WO2022218274A1 - 核苷类似物及其用途 - Google Patents

核苷类似物及其用途 Download PDF

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WO2022218274A1
WO2022218274A1 PCT/CN2022/086215 CN2022086215W WO2022218274A1 WO 2022218274 A1 WO2022218274 A1 WO 2022218274A1 CN 2022086215 W CN2022086215 W CN 2022086215W WO 2022218274 A1 WO2022218274 A1 WO 2022218274A1
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virus
compound
mmol
infection
alkanoyl
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PCT/CN2022/086215
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English (en)
French (fr)
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沈敬山
谢元超
胡天文
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中国科学院上海药物研究所
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Priority to US18/286,416 priority Critical patent/US20240166680A1/en
Publication of WO2022218274A1 publication Critical patent/WO2022218274A1/zh

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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
    • C07H19/06—Pyrimidine radicals
    • C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
    • 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
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K31/7068—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 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • 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
    • C07H19/23—Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22
    • 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
    • C07H19/24—Heterocyclic radicals containing oxygen or sulfur as ring hetero atom
    • 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

  • the present invention relates to a nucleoside analog and its use, in particular, the present invention relates to a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof, its pharmaceutical composition and its use.
  • H1N1 influenza A
  • H1N1 wild-type poliovirus outbreak
  • the 2014 Ebola virus outbreak in West Africa the 2016 The Zika virus outbreak in Brazil in 2018, the Ebola outbreak in Congo (DRC) in 2018, and the novel coronavirus (SARS-CoV-2) outbreak in 2020.
  • viruses There are many kinds of viruses. In addition to the above, many other viruses also have a great impact on human society, such as dengue fever virus, respiratory syncytial virus, bunya virus and animal coronavirus that cause heavy losses to the breeding industry. With the expansion of the scope of human social activities and the strengthening of the trend of globalization, new or re-emerging viruses will continue to appear on a global scale, and the world's medical and health systems will face more severe challenges.
  • Nucleoside analogs are the most important class of antiviral drugs. This type of drug can be converted into the corresponding triphosphate form in vivo. During the virus replication stage, the triphosphate can be "camouflaged" as a substrate and incorporated into the DNA or RNA chain of the virus under the catalysis of viral polymerase. , interfering with the replication of genetic material, thereby exerting an antiviral effect. Most viral polymerases have conserved active centers, so nucleosides as antiviral drugs have a high resistance barrier and often exhibit broad-spectrum antiviral effects.
  • ⁇ -d-N4-Hydroxycytidine is a cytosine derivative first reported in 1959.
  • the compound exhibits significant inhibitory effect on the replication of various viruses (influenza virus, hepatitis C virus, SARS, MERS, SARS-CoV-2, etc.), and is a broad-spectrum antiviral nucleoside analog.
  • (2R,3R,4S,5R)-2-(4-Aminopyrrolo[2,1-F][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-( Hydroxymethyl)tetrahydrofuran-2-carbonitrile is also a nucleoside with broad-spectrum antiviral activity.
  • La virus, Marburg virus), paramyxovirus (parainfluenza virus, measles virus, respiratory syncytial virus), coronavirus (SARS, MERS, SARS-CoV-2), etc. have inhibitory activity.
  • both compounds have the disadvantage of low oral bioavailability, which is less than 10% in monkeys, making it difficult to develop as oral drugs.
  • Prodrug modification is an important means to improve the druggability of nucleoside analogs.
  • Appropriate prodrug forms are not only beneficial to improve the metabolic properties of such compounds, but also improve their therapeutic effects on diseases and reduce toxic and side effects.
  • the purpose of the present invention is to provide an active ingredient that can effectively inhibit virus replication and its new use in related diseases caused by virus infection.
  • the present invention provides the nucleoside analogs shown in formula I or their pharmaceutically acceptable salts and compositions thereof in anti-virus, such as coronavirus (SARS, MERS, SARS-CoV-2, porcine epidemic diarrhea) virus, feline infectious peritonitis virus, etc.), paramyxovirus (parainfluenza virus, measles virus, respiratory syncytial virus, etc.), influenza virus, Flaviviridae (hepatitis C virus, dengue virus, Zika virus, etc.), filamentous Use against viruses (Ebola virus, Marburg virus), bunya virus and/or arenavirus, especially against novel coronavirus (SARS-CoV-2), influenza virus.
  • coronavirus SARS, MERS, SARS-CoV-2, porcine epidemic diarrhea
  • paramyxovirus parainfluenza virus, measles virus, respiratory syncytial virus, etc.
  • influenza virus Flaviviridae (hepatitis C virus, dengue virus, Zika virus, etc.),
  • X is selected from oxygen, sulfur, CH2 , NH;
  • R 1 is selected from hydrogen, deuterium, cyano
  • R 2 is selected from hydrogen, C 1-18 alkyl, C 3-8 cycloalkyl, C 6-20 aryl, 5-15 membered heteroaryl, wherein alkyl and cycloalkyl are unsubstituted or independently One to three substituents selected from halogen, hydroxyl, carboxyl and C 1-4 alkoxy are substituted, aryl and heteroaryl are unsubstituted or substituted with one to five substituents independently selected from R 9 ;
  • R 3 is selected from hydrogen, C 1-4 alkoxy
  • R 2 , R 3 form together with the carbon to which they are attached
  • R 4 is selected from hydrogen, deuterium, halogen, azide, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, azide C 1-6 alkyl, cyano C 1-6 alkyl, Hydroxy C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy C 1-6 alkyl;
  • R 5 is selected from hydrogen, C 1-20 alkanoyl, C 3-20 cycloalkanoyl, amino C 1-20 alkanoyl, C 1-20 alkylamino C 1-6 alkanoyl, C 1-6 cycloalkanoyl C 1-6 alkanoyl, C 1-20 dialkylamino C 1-6 alkanoyl, C 1-20 alkoxy C 1-6 alkanoyl, amino acids in which the carbonyl group of the carboxyl group on the amino acid forms an ester bond with the connected oxygen group, C 6-20 arylamino C 1-6 alkanoyl, 3-20-membered heterocycloalkyl C 1-6 alkanoyl, wherein C 1-20 alkanoyl and C 3-20 cycloalkanoyl are unsubstituted or substituted with one to three halogens, and the 3-20-membered heterocycloalkyl is unsubstituted or substituted with C 1-6 alkyl;
  • R 6 is selected from hydroxyl, amino, hydroxylamine (-NHOH), -NHOR 13 ;
  • R 7 is selected from hydrogen, deuterium, halogen
  • R 8 is selected from hydrogen, deuterium, halogen, cyano, carbamoyl
  • R 9 is selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, cyano, nitro, amino, phenyl, carboxyl, trifluoromethyl, difluoromethyl Fluoromethoxy, trifluoromethoxy, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkylcarbonyl, C 1-4 alkylcarbonyloxy, C 1-4 alkoxycarbonyl;
  • R 10 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 6-20 aryl, 5-15-membered heteroaryl;
  • R 11 is selected from C 1-18 alkyl, methylene C 6-20 aryl
  • R 12 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 6-20 aryl, 5-15-membered heteroaryl;
  • R 13 is selected from C 1-20 alkanoyl, C 3-20 cycloalkanoyl, amino C 1-20 alkanoyl, C 1-20 alkylamino C 1-6 alkanoyl, C 1-6 cycloalkylamino C 1- 6 alkanoyl, C 1-20 dialkylamino C 1-6 alkanoyl, C 1-20 alkoxy C 1-6 alkanoyl, C 1-6 alkoxycarbonyloxymethylene;
  • the compound of formula I is of formula I-I
  • the compound of formula I is of formula I-II,
  • Formula (I-II) contains an asymmetric center represented by * and thus can have two diastereomers of structural formulae I-IIA and I-IIB, either individually as a pure single diastereomer, or as two mixture of diastereomers
  • the compound of formula I is selected from the following formula,
  • R 1 is selected from hydrogen, deuterium
  • R 2 , R 5 , R 7 , R 8 , R 13 are the same as above;
  • R4 is selected from hydrogen, deuterium, halogen.
  • the compound of formula I is selected from any one of compounds A1 to A56, B1 to B46, C1 to C42, D1 to D13, or a combination thereof:
  • the compound represented by the formula I-III is equivalent to the compound represented by the formula I-III' and is a tautomer, and the hydroxylamine group at the 4-position of the pyrimidine base can be represented by an oximo group.
  • the above-mentioned compounds or pharmaceutically acceptable salts thereof according to the present invention may exist in the form of crystalline hydrates, solvates or co-crystalline compounds, and thus, these crystalline hydrates, solvates and co-crystalline compounds are also included within the scope of the present invention.
  • the above-mentioned compounds or pharmaceutically acceptable salts thereof according to the present invention may exist in the form of enantiomers, diastereomers, or combinations thereof. These enantiomers, diastereomers and combinations thereof are also included within the scope of the present invention.
  • a pharmaceutical composition in a second aspect of the present invention, contains:
  • the first active ingredient is one or more selected from the above-mentioned compound of formula I and its pharmaceutically acceptable salt:
  • the composition may also contain (a2) a second active ingredient; wherein, the second active ingredient is selected from antiviral active ingredients, corticosteroid anti-inflammatory drugs, adjuvant therapy drugs, etc. one or more of.
  • the antiviral active ingredient is one or more selected from the following: interferon, RNA-dependent RNA polymerase inhibitor (such as Remdesivir (Remdesivir or GS-5734), favipiravir (favipiravir), Galidesivir, GS-441524, NHC (EIDD-1931), EIDD-2801), 3CL protease inhibitors (such as GC-376), Lopinavir, Ritonavir, Nelfinavir, Chloroquine, hydroxychloroquine, cyclosporine, Carrimycin, baicalin, baicalein, forsythiaside (forsythoside), chlorogenic acid, emodin, mycophenolic acid, mycophenolate mofetil, naphthoquine, ciclesonide, Ribavirin, Penciclovir, Leflunomide, Teriflunomide, Nafamostat, Nitazoxanide, Darrut Darunavir, Arbidol
  • the corticosteroid anti-inflammatory drug is one or more selected from the group consisting of dexamethasone, dexamethasone sodium phosphate, fluorometholone, fluorometholone acetate, loteprednol, Loteprednol Carbonate, Hydrocortisone, Prednisolone, Fludrocortisone, Triamcinolone, Triamcinolone Acetonide, Betamethasone, Beclomethasone Dipropionate, Methylprednisolone, Fluocinolone, Fluocinolone Sinide, flunisolide, fluocortin-21-butylate, flumetasone, flumetasone pivalate, budesonide, halobetasol propionate, mometasone furoate , fluticasone propionate, ciclesonide, or a pharmaceutically acceptable salt thereof;
  • the adjuvant therapy drug is selected from one or more of the following: Zinc (Zinc), Fingolimod (Fingolimod), Vitamin C (Vitamin C), Olmesartan Medoxomil (Olmesartan Medoxomil) , Valsartan, Losartan, Thalidomide, Glycyrrhizic acid, Artemisinin, Dihydroartemisinin, Artesunate (Artesunate), Artemisone (Artemisone), Azithromycin (Azithromycin), Escin (Escin), Naproxen (Naproxen).
  • the pharmaceutical composition is prepared as a formulation.
  • the formulations include: oral formulations and non-oral formulations.
  • the preparations include: powders, granules, capsules, injections, inhalants, tinctures, oral liquids, tablets, lozenges, or drop pills.
  • a third aspect of the present invention there is provided the use of the above-mentioned compound of formula I or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a medicament that is (a) an inhibitor that inhibits viral replication; and /or (b) Medicines for the treatment and/or prevention or alleviation of diseases caused by viral infections.
  • the virus is one or more selected from the following:
  • Coronaviruses including coronaviruses that infect humans: such as severe acute respiratory syndrome coronavirus SARS-CoV (Severe acute respiratory syndrome coronavirus, SARS-CoV), 2019 new coronavirus (2019-nCoV or SARS-CoV-2) ), Middle East respiratory syndrome coronavirus MERS-CoV (Middle East respiratory syndrome coronavirus, MERS-CoV), human coronavirus OC43 (Human coronavirus OC43), human coronavirus 229E (Human coronavirus 229E), human coronavirus NL63 (Human coronavirus ) NL63), human coronavirus HKU1 (Human coronavirus HKU1); and coronaviruses that infect animals: such as porcine epidemic diarrhea virus (PEDV), feline infectious peritonitis virus (FIFV);
  • PEDV porcine epidemic diarrhea virus
  • FMV feline infectious peritonitis virus
  • Paramyxovirus such as parainfluenza virus, measles virus, respiratory syncytial virus (RSV);
  • Influenza virus such as influenza A virus, influenza B virus, influenza C virus, influenza D virus;
  • Flaviviridae viruses such as hepatitis C virus (HCV), dengue virus (DENV), Zika virus (Zika);
  • Filoviruses such as Marburg virus (MBV), Ebola virus (EBV), Queva virus;
  • Bunyaviridae viruses such as Bunyavirus, Sandfly virus, Neirovirus, Hantavirus;
  • Arenaviruses for example, Lassa fever virus (LASV), Junin virus (JUNV), Maqiubo virus (MACV), and the like.
  • LASV Lassa fever virus
  • JUNV Junin virus
  • MMV Maqiubo virus
  • the virus is 2019 Novel Coronavirus (SARS-CoV-2).
  • the virus is an influenza virus.
  • the disease caused by the virus is selected from one or more of the following:
  • D2 Porcine epidemic diarrhea caused by porcine epidemic diarrhea virus (PEDV);
  • D4 Common cold, high-risk symptom infection, respiratory tract infection, pneumonia and its complications caused by human respiratory syncytial virus (RSV) infection;
  • D7 Dengue fever and its complications caused by dengue virus (DENV);
  • the disease caused by the virus is a disease caused by infection with the 2019 novel coronavirus (SARS-CoV-2).
  • the disease caused by the 2019 novel coronavirus infection is one or more selected from the following: respiratory tract infection, pneumonia and its complications.
  • the disease caused by the virus is a disease caused by influenza virus infection.
  • the disease caused by influenza virus infection is one or more selected from the group consisting of common cold, high-risk symptom infection, respiratory infection, pneumonia and its complications.
  • nucleoside prodrugs of the present invention have high oral bioavailability and significant antiviral activity, and are expected to be used for 2019 novel coronavirus (SARS-CoV-2), influenza virus, respiratory syncytial virus and other viruses.
  • SARS-CoV-2 2019 novel coronavirus
  • influenza virus influenza virus
  • respiratory syncytial virus respiratory syncytial virus
  • other viruses 2019 novel coronavirus
  • the present invention discloses the use of nucleoside analog prodrugs represented by formula (I) and their compositions in antiviral, in the preparation of inhibitors of viruses, and in the preparation of treatment caused by viral infection use in medicine for a disease, condition or indication.
  • the virus is coronavirus (SARS, MERS, SARS-CoV-2, porcine epidemic diarrhea virus, feline infectious peritonitis virus, etc.), paramyxovirus (parainfluenza virus, measles virus, respiratory syncytial virus, etc.), influenza Viruses, Flaviviridae (hepatitis C, dengue, Zika, etc.), filoviruses (Ebola, Marburg), bunyaviruses and/or arenaviruses.
  • coronavirus coronavirus
  • MERS coronavirus
  • SARS-CoV-2 porcine epidemic diarrhea virus
  • feline infectious peritonitis virus etc.
  • paramyxovirus parainfluenza virus, measles virus, respiratory
  • nucleoside analog prodrugs and compositions thereof represented by formula (I) in anti-virus, for example, in the preparation of (a) anti-coronavirus (SARS, MERS, SARS-CoV- 2.
  • the nucleoside analog prodrug shown in formula (I) has a high exposure of nucleoside metabolites in vivo, and has a strong inhibitory effect on the replication of viruses such as SARS-CoV-2, influenza virus, respiratory syncytial virus, etc., It has good clinical application prospects.
  • nucleoside analogs of the present invention can be used interchangeably and refer to nucleoside analogs with excellent antiviral effects in vivo or in vitro, including compounds shown in formula I, or pharmaceutically acceptable salts thereof, or a solvate thereof, or a prodrug thereof, or a combination thereof.
  • formulation of the present invention refers to a formulation containing a nucleoside analog of the present invention.
  • the terms "novel coronavirus”, “2019-nCoV” or “SARS-CoV-2” are used interchangeably, the 2019 novel coronavirus is the seventh coronavirus known to infect humans and cause COVID-19 (COVID-19), is one of the serious infectious diseases threatening human health worldwide.
  • halogen generally refers to fluorine, chlorine, bromine and iodine; preferably fluorine, chlorine or bromine; more preferably fluorine or chlorine.
  • Cn- Cm is used interchangeably with Cnm and refers to having n to m carbon atoms.
  • C 1-18 alkyl alone or as part of a composite group refers to a straight or branched chain saturated hydrocarbon group containing 1-18 carbon atoms, eg, a C 1-6 alkyl group, eg Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-ethylpropyl, isopentyl, neopentyl, isohexyl methyl, 3-methylpentyl or n-hexyl, preferably methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl or tert-butyl.
  • a C 1-6 alkyl group eg Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl
  • halo-C 1-6 alkyl alone or as part of a composite group means that the hydrogen atoms of the above - mentioned C 1-6 alkyl groups are replaced by 1 or more halogen atoms, the same or different, For example, trifluoromethyl, fluoromethyl, difluoromethyl, chloromethyl, bromomethyl, dichlorofluoromethyl, chloroethyl, bromopropyl, 2-chlorobutyl or pentafluoroethyl and the like.
  • C 1-6 alkoxy alone or as part of a composite group refers to a straight or branched chain alkoxy group containing 1-6 carbon atoms, eg, methoxy, ethoxy , n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentoxy, isopentyloxy, neopentyloxy, isohexyloxy, 3-methylpentyloxy, n-hexyloxy, etc., preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy.
  • C 3-20 cycloalkyl alone or as part of a composite group refers to a cyclic saturated hydrocarbon group containing 1-20 carbon atoms, eg, C 3-8 cycloalkyl, eg, cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.
  • R is selected from hydrogen or C 1-19 alkyl
  • C 1-20 alkanoyl Examples are formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, t-butyryl or hexanoyl and the like.
  • an alkanoyl group may also be referred to as an alkylcarbonyl group, such as a C1-4 alkylcarbonyl group.
  • C 2-6 alkenyl alone or as part of a composite group refers to a straight or branched chain unsaturated hydrocarbon group containing 1-3 double bonds and 2-6 carbon atoms, including both
  • the cis configuration also includes the trans configuration, eg, vinyl, 1-propenyl, 2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl -2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1, 3-butadienyl, 1,3-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 3,3- Dimethyl-1-propenyl or 2-ethyl-1-propenyl, etc.
  • C 2-6 alkynyl alone or as part of a composite group refers to a straight or branched chain alkynyl group containing 2-6 carbon atoms, eg, ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl or 2-hexynyl and the like.
  • amino C 1-20 alkanoyl alone or as part of a composite group refers to a C 1-20 alkanoyl group having one hydrogen replaced by an amino group (-NH 2 ), such as -CONH 2 , -COCH 2 NH 2 , -COCH 2 CH 2 NH 2 and the like.
  • C 1-20 alkylamino alone or as part of a composite group refers to a group in which one hydrogen on an amino group (-NH 2 ) is replaced by a C 1-20 alkyl group, eg, -NHCH 3 , -NHCH 2 CH 3 , etc.
  • Alkylamino groups are sometimes also referred to as alkylamino groups.
  • C 1-6 cycloalkylamino alone or as part of a composite group refers to a group in which one hydrogen on an amino group (-NH 2 ) is replaced by a C 1-6 cycloalkyl, such as a ring propylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, etc.
  • C 1-20 alkylamino C 1-6 alkanoyl alone or as part of a composite group refers to a C 1-6 alkanoyl group on which one hydrogen is replaced by a C 1-20 alkylamino group, Such as -CONHCH 3 , -COCH 2 NHCH 3 , -COCH 2 CH 2 NHCH 2 CH 3 and the like.
  • C 1-6 cycloalkylamino C 1-6 alkanoyl alone or as part of a composite group refers to a C 1-6 alkane on which one hydrogen is replaced by a C 1-6 cycloalkylamino group Acyl groups, such as cyclopropylamino C 1-6 alkanoyl, cyclobutylamino C 1-6 alkanoyl, cyclopentylamino C 1-6 alkanoyl, cyclohexylamino C 1-6 alkanoyl and the like.
  • C 1-20 bisalkylamino alone or as part of a composite group refers to a group in which two hydrogens on an amino group (-NH 2 ) are each independently replaced by a C 1-20 alkyl group , such as dimethylamino, diethylamino, methylethylamino, etc.
  • C 1-6 dialkylamino may also be referred to as di(C 1-6 alkyl)amine, eg, di(C 1-4 alkyl)amine.
  • C 1-20 dialkylamino C 1-6 alkanoyl alone or as part of a composite group refers to a C 1-6 alkane on which one hydrogen is replaced by a C 1-20 dialkylamino group Acyl groups, such as -CON(CH 3 ) 2 , -CON(CH 2 CH 3 ) 2 , -COCH 2 N(CH 2 CH 3 ) 2 , -COCH 2 CH 2 N(CH 2 CH 3 ) 2 and the like.
  • C 1-6 alkoxy C 1-6 alkyl alone or as part of a composite group refers to a C 1-6 alkane on which one hydrogen is replaced by a C 1-6 alkoxy group base, such as -CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 3 and the like.
  • amino C 1-6 alkyl alone or as part of a composite group refers to a C 1-6 alkyl group on which one of the hydrogens is replaced by an amino group (-NH 2 ), such as -CH 2 NH 2 , -CH2CH2NH2 , -CH ( NH2 ) CH3 , -CH2CH2CH2NH2 or -CH2CH2CH2CH2NH2 , etc.
  • hydroxy C 1-6 alkyl alone or as part of a composite group refers to a C 1-6 alkyl group in which one hydrogen is replaced by a hydroxy group, such as -CH 2 OH, -CH 2 CH 2 OH, -CH(OH)CH 3 , -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH or -CH 2 CH(CH 3 )CH 2 OH, etc.
  • amino acid refers to naturally occurring and synthetic amino acids such as L-valine, L-alanine, L-phenylalanine, L-phenylglycine, D-valine, D- Alanine, which is attached to the core structure through the formation of an ester bond with the oxygen attached to the carbonyl group on its carboxyl group to R5.
  • C 6-20 aryl alone or as part of a composite group refers to a monocyclic or polycyclic (eg, bicyclic or tricyclic) ring having 6-20 carbon atoms in the ring and no heteroatoms
  • Aromatic rings such as C6-12 aryl, C6-10 aryl, such as phenyl, naphthyl, phenanthryl, anthracenyl, and the like.
  • the term "5-15 membered heteroaryl" alone or as part of a composite group refers to a group having 5-15 atoms in the ring and including 1-4 ring heteroatoms selected from nitrogen, oxygen and sulfur.
  • Monocyclic or polycyclic (eg, bicyclic or tricyclic) aromatic rings such as 5-10 membered heteroaryl, 5-6 membered heteroaryl, such as pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl , oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, iso Indolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl,
  • a quantity or other value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that any upper or preferred value of the range and the lower limit of the range have been specifically disclosed herein or all ranges of preferred values, whether or not those ranges are disclosed separately. Furthermore, when a range of values is referred to herein, unless otherwise indicated, the range shall include its endpoints and all integers and fractions within the range.
  • Coronavirus belongs to the family Coronaviridae of the order Nidovirales. It is an enveloped positive-strand RNA virus.
  • HCoV-229E and HCoV-NL63 belong to alpha coronaviruses
  • HCoV-OC43, SARS-CoV, HCoV-HKU1, MERS-CoV and SARS-CoV-2 are all beta coronaviruses Virus.
  • the genome of this virus is a single-stranded positive-stranded RNA, which is one of the largest RNA viruses in the genome, encoding replicase, spike protein, envelope protein, envelope protein and nucleocapsid protein.
  • the genome is translated into two peptide chains of several thousand amino acids, the precursor polyprotein (Polyprotein), and then the precursor protein is cleaved by proteases to generate non-structural proteins (such as RNA polymerase and unwinding). enzymes) and structural proteins (such as spike proteins) and accessory proteins.
  • Influenza virus is referred to as influenza virus, and common influenza viruses are divided into A (A), B (B), C (C) and D (D) types. Influenza virus can cause human, poultry, pig, horse, bat and other animals to infect and develop disease.
  • influenza virus Clinical symptoms caused by influenza virus include acute high fever, generalized pain, significant fatigue, and respiratory symptoms.
  • Human influenza is mainly caused by influenza A and B viruses.
  • Influenza A virus frequently undergoes antigenic variation and can be further divided into subtypes such as H1N1, H3N2, H5N1, and H7N9.
  • Respiratory syncytial virus (RSV, referred to as syncytial virus, belonging to Paramyxoviridae) is the most common pathogen causing viral pneumonia in children, which can cause interstitial pneumonia.
  • RSV is similar to parainfluenza virus, with a virus particle size of about 150 nm, which is slightly smaller than that of parainfluenza virus, and is an RNA virus.
  • Flaviviridae are a class of RNA viruses that mainly infect mammals, including three genera, flavivirus, pestivirus and hepacivirus.
  • Dengue virus (DENV) and Zika virus (ZIKV) belong to the genus Flavivirus and are transmitted by mosquito vectors. Dengue virus infection can cause obvious symptoms of fever and pain. Severe dengue fever symptoms also include headache, nausea, vomiting, unconsciousness, and even shock. Symptoms of Zika virus (ZIKV) infection are similar to those of dengue fever and are generally milder.
  • Hepatitis C virus (HCV) belongs to the genus Hepatitis C virus and is the causative agent of chronic hepatitis C, which can cause liver cirrhosis and liver cancer.
  • the Filoviridae currently contains three genera: Ebola virus, Marburg virus, and Quiwa virus. Both Marburg virus and Ebola virus can cause severe hemorrhagic fever, high fever and hemorrhagic symptoms after infection, which can further lead to shock, organ failure, and even death.
  • PEDV Porcine epidemic diarrhea virus
  • Porcine epidemic diarrhea virus belongs to the family Coronaviridae. Porcine epidemic diarrhea is an acute intestinal infectious disease in piglets and fattening pigs caused by PEDV virus.
  • the PEDV virus enters the small intestine directly after infection through the mouth and nose.
  • the replication of PEDV virus can be carried out in the cytoplasm of the small intestine and colonic villus epithelium.
  • PEDV can cause diarrhea, which is osmotic diarrhea. Dehydration caused by severe diarrhea is the leading cause of death in sick pigs.
  • Buniaviruses are a large group of enveloped, segmented negative-strand RNA viruses belonging to arboviruses.
  • the Buniaviridae family includes multiple genera (Bunyavirus, Sandfly virus, Nairovirus, Hantavirus, etc.), which can cause a variety of natural foci of infectious diseases, such as renal syndrome Hemorrhagic fever, Hantavirus pulmonary syndrome, sand fly fever, etc.
  • Arenaviruses are a class of enveloped, single-stranded negative-stranded RNA viruses, shaped like sand grains, which are a small branch of viruses. At present, a variety of viruses have been found to be pathogenic to humans, such as Lassa fever (LASV) virus, Junin (JUNV) virus, Ma Qiubo (MACV) and other viruses. These three viruses can cause hemorrhagic fever and other diseases. threaten human health.
  • LASV Lassa fever
  • Junin Junin
  • MMV Ma Qiubo
  • the raw materials (Cytidine A39-0, Uridine B1-0, NHC, GS-441524, A2-0, C22-0) were purchased from Shanghai Haohong Biomedical Technology Co., Ltd. or Wuhu Novi Chemical Technology Co., Ltd. or prepared according to the protocol described in the literature (Chemical Communications, 2020, 56, 13363-13364; Nature, 2016, 531, 381-385; Chinese Patent 202010313870.X).
  • ⁇ -D-N4-Hydroxycytidine NHC (0.97g, 3.75mmol) was added to dichloromethane (5mL), followed by 4-dimethylaminopyridine (76mg, 0.75mmol), triethylamine (1.14g, 11.25g) mmol) and 4,4'-bismethoxytrityl chloride (2.80 g, 8.25 mmol) and stirred at room temperature.
  • A2-0 (1.00 g, 3.04 mmol) and propionaldehyde (882 mg, 15.20 mmol) were added to dichloromethane (20 mL), and under ice bath, p-toluenesulfonic acid monohydrate (1.16 g, 6.08 mmol) was slowly added, After the addition was completed, it was warmed to room temperature and stirred for 2h. A 10% aqueous sodium carbonate solution and dichloromethane were added to the reaction solution, and the organic phase was separated.
  • A2-0 (1.00 g, 3.04 mmol) and n-heptaldehyde (1.73 g, 15.20 mmol) were added to dichloromethane (20 mL), and under ice bath, p-toluenesulfonic acid monohydrate (1.16 g, 6.08 mmol) was slowly added , After the addition, it was warmed to room temperature and stirred for 2h.
  • A37 (0.15 g, 0.33 mmol) and potassium carbonate (0.04 g, 0.33 mmol) were added to anhydrous methanol (5 mL) and stirred at room temperature for 4 hours.
  • reaction solution was added to water, extracted with ethyl acetate, the organic phase was separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness. Slurried with a mixed solution of ethyl acetate and methyl tert-butyl ether to obtain compound A38 as a pair of diastereomers (6:4), white solid 1.08 g, yield 80%.
  • Triphenylphosphine (11.79 g, 45 mmol) was added to pyridine (50 mL), iodine (11.42 g, 45 mmol) was added under an ice bath, and after stirring for 10 minutes, the temperature was raised to room temperature.
  • Uridine B1-0 (7.32 g, 20 mmol) was added and stirred at 25°C overnight. Saturated sodium thiosulfate and saturated sodium bicarbonate were sequentially added, the reaction solution was spin-dried, tetrahydrofuran and saturated brine were added to the concentrate, and the organic phase and the aqueous phase were separated.
  • Trifluoroacetic acid was added to an aqueous solution of tetrabutylammonium hydroxide (1.45 g, 5.5 mmol) to adjust the pH to about 4.
  • the above solution was added to a dichloromethane solution (5 mL) of B1-4 (440 mg, 1.1 mmol), and then Meta-chloroperoxybenzoic acid (952 mg, 5.5 mmol) was added and stirred at room temperature. After 7 h, saturated sodium thiosulfate solution was added, then saturated brine and ethyl acetate were added, and the ethyl acetate layer and the water layer were separated.
  • Compound A54-5 (15.27 g, 27.39 mmol) was added to dichloromethane (200 mL), and under ice bath, triethylamine (11.09 g, 109.56 mmol), Boc-L-valine (8.34 g, 38.35 mmol) were added successively mmol), 1-hydroxybenzotriazole (5.56g, 41.09mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11.56g, 60.26mmol), 4-Dimethylaminopyridine (3.35 g, 27.39 mmol) was added, and the mixture was warmed to room temperature and stirred.
  • reaction solution was concentrated, water and ethyl acetate were added, the organic phase was separated, washed successively with dilute hydrochloric acid, saturated sodium bicarbonate, and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound B1-1.
  • 0.2 mL of blood was collected from the jugular vein at 5 min (intravenous only), 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h after administration, placed in an EDTA-K2 test tube, centrifuged at 11000 rpm for 5 min, and the plasma was separated at –70 °C frozen in the refrigerator for testing. Ice water bath operation. The concentration of metabolized nucleosides in plasma was determined by LC-MS-MS, and the pharmacokinetic parameters were calculated.
  • the rat PK test showed that when compounds A1, A2 and C38 were orally administered, the exposure of nucleoside metabolites was high, and the bioavailability could reach 122.3%, 93% and 87%, respectively.
  • Test Example 2 Inhibitory effect of compound on virus replication
  • Cytopathogenic effect (CPE) assay was used to determine the inhibitory activity of compounds against respiratory syncytial virus (RSV), human coronavirus OC43, influenza A virus, and Zika virus replication: experimental cells were inoculated into 96 cells at a certain cell density In a well cell culture plate, the cells were cultured overnight in a 5% CO 2 , 37° C. incubator. Compound and virus were added the next day. Depending on the virus tested, cells were cultured in an incubator under 5% CO 2 , 33° C. or 37° C. for 3-7 days, until 80-95% cytopathic effect was achieved in control wells infected with no compound virus.
  • RSV respiratory syncytial virus
  • OC43 human coronavirus OC43
  • influenza A virus influenza A virus
  • Zika virus replication Zika virus replication
  • Cell viability in each well was then assayed with CellTiter-Glo or CCK-8. If the cell viability of the compound-containing wells is higher than that of the virus-infected control wells, that is, the CPE is weakened, it indicates that the compound has an inhibitory effect on the tested virus.
  • the cytotoxicity test method is the same as the corresponding antiviral test method, but without virus infection.
  • the antiviral activity and cytotoxicity of the compounds were expressed by the inhibition rate (%) and cell viability (%) of the compounds against virus-induced cellular viral effects, respectively. Calculated as follows:
  • Inhibition rate (%) (reading value of test well-mean value of virus control)/(mean value of cell control-mean value of virus control) ⁇ 100;
  • Cell viability (%) (reading value of test well-mean value of medium control)/(mean value of cell control-mean value of medium control) ⁇ 100;
  • EC50 and CC50 values were calculated by Prism software, and the inhibition curve fitting method was "log(inhibitor) vs. response--Variable slope".
  • Plaque reduction assay to determine the inhibitory activity of compounds against dengue fever virus Vero cells were seeded at a density of 600,000 cells per well into 6-well cell culture plates and cultured overnight in a 5% CO 2 , 37°C incubator. Compound and virus (40-50 PFU/well) were added the next day. The cells were cultured in an incubator under the conditions of 5% CO 2 and 37° C. for 2 hours, and then the supernatant was aspirated, and a low-melting point agarose medium containing the corresponding concentration of compounds was added. Cells were cultured in an incubator at 5% CO 2 at 33° C. or 37° C. for 6-7 days until obvious viral plaques were observed in control wells without compound under the microscope.
  • Fluorescence quantitative PCR was used to determine the inhibitory activity of compounds on porcine epidemic diarrhea virus (PEDV) replication: Vero cells were digested and passaged, and the cell density was adjusted to 1 ⁇ 10 5 /mL with cell growth medium, and inoculated into 96-well plates, 100 ⁇ L/mL The wells were placed in a 37°C, 5% CO 2 incubator for 24 hours; the 96-well plate was taken out, the medium in the wells was discarded, washed three times with 1 ⁇ PBS, and after drying, compounds (10 concentration points) and viruses were added to each well (0.01MOI per well), 8 replicate wells were set for each concentration, cultured in a 37°C, 5% CO 2 incubator, and virus control and cell control were set at the same time. After 36 hours, cell samples were collected, and the changes of virus content in different treatment groups were determined by fluorescence quantitative PCR, and the EC 50 of the compounds was calculated.
  • PEDV porcine epidemic diarrhea virus
  • a total of 18 male SD rats were divided into an intravenous group (IV) and a gavage group (PO).
  • Test Example 4 Pharmacokinetic evaluation in cynomolgus monkeys
  • Compounds C22 and C23 were administered orally at 16 mg/kg and 20 mg/kg, respectively, and the administration vehicle was 5% DMSO+5% solutol+90% saline.
  • the intravenous doses were 4 mg/kg and 5 mg/kg, respectively, and the administration vehicle was DMSO/EtOH/PEG300/0.9%NaCl (5/5/40/50, v/v/v/v).
  • 0.2 mL of blood was collected from the jugular vein, placed in an EDTA-K2 test tube, centrifuged at 11,000 rpm for 5 min, and the plasma was separated and frozen at –70°C To be tested. Ice water bath operation. The concentration of metabolized nucleosides in plasma was determined by LC-MS-MS, and the pharmacokinetic parameters were calculated.
  • the rat PK test showed that when compounds C22 and C23 were orally administered, the exposure of nucleoside metabolites was high, and the bioavailability could reach 75.3% and 71.8%, respectively.

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Abstract

本发明涉及一种下式所示的核苷类似物及其用途。具体而言，本发明涉及下式所示的核苷类似物或其药学上可接受的盐，及其药物组合物，以及它们在制备(a)抑制冠状病毒、副粘病毒、流感病毒、黄病毒科病毒、丝状病毒、布尼亚病毒和/或沙粒病毒复制的抑制剂；和/或(b)治疗和/或预防、缓解由冠状病毒、副粘病毒、流感病毒、黄病毒科病毒、丝状病毒、布尼亚病毒和/或沙粒病毒感染引起的疾病的药物中的用途。

Description

核苷类似物及其用途 技术领域
本发明涉及一种核苷类似物及其用途，具体而言，本发明涉及一种具有式(I)结构的化合物或其药学上可接受的盐，其药物组合物以及其用途。
背景技术
由病毒引起的传染性疾病对全球公共卫生安全构成了重大的威胁。自2007以来，世界卫生组织已宣布了多起全球紧急公共卫生事件，如2009年甲型H1N1型流感病毒疫情、2014年野生型脊髓灰质炎病毒疫情、2014年西非的埃博拉病毒疫情、2016年巴西的寨卡病毒疫情、2018年刚果(金)的埃博拉疫情和2020年的新型冠状病毒(SARS-CoV-2)疫情。
病毒种类众多，除上述外，很多其它病毒同样对人类社会产生了较大影响，如登革热病毒、呼吸道合胞病毒、布尼亚病毒以及造成养殖业重大损失的动物冠状病毒。随着人类社会活动范围的扩大以及全球化趋势的加强，新的病毒或再发病毒在全球范围内将不断出现，世界医疗卫生体系将面临更为严峻的挑战。
核苷类似物是最重要的一类抗病毒药物。该类药物在生物体内可转化为相应的三磷酸形式，在病毒复制阶段，该三磷酸能“伪装”成底物，在病毒聚合酶的催化作用下，掺入到病毒的DNA或RNA链中，干扰遗传物质的复制，从而发挥抗病毒作用。病毒聚合酶大都具有保守的活性中心，因此核苷类物作为抗病毒药物具有较高的耐药屏障，同时也常表现出广谱抗病毒作用。
β-d-N4-羟胞苷(NHC)是一个胞嘧啶核苷衍生物，最早于1959年被报道。该化合物对多种病毒(流感病毒、丙肝病毒、SARS、MERS、SARS-CoV-2等)复制表现出显著的抑制作用，是一个广谱抗病毒核苷类似物。(2R,3R,4S,5R)-2-(4-氨基吡咯并[2,1-F][1,2,4]三嗪-7-基)-3,4-二羟基-5-(羟甲基)四氢呋喃-2-甲腈(GS-441524)也是一个具有广谱抗病毒活性的核苷，该化合物最先被发现具有抗丙肝病毒作用，随后又被发现对丝状病毒(埃博拉病毒、马尔堡病毒)、副黏病毒(副流感病毒、麻疹病毒、呼吸道合胞病毒)、冠状病毒(SARS、MERS、SARS-CoV-2)等有抑制活性。然而，这两个化合物都有口服生物利用度低的缺点，在猴子体内口服生物利用度低于10％，难以作为口服药物进行开发。
前药修饰是提高核苷类似物成药性的重要手段，合适的前药形式不但有利于改善该类化合物的代谢性质，也可提高其对疾病的治疗效果，减少毒副作用等。
发明内容
因此，本发明的目的是提供一种可有效抑制病毒复制的活性成分及其在病毒感染引起的相关疾病中的新用途。
具体地，本发明提供了式I所示的核苷类似物或其药学上可接受的盐及其组合物在抗病毒，如冠状病毒(SARS、MERS、SARS-CoV-2、猪流行性腹泻病毒、猫传染性腹膜炎病毒等)、 副粘病毒(副流感病毒、麻疹病毒、呼吸道合胞病毒等)、流感病毒、黄病毒科病毒(丙肝病毒、登革热病毒、寨卡病毒等)、丝状病毒(埃博拉病毒、马尔堡病毒)、布尼亚病毒和/或沙粒病毒，尤其是抗新型冠状病毒(SARS-CoV-2)、流感病毒中的用途。
根据本发明第一方面，其提供了一种式I所示的化合物或其药学上可接受的盐：
Figure PCTCN2022086215-appb-000001
其中，
B选自
Figure PCTCN2022086215-appb-000002
X选自氧、硫、CH 2、NH；
R 1选自氢、氘、氰基；
R 2选自氢、C 1-18烷基、C 3-8环烷基、C 6-20芳基、5-15元杂芳基，其中烷基和环烷基未经取代或被独立地选自卤素、羟基、羧基和C 1-4烷氧基的一到三个取代基取代，芳基和杂芳基未被取代或被一到五个独立地选自R 9的取代基取代；
R 3选自氢、C 1-4烷氧基；
或R 2、R 3与它们连接的碳一起形成
Figure PCTCN2022086215-appb-000003
R 4选自氢、氘、卤素、叠氮、氰基、C 1-6烷基、卤代C 1-6烷基、叠氮C 1-6烷基、氰基C 1-6烷基、羟基C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 1-6烷氧基C 1-6烷基；
R 5选自氢、C 1-20烷酰基、C 3-20环烷酰基、氨基C 1-20烷酰基、C 1-20烷氨基C 1-6烷酰基、C 1-6环烷氨基C 1-6烷酰基、C 1-20双烷氨基C 1-6烷酰基、C 1-20烷氧基C 1-6烷酰基、以氨基酸上羧基的羰基与相连接的氧形成酯键的氨基酸基团、C 6-20芳基氨基C 1-6烷酰基、3-20元杂环烷基C 1-6烷酰基、
Figure PCTCN2022086215-appb-000004
Figure PCTCN2022086215-appb-000005
其中C 1-20烷酰基和C 3-20环烷酰基未经取代或被一到三个卤素取代，所述3-20元杂环烷基未经取代或者被C 1-6烷基取代；
R 6选自羟基、氨基、羟胺基(-NHOH)、-NHOR 13；
R 7选自氢、氘、卤素；
R 8选自氢、氘、卤素、氰基、氨甲酰基；
R 9选自选自卤素、C 1-4烷基、C 1-4烷氧基、C 1-4烷硫基、氰基、硝基、氨基、苯基、羧基、三氟甲基、二氟甲氧基、三氟甲氧基、C 1-4烷胺基、二(C 1-4烷基)胺基、C 1-4烷基羰基、C 1-4 烷基羰基氧基，C 1-4烷氧羰基；
R 10选自C 1-6烷基、C 3-6环烷基、C 6-20芳基、5-15元杂芳基；
R 11选自C 1-18烷基、亚甲基C 6-20芳基；
R 12选自C 1-6烷基、C 3-6环烷基、C 6-20芳基、5-15元杂芳基；
R 13选自C 1-20烷酰基、C 3-20环烷酰基、氨基C 1-20烷酰基、C 1-20烷氨基C 1-6烷酰基、C 1-6环烷氨基C 1-6烷酰基、C 1-20双烷氨基C 1-6烷酰基、C 1-20烷氧基C 1-6烷酰基、C 1-6烷氧羰基氧亚甲基；
在一优选实施方式中，式I化合物具有化学式I-I，
Figure PCTCN2022086215-appb-000006
其中，B、X、R 1、R 4、R 5的定义与上文相同。
在另一优选实施方式中，式I化合物具有化学式I-II，
Figure PCTCN2022086215-appb-000007
式(I-II)中含有一个由*表示的不对称中心，因此可以具有结构式I-IIA和I-IIB的两种非对映体，或者单独作为纯单一非对映体，或者作为两种非对映体的混合物
Figure PCTCN2022086215-appb-000008
其中，B、X、R 1、R 2、R 4、R 5的定义与上文相同。
在另一优选实施方式中，式I化合物选自下式，
Figure PCTCN2022086215-appb-000009
R 1选自氢、氘；
R 2、R 5、R 7、R 8、R 13的定义与上文中相同；
R 4选自氢、氘、卤素。
在另一优选实施方式中，式I化合物选自化合物A1至A56，B1至B46，C1至C42，D1至D13中的任一化合物、或其组合：
Figure PCTCN2022086215-appb-000010
Figure PCTCN2022086215-appb-000011
Figure PCTCN2022086215-appb-000012
Figure PCTCN2022086215-appb-000013
Figure PCTCN2022086215-appb-000014
Figure PCTCN2022086215-appb-000015
Figure PCTCN2022086215-appb-000016
Figure PCTCN2022086215-appb-000017
Figure PCTCN2022086215-appb-000018
Figure PCTCN2022086215-appb-000019
Figure PCTCN2022086215-appb-000020
Figure PCTCN2022086215-appb-000021
式I-III所示的化合物与式I-III’所示的化合物等同，为互变异构体，嘧啶碱基4位的羟胺基可用肟基表示。
Figure PCTCN2022086215-appb-000022
在一些实施方式中，根据本发明的上述化合物或其药学上可接受的盐可以以结晶水合物、溶剂化物或共晶化合物的形式存在，因此，这些结晶水合物、溶剂化物和共晶化合物也包括在本发明的范围内。
在一些实施方式中，根据本发明的上述化合物或其药学上可接受的盐可以存在对映异构体、非对映异构体或者它们的组合的形式存在。这些对映异构体、非对映异构体以及它们的组合也包括在本发明的范围内。
在本发明的第二方面，提供了一种药物组合物，所述的药物组合物含有：
(a1)第一活性成分，所述的第一活性成分为选自上述式I化合物和其药学上可接受的盐中的一种或多种：
以及(b)药学上可接受的载体。
在一优选实施方式中，所述的组合物还可以含有(a2)第二活性成分；其中，所述的第二活性成分为选自抗病毒活性成分、皮质类固醇抗炎药物、辅助治疗药物等中的一种或多种。
在一些实施方式中，抗病毒活性成分为选自以下的一种或多种：干扰素、RNA依赖的RNA聚合酶抑制剂(如Remdesivir(瑞德西韦或GS-5734)、法匹拉韦(favipiravir)、Galidesivir、GS-441524、NHC(EIDD-1931)、EIDD-2801)、3CL蛋白酶抑制剂(如GC-376)、洛匹那韦(Lopinavir)、利托那韦(Ritonavir)、奈非那韦(Nelfinavir)、氯喹(Chloroquine)、羟氯喹(hydroxychloroquine)、环孢菌素(cyclosporine)、可利霉素(Carrimycin)、黄芩苷(baicalin)、黄芩素(baicalein)、连翘脂苷(forsythoside)、绿原酸(chlorogenic acid)、大黄素(emodin)、霉酚酸(mycophenolic acid)、霉酚酸酯(Mycophenolate mofetil)、萘酚喹(Naphthoquine)、环索奈德(Ciclesonide)、利巴韦林(Ribavirin)、喷昔洛韦(Penciclovir)、来氟米特(Leflunomide)、特立氟胺(Teriflunomide)、萘莫司他(nafamostat)、硝唑尼特(nitazoxanide)、达芦那韦 (Darunavir)、阿比多尔(Arbidol)、卡莫司他(Camostat)、氯硝柳胺(Niclosamide)、巴瑞替尼(baricitinib)、芦可替尼(Ruxolitinib)、达沙替尼(Dasatinib)、沙奎那韦(Saquinavir)、Beclabuvir、司美匹韦(Simeprevir)、帕利珠单抗、莫维珠单抗(Motavizumab)、RSV-IGIV
Figure PCTCN2022086215-appb-000023
MEDI-557、A-60444(RSV-604)、MDT-637、BMS-433771、或其药学上可接受的盐。
在一些实施方式中，所述的皮质类固醇抗炎药物为选自以下的一种或多种：地塞米松、地塞米松磷酸钠、氟米龙、醋酸氟米龙、氯替泼诺、依碳酸氯替泼诺、氢化可的松、泼尼松龙、氟氢可的松、曲安西龙、曲安奈德、倍他米松、双丙酸倍氯美松、甲泼尼龙、氟轻松、氟西奈德、氟尼缩松、氟可丁-21-丁酯(fluocortin-21-butylate)、氟米松、新戊酸氟米松、布地奈德、丙酸卤贝他索、糠酸莫米他松、丙酸氟替卡松、环索奈德、或其药学上可接受的盐；
在一些实施方式中，所述的辅助治疗药物选自以下的一种或多种：锌(Zinc)、芬戈莫德(Fingolimod)、维生素C(Vitamin C)、奥美沙坦酯(Olmesartan Medoxomil)、缬沙坦(valsartan)、氯沙坦(Losartan)、沙利度胺(Thalidomide)、甘草酸(glycyrrhizic acid)、青蒿素(Artemisinin)、双氢青蒿素(dihydroartemisinin)、青蒿琥酯(Artesunate)、青蒿酮(Artemisone)、阿奇霉素(Azithromycin)、七叶皂苷(Escin)、萘普生(Naproxen)。
在一优选实施方式中，所述药物组合物被制备成制剂。
在一优选实施方式中，所述的制剂包括：口服制剂和非口服制剂。
在一优选实施方式中，所述的制剂包括：粉剂、颗粒剂、胶囊剂、注射剂、吸入剂、酊剂、口服液、片剂、含片、或滴丸。
在本发明的第三方面，提供了上述式I化合物或其药学上可接受的盐，或者上述药物组合物在制备药物中的用途，所述药物是(a)抑制病毒复制的抑制剂；和/或(b)治疗和/或预防、缓解由病毒感染引起的疾病的药物。
在一优选实施方式中，所述的病毒是选自以下的一种或多种：
(1)冠状病毒，包括感染人的冠状病毒：例如重症急性呼吸综合征冠状病毒SARS-CoV(Severe acute respiratory syndrome coronavirus，SARS-CoV)、2019新型冠状病毒(2019-nCoV或SARS-CoV-2)、中东呼吸综合征冠状病毒MERS-CoV(Middle East respiratory syndrome coronavirus，MERS-CoV)、人冠状病毒OC43(Human coronavirus OC43)、人冠状病毒229E(Human coronavirus 229E)、人冠状病毒NL63(Human coronavirus NL63)、人冠状病毒HKUl(Human coronavirus HKUl)；和感染动物的冠状病毒：例如猪流行性腹泻病毒(PEDV)、猫传染性腹膜炎病毒(FIFV)；
(2)副粘病毒：例如副流感病毒、麻疹病毒、呼吸道合胞病毒(RSV)；
(3)流感病毒：例如甲型流感病毒、乙型流感病毒、丙型流感病毒、丁型流感病毒；
(4)黄病毒科病毒：例如丙型肝炎病毒(HCV)、登革热病毒(DENV)、寨卡病毒(Zika)；
(5)丝状病毒：例如马尔堡病毒(MBV)、埃博拉病毒(EBV)、奎瓦病毒；
(6)布尼亚病毒科病毒：例如布尼亚病毒属、白蛉病毒属，内罗病毒属、汉坦病毒属病毒；
(7)沙粒病毒：例如拉沙热病毒(LASV)、鸠宁病毒(JUNV)、马秋波病毒(MACV)等。
在一优选实施方式中，所述病毒为2019新型冠状病毒(SARS-CoV-2)。
在另一优选实施方式中，所述病毒为流感病毒。
在一优选实施方式中，所述病毒引起的疾病选自以下的一种或多种：
(D1)人冠状病毒感染引起的普通感冒、高危症状感染、呼吸道感染、肺炎及其并发症；
(D2)猪流行性腹泻病毒(PEDV)引起的猪流行性腹泻；
(D3)猫冠状病毒(FIFV)引起的猫传染性腹膜炎；
(D4)人呼吸道合胞病毒(RSV)感染引起的普通感冒、高危症状感染、呼吸道感染、肺炎及其并发症；
(D5)流感病毒感染引起的普通感冒、高危症状感染、呼吸道感染、肺炎及其并发症；
(D6)丙型肝炎病毒(HCV)引起的慢性丙型肝炎及其并发症；
(D7)登革热病毒(DENV)引起的登革热及其并发症；
(D8)寨卡病毒(Zika)引起的感染及其并发症；
(D9)马尔堡病毒(MBV)、埃博拉病毒(EBV)引起的出血热及其并发症；
(D10)布尼亚病毒科病毒引起的感染及其并发症；
(D11)沙粒病毒引起的感染及其并发症。
在一优选实施方式中，所述病毒引起的疾病为由2019新型冠状病毒(SARS-CoV-2)感染引起的疾病。特别地，所述由2019新型冠状病毒感染引起的疾病为选自以下的一种或多种：呼吸道感染、肺炎及其并发症。
在另一优选实施方式中，所述病毒引起的疾病为由流感病毒感染引起的疾病。特别地，所述由流感病毒感染引起的疾病为选自以下的一种或多种：普通感冒、高危症状感染、呼吸道感染、肺炎及其并发症。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过广泛而深入的研究，通过大量筛选，意外地开发了一类具有良好药代性质的核苷前药。实验表明，本发明的核苷前药口服生物利用度高，并且具有显著的抗病毒活性，预计用于2019新型冠状病毒(SARS-CoV-2)、流感病毒、呼吸道合胞病毒等多种病毒感染的治疗将具有明显优势，在此基础上完成了本发明。
具体地，本发明揭示了具有式(I)所示的核苷类似物前药及其组合物在抗病毒中的用途，在制备病毒的抑制剂中的用途，以及在制备治疗由病毒感染引起的疾病、状况或适应症的药物中的用途。所述病毒是冠状病毒(SARS、MERS、SARS-CoV-2、猪流行性腹泻病毒、猫传染性腹膜炎病毒等)、副粘病毒(副流感病毒、麻疹病毒、呼吸道合胞病毒等)、流感病毒、黄病毒科病毒(丙肝病毒、登革热病毒、寨卡病毒等)、丝状病毒(埃博拉病毒、马尔堡病毒)、布尼亚病毒和/或沙粒病毒。
具体地，本发明揭示了具有式(I)所示的核苷类似物前药及其组合物在抗病毒中的用途，例如在制备(a)抗冠状病毒(SARS、MERS、SARS-CoV-2、猪流行性腹泻病毒、猫传染性腹膜炎病毒等)、副粘病毒(副流感病毒、麻疹病毒、呼吸道合胞病毒等)、流感病毒、黄病毒科病毒(丙肝病毒、登革热病毒、寨卡病毒等)、丝状病毒(埃博拉病毒、马尔堡病毒)、 布尼亚病毒和/或沙粒病毒复制的抑制剂；和/或(b)治疗和/或预防、缓解由人冠状病毒(SARS、MERS、SARS-CoV-2、猪流行性腹泻病毒、猫传染性腹膜炎病毒等)、副粘病毒(副流感病毒、麻疹病毒、呼吸道合胞病毒等)、流感病毒、黄病毒科病毒(丙肝病毒、登革热病毒、寨卡病毒等)、丝状病毒(埃博拉病毒、马尔堡病毒)、布尼亚病毒和/或沙粒病毒感染引起的疾病的药物中的用途。式(I)所示的核苷类似物前药在体内的核苷代谢产物的暴露量高，对SARS-CoV-2、流感病毒、呼吸道合胞病毒等病毒的复制具有较强的抑制作用，具有良好的临床应用前景。
术语
如本文所用，“本发明的化合物”、“本发明的核苷类似物”、“本发明的核苷类似物前药”、“本发明的核苷前药”、“本发明的活性化合物”、“本发明的抗病毒核苷类似物”可互换使用，指在体内或体外具有优异抗病毒作用的核苷类似物，包括式I所示的化合物，或其药学上可接受的盐、或其溶剂合物、或其前药、或其组合。
如本文所用，“本发明的制剂”指含有本发明核苷类似物的制剂。
如本文所用，术语“包括”或其变换形式如“包含”或“包括有”等等，被理解为包括所述的元件或组成部分，而并未排除其它元件或其它组成部分。
如本文所用，术语“新型冠状病毒”、“2019-nCoV”或“SARS-CoV-2”可互换使用，该2019新型冠状病毒是已知感染人的第7种冠状病毒，并且造成新冠肺炎(COVID-19)，是威胁全球人类健康的严重传染性疾病之一。
如本文所用，“卤素”通常是指氟、氯、溴及碘；优选为氟、氯或溴；更优选为氟或氯。
如本文所用，术语“C n-C m”与C n-m可互换使用，指具有n至m个碳原子。
如本文所用，单独或者作为复合基团的一部分的术语“C 1-18烷基”指含有1-18个碳原子的直链或支链的饱和烃基，例如，C 1-6烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1-乙基丙基、异戊基、新戊基、异己基、3-甲基戊基或正己基等，优选为甲基、乙基、正丙基、异丙基、丁基、异丁基或叔丁基。
如本文所用，单独或者作为复合基团的一部分的术语“卤代C 1-6烷基”是指上述C 1- 6烷基的氢原子被1个或多个相同或不同的卤素原子取代，例如三氟甲基、氟甲基、二氟甲基、氯甲基、溴甲基、二氯氟甲基、氯乙基、溴丙基、2-氯丁基或五氟乙基等。
如本文所用，单独或者作为复合基团的一部分的术语“C 1-6烷氧基”指含有1-6个碳原子的直链或支链烷氧基，例如，甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、仲丁氧基、正戊氧基、异戊氧基、新戊氧基、异己氧基、3-甲基戊氧基或正己氧基等，优选为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基。
如本文所用，单独或者作为复合基团的一部分的术语“C 3-20环烷基”指含有1-20个碳原子的环状饱和烃基，例如，C 3-8环烷基，例如环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。
如本文所用，单独或者作为复合基团的一部分的术语“C 1-20烷酰基”指RC(＝O)-，其中，R选自氢或C 1-19烷基，C 1-20烷酰基的实例如甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、叔丁酰基或己酰基等。有时候烷酰基也可以称为烷基羰基，例如C 1-4烷基羰基。
如本文所用，单独或者作为复合基团的一部分的术语“C 2-6烯基”指含有1-3个双键和2-6个碳原子的直链或支链的不饱和烃基，既包括顺式构型也包括反式构型，例如，乙烯基、1- 丙烯基、2-丙烯基、1-甲基-1-丙烯基、2-甲基-1-丙烯基、2-甲基-2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1,3-丁二烯基、1,3-戊二烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、3,3-二甲基-1-丙烯基或2-乙基-1-丙烯基等。
如本文所用，单独或者作为复合基团的一部分的术语“C 2-6炔基”指含有2-6个碳原子的直链或支链炔基，例如，乙炔基、2-丙炔基、2-丁炔基、3-丁炔基、1-甲基-2-丙炔基、2-戊炔基或2-己炔基等。
如本文所用，单独或者作为复合基团的一部分的术语“氨基C 1-20烷酰基”指其上的一个氢被氨基(-NH 2)取代的C 1-20烷酰基，如-CONH 2、-COCH 2NH 2、-COCH 2CH 2NH 2等。
如本文所用，单独或者作为复合基团的一部分的术语“C 1-20烷氨基”指氨基(-NH 2)上的一个氢被C 1-20烷基取代所得的基团，例如-NHCH 3、-NHCH 2CH 3等。有时候烷氨基也被称为烷胺基。
如本文所用，单独或者作为复合基团的一部分的术语“C 1-6环烷氨基”指氨基(-NH 2)上的一个氢被C 1-6环烷基取代所得的基团，例如环丙基氨基、环丁基氨基、环戊基氨基、环己基氨基等。
如本文所用，单独或者作为复合基团的一部分的术语“C 1-20烷氨基C 1-6烷酰基”指其上的一个氢被C 1-20烷氨基取代的C 1-6烷酰基，如-CONHCH 3、-COCH 2NHCH 3、-COCH 2CH 2NHCH 2CH 3等。
如本文所用，单独或者作为复合基团的一部分的术语“C 1-6环烷氨基C 1-6烷酰基”指其上的一个氢被C 1-6环烷氨基取代的C 1-6烷酰基，如环丙基氨基C 1-6烷酰基、环丁基氨基C 1-6烷酰基、环戊基氨基C 1-6烷酰基、环己基氨基C 1-6烷酰基等。
如本文所用，单独或者作为复合基团的一部分的术语“C 1-20双烷氨基”指氨基(-NH 2)上的两个氢各自独立地被C 1-20烷基取代所得的基团，例如二甲氨基、二乙基氨基、甲基乙基氨基等。有时候C 1-6双烷氨基也可以称为二(C 1-6烷基)胺基，例如二(C 1-4烷基)胺基。
如本文所用，单独或者作为复合基团的一部分的术语“C 1-20双烷氨基C 1-6烷酰基”指其上的一个氢被C 1-20双烷氨基取代的C 1-6烷酰基，如-CON(CH 3) 2、-CON(CH 2CH 3) 2、-COCH 2N(CH 2CH 3) 2、-COCH 2CH 2N(CH 2CH 3) 2等。
如本文所用，单独或者作为复合基团的一部分的术语“C 1-6烷氧基C 1-6烷基”指其上的一个氢被C 1-6烷氧基取代的C 1-6烷基，如-CH 2OCH 3、-CH 2CH 2OCH 2CH 3等。
如本文所用，单独或者作为复合基团的一部分的术语“氨基C 1-6烷基”指其上的一个氢被氨基(-NH 2)取代的C 1-6烷基，如-CH 2NH 2、-CH 2CH 2NH 2、-CH(NH 2)CH 3、-CH 2CH 2CH 2NH 2或-CH 2CH 2CH 2CH 2NH 2等。
如本文所用，单独或者作为复合基团的一部分的术语“羟基C 1-6烷基”指其上的一个氢被羟基取代的C 1-6烷基，如-CH 2OH、-CH 2CH 2OH、-CH(OH)CH 3、-CH 2CH 2CH 2OH、-CH 2CH 2CH 2CH 2OH或-CH 2CH(CH 3)CH 2OH等。
如本文所用，单独或者作为复合基团的一部分的术语“C 1-4烷基羰基氧基”指C 1-4烷基C(＝O)O-基团，例如，CH 3C(＝O)O-、CH 3CH 2C(＝O)O-、CH 3CH 2CH 2C(＝O)O-等。
如本文所用，单独或者作为复合基团的一部分的术语“C 1-4烷氧羰基”指C 1-4烷基-OC(＝O)-基团，例如，CH 3OC(＝O)-、CH 3CH 2OC(＝O)-、CH 3CH 2CH 2OC(＝O)-等。
如本文所用，单独或者作为复合基团的一部分的术语“C 1-20烷氧基C 1-6烷酰基”指其上的一个氢被C 1-20烷氧基取代的C 1-6烷酰基，例如，CH 3OC(＝O)-、CH 3CH 2OC(＝O)-、(CH 3) 2CHOC(＝O)-、CH 3OCH 2C(＝O)-等。
如本文所用，单独或者作为复合基团的一部分的术语“C 1-6烷氧羰基氧亚甲基”指C 1-6烷基-OC(＝O)OCH 2-基团，例如，CH 3OC(＝O)OCH 2-、CH 3CH 2OC(＝O)OCH 2-、(CH 3) 2CHOC(＝O)OCH 2-等。
如本文所用，术语“氨基酸”指天然存在的和合成的氨基酸，例如L-缬氨酸、L-丙氨酸、L-苯丙氨酸、L-苯甘氨酸、D-缬氨酸、D-丙氨酸，所述氨基酸通过其羧基上羰基与R5相连接的氧形成酯键而连接到母核结构上。
如本文所用，单独或者作为复合基团的一部分的术语“C 6-20芳基”指环上具有6-20个碳原子且不含有杂原子的单环或多环(例如，双环或三环)芳族环，例如C 6-12芳基，C 6-10芳基，例如苯基、萘基、菲基、蒽基等。
如本文所用，单独或者作为复合基团的一部分的术语“5-15元杂芳基”指环上具有5-15个原子并且其中包括选自氮、氧和硫的1-4个环杂原子的单环或多环(例如，双环或三环)芳族环，例如5-10元杂芳基，5-6元杂芳基，例如吡咯基，呋喃基，噻吩基，咪唑基，吡唑基，噁唑基，异噁唑基，噻唑基，异噻唑基，三唑基，噁二唑基，噻二唑基，吡啶基，哒嗪基，嘧啶基，吡嗪基，吲哚基，异吲哚基，吲唑基，苯并三唑基，苯并噻吩基，异苯并噻吩基，苯并呋喃基，苯并异呋喃基，苯并咪唑基，苯并噁唑基，苯并异噁唑基，苯并噻唑基，苯并异噻唑基，苯并噻二唑基，吲哚嗪基，嘌呤基，咪唑并吡啶基，咪唑并嘧啶基，咪唑并吡嗪基，咪唑并哒嗪基，咪唑并三嗪基，吡唑并吡啶基，吡唑并嘧啶基，吡唑并吡嗪基，吡唑并吡嗪基，吡唑并三嗪基，吡咯并吡啶基，吡咯并嘧啶基，吡咯并哒嗪基，吡咯并吡嗪基和吡咯并三嗪基等。
在本文中，所有以数值范围形式界定的特征或条件仅是为了简洁及方便。据此，数值范围的描述应视为已涵盖且具体公开所有可能的次级范围及范围内的个别数值，特别是整数数值。举例而言，“1-6”的范围描述应视为已经具体公开如1至6、2至6、2至5、3至5、4至6、3至6等等所有次级范围，特别是由所有整数数值所界定的次级范围，且应视为已经具体公开范围内如1、2、3、4、5、6等个别数值。除非另有指明，否则前述解释方法适用于本发明全文的所有内容，不论范围广泛与否。
若数量或其他数值或参数是以范围、较佳范围或一系列上限与下限表示，则其应理解成是本文已特定公开了由任一对该范围的上限或较佳值与该范围的下限或较佳值构成的所有范围，不论这些范围是否有分别公开。此外，本文中若提到数值的范围时，除非另有说明，否则该范围应包括其端点以及范围内的所有整数与分数。
冠状病毒
冠状病毒(Coronavirus，CoV)属于套式病毒目(Nidovirales)冠状病毒科(Coronaviridae)，是一种有包膜的正链RNA病毒，其亚科包含α、β、δ及γ四属。
目前已知的感染人的冠状病毒中，HCoV-229E和HCoV-NL63属于α属冠状病毒，HCoV-OC43、SARS-CoV、HCoV-HKU1、MERS-CoV和SARS-CoV-2均为β属冠状病毒。
该类病毒的基因组是一条单股正链RNA，是基因组最大的RNA病毒之一，编码包括复制酶、刺突蛋白、囊膜蛋白、包膜蛋白和核壳蛋白等。在病毒复制的初始阶段，基因组被翻 译成两条长达几千个氨基酸的肽链即前体多聚蛋白(Polyprotein)，随后前体蛋白被蛋白酶切割生成非结构蛋白(如RNA聚合酶和解旋酶)和结构蛋白(如刺突蛋白)及辅助蛋白。
流感病毒
流行性感冒病毒简称流感病毒,常见的流感病毒分为甲(A)、乙(B)、丙(C)和丁(D)型。流感病毒可引起人、禽、猪、马、蝙蝠等多种动物感染和发病，是人流感、禽流感、猪流感、马流感等人与动物疫病的病原体。
流感病毒引起的临床症状包括急性高热、全身疼痛、显著乏力和呼吸道症状。人流感主要是甲型流感病毒和乙型流感病毒引起的。甲型流感病毒经常发生抗原变异，可以进一步分为H1N1、H3N2、H5N1、H7N9等亚型。
呼吸道合胞病毒
呼吸道合胞病毒(RSV，简称合胞病毒，属副粘病毒科)是引起小儿病毒性肺炎最常见的病原，可引起间质性肺炎。
RSV与副流感病毒类似，病毒颗粒大小约为150nm，较副流感病毒稍小，为RNA病毒。
黄病毒科病毒
黄病毒科病毒是一类主要感染哺乳类动物的RNA病毒，包括3个病毒属，黄病毒属(flavivirus)、瘟病毒属(pestivirus)和丙型肝炎病毒属(hepacivirus)。登革热病毒(DENV)和寨卡病毒(ZIKV)属于黄病毒属，由蚊媒传播。登革病毒感染可引起明显的发热和疼痛症状，重度的登革热症状还表现为头痛，恶心，呕吐，意识不清，甚至休克等。寨卡病毒(ZIKV)感染后症状与登革热相似，一般较轻。丙肝病毒(HCV)属于丙型肝炎病毒属，是慢性丙型肝炎的病原体，可导致肝硬化、肝癌。
丝状病毒科病毒
丝状病毒科目前包含三个属，分别为埃博拉病毒属、马尔堡病毒属、奎瓦病毒属。马尔堡病毒和埃博拉病毒都可以引起严重的出血热，人感染后会出现高烧和出血症状，进一步会导致患者休克、器官衰竭，直至死亡。
猪流行性腹泻病毒(PEDV)
猪流行腹泻病毒(PEDV),属于冠状病毒科冠状病毒属。猪流行性腹泻是由PEDV病毒引起的仔猪和育肥猪的一种急性肠道传染病。
PEDV病毒经口和鼻感染后，直接进入小肠。PEDV病毒的复制可在小肠和结肠绒毛上皮细胞浆中进行。PEDV可导致腹泻，属于渗透性腹泻。严重腹泻引起脱水，是导致病猪死亡的主要原因。
布尼亚病毒(Bunya virus)
布尼亚病毒是一大类具有包膜、分节段的负链RNA病毒，属于虫媒病毒。布尼亚病毒科包括多个属(布尼亚病毒属、白蛉病毒属，内罗病毒属、汉坦病毒属等)，该类病毒可导致多种自然疫源性传染病，如肾综合征出血热、汉坦病毒肺综合征、白蛉热等。
沙粒病毒(arenavirus)
沙粒病毒是一类有囊膜的单股负链RNA病毒，形状像沙粒，是病毒的一个小分支。目前，多种病毒被发现对人类有致病性，如拉沙热(LASV)病毒、鸠宁(JUNV)病毒、马秋波(MACV)等病毒，这三种病毒能够引起出血热等疾病，严重威胁人类的健康。
在以下实施例中，原料(胞苷A39-0，尿苷B1-0，NHC，GS-441524，A2-0，C22-0)购 自上海皓鸿生物医药科技有限公司或芜湖诺威化学技术有限公司或者根据文献(Chemical Communications，2020，56，13363-13364；Nature，2016，531，381-385；中国专利202010313870.X)中记载的方案制备。
实施例
制备实施例1：化合物A1的合成
Figure PCTCN2022086215-appb-000024
β-D-N4-羟胞苷NHC(0.97g,3.75mmol)加入到二氯甲烷(5mL)中，依次加入4-二甲氨基吡啶(76mg,0.75mmol)、三乙胺(1.14g,11.25mmol)和4,4'-双甲氧基三苯甲基氯(2.80g,8.25mmol)，室温下搅拌。6小时后，向反应液中加入二氯甲烷(20mL)和饱和食盐水，分出有机相，无水硫酸钠干燥后，蒸干，硅胶柱层析分离(石油醚：乙酸乙酯＝1：1)，得化合物A1-1，白色固体1.81g，收率56％。
羰基二咪唑(134.5mg,0.83mmol)和A1-1(600mg,0.69mmol)加入到二氯甲烷(5mL)中，室温下搅拌。2小时后，蒸干反应液，硅胶柱层析分离(石油醚：乙酸乙酯＝2：1)，得化合物A1-2，白色泡沫状固体420mg，收率68％。
A1-2(420mg，0.47mmol)加入到甲醇(10mL)中，加入三氟乙酸(107mg,0.94mmol)，室温搅拌。10分钟后，加入饱和碳酸氢钠溶液，调节PH至中性。将反应液浓缩，硅胶柱层析(二氯甲烷：甲醇＝15：1)分离，得泡沫状固体，乙酸乙酯打浆，得化合物A1，白色粉末状固体30mg，收率22％。 1H NMR(500MHz,DMSO-d 6)δ10.10(s,1H),9.85(s,1H),6.96(d,J＝8.1Hz,1H),5.88(d,J＝2.6Hz,1H),5.60(d,J＝8.1Hz,1H),5.50(dd,J＝7.8,2.6Hz,1H),5.21(dd,J＝7.8,4.1Hz,1H),5.14(t,J＝5.6Hz,1H),4.20–4.15(m,1H),3.60(t,J＝5.8Hz,2H)。
制备实施例2：化合物A2的合成
Figure PCTCN2022086215-appb-000025
A2-0(296mg，0.9mmol)加入到二氯甲烷(3mL)中。冰浴下，加入羰基二咪唑(225mg，1.4mmol)，加毕，室温下搅拌。待原料反应完全后，过滤，滤饼用二氯甲烷冲洗，得化合物A2，白色固体200mg，收率63％。 1H NMR(500MHz,DMSO-d 6)δ10.13(s,1H),9.92(d,J＝2.3Hz,1H),6.96(d,J＝8.1Hz,1H),5.88(d,J＝2.1Hz,1H),5.60(dd,J＝8.1,2.1Hz,1H),5.57(dd,J＝7.7,2.2Hz,1H),5.29(dd,J＝7.8,4.2Hz,1H),4.44–4.40(m,1H),4.32(dd,J＝11.6,5.1Hz,1H),4.21(dd,J＝11.5,6.8Hz,1H),2.62–2.54(m,1H),1.12–1.08(m,6H)。
制备实施例3：化合物A35和A31的合成
Figure PCTCN2022086215-appb-000026
A2-0(1.00g，3.04mmol)和丙醛(882mg，15.20mmol)加入到二氯甲烷(20mL)中，冰浴下，缓慢加入对甲苯磺酸一水合物(1.16g，6.08mmol)，加毕，升至室温，搅拌2h。向反应液加入10％碳酸钠水溶液和二氯甲烷，分出有机相。有机相用饱和食盐水洗涤，无水硫酸钠干燥，硅胶柱层析(石油醚：乙酸乙酯＝20：1～1：1)分离，得化合物A35，白色固体897mg，收率80％。 1H NMR(500MHz,MeOD)δ6.87(d,J＝8.2Hz,1H),5.69(d,J＝2.3Hz,1H),5.57(d,J＝8.1Hz,1H),5.07(t,J＝4.5Hz,1H),4.93(dd,J＝6.7,2.3Hz,1H),4.74(dd,J＝6.7,3.7Hz,1H),4.30–4.26(m,2H),4.26–4.22(m,1H),2.64–2.55(m,1H),1.78–1.72(m,2H),1.18–1.14(m,6H),0.99(t,J＝7.5Hz,3H)。
A35(400mg,1.08mmol)加入到7M的氨甲醇溶液(15mL)中，室温下搅拌过夜。将反应液浓缩，硅胶柱层析(二氯甲烷：甲醇＝50：1～15：1)分离，得化合物A31，白色固体259mg，收率80％。 1H NMR(600MHz,CD 3OD)δ7.03(d,J＝8.2Hz,1H),5.81(d,J＝3.2Hz,1H),5.58(d,J＝8.2Hz,1H),5.07(t,J＝4.5Hz,1H),4.81(dd,J＝6.7,3.2Hz,1H),4.71(dd,J＝6.7,3.4Hz,1H),4.15–4.12(m,1H),3.75(dd,J＝11.9,3.8Hz,1H),3.71(dd,J＝11.9,4.7Hz,1H),1.79–1.73(m,2H),1.00(t,J＝7.5Hz,3H)。
制备实施例4：化合物A36和A32的合成
Figure PCTCN2022086215-appb-000027
A2-0(1.00g,3.04mmol)和正庚醛(1.73g,15.20mmol)加入到二氯甲烷(20mL)中，冰浴下，缓慢加入对甲苯磺酸一水合物(1.16g,6.08mmol)，加毕，升至室温，搅拌2h。向反应液中加入10％碳酸钠水溶液和二氯甲烷，分出有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥，硅胶柱层析(石油醚：乙酸乙酯＝20：1～1：1)纯化，得化合物A36，白色固体1.03g，收率80％。 1H NMR(500MHz,CD 3OD)δ6.87(d,J＝8.2Hz,1H),5.68(d,J＝2.3Hz,1H),5.57(d,J＝8.2Hz,1H),5.09(t,J＝4.7Hz,1H),4.92(dd,J＝6.7,2.3Hz,1H),4.73(dd,J＝6.7,3.6Hz,1H),4.30–4.26(m,2H),4.25–4.22(m,1H),2.64–2.55(m,1H),1.76–1.70(m,2H),1.49–1.41(m,2H),1.39–1.27(m,6H),1.18–1.13(m,6H),0.91(t,J＝6.9Hz,3H)。
A36(600mg,1.41mmol)加入到7M的氨甲醇溶液(15mL)中，室温下搅拌过夜，将反应液浓缩，硅胶柱层析(二氯甲烷：甲醇＝50：1～15：1)分离，得化合物A32，白色固体375mg，收率75％。 1H NMR(500MHz,CD 3OD)δ7.04(d,J＝8.2Hz,1H),5.80(d,J＝3.1Hz,1H),5.58(d,J＝8.2Hz,1H),5.10(t,J＝4.7Hz,1H),4.80(dd,J＝6.6,3.1Hz,1H),4.70(dd,J＝6.6,3.4Hz,1H),4.15–4.11(m,1H),3.75(dd,J＝11.9,3.8Hz,1H),3.70(dd,J＝11.9,4.7Hz,1H),1.77–1.70(m,2H),1.51–1.42(m,2H),1.40–1.28(m,6H),0.91(t,J＝6.9Hz,3H)。
制备实施例5：化合物A37和A33的合成
Figure PCTCN2022086215-appb-000028
A2-0(0.33g，1mmol)、无水氯化锌(0.68g，5mol)和4-氯苯甲醛(1.40g，10mmol)依次加入到无水四氢呋喃(10mL)中，70℃下搅拌过夜。将反应液倒入碳酸钠的水溶液中，乙酸乙酯萃取，分出有机相。有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱层析(二氯甲烷：甲醇＝50：1)分离，得化合物A37，白色固体0.15g，收率33％。 1H NMR(500MHz,CD 3OD)δ7.57–7.54(m,2H),7.49–7.44(m,2H),6.93(d,J＝8.2Hz,1H),6.01(s,1H),5.81(d,J＝2.3Hz,1H),5.61(d,J＝8.2Hz,1H),5.18(dd,J＝6.8,2.2Hz,1H),4.44–4.30(m,3H),2.67–2.58(m,1H),1.20–1.17(m,6H)。ESI-MS m/z＝450.0[M-1] -。
A37(0.15g，0.33mmol)和碳酸钾(0.04g，0.33mmol)加入到无水甲醇(5mL)中，室温下搅拌4小时。蒸干反应液，加入乙酸乙酯和水，分出有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥，硅胶柱层析(二氯甲烷：甲醇＝30：1)分离，得化合物A33，白色固体0.1g，收率78.8％。 1H NMR(500MHz,CD 3OD)δ7.59–7.56(m,2H),7.47–7.44(m,2H),7.10(d,J＝8.2Hz,1H),6.02(s,1H),5.95(d,J＝3.1Hz,1H),5.62(d,J＝8.2Hz,1H),5.05(dd,J＝6.7,3.1Hz,1H),4.94(dd,J＝6.7,3.3Hz,1H),4.31–4.27(m,1H),3.84–3.75(m,2H)。
制备实施例6：化合物A38和A34的合成
Figure PCTCN2022086215-appb-000029
冰浴下，向N,N-二甲基甲酰胺(20mL)中依次加入对甲苯磺酸一水合物(1.16g，6.08mmol)、对甲氧基苯甲醛(2.07g，15.20mmol)和2,2-二甲氧基丙烷(1.58g，15.20mmol)，加毕，升至室温，搅拌2小时。加入A2-0(1.00g，3.04mmol)，继续搅拌4小时。将反应液加入到水中，用乙酸乙酯萃取，分出有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥，蒸干。用乙酸乙酯和甲基叔丁基醚的混合溶液打浆，得化合物A38，为一对非对映异构体(6:4)，白色固体1.08g，收率80％。其中主要异构体的 1H NMR数据如下： 1H NMR(600MHz,DMSO-d 6)δ10.07(s,1H),9.73(d,J＝2.2Hz,1H),7.47–7.43(m,2H),6.99–6.96(m,2H),6.95(d,J＝8.1Hz,1H),5.93(s,1H),5.82(d,J＝2.3Hz,1H),5.58(dd,J＝8.2,1.9Hz,1H),5.08(dd,J＝6.8,2.4Hz,1H),4.85(dd,J＝6.9,3.8Hz,1H),4.33–4.29(m,1H),4.26(dd,J＝11.5,4.7Hz,1H),4.20(dd,J＝11.5,6.5Hz,1H),3.78(s,3H),2.60–2.52(m,1H),1.10–1.07(m,6H)。
无水碳酸钾(62mg，0.46mmol)和A38(335mg，0.75mmol)加入到甲醇(8mL)中， 35℃下搅拌3h。用2M的稀盐酸调节PH至中性。蒸干反应液，加入饱和食盐水和乙酸乙酯，分出有机相，有机相用无水硫酸钠干燥后，浓缩。硅胶柱层析分离(二氯甲烷：甲醇＝20：1)，得化合物A34，白色固体143mg，收率50.6％。
制备实施例7：化合物A39的合成
Figure PCTCN2022086215-appb-000030
将胞苷A39-0(1.2g，4.94mmol)加入到无水吡啶中，冰浴下依次加入咪唑(1.34g，19.69mmol)和叔丁基二甲基氯硅烷(1.12g，7.41mmol)，冰浴下搅拌。2小时后，向反应液中加入甲醇(5mL)，蒸干反应液，硅胶柱层析分离(二氯甲烷：甲醇＝25：1)，得化合物A39-1，油状物1.62g，收率92％。
将化合物A39-1(2.72g，7.61mmol)加入到水中，室温下加入硫酸羟胺(1.51g，9.14mmol)，70℃下搅拌过夜。过夜后，向反应液中加入乙酸乙酯，分出有机相，依次用饱和碳酸氢钠和饱和氯化钠水溶液洗涤，无水硫酸钠干燥，蒸干后，得粗品A39-2，泡沫状固体1.32g，收率47％。
将化合物A39-2(54.6mg，0.147mmol)加入到二氯甲烷中，冰浴下依次加入三乙胺(30mg，0.294mmol)和异丁酸酐(24mg，0.147mmol)，冰浴下搅拌。4小时后，向反应液中加入甲醇(1mL)，浓缩反应液，加入水，乙酸乙酯萃取，分出有机相，饱和氯化钠洗涤，无水硫酸钠干燥，硅胶柱层析分离(二氯甲烷：甲醇＝75：1)，得到化合物A39-3，白色固体40mg，收率62％。
将化合物A39-3(125mg，0.282mmol)加入到二氯甲烷中，缓慢加入羰基二咪唑(46mg，0.282mmol)，室温下搅拌。15分钟后，蒸干反应液，加入水，乙酸乙酯萃取，分出有机相，饱和氯化钠洗涤，无水硫酸钠干燥，硅胶柱层析分离(乙酸乙酯：石油醚＝2：1)，得到化合物A39-4，白色泡沫状固体127mg，收率97％。
将化合物A39-4(71mg，0.152mmol)加入到四氢呋喃中，依次加入醋酸(4.6mg，0.076mmol)和四丁基氟化铵(0.15mL，0.152mmol)，室温下搅拌。2小时后，向反应液中加入水和乙酸乙酯，分出有机相，依次用饱和碳酸氢钠和饱和氯化钠洗涤，无水硫酸钠干燥，硅胶柱层析分离(乙酸乙酯：石油醚：甲醇＝10：10：1)，得到化合物A39，白色固体45mg，收率83％。 1H NMR显示A39在氘代甲醇中存在互变异构体，二者比例约为6:1， 1H NMR(500MHz,CD 3OD)δ7.36–7.26(m,1H),5.85(d,J＝2.2Hz,1H),5.74(d,J＝8.1Hz,1H),5.57(dd,J＝7.7,2.2Hz,1H),5.33(dd,J＝7.6,3.9Hz,1H),4.33(q,J＝4.8Hz,1H),3.85–3.79(m,2H),2.91–2.71(m,1H),1.24(d,J＝6.9Hz,6H)。
制备实施例8：化合物A41的合成
Figure PCTCN2022086215-appb-000031
将化合物A39-2(208mg，0.557mmol)加入到二氯甲烷中，冰浴下依次加入三乙胺(113mg，1.114mmol)和氯甲酸异丙酯(76mg，0.613mmol)，冰浴下搅拌。4小时后，向反应液中加入甲醇(1mL)，浓缩反应液，加入水，乙酸乙酯萃取，分出有机相，饱和氯化钠洗涤，无水硫酸钠干燥，硅胶柱层析分离(二氯甲烷：甲醇＝75：1)，得到化合物A41-1，白色泡沫状固体148mg，收率58％。
将化合物A41-1(275mg，0.599mmol)加入到二氯甲烷中，缓慢加入羰基二咪唑(146mg，0.899mmol)，室温下搅拌。15分钟后，蒸干反应液，加入水，乙酸乙酯萃取，分出有机相，饱和氯化钠洗涤，无水硫酸钠干燥，硅胶柱层析分离(乙酸乙酯：石油醚＝2：1)得到化合物A41-2，白色粉末状固体233mg，收率80％。
将化合物A41-2(233mg，0.481mmol)加入到四氢呋喃中，依次加入醋酸(15mg，0.241mmol)和四丁基氟化铵(0.48mL，0.152mmol)，室温下搅拌。2小时后，向反应液中加入水和乙酸乙酯，分出有机相，依次用饱和碳酸氢钠和饱和氯化钠洗涤，无水硫酸钠干燥，硅胶柱层析分离(乙酸乙酯：石油醚：甲醇＝10：10：1)，得到化合物A41，白色固体112mg，收率63％。 1H NMR显示A41在氘代甲醇中存在互变异构体，二者比例约为7:1， 1H NMR(500MHz,CD 3OD)δ7.34–7.24(m,1H),5.83(d,J＝2.1Hz,1H),5.72(d,J＝8.1Hz,1H),5.56(dd,J＝7.6,2.2Hz,1H),5.32(dd,J＝7.6,3.9Hz,1H),5.02–4.94(m,1H),4.32(q,J＝4.9Hz,1H),3.84–3.78(m,2H),1.36(d,J＝6.2Hz,6H)。
制备实施例9：化合物A52的合成
Figure PCTCN2022086215-appb-000032
将化合物A39-2(373mg，1.0mmol)加入到吡啶(10mL)中，冰浴下入二甲氨基甲酰氯(113mg，1.114mmol)，室温下反应过夜。将反应液蒸干，加入水，乙酸乙酯萃取，分出有机相，饱和氯化钠洗涤，无水硫酸钠干燥，硅胶柱层析分离(二氯甲烷：甲醇＝60：1)，得到化合物A52-1，白色泡沫状固体186mg，收率42％。
参考实施例8中的第二步和第三步反应条件，以A52-1(186mg，0.42mmol)为原料，制得化合物A52，泡沫状固体60mg，收率40％。
制备实施例10：化合物B1的合成
Figure PCTCN2022086215-appb-000033
三苯基膦(11.79g，45mmol)加入到吡啶(50mL)中，冰浴下，加入碘(11.42g，45mmol)，搅拌10分钟后，升至室温。加入尿苷B1-0(7.32g，20mmol)，25℃下搅拌过夜。依次加入饱和硫代硫酸钠和饱和碳酸氢钠，旋干反应液，浓缩物中加入四氢呋喃和饱和食盐水，分离有机相和水相。水相用四氢呋喃再萃取两次，合并有机相，无水硫酸钠干燥，浓缩，硅胶柱层析分离(二氯甲烷：甲醇＝15：1)，得化合物B1-1，黄色固体5.30g，收率75％。
冰浴下，钠(1.04g，45mmol)加入到甲醇(40mL)中制备甲醇钠的甲醇溶液。B1-1(5.30g，15mmol)加入到甲醇(50mL)中，再加入上述配制的甲醇钠甲醇溶液，67℃下回流搅拌。2h后，加入稀盐酸调节PH至8-9，旋干反应液，硅胶柱层析分离(二氯甲烷：甲醇＝15:1)，得化合物B1-2，白色固体2.1g，收率62％。
B1-2(2.10g，9.3mmol)和三乙胺三氢氟酸盐(1.80g，11.2mmol)加入到乙腈(30mL)中，冰浴下，分批加入N-碘代丁二酰亚胺(2.51g，11.2mmol)，搅拌30分钟，自然沉降1h，过滤，二氯甲烷冲洗，得化合物B1-3，1.5g，收率43％。
B1-3(950mg，2.55mmol)加入到无水四氢呋喃(5mL)中，再加入羰基二咪唑(616mg,3.8mmol),室温下搅拌30min，蒸干反应液，硅胶柱层析分离(石油醚：乙酸乙酯＝1：1～1：2)，得化合物B1-4，白色泡沫状固体520mg，收率51％。
向四丁基氢氧化铵(1.45g，5.5mmol)的水溶液中加入三氟乙酸，调节pH至4左右，上述溶液加入到B1-4(440mg，1.1mmol)的二氯甲烷溶液(5mL)中，再加入间氯过氧苯甲酸(952mg，5.5mmol),室温下搅拌。7h后，加入饱和硫代硫酸钠溶液，再加入饱和食盐水和乙酸乙酯，分出乙酸乙酯层和水层。水层再用四氢呋喃萃取，分出四氢呋喃层，合并有机相，有机相用无水硫酸钠干燥，浓缩，硅胶柱层析色分离(石油醚：乙酸乙酯＝1:3)，乙酸乙酯打浆，得化合物B1，白色固体220mg，收率69％。 1H NMR(500MHz,DMSO-d 6)δ11.62(s,1H),7.80(d,J＝8.1Hz,1H),6.29(d,J＝1.3Hz,1H),5.75(dd,J＝7.3,1.3Hz,1H),5.71(d,J＝8.1Hz,1H),5.61(t,J＝6.6Hz,1H),5.55(dd,J＝12.4,7.3Hz,1H),3.78–3.69(m,1H),3.67–3.58(m,1H)。
制备实施例11：化合物B2的合成
Figure PCTCN2022086215-appb-000034
化合物B1(57mg，0.2mmol)，三乙胺(81mg，0.8mmol)和4-二甲氨基吡啶(12mg，0.1mmol)依次加入到二氯甲烷(3mL)中，再加入异丁酰氯(32mg，0.3mmol)，室温下搅拌。2小时后，加入二氯甲烷和饱和食盐水，分出有机相，无水硫酸钠干燥，浓缩，硅胶柱层析(二氯甲烷：甲醇＝30：1)，得化合物B2，白色固体54mg，收率75％。 1H NMR(400MHz,DMSO-d 6)δ11.63(s,1H),7.79(d,J＝8.0Hz,1H),6.35(s,1H),5.77(d,J＝7.3Hz,1H),5.71(d,J＝8.0Hz,1H),5.62(dd,J＝11.7,7.3Hz,1H),4.47–4.35(m,2H),2.66–2.57(m,1H),1.11(d,J＝7.0Hz,6H)。
制备实施例12：化合物C1的合成
Figure PCTCN2022086215-appb-000035
化合物GS-441524(85mg，0.292mmol)加入到N,N-二甲基甲酰胺中，加入羰基二咪唑(48mg，0.292mmol)，室温下搅拌。15分钟后，向反应液中加入水和乙酸乙酯，分出有机相，饱和食盐水洗涤，无水硫酸钠干燥，硅胶柱层析分离(二氯甲烷：甲醇＝20：1)，得化合物C1，白色固体19mg，收率21％。 1H NMR(500MHz,DMSO-d 6)δ8.16(s,1H),8.02(s,1H),8.00(s,1H),7.02–6.98(m,2H),5.96(d,J＝7.9Hz,1H),5.40(dd,J＝7.8,4.0Hz,1H),5.28(t,J＝5.7Hz,1H),4.50(q,J＝4.7Hz,1H),3.72–3.65(m,1H),3.64–3.58(m,1H)。
制备实施例13：化合物C22的合成
Figure PCTCN2022086215-appb-000036
C22-0(48.7mg，0.17mmol)加入到N,N-二甲基甲酰胺(1mL)中，再加入羰基二咪唑(28mg，0.17mmol)，室温搅拌。5分钟后，加入水和乙酸乙酯，分离水层和乙酸乙酯层，水层用乙酸乙酯再萃取三次，合并有机相，无水硫酸钠干燥，浓缩，硅胶柱层析(二氯甲烷：甲醇＝20：1)纯化，得化合物C22，白色固体18mg。 1H NMR(500MHz,DMSO-d 6)δ8.12(s,1H),8.02(s,1H),8.00(s,1H),6.99(s,1H),5.95(d,J＝7.8Hz,1H),5.39(dd,J＝7.8,4.0Hz,1H),5.25(t,J＝5.7Hz,1H),4.52–4.48(m,1H),3.71–3.66(m,1H),3.64–3.58(m,1H)。
制备实施例14：化合物C38的合成
Figure PCTCN2022086215-appb-000037
丙醛(290mg,5.0mmol)和C22-0(292mg,1.0mmol)加入到二氯甲烷(10mL)中，冰浴下，加入对甲苯磺酸一水合物(380mg,2.0mmol)，搅拌10分钟，然后升至室温，继续搅拌2小时。将反应液倒入饱和碳酸氢钠溶液中，二氯甲烷萃取。向有机层中加氨乙醇溶液，浓缩，得油状物。向浓缩物中加入乙酸乙酯和饱和食盐水，分出有机相，无水硫酸钠干燥，硅胶柱层析(二氯甲烷：甲醇＝50：1～15：1)分离，得化合物C38，白色固体96mg,收率30％。 1H NMR(500MHz,DMSO-d 6)δ8.05–7.88(m,3H),6.91(s,1H),5.35(d,J＝6.7Hz,1H),5.17(t,J＝5.0Hz,1H),5.03(t,J＝5.6Hz,1H),4.80(dd,J＝6.7,2.9Hz,1H),4.38–4.35(m,1H),3.59–3.48(m,2H),1.90–1.83(m,2H),0.99(t,J＝7.5Hz,3H)。
制备实施例15：化合物A54的合成
Figure PCTCN2022086215-appb-000038
化合物NHC(15.0g，61.67mmol)，咪唑(12.6g，185.29mmol)加入到N,N-二甲基甲酰胺(50mL)中，冰浴下，滴加叔丁基二苯基氯硅烷(25.4g，92.51mmol)，加完后升至室温搅拌。4小时后，向反应液中滴加蒸馏水(100mL)，析出固体，过滤，滤饼50℃鼓风干燥得化合物A54-1，白色固体25g，收率84％。
化合物A54-1(25.0g，51.90mmol)，硫酸羟胺(25.0g，152.44mmol)加入到乙腈/水(120mL/120mL)中，加完后升至60℃搅拌过夜。反应完全后，将反应液冷却至室温，分离有机层，水层用乙酸乙酯萃取，合并有机层，依次用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，得到化合物A54-2，白色固体，直接投下一步反应。
将上步得到的产物，4-甲氧基三苯基氯甲烷(19.2g，62.30mmol)，三乙胺(10.5g，103.80mmol)加入到二氯甲烷(200mL)中，室温下搅拌。2-3小时后，向反应液中加入甲醇(1mL)，浓缩，得到化合物A54-3，黄色泡沫状固体，直接投下一步反应。
将上步得到的产物加入到二氯甲烷(200mL)中，冰浴下，加入羰基二咪唑(10.1g，62.28mmol)，加完后升至室温搅拌。2小时后，将反应液倒入水中，用二氯甲烷萃取，合并有机 层，无水硫酸钠干燥，浓缩，硅胶柱层析分离(二氯甲烷：甲醇＝30：1)，得到化合物A54-4，类白色固体31.5g，三步收率76％。
化合物A54-4(31.5g，39.57mmol)，醋酸(1.2g，19.79mmol)加入到四氢呋喃(200mL)中，室温下，加入1M四丁基氟化铵(43.5mL，43.5mmol)的四氢呋喃溶液，室温下搅拌。2小时后，将反应液浓缩，再加入水和乙酸乙酯，分出有机相，依次用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱层析分离(二氯甲烷：甲醇＝30：1)，得到化合物A54-5，类白色固体15g，收率68％。
化合物A54-5(800mg，1.43mmol)，三乙胺(289mg，2.86mmol)，4-二甲氨基吡啶(35mg，0.29mmol)，醋酸酐(220mg，2.15mmol)依次加入到二氯甲烷(10mL)中，室温下搅拌。2小时后，向反应液中加入二氯甲烷和水，分出有机相，依次用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，得到化合物A54-6，直接用于下一步反应。
将上步得到的产物加入到甲醇(5mL)中，随后加入三氟乙酸(326mg，2.86mmol)，室温下搅拌。1小时后，将反应液浓缩，硅胶柱层析分离(二氯甲烷：甲醇＝30：1)，得到化合物A54，白色固体40mg，收率9％。 1H NMR(500MHz,DMSO-d 6)δ10.10(s,1H),9.88(s,1H),6.95(d,J＝8.1Hz,1H),5.86(d,J＝2.1Hz,1H),5.59(d,J＝8.1Hz,1H),5.56(dd,J＝7.7,2.2Hz,1H),5.27(dd,J＝7.7,4.2Hz,1H),4.43–4.37(m,1H),4.31(dd,J＝11.6,4.7Hz,1H),4.18(dd,J＝11.6,7.0Hz,1H),2.04(s,3H)。MS m/z＝328.2[M+1] +。
制备实施例16：化合物A55的合成
Figure PCTCN2022086215-appb-000039
化合物A54-5(800mg，1.43mmol)，棕榈酸(554mg，2.16mmol)，1-羟基苯并三氮唑(350mg，2.59mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(663mg，3.46mmol)，4-二甲氨基吡啶(176mg，1.44mmol)加入到二氯甲烷(10mL)中，室温下搅拌。2小时后，向反应液中加入二氯甲烷和水，分出有机相，依次用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，得到化合物A55-0，直接用于下一步反应。
化合物A55-0，三氟乙酸(328mg，2.88mmol)加入到甲醇(5mL)中，室温下搅拌。1小时后，将反应液浓缩，硅胶柱层析分离(二氯甲烷：甲醇＝30：1)，得到化合物A55，白色固体70mg，收率9％。 1H NMR(500MHz,DMSO-d 6)δ10.11(s,1H),9.88(s,1H),6.95(d,J＝8.1Hz,1H),5.86(d,J＝2.2Hz,1H),5.58(d,J＝8.1Hz,1H),5.55(dd,J＝7.7,2.2Hz,1H),5.26(dd,J＝7.8,4.1Hz,1H),4.42–4.36(m,1H),4.31(dd,J＝11.5,4.9Hz,1H),4.19(dd,J＝11.6,7.0Hz,1H),2.31(t,J＝7.4Hz,2H),1.31–1.14(m,27H),0.85(t,J＝6.8Hz,3H)。MS m/z＝524.5[M+1] +。
制备实施例17：化合物A56的合成
Figure PCTCN2022086215-appb-000040
化合物A54-5(600mg，1.08mmol)，三乙胺(216mg，2.16mmol)，4-二甲氨基吡啶(27mg，0.22mmol)，特戊酰氯(195mg，1.62mmol)加入到二氯甲烷(10mL)中，室温下搅拌。2小时后，加入水和二氯甲烷，分出有机相，依次用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，得到化合物A56-0，直接用于下一步反应。
化合物A56-0，三氟乙酸(246mg，2.16mmol)加入到甲醇(5mL)中，室温下搅拌。1小时后，将反应液浓缩，硅胶柱层析分离(二氯甲烷：甲醇＝30：1)，得到化合物A56，白色固体140mg，收率35％。 1H NMR(500MHz,DMSO-d 6)δ10.10(s,1H),9.88(d,J＝2.0Hz,1H),6.94(d,J＝8.1Hz,1H),5.86(d,J＝2.0Hz,1H),5.61–5.54(m,2H),5.27(dd,J＝7.7,4.2Hz,1H),4.40(q,J＝5.6Hz,1H),4.31–4.18(m,2H),1.15(s,9H)。MS m/z＝370.0[M+1] +。
制备实施例18：化合物A4的合成
Figure PCTCN2022086215-appb-000041
化合物A54-5(700mg，1.26mmol)，三乙胺(255mg，2.52mmol)，4-二甲氨基吡啶(31mg，0.25mmol)，环丙基甲酰氯(198mg，1.89mmol)加入到二氯甲烷(10mL)中，室温下搅拌。2小时后，加入水和二氯甲烷，分出有机相，依次用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，得到化合物A4-0，直接用于下一步反应。
化合物A4-0，三氟乙酸(287mg，2.52mmol)加入到甲醇(5mL)中，室温下搅拌。1小时后，将反应液浓缩，硅胶柱层析分离(二氯甲烷：甲醇＝30：1)，得到化合物A4，白色固体150mg，收率34％。 1H NMR(500MHz,DMSO-d 6)δ10.10(s,1H),9.87(d,J＝2.1Hz,1H),6.95(d,J＝8.1Hz,1H),5.87(d,J＝2.1Hz,1H),5.59(dd,J＝8.1,2.0Hz,1H),5.56(dd,J＝7.7,2.2Hz,1H),5.27(dd,J＝7.7,4.2Hz,1H),4.44–4.38(m,1H),4.32(dd,J＝11.6,4.9Hz,1H),4.20(dd,J＝11.6,7.0Hz,1H),1.69–1.61(m,1H),0.93–0.88(m,2H),0.87–0.82(m,2H)。MS m/z＝354.2[M+1] +。
制备实施例19：化合物A6的合成
Figure PCTCN2022086215-appb-000042
化合物A54-5(15.27g，27.39mmol)加入到二氯甲烷(200mL)中，冰浴下，依次加入三乙胺(11.09g，109.56mmol)，Boc-L-缬氨酸(8.34g，38.35mmol)，1-羟基苯并三氮唑(5.56g，41.09mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(11.56g，60.26mmol)， 4-二甲氨基吡啶(3.35g，27.39mmol)，加完后升至室温搅拌。3小时后，将反应液浓缩，再加入水和乙酸乙酯，分出有机相，依次用饱和碳酸氢钠、饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到化合物A6-0。
化合物A6-0(20.73g，27.39mmol)加入到二氯甲烷/甲醇(10:1)中，再加入三氟乙酸(6.37g，55.82mmol)，室温下搅拌4小时，将反应液浓缩，硅胶柱层析分离(二氯甲烷：甲醇＝40：1)，得到化合物A6-1。
化合物A6-1(5.81g，12.00mmol)加入到四氢呋喃(50mL)中，再加入浓盐酸(12mL，144.00mmol)，室温下搅拌过夜，将反应液浓缩，异丙醇打浆，过滤，得到化合物A6盐酸盐，白色固体3.4g，三步总收率29％。 1H NMR(500MHz,CD 3OD)δ7.87(d,J＝7.9Hz,1H),6.08(d,J＝7.9Hz,1H),5.96(d,J＝1.2Hz,1H),5.81(dd,J＝7.4,1.3Hz,1H),5.49(dd,J＝7.5,3.8Hz,1H),4.75(dd,J＝11.5,7.6Hz,1H),4.64(dt,J＝7.8,4.2Hz,1H),4.54(dd,J＝11.6,4.5Hz,1H),4.04(d,J＝4.4Hz,1H),2.41–2.26(m,1H),1.10(dd,J＝6.9,4.5Hz,6H)。
制备实施例20：化合物B4的合成
Figure PCTCN2022086215-appb-000043
化合物B1(100.0mg，0.35mmol)加入到二氯甲烷(6mL)中，冰浴下，依次加入环丙甲酸(42.0mg，0.49mmol)，1-羟基苯并三氮唑(112.4mg，0.53mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(147.8mg，0.77mmol)，4-二甲氨基吡啶(170.8mg，1.40mmol)，加完后升至室温搅拌。3小时后，将反应液浓缩，再加入水和乙酸乙酯，分出有机相，依次用稀盐酸、饱和碳酸氢钠、饱和食盐水洗涤，无水硫酸钠干燥，硅胶柱层析分离(石油醚：丙酮＝1：1)，得到化合物B4，白色固体95mg，收率80％。 1H NMR(500MHz,DMSO-d 6)δ11.64(s,1H),7.79(d,J＝8.0Hz,1H),6.35(d,J＝1.2Hz,1H),5.78(dd,J＝7.2,1.2Hz,1H),5.72(dd,J＝8.0,2.2Hz,1H),5.64(dd,J＝11.7,7.3Hz,1H),4.47–4.35(m,2H),1.73–1.67(m,1H),0.99–0.88(m,4H)。
制备实施例21：化合物B41的合成
Figure PCTCN2022086215-appb-000044
化合物B1(60.0mg，0.21mmol)加入到二氯甲烷(4mL)中，冰浴下，依次加入棕榈酸(74.5mg，0.29mmol)，1-羟基苯并三氮唑(67.8mg，0.32mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(88.3mg，0.46mmol)，4-二甲氨基吡啶(102.5mg，0.84mmol)，加完后升至室温搅拌。3小时后，将反应液浓缩，再加入水和乙酸乙酯，分出有机相，依次用稀盐酸、饱和碳酸氢钠、饱和食盐水洗涤，无水硫酸钠干燥，硅胶柱层析分离(二氯甲烷： 甲醇＝30：1)，得到化合物B41，白色固体90mg，收率82％。 1H NMR(400MHz,DMSO-d 6)δ11.63(s,1H),7.78(d,J＝8.1Hz,1H),6.34(s,1H),5.77(d,J＝7.5Hz,1H),5.70(d,J＝7.9Hz,1H),5.62(t,J＝9.7Hz,1H),4.48–4.31(m,2H),2.38–2.32(m,2H),1.56–1.48(m,2H),1.31–1.21(m,24H),0.85(t,J＝6.6Hz,3H)。
制备实施例22：化合物B6的合成
Figure PCTCN2022086215-appb-000045
化合物B1(200.0mg，0.695mmol)加入到二氯甲烷(10mL)中，冰浴下，依次加入Boc-L-缬氨酸(211.0mg，0.973mmol)，1-羟基苯并三氮唑(221.1mg，1.043mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(293.6mg，1.529mmol)，4-二甲氨基吡啶(339.2mg，2.780mmol)，加完后升至室温搅拌。3小时后，将反应液浓缩，再加入水和乙酸乙酯，分出有机相，依次用稀盐酸、饱和碳酸氢钠、饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到化合物B1-1。
化合物B1-1加入到二氯甲烷(2mL)中，再加入三氟乙酸(1mL)，室温下搅拌30分钟，将反应液浓缩，硅胶柱层析分离(二氯甲烷：甲醇＝20：1)，得到化合物B6，淡黄色固体245mg，收率90％。 1H NMR(500MHz,DMSO-d 6)δ11.66(s,1H),8.44(s,2H),7.80(d,J＝8.0Hz,1H),6.38(s,1H),5.81(d,J＝7.2Hz,1H),5.74–5.66(m,2H),4.72(dd,J＝15.7,12.3Hz,1H),4.48(dd,J＝16.2,12.4Hz,1H),4.02(d,J＝4.4Hz,1H),2.22–2.15(m,1H),0.98(d,J＝6.9Hz,3H),0.94(d,J＝6.9Hz,3H)。
制备实施例23：化合物B13的合成
Figure PCTCN2022086215-appb-000046
化合物B1(50.0mg，0.17mmol)，N-[(S)-(2,3,4,5,6-五氟苯氧基)苯氧基磷酰基]-L-丙氨酸异丙酯(86.7mg，0.19mmol)，无水氯化镁(24.8mg，0.26mmol)加入到无水四氢呋喃(4mL)中，冰浴下，加入N,N-二异丙基乙胺(44.9mg，0.35mmol)，搅拌10分钟后升至室温。4小时后，将反应液浓缩，再加入水和乙酸乙酯，分出有机相，依次用稀盐酸、饱和碳酸氢钠、饱和食盐水洗涤，无水硫酸钠干燥，硅胶柱层析分离(二氯甲烷：甲醇＝30：1)，得到化合物B13，白色固体56mg，收率58％。 1H NMR(500MHz,CD 3OD)δ7.67(d,J＝8.0Hz,1H),7.37(t,J＝7.8Hz,2H),7.26(d,J＝8.1Hz,2H),7.20(t,J＝7.5Hz,1H),6.15(s,1H),5.70(d,J＝8.0Hz,1H),5.68–5.64(m,2H),5.02–4.94(m,1H),4.43–4.36(m,1H),4.35–4.27(m,1H),3.96–3.89(m,1H),1.36(d,J＝7.1Hz,3H),1.25–1.21(m,6H)。
制备实施例24：化合物B14的合成
Figure PCTCN2022086215-appb-000047
化合物B1(50.0mg，0.17mmol)，N-[(S)-(2,3,4,5,6-五氟苯氧基)苯氧基磷酰基]-L-丙氨酸乙基正丁基酯(95.1mg，0.19mmol)，无水氯化镁(24.8mg，0.26mmol)加入到无水四氢呋喃(3mL)中，冰浴下，加入N,N-二异丙基乙胺(44.9mg，0.35mmol)，搅拌10分钟后升至室温。12小时后，将反应液浓缩，再加入水和乙酸乙酯，分出有机相，依次用稀盐酸、饱和碳酸氢钠、饱和食盐水洗涤，无水硫酸钠干燥，硅胶柱层析分离(二氯甲烷：甲醇＝30：1)，得到化合物B14，白色固体51mg，收率50％。 1H NMR(500MHz,CD 3OD)δ7.67(d,J＝7.9Hz,1H),7.37(t,J＝7.8Hz,2H),7.26(d,J＝8.1Hz,2H),7.20(t,J＝7.5Hz,1H),6.15(s,1H),5.70(d,J＝8.0Hz,1H),5.68–5.63(m,2H),4.42–4.27(m,2H),4.10–4.02(m,2H),4.01–3.95(m,1H),1.55–1.49(m,1H),1.40–1.34(m,4H),1.22(d,J＝6.2Hz,3H),0.90(t,J＝7.4Hz,6H)。
制备实施例25：化合物B44的合成
Figure PCTCN2022086215-appb-000048
化合物B1(30.0mg，0.10mmol)，4-二甲氨基吡啶(15.3mg，0.125mmol)，吡啶(0.1mL)加入到二氯甲烷(2mL)中，冰浴下，加入氯甲酸乙酯(13.6mg，0.125mmol)，加完后升至室温搅拌。4小时后，将反应液浓缩，再加入水和乙酸乙酯，分出有机相，依次用稀盐酸、饱和碳酸氢钠、饱和食盐水洗涤，无水硫酸钠干燥，硅胶柱层析分离(二氯甲烷：甲醇＝20：1)，得到化合物B44，白色固体32mg，收率89％。 1H NMR(500MHz,DMSO-d 6)δ11.64(s,1H),7.79(d,J＝8.0Hz,1H),6.35(s,1H),5.78(d,J＝8.0Hz,1H),5.71(dd,J＝8.0,2.2Hz,1H),5.67(dd,J＝11.4,7.3Hz,1H),4.49–4.39(m,2H),4.16(q,J＝7.1Hz,2H),1.23(t,J＝7.1Hz,3H)。
制备实施例26：化合物B38的合成
Figure PCTCN2022086215-appb-000049
化合物B1(73.0mg，0.25mmol)加入到二氯甲烷(3mL)中，冰浴下，依次加入三乙胺(38.4mg，0.38mmol)，4-二甲氨基吡啶(6.1mg，0.05mmol)，乙酸酐(31.0mg，0.30mmol)，加完后升至室温搅拌。1小时后，向反应液中加入二氯甲烷(20mL)，依次用1M 盐酸水溶液，饱和碳酸氢钠溶液，饱和食盐水洗涤，分出有机相，无水硫酸钠干燥，浓缩，硅胶柱层析分离(石油醚：乙酸乙酯＝1：1)，得到化合物B38，白色固体63mg，收率76％。 1H NMR(500MHz,DMSO-d 6)δ11.63(s,1H),7.79(d,J＝8.0Hz,1H),6.34(s,1H),5.77(d,J＝7.3Hz,1H),5.71(d,J＝8.0Hz,1H),5.64(dd,J＝11.7,7.3Hz,1H),4.46–4.31(m,2H),2.08(s,3H)。
制备实施例27：化合物C2的合成
Figure PCTCN2022086215-appb-000050
参考制备实施例11的反应条件，C1(95mg，0.3mmol)与异丁酰氯(38mg，0.36mmol)反应，制得化合物C2，白色固体27mg，收率23％。 1H NMR(400MHz,DMSO-d 6)δ8.10(s,1H),8.02(s,1H),7.99(s,1H),6.96(d,J＝4.6Hz,1H),6.91(d,J＝4.6Hz,1H),6.00(d,J＝7.7Hz,1H),5.50(dd,J＝7.7,3.7Hz,1H),4.86–4.79(m,1H),4.34(dd,J＝12.3,4.0Hz,1H),4.24(dd,J＝12.2,5.2Hz,1H),2.49–2.39(m,1H),1.03(d,J＝7.0Hz,3H),0.99(d,J＝7.0Hz,3H)。
制备实施例28：化合物C23的合成
Figure PCTCN2022086215-appb-000051
参考制备实施例11的反应条件，C22(477mg，1.5mmol)与异丁酰氯(192mg，0.18mmol)反应，制得化合物C23，白色固体105mg，收率18％。 1H NMR(500MHz,DMSO-d 6)δ8.11(s,1H),8.03(s,1H),7.98(s,1H),6.90(s,1H),5.99(d,J＝7.7Hz,1H),5.49(dd,J＝7.6,3.7Hz,1H),4.82(dt,J＝5.2,3.8Hz,1H),4.33(dd,J＝12.3,3.9Hz,1H),4.22(dd,J＝12.3,5.2Hz,1H),2.47–2.39(m,1H),1.01(d,J＝7.0Hz,3H),0.98(d,J＝7.0Hz,3H). 13C NMR(126MHz,DMSO-d 6)δ175.5,155.5,152.9,148.5,120.0,117.1,114.1,110.5,82.7,81.5,80.1,79.5,62.1,33.0,18.6,18.5.
制备实施例29：化合物C54的合成
Figure PCTCN2022086215-appb-000052
化合物GS-441524(611mg，2.1mmol)加入到吡啶(5mL)中，加入N,N-二甲基甲酰胺二甲基缩醛(1g，8.4mmol)，室温下搅拌过夜。将反应液浓缩干，得C54-1粗品，直接投入下一步。
C54-1加入到二氯甲烷(5mL)中，冰浴下依次加入三乙胺(142mg，1.4mmol)、环丁基甲酰氯(125mg，1.05mmol)和4-二甲氨基吡啶(86mg，0.7mmol)，室温下搅拌。1小时后，向反应液中加入甲醇，随后浓缩反应液，加入乙酸乙酯和水，搅拌后分层，分出有机相，有机相分别用稀盐酸水溶液、饱和碳酸氢钠和饱和氯化钠水溶液洗涤，无水硫酸钠干燥后，蒸干，得到化合物C54-2。
化合物C54-2(0.35mmol)加入到乙醇(3mL)中，加入乙酸(0.6mL，10.5mmol)，50℃加热搅拌过夜。浓缩反应液，向反应液中加入饱和食盐水中，乙酸乙酯萃取，分出有机相，有机相分别用饱和碳酸氢钠和饱和食盐水洗涤，无水硫酸钠干燥后，浓缩反应液，用醋酸异丙酯打浆，得到化合物C54-3，白色粉末状固体93mg，三步总收率66.0％。 1H NMR(500MHz,DMSO-d 6)δ8.06–7.79(m,3H),6.93(d,J＝4.5Hz,1H),6.82(d,J＝4.5Hz,1H),6.34(d,J＝6.0Hz,1H),5.38(d,J＝5.9Hz,1H),4.74–4.68(m,1H),4.31(dd,J＝12.2,2.9Hz,1H),4.26–4.21(m,1H),4.15(dd,J＝12.2,5.0Hz,1H),4.00–3.94(m,1H),2.30–2.22(m,1H),1.81–1.54(m,5H),1.34–1.11(m,5H)。
冰浴下，将C54-3(100mg，0.25mmol，1eq)加到四氢呋喃(4mL)中，加入羰基二咪唑(83mg，0.51mmol，2eq)，撤去冰浴，室温下搅拌3h后，加入甲醇，加入1N稀盐酸溶液，乙酸乙酯萃取，有机相用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，蒸干，柱层析分离，得化合物C54，白色固体72mg，收率67％。 1H NMR(500MHz,DMSO-d 6)δ8.10(s,1H),8.02(s,1H),7.98(s,1H),6.95(d,J＝4.6Hz,1H),6.89(d,J＝4.6Hz,1H),5.99(d,J＝7.5Hz,1H),5.49(dd,J＝7.5,3.4Hz,1H),4.85(q,J＝3.8Hz,1H),4.31(dd,J＝12.3,3.7Hz,1H),4.21(dd,J＝12.3,5.0Hz,1H),1.71–1.50(m,5H),1.28–1.02(m,5H).MS m/z 428.4(M+1)。
制备实施例30：化合物B50的合成
Figure PCTCN2022086215-appb-000053
B0参考文献方法合成(WO2014100505)。将B0(700.0mg,2.67mmol,1eq)加入到原甲酸三甲酯(7mL)中，随后加入对甲苯磺酸一水合物(507.4mg,2.67mmol,1eq)，室温下反应，反应液逐渐澄清。TLC显示反应完全后，用7N氨/甲醇溶液将反应液pH调至6-7。过滤，滤液浓缩，硅胶柱色谱分离(二氯甲烷：甲醇＝60:1～40:1)，得B50，白色泡沫状固体，收率84％。 1H NMR(500MHz,DMSO-d 6)δ11.52(d,J＝2.2Hz,1H),7.73(d,J＝8.1Hz,1H),6.09–6.05(m,2H),5.67(dd,J＝8.0,2.2Hz,1H),5.47(t,J＝6.4Hz,1H),5.29(dd,J＝14.3,6.4Hz,1H),5.11(dd,J＝6.4,1.3Hz,1H),3.65–3.53(m,2H),3.22(s,3H).
测试实施例1：大鼠体内的药代动力学评价
实验方法：
雄性SD大鼠，每个化合物6只，分2组(灌胃组和静脉注射组)，每组3只，实验前禁食12h(静脉实验组不禁食)，自由饮水，给药后4h统一进食。化合物A1、A2灌胃给药剂量为20mg/kg，静脉注射剂量为5mg/kg，给药溶媒为5％DMSO+5％solutol+90％saline。化合物C38灌胃给药剂量为10mg/kg，静脉注射剂量为2mg/kg，给药溶媒为DMSO/EtOH/PEG300/0.9％NaCl(5/5/40/50,v/v/v/v)。于给药后5min(仅静脉)、0.25，0.5，1.0，2.0，4.0，6.0，8.0和24h经颈静脉取血0.2mL，置EDTA-K2试管中，11000rpm离心5min，分离血浆，于–70℃冰箱中冷冻待测。冰水浴操作。采用LC-MS-MS法测定血浆中代谢所得核苷的浓度，计算药动学参数。
表1，化合物A1、A2、C38大鼠体内核苷代谢产物药动学参数
Figure PCTCN2022086215-appb-000054
mpk：mg/kg体重
大鼠PK试验显示，化合物A1、A2、C38口服，核苷代谢产物的暴露量较高，生物利用度分别可达122.3％、93％和87％。
测试实施例2：化合物对病毒复制的抑制作用
测定化合物对2019新型冠状病毒(SARS-CoV-2)复制的抑制活性：NHC和GS-441524的抗新冠病毒活性测试方法如文献报道。向感染新冠病毒的Vero细胞中，加入不同浓度的测试化合物，培养48小时后，通过定量实时RT-PCR(qRT-PCR)定量细胞上清液中的病毒拷贝数来评估化合物对病毒的抑制活性(Sci Transl Med,2020,12:eabb5883；Cell Rep,2020,32:107940；中国专利202010313870.X)。
细胞病变效应法(Cytopathogenic effect，CPE)测定化合物对呼吸道合胞病毒(RSV)，人冠状病毒OC43，A型流感病毒，寨卡病毒复制的抑制活性：将实验细胞以一定的细胞密度接种到96孔细胞培养板中，于5％CO 2、37℃培养箱中培养过夜。第二天加入化合物和病毒。依所测病毒不同而异，细胞在5％CO 2、33℃或37℃条件下于培养箱中培养3-7天，直至无化合物的病毒感染对照孔内细胞病变达80-95％。然后用CellTiter-Glo或CCK-8检测每孔细胞活力。如含化合物孔的细胞活力较病毒感染对照孔高，即CPE减弱，则表明化合物对所测病毒有抑制作用。细胞毒性实验方法与相应的抗病毒实验方法相同，但无病毒感染。
化合物的抗病毒活性和细胞毒性分别由化合物对病毒引起的细胞病毒效应的抑制率(％) 和细胞活率(％)表示。计算公式如下：
抑制率(％)＝(测试孔读值-病毒对照平均值)/(细胞对照平均值-病毒对照平均值)×100；
细胞活率(％)＝(测试孔读值-培养基对照平均值)/(细胞对照平均值-培养基对照平均值)×100；
EC 50和CC 50值通过Prism软件计算，抑制曲线拟合方法为“log(inhibitor)vs.response--Variable slope”。
空斑减少实验法测定化合物对登革热病毒的抑制活性：将Vero细胞以每孔600,000个细胞的密度接种到6孔细胞培养板中、于5％CO 2、37℃培养箱中培养过夜。第二天加入化合物和病毒(40-50PFU/孔)。细胞在5％CO 2、37℃条件下于培养箱中培养2个小时，随后吸去上清，加入含对应浓度化合物的低融点琼脂糖培养液。细胞在5％CO 2、33℃或37℃条件下于培养箱中培养6-7天，直至显微镜下无化合物的病毒感染对照孔内可观察到明显的病毒空斑。使用4％多聚甲醛固定细胞，使用结晶紫染色。计算每孔内空斑数量。细胞毒性实验与抗病毒实验平行进行。将Vero细胞以每孔20,000个细胞的密度接种到96孔细胞培养板中、于5％CO 2、37℃培养箱中培养过夜。第二天加入化合物(1-5个浓度点、单点)。细胞在5％CO 2、33℃或37℃条件下于培养箱中培养6-7天。然后用CCK-8检测每孔细胞活力。
荧光定量PCR测定化合物对猪流行性腹泻病毒(PEDV)复制的抑制活性：将Vero细胞进行消化传代，用细胞生长液调整细胞密度为1×10 5/mL，并接种于96孔板，100μL/孔，放置于37℃、5％CO 2培养箱培养24h；取出96孔板，弃去孔中培养基，用1×PBS清洗三次，甩干后每孔加入化合物(10个浓度点)和病毒(每孔0.01MOI)的混合液，每个浓度设置8个重复孔，于37℃、5％CO 2培养箱培养，同时设置病毒对照与细胞对照。36h后，收集细胞样品，荧光定量PCR测定不同处理组病毒含量变化，计算化合物的EC 50。
表2，对新冠病毒(SARS-CoV-2)、人冠状病毒OC43(HCoV OC43)的抑制活性
Figure PCTCN2022086215-appb-000055
表3，对呼吸道合胞病毒(RSV)、流感病毒抑制活性
Figure PCTCN2022086215-appb-000056
Figure PCTCN2022086215-appb-000057
表4，对猪流行性腹泻病毒(PEDV)、寨卡病毒(Zika)、登革热病毒(DENV)复制抑制活性
Figure PCTCN2022086215-appb-000058
Figure PCTCN2022086215-appb-000059
测试实施例3：大鼠体内的药代动力学评价
雄性SD大鼠共18只，分为静脉组(IV)和灌胃组(PO)，实验前禁食12h(静脉组不禁食)，自由饮水，给药后4h统一进食。化合物B1、B2和B6灌胃给药剂量为76μmol/kg(n＝3)，静脉注射剂量为38μmol/kg(n＝3)，给药溶媒为DMSO/EtOH/PEG400/0.9％NaCl(5/5/40/50,v/v/v/v)。于给药后5min(仅静脉)、0.25，0.5，1.0，2.0，4.0，6.0，8.0和24h经颈静脉取血0.2-0.3mL，置肝素钠抗凝管中，轻轻混匀，2000g离心10min，分离血浆，于–70℃冰箱中冷冻待测。采用LC-MS-MS法测定血浆中核苷代谢产物的浓度，计算药动学参数。
表5，化合物B1、B2和B6单次口服给药(76μmol/kg)和注射给药(38μmol/kg)，大鼠体内核苷代谢产物药动学参数
Figure PCTCN2022086215-appb-000060
测试实施例4：食蟹猴体内的药代动力学评价
食蟹猴共6只，化合物A1、A2和A6单次灌胃给药(0.35mmol/kg，n＝2)，每只猴采集给药后48h内10个血样，进行LC-MS/MS分析测试，检测核苷代谢产物NHC和A1的浓度，计算常规药代动力学参数，进行数据汇总。
表6，化合物Molnupiravir(对照化合物，NHC的5'-异丁酸酯前药)、A1、A2和A6单次灌胃给药(0.35mmol/kg)，猴子体内核苷代谢产物药动学参数
Figure PCTCN2022086215-appb-000061
Figure PCTCN2022086215-appb-000062
表7，A1、A2和A6单次灌胃给药(0.35mmol/kg)，猴子体内A1的药动学参数
Figure PCTCN2022086215-appb-000063
测试实施例5：大鼠体内的药代动力学评价
实验方法：
雄性SD大鼠，每个化合物6只，分2组(灌胃组和静脉注射组)，每组3只，实验前禁食12h(静脉实验组不禁食)，自由饮水，给药后4h统一进食。化合物C22、C23灌胃给药剂量分别为16mg/kg和20mg/kg，给药溶媒为5％DMSO+5％solutol+90％saline。静脉注射剂量分别为4mg/kg和5mg/kg，给药溶媒为DMSO/EtOH/PEG300/0.9％NaCl(5/5/40/50,v/v/v/v)。于给药后5min、0.25，0.5，1.0，2.0，4.0，6.0，8.0和24h经颈静脉取血0.2mL，置EDTA-K2试管中，11000rpm离心5min，分离血浆，于–70℃冰箱中冷冻待测。冰水浴操作。采用LC-MS-MS法测定血浆中代谢所得核苷的浓度，计算药动学参数。
表8，化合物A1、A2、C38大鼠体内核苷代谢产物药动学参数
Figure PCTCN2022086215-appb-000064
mpk：mg/kg体重
大鼠PK试验显示，化合物C22、C23口服，核苷代谢产物的暴露量较高，生物利用度分别可达75.3％和71.8％。
根据以上的测试实施例以及表1-表8的结果可以看出，本申请的部分化合物口服生物利用度高，并对多种病毒具有显著的抑制活性，具有良好的抗病毒应用前景。

Claims (10)

  1. 一种式(I)所示的化合物或其药学上可接受的盐：
    Figure PCTCN2022086215-appb-100001
    其中，
    B选自
    Figure PCTCN2022086215-appb-100002
    X选自氧、硫、CH 2、NH；
    R 1选自氢、氘、氰基；
    R 2选自氢、C 1-18烷基、C 3-8环烷基、C 6-20芳基、5-15元杂芳基，其中烷基和环烷基未经取代或被独立地选自卤素、羟基、羧基和C 1-4烷氧基的一到三个取代基取代，芳基和杂芳基未被取代或被一到五个独立地选自R 9的取代基取代；
    R 3选自氢、C 1-4烷氧基；
    或R 2、R 3与它们连接的碳一起形成
    Figure PCTCN2022086215-appb-100003
    R 4选自氢、氘、卤素、叠氮、氰基、C 1-6烷基、卤代C 1-6烷基、叠氮C 1-6烷基、氰基C 1-6烷基、羟基C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 1-6烷氧基C 1-6烷基；
    R 5选自氢、C 1-20烷酰基、C 3-20环烷酰基、氨基C 1-20烷酰基、C 1-20烷氨基C 1-6烷酰基、C 1-6环烷氨基C 1-6烷酰基、C 1-20双烷氨基C 1-6烷酰基、C 1-20烷氧基C 1-6烷酰基、以氨基酸上羧基的羰基与相连接的氧形成酯键的氨基酸基团、C 6-20芳基氨基C 1-6烷酰基、3-20元杂环烷基C 1-6烷酰基、
    Figure PCTCN2022086215-appb-100004
    Figure PCTCN2022086215-appb-100005
    其中C 1-20烷酰基和C 3-20环烷酰基未经取代或被一到三个卤素取代，所述3-20元杂环烷基未经取代或者被C 1-6烷基取代；
    R 6选自羟基、氨基、羟胺基(-NHOH)、-NHOR 13；
    R 7选自氢、氘、卤素；
    R 8选自氢、氘、卤素、氰基、氨甲酰基；
    R 9选自卤素、C 1-4烷基、C 1-4烷氧基、C 1-4烷硫基、氰基、硝基、氨基、苯基、羧基、三氟甲基、二氟甲氧基、三氟甲氧基、C 1-4烷胺基、二(C 1-4烷基)胺基、C 1-4烷基羰基、C 1-4烷基羰基氧基，C 1-4烷氧羰基；
    R 10选自C 1-6烷基、C 3-6环烷基、C 6-20芳基、5-15元杂芳基；
    R 11选自C 1-18烷基、亚甲基C 6-20芳基；
    R 12选自C 1-6烷基、C 3-6环烷基、C 6-20芳基、5-15元杂芳基；
    R 13选自C 1-20烷酰基、C 3-20环烷酰基、氨基C 1-20烷酰基、C 1-20烷氨基C 1-6烷酰基、C 1-6环烷氨基C 1-6烷酰基、C 1-20双烷氨基C 1-6烷酰基、C 1-20烷氧基C 1-6烷酰基、C 1-6烷氧羰基氧亚甲基。
  2. 如权利要求1所述化合物或其药学上可接受的盐，其中，所述化合物具有化学式I-I，
    Figure PCTCN2022086215-appb-100006
    其中，B、X、R 1、R 4、R 5的定义与权利要求1中相同。
  3. 如权利要求1所述化合物或其药学上可接受的盐，其中，所述化合物具有化学式I-II，
    Figure PCTCN2022086215-appb-100007
    优选地，式(I-II)选自结构式I-IIA和I-IIB，
    Figure PCTCN2022086215-appb-100008
    其中，B、X、R 1、R 2、R 4、R 5的定义与权利要求1中相同。
  4. 如权利要求1所述化合物或其药学上可接受的盐，其中，所述化合物选自下式，
    Figure PCTCN2022086215-appb-100009
    其中，
    R 1选自氢、氘；
    R 2、R 5、R 7、R 8、R 13的定义与权利要求1中相同；
    R 4选自氢、氘、卤素。
  5. 如权利要求1所述化合物或其药学上可接受的盐，其中，所述化合物选自如下化合物：
    Figure PCTCN2022086215-appb-100010
    Figure PCTCN2022086215-appb-100011
    Figure PCTCN2022086215-appb-100012
    Figure PCTCN2022086215-appb-100013
    Figure PCTCN2022086215-appb-100014
    Figure PCTCN2022086215-appb-100015
    Figure PCTCN2022086215-appb-100016
    Figure PCTCN2022086215-appb-100017
    Figure PCTCN2022086215-appb-100018
    Figure PCTCN2022086215-appb-100019
    Figure PCTCN2022086215-appb-100020
    Figure PCTCN2022086215-appb-100021
  6. 一种药物组合物，其中，所述的药物组合物含有：
    (a)选自权利要求1-5任一项中所述的化合物和其药学上可接受的盐中的一种或多种，以及
    (b)药学上可接受的载体。
  7. 根据权利要求1-5中任一项所述的化合物或其药学上可接受的盐或者根据权利要求6所述的药物组合物在制备药物中的用途，其中，所述药物是(a)抑制病毒复制的抑制剂；和/或(b)用于治疗和/或预防、缓解由病毒感染引起的疾病的药物。
  8. 如权利要求7所述的用途，其特征在于，所述的病毒是选自以下的一种或多种：
    (1)冠状病毒，例如感染人的冠状病毒：例如重症急性呼吸综合征冠状病毒SARS-CoV、2019新型冠状病毒SARS-CoV-2、中东呼吸综合征冠状病毒MERS-CoV、人冠状病毒OC43、人冠状病毒229 E、人冠状病毒NL63、人冠状病毒HKUl；和感染动物的冠状病毒：例如猪流行性腹泻病毒PEDV、猫传染性腹膜炎病毒FIFV；
    (2)副粘病毒，例如副流感病毒、麻疹病毒、呼吸道合胞病毒RSV；
    (3)流感病毒，例如甲型流感病毒、乙型流感病毒、丙型流感病毒、丁型流感病毒；
    (4)黄病毒科病毒，例如丙型肝炎病毒HCV、登革热病毒DENV、寨卡病毒ZIKV；
    (5)丝状病毒，例如马尔堡病毒MBV、埃博拉病毒EBV、奎瓦病毒；
    (6)布尼亚病毒科病毒，例如布尼亚病毒属、白蛉病毒属、内罗病毒属、汉坦病毒属病毒；
    (7)沙粒病毒，例如拉沙热病毒LASV、鸠宁病毒JUNV、马秋波病毒MACV；
    特别地，所述病毒为SARS-CoV-2或流感病毒。
  9. 如权利要求7所述的用途，其特征在于，所述由病毒感染引起的疾病为选自以下的一种或多种：
    (D1)人冠状病毒感染引起的普通感冒、高危症状感染、呼吸道感染、肺炎及其并发症；
    (D2)猪流行性腹泻病毒引起的猪流行性腹泻；
    (D3)猫冠状病毒引起的猫传染性腹膜炎；
    (D4)人呼吸道合胞病毒感染引起的普通感冒、高危症状感染、呼吸道感染、肺炎及其并发症；
    (D5)流感病毒感染引起的普通感冒、高危症状感染、呼吸道感染、肺炎及其并发症；
    (D6)丙型肝炎病毒引起的慢性丙型肝炎及其并发症；
    (D7)登革热病毒引起的登革热及其并发症；
    (D8)寨卡病毒引起的感染及其并发症；
    (D9)马尔堡病毒或埃博拉病毒引起的出血热及其并发症；
    (D10)布尼亚病毒引起的感染及其并发症；
    (D11)沙粒病毒引起的感染及其并发症。
  10. 如权利要求7所述的用途，其特征在于，
    所述由病毒感染引起的疾病为SARS-CoV-2感染引起的疾病，特别地，为选自以下的一种或多种：呼吸道感染、肺炎及其并发症；或者
    所述病毒引起的疾病为由流感病毒感染引起的疾病；特别地，所述由流感病毒感染引起的疾病为选自以下的一种或多种：普通感冒、高危症状感染、呼吸道感染、肺炎及其并发症。
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