, D. M, and Howley, P.
  • Flaviviruses of global concern that are associated with human disease include the Dengue Hemorrhagic Fever viruses (DHF), yellow fever virus, shock syndrome and Japanese encephalitis virus (Halstead, S. B., Rev. Infect. Dis., 1984, 6, 251 -264; Halstead, S. B., Science, 239:476-481 , 1988; Monath, T. P., New Eng. J. Med, 1988, 319, 64 1-643).
  • DHF Dengue Hemorrhagic Fever viruses
  • yellow fever virus yellow fever virus
  • shock syndrome and Japanese encephalitis virus
  • 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 infections of domesticated livestock (cattle, pigs and sheep) cause significant economic losses worldwide. BVDV causes mucosal disease in cattle and is of significant economic importance to the livestock industry (Meyers, G. and Thiel, H.J., Advances in Virus Research, 1996, 47, 53-118; Moennig V., et al, Adv. Vir. Res. 1992, 41 , 53-98). Human pestiviruses have not been as extensively
  • Pestiviruses and hepaciviruses are closely related virus groups within the
  • Flaviviridae family Other closely related viruses in this family include the GB virus A, GB virus A-like agents, GB virus-B and GB virus-C (also called hepatitis G virus, HGV).
  • the hepaci virus 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 hepaciviruses to grow efficiently in cell culture, bovine viral diarrhea virus (BVDV) is often used as a surrogate to study the HCV virus.
  • BVDV bovine viral diarrhea virus
  • RNA viruses possess a single large open reading frame (ORF) encoding all the viral proteins necessary for virus replication. These proteins are expressed as a polyprotein that is co- and post-translationally processed by both cellular and virus-encoded proteinases to yield the mature viral proteins.
  • ORF open reading frame
  • the viral proteins responsible for the replication of the viral genome RNA are located within approximately the carboxy-terminal. Two-thirds of the ORF are termed
  • nonstructural (NS) proteins The genetic organization and polyprotein processing of the nonstructural protein portion of the ORF for pestiviruses and hepaciviruses is very similar.
  • the mature nonstructural (NS) proteins in sequential order from the amino-terminus of the nonstructural protein coding region to the carboxy-terminus of the ORF, consist of p7, NS2, NS3, NS4A, NS4B, NS5 A, and NS5B.
  • the NS proteins of pestiviruses and hepaciviruses share sequence domains that are characteristic of specific protein functions.
  • the NS3 proteins of viruses in both groups possess amino acid sequence motifs characteristic of serine proteinases and of helicases (Gorbalenya et al., Nature, 1988, 333, 22; Bazan and Fletterick Virology, 1989,171 ,637-639; Gorbalenya et al., Nucleic Acid Res., ⁇ 989, 17, 3889-3897).
  • the NS5B proteins of pestiviruses and hepaciviruses have the motifs characteristic of RNA-directed RNA polymerases (Koonin, E.V. and Dolja, V.V., Crir. Rev. Biochem. Molec. Biol. 1993, 28, 375-430).
  • NS3 serine proteinase is responsible for all proteolytic processing of polyprotein precursors downstream of its position in the ORF (Wiskerchen and Collett,
  • the NS4A protein acts as a cofactor with the NS3 serine protease (Bartenschlager et 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.
  • NS5B proteins of pestiviruses and hepaci viruses have the predicted RNA-directed RNA polymerases activity (Behrens et al, EMBO, 1996, 15, 12-22; Lechmann et al., J. Virol, 1997, 71, 8416-8428; Yuan et al., Biochem. Biophys. Res. Comm. 1997, 232, 231-235; Hagedorn, PCT WO 97/12033; Zhong et al, J. Virol, 1998, 72, 9365-9369).
  • RNA-dependent RNA polymerase is absolutely essential for 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, 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.
  • Nucleoside inhibitors of NS5B 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.
  • 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 imparts additional structural requirements on a potential nucleoside polymerase inhibitor. Unfortunately, this limits the direct evaluation of nucleosides as inhibitors of HCV replication to cell-based assays capable of in situ phosphorylation.
  • nucleoside phosphoramidate prodrugs have been 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.
  • nucleosides are also known: C. Schultz, Biorg. & Med. Chem.
  • R 2 is selected from among
  • R 3 is selected from among
  • Y is selected from among
  • X is selected from among
  • A is selected from among
  • b) D is selected from among
  • R 4 , R 4' , R 5 , R 5' , R 6 , R 7 , R 8 , R 8 , R 9 , and R 9' are independently selected from among
  • B is selected from among Bl, B2, and B3 represented by the following structures:
  • R and R are independently selected from among
  • a) R is selected from among
  • B3 m is 0 or 1 , and is a single or double bond
  • R 16 is selected from among
  • R 17 is selected from among
  • each bonding pair, W 1 -— W 2 , W 2 : -C, W 4 , W 4 ⁇ W 3 , and W ⁇ W 1 , contained in the five- membered ring comprises a single or a double bond and
  • W 1 is O, S, N, or CR 14 ,
  • W 2 is N or CR 15 ,
  • W 3 is C or N
  • R 14 and R 15 are independently selected from among
  • a or “an” entity refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound.
  • a compound refers to one or more compounds or at least one compound.
  • the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably herein.
  • 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.
  • a phosphorus-containing radical does not expressly include an "*" next to the phosphorus atom, e.g., -P(0)(0(CH 2 )i. 3 OC(0)(alkyl)) 2 ,
  • salts refers to a compound comprising a cation and an anion, which can prepared by any process known to one of ordinary skill, e.g., by the protonation of a proton-accepting moiety and/or deprotonation of a proton-donating moiety.
  • the salt can be prepared by a cation/anion metathesis reaction. It should be noted that protonation of the proton-accepting moiety results in the formation of a cationic species in which the charge is balanced by the presence of a anion, whereas deprotonation of the proton- donating moiety results in the formation of an anionic species in which the charge is balanced by the presence of a cation.
  • salt formation can occur under synthetic conditions, such as formation of pharmaceutically acceptable salts, or under conditions formed in the body, in which case the corresponding cation or anion is one that is present in the body.
  • Examples of common cations found in the body include, but are not limited to: H + , Na + , K + , g 2+ , Ca 2+ , etc.
  • Examples of common anions found in the body include, but are not limited to, C1-, HCO3 " , C0 3 2" , H 2 P0 4 " , HP0 4 2” , etc.
  • pharmaceutically acceptable salt means a salt that is pharmaceutically acceptable. It is understood that the term “pharmaceutically acceptable salt” is encompassed by the expression “salt.” Examples of
  • pharmaceutically acceptable salts include, but are not limited to acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane- disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, salicylic acid, muconic
  • benzenesulfonate benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate (camphorsulfonate), carbonate, chloride, citrate, edetate, edisylate (1 ,2- ethanedisulfonate), estolate (lauryl sulfate), esylate (ethanesulfonate), fumarate, gluceptate (glucoheptonate), gluconate, glutamate, glycollylarsanilate (p- glycollamidophenylarsonate), hexylresorcinate, hydrabamine ( ⁇ , ⁇ '- di(dehydroabietyl)ethylenediamine), hydroxynaphthoate, iodide, isethionate (2- hydroxyethanesulfonate), lactate, lactobionate, malate, maleate, mandelate, mesylate, methylnitrate,
  • metabolite refers to a compound produced in vivo after administration of a compound or its stereoisomer or its salt or its deuteride thereof represented by formula I to a subject in need thereof or as formed in vitro in an assay. Said metabolite may exist as a salt.
  • deuteride refers to a deuterated analog of the compound represented by formula I where a hydrogen atom is enriched with its 2 H- isotope, i.e., deuterium (D).
  • Deuterium substitution can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted by at least one deuterium. .
  • halo or halogen as used herein, includes chloro, bromo, iodo and fluoro.
  • alkyl refers to an unbranched or branched chain, saturated, monovalent hydrocarbon residue containing 1 to 30 carbon atoms.
  • C_M alkyl refers to an alkyl comprising 1 to M carbon atoms, where M is an integer having the following values: 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.
  • Ci- alkyl refers to an alkyl containing 1 to 6 carbon atoms.
  • Examples of a C 1- alkyl group include, but are not limited to, methyl, ethyl, n- propyl, /-propyl, n-butyl, z ' -butyl, s-butyl, /-butyl, n-pentyl, isopentyl, neopentyl, t- pentyl, and hexyl.
  • C 1-6 -alkylene refers to an alkylene radical containing 1 to 6 carbon atoms.
  • Examples of a C 1-6 -alkylene include, but are not limited to, a methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), methyl-ethylene (-CH(CH 3 )CH 2 -), propylene (-CH 2 CH 2 CH 2 -), methyl-propylene (-CH(CH 3 )CH 2 CH 2 - or - CH 2 CH(CH 3 )CH 2 -), etc.
  • branched C ]-6 -alkylene such as methyl-ethylene or methyl-propylene, contains a chiral center, in which case the individual stereoisomers are contemplated. It is contemplated that a methylene may be substituted with one or two C 1-6 alkyls.
  • cycloalkyl refers to an unsubstituted or substituted carbocycle, in which the carbocycle contains 3 to 10 carbon atoms; preferably 3 to 8 carbon atoms (i.e., a C 3-8 -cycloalkyl); more preferably 3 to 6 carbon atoms (i.e., a C 3-6 -cycloalkyl).
  • the substituents are not to be counted for the carbocycle carbon count.
  • a cyclohexyl substituted with one or more Q ⁇ -alkyl is still, within the meaning contemplated herein, a C 3 _ 6 -cycloalkyl.
  • Examples of a C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, 2-methyl-cyclopropyl, cyclobutyl, 2- methyl-cyclobutyl, cyclopentyl, 2-methyl-cylcopentyl, cyclohexyl, 2-methyl- cyclohexyl, etc.
  • cycloalkylamino refers to a unsubstituted or substituted carbocycle comprising an "amino" (-NH-) functional group.
  • the carbocycle contains 3 to 10 carbon atoms; preferably 3 to 8 carbon atoms (i.e., a C 3-8 - cycloalkyl); more preferably 3 to 6 carbon atoms (i.e., a C 3-6 -cycloalkyl).
  • the substituents are not to be counted for the carbocycle carbon count.
  • a cyclohexyl substituted with one or more C 1-6 -alkyl is still, within the meaning contemplated herein, a C 3-6 -cycloalkyl.
  • Examples of a C 3-6 cycloalkylamino include, but are not limited to, cyclopropylamino, 2-methyl-cyclopropylamino, cyclobutylamino, 2-methyl- cyclobutylamino, cyclopentylamino, 2-methyl-cyclopentylamino, cyclohexylamino, 2-methyl-cyclohexylamino, etc.
  • cycloalkylaminos are derived from cycloalkylamines, i.e., cycloalkyls substituted by an amine (-NH 2 ) functional group.
  • alkoxy refers to an -O-alkyl group or an -O-cycloalkyl group, wherein alkyl and cycloalkyl are as defined above.
  • -O-alkyl groups include, but are not limited to, methoxy, ethoxy, «-propyloxy, z ' -propyloxy, n- butyloxy, -butyloxy, -butyloxy, etc.
  • -O-cycloalkyl groups include, but are not limited to, -O-opropyl, -O-c-butyl, -O-c-pentyl -O-c-hexyl, etc.
  • C -6 -alkoxy refers to an -0-Ci -6 -alkyl group, wherein C 1-6 alkyl is defined herein.
  • C 3 . 6 -cycloalkoxy refers to an -0-C 3-6 -cycloalkyl group
  • C) -6 -alkylene-oxy refers to an -0-Ci -6 -alkylene group, wherein Ci -6 -alkylene is defined as above.
  • Examples of a C] -6 -alkylene-oxy include, but are not limited to, methylene-oxy (-CH 2 0-), ethylene-oxy (-CH 2 CH 2 0-), methyl- ethylene-oxy (-CH(CH 3 )CH 2 0-), propylene-oxy (-CH 2 CH 2 CH 2 0-), methyl- propylene-oxy (-CH(CH 3 )CH 2 CH 2 0- or -CH 2 CH(CH 3 )CH 2 0-), etc.
  • alkaryl or "alkylaryl” refer to an alkylene group having 1 to 10 carbon atoms with an aryl substituent, such as benzyl.
  • aryl such as benzyl.
  • Ci -3 alkaryl refers to a Ci -3 alkylene group with an aryl substituent.
  • Benzyl is embraced by the term Cj. 3 alkaryl.
  • -OCi -3 alkaryl refers a oxygen (-0 ⁇ ) bound to a Ci -3 alkaryl group.
  • Benzyloxy (-OCH 2 Ph) is embraced by the term -OCi -3 alkaryl.
  • aryl refers to substituted or unsubstituted phenyl (Ph), biphenyl, or naphthyl.
  • the aryl group can be substituted with one or more moieties selected from among alkyl, hydroxyl, F, CI, Br, I, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and 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.
  • heteroaryl refers to an unsubstituted or substituted aromatic heterocycle containing carbon, hydrogen, and at least one of N, O, and S.
  • heteroaryls include, but are not limited to, a pyrrole, an imidazole, a diazole, a triazole, a tetrazole, a furan, an oxazole, an indole, a thiazole, etc. Additional examples of heteroaryls can be found in T.L. Gilchrist, in "Heterocyclic Chemistry,” John Wiley & Sons, 1985.
  • the heteroaryl group can be substituted with one or more moieties selected from among alkyl, hydroxyl, F, CI, Br, I, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and 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.
  • heterocycle or “heterocyclyl” refers to an unsubstituted or substituted radical containing carbon, hydrogen and at least one of N, O, and S.
  • heterocycles include, but are not limited to, an aziridine, an azetidine, a pyrrolidine, a piperidine, a piperazine, etc. Additional examples of heterocycles can be found in T.L. Gilchrist, in “Heterocyclic Chemistry,” John Wiley & Sons, 1985.
  • the heterocycle can be substituted with one or more moieties selected from among alkyl, hydroxyl, F, CI, Br, I, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and 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 "alk(heteroaryl)” and “alk(heterocyclyl)” refers to a Ci -6 -alkylene group with a heteroaryl and heterocyclyl substituent, respectively.
  • cycloheteroalkyl refers to an unsubstituted or substituted heterocycle, in which the heterocycle contains 2 to 9 carbon atoms; preferably 2 to 7 carbon atoms; more preferably 2 to 5 carbon atoms.
  • examples of cycloheteroalkyls include, but are not limited to, aziridin-l-yl, aziridin-2-yl, iV-Ci, 3 -alkyl-aziridin-2-yl, azetidinyl, azetidin-l-yl, N-Ci_ 3 -alkyl-azetidin-m'-yl, pyrrolidin-m'-yl, pyrrolidin-1- yl, 7V-Ci -3 -alkyl-pyrrolidin-m'-yl, piperidin-m'-yl, piperidin-l -yl, and N-Ci -3 -alkyl- piperidin-m'-
  • N-Ci -3 -alkyl-cycloheteroalkyls include, but are not limited to, N- methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl- pyrrolidin-4-yl, N-methyl-piperidin-2-yl, N-methyl-piperidin-3-yl, and N-methyl- piperidin-4-yl.
  • R 10 , R 16 , and R 17 the point of attachment between the cycloheteroalkyl ring carbon and the ring occurs at any one of m'.
  • acyl refers to a substituent containing a carbonyl moiety and a non-carbonyl moiety and is meant to include an amino-acyl.
  • the carbonyl moiety contains a double-bond between the carbonyl carbon and a heteroatom, where the heteroatom is selected from among O, N and S. When the heteroatom is N, the N is substituted by a
  • Ci- 6 - The non-carbonyl moiety is selected from straight, branched, and cyclic alkyl, which includes, but is not limited to, a straight, branched, or cyclic Ci-20 alkyl, CMO alkyl, or a Ci -6 -alkyl; alkoxyalkyl, including methoxymethyl; aralkyl, including benzyl; aryloxyalkyl, such as phenoxymethyl; or aryl, including phenyl optionally substituted with halogen (F, CI, Br, I), hydroxyl, Q to C 4 alkyl, or Ci to C 4 alkoxy, sulfonate esters, such as alkyl or aralkyl sulphonyl, including methanesulfonyl, the mono, di or triphosphate ester, trityl or monomethoxytrityl, substituted benzyl, trialkylsilyl (e.g. dimethyl-t-butyl
  • C 2-7 acyl refers to an acyl group in which the non-carbonyl moiety comprises a Ci -6 alkyl.
  • Examples of a C 2-7 -acyl include, but are not limited to: -C(0)CH 3 , -C(0)CH 2 CH 3 , -C(0)CH(CH 3 ) 2 , -C(0)CH(CH 3 )CH 2 CH 3 , - C(0)C(CH 3 ) 3 , etc.
  • aminoacyl includes ⁇ , ⁇ -unsubstituted, N,N-monosubstituted, and ⁇ , ⁇ -disubstituted derivatives of naturally occurring and synthetic ⁇ , ⁇ ⁇ or ⁇ amino acyls, where the amino acyls are derived from amino acids.
  • the amino- nitrogen can be substituted or unsubstituted or exist as a salt thereof. When the amino-nitrogen is substituted, the nitrogen is either mono- or di-substituted, where the substituent bound to the amino-nitrogen is a Ci_ 6 alkyl or an alkaryl.
  • amino acid includes naturally occurring and synthetic ⁇ , ⁇ ⁇ or ⁇ amino acids, and includes but is not limited to, amino acids found in proteins, i.e. glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine.
  • the amino acid is in the L-configuration.
  • 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, ⁇ -alanyl, ⁇ -valinyl, ⁇ -leucinyl, ⁇ -isoleucinyl, ⁇ -prolinyl, ⁇ -phenylalaninyl, ⁇ -tryptophanyl, ⁇ -methioninyl, ⁇ -glycinyl, ⁇ -serinyl, ⁇ - threoninyl, ⁇ -cysteiny
  • amino acid When the term amino acid is used, it is considered to be a specific and independent disclosure of each of the esters of ⁇ , ⁇ ⁇ or ⁇ 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.
  • Ci_ 6 -alkylene-oxy-acyl refers to an -0-C). 6 -alkylene-acyl group, wherein Ci -6 -alkylene and acyl are defined as above. Examples of a Cj.
  • 6 -alkylene- oxy-acyl include, but are not limited to, methylene-oxy-acyl (-CH 2 0-C(0)alkyl), ethylene-oxy-acyl (-CH 2 CH 2 0-C(0)alkyl), methyl-ethylene-oxy-acyl (- CH(CH 3 )CH 2 0-C(0)alkyl), propylene-oxy-acyl (-CH 2 CH 2 CH 2 0- C(O)alkyl), methyl-propylene-oxy-acyl (-CH(CH 3 )CH 2 CH 2 0- C(0)alkyl or -
  • acyl encompasses “aminoacyl,” further contemplated radicals include but are not limited to C 1-6 -alkyl- oxy-aminoacyl, where aminoacyl is defined above.
  • alkenyl refers to an unsubstituted or a substituted hydrocarbon chain radical having from 2 to 10 carbon atoms having one or more olefinic double bonds.
  • C 2- N 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.
  • C2- 10 alkenyl refers to an alkenyl comprising 2 to 10 carbon atoms.
  • C 2-4 alkenyl refers to an alkenyl comprising 2 to 4 carbon atoms. Examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl (allyl) or 2- butenyl (crotyl). It is understood that the alkenyl or C 2- N-alkenyl can be substituted with one or more radicals selected from among alkyl, halo, alkoxy, aryloxy, nitro, and cyano.
  • vinyl which is embraced by the term “C 2-4 alkenyl,” refers to -CR— CR"R"', where R', R", and R'" are independently selected from among hydrogen, Ci -6 -alkyl, halo, and Ci -6 -alkoxy.
  • ethynyl refers to -C ⁇ CR', where R' is selected from among hydrogen, Ci -6 -alkyl, halo, and C]_ 6 -alkoxide.
  • metal refers to the radical -CR— , where R' is selected from among hydrogen, Ci -6 alkyl, halo, and Ci_ 6 -alkoxide.
  • -P(0)(OH) 2 , -P(0)(OH)-OP(0)(OH) 2 , and -P(0)(OH)-0- P(0)(OH)-0-P(0)(OH) 2 refer to mono- (P,), di- (P 2 ), and tri- (P 3 ) phosphate radicals, respectively.
  • the Pi, P 2 , and P 3 phosphate radicals may be introduced at the 5'-OH of a nucleoside compound either by synthetic means in the lab or by enzymatic (or metabolic) means in a cell or biological fluid (either in vivo or in vitro). It is understood that the acidities of the hydroxyl (-OH) substituents vary and that salts of the phosphate radicals are possible.
  • the term "-P*(0)(OR la )(NHCHR lb C(0)OR lc )" or "phosphoramidate" as used herein is represented by the following structure:
  • R la , R lb , and R lc are as defined above.
  • Examples of phosphoramidate moieties are described in U.S. Patent No. 7,964,580. It will be understood that the ⁇ NHCH*(R lb )C(0)OR lc fragment can be derived from an amino acid, which is defined above.
  • R 1 , 1)1), and Y, 4)d include the expressions "-P*(0)(OR lc ) ⁇ " (see R 1 , 1)1)) and "-0 ⁇ ” (see Y, 4)d)). It is understood that when R 1 is “-P*(0)(OR lc ) ⁇ " and Y is "-0 ⁇ ” or when Y is "-0 ⁇ ' and R 1 is "-P(0)(OR lc ) ⁇ ", then compound I has the structure shown on the left, where the R 1 and Y substituents are identified on the ri ht:
  • a l ,3,2-dioxaphosphinane-2-oxide is represented by an unsubstituted form (jl) or a substituted form (j2), as represented by the following structures:
  • R n is selected from among hydroxy, an alkyl, a hydroxyalkyl, an aryloxide, an aryl, such as phenyl, a heteroaryl, such as pyridinyl, where the aryl and the heteroaryl can be substituted by 1 -3 substituents independently selected from among an alkyl, an alkoxy, and a halo.
  • a preferred R n is pyridinyl which can be substituted by 1-3 substituents independently selected from among a Ci- alkyl, a Ci -6 -alkoxy, and a halo.
  • aryloxide refers to substituted or unsubstituted phenoxide (PhO-), p-phenyl- phenoxide (p-Ph-PhO-), or naphthoxide, preferably the term aryloxide refers to substituted or unsubstituted phenoxide.
  • the aryloxide group can be substituted with one or more moieties selected from among hydroxyl, F, CI, Br, I, -C(0)(Ci -6 alkyl), -C(0)0(Ci -6 alkyl), amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and 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.
  • R n and R' n where R n is hydrogen and one alkyl radical, or two alkyl radicals independent of one another, and R' n is one, two, or three radicals selected from among alkyl, alkoxy, aryloxy, and halo.
  • R' n is one, two, or three radicals selected from among a Ci -6 alkyl, a C 1-6 , alkoxy, and a halo. More preferably, R' n is one radical selected from among a C 1-6 -akyl, a Ci -6 -alkoxy, and a halo.
  • the bonding arrangement of the five-membered ring satisfies Huckel's rule, i.e., the total number of pi-bond and lone-pair electrons for the selected radicals is 6.
  • Huckel's rule i.e., the total number of pi-bond and lone-pair electrons for the selected radicals is 6.
  • an effective amount means an amount required to reduce symptoms of the disease in a subject.
  • subject means a mammal.
  • the term "medicament,” as used herein means a substance used in a method of treatment and/or prophylaxis of a subject in need thereof.
  • preparation or “dosage form” is intended to include both solid and liquid formulations of the active compound and one skilled in the art will appreciate that an active ingredient can exist in different preparations depending on the desired dose and pharmacokinetic parameters.
  • excipient refers to a compound that is used to prepare a pharmaceutical composition, and is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use.
  • treatment is an approach for obtaining beneficial or desired clinical results.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • Treatment is an intervention performed with the intention of preventing the development or altering the pathology of a disorder.
  • treatment of an HCV infection, as used herein, also includes treatment or prophylaxis of a disease or a condition associated with or mediated by HCV infection, or the clinical symptoms thereof.
  • protecting group which is derived from a “protecting compound,” has its plain and ordinary meaning, i.e., at least one protecting or blocking group is bound to at least one functional group (e.g., -OH, -NH 2 , etc.) that allows chemical modification of at least one other functional group.
  • at least one protecting or blocking group is bound to at least one functional group (e.g., -OH, -NH 2 , etc.) that allows chemical modification of at least one other functional group.
  • protecting groups include, but are not limited to, benzoyl, acetyl, phenyl-substituted benzoyl, tetrahydropyranyl, trityl, DMT (4,4'-dimethoxytrityl), MMT (4-monomethoxytrityl), trimethoxytrityl, pixyl (9-phenylxanthen-9-yl) group, thiopixyl (9- phenylthioxanthen-9-yl) or 9-(p-methoxyphenyl)xanthine-9-yl (MOX), etc.; C(O)- alkyl, C(0)Ph, C(0)aryl,
  • C(0)0(C 1-6 alkyl), C(0)0(C ]-6 alkylene)aryl e.g., -C(0)OCH 2 Ph
  • C(0)Oaryl CH 2 0-alkyl, CH 2 0-aryl, S0 2 -alkyl, S0 2 -aryl, a protecting group comprising at least one silicon atom, such as, teri-butyldimefhylsilyl, feri-butyldiphenylsilyl,
  • Si(Ci -6 alkyl) 2 OSi(C 1-6 alkyl) 2 OH such as, -Si PrhOSiCPrhOH or
  • LG leaving group
  • halogen CI, Br, or I
  • tosylate mesylate, triflate, acetate, etc.
  • R is selected from among
  • R 2 is selected from among
  • R 3 is selected from among
  • Y is selected from among
  • X is selected from among
  • A is selected from among
  • b) D is selected from among
  • R 4 , R 5 , R 8 , and R 9 are independently selected from among
  • n 0, is a double-bond and R 10 is selected from among
  • n 1, is a single-bond and R 10 is selected from among
  • R 11 and R 12 are independently selected from among
  • a second aspect of the first embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula 1-1
  • R 1 is selected from among
  • Ci_6-alkylene-oxy-C 2 - 7 acyl a Ci_6-alkylene-oxy-C 2 - 7 acyl
  • R 2 is hydrogen
  • R 3 is hydrogen
  • Y is selected from among
  • A is selected from among
  • b) D is selected from among
  • R 4 , R 5 , R 8 , and R 9 are independently selected from among i) hydrogen,
  • n 0, is a double-bond and R 10 is selected from among
  • n 1 , is a single-bond and R 10 is selected from among
  • R 1 1 and R 12 are independently selected from among
  • a third aspect of the first embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula 1-1
  • R 1 is selected from among
  • R 2 is hydrogen
  • R 3 is hydrogen
  • Y is selected from among
  • A is -0-
  • D is -0- or -CH 2 -
  • R 4 , R 5 , R 8 , and R 9 are each hydrogen
  • n 0, is a double-bond and R 10 is selected from among i) -NH 2 ,
  • n 1 , is a single-bond and R 10 is selected from among
  • R 1 1 and R 12 are independently selected from among
  • a fourth aspect of the first embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula 1-1
  • R 1 is selected from among
  • Ci -6 -alkylene-oxy-C 2-7 acyl a Ci -6 -alkylene-oxy-C 2-7 acyl, and r) a -C(0)-0-C,. 6 alkyl;
  • R 2 is hydrogen
  • R is hydrogen
  • Y is selected from among
  • A is -0-
  • D is -0- or -CH 2 -
  • R 4 , R 5 , R 8 , and R 9 are each hydrogen
  • n 0, is a double-bond and R 10 is selected from among
  • n 1 , is a single-bond and R 10 is selected from among
  • R 1 1 and R 12 are independently selected from among
  • a second embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula 1-2
  • R 1 , R 2 , Y, R 1J have the meanings described above.
  • a first aspect of the second embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula 1-2 wherein
  • R 2 is selected from among
  • R 3 is selected from among
  • Y is selected from among
  • X is selected from among
  • A is selected from among
  • b) D is selected from among
  • R 4 , R 5 , R 8 , and R 9 are independently selected from among
  • R 13 is hydrogen.
  • a second aspect of the second embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula 1-2
  • R 1 is selected from among
  • R 2 is hydrogen
  • R 3 is hydrogen
  • Y is selected from among
  • A is selected from among
  • b) D is selected from among
  • R 4 , R 5 , R 8 , and R 9 are independently selected from among i) hydrogen,
  • R 13 is hydrogen.
  • a third aspect of the second embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula 1-2
  • R 1 is selected from among
  • R 2 is hydrogen
  • R 3 is hydrogen
  • Y is selected from among
  • A is -0-
  • D is -O- or -CH 2 -
  • R 4 , R 5 , R 8 , and R 9 are each hydrogen
  • R is hydrogen
  • a fourth aspect of the second embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula 1-2
  • R 1 is selected from among
  • R 2 is hydrogen
  • R 3 is hydrogen
  • Y is selected from among
  • A is -0-
  • D is -O- or -CH 2 -
  • R 4 , R 5 , R 8 , and R 9 are each hydrogen
  • R 13 is hydrogen.
  • a third embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula 1-3
  • R 1 , R 2 , Y, R 3 , 0, X, W 1 , W 2 , W 3 , W 4 , R 16 , R 17 , m, andTM have meanings described above.
  • a first aspect of the third embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula 1-3
  • R 1 is selected from among
  • Ci_6-alkylene-oxy-C 2-7 acyl a Ci_6-alkylene-oxy-C 2-7 acyl
  • R 2 is selected from among
  • R 3 is selected from among
  • Y is selected from among
  • X is selected from among
  • A is selected from among
  • b) D is selected from among
  • R 4 , R 5 , R 8 , and R 9 are independently selected from among
  • m 0, is a double-bond and R 16 and R 17 are independently selected from among
  • R 16 is selected from among
  • R 17 is selected from among
  • each bonding pair, W 1 — W 2 , W 2 ⁇ personallyC, C ⁇ W 4 , W ⁇ W 3 , and W 3 - ⁇ -W contained in the five- membered ring comprises a single or a double bond and i) W 1 is O, S, N, or CR 14 ,
  • W 2 is N or CR 15 ,
  • W 3 is C or N
  • W 4 is C or N
  • R 14 and R 15 are independently selected from among i) hydrogen,
  • a second aspect of the third embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula 1-3
  • R 1 is selected from among
  • R la is i) hydrogen
  • R 2 is hydrogen
  • R 3 is hydrogen
  • Y is selected from among
  • A is selected from among ii) -S- iii) -S(O)- iv) -S(0) 2 - and
  • b) D is selected from among

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US20140147412A1 (en) * 2011-07-09 2014-05-29 Sunshine Lake Pharma Co., Ltd. Spiro compounds as hepatitis c virus inhibitors
CN104151384A (zh) * 2014-08-20 2014-11-19 济南卡博唐生物科技有限公司 一种制备n6-苯甲酰基-d-腺苷的改进方法
US8921384B2 (en) 2012-02-14 2014-12-30 Unversity Of Georgia Research Foundation, Inc. Spiro[2.4]heptanes for treatment of flaviviridae infections
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ES2716158T3 (es) 2019-06-10
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US20120142626A1 (en) 2012-06-07
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EP3042910A3 (en) 2016-09-07
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AU2011336632A1 (en) 2013-05-02
AU2011336632B2 (en) 2015-09-03
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