WO2022011554A1 - 3-去氧-2-酮糖酸含氮衍生物及其制备方法和用途 - Google Patents

3-去氧-2-酮糖酸含氮衍生物及其制备方法和用途 Download PDF

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WO2022011554A1
WO2022011554A1 PCT/CN2020/101906 CN2020101906W WO2022011554A1 WO 2022011554 A1 WO2022011554 A1 WO 2022011554A1 CN 2020101906 W CN2020101906 W CN 2020101906W WO 2022011554 A1 WO2022011554 A1 WO 2022011554A1
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pharmaceutically acceptable
stereoisomer
hydrate
ester
acceptable salt
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PCT/CN2020/101906
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English (en)
French (fr)
Inventor
刘小宇
秦勇
钟武
曹瑞源
何欢
郑志兵
李松
Original Assignee
四川大学
中国人民解放军军事科学院军事医学研究院
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Application filed by 四川大学, 中国人民解放军军事科学院军事医学研究院 filed Critical 四川大学
Priority to JP2023502798A priority Critical patent/JP2023542455A/ja
Priority to PCT/CN2020/101906 priority patent/WO2022011554A1/zh
Priority to US18/016,062 priority patent/US20230271993A1/en
Priority to EP20944871.1A priority patent/EP4183792A4/en
Priority to CN202080001245.XA priority patent/CN114190092B/zh
Publication of WO2022011554A1 publication Critical patent/WO2022011554A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C07H5/04—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to nitrogen
    • C07H5/06—Aminosugars
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
    • C07H7/06—Heterocyclic radicals
    • 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
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the application belongs to the technical field of medicine, and specifically relates to a nitrogen-containing derivative of 3-deoxy-2-ketonic acid, which has antiviral activity.
  • the present application also relates to a pharmaceutical composition containing the compound, as well as the preparation method and use of the compound.
  • 3-Deoxy-2-ketonic acid is widely found in nature and plays an important role in life processes.
  • 3-deoxy-D-manno-2-octanulonic acid (Kdo) is an important component of bacterial cell wall lipopolysaccharides and capsular polysaccharides, and lipopolysaccharides or capsular polysaccharides containing Kdo fragments are potential antibacterial vaccines or diagnostics.
  • N-acetylneuraminic acid is the main member of the sialic acid family. It is widely present in the glycoproteins and glycolipids of animal cell membranes or secretion fluids. .
  • Structural modification based on the corresponding 3-deoxy-2-ketonic acid molecules is an important means to develop new antiviral drugs.
  • oseltamivir and zanamivir are currently widely used antiviral drugs in clinical practice, and derivative 1 containing 2,3-difluoro is a broad-spectrum antiviral candidate molecule (Science, 2013, 340, 71-75), Derivative 2 containing triazole substitution at position 3 is a potent inhibitor of human parainfluenza virus 3 (ACS Chem. Biol. 2018, 13, 1544-1550).
  • the preparation of novel derivatives of 3-deoxy-2-ketonic acid by an efficient synthetic method has important scientific significance and application value for the discovery of novel antiviral drugs.
  • the purpose of this application is to find and develop a new class of nitrogen-containing derivatives of 3-deoxy-2-ketonic acid with antiviral activity. After research in the present application, it has been found that the compound having the structure represented by the general formula I has antiviral activity. The present application has been completed based on the above findings.
  • the present application relates to the compound represented by the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvate,
  • R 1 is hydrogen, C 1 -C 6 alkyl, allyl, phenyl or benzyl;
  • R 2 and R 3 are each independently azido, amino, amino substituted with one or two R a , five- or six-membered nitrogen-containing heterocyclyl, or five- or six-membered nitrogen-containing heterocyclic substituted with R b cycloalkyl group, wherein each R a is independently C 1 -C 6 alkyl, allyl, phenyl, benzyl, formyl, acetyl, benzoyl, trifluoroacetyl, carbomethoxy, tert-butoxyformyl or benzyloxyacyl, R b is C 1 -C 6 alkyl, halogen or -(CH 2 ) m OH, wherein m is 0, 1, 2, 3 or 4;
  • R 4 and R 5 are each independently hydroxy, amino, guanidino, R c is substituted with hydroxy, R c of substituted amino group, R c is substituted guanidino group, five- or six-membered nitrogen-containing heterocyclic group or Five- or six-membered nitrogen-containing heterocyclic group substituted by R b , wherein each R c is independently C 1 -C 6 alkyl, allyl, phenyl, benzyl, trimethylsilyl, triethyl Silyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, formyl, acetyl, benzoyl, trifluoroacetyl, methoxyformyl, tertiary Butoxyformyl or benzyloxyacyl, R b is C 1 -C 6 alkyl, halogen or -(CH 2 ) m
  • R 4 and R 5 together with the carbon atoms to which they are attached together form a five- or six-membered oxygen-containing or nitrogen-containing heterocyclic ring (e.g., 1,3-dioxolane, 1,3-dioxolan-2-one , dioxane, dioxanone, oxazolidine or oxazolidinone);
  • a five- or six-membered oxygen-containing or nitrogen-containing heterocyclic ring e.g., 1,3-dioxolane, 1,3-dioxolan-2-one , dioxane, dioxanone, oxazolidine or oxazolidinone
  • R 6 is hydrogen, C 1 -C 6 alkyl, allyl, phenyl, benzyl, trimethylsilicon, triethylsilicon, triisopropylsilicon, tert-butyldimethylsilicon, tert-butyl Diphenylsilicon, formyl, acetyl, benzoyl, trifluoroacetyl;
  • R 7 is hydrogen, R 6 OCH 2 - or R 6 OCH 2 (R 6 O)CH-, wherein R 6 is as defined above;
  • n 0, 1, 2 or 3.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 1 is hydrogen or C 1 -C 4 alkyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 2 and R 3 are each independently azido, amino, or a five- or six-membered nitrogen-containing heterocyclic group substituted by R b , wherein R b is -(CH 2 ) m OH, wherein m is 0, 1, 2, 3 or 4, and the five- or six-membered nitrogen-containing heterocyclic group is triazolyl, tetrazolyl, pyrrolyl, tetrahydropyrrolyl, piperidinyl , pyridyl, oxazolyl or imidazolyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate
  • R 4 and R 5 are each independently hydroxy, amino, hydroxy substituted with R c , amino substituted with R c , wherein each R c is each independently C 1 -C 4 alkyl, allyl, phenyl, benzyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl , formyl, acetyl, benzoyl, trifluoroacetyl, methoxyformyl, tert-butoxyformyl or benzyloxyacyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvate thereof, wherein: R 4 and R 5 together with the carbon atoms to which they are attached, form a five-membered oxygen-containing heterocyclic ring (e.g., 1,3-dioxolane, 1,3-dioxolane -2-keto).
  • R 4 and R 5 together with the carbon atoms to which they are attached, form a five-membered oxygen-containing heterocyclic ring (e.g., 1,3-dioxolane, 1,3-dioxolane -2-keto).
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 6 is formyl, acetyl, benzoyl or trifluoroacetyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 7 is R 6 OCH 2 - or R 6 OCH 2 (R 6 O)CH-, wherein R 6 is as defined above.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate wherein: n is 0, 1 or 2.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate wherein: R 1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 2 and R 3 are each independently azido, amino or a five-membered nitrogen-containing heterocyclic group substituted by R b , wherein R b is -(CH 2 ) m OH, wherein m is 0, 1, 2 or 3, and the five-membered nitrogen-containing heteroaryl group is triazolyl, tetrazolyl, pyrrolyl, tetrahydropyrrolyl, oxazolyl or imidazolyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvate thereof, wherein: R 4 and R 5 are each independently a hydroxyl group, R c is substituted with a hydroxyl group, an amino group substituted by R c, wherein each R c each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl group, formyl, acetyl, benzoyl, trifluoroacetyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate wherein: R 1 is hydrogen or methyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 2 is azide or
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 3 is azido, amino or
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 4 is hydroxy, tert-butyldimethylsilyloxy, benzoyloxy, acetylamino or acetyloxy.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 5 is hydroxy, trifluoroacetyloxy, acetylamino or acetyloxy.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 6 is acetyl or benzoyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 7 is or R 6 OCH 2 -, wherein R 6 is as defined above.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvate thereof, wherein: R 7 is R 6 OCH 2 - or R 6 OCH 2 (R 6 O ) CH-, wherein R 6 is defined above.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate wherein: n is 0, 1 or 2.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate wherein: R 1 is hydrogen.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 1 is C 1 -C 6 alkyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 1 is C 1 -C 4 alkyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 1 is allyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 1 is phenyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 1 is benzyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 1 is methyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate wherein: R 1 is ethyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 1 is n-propyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 1 is isopropyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 1 is n-butyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 1 is isobutyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 1 is sec-butyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 1 is tert-butyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate wherein: R 2 is azide.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 2 is amino.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 2 is amino substituted with one or two R a , wherein each R a is independently C 1 -C 6 alkyl, allyl, phenyl, benzyl , formyl, acetyl, benzoyl, trifluoroacetyl, methoxyformyl, tert-butoxyformyl or benzyloxyacyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 2 is a five- or six-membered nitrogen-containing heterocyclic group.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 2 is a five- or six-membered nitrogen-containing heterocyclic group substituted by R b , wherein R b is C 1 -C 6 alkyl, halogen or -(CH 2 ) m OH , where m is 0, 1, 2, 3, or 4.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 2 is a five-membered nitrogen-containing heterocyclic group substituted by R b , wherein R b is -(CH 2 ) 3 OH, and the five-membered nitrogen-containing heteroaryl group is triazole tetrazolyl, tetrazolyl, pyrrolyl, tetrahydropyrrolyl, oxazolyl or imidazolyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 2 is a five-membered nitrogen-containing heterocyclic group substituted by R b , wherein R b is -(CH 2 ) 2 OH, and the five-membered nitrogen-containing heteroaryl group is triazole tetrazolyl, tetrazolyl, pyrrolyl, tetrahydropyrrolyl, oxazolyl or imidazolyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 2 is a five-membered nitrogen-containing heterocyclic group substituted by R b , wherein R b is -CH 2 OH, and the five-membered nitrogen-containing heteroaryl group is triazolyl, tetrazolium Azazolyl, pyrrolyl, tetrahydropyrrolyl, oxazolyl or imidazolyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvate thereof, wherein: R 2 is
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvate thereof, wherein: R 3 is an azido group, an amino group, substituted amino group with one or two R a five- or six-membered nitrogen-containing heterocyclic group or R b substituted five- or six membered nitrogen-containing heterocyclic group, wherein each R a is independently C 1 -C 6 alkyl, allyl, phenyl, benzyl, formyl, acetyl, benzoyl, trifluoroacetyl, A Oxyformyl, tert-butoxyformyl or benzyloxyacyl, R b is C 1 -C 6 alkyl, halogen or -(CH 2 ) m OH, where m is 0, 1, 2, 3 or 4.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 2 and R 3 are each independently azido, amino or a five-membered nitrogen-containing heterocyclic group substituted by R b , wherein R b is -(CH 2 ) m OH, wherein m is 0, 1, 2 or 3, and the five-membered nitrogen-containing heteroaryl group is triazolyl, tetrazolyl, pyrrolyl, tetrahydropyrrolyl, oxazolyl or imidazolyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 3 is a five-membered nitrogen-containing heterocyclic group substituted by R b , wherein R b is -(CH 2 ) 3 OH, and the five-membered nitrogen-containing heteroaryl group is triazole tetrazolyl, tetrazolyl, pyrrolyl, tetrahydropyrrolyl, oxazolyl or imidazolyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 3 is a five-membered nitrogen-containing heterocyclic group substituted by R b , wherein R b is -(CH 2 ) 2 OH, and the five-membered nitrogen-containing heteroaryl group is triazole tetrazolyl, tetrazolyl, pyrrolyl, tetrahydropyrrolyl, oxazolyl or imidazolyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 3 is a five-membered nitrogen-containing heterocyclic group substituted by R b , wherein R b is -CH 2 OH, and the five-membered nitrogen-containing heteroaryl group is triazolyl, tetrazolium Azazolyl, pyrrolyl, tetrahydropyrrolyl, oxazolyl or imidazolyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 3 is azido.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 3 is amino.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvate thereof, wherein: R 3 is
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvate thereof, wherein: R 4 is hydroxy, amino, guanidino, R c of substituted hydroxyl group, an amino group substituted by R c, R c of substituted guanidino, five- or six-membered nitrogen-containing cycloalkyl group or R b substituted five- or six-membered nitrogen-containing heterocyclic group, wherein each R c each independently C 1 -C 6 alkyl, allyl, phenyl, benzyl, trimethylsilyl , triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, formyl, acetyl, benzoyl, trifluoroacetyl
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvate thereof, wherein: R 5 is hydroxy, amino, guanidino, R c is substituted with a hydroxyl group, an amino group substituted by R c, R c being a substituted guanidino group, five- or six-membered nitrogen-containing cycloalkyl group or R b substituted five- or six-membered nitrogen-containing heterocyclic group, wherein each R c each independently C 1 -C 6 alkyl, allyl, phenyl, benzyl, trimethylsilyl , triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, formyl, acetyl, benzoyl, triflu
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvate thereof, wherein: R 4 is hydroxy, R c of substituted hydroxyl group, R c of substituted amino, wherein each R c each independently methyl, ethyl, n-propyl, isopropyl, , n-butyl, isobutyl, sec-butyl, tert-butyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, formyl, acetyl group, benzoyl group, trifluoroacetyl group.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvate thereof, wherein: R 5 is hydroxy, R c of substituted hydroxyl groups, substituted amino group R c, wherein each R c each independently methyl, ethyl, n-propyl, isopropyl, , n-butyl, isobutyl, sec-butyl, tert-butyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, formyl, acetyl group, benzoyl group, trifluoroacetyl group.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 4 is hydroxy.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 4 is tert-butyldimethylsilyloxy.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 4 is benzoyloxy.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 4 is acetylamino.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 4 is acetyloxy.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate wherein: R 5 is hydroxy.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 5 is trifluoroacetyloxy.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 5 is acetylamino.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 5 is acetyloxy.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvate thereof, wherein: R 4 and R 5 together with the carbon atoms to which they are attached, form a five or six-membered heterocyclic ring containing oxygen or nitrogen.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvate thereof, wherein: R 4 and R 5 together with the carbon atoms to which they are attached, form a five-membered oxygen-containing or nitrogen-containing heterocyclic ring.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvate thereof, wherein: R 4 and R 5 together with the carbon atoms to which they are attached, form a five-membered oxygen-containing heterocyclic ring.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvate thereof, wherein: R 4 and R 5 together with the carbon atoms to which they are attached form 1,3-dioxolane, 1,3-dioxolan-2-one, oxazolidine or oxazolidinone.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvate thereof, wherein: R 4 and R 5 together with the carbon atoms to which they are attached form dioxane, dioxanone.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvate thereof, wherein: R 4 and R 5 together with the carbon atoms to which they are attached form 1,3-dioxolane or 1,3-dioxolan-2-one.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvate thereof, wherein: R 4 and R 5 together with the carbon atoms to which they are attached form 1,3-dioxolan-2-one.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate wherein: R 6 is hydrogen.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 6 is C 1 -C 6 alkyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 6 is C 1 -C 4 alkyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 6 is methyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 6 is ethyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 6 is n-propyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 6 is isopropyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 6 is n-butyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 6 is isobutyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 6 is sec-butyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 6 is tert-butyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 6 is allyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 6 is phenyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 6 is benzyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 6 is trimethylsilyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 6 is triethyl silicon.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 6 is triisopropylsilicon.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 6 is tert-butyldimethylsilicon.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 6 is tert-butyldiphenylsilicon.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 6 is formyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 6 is acetyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 6 is benzoyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 6 is trifluoroacetyl.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate wherein: R 7 is hydrogen.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 7 is
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvate thereof, wherein: R 7 is R 6 OCH 2 -, wherein R 6 is defined as the present application.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein: R 7 is R 6 OCH 2 (R 6 O)CH-, wherein R 6 is as defined herein.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate wherein: n is 0.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate wherein: n is 1.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate wherein: n is 2.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate wherein: n is 3.
  • the present application relates to the compound shown in the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its A pharmaceutically acceptable solvate, wherein the compound is selected from:
  • the present application also relates to the preparation of the compound represented by the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvent methods of compounding, including:
  • the diazide compound shown in formula III generates the compound shown in general formula I by hydrolysis of ester group, reduction of azide group, removal of each protecting group on hydroxyl or amine group or formation of nitrogen heterocycle,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are as defined in any one of claims 1 to 5 .
  • the present application relates to the preparation of the compound represented by the general formula I, its stereoisomers, its pharmaceutically acceptable salts, its pharmaceutically acceptable esters, and its pharmaceutically acceptable hydrates or a method for a pharmaceutically acceptable solvate thereof, wherein the hypervalent iodine reagent in step a) is selected from etc., preferably
  • the present application relates to the preparation of the compound represented by the general formula I, its stereoisomers, its pharmaceutically acceptable salts, its pharmaceutically acceptable esters, and its pharmaceutically acceptable hydrates or the method of a pharmaceutically acceptable solvate thereof, wherein the solvent in step a) is selected from dichloromethane, acetone, dimethyl sulfoxide, acetonitrile, etc., preferably acetonitrile.
  • the present application relates to the preparation of the compound represented by the general formula I, its stereoisomers, its pharmaceutically acceptable salts, its pharmaceutically acceptable esters, and its pharmaceutically acceptable hydrates or the method of a pharmaceutically acceptable solvate thereof, wherein the light source of the illumination in step a) is natural light or LED light of various colors, etc., preferably blue LED light.
  • the present application relates to the preparation of the compound represented by the general formula I, its stereoisomers, its pharmaceutically acceptable salts, its pharmaceutically acceptable esters, and its pharmaceutically acceptable hydrates or the method of a pharmaceutically acceptable solvate thereof, wherein the reaction in step a) is carried out at a temperature of 0 to 60°C, preferably under a condition of illumination and a temperature of 20 to 40°C.
  • the present application relates to the preparation of the compound represented by the general formula I, its stereoisomers, its pharmaceutically acceptable salts, its pharmaceutically acceptable esters, and its pharmaceutically acceptable hydrates
  • the method for its pharmaceutically acceptable solvate, wherein the ester hydrolysis in step b) is carried out in the presence of a base and a solvent preferably, the base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide , sodium methoxide, sodium carbonate, potassium carbonate, sodium tert-butoxide, potassium tert-butoxide, the solvent is one or both of water or alcoholic solvents such as methanol, ethanol, isopropanol, tert-butanol, etc. mixture.
  • the present application relates to the preparation of the compound represented by the general formula I, its stereoisomers, its pharmaceutically acceptable salts, its pharmaceutically acceptable esters, and its pharmaceutically acceptable hydrates
  • a reducing agent is selected from triphenylphosphine, trimethyl Phosphine, tributylphosphine, palladium carbon/hydrogen, palladium hydroxide/hydrogen, Raney nickel/hydrogen, etc.
  • the solvent is selected from water, tetrahydrofuran or alcoholic solvents such as methanol, ethanol, isopropanol, tert-butanol, etc. one or a mixture of both.
  • the present application relates to the preparation of the compound represented by the general formula I, its stereoisomers, its pharmaceutically acceptable salts, its pharmaceutically acceptable esters, and its pharmaceutically acceptable hydrates
  • the protecting group is removed in the presence of an acid or a base and a solvent
  • the acid is selected from hydrochloric acid, sulfuric acid, p-toluenesulfonic acid acid, trifluoroacetic acid, etc.
  • the base is selected from sodium hydroxide, potassium hydroxide, sodium methoxide, sodium carbonate, potassium carbonate, sodium tert-butoxide, potassium tert-butoxide, etc.
  • the solvent is selected from water, dichloromethane , tetrahydrofuran or alcohol solvents such as methanol, ethanol, isopropanol, tert-butanol, etc. one or a mixture of two.
  • the present application relates to the preparation of the compound represented by the general formula I, its stereoisomers, its pharmaceutically acceptable salts, its pharmaceutically acceptable esters, and its pharmaceutically acceptable hydrates or a method for a pharmaceutically acceptable solvate thereof, wherein said nitrogen heterocycle formation in step b) is carried out in the presence of an alkyne, a copper catalyst and a solvent, preferably the alkyne is selected from various lengths, with Or terminal alkyne or internal alkyne without various functional groups, the copper catalyst is selected from cuprous chloride, cuprous bromide, cuprous iodide, copper sulfate/sodium ascorbate, etc., and the solvent is selected from One or a mixture of two of water, dichloromethane, tetrahydrofuran or alcoholic solvents such as methanol, ethanol, isopropanol, tert-butanol, etc.
  • an alkyne preferably the alkyne is selected from various lengths, with
  • the present application also relates to a pharmaceutical composition, comprising at least one compound represented by the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or a pharmaceutically acceptable solvate thereof, and one or more pharmaceutically acceptable carriers or excipients.
  • the present application also relates to the compound represented by the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvate Use of the drug or the pharmaceutical composition in the preparation of antiviral drugs (eg, anti-Zika virus, rhinovirus).
  • antiviral drugs eg, anti-Zika virus, rhinovirus.
  • the present application also relates to the compound represented by the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvent.
  • viruses eg, anti-Zika virus, rhinovirus
  • the present application also relates to the compound represented by the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvate Use of the compound or the pharmaceutical composition in the preparation of a medicament as a virus (eg, anti-Zika virus, rhinovirus) inhibitor.
  • a virus eg, anti-Zika virus, rhinovirus
  • the present application also relates to the compound represented by the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvate Use of the compound or the pharmaceutical composition in the preparation of a medicament for preventing and/or treating a disease or infection caused by a virus (eg, anti-Zika virus, rhinovirus).
  • a virus eg, anti-Zika virus, rhinovirus
  • the present application also relates to the compound represented by the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvate
  • antiviral drugs eg, anti-Zika virus, rhinovirus
  • the present application also relates to the compound represented by the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvate or the pharmaceutical composition for inhibiting the replication or propagation of viruses (eg, anti-Zika virus, rhinovirus) in cells (eg, mammalian cells).
  • viruses eg, anti-Zika virus, rhinovirus
  • the present application also relates to the compound represented by the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvate or said pharmaceutical composition, which is used as a virus (eg, anti-Zika virus, rhinovirus) inhibitor.
  • a virus eg, anti-Zika virus, rhinovirus
  • the present application also relates to the compound represented by the general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvate
  • the drug or the pharmaceutical composition for preventing and/or treating diseases or infections caused by viruses (eg, anti-Zika virus, rhinovirus).
  • the present application also relates to a method of preventing and/or treating a disease or infection caused by a virus (eg, anti-Zika virus, rhinovirus) in a mammal in need thereof, the method comprising administering to the mammal in need thereof the prophylaxis and/or treatment Or the compound shown in the described general formula I of therapeutically effective dose, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvent compound or the pharmaceutical composition.
  • a virus eg, anti-Zika virus, rhinovirus
  • the present application also relates to a method of inhibiting the replication or propagation of a virus (eg, anti-Zika virus, rhinovirus) in a mammal in need thereof, the method comprising administering to the mammal in need thereof a therapeutically and/or prophylactically effective amount of all Described compound shown in general formula I, its stereoisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvate or described pharmaceutical composition.
  • a virus eg, anti-Zika virus, rhinovirus
  • the present application also relates to a method for inhibiting the replication or reproduction of viruses (eg, anti-Zika virus, rhinovirus) in cells (eg, mammalian cells), the method comprising mixing the compound represented by the general formula I, its stereoisomer The isomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, its pharmaceutically acceptable hydrate or its pharmaceutically acceptable solvate or said pharmaceutical composition is contacted with cells.
  • viruses eg, anti-Zika virus, rhinovirus
  • the mammals described herein include bovines, equines, ovines, porcines, canines, felines, rodents, primates, of which preferred Mammals are humans, cats, dogs or pigs.
  • C 1-6 alkyl refers to a saturated straight or branched monovalent hydrocarbon group having 1 to 6 carbon atoms.
  • Typical examples of “C 1-6 alkyl” include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, tert-amyl, neo- Amyl, hexyl, etc.
  • hydroxy as used herein means -OH.
  • halogen as used herein means fluorine, chlorine, bromine or iodine. Preferred halogen groups are fluorine, chlorine or bromine.
  • five- or six-membered nitrogen-containing heterocyclic group as used herein means an alicyclic or aromatic heterocyclic group having 5 or 6 ring members and containing at least one nitrogen atom.
  • Typical examples of "five- or six-membered nitrogen-containing heterocyclic groups” include, but are not limited to, triazole, tetrazolium, pyrrole, tetrahydropyrrole, piperidine, pyridine, oxazole, imidazole, and the like.
  • five- or six-membered oxygen- or nitrogen-containing heterocyclic group as used herein means an alicyclic or aromatic heterocyclic group having five or six ring members and containing at least one oxygen atom or one nitrogen atom .
  • Typical examples of "five- or six-membered nitrogen-containing heterocyclic groups” include, but are not limited to, 1,3-dioxolane, 1,3-dioxolane-2-one, dioxane, dioxanone, oxazolidine or oxazolidinone etc.
  • the pharmaceutically acceptable salts of the compounds represented by the general formula I described in this application include inorganic or organic acid salts thereof, and inorganic or organic base salts, and this application refers to all forms of the above-mentioned salts.
  • the pharmaceutically acceptable salt of the compound shown in the general formula I includes, but is not limited to: sodium salt, potassium salt, calcium salt, lithium salt, meglumine salt, hydrochloride, hydrogen oxalate, hydrogen citrate , nitrate, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, acetate, propionate, butyrate, oxalate, trimethyl acetate, adipate, alginate, Lactate, Citrate, Tartrate, Succinate, Maleate, Fumarate, Picrate, Aspartate, Gluconate, Benzoate, Mesylate, Ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate, etc.
  • the compound represented by the general formula I described in this application when it includes a hydroxyl group, it can form a pharmaceutically acceptable ester with an organic acid or an inorganic acid, and the pharmaceutically acceptable ester includes a phosphate ester , sulfate, nitric acid, formate, acetate, propionate, butyrate, valerate, caproate and other esters that can be hydrolyzed in vivo.
  • the pharmaceutically acceptable ester includes a phosphate ester , sulfate, nitric acid, formate, acetate, propionate, butyrate, valerate, caproate and other esters that can be hydrolyzed in vivo.
  • the compound represented by the general formula I described in this application when it includes a carboxyl group, it can also form a pharmaceutically acceptable ester with an alcohol compound, and the pharmaceutically acceptable ester includes a methyl ester , ethyl ester, propyl ester, n-butyl ester, tert-butyl ester and other esters that can be hydrolyzed in vivo.
  • Carriers described in this application include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human albumin, buffer substances such as phosphate, glycerol, sorbic acid, potassium sorbate, saturated Partial glyceride mixtures of vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, Cellulosic substance, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax, lanolin.
  • excipient refers to an addition other than the main drug in a pharmaceutical formulation. It is stable in nature, has no incompatibility with the main drug, does not produce side effects, and does not affect the curative effect. It does not affect the determination of the content of the main drug.
  • excipients such as binders, fillers, disintegrants, lubricants in tablets; preservatives, antioxidants, flavoring agents, fragrances, cosolvents, emulsifiers, solubilizers, osmotic pressure regulators in oral liquid preparations , colorants, etc. can be called excipients, and so on.
  • compositions described herein can be administered by various routes, such as oral tablets, capsules, powders, oral liquids, injections and transdermal formulations.
  • the medicines in the above-mentioned various dosage forms can be prepared according to the conventional methods in the pharmaceutical field.
  • pharmaceutically acceptable carriers include diluents, fillers, disintegrating agents, wetting agents, lubricants, coloring agents, flavoring agents or other conventional additives.
  • Typical pharmaceutically acceptable carriers include, for example, microcrystalline cellulose, starch, crospovidone, povidone, polyvinylpyrrolidone, maltitol, citric acid, sodium lauryl sulfonate or magnesium stearate, and the like .
  • the pharmaceutical composition can be administered in any of the following ways: oral, spray inhalation, rectal, nasal, buccal, vaginal, topical, parenteral such as subcutaneous, intravenous, intramuscular, Intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or via an explanted reservoir.
  • an "effective amount” refers to an amount sufficient to prevent or treat disease in a patient but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment.
  • a prophylactically or therapeutically effective amount of a compound will depend on the particular compound selected (eg, taking into account the potency, effectiveness and half-life of the compound), the route of administration selected, the disease being prevented or treated, and the severity of the disease being prevented or treated. , factors such as age, size, weight, and physical ailment of the patient being treated, medical history of the patient being treated, duration of prophylaxis or treatment, nature of concurrent therapy, and desired prophylactic or therapeutic effect vary, but can still be determined by this It is routinely determined by those skilled in the art.
  • the specific dosage and method of use of the compound of general formula (I) described in this application for different patients depends on many factors, including the patient's age, weight, sex, natural health status, nutritional status, and the active strength of the compound, Time of administration, rate of metabolism, severity of condition, and subjective judgment of the treating physician. It is preferred here to use doses between 0.001 and 1000 mg/kg body weight/day.
  • Unsaturated glycal compound 3 (201mg, 0.351mmol, 1.0eq.) and BI-OAc (215mg, 0.702mmol, 2.0eq.) were placed in a dry round-bottom flask, and freshly dried MeCN ( 3.5 mL) was dissolved, and then TMSN 3 (138 ⁇ L, 1.05 mmol, 3.0 eq.) was added.
  • the reaction was stirred under 34W blue LED light, and the temperature was controlled at 25-30 °C. After 2 h of reaction, TLC detection showed that the raw materials had disappeared.
  • the reaction solution was quenched by adding saturated KHCO 3 solution, diluted with EtOAc, vigorously stirred at room temperature for 5 min, and then extracted four times with EtOAc.
  • Example 2 The preparation method is the same as in Example 1.
  • Compound 11 (1.20 g, 4.00 mmol, 1.0 eq.) was reacted with BIOAc (2.45 g, 8.00 mmol, 2.0 eq.), TMSN 3 (1.58 mL, 12.0 mmol, 3.0 eq.) in dry MeCN.
  • Test subject Zika virus-infected BHK cells
  • DMEM medium purchased from Gibco, Item No. 16000044
  • FBS Gibco 10% FBS Gibco, Cat. No. 11995065
  • DMEM medium purchased from Gibco, Item No. 11995065
  • FBS purchased from Gibco, Item No. 16000044
  • test compound stock solution was serially diluted with the above DMEM medium to 800 ⁇ M, 266.67 ⁇ M, 88.89 ⁇ M, 29.63 ⁇ M, 9.88 ⁇ M, 3.29 ⁇ M, 1.10 ⁇ M, 0.37 ⁇ M, and 50 ⁇ L was added to the cell culture plate.
  • the stock solution of the positive compound NITD008 purchasedd from MCE Company, Cat. No.
  • HY-12957 was serially diluted with the above DMEM medium to 80 ⁇ M, 26.67 ⁇ M, 8.89 ⁇ M, 2.96 ⁇ M, 0.99 ⁇ M, 0.33 ⁇ M, 0.11 ⁇ M, 0.04 ⁇ M, and 50 ⁇ L was added. into the cell culture plate. Finally, 50 ⁇ L of Zika virus SZ-SMGC-01 strain (preserved by the Military Medical Research Institute) diluted with DMEM medium containing 2% FBS was added to the cells, so that the amount of virus contained in each well was 100 TCID 50 . The final concentration of the test compound was 0.25 times the pretreatment concentration, that is, 200 ⁇ M was used as the initial concentration and 3-fold dilution.
  • the final concentrations of the test compounds were: 200 ⁇ M, 66.67 ⁇ M, 22.22 ⁇ M, 7.41 ⁇ M, 2.47 ⁇ M, 0.82 ⁇ M , 0.27 ⁇ M, 0.09 ⁇ M.
  • the final concentrations of positive compounds were: 20 ⁇ M, 6.67 ⁇ M, 2.22 ⁇ M, 0.74 ⁇ M, 0.25 ⁇ M, 0.082 ⁇ M, 0.027 ⁇ M, 0.009 ⁇ M.
  • a negative control DMSO and medium, but no drug added to cell wells
  • DMSO, medium, and virus but no drug added to cell wells
  • chemiluminescent cell viability detection reagent purchased from Promega, product number G7573
  • the working solution was mixed with PBS (purchased from Gibco, Cat. No. 10010049) at a ratio of 4:6. After the cell culture plate was discarded, 100 ⁇ l of detection reagent was added to each well, and the 96-well plate was shaken by an orbital shaker for 5 min to induce cell lysis.
  • Test subject H1Hela cells infected with rhinovirus (HRV-1059)
  • H1Hela cells purchased from National Experimental Cell Resource Sharing Platform, Item No. 3111C0001CCC000344
  • the cell culture medium is 10% FBS (purchased from Gibco, Item No. 16000044).
  • FBS purchased from Gibco, Item No. 16000044
  • DMEM medium purchased from Gibco Company, product number 11995065
  • DMEM medium purchased from Gibco, Item No. 11995065
  • FBS purchased from Gibco, Item No. 16000044
  • the test compound stock solution was serially diluted with the above DMEM medium to 800 ⁇ M, 266.67 ⁇ M, 88.89 ⁇ M, 29.63 ⁇ M, 9.88 ⁇ M, 3.29 ⁇ M, 1.10 ⁇ M, 0.37 ⁇ M, 0.12 ⁇ M, 0.04 ⁇ M, and 50 ⁇ L was added to the cell culture in the board.
  • the stock solution of the positive compound NITD008 purchasedd from MCE Company, Cat. No.
  • HY-12957 was serially diluted with the above DMEM medium to 80 ⁇ M, 26.67 ⁇ M, 8.89 ⁇ M, 2.96 ⁇ M, 0.99 ⁇ M, 0.33 ⁇ M, 0.11 ⁇ M, 0.04 ⁇ M, 0.012 ⁇ M, 0.004 ⁇ M, 50 ⁇ L was added to the cell culture plate. Finally, 50 ⁇ L of rhinovirus HRV-1059 strain (purchased from ATCC, product number VR-482) diluted with DMEM medium containing 2% FBS was added to the cells, so that each well contained 100 TCID 50 of virus. The final concentration of the test compound was 0.25 times the pretreatment concentration, that is, 200 ⁇ M was used as the initial concentration and 3-fold dilution.
  • the final concentrations of the test compounds were: 200 ⁇ M, 66.67 ⁇ M, 22.22 ⁇ M, 7.41 ⁇ M, 2.47 ⁇ M, 0.82 ⁇ M , 0.27 ⁇ M, 0.09 ⁇ M, 0.03 ⁇ M, 0.01 ⁇ M.
  • the final concentrations of positive compounds were: 20 ⁇ M, 6.67 ⁇ M, 2.22 ⁇ M, 0.74 ⁇ M, 0.25 ⁇ M, 0.082 ⁇ M, 0.027 ⁇ M, 0.009 ⁇ M, 0.003 ⁇ M, 0.001 ⁇ M.
  • Negative controls DMSO and medium without drug added to cell wells
  • positive controls DMSO, medium and virus added to cell wells without drug addition
  • chemiluminescent cell viability detection reagent purchased from Promega, product number G7573
  • the working solution was mixed with PBS (purchased from Gibco, Cat. No. 10010049) at a ratio of 4:6. After the cell culture plate was discarded, 100 ⁇ l of detection reagent was added to each well, and the 96-well plate was shaken by an orbital shaker for 5 min to induce cell lysis.

Abstract

涉及通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，还涉及含有该化合物的药物组合物，以及该化合物的制备方法和用途。

Description

3-去氧-2-酮糖酸含氮衍生物及其制备方法和用途 技术领域
本申请属于医药技术领域，具体涉及一种3-去氧-2-酮糖酸含氮衍生物，该化合物具有抗病毒活性。本申请还涉及含有该化合物的药物组合物，以及该化合物的制备方法和用途。
背景技术
3-去氧-2-酮糖酸广泛存在于自然界中，并在生命过程中发挥着重要作用。例如，3-去氧-D-甘露-2-辛酮糖酸(Kdo)是细菌细胞壁脂多糖和荚膜多糖的重要组份，包含有Kdo片段的脂多糖或荚膜多糖是潜在的抗菌疫苗或诊断剂。N-乙酰神经氨酸为唾液酸家族的主要成员，广泛存在于动物细胞膜或分泌液的糖蛋白、糖脂质中，具有抗炎、抗病毒、抗肿瘤、抗老年痴呆等多方面生物学功能。
Figure PCTCN2020101906-appb-000001
基于相应3-去氧-2-酮糖酸分子进行结构改造是发展新型抗病毒药物的重要手段。例如奥司他韦(oseltamivir)和扎那米韦(zanamivir)为目前在临床上广泛使用的抗病毒药物，含有2,3-二氟的衍生物1是一个广谱抗病毒候选分子(Science,2013,340,71-75)，含有3位三氮唑取代的衍生物2则是一个有效的人副流感病毒3抑制剂(ACS Chem.Biol.2018,13,1544-1550)。利用高效合成方法制备3-去氧-2-酮糖酸新颖衍生物对于发现新型抗病毒药物具有重要的科学意义和应用价值。
申请内容
本申请的目的是寻找并开发一类新型的具有抗病毒活性的3-去氧-2-酮糖酸的含氮衍生物。本申请经过研究现已发现，具有通式I所示结构的化合物具有抗病毒活性。本申请 基于上述发现而得以完成。
本申请涉及通式I所示的化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，
Figure PCTCN2020101906-appb-000002
其中：
R 1为氢、C 1-C 6烷基、烯丙基、苯基或苄基；
R 2和R 3各自独立地为叠氮基、氨基、被一个或两个R a取代的氨基、五元或六元含氮杂环基或被R b取代的五元或六元含氮杂环基，其中每个R a各自独立地为C 1-C 6烷基、烯丙基、苯基、苄基、甲酰基、乙酰基、苯甲酰基、三氟乙酰基、甲氧甲酰基、叔丁氧甲酰基或苄氧酰基，R b为C 1-C 6烷基、卤素或-(CH 2) mOH，其中m为0、1、2、3或4；
R 4和R 5各自独立地为羟基、氨基、胍基、被R c取代的羟基、被R c取代的氨基、被R c取代的胍基、五元或六元含氮杂环基或被R b取代的五元或六元含氮杂环基，其中每个R c各自独立地为C 1-C 6烷基、烯丙基、苯基、苄基、三甲基硅基、三乙基硅基、三异丙基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基、甲酰基、乙酰基、苯甲酰基、三氟乙酰基、甲氧甲酰基、叔丁氧甲酰基或苄氧酰基，R b为C 1-C 6烷基、卤素或-(CH 2) mOH，其中m为0、1、2、3或4，或者，
R 4和R 5与它们所连接的碳原子共同形成五元或六元含氧或含氮的杂环(例如1,3-二氧戊环、1,3-二氧戊环-2-酮、二噁烷、二噁烷酮、噁唑烷或噁唑烷酮)；
R 6为氢、C 1-C 6烷基、烯丙基、苯基、苄基、三甲基硅、三乙基硅、三异丙基硅、叔丁基二甲基硅、叔丁基二苯基硅、甲酰基、乙酰基、苯甲酰基、三氟乙酰基；
R 7为氢、
Figure PCTCN2020101906-appb-000003
R 6OCH 2-或R 6OCH 2(R 6O)CH-，其中R 6的定义如上所述；
n为0、1、2或3。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 1为氢或C 1-C 4烷基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 2和R 3各自独立地为叠氮基、氨基或被R b取代的五元或六元含氮杂环基，其中R b为-(CH 2) mOH，其中m为0、1、2、3或4，所述五元或六元含氮杂环基为三氮唑基、四氮唑基、吡咯基、四氢吡咯基、哌啶基、吡啶基、噁唑基或咪唑基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 4和R 5各自独立地为羟基、氨基、被R c取代的羟基、被R c取代的氨基，其中每个R c各自独立地为C 1-C 4烷基、烯丙基、苯基、苄基、三甲基硅基、三乙基硅基、三异丙基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基、甲酰基、乙酰基、苯甲酰基、三氟乙酰基、甲氧甲酰基、叔丁氧甲酰基或苄氧酰基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 4和R 5与它们所连接的碳原子共同形成五元含氧的杂环(例如1,3-二氧戊环、1,3-二氧戊环-2-酮)。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 6为甲酰基、乙酰基、苯甲酰基或三氟乙酰基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 7为
Figure PCTCN2020101906-appb-000004
R 6OCH 2-或R 6OCH 2(R 6O)CH-，其中R 6的定义如上所述。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：n为0、1或2。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 1为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其 中：R 2和R 3各自独立地为叠氮基、氨基或被R b取代的五元含氮杂环基，其中R b为-(CH 2) mOH，其中m为0、1、2或3，所述五元含氮杂芳基为三氮唑基、四氮唑基、吡咯基、四氢吡咯基、噁唑基或咪唑基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 4和R 5各自独立地为羟基、被R c取代的羟基、被R c取代的氨基，其中每个R c各自独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、三甲基硅基、三乙基硅基、三异丙基硅基、叔丁基二甲基硅基、甲酰基、乙酰基、苯甲酰基、三氟乙酰基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 1为氢或甲基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 2为叠氮基或
Figure PCTCN2020101906-appb-000005
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 3为叠氮基、氨基或
Figure PCTCN2020101906-appb-000006
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 4为羟基、叔丁基二甲基硅基氧基、苯甲酰基氧基、乙酰基氨基或乙酰基氧基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 5为羟基、三氟乙酰基氧基、乙酰基氨基或乙酰基氧基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 6为乙酰基或苯甲酰基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可 接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 7为
Figure PCTCN2020101906-appb-000007
或R 6OCH 2-，其中R 6的定义如上所述。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 7为R 6OCH 2-或R 6OCH 2(R 6O)CH-，其中R 6的定义如上所述。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：n为0、1或2。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 1为氢。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 1为C 1-C 6烷基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 1为C 1-C 4烷基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 1为烯丙基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 1为苯基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 1为苄基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 1为甲基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 1为乙基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 1为正丙基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 1为异丙基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 1为正丁基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 1为异丁基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 1为仲丁基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 1为叔丁基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 2为叠氮基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 2为氨基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 2为被一个或两个R a取代的氨基，其中每个R a各自独立地为C 1-C 6烷基、烯丙基、苯基、苄基、甲酰基、乙酰基、苯甲酰基、三氟乙酰基、甲氧甲酰基、叔丁氧甲酰基或苄氧酰基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可 接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 2为五元或六元含氮杂环基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 2为被R b取代的五元或六元含氮杂环基，其中R b为C 1-C 6烷基、卤素或-(CH 2) mOH，其中m为0、1、2、3或4。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 2为R b取代的五元含氮杂环基，其中R b为-(CH 2) 3OH，所述五元含氮杂芳基为三氮唑基、四氮唑基、吡咯基、四氢吡咯基、噁唑基或咪唑基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 2为R b取代的五元含氮杂环基，其中R b为-(CH 2) 2OH，所述五元含氮杂芳基为三氮唑基、四氮唑基、吡咯基、四氢吡咯基、噁唑基或咪唑基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 2为R b取代的五元含氮杂环基，其中R b为-CH 2OH，所述五元含氮杂芳基为三氮唑基、四氮唑基、吡咯基、四氢吡咯基、噁唑基或咪唑基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 2为
Figure PCTCN2020101906-appb-000008
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 3为叠氮基、氨基、被一个或两个R a取代的氨基、五元或六元含氮杂环基或被R b取代的五元或六元含氮杂环基，其中每个R a各自独立地为C 1-C 6烷基、烯丙基、苯基、苄基、甲酰基、乙酰基、苯甲酰基、三氟乙酰基、甲氧甲酰基、叔丁氧甲酰基或苄氧酰基，R b为C 1-C 6烷基、卤素或-(CH 2) mOH，其中m为0、1、2、3或4。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 2和R 3各自独立地为叠氮基、氨基或被R b取代的五元含氮杂环基，其中R b为 -(CH 2) mOH，其中m为0、1、2或3，所述五元含氮杂芳基为三氮唑基、四氮唑基、吡咯基、四氢吡咯基、噁唑基或咪唑基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 3为R b取代的五元含氮杂环基，其中R b为-(CH 2) 3OH，所述五元含氮杂芳基为三氮唑基、四氮唑基、吡咯基、四氢吡咯基、噁唑基或咪唑基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 3为R b取代的五元含氮杂环基，其中R b为-(CH 2) 2OH，所述五元含氮杂芳基为三氮唑基、四氮唑基、吡咯基、四氢吡咯基、噁唑基或咪唑基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 3为R b取代的五元含氮杂环基，其中R b为-CH 2OH，所述五元含氮杂芳基为三氮唑基、四氮唑基、吡咯基、四氢吡咯基、噁唑基或咪唑基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 3为叠氮基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 3为氨基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 3为
Figure PCTCN2020101906-appb-000009
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 4为羟基、氨基、胍基、被R c取代的羟基、被R c取代的氨基、被R c取代的胍基、五元或六元含氮杂环基或被R b取代的五元或六元含氮杂环基，其中每个R c各自独立地为C 1-C 6烷基、烯丙基、苯基、苄基、三甲基硅基、三乙基硅基、三异丙基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基、甲酰基、乙酰基、苯甲酰基、三氟乙酰基、甲氧甲酰基、叔丁氧甲酰基或苄氧酰基，R b为C 1-C 6烷基、卤素或-(CH 2) mOH，其中m为0、1、2、3 或4。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 5为羟基、氨基、胍基、被R c取代的羟基、被R c取代的氨基、被R c取代的胍基、五元或六元含氮杂环基或被R b取代的五元或六元含氮杂环基，其中每个R c各自独立地为C 1-C 6烷基、烯丙基、苯基、苄基、三甲基硅基、三乙基硅基、三异丙基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基、甲酰基、乙酰基、苯甲酰基、三氟乙酰基、甲氧甲酰基、叔丁氧甲酰基或苄氧酰基，R b为C 1-C 6烷基、卤素或-(CH 2) mOH，其中m为0、1、2、3或4。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 4为羟基、被R c取代的羟基、被R c取代的氨基，其中每个R c各自独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、三甲基硅基、三乙基硅基、三异丙基硅基、叔丁基二甲基硅基、甲酰基、乙酰基、苯甲酰基、三氟乙酰基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 5为羟基、被R c取代的羟基、被R c取代的氨基，其中每个R c各自独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、三甲基硅基、三乙基硅基、三异丙基硅基、叔丁基二甲基硅基、甲酰基、乙酰基、苯甲酰基、三氟乙酰基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 4为羟基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 4为叔丁基二甲基硅基氧基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 4为苯甲酰基氧基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 4为乙酰基氨基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其 中：R 4为乙酰基氧基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 5为羟基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 5为三氟乙酰基氧基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 5为乙酰基氨基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 5为乙酰基氧基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 4和R 5与它们所连接的碳原子共同形成五元或六元含氧或含氮的杂环。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 4和R 5与它们所连接的碳原子共同形成五元含氧或含氮的杂环。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 4和R 5与它们所连接的碳原子共同形成五元含氧的杂环。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 4和R 5与它们所连接的碳原子共同形成1,3-二氧戊环、1,3-二氧戊环-2-酮、噁唑烷或噁唑烷酮。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 4和R 5与它们所连接的碳原子共同形成二噁烷、二噁烷酮。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 4和R 5与它们所连接的碳原子共同形成1,3-二氧戊环或1,3-二氧戊环-2-酮。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可 接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 4和R 5与它们所连接的碳原子共同形成1,3-二氧戊环-2-酮。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 6为氢。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 6为C 1-C 6烷基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 6为C 1-C 4烷基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 6为甲基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 6为乙基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 6为正丙基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 6为异丙基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 6为正丁基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 6为异丁基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 6为仲丁基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可 接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 6为叔丁基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 6为烯丙基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 6为苯基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 6为苄基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 6为三甲基硅。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 6为三乙基硅。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 6为三异丙基硅。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 6为叔丁基二甲基硅。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 6为叔丁基二苯基硅。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 6为甲酰基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 6为乙酰基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可 接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 6为苯甲酰基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 6为三氟乙酰基。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 7为氢。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 7为
Figure PCTCN2020101906-appb-000010
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 7为R 6OCH 2-，其中R 6的定义如本申请所述。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：R 7为R 6OCH 2(R 6O)CH-，其中R 6的定义如本申请所述。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：n为0。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：n为1。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：n为2。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：n为3。
在某些实施方案中，本申请涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中所述化合物选自：
Figure PCTCN2020101906-appb-000011
本申请还涉及制备所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物的方法，包括：
Figure PCTCN2020101906-appb-000012
a)在溶剂中，式II所示化合物、高价碘试剂和叠氮三甲基硅烷在光照的条件下反应生成式III所示的双叠氮化产物；
b)式III所示的双叠氮化合物通过酯基水解、叠氮基还原、羟基或胺基上各保护基团脱除或氮杂环形成生成通式I所示化合物，
其中：R 1、R 2、R 3、R 4、R 5、R 6、R 7的定义如权利要求1至5任一项所述。
在某些实施例方案中，本申请涉及制备所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物的方法，其中步骤a)中所述高价碘试剂选自
Figure PCTCN2020101906-appb-000013
Figure PCTCN2020101906-appb-000014
等，优选
Figure PCTCN2020101906-appb-000015
在某些实施例方案中，本申请涉及制备所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物的方法，其中步骤a)中所述溶剂选自二氯甲烷、丙酮、二甲亚砜、乙腈等，优选乙腈。
在某些实施例方案中，本申请涉及制备所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物的方法，其中步骤a)中所述光照的光源为自然光或各种颜色的LED光等，优选蓝色LED光。
在某些实施例方案中，本申请涉及制备所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物的方法，其中步骤a)所述反应在温度为0～60℃的条件下进行，优选在光照条件并且温度为20～40℃的条件下进行。
在某些实施例方案中，本申请涉及制备所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物的方法，其中步骤b)中所述酯基水解在碱和溶剂的存在下进行，优选地，所述碱选自氢氧化锂、氢氧化钠、氢氧化钾、甲醇钠、碳酸钠、碳酸钾、叔丁醇钠、叔丁醇钾，所述溶剂为水或醇类溶剂如甲醇、乙醇、异丙醇、叔丁醇等中的一种或两种的混合物。
在某些实施例方案中，本申请涉及制备所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物的方法，其中步骤b)中所述叠氮基还原在还原剂和溶剂的存在下进行，优选地，所述 还原剂选自三苯基膦、三甲基膦、三丁基膦、钯碳/氢气、氢氧化钯/氢气、雷尼镍/氢气等，所述溶剂选自水、四氢呋喃或醇类溶剂如甲醇、乙醇、异丙醇、叔丁醇等中的一种或两种的混合物。
在某些实施例方案中，本申请涉及制备所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物的方法，其中步骤b)中所述保护基团脱除在酸或碱和溶剂的存在下进行，优选地，所述酸选自盐酸、硫酸、对甲苯磺酸、三氟乙酸等，所述碱选自氢氧化钠、氢氧化钾、甲醇钠、碳酸钠、碳酸钾、叔丁醇钠、叔丁醇钾等，所述溶剂选自水、二氯甲烷、四氢呋喃或醇类溶剂如甲醇、乙醇、异丙醇、叔丁醇等中的一种或两种的混合物。
在某些实施例方案中，本申请涉及制备所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物的方法，其中步骤b)中所述氮杂环形成在炔烃，铜催化剂和溶剂的存在下进行，优选地，所述炔烃选自各种长度，带或不带各种官能基团的末端炔烃或内部炔烃，所述铜催化剂选自氯化亚铜、溴化亚铜、碘化亚铜、硫酸铜/抗坏血酸钠等，所述溶剂选自水、二氯甲烷、四氢呋喃或醇类溶剂如甲醇、乙醇、异丙醇、叔丁醇等中的一种或两种的混合物。
本申请还涉及一种药物组合物，其包括至少一种所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，以及一种或多种药学上可接受的载体或赋形剂。
本申请还涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物或所述的药物组合物在制备用于抗病毒的药物(例如抗寨卡病毒、鼻病毒)中的用途。
本申请还涉及本所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物或所述的药物组合物在制备用于抑制病毒(例如抗寨卡病毒、鼻病毒)在细胞(例如哺乳动物细胞)中复制或繁殖的药物中的用途。
本申请还涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物或所述的药物组合物在制备作为病毒(例如抗寨卡病毒、鼻病毒)抑制剂的药物中的用途。
本申请还涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物或所述的药物组合物在制备用于预防和/或治疗病毒(例如抗寨卡病毒、鼻病毒)引起的疾病或感染的药物中的用途。
本申请还涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学 上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物或所述的药物组合物，其用于抗病毒的药物(例如抗寨卡病毒、鼻病毒)。
本申请还涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物或所述的药物组合物，其用于抑制病毒(例如抗寨卡病毒、鼻病毒)在细胞(例如哺乳动物细胞)中复制或繁殖。
本申请还涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物或所述的药物组合物，其用作病毒(例如抗寨卡病毒、鼻病毒)抑制剂。
本申请还涉及所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物或所述的药物组合物，其用于预防和/或治疗病毒(例如抗寨卡病毒、鼻病毒)引起的疾病或感染。
本申请还涉及一种在有需要的哺乳动物中预防和/或治疗病毒(例如抗寨卡病毒、鼻病毒)引起的疾病或感染的方法，该方法包括给有需要的哺乳动物施用预防和/或治疗有效量的所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物或所述的药物组合物。
本申请还涉及一种在有需要的哺乳动物中抑制病毒(例如抗寨卡病毒、鼻病毒)复制或繁殖的方法，该方法包括给有需要的哺乳动物施用治疗和/或预防有效量的所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物或所述的药物组合物。
本申请还涉及一种抑制病毒(例如抗寨卡病毒、鼻病毒)在细胞(例如哺乳动物细胞)中复制或繁殖的方法，该方法包括将所述的通式I所示化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物或所述的药物组合物与细胞接触。
在某些实施方案中，本申请所述哺乳动物包括牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物，其中优选的哺乳动物为人、猫、狗或猪。
取代基定义
本文中使用的术语“C 1-6烷基”是指具有1-6个碳原子的饱和的直链或支链一价烃基。“C 1-6烷基”的典型实例包括但不限于甲基，乙基，正丙基，异丙基，正丁基，异丁基，叔丁基，正戊基，叔戊基，新戊基，己基等。
本文中使用的术语“羟基”意指-OH。
本文所用的术语“卤素”意指氟，氯，溴或碘。优选的卤素基团为氟、氯或溴。
本文所用的术语“五元或六元含氮杂环基”意指具有5个或6个环成员，并且至少包含一个氮原子的脂杂环或芳杂环基团。“五元或六元含氮杂环基”的典型实例包括但不限于三氮唑、四氮唑、吡咯、四氢吡咯、哌啶、吡啶、噁唑、咪唑等。
本文所用的术语“五元或六元含氧或含氮杂环基”意指具有5个或6个环成员，并且至少包含一个氧原子或一个氮原子的脂杂环或芳杂环基团。“五元或六元含氮杂环基”的典型实例包括但不限于1,3-二氧戊环、1,3-二氧戊环-2-酮、二噁烷、二噁烷酮、噁唑烷或噁唑烷酮等。
在某些实施方案中，本申请所述通式I所示化合物的药学上可接受的盐包括其无机或有机酸盐，以及无机或有机碱盐，本申请涉及上述盐的所有形式。所述通式I所示化合物的药学上可接受的盐包括但不限于:钠盐、钾盐、钙盐、锂盐、葡甲胺盐、盐酸盐，氢澳酸盐，氢腆酸盐，硝酸盐，硫酸盐，硫酸氢盐，磷酸盐，磷酸氢盐，乙酸盐，丙酸盐，丁酸盐，草酸盐，三甲基乙酸盐，己二酸盐，藻酸盐，乳酸盐，柠檬酸盐，酒石酸盐，琥珀酸盐，马来酸盐，富马酸盐，苦味酸盐，天冬氨酸盐，葡糖酸盐，苯甲酸盐，甲磺酸盐，乙磺酸盐，苯磺酸盐，对甲苯磺酸盐和双羟萘酸盐等。
在某些实施方案中，本申请所述通式I所示化合物中包括羟基时，其可以与有机酸或无机酸形成药学上可接受的酯，所述的药学上可接受的酯包括磷酸酯、硫酸酯、硝酸、甲酸酯、乙酸酯、丙酸酯、丁酸酯、戊酸酯、己酸酯等在生物体内可水解的酯类。
在某些实施方案中，本申请所述通式I所示化合物中包括羧基时，其还可以与醇类化合物形成药学上可接受的酯，所述的药学上可接受的酯包括甲基酯、乙基酯、丙基酯、正丁基酯、叔丁基酯等在生物体内可水解的酯类。
本申请所述的载体包括但不限于：离子交换剂，氧化铝，硬脂酸铝，卵磷脂，血清蛋白如人血白蛋白，缓冲物质如磷酸盐，甘油，山梨酸，山梨酸钾，饱和植物脂肪酸的部分甘油酯混合物，水，盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐，胶态氧化硅，三硅酸镁，聚乙烯吡咯烷酮，纤维素物质，聚乙二醇，羧甲基纤维素钠，聚丙烯酸酯，蜂蜡，羊毛脂。
本申请中使用的术语“赋形剂”是指在药物制剂中除主药以外的附加物。其性质稳定，与主药无配伍禁忌，不产生副作用，不影响疗效，在常温下不易变形、干裂、霉变、虫蛀、对人体无害、无生理作用，不与主药产生化学或物理作用，不影响主药的含量测定等。如片剂中的黏合剂、填充剂、崩解剂、润滑剂；口服液体制剂中的防腐剂、抗氧剂、矫味剂、芳香剂、助溶剂、乳化剂、增溶剂、渗透压调节剂、着色剂等均可称为赋形剂，等等。
本申请所述的药物组合物可以经多种途径施用，例如口服片剂，胶囊，粉剂，口服液，注射剂和透皮制剂。上述各种剂型的药物均可以按照药学领域的常规方法制备。 根据常规的药物上的惯例，药学上可接受的载体包括稀释剂、填充剂、崩解剂、润湿剂、润滑剂、着色剂、调味剂或其它常规添加剂。典型的药学上可接受的载体包括例如微晶纤维素、淀粉、交连聚维酮、聚维酮、聚乙烯吡咯烷酮、麦芽糖醇，柠檬酸，十二烷基磺酸钠或硬脂酸镁等。
根据申请，所述的药物组合物可以以下面的任意方式施用：口服、喷雾吸入、直肠用药、鼻腔用药、颊部用药、阴道用药、局部用药、非肠道用药如皮下、静脉、肌内、腹膜内、鞘内、心室内、胸骨内和颅内注射或输入、或借助一种外植储器用药。
如本文所述的，“有效量”是指在合理的医学判断范围内，足以预防或治疗患者疾病但足够低地避免严重副作用(在合理的利益/风险比)的量。化合物的预防或治疗有效量将根据所选择的具体化合物(例如考虑化合物的效力、有效性和半衰期)、所选择的给药途径、所预防或治疗的疾病、所预防或治疗的疾病的严重性、所治疗的患者的年龄、大小、体重和身体疾病、所治疗的患者的医疗史、预防或治疗持续时间、并行疗法的性质、所需的预防或治疗效果等因素发生变化，但仍可以由本领域技术人员常规确定。
另外需要指出，本申请所述通式(I)化合物针对不同患者的特定使用剂量和使用方法决定于诸多因素，包括患者的年龄，体重，性别，自然健康状况，营养状况，化合物的活性强度，服用时间，代谢速率，病症的严重程度以及诊治医师的主观判断。这里优选使用剂量介于0.001-1000mg/kg体重/天。
具体实施方式
通过下面的实施例和试验例可以对本申请进行进一步的描述。然而，本申请的范围并不限于下述实施例或试验例。本领域的专业人员能够理解，在不背离本申请的精神和范围的前提下，可以对本申请进行各种变化和修饰。本申请对试验中所使用到的材料以及试验方法进行一般性和/或具体的描述。虽然为实现本申请目的所使用的许多材料和操作方法是本领域公知的，但是本申请仍然在此作尽可能详细描述。
对于以下全部实施例，可以使用本领域技术人员已知的标准操作和纯化方法。除非另有说明，所有温度以℃(摄氏度)表示。
为了进一步描述本申请的技术方案，以下给出一些实施例，但本申请的保护范围不局限于以下所述。
实施例1化合物4a和4b的合成
Figure PCTCN2020101906-appb-000016
将不饱和烯糖化合物3(201mg,0.351mmol,1.0eq.)和BI-OAc(215mg,0.702mmol,2.0eq.)置于干燥圆底烧瓶中，抽换氩气后加入现干燥的MeCN(3.5mL)溶解，再加入TMSN 3(138μL,1.05mmol,3.0eq.)。反应置于34W蓝色LED灯光照下搅拌，温度控制在25-30℃，反应2h后，TLC检测显示原料消失完。向反应液中加入饱和KHCO 3溶液淬灭，EtOAc稀释，在室温下剧烈搅拌5min，然后用EtOAc萃取四次，合并有机相用水、饱和食盐水溶液分别洗一次，加无水Na 2SO 4干燥，过滤，减压浓缩，粗品经硅胶柱层析分离纯化(petroleum ether:EtOAc＝12:1 to 8:1v/v)，得白色固体4a(65.3mg，28％)和4b(131mg，57％)。
化合物4a: 1H NMR(400MHz,CDCl 3)δ:5.26(d,J＝8.4Hz,1H),4.41(dd,J＝10.8,1.2Hz,1H),4.14(q,J＝6.4Hz,1H),4.07–3.86(m,3H),3.92(s,3H),3.85–3.75(m,1H),3.70–3.55(m,2H),1.98(s,3H),1.39(s,3H),1.29(s,3H),0.89(s,18H),0.17(s,3H),0.13(s,6H),0.06(s,3H)； 13C NMR(150MHz,CDCl 3)δ:169.6,166.3,108.6,91.4,76.0,73.2,71.5,70.6,66.4,66.3,53.9,53.6,26.6,25.9,25.6,24.8,23.9,18.5,18.0,-3.6,-4.0,-4.6,-4.6；[α]25D＝-16.0(c 0.4,CHCl 3)；IR(neat):ν max＝2955,2930,2858,2112,1757,1666,1253,1120,1069,1023,836,777,736；HRMS:calcd.for C 27H 51N 7NaO 8Si 2[M+Na] +m/z 680.3235；found m/z 680.3249.
化合物4b: 1H NMR(400MHz,CDCl 3)δ:5.29(d,J＝8.0Hz,1H),4.73(dd,J＝10.0,3.6Hz,1H),4.59(d,J＝10.8Hz,1H),4,24–4.16(m,1H),4.07–4.01(m,2H),3.97–3.83(m,2H),3.85(s,3H),3.67–3.55(m,1H),1.96(s,3H),1.40(s,3H),1.29(s,3H),0.92(s,9H),0.91(s,9H),0.15(s,3H),0.13(s,3H),0.12(s,3H),0.07(s,3H)； 13C NMR(150MHz,CDCl 3)δ:170.2,165.4,108.1,91.0,72.7,70.6,67.8,65.7,64.9,53.2,50.8,29.7,26.4,25.9,25.6,24.7,23.9,18.5,17.9,-3.4,-4.1,-4.4,-5.1；[α]25D＝-0.9(c 0.4,CHCl 3)；IR(neat):ν max＝2955,2930,2858,2111,1758,1668,1256,1068,1039,837,779,734；HRMS calcd.for C 27H 51N 7NaO 8Si 2[M+Na] +m/z 680.3235；found m/z 680.3235.
实施例2化合物6a–d的合成
Figure PCTCN2020101906-appb-000017
制备方法同实施例1。化合物5(2.03g,2.82mmol,1.0eq.)与BIOAc(1.72g,5.63mmol,2.0eq.)，TMSN 3(1.11mL,8.45mmol,3.0eq.)在干燥MeCN中反应。产物粗品经硅胶柱分离纯化(petroleum ether:acetone＝4:1v/v)可得白色固体状混合物6(1.92g,85％)，经硅胶柱分离(petroleum ether:EtOAc＝4:1to 2:1v/v)可得化合物6a、6b、6c三者混合物1.50g和纯化合物6d(416mg)，其中三者混合物经分析型HPLC(Waters e2695,2489UV Detector,ZORBAX 300SB-C8,流速：1mL/min,温度：25℃，流动相为水:甲醇＝60:40－40:60－30:70－20:80)分离可得三个异构体比例为：6a:6b:6c＝1:1:5.2，结合硅胶柱纯化得到的质量比分析可知四个异构体比例依次为：6a:6b:6c:6d＝1:1:5.2:2。化合物6a、6b和6c混合物可经反复硅胶柱层析(petroleum ether:acetone＝8:1v/v及petroleum ether:EtOAc＝5:1v/v)及制备型硅胶板分离(petroleum ether:EtOAc＝1.5:1v/v)分别得到纯化合物6a(52.3mg)、6b(32.8mg)和6c(638mg)及部分交叉。
化合物6a: 1H NMR(400MHz,CDCl 3)δ:8.09–7.91(m,8H),7.63–7.32(m,12H),5.90(dd,J＝6.4,1.6Hz,1H),5.87–5.81(m,1H),5.64(d,J＝9.6Hz,1H),5.55(t,J＝2.0Hz,1H),4.94(dd,J＝12.4,3.2Hz,1H),4.64(dd,J＝10.8,2.0Hz,1H),4.50–4.35(m,2H),4.21(d,J＝10.0Hz,1H),3.96(s,3H),1.78(s,3H)； 13C NMR(100MHz,CDCl 3)δ:170.0,166.6,166.0,165.6,165.2,165.2,133.8,133.5,133.4,133.1,130.0,129.9,129.9,129.7,129.5,129.4,129.2,128.6,128.6,128.5,128.3,91.6,72.9,71.5,70.6,68.4,62.9,62.8,54.1,49.8,23.0；[α]25D＝+6.1(c 0.8,CHCl 3)；IR(neat):ν max＝2967,2132,2113,1722,1451,1257,1091,1067,1024,800,707,686；HRMS calcd.for C 40H 35N 7NaO 12[M+Na] +m/z 828.2241；found m/z 828.2232.
化合物6b: 1H NMR(400MHz,CDCl 3)δ:8.17–7.88(m,8H),7.65–7.31(m,12H),5.96–5.76(m,3H),5.53(d,J＝9.6Hz,1H),4.79(dd,J＝12.4,2.8Hz,1H),4.67(dd,J＝10.8,2.0Hz,1H),4.49–4.32(m,2H),3.75(d,J＝10.0Hz,1H),3.48(s,3H),1.80(s,3H)； 13C NMR(100MHz,CDCl 3)δ:170.0,166.5,166.0,165.6,165.3,164.8,133.7,133.5,133.0,130.0,129.9,129.9,129.7,129.6,129.2,129.2,128.6,128.6,128.5,128.3,91.2,73.8,71.5,69.3,67.9,65.7,63.0,53.3,49.3,23.0；[α]25D＝+29.5(c 0.9,CHCl 3)；IR(neat):ν max＝3364,2963,2932,2114,1726,1249,1093,1068,1026,709；HRMS calcd.for C 40H 35N 7NaO 12[M+Na] +m/z 828.2241；found 828.2235.
化合物6c: 1H NMR(400MHz,CDCl 3)δ:8.18–8.13(m,2H),8.05–7.98(m,4H),7.98–7.92(m,2H),7.64–7.45(m,6H),7.45–7.31(m,6H),5.94–5.86(m,2H),5.84(dd,J＝10.4,3.2Hz,1H),5.69–5.94(m,1H),5.11(dd,J＝12.4,2.8Hz,1H),4.68(dd,J＝10.8,2.0Hz,1H),4.59(dd,J＝12.4,6.4Hz,1H),4.49(q,J＝10.4Hz,1H),4.36(d,J＝3.2Hz,1H), 3.96(s,3H),1.81(s,3H)； 13C NMR(100MHz,CDCl 3)δ:170.1,166.1,166.0,165.7,165.6,164.6,133.8,133.5,133.3,133.0,130.1,130.0,129.9,129.7,129.7,129.5,129.2,128.6,128.6,128.4,128.4,128.3,91.2,72.78,71.5,670.0,69.0,63.1,62.5,53.7,45.9,23.2；[α]25D＝-1.3(c0.7,CHCl 3)；IR(neat):ν max＝3375,2970,2924,2112,1723,1695,1257,1092,1068,1026,803,709；HRMS calcd.for C 40H 35N 7NaO 12[M+Na] +m/z 828.2241；found m/z 828.2232.
化合物6d: 1H NMR(400MHz,CDCl 3)δ:8.19–8.13(m,2H),8.07–7.98(m,4H),7.97–7.92(m,2H),7.67–7.32(m,12H),5.97–5.90(m,1H),5.86(dd,J＝7.6,1.6Hz,1H),5.80(dd,J＝10.8,3.2Hz,1H),5.64–5.55(m,1H),4.95(dd,J＝12.4,3.2Hz,1H),4.64(dd,J＝10.8,1.6Hz,1H),4.59–4.49(m,2H),4.20–4.08(m,1H),3.62(s,3H),1.85(s,3H)； 13C NMR(100MHz,CDCl 3)δ:170.4,166.0,165.9,165.9,165.7,165.3,133.8,133.7,133.3,133.0,130.2,123.0,129.9,129.7,129.6,129.0,128.7,128.6,128.5,128.3,89.5,73.0,69.9,69.4,68.7,63.1,62.8,53.7,46.6,23.3；[α]25D＝+41.2(c 0.7,CHCl 3)；IR(neat):ν max＝3375,2963,2111,1724,1255,1106,1094,1069,1026,709；HRMS calcd.for C 40H 35N 7NaO 12[M+Na] +m/z 828.2241；found m/z 828.2237.
实施例3化合物8a和8b的合成
Figure PCTCN2020101906-appb-000018
制备方法同实施例1。化合物7(4.21g,5.91mmol,1.0eq.)与BIOAc(3.62g,11.8mmol,2.0eq.)，TMSN 3(2.33mL,17.7mmol,3.0eq.)在干燥MeCN中反应。产物粗品经硅胶柱分离纯化(petroleum ether:EtOAc＝3:1to 2:1v/v)得白色固体8a(1.27g，57％)和8b(0.732g，32％)。
化合物8a: 1H NMR(400MHz,CDCl 3)δ:8.10–7.98(m,4H),7.97–7.90(m,2H),7.65–7.31(m,9H),7.16–7.07(m,1H),6.72(d,J＝8.8Hz,1H),5.91–5.81(m,2H),5.12(dd,J＝12.8,2.4Hz,1H),4.93(d,J＝10.8Hz,1H),4.70–4.61(m,1H),4.53(dd,J＝12.4,5.6Hz,1H),4.35–4.25(m,1H),4.02(d,J＝3.6Hz,1H),3.94(s,3H),2.01(s,3H)； 13C NMR(100MHz,CDCl 3)δ:171.1,166.1,166.0,165.3,164.4,158.4,158.1,157.7,157.3,133.8,133.6,133.1,130.1,129.9,129.6,129.5,129.2,128.8,128.6,128.6,128.5,128.3,119.7,116.9,114.0,111.1,91.2,71.4,68.9,68.5,62.7,61.1,53.7,49.8,44.6,23.2；[α]25D＝+63.1(c 1.7,CHCl 3)；IR(Neat):ν max＝2114,1725,1259,1088,1068,735,709；HRMS calcd.for C 35H 31F 3N 8NaO 11[M+Na] +m/z 819.1962；found m/z 819.1954.
化合物8b: 1H NMR(400MHz,CDCl 3)δ:8.09–7.98(m,4H),7.94(d,J＝7.6Hz,2H), 7.64–7.49(m,4H),7.49–7.41(m,3H),7.41–7.32(m,2H),6.71–6.56(m,1H),5.92–5.85(m,1H),5.80(dd,J＝7.6,1.6Hz,1H),5.22(d,J＝11.2,Hz,1H),4.92(dd,J＝12.8,2.8Hz,1H),4.61(d,J＝7.2Hz,1H),4.46(dd,J＝12.4,4.8Hz,1H),4.33–4.20(m,1H),4.15(q,J＝6.8Hz,1H),3.68(s,3H),1.96(s,3H)； 13C NMR(100MHz,CDCl 3)δ:172.4,166.4,166.0,165.6,165.5,159.2,158.8,158.4,158.05,134.0,133.6,133.1,130.1,129.8,129.6,129.4,129.2,128.7,128.6,128.3,128.3,119.8,117.0,114.1,111.2,89.6,70.1,69.9,68.5,62.5,59.0,53.6,50.6,46.0,22.9；[α]25D＝+53.4(c 1.0,CHCl 3)；IR(neat):ν max＝2116,1726,1263,1247,1091,1069,734,708；HRMS calcd.for C 35H 31F 3N 8NaO 11[M+Na] +m/z 819.1962；found m/z 819.1961.
实施例4化合物10a–d的合成
Figure PCTCN2020101906-appb-000019
制备方法同实施例1。化合物9(1.01g,2.51mmol,1.0eq.)与BIOAc(1.54g,5.02mmol,2.0eq.)，TMSN 3(0.991mL,7.53mmol,3.0eq.)在干燥MeCN中反应。产物粗品经硅胶柱纯化(petroleum ether:acetone＝8:1v/v)得四个异构体(化合物10a、10b、10c、10d)混合总产物1.05g，经分析型HPLC分离(Waters e2695,2424ELS Detector,ZORBAX300SB－C8,流速：1mL/min,温度：20℃，流动相为水:甲醇＝60:40－50:50－40:60)可得四个异构体比例为：10a:10b:10c:10d＝7:11:5:1。总产物经反复多次硅胶柱层析(petroleum ether:acetone＝13:1v/v,petroleum ether:EtOAc＝7:1v/v)分离纯化得白色固体10a(34.0mg),10b(163mg),10c(194mg),10d(41.3mg)及部分交叉。
化合物10a: 1H NMR(600MHz,CDCl 3)δ:5.48(d,J＝1.8Hz,1H),5.21–5.16(m,2H),4.47(dd,J＝12.6,2.4Hz,1H),4.43(d,J＝9.6Hz,1H),4.23(d,J＝10.8Hz,1H),4.09(dd,J＝12.6,3Hz,1H),3.97(s,3H),2.14(s,3H),2.09(s,3H),2.06(s,3H),2.01(s,3H)； 13C NMR(150MHz,CDCl 3)δ:170.6,170.1,169.6,169.5,165.3,91.6,69.8,69.2,66.8,65.4,61.8,58.0,56.2,54.1,20.7,20.6,20.6；[α]25D＝+64.5(c 0.11,CHCl 3)；IR(neat):ν max＝2927,2118,1752,1437,1370,1226,1076,957,750cm –1；HRMS calcd.for C 17H 22N 6NaO 11[M+Na] + m/z 509.1244；found m/z 509.1253.
化合物10b: 1H NMR(400MHz,CDCl 3)δ:5.48(d,J＝9.2Hz,2H),5.14(d,J＝9.2Hz,1H),4.36(t,J＝8.8Hz,2H),4.22(dd,J＝12,2.8Hz,1H),3.92(s,3H),3.76(d,J＝10Hz,1H),2.14(s,3H),2.07(s,3H),2.04(s,3H),2.01(s,3H)； 13C NMR(150MHz,CDCl 3)δ:170.3,170.1,169.5,169.5,165.7,91.2,71.5,69.4,67.4,65.1,61.8,61.3,53.6,20.7,20.6,20.6,20.6；[α]25D＝+32.5c 0.08,CHCl 3)；IR(neat):ν max＝2926,2118,1752,1437,1372,1228,1080,804,735cm –1；HRMS calcd.for C 17H 22N 6NaO 11[M+Na] +m/z 509.1244；found m/z 509.1253.
化合物10c: 1H NMR(400MHz,CDCl 3)δ:5.42(d,J＝2.4Hz,2H),5.34(d,J＝10Hz,1H),4.55(dd,J＝12.4,2Hz,1H),4.42(d,J＝9.6Hz,1H),4.24(dd,J＝12.8,2.8Hz,1H),4.07(t,J＝2.0Hz,1H),3.93(s,3H),2.13(s,3H),2.08(s,6H),1.99(s,3H)； 13C NMR(150MHz,CDCl 3)δ:170.5,170.5,169.4,169.2,164.4,91.5,69.4,67.3,67.1,63.3,61.8,58.5,53.7,20.7,20.6,20.6,20.3；[α]25D＝+116.2(c 0.32,CHCl 3)；IR(neat):ν max＝2959,2118,1748,1438,1372,1223,1053,924,732cm –1；HRMS calcd.for C 17H 22N 6NaO 11[M+Na] +m/z 509.1244；found m/z 509.1231.
化合物10d: 1H NMR(400MHz,CDCl 3)δ:5.34(s,1H),5.30(d,J＝9.6Hz,1H),5.15(t,J＝2.8Hz,1H),4.46(d,J＝12.4Hz,1H),4.29(dd,J＝12.4,3.2Hz,1H),4.22(d,J＝3.2Hz,1H),3.97(d,J＝9.6Hz,1H),3.92(s,3H),2.16(s,3H),2.11(s,3H),2.09(s,3H),1.98(s,3H)； 13C NMR(150MHz,CDCl 3)δ:170.5,170.4,169.3,169.3,165.8,90.1,71.9,67.7,67.3,62.9,61.7,58.7,53.9,20.7,20.6,20.5,20.4；[α]25D＝+101.8(c 0.09,CHCl 3)；IR(neat):ν max＝2918,2115,1747,1436,1372,1225,1045,923,733cm –1；HRMS calcd.for C 17H 22N 6NaO 11[M+Na] +m/z 509.1244；found m/z 509.1258.
实施例5化合物12a和12b的合成
Figure PCTCN2020101906-appb-000020
制备方法同实施例1。化合物11(1.20g,4.00mmol,1.0eq.)与BIOAc(2.45g,8.00mmol,2.0eq.)，TMSN 3(1.58mL,12.0mmol,3.0eq.)在干燥MeCN中反应。产物粗品经硅胶柱分离纯化(petroleum ether:EtOAc＝8:1to 5:1v/v)得白色固体12a(537mg，35％)和12b(845mg，55％)。
化合物12a: 1H NMR(400MHz,CDCl 3)δ:4.91(dd,J＝6.8,2Hz,1H),4.77(t,J＝6.8 Hz,1H),4.37–4.32(m,1H),4.21(d,J＝6.8Hz,1H),4.18–4.12(m,1H),4.01(d,J＝2Hz,1H),3.99–3.95(m,1H),3.94(s,3H),1.44(s,3H),1.36(s,3H)； 13C NMR(100MHz,CDCl 3)δ:165.1,152.5,110.2,90.0,74.5,73.3,72.7,71.2,67.0,60.1,54.2,26.8,24.8；[α]25D＝+76.7(c 0.68,CHCl 3)；IR(neat):ν max＝2988,2968,2121,1820,1768,1079,846,759cm –1；HRMS calcd.for C 13H 16N 6NaO 8[M+Na] +m/z 407.0927；found m/z 407.0932.
化合物12b： 1H NMR(400MHz,CDCl 3)δ:5.02(dd,J＝8.0,5.2Hz,1H),4.96(dd,J＝8.0,1.6Hz,1H),4.36–4.31(m,1H),4.19–4.12(m,2H),3.94(s,3H),3.91(d,J＝4.8Hz,1H),3.79(dd,J＝8.4,1.6Hz,1H),1.41(s,3H),1.35(s,3H)； 13C NMR(100MHz,CDCl 3)δ:165.4,152.7,110.2,89.3,73.7,72.8,72.5,72.4,66.7,61.2,53.7,26.9,24.8；[α]25D＝+40.0(c0.08,CHCl 3)；IR(neat):ν max＝2988,2967,2111,1820,1767,1078,846,759cm –1；HRMS calcd.for C 13H 16N 6NaO 8[M+Na] +m/z 407.0927；found m/z 407.0915.
实施例6化合物13的合成
Figure PCTCN2020101906-appb-000021
将化合物6c(50.3mg,0.062mmol,1.0eq.)和LiI(83.1mg,0.621mmol,10.0eq.)置于干燥试管中，抽换Ar气后加1mL吡啶溶解，于90℃油浴中搅拌过夜，减压浓缩，经硅胶柱纯化(CH 2Cl 2:MeOH＝20:1v/v)得白色固体状产物13(42.5mg,86％)。 1H NMR(400MHz,CD 3OD)δ:8.17(d,J＝7.2Hz,2H),8.05(d,J＝7.2Hz,2H),8.00(d,J＝7.2Hz,2H),7.94(d,J＝7.2Hz,2H),7.69–7.34(m,12H),6.05–5.93(m,2H),5.54(dd,J＝10.4,3.6Hz,1H),5.08(dd,J＝12.4,2.4Hz,1H),4.68–4.47(m,4H),4.44(d,J＝3.6Hz,1H),1.80(s,3H)； 13C NMR(100MHz,CD 3OD)δ:173.3,167.6,167.1,167.0,166.8,150.0,134.7,134.6,134.6,134.3,131.3,131.0,131.0,131.0,130.9,130.8,130.7,130.3,129.7,129.6,129.6,129.5,73.3,73.1,71.6,69.6,64.9,63.6,46.0,30.7,22.7；[α]25D＝+21.4(c 0.44,CHCl 3:MeOH＝4:1)；IR(neat):ν max＝3398,2119,1725,1662,1261,1090,1069,1025,707,686；HRMS calcd.for C 39H 33N 7NaO 12[M+Na] +m/z 814.2085；found m/z 814.2055.
实施例7化合物14的合成
Figure PCTCN2020101906-appb-000022
将化合物6c(140mg,0.174mmol,1.0eq.)和Pd/C(14.0mg)置于圆底烧瓶中，抽换H 2后加10mL甲醇溶解，于室温下搅拌4h，硅藻土过滤，减压浓缩，经硅胶柱纯化(petroleum ether:EtOAc＝2:1v/v)可得白色固体状产物14(110mg,81％)。 1H NMR(400MHz,CDCl 3)δ:8.21–8.14(m,2H),8.03–7.97(m,4H),7.96–7.90(m,2H),7.64–7.45(m,6H),7.45–7.30(m,6H),5.98(dd,J＝10.8,3.6Hz,1H),5.95–5.80(m,1H),5.84(dd,J＝5.6,2.0Hz,1H),5.58(d,J＝9.6Hz,1H),5.19(dd,J＝12.4,2.8Hz,1H),4.81(dd,J＝10.4,2.0Hz,1H),4.56(dd,J＝12.0,7.6Hz,1H),4.44(q,J＝10.0Hz,1H),4.32(d,J＝3.6Hz,1H),3.88(s,3H),2.13(s,2H),1.81(s,3H)； 13C NMR(100MHz,CDCl 3)δ:170.3,170.1,166.4,166.2,165.9,133.7,133.4,132.9,130.2,130.0,129.8,129.8,129.6,129.4,129.4,128.6,128.5,128.5,128.5,128.3,86.3,72.0,71.2,70.3,69.5,63.8,63.7,53.0,46.5,23.3；[α]25D＝+4.4(c 0.50,CHCl 3)；IR(neat):ν max＝3378,2928,2855,2111,1718,1261,1107,1094,1069,1026,708；HRMS calcd.for C 40H 37N 5NaO 12[M+Na] +m/z 802.2336；found m/z 802.2325.
实施例8化合物15的合成
Figure PCTCN2020101906-appb-000023
制备方法同实施例6。化合物8a(100mg,0.126mmol,1.0eq.)和LiI(168.1mg,1.26mmol,10.0eq.)在2mL吡啶中进行反应。粗产物经硅胶柱纯化(CH 2Cl 2:MeOH＝20:1to 15:1v/v)得白色固体状产物15(74.7mg,76％)。 1H NMR(400MHz,CD 3OD)δ:8.13(d,J＝7.6Hz,2H),8.02(d,J＝7.2Hz,2H),7.93(d,J＝7.2Hz,2H),7.70–7.34(m,9H),6.10–6.02(m,1H),5.98(dd,J＝8.0,2.0Hz,1H),5.16(dd,J＝12.4,2.0Hz,1H),4.70(dd,J＝11.2,1.6Hz,1H),4.65–4.55(m,3H),4.49(dd,J＝12.4,4.8Hz,1H),4.39(dd,J＝11.2,4.4Hz,1H),4.00(d,J＝3.2Hz,1H),2.01(s,3H)； 13C NMR(150MHz,CD 3OD)δ:171.4,168.3,165.6,164.9,164.7,157.1,156.8,132.8,132.6,132.4,129.2,129.0,128.9,128.7,128.6,128.5,128.5,127.7,127.6,127.5,127.5,127.5,127.5,127.4,116.1,114.2,91.7,69.5,67.9,66.9,61.5,61.3,48.3,42.9,20.9；[α]25D＝+45.0(c 0.50,CHCl 3)；IR(neat):ν max＝2117,1718,1654,1452,1259,1177,1091,1068,709；HRMS calcd.for C 34H 29F 3N 8NaO 11[M+Na] +m/z 805.1806；found m/z 805.1803.
实施例9化合物16的制备：
Figure PCTCN2020101906-appb-000024
制备方法同实施例7。将化合物8a(100mg,0.126mmol)和Pd/C(10.2mg)置于圆底烧瓶中，抽换H 2后加5mL甲醇溶解，于室温下搅拌3h，硅藻土过滤，减压浓缩，经硅胶柱纯化(petroleum ether:EtOAc＝1.5:1v/v)得白色固体状产物16(58.9mg,63％)。 1H NMR(400MHz,CDCl 3)δ:8.15–8.07(m,2H),8.06–7.99(m,2H),7.98–7.89(m,2H),7.72(d,J＝9.2Hz,1H),7.64–7.32(m,9H),6.76(d,J＝9.2Hz,1H),5.91–5.85(m,1H),5.75(dd,J＝4.8,1.6Hz,1H),5.31(dd,J＝12.4,2.4Hz,1H),4.78–4.69(m,2H),4.46(dd,J＝12.4,7.2Hz,1H),4.43–4.35(m,1H),3.89(s,3H),3.84(d,J＝3.2Hz,1H),2.02(s,3H)； 13C NMR(100MHz,CDCl 3)δ:170.6,170.0,166.4,166.4,165.3,158.0,157.5,157.1,156.8,133.6,133.5,133.1,130.1,129.9,129.6,129.6,129.2,129.0,128.6,128.6,128.4,116.9,114.0,86.0,72.4,69.2,67.6,63.8,62.7,53.2,49.8,44.5,23.5；[α]25D＝+124.8(c 0.40,CHCl 3)；IR(neat):ν max＝3377,3287,2115,1718,1259,1250,1089,1068,1025,708；HRMS calcd.for C 35H 33F 3N 6NaO 11[M+Na] +m/z 793.2057；found m/z 793.2049.
实施例10化合物17的制备：
Figure PCTCN2020101906-appb-000025
将化合物8a(150mg,0.188mmol,1.0eq.)溶于THF和H 2O的混合溶剂(14mL,1:1v/v)中，然后依次加入炔戊醇(38.6μL,0.414mmol,2.2eq.)、CuSO 4·5H 2O(18.8mg,0.075mmol,0.4eq.)和抗坏血酸钠(149mg,0.754mmol,4.0eq.)。反应在室温下搅拌2h，TLC监测原料反应完，直接将反应液减压浓缩，先经反相硅胶柱纯化(MeOH:H 2O＝1:4to 1:1v/v)，再经正相硅胶柱纯化(CH 2Cl 2:MeOH＝15:1v/v)，得到白色固体状产物17(151mg,83％)。 1H NMR(400MHz,CD 3OD)δ:8.25–8.18(m,2H),8.02(s,1H),7.93–7.87(m,4H),7.85(s,1H),7.74–7.53(m,5H),7.46(t,J＝8.0Hz,2H),7.39(t,J＝8.0Hz,2H),6.95(d,J＝8.0Hz,1H),5.95(dd,J＝8.0,1.6Hz,1H),5.78–5.71(m,1H),5.17–5.06(m,2H),5.02(dd,J＝10.8,6.8Hz,1H),4.63(dd,J＝10.8,1.6Hz,1H),4.60(s,1H),4.39(dd,J＝12.8,4.8Hz,1H),3.62(s,3H),3.57–3.50(m,4H),2.74(t,J＝7.2Hz,2H),2.49(t,J＝ 7.6Hz,2H),1.88–1.70(m,4H),1.82(s,3H)； 13C NMR(100MHz,CD 3OD)δ:173.7,167.5,166.7,166.6,165.4,160.0,159.6,159.3,158.9,150.8,148.3,135.1,134.9,134.5,131.3,130.8,130.7,130.7,130.4,130.2,129.9,129.8,129.7,129.6,129.5,126.2,123.0,118.6,115.7,92.6,71.3,70.8,69.8,63.1,62.0,61.8,58.5,54.8,49.9,47.2,33.1,32.5,22.8,22.5,22.4；[α]25D＝+36.4(c 0.52,CHCl 3)；IR(neat):ν max＝3339,2936,1721,1260,1106,1068,708cm –1；HRMS calcd.for C 45H 47F 3N 8NaO 13[M+Na] +m/z 987.3112；found m/z 987.3072.
实施例11化合物18的制备：
Figure PCTCN2020101906-appb-000026
制备方法同实施例6。化合物8b(52.3mg,0.066mmol,1.0eq.)和LiI(87.9mg,0.657mmol,10.0eq.)在1mL吡啶中进行反应。粗产物经硅胶柱纯化(CH 2Cl 2:MeOH＝20:1to 10:1v/v)得白色固体状产物18(42.6mg,83％)。 1H NMR(400MHz,CD 3OD)δ:8.11(dd,J＝8.0,1.2Hz,2H),7.96(dd,J＝8.0,1.2Hz,2H),7.90(dd,J＝8.4,1.6Hz,2H)；7.68–7.30(m,9H),5.98–5.85(m,2H),5.10(dd,J＝12.4,3.2Hz,1H),4.78(dd,J＝10.4,2.0Hz,1H),4.70(dd,J＝12.4,6.4Hz,1H),4.61–4.50(m,1H),4.44(t,J＝5.2Hz,1H),4.21(d,J＝4.8Hz,1H),1.95(s,3H)； 13C NMR(100MHz,CD 3OD)δ:173.8,172.6,167.6,167.0,166.7,159.5,159.2,158.8,158.4,134.7,134.4,134.3,134.1,131.1,131.1,131.0,130.9,130.8,130.7,130.6,130.5,130.5,129.7,129.6,129.5,129.5,129.4,129.3,121.5,118.6,115.8,93.6,72.6,70.9,63.8,62.6,50.2,46.0,22.9,13.9；[α]25D＝+82.8(c 0.40,CHCl 3)；IR(neat):ν max＝3726,3083,2889,2114,1722,1647,1262,1177,1093,1069,707；HRMS calcd.for C 34H 29F 3N 8NaO 11[M+Na] +m/z 805.1806；found m/z 805.1811.
实施例12化合物19的制备：
Figure PCTCN2020101906-appb-000027
将化合物12b(50.4mg,0.131mmol,1.0eq.)溶于MeOH(1mL)，滴加1M的NaOH水溶液(0.131mL)，滴完继续在室温下搅拌1h，然后加入H +型离子交换树脂调节pH至中性，过滤、减压浓缩，经反相硅胶柱纯化(MeOH:H 2O＝1:9v/v)得白色固体状产 物19(34.2mg,76％)。 1H NMR(400MHz,CD 3OD)δ:4.41(dd,J＝10.4,3.6Hz,1H),4.34–4.25(m,1H),4.08(dd,J＝8.8,6.0Hz,1H),4.02–3.90(m,3H),3.46(d,J＝10.4Hz,1H),1.35(s,3H),1.32(s,3H)； 13C NMR(100MHz,CD 3OD)δ:171.7,110.4,94.4,77.7,74.6,71.0,69.3,68.3,66.3,27.0,25.6；[α]25D＝+91.2(c 0.17,CHCl 3)；IR(neat):ν max＝3383,2925,2114,1622,1615,1384,1375,1247,1226,1071,1059,842；HRMS calcd.for C 11H 16N 6NaO 7[M+Na] +m/z 367.0978；found m/z 367.0961.
实施例13生物活性试验
将上述实施例所得3-去氧-2-酮糖酸含氮衍生物进行抗病毒试验，结果如表1所示。
(1)抗寨卡(ZIKV)病毒活性测试
测试对象：寨卡病毒感染的BHK细胞
测试方法：
①将BHK细胞(军事医学研究院保存)按照5×10 3细胞/孔的浓度接种96孔板，细胞培养基为含10％FBS(购自Gibco公司，货号16000044)的DMEM培养基(购自Gibco公司，货号11995065)，置入CO 2孵箱，37℃培养24小时。
②弃96孔板中原培养基，取100μL含2％FBS(购自Gibco公司，货号16000044)的DMEM培养基(购自Gibco公司，货号11995065)加入到细胞中。然后将待测化合物母液，用上述DMEM培养基系列稀释至800μM，266.67μM，88.89μM，29.63μM，9.88μM，3.29μM，1.10μM，0.37μM，取50μL加入到细胞培养板中。阳性化合物NITD008(购自MCE公司，货号HY-12957)母液，用上述DMEM培养基系列稀释至80μM，26.67μM，8.89μM，2.96μM，0.99μM，0.33μM，0.11μM，0.04μM，取50μL加入到细胞培养板中。最后细胞中加入50μL用含2％FBS的DMEM培养基稀释好的寨卡病毒SZ-SMGC-01株(军事医学研究院保存)，使每孔含有病毒量为100TCID 50。最终待测化合物终浓度为预处理浓度的0.25倍，即以200μM为初始浓度，3倍倍比稀释，待测化合物终浓度为：200μM，66.67μM，22.22μM，7.41μM，2.47μM，0.82μM，0.27μM，0.09μM。阳性化合物终浓度为：20μM，6.67μM，2.22μM，0.74μM，0.25μM，0.082μM，0.027μM，0.009μM。注意设置阴性对照(细胞孔中加DMSO和培养基，而不加药物)和阳性对照(细胞孔中加DMSO、培养基和病毒，而不加药物)。将细胞培养板在37℃培养9天。
③将
Figure PCTCN2020101906-appb-000028
化学发光细胞活力检测试剂(购自Promega公司，货号G7573)的Buffer和底物避光混合，配制为工作液。将工作液与PBS(购自Gibco公司，货号10010049)按4:6比例混合。细胞培养板弃液后，每孔加入100μl检测试剂，利用轨道振荡器将96孔板震荡5min，以诱导细胞裂解。避光稳定信号2min后，使用酶标仪(购自Molecular Devices公司，型号SpectraMax M5)测定化学发光单位，读板程序为 CellTiter-Glo预设程序，计算细胞活性：
细胞活性(％)＝(A (药物处理组)-A (阳性对照))/(A (阴性对照)-A (阳性对照))×100％
其中A为酶标仪读数。
结果评价：利用origin8.0软件对抑制率-浓度进行S型曲线拟合，计算待测化合物的IC 50值。
(2)抗鼻病毒(HRV-1059)活性测试
测试对象：鼻病毒(HRV-1059)感染的H1Hela细胞
测试方法：
①将H1Hela细胞(购自国家实验细胞资源共享平台，货号3111C0001CCC000344)按照1.5×10 4细胞/孔的浓度接种96孔板，细胞培养基为含10％FBS(购自Gibco公司，货号16000044)的DMEM培养基(购自Gibco公司，货号11995065)，置入CO 2孵箱，37℃培养24小时。
②弃96孔板中原培养基，取100μL含2％FBS(购自Gibco公司，货号16000044)的DMEM培养基(购自Gibco公司，货号11995065)加入到细胞中。然后将待测化合物母液，用上述DMEM培养基系列稀释至800μM，266.67μM，88.89μM，29.63μM，9.88μM，3.29μM，1.10μM，0.37μM，0.12μM，0.04μM，取50μL加入到细胞培养板中。阳性化合物NITD008(购自MCE公司，货号HY-12957)母液，用上述DMEM培养基系列稀释至80μM，26.67μM，8.89μM，2.96μM，0.99μM，0.33μM，0.11μM，0.04μM，0.012μM，0.004μM，取50μL加入到细胞培养板中。最后细胞中加入50μL用含2％FBS的DMEM培养基稀释好的鼻病毒HRV-1059株(购自ATCC，货号VR-482)，使每孔含有病毒量为100TCID 50。最终待测化合物终浓度为预处理浓度的0.25倍，即以200μM为初始浓度，3倍倍比稀释，待测化合物终浓度为：200μM，66.67μM，22.22μM，7.41μM，2.47μM，0.82μM，0.27μM，0.09μM，0.03μM，0.01μM。阳性化合物终浓度为：20μM，6.67μM，2.22μM，0.74μM，0.25μM，0.082μM，0.027μM，0.009μM，0.003μM，0.001μM。设置阴性对照(细胞孔中加DMSO和培养基，而不加药物)和阳性对照(细胞孔中加DMSO、培养基和病毒，而不加药物)。将细胞培养板在37℃培养6天。
③将
Figure PCTCN2020101906-appb-000029
化学发光细胞活力检测试剂(购自Promega公司，货号G7573)的Buffer和底物避光混合，配制为工作液。将工作液与PBS(购自Gibco公司，货号10010049)按4:6比例混合。细胞培养板弃液后，每孔加入100μl检测试剂，利用轨道振荡器将96孔板震荡5min，以诱导细胞裂解。避光稳定信号2min后，使用酶标仪(购自Molecular Devices公司，型号SpectraMax M5)测定化学发光单位，读板程序为CellTiter-Glo预设程序，计算细胞活性：
细胞活性(％)＝(A (药物处理组)-A (阳性对照))/(A (阴性对照)-A (阳性对照))×100％
其中A为酶标仪读数。
结果评价：利用origin8.0软件对抑制率-浓度进行S型曲线拟合，计算待测化合物的IC 50值。
表1：代表性3-去氧-2-酮糖酸含氮衍生物的抗病毒活性结果
Figure PCTCN2020101906-appb-000030
Figure PCTCN2020101906-appb-000031
以上试验结果显示，本申请各实施例制备的3-去氧-2-酮糖酸含氮衍生物对寨卡病毒(ZIKV)和鼻病毒(HRV)显示出中等到较强抗病毒活性。
尽管本申请的具体实施方式已经得到详细的描述，本领域技术人员将会理解，根据已经公开的所有教导，可以对那些细节进行各种修改和替换，这些改变均在本申请的保护范围之内。本申请的全部范围由所附权利要求及其任何等同物给出。

Claims (19)

  1. 通式I所示的化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，
    Figure PCTCN2020101906-appb-100001
    其中：
    R 1为氢、C 1-C 6烷基、烯丙基、苯基或苄基；
    R 2和R 3各自独立地为叠氮基、氨基、被一个或两个R a取代的氨基、五元或六元含氮杂环基或被R b取代的五元或六元含氮杂环基，其中每个R a各自独立地为C 1-C 6烷基、烯丙基、苯基、苄基、甲酰基、乙酰基、苯甲酰基、三氟乙酰基、甲氧甲酰基、叔丁氧甲酰基或苄氧酰基，R b为C 1-C 6烷基、卤素或-(CH 2) mOH，其中m为0、1、2、3或4；
    R 4和R 5各自独立地为羟基、氨基、胍基、被R c取代的羟基、被R c取代的氨基、被R c取代的胍基、五元或六元含氮杂环基或被R b取代的五元或六元含氮杂环基，其中每个R c各自独立地为C 1-C 6烷基、烯丙基、苯基、苄基、三甲基硅基、三乙基硅基、三异丙基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基、甲酰基、乙酰基、苯甲酰基、三氟乙酰基、甲氧甲酰基、叔丁氧甲酰基或苄氧酰基，R b为C 1-C 6烷基、卤素或-(CH 2) mOH，其中m为0、1、2、3或4，或者，
    R 4和R 5与它们所连接的碳原子共同形成五元或六元含氧或含氮的杂环(例如1,3-二氧戊环、1,3-二氧戊环-2-酮、二噁烷、二噁烷酮、噁唑烷或噁唑烷酮)；
    R 6为氢、C 1-C 6烷基、烯丙基、苯基、苄基、三甲基硅、三乙基硅、三异丙基硅、叔丁基二甲基硅、叔丁基二苯基硅、甲酰基、乙酰基、苯甲酰基、三氟乙酰基；
    R 7为氢、
    Figure PCTCN2020101906-appb-100002
    R 6OCH 2-或R 6OCH 2(R 6O)CH-，其中R 6的定义如上所述；
    n为0、1、2或3。
  2. 权利要求1所述的化合物、其立体异构体、其药学可接受的盐、其药学上可接受 的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：
    优选地，R 1为氢或C 1-C 4烷基；
    优选地，R 2和R 3各自独立地为叠氮基、氨基或被R b取代的五元或六元含氮杂环基，其中R b为-(CH 2) mOH，其中m为0、1、2、3或4，所述五元或六元含氮杂环基为三氮唑基、四氮唑基、吡咯基、四氢吡咯基、哌啶基、吡啶基、噁唑基或咪唑基；
    优选地，R 4和R 5各自独立地为羟基、氨基、被R c取代的羟基、被R c取代的氨基，其中每个R c各自独立地为C 1-C 4烷基、烯丙基、苯基、苄基、三甲基硅基、三乙基硅基、三异丙基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基、甲酰基、乙酰基、苯甲酰基、三氟乙酰基、甲氧甲酰基、叔丁氧甲酰基或苄氧酰基；
    优选地，R 4和R 5与它们所连接的碳原子共同形成五元含氧的杂环(例如1,3-二氧戊环、1,3-二氧戊环-2-酮)；
    优选地，R 6为甲酰基、乙酰基、苯甲酰基或三氟乙酰基；
    优选地，R 7为
    Figure PCTCN2020101906-appb-100003
    R 6OCH 2-或R 6OCH 2(R 6O)CH-，其中R 6的定义如上所述；
    优选地，n为0、1或2。
  3. 权利要求1或2所述的化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：
    优选地，R 1为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    优选地，R 2和R 3各自独立地为叠氮基、氨基或被R b取代的五元含氮杂环基，其中R b为-(CH 2) mOH，其中m为0、1、2或3，所述五元含氮杂芳基为三氮唑基、四氮唑基、吡咯基、四氢吡咯基、噁唑基或咪唑基；
    优选地，R 4和R 5各自独立地为羟基、被R c取代的羟基、被R c取代的氨基，其中每个R c各自独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、三甲基硅基、三乙基硅基、三异丙基硅基、叔丁基二甲基硅基、甲酰基、乙酰基、苯甲酰基、三氟乙酰基。
  4. 权利要求1至3任一项所述的化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中：
    优选地，R 1为氢或甲基；
    优选地，R 2为叠氮基或
    Figure PCTCN2020101906-appb-100004
    优选地，R 3为叠氮基、氨基或
    Figure PCTCN2020101906-appb-100005
    优选地，R 4为羟基、叔丁基二甲基硅基氧基、苯甲酰基氧基、乙酰基氨基或乙酰基氧基；
    优选地，R 5为羟基、三氟乙酰基氧基、乙酰基氨基或乙酰基氧基；
    优选地，R 4和R 5与它们所连接的碳原子共同形成1,3-二氧戊环或1,3-二氧戊环-2-酮；
    优选地，R 6为乙酰基或苯甲酰基；
    优选地，R 7为
    Figure PCTCN2020101906-appb-100006
    或R 6OCH 2，其中R 6的定义如上所述；
    优选地，n为0、1或2。
  5. 权利要求1至4任一项所述的化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，其中所述化合物选自：
    Figure PCTCN2020101906-appb-100007
    Figure PCTCN2020101906-appb-100008
  6. 制备权利要求1至5任一项所述的化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物的方法，包括：
    Figure PCTCN2020101906-appb-100009
    a)在溶剂中，式II所示化合物、高价碘试剂和叠氮三甲基硅烷在光照的条件下反应生成式III所示的双叠氮化产物；
    b)式III所示的双叠氮化合物通过酯基水解、叠氮基还原、羟基或胺基上各保护基团脱除或氮杂环形成生成通式I所示化合物，
    其中：R 1、R 2、R 3、R 4、R 5、R 6、R 7的定义如权利要求1至5任一项所述，
    优选地，步骤a)中所述高价碘试剂选自
    Figure PCTCN2020101906-appb-100010
    Figure PCTCN2020101906-appb-100011
    等，优选
    Figure PCTCN2020101906-appb-100012
    优选地，步骤a)中所述溶剂选自二氯甲烷、丙酮、二甲亚砜、乙腈等，优选乙腈；
    优选地，步骤a)中所述光照的光源为自然光或各种颜色的LED光等，优选蓝色LED光；
    优选地，步骤a)所述反应在温度为0～60℃的条件下进行，优选在光照条件并且温度为20～40℃的条件下进行；
    优选地，步骤b)中所述酯基水解在碱和溶剂的存在下进行，优选地，所述碱选自氢氧化锂、氢氧化钠、氢氧化钾、甲醇钠、碳酸钠、碳酸钾、叔丁醇钠、叔丁醇钾，所述溶剂为水或醇类溶剂如甲醇、乙醇、异丙醇、叔丁醇等中的一种或两种的混合物；
    优选地，步骤b)中所述叠氮基还原在还原剂和溶剂的存在下进行，优选地，所述还原剂选自三苯基膦、三甲基膦、三丁基膦、钯碳/氢气、氢氧化钯/氢气、雷尼镍/氢气等，所述溶剂选自水、四氢呋喃或醇类溶剂如甲醇、乙醇、异丙醇、叔丁醇等中的一种或两种的混合物；
    优选地，步骤b)中所述保护基团脱除在酸或碱和溶剂的存在下进行，优选地，所述酸选自盐酸、硫酸、对甲苯磺酸、三氟乙酸等，所述碱选自氢氧化钠、氢氧化钾、甲醇钠、碳酸钠、碳酸钾、叔丁醇钠、叔丁醇钾等，所述溶剂选自水、二氯甲烷、四氢呋喃或醇类溶剂如甲醇、乙醇、异丙醇、叔丁醇等中的一种或两种的混合物；
    优选地，步骤b)中所述氮杂环形成在炔烃，铜催化剂和溶剂的存在下进行，优选地，所述炔烃选自各种长度，带或不带各种官能基团的末端炔烃或内部炔烃，所述铜催化剂选自氯化亚铜、溴化亚铜、碘化亚铜、硫酸铜/抗坏血酸钠等，所述溶剂选自水、二氯甲烷、四氢呋喃或醇类溶剂如甲醇、乙醇、异丙醇、叔丁醇等中的一种或两种的混合物。
  7. 一种药物组合物，其包括至少一种权利要求1～5任一项所述的化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物，以及一种或多种药学上可接受的载体或赋形剂。
  8. 权利要求1～5任一项所述的化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物或权利要求7所述的药物组合物在制备用于抗病毒的药物(例如抗寨卡病毒、鼻病毒)中的用途。
  9. 权利要求1～5任一项所述的化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物或权利要求7所述的药物组合物在制备用于抑制病毒(例如抗寨卡病毒、鼻病毒)在细胞(例如哺乳动物细胞)中复制或繁殖的药物中的用途。
  10. 权利要求1～5任一项所述的化合物、其立体异构体、其药学可接受的盐、其药学 上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物或权利要求7所述的药物组合物在制备作为病毒(例如抗寨卡病毒、鼻病毒)抑制剂的药物中的用途。
  11. 权利要求1～5任一项所述的化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物或权利要求7所述的药物组合物在制备用于预防和/或治疗病毒(例如抗寨卡病毒、鼻病毒)引起的疾病或感染的药物中的用途。
  12. 权利要求1～5任一项所述的化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物或权利要求7所述的药物组合物，其用于抗病毒的药物(例如抗寨卡病毒、鼻病毒)。
  13. 权利要求1～5任一项所述的化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物或权利要求7所述的药物组合物，其用于抑制病毒(例如抗寨卡病毒、鼻病毒)在细胞(例如哺乳动物细胞)中复制或繁殖。
  14. 权利要求1～5任一项所述的化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物或权利要求7所述的药物组合物，其用作病毒(例如抗寨卡病毒、鼻病毒)抑制剂。
  15. 权利要求1～5任一项所述的化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物或权利要求7所述的药物组合物，其用于预防和/或治疗病毒(例如抗寨卡病毒、鼻病毒)引起的疾病或感染。
  16. 一种在有需要的哺乳动物中预防和/或治疗病毒(例如抗寨卡病毒、鼻病毒)引起的疾病或感染的方法，该方法包括给有需要的哺乳动物施用预防和/或治疗有效量的权利要求1～5任一项所述的化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物或权利要求7所述的药物组合物。
  17. 一种在有需要的哺乳动物中抑制病毒(例如抗寨卡病毒、鼻病毒)复制或繁殖的方法，该方法包括给有需要的哺乳动物施用治疗和/或预防有效量的权利要求1～5任一项所述的化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物或权利要求7所述的药物组合物。
  18. 一种抑制病毒(例如抗寨卡病毒、鼻病毒)在细胞(例如哺乳动物细胞)中复制或繁殖的方法，该方法包括将权利要求1～5任一项所述的化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合 物或权利要求7所述的药物组合物与细胞接触。
  19. 权利要求9所述的用途，权利要求13所述的化合物、其立体异构体、其药学可接受的盐、其药学上可接受的酯、其药学可接受的水合物或其药学可接受的溶剂合物或药物组合物或权利要求16～18所述的方法，其中所述的哺乳动物包括牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物，其中优选的哺乳动物为人、猫、狗或猪。
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See also references of EP4183792A4

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EP4183792A4 (en) 2024-03-20
CN114190092A (zh) 2022-03-15
CN114190092B (zh) 2023-07-18
JP2023542455A (ja) 2023-10-10
US20230271993A1 (en) 2023-08-31

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