WO2022028389A1 - Fused tricyclic derivative, preparation method therefor, and pharmaceutical use thereof - Google Patents

Fused tricyclic derivative, preparation method therefor, and pharmaceutical use thereof Download PDF

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Publication number
WO2022028389A1
WO2022028389A1 PCT/CN2021/110197 CN2021110197W WO2022028389A1 WO 2022028389 A1 WO2022028389 A1 WO 2022028389A1 CN 2021110197 W CN2021110197 W CN 2021110197W WO 2022028389 A1 WO2022028389 A1 WO 2022028389A1
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general formula
group
enantiomer
pharmaceutically acceptable
racemate
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PCT/CN2021/110197
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French (fr)
Chinese (zh)
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张晓敏
张睿
原慧卿
贺峰
陶维康
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Publication of WO2022028389A1 publication Critical patent/WO2022028389A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • 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 present disclosure belongs to the field of medicine, and relates to a fused tricyclic derivative, a preparation method thereof and its application in medicine.
  • the present disclosure relates to the fused tricyclic derivatives represented by the general formula (I), their preparation methods and pharmaceutical compositions containing the derivatives, and their use as TLR7/8/9 inhibitors in the treatment of inflammation and autoimmunity. Use in immune diseases.
  • TLRs Toll-like receptors
  • PAMPs pathogen-associated molecular patterns
  • TLR7/8/9 were mainly highly expressed in DC cells and B cells, TLR7/8 mainly recognized ssRNA, and TLR9 mainly recognized CpG-DNA.
  • TLR7/8/9 is activated after binding its ligands, and binds to the adaptor protein MyD88 in the cytoplasm to initiate NF- ⁇ B and IRF pathways, activate DC cells, and produce type I interferon and various other inflammatory cytokines.
  • B cells the combination of TLR7/8/9 and nucleic acids plays an important role in the production of antinuclear antibodies by B cells, and the type I interferon secreted by DC cells also promotes this autoimmune B cell. The further proliferation and activation of cells causes a series of inflammatory responses.
  • SLE Systemic lupus erythematosus
  • hormones include hormones, immunosuppressants and antimalarial drugs.
  • belimumab Only one new drug, belimumab, has been approved by the FDA this century, but it has only modest and delayed efficacy in a small subset of SLE patients (Navarra, SV et al., Lancet 2011, 377, 721), and the treatment options are very limited. Therefore, there is an urgent need for new treatments that improve a larger proportion of the patient population and that can be used safely and long-term.
  • TLR7/9 and type I interferon were found to be significantly up-regulated in PBMCs of systemic lupus erythematosus (SLE) patients (Beverly D.LC et al., Mol Immunol., 2014, 61:38-43).
  • Mice overexpressing TLR7 have been reported to exacerbate autoimmune disease and autoinflammation (Santiago-Raber ML et al., J Immunol., 2008, 181:1556-1562), while functional inhibition of TLR7/9 alleviates B6-Fas lpr and BXSB and other pathological manifestations of lupus mice (Dwight H.
  • TLR7/8/9 TLR7/8/9 with antinuclear antibodies and type I interferons
  • small-molecule inhibitors targeting TLR7/8/9 are likely to have potential in the treatment of SLE.
  • TLR7/8/9 inhibitors include WO2019233941A1, WO2020020800A1, WO2018049089A1, WO2019238616A1, WO2017106607A1, CN109923108A, and WO2020048605A1, among others.
  • the purpose of the present disclosure is to provide a compound represented by the general formula (I) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or its Medicinal salts:
  • Ring A is selected from one of the following groups:
  • R 1 and R 2 are the same or different, and are independently selected from hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkoxy groups group, halogen, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein, the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heteroalkyl substituted with one or more substituents in cyclic, aryl and heteroaryl;
  • R 3 and R 4 are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, oxo, halogen, cyano, amino, nitro, hydroxyl, aldehyde and carboxyl;
  • Z is selected from CH 2 , CR 7a R 7b , NR 8a and oxygen atoms;
  • L 1 and L 2 are the same or different, and are each independently selected from a chemical bond, CH 2 , CR 7c R 7d and C(O);
  • L 3 is selected from chemical bonds, CH 2 , CR 7e R 7f , NH, C(O)NR 8b , NR 8b (CH 2 ) m and C(O);
  • X and Y are the same or different, and are each independently a CR 5a or a nitrogen atom;
  • W 1 , W 2 , W 3 and W 4 is a carbon atom, and the other three are the same or different, and each independently is a CR 5b or a nitrogen atom;
  • R 5a is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, halogen, cyano, amino, nitro, hydroxyl , aldehyde group and carboxyl group;
  • R 5b is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, halogen, cyano, amino, -NR 9a R 9b , -COR 10 , -C (O) OR 11 , -OR 12 , nitro group, hydroxyl group, aldehyde group, carboxyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group; wherein, the alkyl group, cycloalkyl group, heterocyclic group , aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy, cyano, amino, -( CH 2 ) s NR 13a R 13b , nitro, hydroxy, hydroxyalkyl
  • Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 6 are the same or different, and each is independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an oxo group, a halogen group, a cyano group, an amino group, -NR 9a R 9b , -COR 10 , -C(O)OR 11 , -OR 12 , -(CH 2 ) s NR 13a R 13b , -CO(CH 2 ) s NR 13a R 13b , nitro, hydroxyl, Aldehyde, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkeny
  • R 7a , R 7b , R 7c , R 7d , R 7e and R 7f are the same or different, and are each independently selected from hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkenyl groups , alkynyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 8a and R 8b are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group ;
  • R 9a and R 9b are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group ; wherein, the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkane One or more substituents of oxy, cyano, amino, -(CH 2 ) s NR 13a R 13b , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl replaced;
  • R 10 is selected from hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group; wherein, the alkyl group, cycloalkyl group, heterocyclic group , aryl, and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -( CH2 ) sNR 13a R 13b , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted with one or more substituents;
  • R 11 and R 12 are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group ; wherein, the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkane One or more substituents of oxy, cyano, amino, -(CH 2 ) s NR 13a R 13b , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl replaced;
  • R 13a and R 13b are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, and a hydroxyalkyl group;
  • n 0, 1, 2, 3;
  • p 0, 1, 2, 3;
  • q 0, 1, 2, 3;
  • t 0, 1, 2, 3, 4, 5;
  • s 0, 1, 2, 3, 4, 5, 6;
  • n 0, 1, 2, 3, 4, 5, 6.
  • Ring A is selected from one of the following groups:
  • R 1 and R 2 are the same or different, and are independently selected from hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkoxy groups group, halogen, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein, the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heteroalkyl substituted with one or more substituents in cyclic, aryl and heteroaryl;
  • R 3 and R 4 are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, oxo, halogen, cyano, amino, nitro, hydroxyl, aldehyde and carboxyl;
  • Z is selected from CH 2 , CR 7a R 7b , NR 8a and oxygen atoms;
  • L 1 and L 2 are the same or different, and are each independently selected from a chemical bond, CH 2 , CR 7c R 7d and C(O);
  • L 3 is selected from chemical bonds, CH 2 , CR 7e R 7f , NH, NR 8b (CH 2 ) m and C(O);
  • X and Y are the same or different, and are each independently a CR 5a or a nitrogen atom;
  • W 1 , W 2 , W 3 and W 4 are the same or different, and are each independently CR 5b or a nitrogen atom;
  • R 5a is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, halogen, cyano, amino, nitro, hydroxyl , aldehyde group and carboxyl group;
  • R 5b is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, halogen, cyano, amino, -NR 9a R 9b , -COR 10 , -C (O) OR 11 , -OR 12 , nitro group, hydroxyl group, aldehyde group, carboxyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group; wherein, the alkyl group, cycloalkyl group, heterocyclic group , aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy, cyano, amino, -( CH 2 ) s NR 13a R 13b , nitro, hydroxy, hydroxyalkyl
  • Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl , alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy, cyano, amino, -(CH 2 ) s NR 13a R 13b , nitro, hydroxy, hydroxyalkyl, ring substituted with one or more substituents of alkyl, heterocyclyl, aryl and heteroaryl;
  • R 6 are the same or different, and each is independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an oxo group, a halogen group, a cyano group, an amino group, -NR 9a R 9b , -COR 10 , -C(O)OR 11 , -OR 12 , nitro, hydroxyl, aldehyde, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein, the Said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkyl , one or more of halo
  • R 7a , R 7b , R 7c , R 7d , R 7e and R 7f are the same or different, and are each independently selected from hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkenyl groups , alkynyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 8a and R 8b are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group ;
  • R 9a and R 9b are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group ; wherein, the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkane One or more substituents of oxy, cyano, amino, -(CH 2 ) s NR 13a R 13b , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl replaced;
  • R 10 is selected from hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group; wherein, the alkyl group, cycloalkyl group, heterocyclic group , aryl, and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -( CH2 ) sNR 13a R 13b , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted with one or more substituents;
  • R 11 and R 12 are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group ; wherein, the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkane One or more substituents of oxy, cyano, amino, -(CH 2 ) s NR 13a R 13b , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl replaced;
  • R 13a and R 13b are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, and a hydroxyalkyl group;
  • n 0, 1, 2, 3;
  • p 0, 1, 2, 3;
  • q 0, 1, 2, 3;
  • t 0, 1, 2, 3, 4, 5;
  • s 0, 1, 2, 3, 4, 5, 6;
  • n 0, 1, 2, 3, 4, 5, 6.
  • the compound represented by the general formula (I) or its tautomer, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof, the compound represented by the general formula (I-1) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
  • Ring B is a 4- to 12-membered heterocyclic group containing at least 1 N atom
  • R 6a is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, -NR 9a R 9b , -COR 10 , -C(O)OR 11 , - OR 12 , -(CH 2 ) s NR 13a R 13b , -CO(CH 2 ) s NR 13a R 13b and cycloalkyl;
  • t 1, 2, 3, 4, 5;
  • Rings A, X, Y, Z, L 1 , L 2 , L 3 , W 1 to W 4 , R 3 , R 4 , R 6 , R 9a , R 9b , R 10 to R 12 , R 13a , R 13b , s and n are as defined in general formula (I).
  • the compound represented by the general formula (I) or its tautomer, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof the compound represented by the general formula (II) or its tautomer, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof:
  • Rings B, X, Y, Z, L 1 , L 2 , L 3 , W 1 to W 4 , R 1 to R 4 , R 6 , q, n and t are as defined in general formula (I).
  • the compound represented by general formula (I), general formula (I-1) or general formula (II) or its tautomer, racemate, para- Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by general formula (II-1) or tautomers and racemates thereof , enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • Ring B is a 4- to 12-membered heterocyclic group containing at least 1 N atom
  • R 6a is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, -NR 9a R 9b , -COR 10 , -C(O)OR 11 , - OR 12 , -(CH 2 ) s NR 13a R 13b , -CO(CH 2 ) s NR 13a R 13b and cycloalkyl;
  • t 1, 2, 3, 4, 5;
  • X, Y, Z, L 1 , L 2 , L 3 , W 1 to W 4 , R 1 to R 4 , R 6 , R 9a , R 9b , R 10 to R 12 , R 13a , R 13b , s, q and n are as defined in general formula (I), general formula (I-1) or general formula (II).
  • the compound represented by the general formula (I), the general formula (I-1), the general formula (II) or the general formula (II-1) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein Z is an oxygen atom.
  • the compound represented by the general formula (I), the general formula (I-1), the general formula (II) or the general formula (II-1) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein X and Y are the same and are nitrogen atoms.
  • the compound represented by the general formula (I), the general formula (I-1), the general formula (II) or the general formula (II-1) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein W 1 , W 2 and W 4 are CR 5b , and W 3 is carbon atom; or W 1 and W 4 are CR 5b , W 2 is a nitrogen atom, and W 3 is a carbon atom; or W 1 and W 2 are CR 5b , W 3 is a carbon atom, and W 4 is a nitrogen atom; wherein R 5b is a hydrogen atom or a C 1-6 alkyl group.
  • the compound represented by general formula (I) or general formula (II) or its tautomers, racemates, enantiomers, diastereomers Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by general formula (III) or tautomers, racemates, enantiomers, diastereomers thereof Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • Ring B, L 1 to L 3 , R 1 to R 4 , R 6 , q, n and t are as defined in general formula (I) or general formula (II).
  • the compound represented by the general formula (I), the general formula (I-1), the general formula (II), the general formula (II-1) or the general formula (III) or its tautomer, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable salt which is represented by the general formula (III-1)
  • Ring B is a 4- to 12-membered heterocyclic group containing at least 1 N atom
  • R 6a is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, -NR 9a R 9b , -COR 10 , -C(O)OR 11 , - OR 12 , -(CH 2 ) s NR 13a R 13b , -CO(CH 2 ) s NR 13a R 13b and cycloalkyl;
  • t 1, 2, 3, 4, 5;
  • L 1 , L 2 , L 3 , R 1 to R 4 , R 6 , R 9a , R 9b , R 10 to R 12 , R 13a , R 13b , s, q and n are as in general formula (I), general formula (I-1), general formula (II), general formula (II-1) or general formula (III) as defined.
  • the compound represented by the general formula (I), the general formula (II) or the general formula (III) or its tautomers, racemates, enantiomers A isomer, a diastereomer, a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by the general formula (IV) or a tautomer, racemate, enantiomer thereof A isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
  • Ring B, L 3 , R 1 to R 3 , R 6 , q and t are as defined in general formula (I), general formula (II) or general formula (III).
  • R 3 is C 1-6 alkyl
  • Rings B, L3, R1, R2, R6, q and t are as defined in general formula (I), general formula (II), general formula (III) or general formula (IV).
  • the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1) or the compound represented by the general formula (IV) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable form thereof salt which is the compound represented by general formula (IV-1), or its tautomer, racemate, enantiomer, diastereomer, or its mixture form, or its Medicinal salts:
  • Ring B is a 4- to 12-membered heterocyclic group containing at least 1 N atom
  • R 6a is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, -NR 9a R 9b , -COR 10 , -C(O)OR 11 , - OR 12 , -(CH 2 ) s NR 13a R 13b , -CO(CH 2 ) s NR 13a R 13b and cycloalkyl;
  • t 1, 2, 3, 4, 5;
  • L 3 , R 1 to R 3 , R 6 , R 9a , R 9b , R 10 to R 12 , R 13a , R 13b , s and q are as in general formula (I), general formula (I-1), general formula (II), as defined in general formula (II-1), general formula (III), general formula (III-1) or general formula (IV).
  • the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), the compound represented by general formula (IV) or general formula (IV') or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IV'-1), or its tautomer, racemate, enantiomer, and diastereomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof:
  • R 3 is C 1-6 alkyl
  • Ring B is a 4- to 12-membered heterocyclic group containing at least 1 N atom
  • R 6a is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, -NR 9a R 9b , -COR 10 , -C(O)OR 11 , - OR 12 , -(CH 2 ) s NR 13a R 13b , -CO(CH 2 ) s NR 13a R 13b and cycloalkyl;
  • t 1, 2, 3, 4, 5;
  • L 3 , R 1 , R 2 , R 6 , R 9a , R 9b , R 10 to R 12 , R 13a , R 13b , s and q are as in general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula (III-1), general formula (IV) or general formula (IV').
  • R 3 is C 1-6 alkyl
  • Rings B, L3, R1, R2, R6, q and t are as defined in general formula (I), general formula (II), general formula (III) or general formula (IV).
  • R 3 is C 1-6 alkyl
  • Ring B is a 4- to 12-membered heterocyclic group containing at least 1 N atom
  • R 6a is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, -NR 9a R 9b , -COR 10 , -C(O)OR 11 , - OR 12 , -(CH 2 ) s NR 13a R 13b , -CO(CH 2 ) s NR 13a R 13b and cycloalkyl;
  • t 1, 2, 3, 4, 5;
  • L 3 , R 1 , R 2 , R 6 , R 9a , R 9b , R 10 to R 12 , R 13a , R 13b , s and q are as in general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula (III-1), general formula (IV), general formula (IV-1) or general formula (IV-1-a) defined.
  • R 3 is C 1-6 alkyl
  • Ring B is a 4- to 12-membered heterocyclic group containing at least 1 N atom
  • R 6a is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, -NR 9a R 9b , -COR 10 , -C(O)OR 11 , - OR 12 , -(CH 2 ) s NR 13a R 13b , -CO(CH 2 ) s NR 13a R 13b and cycloalkyl;
  • t 1, 2, 3, 4, 5;
  • L 3 , R 1 , R 2 , R 6 , R 9a , R 9b , R 10 to R 12 , R 13a , R 13b , s and q are as in general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula (III-1), general formula (IV), general formula (IV-1) or general formula (IV-1-b) defined.
  • the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) the compound represented by the general formula (IV-1-a), the general formula (IV-1-b), the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein L 3 is selected from a bond, NH, and C(O)NR 8b , wherein R 8b is a hydrogen atom.
  • the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) the compound represented by the general formula (IV-1-a), the general formula (IV-1-b), the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 1 is selected from a hydrogen atom, a deuterium atom, a C 1-6 alkyl group , C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, cyano, amino, nitro
  • the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) the compound represented by the general formula (IV-1-a), the general formula (IV-1-b), the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomerism body, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen atom, deuterium atom, C 1-6 alkyl , C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl and halogen; preferably, R 2 is a hydrogen atom.
  • the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) the compound represented by the general formula (IV-1-a), the general formula (IV-1-b), the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 6 is selected from hydrogen atom, deuterium atom, C 1-6 alkyl group , C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, -COR 10 , -C(O) OR 11
  • the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) the compound represented by the general formula (IV-1-a), the general formula (IV-1-b), the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R5a is a hydrogen atom.
  • the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) the compound represented by the general formula (IV-1-a), the general formula (IV-1-b), the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 5b is a hydrogen atom or a C 1-6 alkyl group; preferably, R 5b is a hydrogen atom.
  • the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) the compound represented by the general formula (IV-1-a), the general formula (IV-1-b), the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 7a , R 7b , R 7c , R 7d , R 7e and R 7f are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a C 1-6 alkyl group, a C 1-6 deuterated alkyl group, a C 1-6 haloalkyl group,
  • the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) the compound represented by the general formula (IV-1-a), the general formula (IV-1-b), the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 8a and R 8b are the same or different, and are each independently selected from hydrogen atom, deuterium atom, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl; preferably, R 8a and R 8b are hydrogen atoms.
  • the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) the compound represented by the general formula (IV-1-a), the general formula (IV-1-b), the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 9a and R 9b are the same or different, and are each independently selected from hydrogen atom, deuterium atom, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl.
  • the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) the compound represented by the general formula (IV-1-a), the general formula (IV-1-b), the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomerism body, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from hydrogen atom, deuterium atom, C 1-6 alkyl , C 1-6 deuterated alkyl, C 1-6 haloalkyl, 3 to 8 membered cycloalkyl, 3 to 12 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl; wherein
  • the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) the compound represented by the general formula (IV-1-a), the general formula (IV-1-b), the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 11 and R 12 are the same or different, and are each independently selected from hydrogen atom, deuterium atom, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, 3- to 8-membered cycloalkyl, 3- to 12-membered heterocycle C 1-6 al
  • the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) the compound represented by the general formula (IV-1-a), the general formula (IV-1-b), the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 13a and R 13b are the same or different, and are each independently selected from hydrogen atom, deuterium atom and C 1-6 alkyl group; preferably, R 13a and R 13b are the same or different, and are each independently a hydrogen atom or a C 1-6 alkyl group.
  • the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) the compound represented by the general formula (IV-1-a), the general formula (IV-1-b), the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein q is 0 or 1; preferably, q is 1.
  • the general formula (I-1), general formula (II-1), general formula (III-1), general formula (IV-1), general formula (IV') -1 the compound represented by general formula (IV-2) or general formula (IV-3) or its tautomer, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein t is 1 or 2.
  • the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) the compound represented by the general formula (IV-1-a), the general formula (IV-1-b), the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein s is 0, 1, or 2.
  • the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) the compound represented by the general formula (IV-1-a), the general formula (IV-1-b), the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein m is 0 or 6.
  • R 6a is selected from hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, -COR 10 , -(CH 2 ) s NR 13a R 13b , -CO(CH 2 ) s NR 13a R 13b and 3- to 8-membered cycloalkyl;
  • R 6 is selected from hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, Halogen, -COR 10 , -(CH 2 ) s NR 13a R 13
  • Typical compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure pertains to compounds of formula (Ia) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or tautomers, racemates, enantiomers, or mixtures thereof.
  • Medicinal salt :
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • Ring A, Ring B, X, Y, Z, L 1 to L 3 , R 3 , R 4 , R 6 , W 1 to W 4 , n and t are as defined in general formula (I).
  • Another aspect of the present disclosure relates to a compound represented by general formula (I-1a) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or Its pharmaceutically acceptable salts:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • t 1, 2, 3, 4, 5;
  • Ring A, Ring B, X, Y, Z, L 1 to L 3 , R 3 , R 4 , R 6 , W 1 to W 4 and n are as defined in the general formula (I-1).
  • Another aspect of the present disclosure pertains to compounds of general formula (IIa) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or tautomers, racemates, enantiomers, or mixtures thereof Medicinal salt:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • Rings B, X, Y, Z, L 1 , L 2 , L 3 , R 1 to R 4 , R 6 , W 1 to W 4 , q, n and t are as defined in general formula (II).
  • Another aspect of the present disclosure relates to a compound represented by general formula (II-1a) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or Its pharmaceutically acceptable salts:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • t 1, 2, 3, 4, 5;
  • Rings B, X, Y, Z, L 1 , L 2 , L 3 , R 1 to R 4 , R 6 , q and n are as defined in general formula (II-1).
  • Another aspect of the present disclosure pertains to compounds of general formula (IIIa) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or isomers thereof Medicinal salt:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • Ring B, L 1 to L 3 , R 1 to R 4 , R 6 , q, n and t are as defined in general formula (III).
  • Another aspect of the present disclosure relates to a compound represented by general formula (III-1a) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Its pharmaceutically acceptable salts:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • t 1, 2, 3, 4, 5;
  • Ring B, L 1 to L 3 , R 1 to R 4 , R 6 , q and n are as defined in general formula (III-1).
  • Another aspect of the present disclosure pertains to compounds of formula (IVa) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or tautomers, racemates, enantiomers, or mixtures thereof Medicinal salt:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • Rings B, L 3 , R 1 to R 3 , R 6 , q and t are as defined in general formula (IV).
  • Another aspect of the present disclosure relates to a compound of formula (IV'a) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Its pharmaceutically acceptable salts:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • Rings B, L3, R1 to R3 , R6, q and t are as defined in general formula (IV').
  • Another aspect of the present disclosure relates to a compound represented by general formula (IV-1a) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or Its pharmaceutically acceptable salts:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • t 1, 2, 3, 4, 5;
  • Ring B, L 3 , R 1 to R 3 , R 6 and q are as defined in general formula (IV-1).
  • Another aspect of the present disclosure relates to the compound represented by general formula (IV'-1a) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • t 1, 2, 3, 4, 5;
  • Ring B, L 3 , R 1 to R 3 , R 6 and q are as defined in general formula (IV'-1).
  • Another aspect of the present disclosure relates to a compound represented by general formula (IV-2a) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Its pharmaceutically acceptable salts:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • t 1, 2, 3, 4, 5;
  • Ring B, L 3 , R 1 to R 3 , R 6 and q are as defined in general formula (IV-2).
  • Another aspect of the present disclosure relates to a compound represented by general formula (IV-3a) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Its pharmaceutically acceptable salts:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • t 1, 2, 3, 4, 5;
  • Ring B, L 3 , R 1 to R 3 , R 6 and q are as defined in general formula (IV-3).
  • Typical compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure relates to the preparation of a compound of general formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof in the form of , or a method of a pharmaceutically acceptable salt thereof, the method comprising:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • Ring A, Ring B, X, Y, Z, L 1 to L 3 , R 3 , R 4 , R 6 , W 1 to W 4 , n and t are as defined in general formula (I).
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (I-1) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof form, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • R 6a is a hydrogen atom
  • t 1, 2, 3, 4, 5;
  • Ring A, Ring B, X, Y, Z, L 1 to L 3 , R 3 , R 4 , R 6 , W 1 to W 4 and n are as defined in the general formula (I-1).
  • Another aspect of the present disclosure relates to a preparation of the compound represented by the general formula (II) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • Rings B, X, Y, Z, L 1 , L 2 , L 3 , W 1 to W 4 , R 1 to R 4 , R 6 , q, n and t are as defined in general formula (II).
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (II-1) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof form, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • R 6a is a hydrogen atom
  • t 1, 2, 3, 4, 5;
  • Rings B, X, Y, Z, L 1 , L 2 , L 3 , W 1 to W 4 , R 1 to R 4 , R 6 , q and n are as defined in the general formula (II-1).
  • Another aspect of the present disclosure relates to a preparation of the compound represented by the general formula (III) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • Ring B, L 1 to L 3 , R 1 to R 4 , R 6 , q, n and t are as defined in general formula (III).
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (III-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof form, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • R 6a is a hydrogen atom
  • t 1, 2, 3, 4, 5;
  • Ring B, L 1 to L 3 , R 1 to R 4 , R 6 , q and n are as defined in general formula (III-1).
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (IV) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • Rings B, L 3 , R 1 to R 3 , R 6 , q and t are as defined in general formula (IV).
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (IV') or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof , or a method of a pharmaceutically acceptable salt thereof, the method comprising:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • Rings B, L3, R1 to R3 , R6, q and t are as defined in general formula (IV').
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (IV-1) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof form, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • R 6a is a hydrogen atom
  • t 1, 2, 3, 4, 5;
  • Ring B, L 3 , R 1 to R 3 , R 6 and q are as defined in general formula (IV-1).
  • Another aspect of the present disclosure relates to a preparation of the compound represented by the general formula (IV'-1) or its tautomer, racemate, enantiomer, diastereomer, or its A method in the form of a mixture, or a pharmaceutically acceptable salt thereof, comprising:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • R 6a is a hydrogen atom
  • t 1, 2, 3, 4, 5;
  • Ring B, L 3 , R 1 to R 3 , R 6 and q are as defined in general formula (IV'-1).
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (IV-2) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof form, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • R 6a is a hydrogen atom
  • t 1, 2, 3, 4, 5;
  • Ring B, L 3 , R 1 to R 3 , R 6 and q are as defined in general formula (IV-2).
  • Another aspect of the present disclosure relates to a preparation of a compound represented by general formula (IV-3) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof form, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • R 6a is a hydrogen atom
  • t 1, 2, 3, 4, 5;
  • Ring B, L 3 , R 1 to R 3 , R 6 and q are as defined in general formula (IV-3).
  • Another aspect of the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (II-1), general formula formula (III), general formula (III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2) , general formula (IV-3), general formula (IV-1-a), general formula (IV-1-b), general formula (IV-2-a), general formula (IV-2-b) and table A compound represented by A, or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more A pharmaceutically acceptable carrier, diluent or excipient.
  • the present disclosure further relates to general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula (III-1), general formula (IV) ), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3), general formula (IV-1-a) ), general formula (IV-1-b), general formula (IV-2-a), general formula (IV-2-b) and the compounds shown in Table A or their tautomers and racemates , use of an enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting TLR7, TLR8 and TLR9.
  • the present disclosure further relates to general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula (III-1), general formula (IV) ), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3), general formula (IV-1-a) ), general formula (IV-1-b), general formula (IV-2-a), general formula (IV-2-b) and the compounds shown in Table A or their tautomers and racemates , enantiomers, diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same in the manufacture of a medicament for inhibiting TLR7, TLR8 or TLR9; Preferred is the use in the manufacture of a medicament for inhibiting TLR7 and TLR8, or the use in the manufacture of a medicament for inhibiting TLR7 and TLR9.
  • the present disclosure further relates to general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula (III-1), general formula (IV) ), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3), general formula (IV-1-a) ), general formula (IV-1-b), general formula (IV-2-a), general formula (IV-2-b) and the compounds shown in Table A or their tautomers and racemates , enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation for the treatment and/or prevention of inflammatory or autoimmune diseases use in medicines.
  • the inflammatory or autoimmune disease described therein is preferably selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS) and Shoghren's syndrome.
  • the present disclosure further relates to a method of inhibiting TLR7, TLR8 and TLR9, comprising administering to a patient in need thereof an inhibitory effective amount of formula (I), formula (I-1), formula (II), formula (II- 1), general formula (III), general formula (III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula ( IV-2), general formula (IV-3), general formula (IV-1-a), general formula (IV-1-b), general formula (IV-2-a), general formula (IV-2- b) and the compounds shown in Table A or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or including its pharmaceutical composition.
  • the present disclosure further relates to a method of inhibiting TLR7, TLR8 or TLR9, preferably a method of inhibiting TLR7 and TLR8, or a method of inhibiting TLR7 and TLR9, comprising administering to a patient in need thereof an inhibitory effective amount of general formula (I), general formula ( I-1), general formula (II), general formula (II-1), general formula (III), general formula (III-1), general formula (IV), general formula (IV'), general formula (IV) -1), general formula (IV'-1), general formula (IV-2), general formula (IV-3), general formula (IV-1-a), general formula (IV-1-b), general formula Compounds of formula (IV-2-a), general formula (IV-2-b) and Table A or their tautomers, racemates, enantiomers, diastereomers , or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present disclosure further relates to a method of treating and/or preventing an inflammatory or autoimmune disease, comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), formula (I-1), formula (II) , general formula (II-1), general formula (III), general formula (III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'- 1), general formula (IV-2), general formula (IV-3), general formula (IV-1-a), general formula (IV-1-b), general formula (IV-2-a), general formula Compounds of formula (IV-2-b) and Table A or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable compounds thereof A salt for use, or a pharmaceutical composition comprising the same; wherein said inflammatory or autoimmune disease is preferably selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS) and Xia
  • the present disclosure further relates to a general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula (III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3), general formula (IV-1) -a), the general formula (IV-1-b), the general formula (IV-2-a), the general formula (IV-2-b) and the compounds shown in Table A or their tautomers, Rotomers, enantiomers, diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.
  • the present disclosure further relates to a general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula (III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3), general formula (IV-1) -a), the general formula (IV-1-b), the general formula (IV-2-a), the general formula (IV-2-b) and the compounds shown in Table A or their tautomers, Rotomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in inhibiting TLR7, TLR8, and TLR9.
  • the present disclosure further relates to a general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula (III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3), general formula (IV-1) -a), the general formula (IV-1-b), the general formula (IV-2-a), the general formula (IV-2-b) and the compounds shown in Table A or their tautomers, Rotomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in inhibiting TLR7, TLR8 or TLR9; preferably for use in Inhibits TLR7 and TLR8, or is used to inhibit TLR7 and TLR9.
  • the present disclosure further relates to a general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula (III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3), general formula (IV-1) -a), the general formula (IV-1-b), the general formula (IV-2-a), the general formula (IV-2-b) and the compounds shown in Table A or their tautomers, Rotomomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in the treatment and/or prevention of inflammation or autoimmunity inflammatory or autoimmune disease; wherein said inflammatory or autoimmune disease is preferably selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS) and Xiaogren's syndrome.
  • pancreatitis acute or chronic
  • asthma allergies
  • adult respiratory distress syndrome chronic obstructive pulmonary disease
  • glomerulonephritis rheumatoid joints inflammation
  • systemic lupus erythematosus scleroderma
  • chronic thyroiditis Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopy Dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft-versus-host disease, endotoxin-induced inflammatory response, tuberculosis, Atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, rubella arthritis
  • the condition is selected from the group consisting of Crohn's disease, ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis and pemphigus vulgaris of those.
  • the condition is ischemia-reperfusion injury, including cerebral ischemia-reperfusion injury caused by stroke and myocardial ischemia-reperfusion injury caused by myocardial infarction.
  • the disorder is multiple myeloma.
  • the active compounds can be formulated in a form suitable for administration by any suitable route, and the compositions of the present disclosure can be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure can be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular, or subcutaneous) administration, inhalation or insufflation.
  • the compounds of the present disclosure may also be formulated in sustained release dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injectable solutions, dispersible powders or granules, suppositories, lozenges or syrups.
  • the active compound is preferably presented in a unit dose or in a form that the patient can self-administer in a single dose.
  • a unit dose of a compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, vial, powder, granule, lozenge, suppository, reconstituted powder, or liquid.
  • a suitable unit dose may be 0.1 to 1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait.
  • the composition may contain from 0.1 to 99% by weight of active compound.
  • Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients may be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.
  • Oral formulations can also be presented in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble or oily vehicle.
  • Aqueous suspensions contain the active substances in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents.
  • the aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.
  • Oily suspensions can be formulated by suspending the active ingredient in vegetable or mineral oils.
  • the oily suspensions may contain thickening agents.
  • the aforementioned sweetening and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
  • compositions of the present disclosure may also be in the form of oil-in-water emulsions.
  • the oily phase can be vegetable oil, or mineral oil or a mixture thereof.
  • Suitable emulsifying agents may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents.
  • Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous solutions.
  • acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • a sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase.
  • the injectable solution or microemulsion can be injected into the bloodstream of a patient by local bulk injection.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the present disclosure.
  • a continuous intravenous drug delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM.5400 IV pump.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blending and fixing oil can be used.
  • fatty acids are also available in the preparation of injectables.
  • the compounds of the present disclosure can be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.
  • the compounds of the present disclosure can be administered by the addition of water to prepare dispersible powders and granules for aqueous suspension.
  • These pharmaceutical compositions can be prepared by admixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.
  • the dosage of a drug to be administered depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient , patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, severity of disease, etc.; in addition, optimal treatment mode such as mode of treatment, daily dose of compound or pharmaceutically acceptable salt Species can be verified against conventional treatment protocols.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) alkyl groups, more preferably alkyl groups containing 1 to 6 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylpropyl butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl base and 2,3-dimethylbutyl, etc.
  • Alkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably the substituents are independently optionally selected from H atoms, D atoms, halogens, alkyls, alkanes Oxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl one or more substituents in .
  • alkylene refers to a saturated straight or branched chain aliphatic hydrocarbon group, which is a residue derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is a residue containing 1 straight or branched chain groups of up to 20 carbon atoms, preferably containing 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, More preferred are alkylene groups containing 1 to 6 carbon atoms.
  • Non-limiting examples of alkylene groups include, but are not limited to, methylene ( -CH2- ), 1,1-ethylene (-CH( CH3 )-), 1,2-ethylene ( -CH2) CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -) and 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -) and the like.
  • the alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably the substituents are independently optionally selected from alkyl, alkenyl, alkynyl, alkoxy group, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, hetero One or more substituents of aryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.
  • heteroalkylene refers to an alkylene where one or more -CH2- is replaced by a group selected from N, O, S and S(O); wherein said alkyl is as defined above; heteroalkylene
  • the radicals may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably independently optionally selected from H atoms, D atoms, halogen, alkyl, alkoxy substituted with one or more of the substituents selected from the group consisting of radicals, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkenyl refers to an alkyl compound having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl groups containing 2 to 12 (eg, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms are preferred, and alkenyl groups containing 2 to 6 carbon atoms are more preferred.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, it is preferably one or more of the following groups independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, haloalkyl groups, haloalkoxy groups , cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkynyl refers to an alkyl compound having at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl groups containing 2 to 12 (eg, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms are preferred, and alkynyl groups containing 2 to 6 carbon atoms are more preferred.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, haloalkyl groups, haloalkoxy groups alkyl, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms Carbon atoms (eg 3, 4, 5, 6, 7 and 8), more preferably 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene and cyclooctyl, etc.; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
  • spirocycloalkyl refers to a 5- to 20-membered polycyclic group having one carbon atom (called a spiro atom) shared between the monocyclic rings, which may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into mono-spirocycloalkyl groups, double-spirocycloalkyl groups or poly-spirocycloalkyl groups, preferably mono-spirocycloalkyl groups and double-spirocycloalkyl groups.
  • spirocycloalkyl More preferably, it is 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl include:
  • fused cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more rings. Multiple double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan Member/5-membered and 6-membered/6-membered bicycloalkyl.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly attached carbon atoms, which may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl include:
  • the cycloalkyl ring includes a cycloalkyl (including monocyclic, spiro, fused and bridged) as described above fused to an aryl, heteroaryl or heterocycloalkyl ring where it is attached to the parent structure Rings together are cycloalkyl, non-limiting examples include etc.; preferred
  • Cycloalkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl, alkoxy , haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl one or more substituents.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy.
  • Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from H atom, D atom, halogen, alkyl, alkoxy , haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing from 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur,
  • the sulfur may optionally be oxo (ie, to form a sulfoxide or sulfone), but does not include ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • 1 to 4 eg 1, 2, 3 and 4
  • 3 to 8 ring atoms eg 3, 4, 5, 6, 7 and 8
  • 1-3 are heteroatoms
  • 3 to 6 ring atoms of which 1-3 are heteroatoms
  • Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholine base, thiomorpholinyl and homopiperazinyl, etc.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • spiroheterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group with one atom (called a spiro atom) shared between the monocyclic rings, wherein one or more ring atoms are heterocyclic groups selected from nitrogen, oxygen and sulfur.
  • the sulfur may optionally be oxo (ie to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • spiroheterocyclyls are classified into mono-spiroheterocyclyls, bis-spiroheterocyclyls or poly-spiroheterocyclyls, preferably mono-spiroheterocyclyls and bis-spiroheterocyclyls. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl.
  • Non-limiting examples of spiroheterocyclyl include:
  • fused heterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more of the rings may contain one or more Double bonds in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which may be optionally oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • fused heterocyclyl groups include:
  • bridged heterocyclyl refers to a 5- to 14-membered, polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds in which one or more ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which may optionally be oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • bridged heterocyclyl groups include:
  • the heterocyclyl ring includes a heterocyclyl group (including monocyclic, spiroheterocycle, fused heterocycle and bridged heterocycle) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the
  • the rings to which the structure is attached are heterocyclyl, non-limiting examples of which include:
  • Heterocyclyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, alkanes Oxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl one or more substituents in .
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic are rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 10 membered , such as phenyl and naphthyl.
  • the aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include :
  • Aryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, preferably the substituents are independently optionally selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, One of haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl or multiple substituents.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10 membered (eg 5, 6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered, eg furyl, thienyl, pyridyl, pyrrolyl, N-alkane pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl and the like.
  • the heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include :
  • Heteroaryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, preferably the substituents are independently optionally selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups , haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl one or more substituents.
  • cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived by removing one hydrogen atom from the parent ring atom, or removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent
  • residues from which atoms are derived are "divalent cycloalkyl", "divalent heterocyclyl", “arylene” and "heteroarylene”.
  • hydroxyl protecting group is a suitable group for hydroxyl protection known in the art, see the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. GMWuts) for hydroxyl protecting groups.
  • the hydroxyl protecting group can be a (C 1-10 alkyl or aryl) 3 silyl group, such as: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl Silyl, tert-butyldiphenylsilyl, etc.; can be C 1-10 alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C 1-6 alkoxy substituted C 1-6 alkyl or phenyl substituted C 1-6 alkyl, most preferably C 1-4 alkoxy substituted C 1-4 alkyl, for example: methyl, tert-butyl, benzyl, methoxy
  • amino protecting group is used to protect the amino group with a group that is easy to remove in order to keep the amino group unchanged when the other part of the molecule is reacted.
  • Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro.
  • the amino protecting groups are preferably (trimethylsilyl)ethoxymethyl and tert-butoxycarbonyl.
  • heterocyclylalkyl refers to an alkyl group substituted with one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.
  • heteroarylalkyl refers to an alkyl group substituted with one or more heteroaryl groups, wherein heteroaryl and alkyl are as defined above.
  • cycloalkyloxy refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
  • alkylthio refers to alkyl-S-, wherein alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxy refers to -OH.
  • thiol refers to -SH.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • aldehyde group refers to -C(O)H.
  • carboxylate refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl, cycloalkyl are as defined above.
  • the compounds of the present disclosure include isotopic derivatives thereof.
  • isotopic derivatives refers to compounds that differ in structure only by the presence of one or more isotopically enriched atoms. For example, having the structures of the present disclosure, replacing hydrogen with “deuterium” or “tritium”, or replacing fluorine with18F -fluorine labeling ( 18F isotope), or enriching with11C- , 13C- , or14C- Compounds in which carbon ( 11 C-, 13 C-, or 14 C-carbon labels; 11 C-, 13 C-, or 14 C-isotopes) are replaced by carbon atoms are within the scope of the present disclosure.
  • Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies.
  • each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom.
  • Those skilled in the art can refer to the relevant literature to synthesize deuterated forms of the compounds.
  • deuterated starting materials can be used in preparing deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran , Deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc.
  • Deuterated compounds generally retain comparable activity to undeuterated compounds, and when deuterated at certain specific sites can achieve better metabolic stability, resulting in certain therapeutic advantages.
  • the bond Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond can be or both and Two configurations.
  • heterocyclic group optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms in a group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents.
  • a person skilled in the art can determine possible or impossible substitutions (either experimentally or theoretically) without undue effort.
  • amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • “Pharmaceutically acceptable salts” refers to salts of the compounds of the present disclosure that are safe and effective when used in mammals, and that possess the desired biological activity.
  • the salts can be prepared separately during the final isolation and purification of the compounds, or by reacting a suitable group with a suitable base or acid.
  • Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia.
  • Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
  • the term "therapeutically effective amount” refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect.
  • the determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation, allergic response or Other problems or complications with a reasonable benefit/risk ratio and are effective for the intended use.
  • the compound represented by the general formula (I) of the present disclosure or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof includes the following steps:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is a tert-butoxycarbonyl group;
  • Ring A, Ring B, X, Y, Z, L 1 , L 2 , L 3 , R 3 , R 4 , R 6 , n and t are as defined in general formula (I).
  • the compound represented by the general formula (II) of the present disclosure or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof includes the following steps:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is a tert-butoxycarbonyl group;
  • Rings B, X, Y, Z, L 1 , L 2 , L 3 , W 1 to W 4 , R 1 to R 4 , R 6 , q, n and t are as defined in general formula (II).
  • the compound represented by the general formula (III) of the present disclosure or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof includes the following steps:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is a tert-butoxycarbonyl group;
  • Ring B, L 1 to L 3 , R 1 to R 4 , R 6 , q, n and t are as defined in general formula (III).
  • the compound represented by the general formula (IV) of the present disclosure or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof includes the following steps:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is a tert-butoxycarbonyl group;
  • Rings B, L 3 , R 1 to R 3 , R 6 , q and t are as defined in formula (IV).
  • Ring B, L 3 , R 1 to R 3 , R 6 , q and t are as defined in formula (IV').
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (I-1) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof form, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
  • the protective group R W is removed in the presence of the general formula (I-1) to obtain the compound of general formula (I-1) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • R 6a is a hydrogen atom
  • t 1, 2, 3, 4, 5;
  • Ring A, Ring B, X, Y, Z, L 1 to L 3 , R 3 , R 4 , R 6 , W 1 to W 4 and n are as defined in the general formula (I-1).
  • Another aspect of the present disclosure relates to the preparation of the compound represented by the general formula (II-1), or its tautomer, racemate, enantiomer, diastereomer, or its A method in the form of a mixture, or a pharmaceutically acceptable salt thereof, comprising:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • R 6a is a hydrogen atom
  • t 1, 2, 3, 4, 5;
  • Rings B, X, Y, Z, L 1 , L 2 , L 3 , W 1 to W 4 , R 1 to R 4 , R 6 , q and n are as defined in the general formula (II-1).
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (III-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof form, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • R 6a is a hydrogen atom
  • t 1, 2, 3, 4, 5;
  • Ring B, L 1 to L 3 , R 1 to R 4 , R 6 , q and n are as defined in general formula (III-1).
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (IV-1) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof form, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • R 6a is a hydrogen atom
  • t 1, 2, 3, 4, 5;
  • Ring B, L 3 , R 1 to R 3 , R 6 and q are as defined in general formula (IV-1).
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (IV-2) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof form, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • R 6a is a hydrogen atom
  • t 1, 2, 3, 4, 5;
  • Ring B, L 3 , R 1 to R 3 , R 6 and q are as defined in general formula (IV-2).
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (IV-3) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof form, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • R 6a is a hydrogen atom
  • t 1, 2, 3, 4, 5;
  • Ring B, L 3 , R 1 to R 3 , R 6 and q are as defined in general formula (IV-3).
  • Another aspect of the present disclosure relates to the preparation of the compound represented by the general formula (IV') or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof , or a method of a pharmaceutically acceptable salt thereof, the method comprising:
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • Rings B, L3, R1 to R3 , R6, q and t are as defined in general formula (IV').
  • Another aspect of the present disclosure relates to the preparation of a compound represented by the general formula (IV'-1) or its tautomer, racemate, enantiomer, diastereomer, or its A method in the form of a mixture, or a pharmaceutically acceptable salt thereof, comprising:
  • a compound of general formula (IV'a-1) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof The protecting group R W is removed in the presence of an acid to obtain the compound of general formula (IV'-1) or its tautomer, racemate, enantiomer, diastereomer, or its in the form of a mixture, or a pharmaceutically acceptable salt thereof,
  • R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
  • R 6a is a hydrogen atom
  • t 1, 2, 3, 4, 5;
  • Ring B, L 3 , R 1 to R 3 , R 6 and q are as defined in general formula (IV'-1).
  • R 6a is a hydrogen atom
  • t 1, 2, 3, 4, 5;
  • Ring B, L 3 , R 1 to R 3 , R 6 and q are as defined in general formula (IV'-1).
  • the coupling reaction is a well-known coupling reaction in the art, including but not limited to Buchwald-Hartwig coupling reaction, Negishi coupling reaction and the like.
  • the conditions of the coupling reaction include but are not limited to carrying out in the presence of a metal catalyst (preferably a catalyst containing palladium or nickel), preferably palladium acetate, methanesulfonic acid (2-dicyclohexylphosphino-2',6 '-Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (RuPhos Pd G3), methanesulfonic acid (2- Dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium ( II) (
  • the metal catalyst can also be used in combination with a ligand and a base, wherein the ligand includes but is not limited to S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine (S -(-)-BINAP), R-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine (R-(-)-BINAP), 1,1'-binaphthyl-2 ,2'-Bisdiphenylphosphine (BINAP), 1,1'-Bis(diphenylphosphine)ferrocene (DPPF), 4,5-Bisdiphenylphosphine-9,9-dimethyloxa Anthracene (XANTPHOS), 2,2'-bis(diphenylphosphine)benzophenone (DPBP), 2,2'-diallylbisphenol A (DBA), etc., preferably S-(-)
  • Described base includes organic base and inorganic base
  • described organic base includes but is not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylamide lithium, acetic acid Potassium, sodium acetate, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide, preferably sodium tert-butoxide
  • the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, carbonic acid Potassium or cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; potassium carbonate and cesium carbonate are preferred.
  • the acid includes an organic acid and an inorganic acid
  • the organic acid includes but is not limited to trifluoroacetic acid, formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, Me 3 SiCl and TMSOTf, preferably trifluoroacetic acid
  • the inorganic acids include but are not limited to hydrogen chloride, hydrogen chloride solution in 1,4-dioxane, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.
  • the reaction of the above steps (a)-(c) is preferably carried out in a solvent, and the solvent used includes but is not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane Methane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1 , 2-dibromoethane and mixtures thereof.
  • the solvent used includes but is not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane Methane, petroleum ether, ethyl
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • MS used Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).
  • HPLC High performance liquid chromatography
  • Chiral HPLC analysis was determined using an Agilent 1260 DAD high performance liquid chromatograph.
  • HPLC preparations used Waters 2767, Waters 2767-SQ Detector2, Shimadzu LC-20AP and Gilson-281 preparative chromatographs.
  • the CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the average inhibition rate and IC 50 value of kinases were measured with NovoStar microplate reader (BMG, Germany).
  • the known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui chemical companies.
  • Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the microwave reaction used a CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of the column chromatography used for purifying the compound and the developing solvent system of the thin layer chromatography method include: A: n-hexane/ethyl acetate system, B: dichloromethane/methanol system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
  • TLC thin layer chromatography
  • the crude compound 1i (600 mg, 1.3 mmol) was dissolved in 20 mL of toluene, azodicarbonyl dipiperidine (1.6 g, 6.3 mmol) and tributylphosphine (1.3 g, 6.4 mmol) were added, and argon was replaced three times, The mixture was stirred at 60°C for about 1 hour. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, the crude product was slurried with ethyl acetate (10 mL), the obtained solid was filtered, the filter cake was washed with n-hexane, and the solid was dried to obtain the title product 1j (310 mg yield: 53.7%).
  • the crude compound 2 g (2.1 g, 4.49 mmol) was dissolved in 50 mL of toluene, azodicarbonyl dipiperidine (5.7 g, 22.59 mmol) and tributylphosphine (4.6 g, 22.73 mmol) were added, and argon was replaced three times , the mixture was stirred at 60 °C for about 1 hour. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, the crude product was slurried with ethyl acetate (10 mL), the obtained solid was filtered, the filter cake was washed with n-hexane, and the solid was dried to obtain the title product 2h (1.8 g yield: 89.15%).
  • the crude compound 7c (50 mg, 0.11 mmol) was dissolved in 5 mL of N,N-dimethylformamide, sodium tert-butoxide (22 mg, 0.22 mmol) was added, the mixture was stirred at room temperature for about 1 hour, and 10 mL of saturated bicarbonate was added.
  • Liquid chromatography (chromatographic column: SharpSil T-C18, 5 ⁇ m, 30mm*150mm; mobile phase 1: aqueous phase (containing 0.1% trifluoroacetic acid); mobile phase 2: acetonitrile; 25-minute gradient: 25%-95%, Flow rate: 30 mL/min) was purified to give the title product 8 (2 mg, yield: 15.8%).
  • Zinc powder (156 mg, 2.38 mmol) was dissolved in 5 mL of dry N,N-dimethylformamide, 1,2-dibromoethane (45 mg, 0.24 mmol) and trimethylchlorosilane (26 mg, 0.24 mmol) were added mmol), the mixture was stirred at 60 °C for about 10 min and cooled to room temperature. Add 3-iodoazetidine-1-carboxylate tert-butyl ester (68 mg, 0.24 mmol, Yaoshi), and stir at room temperature for 1 hour to form a milky white suspension under nitrogen protection.
  • Liquid chromatography (column: SharpSil T-C18, 5 ⁇ m, 30mm*150mm; mobile phase 1: aqueous phase (containing 0.1% trifluoroacetic acid); mobile phase 2: acetonitrile; 25-minute gradient: 25%-95%, Flow rate: 30 mL/min) was purified to give the title product 15 (30 mg, yield: 73.3%).
  • Liquid chromatography (column: SharpSil T-C18, 5 ⁇ m, 30mm*150mm; mobile phase 1: aqueous phase (containing 0.1% trifluoroacetic acid); mobile phase 2: acetonitrile; 25-minute gradient: 25%-95%, Flow rate: 30 mL/min) was purified to give the title product 20 (22 mg, yield: 71.6%).
  • reaction solution was concentrated under reduced pressure, 10 mL of saturated sodium chloride solution was added, extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography Purification with eluent system A afforded the title product 21a (45 mg, yield: 66.9%).
  • reaction solution was concentrated under reduced pressure, 10 mL of saturated sodium bicarbonate solution was added, stirred for 30 minutes, extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, washed with water (10 mL) and saturated sodium chloride solution (10 mL) in turn, no Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude title product 22f (200 mg), which is directly subjected to the next reaction without purification.
  • the crude compound 22f (200 mg, 0.42 mmol) was dissolved in 10 mL of toluene, azodicarbonyl dipiperidine (525 mg, 2.08 mmol) and tributylphosphine (420 mg, 2.08 mmol) were added, and the argon was replaced three times.
  • the reaction was stirred at 60°C for about 1 hour. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, the crude product was slurried with ethyl acetate (10 mL), the obtained solid was filtered, the filter cake was washed with n-hexane, and the solid was dried to obtain 22 g of the title product (102 mg yield: 52.98%).

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Abstract

A fused tricyclic derivative as shown in general formula (I), a preparation method therefor, a pharmaceutical composition comprising the derivative, and a use thereof as a therapeutic agent, particularly a use as a TLR7/8/9 inhibitor and a use in preparation of a medication for treating and/or preventing inflammatory and autoimmune diseases.

Description

稠三环类衍生物、其制备方法及其在医药上的应用Condensed tricyclic derivative, its preparation method and its application in medicine 技术领域technical field
本公开属于医药领域，涉及一种稠三环类衍生物、其制备方法及其在医药上的应用。特别地，本公开涉及通式(I)所示的稠三环类衍生物、其制备方法及含有该衍生物的药物组合物，以及其作为TLR7/8/9抑制剂在治疗炎性和自身免疫性疾病中的用途。The present disclosure belongs to the field of medicine, and relates to a fused tricyclic derivative, a preparation method thereof and its application in medicine. In particular, the present disclosure relates to the fused tricyclic derivatives represented by the general formula (I), their preparation methods and pharmaceutical compositions containing the derivatives, and their use as TLR7/8/9 inhibitors in the treatment of inflammation and autoimmunity. Use in immune diseases.
背景技术Background technique
Toll样受体(Toll like receptors，TLR)是一类进化保守的跨膜先天免疫受体，它们参与保护人体健康的第一线防御，对于识别病原体相关分子模式(PAMP)起重要作用(Kawai,T.等人,Nature Immunol.,11,2010,373-384)。TLR表达于各种免疫细胞，根据其表达部位的不同可分为两类：表达于细胞膜的TLR(TLR1/2/4/5/6)和表达于内体膜的TLR(TLR3/7/8/9)，分别识别PAMP中的不同成分和分子。其中，TLR7/8/9主要在DC细胞和B细胞中高表达，TLR7/8主要识别ssRNA，TLR9主要识别CpG-DNA。TLR7/8/9结合其配体后被激活，在胞质中与接头蛋白MyD88相结合，启动NF-κB和IRF通路，活化DC细胞，产生I型干扰素和其它多种炎性细胞因子。在B细胞中，TLR7/8/9和核酸类物质相结合后，在B细胞产生抗核抗体的过程中起重要作用，并且DC细胞分泌的I型干扰素还会促进这种自身免疫性B细胞的进一步增殖和活化，从而引起一系列的炎症反应。Toll-like receptors (TLRs) are a class of evolutionarily conserved transmembrane innate immune receptors that are involved in the first-line defense to protect human health and play an important role in recognizing pathogen-associated molecular patterns (PAMPs) (Kawai, T. et al., Nature Immunol., 11, 2010, 373-384). TLRs are expressed in various immune cells and can be divided into two categories according to their expression sites: TLRs expressed on cell membranes (TLR1/2/4/5/6) and TLRs expressed on endosomal membranes (TLR3/7/8) /9), respectively identifying different components and molecules in PAMP. Among them, TLR7/8/9 were mainly highly expressed in DC cells and B cells, TLR7/8 mainly recognized ssRNA, and TLR9 mainly recognized CpG-DNA. TLR7/8/9 is activated after binding its ligands, and binds to the adaptor protein MyD88 in the cytoplasm to initiate NF-κB and IRF pathways, activate DC cells, and produce type I interferon and various other inflammatory cytokines. In B cells, the combination of TLR7/8/9 and nucleic acids plays an important role in the production of antinuclear antibodies by B cells, and the type I interferon secreted by DC cells also promotes this autoimmune B cell. The further proliferation and activation of cells causes a series of inflammatory responses.
系统性红斑狼疮(SLE)属于一种自身免疫性结缔组织病，SLE的临床一线药物有三大类：激素、免疫抑制剂和抗疟类药物。本世纪仅有一款新药贝利木单抗获FDA批准，但它仅对一小部分SLE病人有适度和延迟的疗效(Navarra,S.V等人，Lancet 2011,377,721)，治疗手段非常有限。因此，迫切需要改善更大比例的患者群体的新疗法，并且可以长期、安全使用。在系统性红斑狼疮(SLE)患者的PBMC中发现了TLR7/9以及I型干扰素的表达被明显上调的现象(Beverly D.LC等人,Mol Immunol.,2014,61:38-43)。据报道过度表达TLR7的小鼠可以加剧自身免疫疾病和自身炎症(Santiago-Raber ML等人，J Immunol.,2008,181:1556-1562)，而功能性抑制TLR7/9可以缓解B6-Fas lpr和BXSB等狼疮小鼠的病理表现(Dwight H.Kono等人,PNAS,2009,106(29):12061-12066)。鉴于TLR7/8/9与抗核抗体以及I型干扰素的紧密关系，靶向TLR7/8/9的小分子抑制剂很可能具有治疗SLE的潜力。 Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease, and there are three main clinical first-line drugs for SLE: hormones, immunosuppressants and antimalarial drugs. Only one new drug, belimumab, has been approved by the FDA this century, but it has only modest and delayed efficacy in a small subset of SLE patients (Navarra, SV et al., Lancet 2011, 377, 721), and the treatment options are very limited. Therefore, there is an urgent need for new treatments that improve a larger proportion of the patient population and that can be used safely and long-term. The expression of TLR7/9 and type I interferon was found to be significantly up-regulated in PBMCs of systemic lupus erythematosus (SLE) patients (Beverly D.LC et al., Mol Immunol., 2014, 61:38-43). Mice overexpressing TLR7 have been reported to exacerbate autoimmune disease and autoinflammation (Santiago-Raber ML et al., J Immunol., 2008, 181:1556-1562), while functional inhibition of TLR7/9 alleviates B6-Fas lpr and BXSB and other pathological manifestations of lupus mice (Dwight H. Kono et al., PNAS, 2009, 106(29): 12061-12066). Given the close relationship of TLR7/8/9 with antinuclear antibodies and type I interferons, small-molecule inhibitors targeting TLR7/8/9 are likely to have potential in the treatment of SLE.
公开的TLR7/8/9抑制剂的专利申请包括WO2019233941A1、WO2020020800A1、WO2018049089A1、WO2019238616A1、WO2017106607A1、CN109923108A和WO2020048605A1等。Published patent applications for TLR7/8/9 inhibitors include WO2019233941A1, WO2020020800A1, WO2018049089A1, WO2019238616A1, WO2017106607A1, CN109923108A, and WO2020048605A1, among others.
发明内容SUMMARY OF THE INVENTION
本公开的目的在于提供一种通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：The purpose of the present disclosure is to provide a compound represented by the general formula (I) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or its Medicinal salts:
Figure PCTCN2021110197-appb-000001
Figure PCTCN2021110197-appb-000001
其中：in:
环A选自以下基团中的一种：Ring A is selected from one of the following groups:
Figure PCTCN2021110197-appb-000002
Figure PCTCN2021110197-appb-000002
其中，R 1和R 2相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、烯基、炔基、烷氧基、卤代烷氧基、卤素、氰基、氨基、硝基、羟基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； wherein, R 1 and R 2 are the same or different, and are independently selected from hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkoxy groups group, halogen, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein, the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heteroalkyl substituted with one or more substituents in cyclic, aryl and heteroaryl;
R 3和R 4相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、烯基、炔基、烷氧基、卤代烷氧基、氧代基、卤素、氰基、 氨基、硝基、羟基、醛基和羧基； R 3 and R 4 are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, oxo, halogen, cyano, amino, nitro, hydroxyl, aldehyde and carboxyl;
Z选自CH 2、CR 7aR 7b、NR 8a和氧原子； Z is selected from CH 2 , CR 7a R 7b , NR 8a and oxygen atoms;
L 1和L 2相同或不同，且各自独立地选自化学键、CH 2、CR 7cR 7d和C(O)； L 1 and L 2 are the same or different, and are each independently selected from a chemical bond, CH 2 , CR 7c R 7d and C(O);
L 3选自化学键、CH 2、CR 7eR 7f、NH、C(O)NR 8b、NR 8b(CH 2) m和C(O)； L 3 is selected from chemical bonds, CH 2 , CR 7e R 7f , NH, C(O)NR 8b , NR 8b (CH 2 ) m and C(O);
X和Y相同或不同，且各自独立地为CR 5a或氮原子； X and Y are the same or different, and are each independently a CR 5a or a nitrogen atom;
W 1、W 2、W 3和W 4之一为碳原子，其余三个相同或不同，且各自独立地为CR 5b或氮原子； One of W 1 , W 2 , W 3 and W 4 is a carbon atom, and the other three are the same or different, and each independently is a CR 5b or a nitrogen atom;
R 5a选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、烯基、炔基、烷氧基、卤代烷氧基、卤素、氰基、氨基、硝基、羟基、醛基和羧基； R 5a is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, halogen, cyano, amino, nitro, hydroxyl , aldehyde group and carboxyl group;
R 5b选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、烯基、炔基、卤素、氰基、氨基、-NR 9aR 9b、-COR 10、-C(O)OR 11、-OR 12、硝基、羟基、醛基、羧基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、烷氧基烷基、卤代烷基、卤代烷氧基、氰基、氨基、-(CH 2) sNR 13aR 13b、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R 5b is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, halogen, cyano, amino, -NR 9a R 9b , -COR 10 , -C (O) OR 11 , -OR 12 , nitro group, hydroxyl group, aldehyde group, carboxyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group; wherein, the alkyl group, cycloalkyl group, heterocyclic group , aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy, cyano, amino, -( CH 2 ) s NR 13a R 13b , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted with one or more substituents;
环B选自环烷基、杂环基、芳基和杂芳基；Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 6相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、烯基、炔基、氧代基、卤素、氰基、氨基、-NR 9aR 9b、-COR 10、-C(O)OR 11、-OR 12、-(CH 2) sNR 13aR 13b、-CO(CH 2) sNR 13aR 13b、硝基、羟基、醛基、羧基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、烷氧基烷基、卤代烷基、卤代烷氧基、氰基、氨基、-(CH 2) sNR 13aR 13b、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R 6 are the same or different, and each is independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an oxo group, a halogen group, a cyano group, an amino group, -NR 9a R 9b , -COR 10 , -C(O)OR 11 , -OR 12 , -(CH 2 ) s NR 13a R 13b , -CO(CH 2 ) s NR 13a R 13b , nitro, hydroxyl, Aldehyde, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy, cyano, amino, -(CH 2 ) s NR 13a R 13b , nitro, hydroxy, hydroxy substituted with one or more substituents of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 7a、R 7b、R 7c、R 7d、R 7e和R 7f相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、烯基、炔基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基和杂芳基； R 7a , R 7b , R 7c , R 7d , R 7e and R 7f are the same or different, and are each independently selected from hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkenyl groups , alkynyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 8a和R 8b相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基； R 8a and R 8b are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group ;
R 9a和R 9b相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、-(CH 2) sNR 13aR 13b、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R 9a and R 9b are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group ; wherein, the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkane One or more substituents of oxy, cyano, amino, -(CH 2 ) s NR 13a R 13b , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl replaced;
R 10选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨 基、-(CH 2) sNR 13aR 13b、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R 10 is selected from hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group; wherein, the alkyl group, cycloalkyl group, heterocyclic group , aryl, and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -( CH2 ) sNR 13a R 13b , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted with one or more substituents;
R 11和R 12相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、-(CH 2) sNR 13aR 13b、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R 11 and R 12 are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group ; wherein, the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkane One or more substituents of oxy, cyano, amino, -(CH 2 ) s NR 13a R 13b , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl replaced;
R 13a和R 13b相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基和羟烷基； R 13a and R 13b are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, and a hydroxyalkyl group;
n为0、1、2、3；n is 0, 1, 2, 3;
p为0、1、2、3；p is 0, 1, 2, 3;
q为0、1、2、3；q is 0, 1, 2, 3;
t为0、1、2、3、4、5；t is 0, 1, 2, 3, 4, 5;
s为0、1、2、3、4、5、6；s is 0, 1, 2, 3, 4, 5, 6;
m为0、1、2、3、4、5、6。m is 0, 1, 2, 3, 4, 5, 6.
在本公开一些优选的实施方案中，所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中：In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, racemate, enantiomer, diastereomer, or its In admixture, or a pharmaceutically acceptable salt thereof, wherein:
环A选自以下基团中的一种：Ring A is selected from one of the following groups:
Figure PCTCN2021110197-appb-000003
Figure PCTCN2021110197-appb-000003
其中，R 1和R 2相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、烯基、炔基、烷氧基、卤代烷氧基、卤素、氰基、氨 基、硝基、羟基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； wherein, R 1 and R 2 are the same or different, and are independently selected from hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkoxy groups group, halogen, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein, the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heteroalkyl substituted with one or more substituents in cyclic, aryl and heteroaryl;
R 3和R 4相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、烯基、炔基、烷氧基、卤代烷氧基、氧代基、卤素、氰基、氨基、硝基、羟基、醛基和羧基； R 3 and R 4 are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, oxo, halogen, cyano, amino, nitro, hydroxyl, aldehyde and carboxyl;
Z选自CH 2、CR 7aR 7b、NR 8a和氧原子； Z is selected from CH 2 , CR 7a R 7b , NR 8a and oxygen atoms;
L 1和L 2相同或不同，且各自独立地选自化学键、CH 2、CR 7cR 7d和C(O)； L 1 and L 2 are the same or different, and are each independently selected from a chemical bond, CH 2 , CR 7c R 7d and C(O);
L 3选自化学键、CH 2、CR 7eR 7f、NH、NR 8b(CH 2) m和C(O)； L 3 is selected from chemical bonds, CH 2 , CR 7e R 7f , NH, NR 8b (CH 2 ) m and C(O);
X和Y相同或不同，且各自独立地为CR 5a或氮原子； X and Y are the same or different, and are each independently a CR 5a or a nitrogen atom;
W 1、W 2、W 3和W 4相同或不同，且各自独立地为CR 5b或氮原子； W 1 , W 2 , W 3 and W 4 are the same or different, and are each independently CR 5b or a nitrogen atom;
R 5a选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、烯基、炔基、烷氧基、卤代烷氧基、卤素、氰基、氨基、硝基、羟基、醛基和羧基； R 5a is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, halogen, cyano, amino, nitro, hydroxyl , aldehyde group and carboxyl group;
R 5b选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、烯基、炔基、卤素、氰基、氨基、-NR 9aR 9b、-COR 10、-C(O)OR 11、-OR 12、硝基、羟基、醛基、羧基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、烷氧基烷基、卤代烷基、卤代烷氧基、氰基、氨基、-(CH 2) sNR 13aR 13b、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R 5b is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, halogen, cyano, amino, -NR 9a R 9b , -COR 10 , -C (O) OR 11 , -OR 12 , nitro group, hydroxyl group, aldehyde group, carboxyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group; wherein, the alkyl group, cycloalkyl group, heterocyclic group , aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy, cyano, amino, -( CH 2 ) s NR 13a R 13b , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted with one or more substituents;
环B选自环烷基、杂环基、芳基和杂芳基，其中，所述的环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、烷氧基烷基、卤代烷基、卤代烷氧基、氰基、氨基、-(CH 2) sNR 13aR 13b、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl , alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy, cyano, amino, -(CH 2 ) s NR 13a R 13b , nitro, hydroxy, hydroxyalkyl, ring substituted with one or more substituents of alkyl, heterocyclyl, aryl and heteroaryl;
R 6相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、烯基、炔基、氧代基、卤素、氰基、氨基、-NR 9aR 9b、-COR 10、-C(O)OR 11、-OR 12、硝基、羟基、醛基、羧基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、烷氧基烷基、卤代烷基、卤代烷氧基、氰基、氨基、-(CH 2) sNR 13aR 13b、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R 6 are the same or different, and each is independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an oxo group, a halogen group, a cyano group, an amino group, -NR 9a R 9b , -COR 10 , -C(O)OR 11 , -OR 12 , nitro, hydroxyl, aldehyde, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein, the Said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkyl , one or more of haloalkoxy, cyano, amino, -(CH 2 ) s NR 13a R 13b , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by a substituent;
R 7a、R 7b、R 7c、R 7d、R 7e和R 7f相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、烯基、炔基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基和杂芳基； R 7a , R 7b , R 7c , R 7d , R 7e and R 7f are the same or different, and are each independently selected from hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkenyl groups , alkynyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 8a和R 8b相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基； R 8a and R 8b are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group ;
R 9a和R 9b相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、-(CH 2) sNR 13aR 13b、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R 9a and R 9b are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group ; wherein, the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkane One or more substituents of oxy, cyano, amino, -(CH 2 ) s NR 13a R 13b , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl replaced;
R 10选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、-(CH 2) sNR 13aR 13b、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R 10 is selected from hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group; wherein, the alkyl group, cycloalkyl group, heterocyclic group , aryl, and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -( CH2 ) sNR 13a R 13b , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted with one or more substituents;
R 11和R 12相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、-(CH 2) sNR 13aR 13b、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R 11 and R 12 are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group ; wherein, the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkane One or more substituents of oxy, cyano, amino, -(CH 2 ) s NR 13a R 13b , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl replaced;
R 13a和R 13b相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基和羟烷基； R 13a and R 13b are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, and a hydroxyalkyl group;
n为0、1、2、3；n is 0, 1, 2, 3;
p为0、1、2、3；p is 0, 1, 2, 3;
q为0、1、2、3；q is 0, 1, 2, 3;
t为0、1、2、3、4、5；t is 0, 1, 2, 3, 4, 5;
s为0、1、2、3、4、5、6；s is 0, 1, 2, 3, 4, 5, 6;
m为0、1、2、3、4、5、6。m is 0, 1, 2, 3, 4, 5, 6.
在本公开一些优选的实施方案中，所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(I-1)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof, the compound represented by the general formula (I-1) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
Figure PCTCN2021110197-appb-000004
Figure PCTCN2021110197-appb-000004
其中：in:
环B为至少含有1个N原子的4至12元杂环基；Ring B is a 4- to 12-membered heterocyclic group containing at least 1 N atom;
R 6a选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、烯基、炔基、-NR 9aR 9b、-COR 10、-C(O)OR 11、-OR 12、-(CH 2) sNR 13aR 13b、-CO(CH 2) sNR 13aR 13b和环烷基； R 6a is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, -NR 9a R 9b , -COR 10 , -C(O)OR 11 , - OR 12 , -(CH 2 ) s NR 13a R 13b , -CO(CH 2 ) s NR 13a R 13b and cycloalkyl;
t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
环A、X、Y、Z、L 1、L 2、L 3、W 1至W 4、R 3、R 4、R 6、R 9a、R 9b、R 10至R 12、R 13a、R 13b、s和n如通式(I)中所定义。 Rings A, X, Y, Z, L 1 , L 2 , L 3 , W 1 to W 4 , R 3 , R 4 , R 6 , R 9a , R 9b , R 10 to R 12 , R 13a , R 13b , s and n are as defined in general formula (I).
在本公开一些优选的实施方案中，所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(II)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof, the compound represented by the general formula (II) or its tautomer, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof:
Figure PCTCN2021110197-appb-000005
Figure PCTCN2021110197-appb-000005
其中：in:
环B、X、Y、Z、L 1、L 2、L 3、W 1至W 4、R 1至R 4、R 6、q、n和t如通式(I)中所定义。 Rings B, X, Y, Z, L 1 , L 2 , L 3 , W 1 to W 4 , R 1 to R 4 , R 6 , q, n and t are as defined in general formula (I).
在本公开一些优选的实施方案中，所述的通式(I)、通式(I-1)或通式(II)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(II-1)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：In some preferred embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1) or general formula (II) or its tautomer, racemate, para- Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by general formula (II-1) or tautomers and racemates thereof , enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
Figure PCTCN2021110197-appb-000006
Figure PCTCN2021110197-appb-000006
其中：in:
环B为至少含有1个N原子的4至12元杂环基；Ring B is a 4- to 12-membered heterocyclic group containing at least 1 N atom;
R 6a选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、烯基、炔基、-NR 9aR 9b、-COR 10、-C(O)OR 11、-OR 12、-(CH 2) sNR 13aR 13b、-CO(CH 2) sNR 13aR 13b和环烷基； R 6a is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, -NR 9a R 9b , -COR 10 , -C(O)OR 11 , - OR 12 , -(CH 2 ) s NR 13a R 13b , -CO(CH 2 ) s NR 13a R 13b and cycloalkyl;
t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
X、Y、Z、L 1、L 2、L 3、W 1至W 4、R 1至R 4、R 6、R 9a、R 9b、R 10至R 12、R 13a、R 13b、s、q和n如通式(I)、通式(I-1)或通式(II)中所定义。 X, Y, Z, L 1 , L 2 , L 3 , W 1 to W 4 , R 1 to R 4 , R 6 , R 9a , R 9b , R 10 to R 12 , R 13a , R 13b , s, q and n are as defined in general formula (I), general formula (I-1) or general formula (II).
在本公开一些优选的实施方案中，所述的通式(I)、通式(I-1)、通式(II)或通式(II-1)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中Z为氧原子。In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (I-1), the general formula (II) or the general formula (II-1) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein Z is an oxygen atom.
在本公开一些优选的实施方案中，所述的通式(I)、通式(I-1)、通式(II)或通式(II-1)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中X和Y相同，为氮原子。In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (I-1), the general formula (II) or the general formula (II-1) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein X and Y are the same and are nitrogen atoms.
在本公开一些优选的实施方案中，所述的通式(I)、通式(I-1)、通式(II)或通式(II-1)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中W 1、W 2和W 4为CR 5b，且W 3为碳原子；或者W 1和W 4为CR 5b，W 2为氮原子，且W 3为碳原子；或者W 1和W 2为CR 5b，W 3为碳原子，且W 4为氮原子；其中R 5b为氢原子或C 1-6烷基。 In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (I-1), the general formula (II) or the general formula (II-1) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein W 1 , W 2 and W 4 are CR 5b , and W 3 is carbon atom; or W 1 and W 4 are CR 5b , W 2 is a nitrogen atom, and W 3 is a carbon atom; or W 1 and W 2 are CR 5b , W 3 is a carbon atom, and W 4 is a nitrogen atom; wherein R 5b is a hydrogen atom or a C 1-6 alkyl group.
在本公开一些优选的实施方案中，所述的通式(I)或通式(II)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中W 1、W 2、W 3和W 4之一为碳原子，其余三个相同，为CR 5b；且R 5b为氢原子。 In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or general formula (II) or its tautomers, racemates, enantiomers, diastereomers Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein one of W 1 , W 2 , W 3 and W 4 is a carbon atom, and the remaining three are the same and are CR 5b ; and R 5b is a hydrogen atom .
在本公开一些优选的实施方案中，所述的通式(I)或通式(II)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or general formula (II) or its tautomers, racemates, enantiomers, diastereomers Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by general formula (III) or tautomers, racemates, enantiomers, diastereomers thereof Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
Figure PCTCN2021110197-appb-000007
Figure PCTCN2021110197-appb-000007
其中：in:
环B、L 1至L 3、R 1至R 4、R 6、q、n和t如通式(I)或通式(II)中所定义。 Ring B, L 1 to L 3 , R 1 to R 4 , R 6 , q, n and t are as defined in general formula (I) or general formula (II).
在本公开一些优选的实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)或通式(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(III-1)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (I-1), the general formula (II), the general formula (II-1) or the general formula (III) or its tautomer, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable salt, which is represented by the general formula (III-1) The compound or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
Figure PCTCN2021110197-appb-000008
Figure PCTCN2021110197-appb-000008
其中：in:
环B为至少含有1个N原子的4至12元杂环基；Ring B is a 4- to 12-membered heterocyclic group containing at least 1 N atom;
R 6a选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、烯基、炔基、-NR 9aR 9b、-COR 10、-C(O)OR 11、-OR 12、-(CH 2) sNR 13aR 13b、-CO(CH 2) sNR 13aR 13b和环烷基； R 6a is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, -NR 9a R 9b , -COR 10 , -C(O)OR 11 , - OR 12 , -(CH 2 ) s NR 13a R 13b , -CO(CH 2 ) s NR 13a R 13b and cycloalkyl;
t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
L 1、L 2、L 3、R 1至R 4、R 6、R 9a、R 9b、R 10至R 12、R 13a、R 13b、s、q和n如通式(I)、通式(I-1)、通式(II)、通式(II-1)或通式(III)中所定义。 L 1 , L 2 , L 3 , R 1 to R 4 , R 6 , R 9a , R 9b , R 10 to R 12 , R 13a , R 13b , s, q and n are as in general formula (I), general formula (I-1), general formula (II), general formula (II-1) or general formula (III) as defined.
在本公开一些优选的实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)或通式(III-1)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中L 1为CH 2，且L 2为化学键。 In some preferred embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III) or general formula ( The compound represented by III-1) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 is CH 2 , and L 2 is a chemical bond.
在本公开一些优选的实施方案中，所述的通式(I)、通式(II)或通式(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(IV)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (II) or the general formula (III) or its tautomers, racemates, enantiomers A isomer, a diastereomer, a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IV) or a tautomer, racemate, enantiomer thereof A isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
Figure PCTCN2021110197-appb-000009
Figure PCTCN2021110197-appb-000009
其中：in:
环B、L 3、R 1至R 3、R 6、q和t如通式(I)、通式(II)或通式(III)中所定义。 Ring B, L 3 , R 1 to R 3 , R 6 , q and t are as defined in general formula (I), general formula (II) or general formula (III).
在本公开一些优选的实施方案中，所述的通式(I)、通式(II)、通式(III)或通式(IV)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(IV')所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (II), the general formula (III) or the general formula (IV) or its tautomer, Rotors, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by the general formula (IV') or tautomers, exoisomers thereof Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
Figure PCTCN2021110197-appb-000010
Figure PCTCN2021110197-appb-000010
其中：in:
R 3为C 1-6烷基； R 3 is C 1-6 alkyl;
环B、L 3、R 1、R 2、R 6、q和t如通式(I)、通式(II)、通式(III)或通式(IV)中所定义。 Rings B, L3, R1, R2, R6, q and t are as defined in general formula (I), general formula (II), general formula (III) or general formula (IV).
在本公开一些优选的实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)或通式(IV)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(IV-1)所示的化合物，或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：In some preferred embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1) or the compound represented by the general formula (IV) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable form thereof salt, which is the compound represented by general formula (IV-1), or its tautomer, racemate, enantiomer, diastereomer, or its mixture form, or its Medicinal salts:
Figure PCTCN2021110197-appb-000011
Figure PCTCN2021110197-appb-000011
其中：in:
环B为至少含有1个N原子的4至12元杂环基；Ring B is a 4- to 12-membered heterocyclic group containing at least 1 N atom;
R 6a选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、烯基、炔基、-NR 9aR 9b、-COR 10、-C(O)OR 11、-OR 12、-(CH 2) sNR 13aR 13b、-CO(CH 2) sNR 13aR 13b和环烷基； R 6a is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, -NR 9a R 9b , -COR 10 , -C(O)OR 11 , - OR 12 , -(CH 2 ) s NR 13a R 13b , -CO(CH 2 ) s NR 13a R 13b and cycloalkyl;
t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
L 3、R 1至R 3、R 6、R 9a、R 9b、R 10至R 12、R 13a、R 13b、s和q如通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)或通式(IV)中所定义。 L 3 , R 1 to R 3 , R 6 , R 9a , R 9b , R 10 to R 12 , R 13a , R 13b , s and q are as in general formula (I), general formula (I-1), general formula (II), as defined in general formula (II-1), general formula (III), general formula (III-1) or general formula (IV).
在本公开一些优选的实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)或通式(IV')所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(IV'-1)所示的化合物，或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：In some preferred embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), the compound represented by general formula (IV) or general formula (IV') or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IV'-1), or its tautomer, racemate, enantiomer, and diastereomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof:
Figure PCTCN2021110197-appb-000012
Figure PCTCN2021110197-appb-000012
其中：in:
R 3为C 1-6烷基； R 3 is C 1-6 alkyl;
环B为至少含有1个N原子的4至12元杂环基；Ring B is a 4- to 12-membered heterocyclic group containing at least 1 N atom;
R 6a选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、烯基、炔基、 -NR 9aR 9b、-COR 10、-C(O)OR 11、-OR 12、-(CH 2) sNR 13aR 13b、-CO(CH 2) sNR 13aR 13b和环烷基； R 6a is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, -NR 9a R 9b , -COR 10 , -C(O)OR 11 , - OR 12 , -(CH 2 ) s NR 13a R 13b , -CO(CH 2 ) s NR 13a R 13b and cycloalkyl;
t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
L 3、R 1、R 2、R 6、R 9a、R 9b、R 10至R 12、R 13a、R 13b、s和q如通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)或通式(IV')中所定义。 L 3 , R 1 , R 2 , R 6 , R 9a , R 9b , R 10 to R 12 , R 13a , R 13b , s and q are as in general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula (III-1), general formula (IV) or general formula (IV').
在本公开一些优选的实施方案中，所述的通式(I)、通式(II)、通式(III)或通式(IV)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)或通式(IV-2-b)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (II), the general formula (III) or the general formula (IV) or its tautomer, Rotomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are of general formula (IV-1-a), general formula (IV-1-b) , the compound represented by general formula (IV-2-a) or general formula (IV-2-b) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
Figure PCTCN2021110197-appb-000013
Figure PCTCN2021110197-appb-000013
其中：in:
R 3为C 1-6烷基； R 3 is C 1-6 alkyl;
环B、L 3、R 1、R 2、R 6、q和t如通式(I)、通式(II)、通式(III)或通式(IV)中所定义。 Rings B, L3, R1, R2, R6, q and t are as defined in general formula (I), general formula (II), general formula (III) or general formula (IV).
在本公开一些优选的实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV-1)或通式(IV-1-a)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(IV-2)所示的化合物或其互变异构体、外消旋体、对映异构 体、非对映异构体、或其混合物形式、或其可药用的盐：In some preferred embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( Compounds represented by III-1), general formula (IV), general formula (IV-1) or general formula (IV-1-a) or their tautomers, racemates, enantiomers , diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IV-2) or its tautomer, racemate, enantiomer A isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
Figure PCTCN2021110197-appb-000014
Figure PCTCN2021110197-appb-000014
其中：in:
R 3为C 1-6烷基； R 3 is C 1-6 alkyl;
环B为至少含有1个N原子的4至12元杂环基；Ring B is a 4- to 12-membered heterocyclic group containing at least 1 N atom;
R 6a选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、烯基、炔基、-NR 9aR 9b、-COR 10、-C(O)OR 11、-OR 12、-(CH 2) sNR 13aR 13b、-CO(CH 2) sNR 13aR 13b和环烷基； R 6a is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, -NR 9a R 9b , -COR 10 , -C(O)OR 11 , - OR 12 , -(CH 2 ) s NR 13a R 13b , -CO(CH 2 ) s NR 13a R 13b and cycloalkyl;
t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
L 3、R 1、R 2、R 6、R 9a、R 9b、R 10至R 12、R 13a、R 13b、s和q如通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV-1)或通式(IV-1-a)中所定义。 L 3 , R 1 , R 2 , R 6 , R 9a , R 9b , R 10 to R 12 , R 13a , R 13b , s and q are as in general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula (III-1), general formula (IV), general formula (IV-1) or general formula (IV-1-a) defined.
在本公开一些优选的实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV-1)或通式(IV-1-b)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(IV-3)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：In some preferred embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( Compounds represented by III-1), general formula (IV), general formula (IV-1) or general formula (IV-1-b) or their tautomers, racemates, enantiomers , diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IV-3) or a tautomer, racemate, enantiomer thereof A isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
Figure PCTCN2021110197-appb-000015
Figure PCTCN2021110197-appb-000015
其中：in:
R 3为C 1-6烷基； R 3 is C 1-6 alkyl;
环B为至少含有1个N原子的4至12元杂环基；Ring B is a 4- to 12-membered heterocyclic group containing at least 1 N atom;
R 6a选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、烯基、炔基、-NR 9aR 9b、-COR 10、-C(O)OR 11、-OR 12、-(CH 2) sNR 13aR 13b、-CO(CH 2) sNR 13aR 13b和环烷基； R 6a is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, -NR 9a R 9b , -COR 10 , -C(O)OR 11 , - OR 12 , -(CH 2 ) s NR 13a R 13b , -CO(CH 2 ) s NR 13a R 13b and cycloalkyl;
t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
L 3、R 1、R 2、R 6、R 9a、R 9b、R 10至R 12、R 13a、R 13b、s和q如通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV-1)或通式(IV-1-b)中所定义。 L 3 , R 1 , R 2 , R 6 , R 9a , R 9b , R 10 to R 12 , R 13a , R 13b , s and q are as in general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula (III-1), general formula (IV), general formula (IV-1) or general formula (IV-1-b) defined.
在本公开一些优选的实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)或通式(IV-2-b)所示的化合物，或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中环B选自3至8元环烷基、3至12元杂环基、6至10元芳基和5至10元杂芳基；优选地，环B为3至12元杂环基；更优选地，环B为至少含有1个N原子的4至8元杂环基；最优选地，环B为哌嗪基。In some preferred embodiments of the present disclosure, the general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV-1-a), general formula ( IV-1-b), the compound represented by the general formula (IV-2-a) or the general formula (IV-2-b), or its tautomer, racemate, enantiomer, A diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from 3 to 8 membered cycloalkyl, 3 to 12 membered heterocyclyl, 6 to 10 membered aryl, and 5 to 10 membered aryl 10-membered heteroaryl; preferably, ring B is a 3- to 12-membered heterocyclic group; more preferably, ring B is a 4- to 8-membered heterocyclic group containing at least 1 N atom; most preferably, ring B is piper azinyl.
在本公开一些优选的实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV')、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)或通式(IV-2-b)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中环B选自3至8元环烷基、3至12元杂环基、6至10元芳基和5至10元杂芳基；优选地，环B为3至8元环烷基或至少含有1个N原子的4至8元杂环基；更优选地，环B选自双环[2.2.2]辛-1-基(如
Figure PCTCN2021110197-appb-000016
)、哌嗪基(如
Figure PCTCN2021110197-appb-000017
)、吡咯烷基(如
Figure PCTCN2021110197-appb-000018
)、氮杂螺[3.3]庚烷基(如
Figure PCTCN2021110197-appb-000019
)、双环[2.2.2]辛烷基(如
Figure PCTCN2021110197-appb-000020
)、氮杂环丁烷基(如
Figure PCTCN2021110197-appb-000021
)、1,2,3,6-四氢吡啶基(如
Figure PCTCN2021110197-appb-000022
)、哌啶基(如
Figure PCTCN2021110197-appb-000023
)、2,5-二氮杂二环[2.2.1]庚基(如
Figure PCTCN2021110197-appb-000024
Figure PCTCN2021110197-appb-000025
)和3,6-二氮杂二环[3.1.1]庚基(如
Figure PCTCN2021110197-appb-000026
)。 In some preferred embodiments of the present disclosure, the general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV'), general formula (IV-1) -a), the compound represented by general formula (IV-1-b), general formula (IV-2-a) or general formula (IV-2-b) or its tautomer, racemate, Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein Ring B is selected from 3 to 8 membered cycloalkyl, 3 to 12 membered heterocyclyl, 6 to 10 membered aryl and 5- to 10-membered heteroaryl; preferably, ring B is a 3- to 8-membered cycloalkyl group or a 4- to 8-membered heterocyclic group containing at least 1 N atom; more preferably, ring B is selected from bicyclic [2.2.2]oct-1-yl (as
Figure PCTCN2021110197-appb-000016
), piperazinyl (such as
Figure PCTCN2021110197-appb-000017
), pyrrolidinyl (such as
Figure PCTCN2021110197-appb-000018
), azaspiro[3.3]heptyl (such as
Figure PCTCN2021110197-appb-000019
), bicyclo[2.2.2]octyl (such as
Figure PCTCN2021110197-appb-000020
), azetidinyl (such as
Figure PCTCN2021110197-appb-000021
), 1,2,3,6-tetrahydropyridyl (such as
Figure PCTCN2021110197-appb-000022
), piperidinyl (such as
Figure PCTCN2021110197-appb-000023
), 2,5-diazabicyclo[2.2.1]heptyl (as
Figure PCTCN2021110197-appb-000024
Figure PCTCN2021110197-appb-000025
) and 3,6-diazabicyclo[3.1.1]heptyl (as
Figure PCTCN2021110197-appb-000026
).
在本公开一些优选的实施方案中，所述的通式(I-1)、通式(II-1)、通式(III-1)、通式(IV-1)、通式(IV'-1)、通式(IV-2)或通式(IV-3)所示的化合物或其互变异构体、 外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中环B为至少含有1个N原子的4至8元杂环基；优选地，环B选自哌嗪基(如
Figure PCTCN2021110197-appb-000027
)、吡咯烷基(如
Figure PCTCN2021110197-appb-000028
)、氮杂螺[3.3]庚烷基(如
Figure PCTCN2021110197-appb-000029
)、氮杂环丁烷基(如
Figure PCTCN2021110197-appb-000030
)、1,2,3,6-四氢吡啶基(如
Figure PCTCN2021110197-appb-000031
)、哌啶基(如
Figure PCTCN2021110197-appb-000032
)、2,5-二氮杂二环[2.2.1]庚基(如
Figure PCTCN2021110197-appb-000033
)和3,6-二氮杂二环[3.1.1]庚基(如
Figure PCTCN2021110197-appb-000034
)。 In some preferred embodiments of the present disclosure, the general formula (I-1), general formula (II-1), general formula (III-1), general formula (IV-1), general formula (IV') -1), the compound represented by general formula (IV-2) or general formula (IV-3) or its tautomer, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 4- to 8-membered heterocyclic group containing at least 1 N atom; preferably, Ring B is selected from piperazinyl (such as
Figure PCTCN2021110197-appb-000027
), pyrrolidinyl (such as
Figure PCTCN2021110197-appb-000028
), azaspiro[3.3]heptyl (such as
Figure PCTCN2021110197-appb-000029
), azetidinyl (such as
Figure PCTCN2021110197-appb-000030
), 1,2,3,6-tetrahydropyridyl (such as
Figure PCTCN2021110197-appb-000031
), piperidinyl (such as
Figure PCTCN2021110197-appb-000032
), 2,5-diazabicyclo[2.2.1]heptyl (as
Figure PCTCN2021110197-appb-000033
) and 3,6-diazabicyclo[3.1.1]heptyl (as
Figure PCTCN2021110197-appb-000034
).
在本公开一些优选的实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV')、通式(IV-1)、通式(IV'-1)、通式(IV-2)、通式(IV-3)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)或通式(IV-2-b)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中L 3选自化学键、NH和C(O)NR 8b，其中R 8b为氢原子。 In some preferred embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) , the compound represented by the general formula (IV-1-a), the general formula (IV-1-b), the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein L 3 is selected from a bond, NH, and C(O)NR 8b , wherein R 8b is a hydrogen atom.
在本公开一些优选的实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)或通式(IV-2-b)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中L 3为化学键或NH；优选地，L 3为化学键。 In some preferred embodiments of the present disclosure, the general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV-1-a), general formula ( IV-1-b), the compound represented by the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomer, racemate, enantiomer, An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 3 is a bond or NH; preferably, L 3 is a bond.
在本公开一些优选的实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV')、通式(IV-1)、通式(IV'-1)、通式(IV-2)、通式(IV-3)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)或通式(IV-2-b)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 1选自氢原子、氘原子、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、氨基、硝基、羟基和3至8元环烷基；优选地，R 1为氰基。 In some preferred embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) , the compound represented by the general formula (IV-1-a), the general formula (IV-1-b), the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 1 is selected from a hydrogen atom, a deuterium atom, a C 1-6 alkyl group , C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, cyano, amino, nitro , hydroxy and 3- to 8-membered cycloalkyl; preferably, R 1 is cyano.
在本公开一些优选的实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV')、通式(IV-1)、通式(IV'-1)、通式(IV-2)、通式(IV-3)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)或通式(IV-2-b)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 2选自氢原子、氘原子、C 1-6烷基、C 1-6氘代烷基、 C 1-6卤代烷基、C 1-6羟烷基和卤素；优选地，R 2为氢原子。 In some preferred embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) , the compound represented by the general formula (IV-1-a), the general formula (IV-1-b), the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomerism body, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen atom, deuterium atom, C 1-6 alkyl , C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl and halogen; preferably, R 2 is a hydrogen atom.
在本公开一些优选的实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)或通式(IV-1)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 3选自氢原子、氘原子、C 1-6烷基和C 1-6氘代烷基；优选地，R 3为C 1-6烷基；更优选地，R 3为甲基。 In some preferred embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), the compound represented by general formula (IV) or general formula (IV-1) or its tautomer, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from a hydrogen atom, a deuterium atom, a C 1-6 alkyl group and a C 1-6 deuterated alkyl group; preferably, R 3 is a C 1-6 alkyl group ; more preferably, R 3 is methyl.
在本公开一些优选的实施方案中，所述的通式(IV')、通式(IV'-1)、通式(IV-2)、通式(IV-3)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)或通式(IV-2-b)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 3为C 1-6烷基；优选地，R 3为甲基。 In some preferred embodiments of the present disclosure, the general formula (IV'), general formula (IV'-1), general formula (IV-2), general formula (IV-3), general formula (IV- Compounds represented by 1-a), general formula (IV-1-b), general formula (IV-2-a) or general formula (IV-2-b) or their tautomers and racemates , an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 is C 1-6 alkyl; preferably, R 3 is methyl.
在本公开一些优选的实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)或通式(III-1)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 4选自氢原子、氘原子、C 1-6烷基和C 1-6氘代烷基；优选地，R 4为氢原子。 In some preferred embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III) or general formula ( The compound represented by III-1) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from hydrogen atom, deuterium atom, C 1-6 alkyl and C 1-6 deuterated alkyl; preferably, R 4 is hydrogen atom.
在本公开一些优选的实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV')、通式(IV-1)、通式(IV'-1)、通式(IV-2)、通式(IV-3)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)或通式(IV-2-b)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 6选自氢原子、氘原子、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 2-6烯基、C 2-6炔基、卤素、-COR 10、-C(O)OR 11、-OR 12、-(CH 2) sNR 13aR 13b、-CO(CH 2) sNR 13aR 13b和3至8元环烷基；R 9a、R 9b、R 10～R 12、R 13a、R 13b和s如通式(I)中所定义；优选地，R 6选自氢原子、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、卤素、-COR 10、-(CH 2) sNR 13aR 13b、-CO(CH 2) sNR 13aR 13b和3至8元环烷基；其中R 10选自氢原子、C 1-6烷基、3至8元环烷基和3至12元杂环基；R 13a和R 13b相同或不同，且各自独立地为氢原子或C 1-6烷基；s为0、1或2；更优选地，R 6为氢原子。 In some preferred embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) , the compound represented by the general formula (IV-1-a), the general formula (IV-1-b), the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 6 is selected from hydrogen atom, deuterium atom, C 1-6 alkyl group , C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, -COR 10 , -C(O) OR 11 , -OR 12 , -(CH 2 ) s NR 13a R 13b , -CO(CH 2 ) s NR 13a R 13b and 3- to 8-membered cycloalkyl; R 9a , R 9b , R 10 to R 12 , R 13a , R 13b and s are as defined in general formula (I); preferably, R 6 is selected from hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, halogen , -COR 10 , -(CH 2 ) s NR 13a R 13b , -CO(CH 2 ) s NR 13a R 13b and 3- to 8-membered cycloalkyl; wherein R 10 is selected from hydrogen atom, C 1-6 alkyl , 3- to 8-membered cycloalkyl and 3- to 12-membered heterocyclic groups; R 13a and R 13b are the same or different, and are each independently a hydrogen atom or a C 1-6 alkyl group; s is 0, 1 or 2; more Preferably, R 6 is a hydrogen atom.
在本公开一些优选的实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)或通式(IV-2-b)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 6选自氢原子、氘原子、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、卤素、氰基、氨基、-NR 9aR 9b、-COR 10、-C(O)OR 11、-OR 12、硝基和羟基；优选地，R 6为氢原子。 In some preferred embodiments of the present disclosure, the general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV-1-a), general formula ( IV-1-b), the compound represented by the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomer, racemate, enantiomer, An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from hydrogen atom, deuterium atom, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halogen, cyano, amino, -NR 9a R 9b , -COR 10 , -C(O)OR 11 , -OR 12 , nitro and hydroxy; preferably, R 6 for the hydrogen atom.
在本公开一些优选的实施方案中，所述的通式(I-1)、通式(II-1)、通式(III-1)、通式(IV-1)、通式(IV'-1)、通式(IV-2)或通式(IV-3)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 6a选自氢原子、氘原子、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、 C 2-6烯基、C 2-6炔基、-NR 9aR 9b、-COR 10、-C(O)OR 11、-OR 12、-(CH 2) sNR 13aR 13b、-CO(CH 2) sNR 13aR 13b和3至8元环烷基；R 9a、R 9b、R 10～R 12、R 13a、R 13b和s如通式(I)中所定义；优选地，R 6a选自氢原子、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、-COR 10、-(CH 2) sNR 13aR 13b、-CO(CH 2) sNR 13aR 13b和3至8元环烷基；其中R 10选自氢原子、C 1-6烷基、3至8元环烷基和3至12元杂环基；R 13a和R 13b相同或不同，且各自独立地为氢原子或C 1-6烷基；s为0、1或2；更优选地，R 6a为氢原子。 In some preferred embodiments of the present disclosure, the general formula (I-1), general formula (II-1), general formula (III-1), general formula (IV-1), general formula (IV') -1), the compound represented by general formula (IV-2) or general formula (IV-3) or its tautomer, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 6a is selected from hydrogen atom, deuterium atom, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -NR 9a R 9b , -COR 10 , -C(O)OR 11 , -OR 12 , -(CH 2 ) s NR 13a R 13b , -CO(CH 2 ) s NR 13a R 13b and 3- to 8-membered cycloalkyl; R 9a , R 9b , R 10 to R 12 , R 13a , R 13b and s are as defined in general formula (I); Preferably, R 6a is selected from hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, -COR 10 , -(CH 2 ) s NR 13a R 13b , -CO( CH 2 ) s NR 13a R 13b and 3- to 8-membered cycloalkyl; wherein R 10 is selected from hydrogen atom, C 1-6 alkyl, 3- to 8-membered cycloalkyl and 3- to 12-membered heterocyclyl; R 13a and R 13b are the same or different, and are each independently a hydrogen atom or a C 1-6 alkyl group; s is 0, 1 or 2; more preferably, R 6a is a hydrogen atom.
在本公开一些优选的实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV')、通式(IV-1)、通式(IV'-1)、通式(IV-2)、通式(IV-3)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)或通式(IV-2-b)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 5a为氢原子。 In some preferred embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) , the compound represented by the general formula (IV-1-a), the general formula (IV-1-b), the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R5a is a hydrogen atom.
在本公开一些优选的实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV')、通式(IV-1)、通式(IV'-1)、通式(IV-2)、通式(IV-3)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)或通式(IV-2-b)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 5b为氢原子或C 1-6烷基；优选地，R 5b为氢原子。 In some preferred embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) , the compound represented by the general formula (IV-1-a), the general formula (IV-1-b), the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 5b is a hydrogen atom or a C 1-6 alkyl group; preferably, R 5b is a hydrogen atom.
在本公开一些优选的实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV')、通式(IV-1)、通式(IV'-1)、通式(IV-2)、通式(IV-3)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)或通式(IV-2-b)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 7a、R 7b、R 7c、R 7d、R 7e和R 7f相同或不同，且各自独立地选自氢原子、氘原子、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基和C 1-6羟烷基。 In some preferred embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) , the compound represented by the general formula (IV-1-a), the general formula (IV-1-b), the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 7a , R 7b , R 7c , R 7d , R 7e and R 7f are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a C 1-6 alkyl group, a C 1-6 deuterated alkyl group, a C 1-6 haloalkyl group, and a C 1-6 hydroxyalkyl group.
在本公开一些优选的实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV')、通式(IV-1)、通式(IV'-1)、通式(IV-2)、通式(IV-3)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)或通式(IV-2-b)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 8a和R 8b相同或不同，且各自独立地选自氢原子、氘原子、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基和C 1-6羟烷基；优选地，R 8a和R 8b为氢原子。 In some preferred embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) , the compound represented by the general formula (IV-1-a), the general formula (IV-1-b), the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 8a and R 8b are the same or different, and are each independently selected from hydrogen atom, deuterium atom, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl; preferably, R 8a and R 8b are hydrogen atoms.
在本公开一些优选的实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV')、通式(IV-1)、通式(IV'-1)、通式(IV-2)、通式(IV-3)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)或通式(IV-2-b)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 9a和R 9b相同或不同，且各自独立地选自氢原子、氘原子、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基和C 1-6羟烷基。 In some preferred embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) , the compound represented by the general formula (IV-1-a), the general formula (IV-1-b), the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 9a and R 9b are the same or different, and are each independently selected from hydrogen atom, deuterium atom, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl.
在本公开一些优选的实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV')、通式(IV-1)、通式(IV'-1)、通式(IV-2)、通式(IV-3)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)或通式(IV-2-b)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 10选自氢原子、氘原子、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、3至8元环烷基、3至12元杂环基、6至10元芳基和5至10元杂芳基；其中，所述的C 1-6烷基、3至8元环烷基、3至12元杂环基、6至10元芳基和5至10元杂芳基各自独立地任选被选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、硝基和羟基中的一个或多个取代基所取代；优选地，R 10选自氢原子、C 1-6烷基、3至8元环烷基和3至12元杂环基。 In some preferred embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) , the compound represented by the general formula (IV-1-a), the general formula (IV-1-b), the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomerism body, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from hydrogen atom, deuterium atom, C 1-6 alkyl , C 1-6 deuterated alkyl, C 1-6 haloalkyl, 3 to 8 membered cycloalkyl, 3 to 12 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl; wherein, Said C 1-6 alkyl, 3- to 8-membered cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl are each independently optionally selected from halogen, Substituted by one or more substituents in C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, amino, nitro and hydroxyl; Preferably, R 10 is selected from a hydrogen atom, a C 1-6 alkyl group, a 3- to 8-membered cycloalkyl group, and a 3- to 12-membered heterocyclic group.
在本公开一些优选的实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV')、通式(IV-1)、通式(IV'-1)、通式(IV-2)、通式(IV-3)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)或通式(IV-2-b)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 11和R 12相同或不同，且各自独立地选自氢原子、氘原子、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、3至8元环烷基、3至12元杂环基、6至10元芳基和5至10元杂芳基；其中，所述的C 1-6烷基、3至8元环烷基、3至12元杂环基、6至10元芳基和5至10元杂芳基各自独立地任选被选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、-(CH 2) sNR 13aR 13b、硝基和羟基中的一个或多个取代基所取代，其中s、R 13a和R 13b如通式(I)中所定义。 In some preferred embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) , the compound represented by the general formula (IV-1-a), the general formula (IV-1-b), the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 11 and R 12 are the same or different, and are each independently selected from hydrogen atom, deuterium atom, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, 3- to 8-membered cycloalkyl, 3- to 12-membered heterocycle C 1-6 alkyl, 3- to 8-membered cycloalkyl, 3- to 12-membered heterocyclic, 6- to 10-membered aryl and 5- to 10-membered heteroaryl groups are each independently optionally selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano Substituted with one or more substituents of group, amino, -(CH 2 ) s NR 13a R 13b , nitro and hydroxy, wherein s, R 13a and R 13b are as defined in general formula (I).
在本公开一些优选的实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV')、通式(IV-1)、通式(IV'-1)、通式(IV-2)、通式(IV-3)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)或通式(IV-2-b)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 13a和R 13b相同或不同，且各自独立地选自氢原子、氘原子和C 1-6烷基；优选地，R 13a和R 13b相同或不同，且各自独立地为氢原子或C 1-6烷基。 In some preferred embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) , the compound represented by the general formula (IV-1-a), the general formula (IV-1-b), the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 13a and R 13b are the same or different, and are each independently selected from hydrogen atom, deuterium atom and C 1-6 alkyl group; preferably, R 13a and R 13b are the same or different, and are each independently a hydrogen atom or a C 1-6 alkyl group.
在本公开一些优选的实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)或通式(III-1)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中n为0或1；优选地，n为1。In some preferred embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III) or general formula ( The compound represented by III-1) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1; preferably, n is 1.
在本公开一些优选的实施方案中，所述的通式(I)或通式(I-1)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中p为1。In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (I-1) or its tautomer, racemate, enantiomer, An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein p is 1.
在本公开一些优选的实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式 (II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV')、通式(IV-1)、通式(IV'-1)、通式(IV-2)、通式(IV-3)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)或通式(IV-2-b)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中q为0或1；优选地，q为1。In some preferred embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) , the compound represented by the general formula (IV-1-a), the general formula (IV-1-b), the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein q is 0 or 1; preferably, q is 1.
在本公开一些优选的实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV')、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)或通式(IV-2-b)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中t为0、1或2。In some preferred embodiments of the present disclosure, the general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV'), general formula (IV-1) -a), the compound represented by general formula (IV-1-b), general formula (IV-2-a) or general formula (IV-2-b) or its tautomer, racemate, An enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein t is 0, 1, or 2.
在本公开一些优选的实施方案中，所述的通式(I-1)、通式(II-1)、通式(III-1)、通式(IV-1)、通式(IV'-1)、通式(IV-2)或通式(IV-3)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中t为1或2。In some preferred embodiments of the present disclosure, the general formula (I-1), general formula (II-1), general formula (III-1), general formula (IV-1), general formula (IV') -1), the compound represented by general formula (IV-2) or general formula (IV-3) or its tautomer, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein t is 1 or 2.
在本公开一些优选的实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV')、通式(IV-1)、通式(IV'-1)、通式(IV-2)、通式(IV-3)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)或通式(IV-2-b)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中s为0、1或2。In some preferred embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) , the compound represented by the general formula (IV-1-a), the general formula (IV-1-b), the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein s is 0, 1, or 2.
在本公开一些优选的实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV')、通式(IV-1)、通式(IV'-1)、通式(IV-2)、通式(IV-3)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)或通式(IV-2-b)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中m为0或6。In some preferred embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula ( III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) , the compound represented by the general formula (IV-1-a), the general formula (IV-1-b), the general formula (IV-2-a) or the general formula (IV-2-b) or its tautomerism isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein m is 0 or 6.
在本公开一些优选的实施方案中，所述的通式(IV)、通式(IV')、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)或通式(IV-2-b)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中环B为3至8元环烷基或至少含有1个N原子的4至8元杂环基；L 3选自化学键、NH和C(O)NR 8b，其中R 8b为氢原子；R 1为氰基；R 2为氢原子；R 3为C 1-6烷基；R 6选自氢原子、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、卤素、-COR 10、-(CH 2) sNR 13aR 13b、-CO(CH 2) sNR 13aR 13b和3至8元环烷基；其中R 10选自氢原子、C 1-6烷基、3至8元环烷基和3至12元杂环基；R 13a和R 13b相同或不同，且各自独立地为氢原子或C 1-6烷基；s为0、1或2；t为0、1或2。 In some preferred embodiments of the present disclosure, the general formula (IV), general formula (IV'), general formula (IV-1-a), general formula (IV-1-b), general formula (IV) -2-a) or the compound represented by general formula (IV-2-b) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is a 3- to 8-membered cycloalkyl group or a 4- to 8-membered heterocyclic group containing at least 1 N atom; L 3 is selected from a chemical bond, NH and C(O)NR 8b , R 8b is hydrogen atom; R 1 is cyano group; R 2 is hydrogen atom; R 3 is C 1-6 alkyl group; R 6 is selected from hydrogen atom, C 1-6 alkyl group, C 1-6 alkoxy group , C 1-6 haloalkyl, halogen, -COR 10 , -(CH 2 ) s NR 13a R 13b , -CO(CH 2 ) s NR 13a R 13b and 3- to 8-membered cycloalkyl; wherein R 10 is selected from A hydrogen atom, a C 1-6 alkyl group, a 3- to 8-membered cycloalkyl group, and a 3- to 12-membered heterocyclic group; R 13a and R 13b are the same or different, and are each independently a hydrogen atom or a C 1-6 alkyl group; s is 0, 1 or 2; t is 0, 1 or 2.
在本公开一些优选的实施方案中，所述的通式(IV-1)、通式(IV'-1)、通式(IV-2)或通式(IV-3)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中环B为至少含有1个N原子的4至8元杂环基；R 6a选自氢原子、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、-COR 10、-(CH 2) sNR 13aR 13b、-CO(CH 2) sNR 13aR 13b和3至8元环烷基；R 6选自氢原子、C 1-6烷 基、C 1-6烷氧基、C 1-6卤代烷基、卤素、-COR 10、-(CH 2) sNR 13aR 13b、-CO(CH 2) sNR 13aR 13b和3至8元环烷基；R 10选自氢原子、C 1-6烷基、3至8元环烷基和3至12元杂环基；R 13a和R 13b相同或不同，且各自独立地为氢原子或C 1-6烷基；s为0、1或2；t为1或2；L 3选自化学键、NH和C(O)NR 8b，其中R 8b为氢原子；R 1为氰基；R 2为氢原子；R 3为C 1-6烷基。 In some preferred embodiments of the present disclosure, the compound represented by the general formula (IV-1), the general formula (IV'-1), the general formula (IV-2) or the general formula (IV-3) or Its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring B is 4 containing at least 1 N atom to 8-membered heterocyclic group; R 6a is selected from hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, -COR 10 , -(CH 2 ) s NR 13a R 13b , -CO(CH 2 ) s NR 13a R 13b and 3- to 8-membered cycloalkyl; R 6 is selected from hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, Halogen, -COR 10 , -(CH 2 ) s NR 13a R 13b , -CO(CH 2 ) s NR 13a R 13b and 3- to 8-membered cycloalkyl; R 10 is selected from hydrogen atom, C 1-6 alkyl , 3- to 8-membered cycloalkyl and 3- to 12-membered heterocyclic groups; R 13a and R 13b are the same or different, and are each independently a hydrogen atom or a C 1-6 alkyl group; s is 0, 1 or 2; t is 1 or 2; L 3 is selected from chemical bonds, NH and C(O)NR 8b , wherein R 8b is a hydrogen atom; R 1 is a cyano group; R 2 is a hydrogen atom; R 3 is a C 1-6 alkyl group.
表A本公开的典型化合物包括但不限于：Table A Typical compounds of the present disclosure include, but are not limited to:
Figure PCTCN2021110197-appb-000035
Figure PCTCN2021110197-appb-000035
Figure PCTCN2021110197-appb-000036
Figure PCTCN2021110197-appb-000036
Figure PCTCN2021110197-appb-000037
Figure PCTCN2021110197-appb-000037
Figure PCTCN2021110197-appb-000038
Figure PCTCN2021110197-appb-000038
Figure PCTCN2021110197-appb-000039
Figure PCTCN2021110197-appb-000039
Figure PCTCN2021110197-appb-000040
Figure PCTCN2021110197-appb-000040
Figure PCTCN2021110197-appb-000041
Figure PCTCN2021110197-appb-000041
Figure PCTCN2021110197-appb-000042
Figure PCTCN2021110197-appb-000042
Figure PCTCN2021110197-appb-000043
Figure PCTCN2021110197-appb-000043
Figure PCTCN2021110197-appb-000044
Figure PCTCN2021110197-appb-000044
Figure PCTCN2021110197-appb-000045
Figure PCTCN2021110197-appb-000045
Figure PCTCN2021110197-appb-000046
Figure PCTCN2021110197-appb-000046
Figure PCTCN2021110197-appb-000047
Figure PCTCN2021110197-appb-000047
Figure PCTCN2021110197-appb-000048
Figure PCTCN2021110197-appb-000048
Figure PCTCN2021110197-appb-000049
Figure PCTCN2021110197-appb-000049
Figure PCTCN2021110197-appb-000050
Figure PCTCN2021110197-appb-000050
Figure PCTCN2021110197-appb-000051
Figure PCTCN2021110197-appb-000051
Figure PCTCN2021110197-appb-000052
Figure PCTCN2021110197-appb-000052
Figure PCTCN2021110197-appb-000053
Figure PCTCN2021110197-appb-000053
Figure PCTCN2021110197-appb-000054
Figure PCTCN2021110197-appb-000054
Figure PCTCN2021110197-appb-000055
Figure PCTCN2021110197-appb-000055
Figure PCTCN2021110197-appb-000056
Figure PCTCN2021110197-appb-000056
Figure PCTCN2021110197-appb-000057
Figure PCTCN2021110197-appb-000057
Figure PCTCN2021110197-appb-000058
Figure PCTCN2021110197-appb-000058
Figure PCTCN2021110197-appb-000059
Figure PCTCN2021110197-appb-000059
Figure PCTCN2021110197-appb-000060
Figure PCTCN2021110197-appb-000060
Figure PCTCN2021110197-appb-000061
Figure PCTCN2021110197-appb-000061
Figure PCTCN2021110197-appb-000062
Figure PCTCN2021110197-appb-000062
Figure PCTCN2021110197-appb-000063
Figure PCTCN2021110197-appb-000063
Figure PCTCN2021110197-appb-000064
Figure PCTCN2021110197-appb-000064
Figure PCTCN2021110197-appb-000065
Figure PCTCN2021110197-appb-000065
Figure PCTCN2021110197-appb-000066
Figure PCTCN2021110197-appb-000066
Figure PCTCN2021110197-appb-000067
Figure PCTCN2021110197-appb-000067
Figure PCTCN2021110197-appb-000068
Figure PCTCN2021110197-appb-000068
Figure PCTCN2021110197-appb-000069
Figure PCTCN2021110197-appb-000069
Figure PCTCN2021110197-appb-000070
Figure PCTCN2021110197-appb-000070
Figure PCTCN2021110197-appb-000071
Figure PCTCN2021110197-appb-000071
Figure PCTCN2021110197-appb-000072
Figure PCTCN2021110197-appb-000072
Figure PCTCN2021110197-appb-000073
Figure PCTCN2021110197-appb-000073
Figure PCTCN2021110197-appb-000074
Figure PCTCN2021110197-appb-000074
Figure PCTCN2021110197-appb-000075
Figure PCTCN2021110197-appb-000075
Figure PCTCN2021110197-appb-000076
Figure PCTCN2021110197-appb-000076
Figure PCTCN2021110197-appb-000077
Figure PCTCN2021110197-appb-000077
Figure PCTCN2021110197-appb-000078
Figure PCTCN2021110197-appb-000078
Figure PCTCN2021110197-appb-000079
Figure PCTCN2021110197-appb-000079
Figure PCTCN2021110197-appb-000080
Figure PCTCN2021110197-appb-000080
本公开的另一方面涉及通式(Ia)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：Another aspect of the present disclosure pertains to compounds of formula (Ia) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or tautomers, racemates, enantiomers, or mixtures thereof. Medicinal salt:
Figure PCTCN2021110197-appb-000081
Figure PCTCN2021110197-appb-000081
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
环A、环B、X、Y、Z、L 1至L 3、R 3、R 4、R 6、W 1至W 4、n和t如通式(I)中所定义。 Ring A, Ring B, X, Y, Z, L 1 to L 3 , R 3 , R 4 , R 6 , W 1 to W 4 , n and t are as defined in general formula (I).
本公开的另一方面涉及通式(I-1a)所示的化合物或其互变异构体、外消旋体、 对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：Another aspect of the present disclosure relates to a compound represented by general formula (I-1a) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or Its pharmaceutically acceptable salts:
Figure PCTCN2021110197-appb-000082
Figure PCTCN2021110197-appb-000082
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
环A、环B、X、Y、Z、L 1至L 3、R 3、R 4、R 6、W 1至W 4和n如通式(I-1)中所定义。 Ring A, Ring B, X, Y, Z, L 1 to L 3 , R 3 , R 4 , R 6 , W 1 to W 4 and n are as defined in the general formula (I-1).
本公开的另一方面涉及通式(IIa)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：Another aspect of the present disclosure pertains to compounds of general formula (IIa) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or tautomers, racemates, enantiomers, or mixtures thereof Medicinal salt:
Figure PCTCN2021110197-appb-000083
Figure PCTCN2021110197-appb-000083
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
环B、X、Y、Z、L 1、L 2、L 3、R 1至R 4、R 6、W 1至W 4、q、n和t如通式(II)中所定义。 Rings B, X, Y, Z, L 1 , L 2 , L 3 , R 1 to R 4 , R 6 , W 1 to W 4 , q, n and t are as defined in general formula (II).
本公开的另一方面涉及通式(II-1a)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：Another aspect of the present disclosure relates to a compound represented by general formula (II-1a) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or Its pharmaceutically acceptable salts:
Figure PCTCN2021110197-appb-000084
Figure PCTCN2021110197-appb-000084
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
环B、X、Y、Z、L 1、L 2、L 3、R 1至R 4、R 6、q和n如通式(II-1)中所定义。 Rings B, X, Y, Z, L 1 , L 2 , L 3 , R 1 to R 4 , R 6 , q and n are as defined in general formula (II-1).
本公开的另一方面涉及通式(IIIa)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：Another aspect of the present disclosure pertains to compounds of general formula (IIIa) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or isomers thereof Medicinal salt:
Figure PCTCN2021110197-appb-000085
Figure PCTCN2021110197-appb-000085
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
环B、L 1至L 3、R 1至R 4、R 6、q、n和t如通式(III)中所定义。 Ring B, L 1 to L 3 , R 1 to R 4 , R 6 , q, n and t are as defined in general formula (III).
本公开的另一方面涉及通式(III-1a)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：Another aspect of the present disclosure relates to a compound represented by general formula (III-1a) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Its pharmaceutically acceptable salts:
Figure PCTCN2021110197-appb-000086
Figure PCTCN2021110197-appb-000086
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
环B、L 1至L 3、R 1至R 4、R 6、q和n如通式(III-1)中所定义。 Ring B, L 1 to L 3 , R 1 to R 4 , R 6 , q and n are as defined in general formula (III-1).
本公开的另一方面涉及通式(IVa)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：Another aspect of the present disclosure pertains to compounds of formula (IVa) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or tautomers, racemates, enantiomers, or mixtures thereof Medicinal salt:
Figure PCTCN2021110197-appb-000087
Figure PCTCN2021110197-appb-000087
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
环B、L 3、R 1至R 3、R 6、q和t如通式(IV)中所定义。 Rings B, L 3 , R 1 to R 3 , R 6 , q and t are as defined in general formula (IV).
本公开的另一方面涉及通式(IV'a)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：Another aspect of the present disclosure relates to a compound of formula (IV'a) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Its pharmaceutically acceptable salts:
Figure PCTCN2021110197-appb-000088
Figure PCTCN2021110197-appb-000088
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
环B、L 3、R 1至R 3、R 6、q和t如通式(IV')中所定义。 Rings B, L3, R1 to R3 , R6, q and t are as defined in general formula (IV').
本公开的另一方面涉及通式(IV-1a)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：Another aspect of the present disclosure relates to a compound represented by general formula (IV-1a) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or Its pharmaceutically acceptable salts:
Figure PCTCN2021110197-appb-000089
Figure PCTCN2021110197-appb-000089
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
环B、L 3、R 1至R 3、R 6和q如通式(IV-1)中所定义。 Ring B, L 3 , R 1 to R 3 , R 6 and q are as defined in general formula (IV-1).
本公开的另一方面涉及通式(IV'-1a)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：Another aspect of the present disclosure relates to the compound represented by general formula (IV'-1a) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:
Figure PCTCN2021110197-appb-000090
Figure PCTCN2021110197-appb-000090
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
环B、L 3、R 1至R 3、R 6和q如通式(IV'-1)中所定义。 Ring B, L 3 , R 1 to R 3 , R 6 and q are as defined in general formula (IV'-1).
本公开的另一方面涉及通式(IV-2a)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：Another aspect of the present disclosure relates to a compound represented by general formula (IV-2a) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Its pharmaceutically acceptable salts:
Figure PCTCN2021110197-appb-000091
Figure PCTCN2021110197-appb-000091
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
环B、L 3、R 1至R 3、R 6和q如通式(IV-2)中所定义。 Ring B, L 3 , R 1 to R 3 , R 6 and q are as defined in general formula (IV-2).
本公开的另一方面涉及通式(IV-3a)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：Another aspect of the present disclosure relates to a compound represented by general formula (IV-3a) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Its pharmaceutically acceptable salts:
Figure PCTCN2021110197-appb-000092
Figure PCTCN2021110197-appb-000092
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
环B、L 3、R 1至R 3、R 6和q如通式(IV-3)中所定义。 Ring B, L 3 , R 1 to R 3 , R 6 and q are as defined in general formula (IV-3).
表B本公开的典型化合物包括但不限于：Typical compounds of the present disclosure include, but are not limited to:
Figure PCTCN2021110197-appb-000093
Figure PCTCN2021110197-appb-000093
Figure PCTCN2021110197-appb-000094
Figure PCTCN2021110197-appb-000094
Figure PCTCN2021110197-appb-000095
Figure PCTCN2021110197-appb-000095
Figure PCTCN2021110197-appb-000096
Figure PCTCN2021110197-appb-000096
Figure PCTCN2021110197-appb-000097
Figure PCTCN2021110197-appb-000097
Figure PCTCN2021110197-appb-000098
Figure PCTCN2021110197-appb-000098
Figure PCTCN2021110197-appb-000099
Figure PCTCN2021110197-appb-000099
Figure PCTCN2021110197-appb-000100
Figure PCTCN2021110197-appb-000100
Figure PCTCN2021110197-appb-000101
Figure PCTCN2021110197-appb-000101
Figure PCTCN2021110197-appb-000102
Figure PCTCN2021110197-appb-000102
Figure PCTCN2021110197-appb-000103
Figure PCTCN2021110197-appb-000103
Figure PCTCN2021110197-appb-000104
Figure PCTCN2021110197-appb-000104
Figure PCTCN2021110197-appb-000105
Figure PCTCN2021110197-appb-000105
Figure PCTCN2021110197-appb-000106
Figure PCTCN2021110197-appb-000106
Figure PCTCN2021110197-appb-000107
Figure PCTCN2021110197-appb-000107
Figure PCTCN2021110197-appb-000108
Figure PCTCN2021110197-appb-000108
Figure PCTCN2021110197-appb-000109
Figure PCTCN2021110197-appb-000109
Figure PCTCN2021110197-appb-000110
Figure PCTCN2021110197-appb-000110
Figure PCTCN2021110197-appb-000111
Figure PCTCN2021110197-appb-000111
Figure PCTCN2021110197-appb-000112
Figure PCTCN2021110197-appb-000112
Figure PCTCN2021110197-appb-000113
Figure PCTCN2021110197-appb-000113
Figure PCTCN2021110197-appb-000114
Figure PCTCN2021110197-appb-000114
Figure PCTCN2021110197-appb-000115
Figure PCTCN2021110197-appb-000115
Figure PCTCN2021110197-appb-000116
Figure PCTCN2021110197-appb-000116
本公开的另一方面涉及一种制备通式(I)所示的化合物，或其互变异构体、外 消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to the preparation of a compound of general formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof in the form of , or a method of a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2021110197-appb-000117
Figure PCTCN2021110197-appb-000117
通式(Ia)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐脱去保护基R W，得到通式(I)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐， Compounds of general formula (Ia) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof Deprotection group R W , to obtain a compound of general formula (I) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
环A、环B、X、Y、Z、L 1至L 3、R 3、R 4、R 6、W 1至W 4、n和t如通式(I)中所定义。 Ring A, Ring B, X, Y, Z, L 1 to L 3 , R 3 , R 4 , R 6 , W 1 to W 4 , n and t are as defined in general formula (I).
本公开的另一方面涉及一种制备通式(I-1)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (I-1) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof form, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2021110197-appb-000118
Figure PCTCN2021110197-appb-000118
通式(I-1a)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐脱去保护基R W，得到通式(I-1)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐， Deprotection of a compound of general formula (I-1a) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof group R W to obtain the compound of general formula (I-1) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or its pharmaceutically acceptable of salt,
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
R 6a为氢原子； R 6a is a hydrogen atom;
t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
环A、环B、X、Y、Z、L 1至L 3、R 3、R 4、R 6、W 1至W 4和n如通式(I-1)中所定义。 Ring A, Ring B, X, Y, Z, L 1 to L 3 , R 3 , R 4 , R 6 , W 1 to W 4 and n are as defined in the general formula (I-1).
本公开的另一方面涉及一种制备通式(II)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to a preparation of the compound represented by the general formula (II) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2021110197-appb-000119
Figure PCTCN2021110197-appb-000119
通式(IIa)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐脱去保护基R W，得到通式(II)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐， Compounds of general formula (IIa) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof Deprotection group R W , to obtain the compound of general formula (II) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
环B、X、Y、Z、L 1、L 2、L 3、W 1至W 4、R 1至R 4、R 6、q、n和t如通式(II)中所定义。 Rings B, X, Y, Z, L 1 , L 2 , L 3 , W 1 to W 4 , R 1 to R 4 , R 6 , q, n and t are as defined in general formula (II).
本公开的另一方面涉及一种制备通式(II-1)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (II-1) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof form, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2021110197-appb-000120
Figure PCTCN2021110197-appb-000120
通式(II-1a)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、 或其混合物形式、或其可药用的盐脱去保护基R W，得到通式(II-1)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐， Deprotection of a compound of general formula (II-1a) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof group R W to obtain the compound of general formula (II-1) or its tautomer, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable of salt,
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
R 6a为氢原子； R 6a is a hydrogen atom;
t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
环B、X、Y、Z、L 1、L 2、L 3、W 1至W 4、R 1至R 4、R 6、q和n如通式(II-1)中所定义。 Rings B, X, Y, Z, L 1 , L 2 , L 3 , W 1 to W 4 , R 1 to R 4 , R 6 , q and n are as defined in the general formula (II-1).
本公开的另一方面涉及一种制备通式(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to a preparation of the compound represented by the general formula (III) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2021110197-appb-000121
Figure PCTCN2021110197-appb-000121
通式(IIIa)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐脱去保护基R W，得到通式(III)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐， Compounds of general formula (IIIa) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof Deprotection group R W , to obtain a compound of general formula (III) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
环B、L 1至L 3、R 1至R 4、R 6、q、n和t如通式(III)中所定义。 Ring B, L 1 to L 3 , R 1 to R 4 , R 6 , q, n and t are as defined in general formula (III).
本公开的另一方面涉及一种制备通式(III-1)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (III-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof form, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2021110197-appb-000122
Figure PCTCN2021110197-appb-000122
通式(III-1a)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐脱去保护基R W，得到通式(III-1)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐， Deprotection of a compound of general formula (III-1a) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof group R W to obtain the compound of general formula (III-1) or its tautomer, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable of salt,
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
R 6a为氢原子； R 6a is a hydrogen atom;
t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
环B、L 1至L 3、R 1至R 4、R 6、q和n如通式(III-1)中所定义。 Ring B, L 1 to L 3 , R 1 to R 4 , R 6 , q and n are as defined in general formula (III-1).
本公开的另一方面涉及一种制备通式(IV)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (IV) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2021110197-appb-000123
Figure PCTCN2021110197-appb-000123
通式(IVa)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐脱去保护基R W，得到通式(IV)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐， Compounds of general formula (IVa) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof Deprotection R W , to obtain a compound of general formula (IV) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
环B、L 3、R 1至R 3、R 6、q和t如通式(IV)中所定义。 Rings B, L 3 , R 1 to R 3 , R 6 , q and t are as defined in general formula (IV).
本公开的另一方面涉及一种制备通式(IV')所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (IV') or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof , or a method of a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2021110197-appb-000124
Figure PCTCN2021110197-appb-000124
通式(IV'a)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐脱去保护基R W，得到通式(IV')的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐， Deprotection of a compound of general formula (IV'a) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof group R W to obtain the compound of general formula (IV') or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable form thereof Salt,
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
环B、L 3、R 1至R 3、R 6、q和t如通式(IV')中所定义。 Rings B, L3, R1 to R3 , R6, q and t are as defined in general formula (IV').
本公开的另一方面涉及一种制备通式(IV-1)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (IV-1) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof form, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2021110197-appb-000125
Figure PCTCN2021110197-appb-000125
通式(IV-1a)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐脱去保护基R W，得到通式(IV-1)的化合物或其 互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐， Deprotection of a compound of general formula (IV-1a) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof group R W to obtain the compound of general formula (IV-1) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or its pharmaceutically acceptable of salt,
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
R 6a为氢原子； R 6a is a hydrogen atom;
t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
环B、L 3、R 1至R 3、R 6和q如通式(IV-1)中所定义。 Ring B, L 3 , R 1 to R 3 , R 6 and q are as defined in general formula (IV-1).
本公开的另一方面涉及一种制备通式(IV'-1)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to a preparation of the compound represented by the general formula (IV'-1) or its tautomer, racemate, enantiomer, diastereomer, or its A method in the form of a mixture, or a pharmaceutically acceptable salt thereof, comprising:
Figure PCTCN2021110197-appb-000126
Figure PCTCN2021110197-appb-000126
通式(IV'a-1)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐脱去保护基R W，得到通式(IV'-1)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐， Compounds of general formula (IV'a-1) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof Deprotection group R W is obtained to obtain the compound of general formula (IV'-1) or its tautomer, racemate, enantiomer, diastereomer, or its mixture form, or its medicinal salt,
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
R 6a为氢原子； R 6a is a hydrogen atom;
t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
环B、L 3、R 1至R 3、R 6和q如通式(IV'-1)中所定义。 Ring B, L 3 , R 1 to R 3 , R 6 and q are as defined in general formula (IV'-1).
本公开的另一方面涉及一种制备通式(IV-2)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (IV-2) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof form, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2021110197-appb-000127
Figure PCTCN2021110197-appb-000127
通式(IV-2a)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐脱去保护基R W，得到通式(IV-2)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐， Deprotection of a compound of general formula (IV-2a) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof group R W to obtain the compound of general formula (IV-2) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or its pharmaceutically acceptable of salt,
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
R 6a为氢原子； R 6a is a hydrogen atom;
t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
环B、L 3、R 1至R 3、R 6和q如通式(IV-2)中所定义。 Ring B, L 3 , R 1 to R 3 , R 6 and q are as defined in general formula (IV-2).
本公开的另一方面涉及一种制备通式(IV-3)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to a preparation of a compound represented by general formula (IV-3) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof form, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2021110197-appb-000128
Figure PCTCN2021110197-appb-000128
通式(IV-3a)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐脱去保护基R W，得到通式(IV-3)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐， Deprotection of a compound of general formula (IV-3a) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof group R W to obtain the compound of general formula (IV-3) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or its pharmaceutically acceptable of salt,
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
R 6a为氢原子； R 6a is a hydrogen atom;
t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
环B、L 3、R 1至R 3、R 6和q如通式(IV-3)中所定义。 Ring B, L 3 , R 1 to R 3 , R 6 and q are as defined in general formula (IV-3).
本公开的另一方面涉及一种药物组合物，所述药物组合物含有本公开通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV')、通式(IV-1)、通式(IV'-1)、通式(IV-2)、通式(IV-3)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)、通式(IV-2-b)以及表A所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。Another aspect of the present disclosure relates to a pharmaceutical composition comprising the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (II-1), general formula formula (III), general formula (III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2) , general formula (IV-3), general formula (IV-1-a), general formula (IV-1-b), general formula (IV-2-a), general formula (IV-2-b) and table A compound represented by A, or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more A pharmaceutically acceptable carrier, diluent or excipient.
本公开进一步涉及通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV')、通式(IV-1)、通式(IV'-1)、通式(IV-2)、通式(IV-3)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)、通式(IV-2-b)以及表A所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐、或包括其的药物组合物在制备用于抑制TLR7、TLR8和TLR9的药物中的用途。The present disclosure further relates to general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula (III-1), general formula (IV) ), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3), general formula (IV-1-a) ), general formula (IV-1-b), general formula (IV-2-a), general formula (IV-2-b) and the compounds shown in Table A or their tautomers and racemates , use of an enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting TLR7, TLR8 and TLR9.
本公开进一步涉及通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV')、通式(IV-1)、通式(IV'-1)、通式(IV-2)、通式(IV-3)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)、通式(IV-2-b)以及表A所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐、或包括其的药物组合物在制备用于抑制TLR7、TLR8或TLR9的药物中的用途；优选在制备用于抑制TLR7和TLR8的药物中的用途，或在制备用于抑制TLR7和TLR9的药物中的用途。The present disclosure further relates to general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula (III-1), general formula (IV) ), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3), general formula (IV-1-a) ), general formula (IV-1-b), general formula (IV-2-a), general formula (IV-2-b) and the compounds shown in Table A or their tautomers and racemates , enantiomers, diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same in the manufacture of a medicament for inhibiting TLR7, TLR8 or TLR9; Preferred is the use in the manufacture of a medicament for inhibiting TLR7 and TLR8, or the use in the manufacture of a medicament for inhibiting TLR7 and TLR9.
本公开进一步涉及通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV')、通式(IV-1)、通式(IV'-1)、通式(IV-2)、通式(IV-3)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)、通式(IV-2-b)以及表A所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐、或包括其的药物组合物在制备用于治疗和/或预防炎性或自身免疫性疾病的药物中的用途。其中所述的炎性或自身免疫性疾病优选选自系统性红斑狼疮(SLE)、类风湿性关节炎、多发性硬化(MS)和肖格伦综合症。The present disclosure further relates to general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula (III-1), general formula (IV) ), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3), general formula (IV-1-a) ), general formula (IV-1-b), general formula (IV-2-a), general formula (IV-2-b) and the compounds shown in Table A or their tautomers and racemates , enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation for the treatment and/or prevention of inflammatory or autoimmune diseases use in medicines. The inflammatory or autoimmune disease described therein is preferably selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS) and Shoghren's syndrome.
本公开进一步涉及一种抑制TLR7、TLR8和TLR9的方法，其包括给予所需患者抑制有效量的通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV')、通式(IV-1)、通式(IV'-1)、通式(IV-2)、通式(IV-3)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)、通式(IV-2-b)以及表A所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐、或包括其的药物组合物。The present disclosure further relates to a method of inhibiting TLR7, TLR8 and TLR9, comprising administering to a patient in need thereof an inhibitory effective amount of formula (I), formula (I-1), formula (II), formula (II- 1), general formula (III), general formula (III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula ( IV-2), general formula (IV-3), general formula (IV-1-a), general formula (IV-1-b), general formula (IV-2-a), general formula (IV-2- b) and the compounds shown in Table A or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or including its pharmaceutical composition.
本公开进一步涉及一种抑制TLR7、TLR8或TLR9的方法，优选抑制TLR7和TLR8的方法，或抑制TLR7和TLR9的方法，其包括给予所需患者抑制有效量的通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV')、通式(IV-1)、通式(IV'-1)、通式(IV-2)、通式(IV-3)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)、通式(IV-2-b)以及表A所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐、或包括其的药物组合物。The present disclosure further relates to a method of inhibiting TLR7, TLR8 or TLR9, preferably a method of inhibiting TLR7 and TLR8, or a method of inhibiting TLR7 and TLR9, comprising administering to a patient in need thereof an inhibitory effective amount of general formula (I), general formula ( I-1), general formula (II), general formula (II-1), general formula (III), general formula (III-1), general formula (IV), general formula (IV'), general formula (IV) -1), general formula (IV'-1), general formula (IV-2), general formula (IV-3), general formula (IV-1-a), general formula (IV-1-b), general formula Compounds of formula (IV-2-a), general formula (IV-2-b) and Table A or their tautomers, racemates, enantiomers, diastereomers , or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
本公开进一步涉及一种治疗和/或预防炎性或自身免疫性疾病的方法，其包括给予所需患者治疗有效量的通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV')、通式(IV-1)、通式(IV'-1)、通式(IV-2)、通式(IV-3)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)、通式(IV-2-b)以及表A所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐、或包括其的药物组合物；其中所述的炎性或自身免疫性疾病优选选自系统性红斑狼疮(SLE)、类风湿性关节炎、多发性硬化(MS)和肖格伦综合症。The present disclosure further relates to a method of treating and/or preventing an inflammatory or autoimmune disease, comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), formula (I-1), formula (II) , general formula (II-1), general formula (III), general formula (III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'- 1), general formula (IV-2), general formula (IV-3), general formula (IV-1-a), general formula (IV-1-b), general formula (IV-2-a), general formula Compounds of formula (IV-2-b) and Table A or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable compounds thereof A salt for use, or a pharmaceutical composition comprising the same; wherein said inflammatory or autoimmune disease is preferably selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS) and Xiaogren syndrome.
本公开进一步涉及一种通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV')、通式(IV-1)、通式(IV'-1)、通式(IV-2)、通式(IV-3)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)、通式(IV-2-b)以及表A所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐、或包括其的药物组合物，其用作药物。The present disclosure further relates to a general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula (III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3), general formula (IV-1) -a), the general formula (IV-1-b), the general formula (IV-2-a), the general formula (IV-2-b) and the compounds shown in Table A or their tautomers, Rotomers, enantiomers, diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.
本公开进一步涉及一种通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV')、通式(IV-1)、通式(IV'-1)、通式(IV-2)、通式(IV-3)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)、通式(IV-2-b)以及表A所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐、或包括其的药物组合物，其用于抑制TLR7、TLR8和TLR9。The present disclosure further relates to a general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula (III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3), general formula (IV-1) -a), the general formula (IV-1-b), the general formula (IV-2-a), the general formula (IV-2-b) and the compounds shown in Table A or their tautomers, Rotomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in inhibiting TLR7, TLR8, and TLR9.
本公开进一步涉及一种通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV')、通式(IV-1)、通式(IV'-1)、通式(IV-2)、通式(IV-3)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)、通式(IV-2-b)以及表A所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐、或包括其的药物组合物，其用于抑制TLR7、TLR8或TLR9；优选用于抑制TLR7和TLR8，或用于抑制TLR7和TLR9。The present disclosure further relates to a general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula (III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3), general formula (IV-1) -a), the general formula (IV-1-b), the general formula (IV-2-a), the general formula (IV-2-b) and the compounds shown in Table A or their tautomers, Rotomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in inhibiting TLR7, TLR8 or TLR9; preferably for use in Inhibits TLR7 and TLR8, or is used to inhibit TLR7 and TLR9.
本公开进一步涉及一种通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV')、通式(IV-1)、通式(IV'-1)、通式(IV-2)、通式(IV-3)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)、通式(IV-2-b)以及表A所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐、或包括其的药物组合物，其用于治疗和/或预防炎性或自身免疫性疾病；其中所述的炎性或自身免疫性疾病优选选自系统性红斑狼疮(SLE)、类风湿 性关节炎、多发性硬化(MS)和肖格伦综合症。The present disclosure further relates to a general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula (III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3), general formula (IV-1) -a), the general formula (IV-1-b), the general formula (IV-2-a), the general formula (IV-2-b) and the compounds shown in Table A or their tautomers, Rotomomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in the treatment and/or prevention of inflammation or autoimmunity inflammatory or autoimmune disease; wherein said inflammatory or autoimmune disease is preferably selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS) and Xiaogren's syndrome.
鉴于它们作为TLR7、TLR8或TLR9的选择性抑制剂，通式(I)、通式(I-1)、通式(II)、通式(II-1)、通式(III)、通式(III-1)、通式(IV)、通式(IV')、通式(IV-1)、通式(IV'-1)、通式(IV-2)、通式(IV-3)、通式(IV-1-a)、通式(IV-1-b)、通式(IV-2-a)、通式(IV-2-b)以及表A所示的化合物可用于分别治疗TLR7、TLR8或TLR9家族受体相关疾病，包括但不限于：炎性疾病(诸如克罗恩病、溃疡性结肠炎、哮喘、移植物抗宿主病、同种异体移植排斥、慢性阻塞性肺病)；自身免疫性疾病(诸如格雷夫斯病、类风湿性关节炎、系统性红斑狼疮、狼疮性肾炎、皮肤狼疮、银屑病)；自身炎性疾病(包括Cryopyrin相关的周期性综合征(CAPS)、TNF受体相关的周期性综合征(TRAPS)、家族性地中海热(FMF)、成人斯蒂尔病、全身性发作的幼年特发性关节炎、痛风、痛风性关节炎)；代谢疾病(包括2型糖尿病、动脉粥样硬化、心肌梗塞)；破坏性骨障碍(诸如骨吸收疾病、骨关节炎、骨质疏松症、多发性骨髓瘤相关骨障碍)；增殖性障碍(诸如急性骨髓性白血病、慢性骨髓性白血病)；血管生成障碍(诸如包括实体瘤、眼部新生血管和婴儿血管瘤的血管生成障碍)；感染性疾病(诸如败血症、败血性休克和志贺氏菌病)；神经变性疾病(诸如阿尔茨海默病、帕金森病、由创伤性损伤引起的脑缺血或神经变性疾病)，肿瘤疾病(诸如转移性黑色素瘤、卡波西肉瘤、多发性骨髓瘤)和病毒性疾病(HIV感染、CMV视网膜炎和AIDS)。In view of their use as selective inhibitors of TLR7, TLR8 or TLR9, general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula (III-1), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV'-1), general formula (IV-2), general formula (IV-3) ), general formula (IV-1-a), general formula (IV-1-b), general formula (IV-2-a), general formula (IV-2-b) and compounds shown in Table A can be used for Treat TLR7, TLR8 or TLR9 family receptor-related diseases, respectively, including but not limited to: inflammatory diseases (such as Crohn's disease, ulcerative colitis, asthma, graft-versus-host disease, allograft rejection, chronic obstructive lung disease); autoimmune diseases (such as Graves disease, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, psoriasis); autoinflammatory diseases (including Cryopyrin-related periodic syndromes) (CAPS), TNF receptor-associated periodic syndrome (TRAPS), familial Mediterranean fever (FMF), adult Still's disease, generalized onset juvenile idiopathic arthritis, gout, gouty arthritis); Metabolic diseases (including type 2 diabetes, atherosclerosis, myocardial infarction); destructive bone disorders (such as bone resorption disorders, osteoarthritis, osteoporosis, multiple myeloma-related bone disorders); proliferative disorders (such as acute myeloid leukemia, chronic myeloid leukemia); angiogenic disorders (such as those including solid tumors, ocular neovascularization, and infantile hemangiomas); infectious diseases (such as sepsis, septic shock, and shigellosis) ; Neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, cerebral ischemia or neurodegenerative diseases caused by traumatic injury), neoplastic diseases (such as metastatic melanoma, Kaposi's sarcoma, multiple myeloma) and viral diseases (HIV infection, CMV retinitis and AIDS).
更具体地，可用本公开化合物治疗的具体病症或疾病包括但不限于胰腺炎(急性或慢性)、哮喘、过敏、成人呼吸窘迫综合征、慢性阻塞性肺病、肾小球肾炎、类风湿性关节炎、系统性红斑狼疮、硬皮病、慢性甲状腺炎、格雷夫斯病、自身免疫性胃炎、糖尿病、自身免疫性溶血性贫血、自身免疫性中性粒细胞减少症、血小板减少症、特应性皮炎、慢性活动性肝炎、重症肌无力、多发性硬化、炎性肠病、溃疡性结肠炎、克罗恩病、银屑病、移植物抗宿主病、内毒素诱导的炎症反应、肺结核、动脉粥样硬化、肌肉退化、恶病质、银屑病关节炎、莱特尔氏综合征(Reiter’s syndrome)、痛风、创伤性关节炎、风疹性关节炎、急性滑膜炎、胰腺β细胞病；以大量嗜中性粒细胞浸润为特征的疾病；类风湿性脊椎炎、痛风性关节炎和其他关节炎病症、脑型疟疾、慢性肺部炎性疾病、矽肺病、肺结节病、骨吸收疾病、同种异体移植排斥、感染引起的发热和肌痛、继发于感染的恶病质、瘢痕疙瘩形成、瘢痕组织形成、溃疡性结肠炎、热病(pyresis)、流感、骨质疏松症、骨关节炎、急性骨髓性白血病、慢性骨髓性白血病、转移性黑色素瘤、卡波西肉瘤、多发性骨髓瘤、败血症、败血性休克和志贺氏菌病；阿尔茨海默病、帕金森病、创伤性损伤引起的脑缺血或神经变性疾病；血管生成障碍，包括实体瘤、眼部新生血管和婴儿血管瘤；病毒性疾病，包括急性肝炎感染(包括甲型肝炎、乙型肝炎和丙型肝炎)、HIV感染和CMV视网膜炎、AIDS、ARC或恶性肿瘤和疱疹；中风、心肌缺血、中风心脏病发作中的局部缺血、器官缺氧、血管增生、心 脏和肾脏再灌注损伤、血栓形成、心脏肥大、凝血酶诱导的血小板聚集、内毒素血症和/或中毒性休克综合征、与前列腺素内过氧化酶合酶-2相关的病症、以及寻常型天疱疮。优选的治疗方法中，其病症选自克罗恩病、溃疡性结肠炎、同种异体移植物排斥、类风湿性关节炎、牛皮癣、强直性脊柱炎、牛皮癣性关节炎和寻常型天疱疮的那些。可替代地优选治疗方法中，其病症为缺血再灌注损伤，所述缺血再灌注损伤包括由中风引起的脑缺血再灌注损伤和由心肌梗塞引起的心肌缺血再灌注损伤。另一种优选的治疗方法中，其病症为多发性骨髓瘤。More specifically, specific conditions or diseases that can be treated with compounds of the present disclosure include, but are not limited to, pancreatitis (acute or chronic), asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid joints inflammation, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopy Dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft-versus-host disease, endotoxin-induced inflammatory response, tuberculosis, Atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, pancreatic beta cell disease; in large amounts Diseases characterized by neutrophilic infiltration; rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory diseases, silicosis, pulmonary sarcoidosis, bone resorption diseases, Allograft rejection, fever and myalgia due to infection, cachexia secondary to infection, keloid formation, scar tissue formation, ulcerative colitis, pyresis, influenza, osteoporosis, osteoarthritis , acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock and shigellosis; Alzheimer's disease, Parkinson's disease, traumatic injury Cerebral ischemia or neurodegenerative diseases caused by; angiogenic disorders, including solid tumors, ocular neovascularization, and infantile hemangiomas; viral diseases, including acute hepatitis infection (including hepatitis A, B, and C), HIV infection and CMV retinitis, AIDS, ARC or malignancy and herpes; stroke, myocardial ischemia, ischemia in stroke heart attack, organ hypoxia, vascular hyperplasia, cardiac and renal reperfusion injury, thrombosis, cardiac Hypertrophy, thrombin-induced platelet aggregation, endotoxemia and/or toxic shock syndrome, disorders associated with prostaglandin endoperoxidase synthase-2, and pemphigus vulgaris. In a preferred method of treatment, the condition is selected from the group consisting of Crohn's disease, ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis and pemphigus vulgaris of those. Alternatively, in a preferred method of treatment, the condition is ischemia-reperfusion injury, including cerebral ischemia-reperfusion injury caused by stroke and myocardial ischemia-reperfusion injury caused by myocardial infarction. In another preferred method of treatment, the disorder is multiple myeloma.
可将活性化合物制成适合于通过任何适当途径给药的形式，通过常规方法使用一种或多种药学上可接受的载体来配制本公开的组合物。因此，本公开的活性化合物可以配制成用于口服给药、注射(例如静脉内、肌肉内或皮下)给药，吸入或吹入给药的各种剂型。本公开的化合物也可以配制成持续释放剂型，例如片剂、硬或软胶囊、水性或油性混悬液、乳剂、注射液、可分散性粉末或颗粒、栓剂、锭剂或糖浆。The active compounds can be formulated in a form suitable for administration by any suitable route, and the compositions of the present disclosure can be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure can be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular, or subcutaneous) administration, inhalation or insufflation. The compounds of the present disclosure may also be formulated in sustained release dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injectable solutions, dispersible powders or granules, suppositories, lozenges or syrups.
作为一般性指导，活性化合物优选是以单位剂量的方式，或者是以患者可以以单剂自我给药的方式。本公开化合物或组合物的单位剂量的表达方式可以是片剂、胶囊、扁囊剂、瓶装药水、药粉、颗粒剂、锭剂、栓剂、再生药粉或液体制剂。合适的单位剂量可以是0.1～1000mg。As a general guide, the active compound is preferably presented in a unit dose or in a form that the patient can self-administer in a single dose. A unit dose of a compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, vial, powder, granule, lozenge, suppository, reconstituted powder, or liquid. A suitable unit dose may be 0.1 to 1000 mg.
本公开的药物组合物除活性化合物外，可含有一种或多种辅料，所述辅料选自以下成分：填充剂(稀释剂)、粘合剂、润湿剂、崩解剂或赋形剂等。根据给药方法的不同，组合物可含有0.1至99重量％的活性化合物。In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait. Depending on the method of administration, the composition may contain from 0.1 to 99% by weight of active compound.
片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂、造粒剂、崩解剂、粘合剂和润滑剂。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂。Oral formulations can also be presented in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble or oily vehicle.
水混悬液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。此类赋形剂是悬浮剂、分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。Aqueous suspensions contain the active substances in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. The aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.
油混悬液可通过使活性成分悬浮于植物油，或矿物油配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。Oily suspensions can be formulated by suspending the active ingredient in vegetable or mineral oils. The oily suspensions may contain thickening agents. The aforementioned sweetening and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
本公开的药物组合物也可以是水包油乳剂的形式。油相可以是植物油，或矿物油或其混合物。适宜的乳化剂可以是天然产生的磷脂，乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase can be vegetable oil, or mineral oil or a mixture thereof. Suitable emulsifying agents may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.
本公开的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本公开化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Among the acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. A sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase. The injectable solution or microemulsion can be injected into the bloodstream of a patient by local bulk injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the present disclosure. To maintain this constant concentration, a continuous intravenous drug delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 IV pump.
本公开的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用任何调和固定油。此外，脂肪酸也可以制备注射剂。The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. In addition, sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blending and fixing oil can be used. In addition, fatty acids are also available in the preparation of injectables.
可按用于直肠给药的栓剂形式给予本公开化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。The compounds of the present disclosure can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.
可通过加入水来制备水混悬的可分散粉末和颗粒给予本公开化合物。可通过将活性成分与分散剂或湿润剂、悬浮剂或一种或多种防腐剂混合来制备这些药物组合物。The compounds of the present disclosure can be administered by the addition of water to prepare dispersible powders and granules for aqueous suspension. These pharmaceutical compositions can be prepared by admixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、排泄的速率、药物的组合、疾病的严重性等；另外，最佳的治疗方式如治疗的模式、化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。As is well known to those skilled in the art, the dosage of a drug to be administered depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient , patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, severity of disease, etc.; in addition, optimal treatment mode such as mode of treatment, daily dose of compound or pharmaceutically acceptable salt Species can be verified against conventional treatment protocols.
术语说明Glossary
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, terms used in the specification and claims have the following meanings.
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子(例如1、2、3、4、5、6、7、8、9、10、11和12个)的烷基，更优选为含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4- 乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基和2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基和2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选独立地任选选自H原子、D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基。The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) alkyl groups, more preferably alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 ,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl Alkylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl and 2,2-diethylhexyl, and various branched chain isomers thereof, etc. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylpropyl butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl base and 2,3-dimethylbutyl, etc. Alkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably the substituents are independently optionally selected from H atoms, D atoms, halogens, alkyls, alkanes Oxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl one or more substituents in .
术语“亚烷基”指饱和的直链或支链脂肪族烃基，其为从母体烷的相同碳原子或两个不同的碳原子上除去两个氢原子所衍生的残基，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个(例如1、2、3、4、5、6、7、8、9、10、11和12个)碳原子，更优选含有1至6个碳原子的亚烷基。亚烷基的非限制性实例包括但不限于亚甲基(-CH 2-)、1,1-亚乙基(-CH(CH 3)-)、1,2-亚乙基(-CH 2CH 2)-、1,1-亚丙基(-CH(CH 2CH 3)-)、1,2-亚丙基(-CH 2CH(CH 3)-)、1,3-亚丙基(-CH 2CH 2CH 2-)和1,4-亚丁基(-CH 2CH 2CH 2CH 2-)等。亚烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选独立地任选选自烷基、烯基、炔基、烷氧基、卤代烷氧基、环烷基氧基、杂环基氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基和氧代基中的一个或多个取代基。 The term "alkylene" refers to a saturated straight or branched chain aliphatic hydrocarbon group, which is a residue derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is a residue containing 1 straight or branched chain groups of up to 20 carbon atoms, preferably containing 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, More preferred are alkylene groups containing 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene ( -CH2- ), 1,1-ethylene (-CH( CH3 )-), 1,2-ethylene ( -CH2) CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -) and 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -) and the like. The alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably the substituents are independently optionally selected from alkyl, alkenyl, alkynyl, alkoxy group, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, hetero One or more substituents of aryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.
术语“杂亚烷基”指亚烷基中的一个或多个-CH 2-被选自N、O、S和S(O)所替代；其中所述的烷基如上所定义；杂亚烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选独立地任选选自H原子、D原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代。 The term "heteroalkylene" refers to an alkylene where one or more -CH2- is replaced by a group selected from N, O, S and S(O); wherein said alkyl is as defined above; heteroalkylene The radicals may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably independently optionally selected from H atoms, D atoms, halogen, alkyl, alkoxy substituted with one or more of the substituents selected from the group consisting of radicals, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
术语“烯基”指分子中含有至少一个碳碳双键的烷基化合物，其中烷基的定义如上所述。优选含有2至12个(例如2、3、4、5、6、7、8、9、10、11和12个)碳原子的烯基，更优选含有2至6个碳原子的烯基。烯基可以是取代的或非取代的，当被取代时，其优选为一个或多个以下基团，其独立地选自氢原子、烷基、烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基。The term "alkenyl" refers to an alkyl compound having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl groups containing 2 to 12 (eg, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms are preferred, and alkenyl groups containing 2 to 6 carbon atoms are more preferred. The alkenyl group may be substituted or unsubstituted, and when substituted, it is preferably one or more of the following groups independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, haloalkyl groups, haloalkoxy groups , cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
术语“炔基”指分子中含有至少一个碳碳三键的烷基化合物，其中烷基的定义如上所述。优选含有2至12个(例如2、3、4、5、6、7、8、9、10、11和12 个)碳原子的炔基，更优选含有2至6个碳原子的炔基。炔基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自氢原子、烷基、烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基。The term "alkynyl" refers to an alkyl compound having at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl groups containing 2 to 12 (eg, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms are preferred, and alkynyl groups containing 2 to 6 carbon atoms are more preferred. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, haloalkyl groups, haloalkoxy groups alkyl, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，优选包含3至8个碳原子(例如3、4、5、6、7和8个)，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基和环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms Carbon atoms (eg 3, 4, 5, 6, 7 and 8), more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene and cyclooctyl, etc.; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
术语“螺环烷基”指5至20元，单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group having one carbon atom (called a spiro atom) shared between the monocyclic rings, which may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into mono-spirocycloalkyl groups, double-spirocycloalkyl groups or poly-spirocycloalkyl groups, preferably mono-spirocycloalkyl groups and double-spirocycloalkyl groups. More preferably, it is 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:
Figure PCTCN2021110197-appb-000129
Figure PCTCN2021110197-appb-000129
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/4元、5元/5元、5元/6元、6元/3元、6元/4元、6元/5元和6元/6元的双环烷基。稠环烷基的非限制性实例包括：The term "fused cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more rings. Multiple double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan Member/5-membered and 6-membered/6-membered bicycloalkyl. Non-limiting examples of fused cycloalkyl groups include:
Figure PCTCN2021110197-appb-000130
Figure PCTCN2021110197-appb-000130
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更优选为双环或三环。桥环烷基的非限制性实例包括：The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly attached carbon atoms, which may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:
Figure PCTCN2021110197-appb-000131
Figure PCTCN2021110197-appb-000131
所述环烷基环包括如上所述的环烷基(包括单环、螺环、稠环和桥环)稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括
Figure PCTCN2021110197-appb-000132
等；优选
Figure PCTCN2021110197-appb-000133
Figure PCTCN2021110197-appb-000134
The cycloalkyl ring includes a cycloalkyl (including monocyclic, spiro, fused and bridged) as described above fused to an aryl, heteroaryl or heterocycloalkyl ring where it is attached to the parent structure Rings together are cycloalkyl, non-limiting examples include
Figure PCTCN2021110197-appb-000132
etc.; preferred
Figure PCTCN2021110197-appb-000133
Figure PCTCN2021110197-appb-000134
环烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。Cycloalkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl, alkoxy , haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl one or more substituents.
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基和丁氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自H原子、D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基。The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from H atom, D atom, halogen, alkyl, alkoxy , haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
术语“杂环基”指饱和或部分不饱和单环或多环环状取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个(例如1、2、3和4个)是杂原子；更优选包含3至8个环原子(例如3、4、5、6、7和8个)，其中1-3是杂原子(例如1、2和3个)；更优选包含3至6个环原子，其中1-3个是杂原子；最优选包含5或6个环原子，其中1-3个是杂原子。单环杂环基的非限制性实例包括氧杂环丁基、吡咯烷基、四氢吡喃基、1,2,3,6-四氢吡啶基、哌啶基、哌嗪基、吗啉基、硫代吗啉基和高哌嗪基等。多环杂环基包括螺环、稠环和桥环的杂环基。The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing from 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, The sulfur may optionally be oxo (ie, to form a sulfoxide or sulfone), but does not include ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Preferably it contains 3 to 12 ring atoms, of which 1 to 4 (eg 1, 2, 3 and 4) are heteroatoms; more preferably 3 to 8 ring atoms (eg 3, 4, 5, 6, 7 and 8), of which 1-3 are heteroatoms (eg 1, 2 and 3); more preferably 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably 5 or 6 ring atoms, 1-3 of them are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholine base, thiomorpholinyl and homopiperazinyl, etc. Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
术语“螺杂环基”指5至20元，单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为 单螺杂环基和双螺杂环基。更优选为3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：The term "spiroheterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclic group with one atom (called a spiro atom) shared between the monocyclic rings, wherein one or more ring atoms are heterocyclic groups selected from nitrogen, oxygen and sulfur. atom, the sulfur may optionally be oxo (ie to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of spiro atoms shared between the rings, spiroheterocyclyls are classified into mono-spiroheterocyclyls, bis-spiroheterocyclyls or poly-spiroheterocyclyls, preferably mono-spiroheterocyclyls and bis-spiroheterocyclyls. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl. Non-limiting examples of spiroheterocyclyl include:
Figure PCTCN2021110197-appb-000135
Figure PCTCN2021110197-appb-000135
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括：The term "fused heterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more of the rings may contain one or more Double bonds in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which may be optionally oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclyl groups include:
Figure PCTCN2021110197-appb-000136
Figure PCTCN2021110197-appb-000136
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更优选为双环或三环。桥杂环基的非限制性实例包括：The term "bridged heterocyclyl" refers to a 5- to 14-membered, polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds in which one or more ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which may optionally be oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:
Figure PCTCN2021110197-appb-000137
Figure PCTCN2021110197-appb-000137
所述杂环基环包括如上所述的杂环基(包括单环、螺杂环、稠杂环和桥杂环)稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：The heterocyclyl ring includes a heterocyclyl group (including monocyclic, spiroheterocycle, fused heterocycle and bridged heterocycle) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the The rings to which the structure is attached are heterocyclyl, non-limiting examples of which include:
Figure PCTCN2021110197-appb-000138
等。
Figure PCTCN2021110197-appb-000138
Wait.
杂环基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基。Heterocyclyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, alkanes Oxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl one or more substituents in .
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(稠合多环是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。所述芳基环包括如上所述的芳基环稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic are rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 10 membered , such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include :
Figure PCTCN2021110197-appb-000139
Figure PCTCN2021110197-appb-000139
芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基。Aryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, preferably the substituents are independently optionally selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, One of haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl or multiple substituents.
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元(例如5、6、7、8、9或10元)，更优选为5元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、三唑基和四唑基等。所述杂芳基环包括如上述的杂芳基稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered (eg 5, 6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered, eg furyl, thienyl, pyridyl, pyrrolyl, N-alkane pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl and the like. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include :
Figure PCTCN2021110197-appb-000140
Figure PCTCN2021110197-appb-000140
Figure PCTCN2021110197-appb-000141
Figure PCTCN2021110197-appb-000141
杂芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基。Heteroaryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, preferably the substituents are independently optionally selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups , haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl one or more substituents.
上述环烷基、杂环基、芳基和杂芳基包括从母体环原子上除去一个氢原子所衍生的残基，或从母体的相同环原子或两个不同的环原子上除去两个氢原子所衍生的残基即“二价环烷基”、“二价杂环基”、“亚芳基”和“亚杂芳基”。The above cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived by removing one hydrogen atom from the parent ring atom, or removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent The residues from which atoms are derived are "divalent cycloalkyl", "divalent heterocyclyl", "arylene" and "heteroarylene".
术语“羟基保护基”是本领域已知的适当的用于羟基保护的基团，参见文献(“Protective Groups in Organic Synthesis”，5 Th Ed.T.W.Greene&P.G.M.Wuts)中的羟基保护基团。作为示例，优选地，所述的羟基保护基可以是(C 1-10烷基或芳基) 3硅烷基，例如：三乙基硅基，三异丙基硅基，叔丁基二甲基硅基，叔丁基二苯基硅基等；可以是C 1-10烷基或取代烷基，优选烷氧基或芳基取代的烷基，更优选C 1-6烷氧基取代的C 1-6烷基或苯基取代的C 1-6烷基，最优选C 1-4烷氧基取代的C 1-4烷基，例如：甲基，叔丁基，苄基，甲氧基甲基(MOM)，乙氧基乙基等；可以是(C 1-10烷基或芳香基)酰基，例如：甲酰基，乙酰基，苯甲酰基、对硝基苯甲酰基等；可以是(C 1-6烷基或C 6-10芳基)磺酰基，也可以是(C 1-6烷氧基或C 6-10芳基氧基)羰基。 The term "hydroxyl protecting group" is a suitable group for hydroxyl protection known in the art, see the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. GMWuts) for hydroxyl protecting groups. As an example, preferably, the hydroxyl protecting group can be a (C 1-10 alkyl or aryl) 3 silyl group, such as: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl Silyl, tert-butyldiphenylsilyl, etc.; can be C 1-10 alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C 1-6 alkoxy substituted C 1-6 alkyl or phenyl substituted C 1-6 alkyl, most preferably C 1-4 alkoxy substituted C 1-4 alkyl, for example: methyl, tert-butyl, benzyl, methoxy Methyl (MOM), ethoxyethyl, etc.; can be (C 1-10 alkyl or aryl) acyl, such as: formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.; can be (C 1-6 alkyl or C 6-10 aryl)sulfonyl, or (C 1-6 alkoxy or C 6-10 aryloxy)carbonyl.
术语“氨基保护基”是为了使分子其它部位进行反应时氨基保持不变，用易于脱去的基团对氨基进行保护。非限制性实施例包含(三甲基硅)乙氧基甲基、四氢吡喃基、叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基等。这些基团可任选地被选自卤素、烷氧基或硝基中的1-3个取代基所取代。所述氨基保护基优选为(三甲基硅)乙氧基甲基和叔丁氧羰基。The term "amino protecting group" is used to protect the amino group with a group that is easy to remove in order to keep the amino group unchanged when the other part of the molecule is reacted. Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro. The amino protecting groups are preferably (trimethylsilyl)ethoxymethyl and tert-butoxycarbonyl.
术语“杂环基烷基”指烷基被一个或多个杂环基取代，其中杂环基和烷基如上所定义。The term "heterocyclylalkyl" refers to an alkyl group substituted with one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.
术语“杂芳基烷基”指烷基被一个或多个杂芳基取代，其中杂芳基和烷基如上所定义。The term "heteroarylalkyl" refers to an alkyl group substituted with one or more heteroaryl groups, wherein heteroaryl and alkyl are as defined above.
术语“环烷基氧基”指环烷基-O-，其中环烷基如上所定义。The term "cycloalkyloxy" refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.
术语“杂环基氧基”指杂环基-O-，其中杂环基如上所定义。The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
术语“烷硫基”指烷基-S-，其中烷基如上所定义。The term "alkylthio" refers to alkyl-S-, wherein alkyl is as defined above.
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如上所定义。The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
术语“氘代烷基”指烷基被一个或多个氘原子取代，其中烷基如上所定义。The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
术语“羟烷基”指烷基被一个或多个羟基取代，其中烷基如上所定义。The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.
术语“卤素”指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.
术语“羟基”指-OH。The term "hydroxy" refers to -OH.
术语“巯基”指-SH。The term "thiol" refers to -SH.
术语“氨基”指-NH 2。 The term "amino" refers to -NH2 .
术语“氰基”指-CN。The term "cyano" refers to -CN.
术语“硝基”指-NO 2。 The term "nitro" refers to -NO2 .
术语“氧代”或“氧代基”指“＝O”。The term "oxo" or "oxo" refers to "=O".
术语“羰基”指C＝O。The term "carbonyl" refers to C=O.
术语“醛基”指-C(O)H。The term "aldehyde group" refers to -C(O)H.
术语“羧基”指-C(O)OH。The term "carboxy" refers to -C(O)OH.
术语“羧酸酯基”指-C(O)O(烷基)或-C(O)O(环烷基)，其中烷基、环烷基如上所定义。The term "carboxylate" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl, cycloalkyl are as defined above.
本公开的化合物包括其同位素衍生物。术语“同位素衍生物”指结构不同仅在于存在一种或多种同位素富集原子的化合物。例如，具有本公开的结构，用“氘”或“氚”代替氢，或者用 18F-氟标记( 18F同位素)代替氟，或者用 11C-、 13C-、或者 14C-富集的碳( 11C-、 13C-、或者 14C-碳标记； 11C-、 13C-、或者 14C-同位素)代替碳原子的化合物处于本公开的范围内。这样的化合物可用作例如生物学测定中的分析工具或探针，或者可以用作疾病的体内诊断成像示踪剂，或者作为药效学、药动学或受体研究的示踪剂。其中氘化形式的化合物为与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的化合物。在制备氘代形式的化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。氘代物通常可以保留与未氘代的化合物相当的活性，并且当氘代在某些特定位点时可以取得更好的代谢稳定性，从而获得某些治疗优势。 The compounds of the present disclosure include isotopic derivatives thereof. The term "isotopic derivatives" refers to compounds that differ in structure only by the presence of one or more isotopically enriched atoms. For example, having the structures of the present disclosure, replacing hydrogen with "deuterium" or "tritium", or replacing fluorine with18F -fluorine labeling ( 18F isotope), or enriching with11C- , 13C- , or14C- Compounds in which carbon ( 11 C-, 13 C-, or 14 C-carbon labels; 11 C-, 13 C-, or 14 C-isotopes) are replaced by carbon atoms are within the scope of the present disclosure. Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. In compounds in deuterated form, each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom. Those skilled in the art can refer to the relevant literature to synthesize deuterated forms of the compounds. Commercially available deuterated starting materials can be used in preparing deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran , Deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc. Deuterated compounds generally retain comparable activity to undeuterated compounds, and when deuterated at certain specific sites can achieve better metabolic stability, resulting in certain therapeutic advantages.
本公开所述化合物的化学结构中，键
Figure PCTCN2021110197-appb-000142
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2021110197-appb-000143
可以为
Figure PCTCN2021110197-appb-000144
或者同时包含
Figure PCTCN2021110197-appb-000145
和
Figure PCTCN2021110197-appb-000146
两种构型。 In the chemical structure of the compound described in the present disclosure, the bond
Figure PCTCN2021110197-appb-000142
Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond
Figure PCTCN2021110197-appb-000143
can be
Figure PCTCN2021110197-appb-000144
or both
Figure PCTCN2021110197-appb-000145
and
Figure PCTCN2021110197-appb-000146
Two configurations.
本公开的化合物含有两个或更多个手性中心时，这些化合物的相对立体化学是通过NMR研究和/或X-射线衍射鉴定的。在这些情况中，使用前缀“rel”、随后使用R/S命名法鉴定这些化合物，此时的R/S仅提供相对立体化学信息(例如顺式或反式)，不表示绝对立体化学。When compounds of the present disclosure contain two or more chiral centers, the relative stereochemistry of these compounds is identified by NMR studies and/or X-ray diffraction. In these cases, the compounds are identified using the prefix "rel" followed by the R/S nomenclature, where R/S only provides relative stereochemical information (eg, cis or trans), not absolute stereochemistry.
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团” 意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or instances where it does not. For example, "heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
“取代的”指基团中的一个或多个氢原子，优选为1～5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。本领域技术人员能够在不付出过多努力的情况下(通过实验或理论)确定可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"Substituted" means that one or more hydrogen atoms in a group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. A person skilled in the art can determine possible or impossible substitutions (either experimentally or theoretically) without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
“可药用的盐”是指本公开化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。可以在化合物的最终分离和纯化过程中，或通过使合适的基团与合适的碱或酸反应来单独制备盐。通常用于形成药学上可接受的盐的碱包括无机碱，例如氢氧化钠和氢氧化钾，以及有机碱，例如氨。通常用于形成药学上可接受的盐的酸包括无机酸以及有机酸。"Pharmaceutically acceptable salts" refers to salts of the compounds of the present disclosure that are safe and effective when used in mammals, and that possess the desired biological activity. The salts can be prepared separately during the final isolation and purification of the compounds, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
针对药物或药理学活性剂而言，术语“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
本文所用的术语“药学上可接受的”是指这些化合物、材料、组合物和/或剂型，在合理的医学判断范围内，适用于与患者组织接触而没有过度毒性、刺激性、过敏反应或其他问题或并发症，具有合理的获益/风险比，并且对预期的用途是有效。The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation, allergic response or Other problems or complications with a reasonable benefit/risk ratio and are effective for the intended use.
本文所使用的，单数形式的“一个”、“一种”和“该”包括复数引用，反之亦然，除非上下文另外明确指出。As used herein, the singular forms "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.
当将术语“约”应用于诸如pH、浓度、温度等的参数时，表明该参数可以变化±10％，并且有时更优选地在±5％之内。如本领域技术人员将理解的，当参数不是关键的时，通常仅出于说明目的给出数字，而不是限制。When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is indicated that the parameter can vary by ±10%, and is sometimes more preferably within ±5%. As those skilled in the art will appreciate, when parameters are not critical, numbers are generally given for illustrative purposes only, and not limitations.
本公开化合物的合成方法Synthetic methods of compounds of the present disclosure
为了完成本公开的目的，本公开采用如下技术方案：In order to accomplish the purpose of the present disclosure, the present disclosure adopts the following technical solutions:
方案一Option One
本公开通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的制备方法，包括以下步骤：The compound represented by the general formula (I) of the present disclosure or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof The preparation method includes the following steps:
Figure PCTCN2021110197-appb-000147
Figure PCTCN2021110197-appb-000147
(a)通式(Iaa)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，与通式(V)的化合物或其可药用盐发生偶联反应，得到通式(Ia)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐；其中：X为卤素，优选地，X为氯或溴；R 0选自氢原子或卤素，优选地，R 0为氢原子或碘； (a) a compound of general formula (Iaa) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and A compound of general formula (V) or a pharmaceutically acceptable salt thereof undergoes a coupling reaction to obtain a compound of general formula (Ia) or its tautomer, racemate, enantiomer, and diastereomer body, or a mixture thereof, or a pharmaceutically acceptable salt thereof; wherein: X is halogen, preferably, X is chlorine or bromine; R 0 is selected from hydrogen atom or halogen, preferably, R 0 is hydrogen atom or iodine;
(b)通式(Ia)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，在酸存在下脱去保护基R W，得到通式(I)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐；其中：R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； (b) a compound of general formula (Ia) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in The protecting group R W is removed in the presence of an acid to obtain the compound of general formula (I) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or A pharmaceutically acceptable salt thereof; wherein: R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is a tert-butoxycarbonyl group;
环A、环B、X、Y、Z、L 1、L 2、L 3、R 3、R 4、R 6、n和t如通式(I)中所定义。 Ring A, Ring B, X, Y, Z, L 1 , L 2 , L 3 , R 3 , R 4 , R 6 , n and t are as defined in general formula (I).
方案二Option II
本公开通式(II)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的制备方法，包括以下步骤：The compound represented by the general formula (II) of the present disclosure or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof The preparation method includes the following steps:
Figure PCTCN2021110197-appb-000148
Figure PCTCN2021110197-appb-000148
(a)通式(IIaa)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，与通式(V)的化合物或其可药用盐发生偶联反应，得到通式(IIa)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐；其中：X为卤素，优选地，X为氯或溴；R 0选自氢原子或卤素，优选地，R 0为氢原子或碘； (a) a compound of general formula (IIaa) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and A compound of general formula (V) or a pharmaceutically acceptable salt thereof undergoes a coupling reaction to obtain a compound of general formula (IIa) or its tautomer, racemate, enantiomer and diastereomer body, or a mixture thereof, or a pharmaceutically acceptable salt thereof; wherein: X is halogen, preferably, X is chlorine or bromine; R 0 is selected from hydrogen atom or halogen, preferably, R 0 is hydrogen atom or iodine;
(b)通式(IIa)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，在酸存在下脱去保护基R W，得到通式(II)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐；其中：R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； (b) a compound of general formula (IIa) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in The protecting group R W is removed in the presence of an acid to obtain the compound of general formula (II) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or A pharmaceutically acceptable salt thereof; wherein: R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is a tert-butoxycarbonyl group;
环B、X、Y、Z、L 1、L 2、L 3、W 1至W 4、R 1至R 4、R 6、q、n和t如通式(II)中所定义。 Rings B, X, Y, Z, L 1 , L 2 , L 3 , W 1 to W 4 , R 1 to R 4 , R 6 , q, n and t are as defined in general formula (II).
方案三third solution
本公开通式(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的制备方法，包括以下步骤：The compound represented by the general formula (III) of the present disclosure or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof The preparation method includes the following steps:
Figure PCTCN2021110197-appb-000149
Figure PCTCN2021110197-appb-000149
(a)通式(IIIaa)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，与通式(V)的化合物或其可药用盐发生偶联反应，得到通式(IIIa)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐；其中：X为卤素，优选地，X为氯或溴；R 0选自氢原子或卤素，优选地，R 0为氢原子或碘； (a) a compound of general formula (IIIaa) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, with The compound of general formula (V) or a pharmaceutically acceptable salt thereof undergoes a coupling reaction to obtain the compound of general formula (IIIa) or its tautomer, racemate, enantiomer and diastereomer body, or a mixture thereof, or a pharmaceutically acceptable salt thereof; wherein: X is halogen, preferably, X is chlorine or bromine; R 0 is selected from hydrogen atom or halogen, preferably, R 0 is hydrogen atom or iodine;
(b)通式(IIIa)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，在酸存在下脱去保护基R W，得到通式(III)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐；其中：R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； (b) a compound of general formula (IIIa) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in The protecting group R W is removed in the presence of an acid to obtain the compound of general formula (III) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or A pharmaceutically acceptable salt thereof; wherein: R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is a tert-butoxycarbonyl group;
环B、L 1至L 3、R 1至R 4、R 6、q、n和t如通式(III)中所定义。 Ring B, L 1 to L 3 , R 1 to R 4 , R 6 , q, n and t are as defined in general formula (III).
方案四Option 4
本公开通式(IV)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的制备方法，包括以下步骤：The compound represented by the general formula (IV) of the present disclosure or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof The preparation method includes the following steps:
Figure PCTCN2021110197-appb-000150
Figure PCTCN2021110197-appb-000150
(a)通式(IVaa)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，与通式(V)的化合物或其可药用盐发生偶联反应，得到通式(IVa)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐；其中：X为卤素，优选地，X为氯或溴；R 0选自氢原子或卤素，优选地，R 0为氢原子或碘； (a) a compound of general formula (IVaa) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, with A compound of general formula (V) or a pharmaceutically acceptable salt thereof undergoes a coupling reaction to obtain a compound of general formula (IVa) or its tautomer, racemate, enantiomer and diastereomer body, or a mixture thereof, or a pharmaceutically acceptable salt thereof; wherein: X is halogen, preferably, X is chlorine or bromine; R 0 is selected from hydrogen atom or halogen, preferably, R 0 is hydrogen atom or iodine;
(b)通式(IVa)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，在酸存在下脱去保护基R W，得到通式(IV)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐；其中：R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； (b) a compound of general formula (IVa) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, in The protecting group R W is removed in the presence of an acid to obtain the compound of general formula (IV) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or A pharmaceutically acceptable salt thereof; wherein: R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is a tert-butoxycarbonyl group;
环B、L 3、R 1至R 3、R 6、q和t如式(IV)中所定义。 Rings B, L 3 , R 1 to R 3 , R 6 , q and t are as defined in formula (IV).
方案五Option five
本公开通式(IV-1-a)和通式(IV-1-b)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐制备方法，包括以下步骤：The compounds represented by general formula (IV-1-a) and general formula (IV-1-b) of the present disclosure or their tautomers, racemates, enantiomers, and diastereomers , or a mixture form thereof, or a method for preparing a pharmaceutically acceptable salt thereof, comprising the following steps:
Figure PCTCN2021110197-appb-000151
Figure PCTCN2021110197-appb-000151
通式(IV')的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐经手性拆分制备，得到通式(IV-1-a)和通式(IV-1-b)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐；Compounds of general formula (IV') or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, undergo chiral resolution Preparation to obtain compounds represented by general formula (IV-1-a) and general formula (IV-1-b) or their tautomers, racemates, enantiomers, diastereomers body, or a mixture thereof, or a pharmaceutically acceptable salt thereof;
其中，环B、L 3、R 1至R 3、R 6、q和t如式(IV')中所定义。 wherein Ring B, L 3 , R 1 to R 3 , R 6 , q and t are as defined in formula (IV').
方案六Option 6
本公开的另一方面涉及一种制备通式(I-1)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (I-1) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof form, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2021110197-appb-000152
Figure PCTCN2021110197-appb-000152
通式(I-1a)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，在酸存在下脱去保护基R W，得到通式(I-1)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐， The compound of general formula (I-1a) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, in acid The protective group R W is removed in the presence of the general formula (I-1) to obtain the compound of general formula (I-1) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
R 6a为氢原子； R 6a is a hydrogen atom;
t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
环A、环B、X、Y、Z、L 1至L 3、R 3、R 4、R 6、W 1至W 4和n如通式(I-1)中所定义。 Ring A, Ring B, X, Y, Z, L 1 to L 3 , R 3 , R 4 , R 6 , W 1 to W 4 and n are as defined in the general formula (I-1).
方案七Option 7
本公开的另一方面涉及一种制备通式(II-1)所示的化合物，或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to the preparation of the compound represented by the general formula (II-1), or its tautomer, racemate, enantiomer, diastereomer, or its A method in the form of a mixture, or a pharmaceutically acceptable salt thereof, comprising:
Figure PCTCN2021110197-appb-000153
Figure PCTCN2021110197-appb-000153
通式(II-1a)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，在酸存在下脱去保护基R W，得到通式(II-1)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐， Compounds of general formula (II-1a) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, in acid The protective group R W is removed in the presence of the general formula (II-1) to obtain the compound of general formula (II-1) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
R 6a为氢原子； R 6a is a hydrogen atom;
t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
环B、X、Y、Z、L 1、L 2、L 3、W 1至W 4、R 1至R 4、R 6、q和n如通式(II-1)中所定义。 Rings B, X, Y, Z, L 1 , L 2 , L 3 , W 1 to W 4 , R 1 to R 4 , R 6 , q and n are as defined in the general formula (II-1).
方案八Option 8
本公开的另一方面涉及一种制备通式(III-1)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (III-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof form, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2021110197-appb-000154
Figure PCTCN2021110197-appb-000154
通式(III-1a)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构 体、或其混合物形式、或其可药用的盐，在酸存在下脱去保护基R W，得到通式(III-1)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐， Compounds of general formula (III-1a) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, in acid The protective group R W is removed in the presence of the general formula (III-1) to obtain the compound of general formula (III-1) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
R 6a为氢原子； R 6a is a hydrogen atom;
t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
环B、L 1至L 3、R 1至R 4、R 6、q和n如通式(III-1)中所定义。 Ring B, L 1 to L 3 , R 1 to R 4 , R 6 , q and n are as defined in general formula (III-1).
方案九Option Nine
本公开的另一方面涉及一种制备通式(IV-1)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (IV-1) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof form, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2021110197-appb-000155
Figure PCTCN2021110197-appb-000155
通式(IV-1a)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，在酸存在下脱去保护基R W，得到通式(IV-1)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐， Compounds of general formula (IV-1a) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, in acid The protective group R W is removed in the presence of the general formula (IV-1) to obtain the compound of general formula (IV-1) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
R 6a为氢原子； R 6a is a hydrogen atom;
t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
环B、L 3、R 1至R 3、R 6和q如通式(IV-1)中所定义。 Ring B, L 3 , R 1 to R 3 , R 6 and q are as defined in general formula (IV-1).
方案十Option ten
本公开的另一方面涉及一种制备通式(IV-2)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (IV-2) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof form, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2021110197-appb-000156
Figure PCTCN2021110197-appb-000156
通式(IV-2a)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，在酸存在下脱去保护基R W，得到通式(IV-2)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐， Compounds of general formula (IV-2a) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, in acid The protective group R W is removed in the presence of the general formula (IV-2) to obtain the compound of general formula (IV-2) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
R 6a为氢原子； R 6a is a hydrogen atom;
t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
环B、L 3、R 1至R 3、R 6和q如通式(IV-2)中所定义。 Ring B, L 3 , R 1 to R 3 , R 6 and q are as defined in general formula (IV-2).
方案十一Plan Eleven
本公开的另一方面涉及一种制备通式(IV-3)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (IV-3) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof form, or a method of a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2021110197-appb-000157
Figure PCTCN2021110197-appb-000157
通式(IV-3a)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，在酸存在下脱去保护基R W，得到通式(IV-3)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐， Compounds of general formula (IV-3a) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, in acid The protective group R W is removed in the presence of the general formula (IV-3) to obtain the compound of general formula (IV-3) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
R 6a为氢原子； R 6a is a hydrogen atom;
t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
环B、L 3、R 1至R 3、R 6和q如通式(IV-3)中所定义。 Ring B, L 3 , R 1 to R 3 , R 6 and q are as defined in general formula (IV-3).
方案十二Plan 12
本公开的另一方面涉及一种制备通式(IV')所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to the preparation of the compound represented by the general formula (IV') or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof , or a method of a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2021110197-appb-000158
Figure PCTCN2021110197-appb-000158
通式(IV'a)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，在酸存在下脱去保护基R W，得到通式(IV')的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐， Compounds of general formula (IV'a) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, in acid Removal of the protecting group RW in the presence of the general formula (IV') to obtain a compound of general formula (IV') or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or its pharmaceutically acceptable salts,
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
环B、L 3、R 1至R 3、R 6、q和t如通式(IV')中所定义。 Rings B, L3, R1 to R3 , R6, q and t are as defined in general formula (IV').
方案十三Plan Thirteen
本公开的另一方面涉及一种制备通式(IV'-1)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to the preparation of a compound represented by the general formula (IV'-1) or its tautomer, racemate, enantiomer, diastereomer, or its A method in the form of a mixture, or a pharmaceutically acceptable salt thereof, comprising:
Figure PCTCN2021110197-appb-000159
Figure PCTCN2021110197-appb-000159
通式(IV'a-1)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，在酸存在下脱去保护基R W，得到通式(IV'-1)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐， A compound of general formula (IV'a-1) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, The protecting group R W is removed in the presence of an acid to obtain the compound of general formula (IV'-1) or its tautomer, racemate, enantiomer, diastereomer, or its in the form of a mixture, or a pharmaceutically acceptable salt thereof,
其中：in:
R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
R 6a为氢原子； R 6a is a hydrogen atom;
t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
环B、L 3、R 1至R 3、R 6和q如通式(IV'-1)中所定义。 Ring B, L 3 , R 1 to R 3 , R 6 and q are as defined in general formula (IV'-1).
方案十四Option Fourteen
本公开通式(IV-2)和通式(IV-3)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐制备方法，包括以下步骤：The compounds represented by the general formula (IV-2) and the general formula (IV-3) of the present disclosure or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof form, or a method for preparing a pharmaceutically acceptable salt thereof, comprising the steps of:
Figure PCTCN2021110197-appb-000160
Figure PCTCN2021110197-appb-000160
通式(IV'-1)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐经手性拆分制备，得到通式(IV-2)和通式(IV-3)所示的化合物，或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐；Compounds of general formula (IV'-1) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof are chiral Separation and preparation to obtain compounds represented by general formula (IV-2) and general formula (IV-3), or their tautomers, racemates, enantiomers, and diastereomers , or a mixture thereof, or a pharmaceutically acceptable salt thereof;
其中：in:
R 6a为氢原子； R 6a is a hydrogen atom;
t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
环B、L 3、R 1至R 3、R 6和q如通式(IV'-1)中所定义。 Ring B, L 3 , R 1 to R 3 , R 6 and q are as defined in general formula (IV'-1).
上述步骤(a)的反应中，所述的偶联反应是本领域熟知的偶联反应包括但不限于Buchwald–Hartwig偶联反应、Negishi偶联反应等。所述的偶联反应的条件包括但不限于在金属催化剂(优选在含钯或镍的催化剂)的存在下进行，优选醋酸钯、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(RuPhos Pd G3)、甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(XPhos Pd G3)、氯(2-二环己基膦基-2',6'-二-异丙氧基 -1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(RuPhos Pd G2)、有机锌试剂、双(三苯基膦)氯化钯(II)(Pd(PPh 3)Cl 2)、[1,1’-双(二苯基膦)二茂铁]二氯化钯(II)、三(二亚苄基丙酮)二钯等，更优选醋酸钯、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)、氯(2-二环己基膦基-2',6'-二-异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)和三(二亚苄基丙酮)二钯。所述的金属催化剂还可以和配体和碱联用，其中所述的配体包括但不限于S-(-)-1,1'-联萘-2,2'-双二苯膦(S-(-)-BINAP)、R-(-)-1,1'-联萘-2,2'-双二苯膦(R-(-)-BINAP)、1,1'-联萘-2,2'-双二苯膦(BINAP)、1,1'-双(二苯基膦)二茂铁(DPPF)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(XANTPHOS)、2,2'-双(二苯基膦)二苯酮(DPBP)、2,2'-二烯丙基双酚A(DBA)等，优选S-(-)-1,1'-联萘-2,2'-双二苯膦。所述的碱包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、乙酸钠、乙醇钠、叔丁醇钠或叔丁醇钾，优选叔丁醇钠；所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、醋酸钠、醋酸钾、碳酸钾或碳酸铯、氢氧化钠、氢氧化锂一水合物、氢氧化锂和氢氧化钾；优选碳酸钾和碳酸铯。 In the reaction of the above step (a), the coupling reaction is a well-known coupling reaction in the art, including but not limited to Buchwald-Hartwig coupling reaction, Negishi coupling reaction and the like. The conditions of the coupling reaction include but are not limited to carrying out in the presence of a metal catalyst (preferably a catalyst containing palladium or nickel), preferably palladium acetate, methanesulfonic acid (2-dicyclohexylphosphino-2',6 '-Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (RuPhos Pd G3), methanesulfonic acid (2- Dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium ( II) (XPhos Pd G3), chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'- Biphenyl-2-yl)palladium(II) (RuPhos Pd G2), organozinc reagent, bis(triphenylphosphine)palladium(II) chloride (Pd(PPh 3 )Cl 2 ), [1,1'- Bis(diphenylphosphino)ferrocene]palladium(II) dichloride, tris(dibenzylideneacetone)dipalladium, etc., more preferably palladium acetate, (2-dicyclohexylphosphino-2' methanesulfonate) ,6'-Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II), chloro(2-dicyclohexylphosphino) -2',6'-Di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) and tris(dibenzylidene) acetone) dipalladium. The metal catalyst can also be used in combination with a ligand and a base, wherein the ligand includes but is not limited to S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine (S -(-)-BINAP), R-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine (R-(-)-BINAP), 1,1'-binaphthyl-2 ,2'-Bisdiphenylphosphine (BINAP), 1,1'-Bis(diphenylphosphine)ferrocene (DPPF), 4,5-Bisdiphenylphosphine-9,9-dimethyloxa Anthracene (XANTPHOS), 2,2'-bis(diphenylphosphine)benzophenone (DPBP), 2,2'-diallylbisphenol A (DBA), etc., preferably S-(-)-1, 1'-Binaphthalene-2,2'-bisdiphenylphosphine. Described base includes organic base and inorganic base, described organic base includes but is not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylamide lithium, acetic acid Potassium, sodium acetate, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide, preferably sodium tert-butoxide; the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, carbonic acid Potassium or cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; potassium carbonate and cesium carbonate are preferred.
上述步骤(b)的反应中，所述的酸包括有机酸和无机酸，所述的有机酸包括但不限于三氟乙酸、甲酸、乙酸、甲磺酸、对甲苯磺酸、Me 3SiCl和TMSOTf，优选三氟乙酸；所述的无机酸包括但不限于氯化氢、氯化氢的1,4-二氧六环溶液、盐酸、硫酸、硝酸和磷酸。 In the reaction of the above step (b), the acid includes an organic acid and an inorganic acid, and the organic acid includes but is not limited to trifluoroacetic acid, formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, Me 3 SiCl and TMSOTf, preferably trifluoroacetic acid; the inorganic acids include but are not limited to hydrogen chloride, hydrogen chloride solution in 1,4-dioxane, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.
上述步骤(a)-(c)的反应优选在溶剂中进行，所用的溶剂包括但不限于：乙二醇二甲醚、醋酸、甲醇、乙醇、乙腈、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,2-二溴乙烷及其混合物。The reaction of the above steps (a)-(c) is preferably carried out in a solvent, and the solvent used includes but is not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane Methane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1 , 2-dibromoethane and mixtures thereof.
具体实施方式detailed description
以下结合实施例用于进一步描述本公开，但这些实施例并非限制着本公开的范围。The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.
实施例Example
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE NEO 500M核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。 The structures of the compounds were determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10<" 6 > (ppm). NMR was measured by Bruker AVANCE NEO 500M nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four Methylsilane (TMS).
MS的测定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120 Quadrupole MS)、waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)、THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)。The determination of MS used Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高压液相色谱仪。High performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD and a Waters HPLC e2695-2489 high pressure liquid chromatograph.
手性HPLC分析测定使用Agilent 1260 DAD高效液相色谱仪。Chiral HPLC analysis was determined using an Agilent 1260 DAD high performance liquid chromatograph.
高效液相制备使用Waters 2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson-281制备型色谱仪。HPLC preparations used Waters 2767, Waters 2767-SQ Detector2, Shimadzu LC-20AP and Gilson-281 preparative chromatographs.
手性制备使用Shimadzu LC-20AP制备型色谱仪。Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。The CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ~ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ~0.5mm.
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。 The average inhibition rate and IC 50 value of kinases were measured with NovoStar microplate reader (BMG, Germany).
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG、Acros Organics、Aldrich Chemical Company、韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。The known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui chemical companies.
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。There is no special description in the examples, and the reactions can all be carried out in an argon atmosphere or a nitrogen atmosphere.
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
氢气氛是指反应瓶连接一个约1L容积的氢气气球。Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。The pressure hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.
氢化反应通常抽真空，充入氢气，反复操作3次。The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
微波反应使用CEM Discover-S 908860型微波反应器。The microwave reaction used a CEM Discover-S 908860 microwave reactor.
实施例中无特殊说明，溶液是指水溶液。There is no special description in the examples, and the solution refers to an aqueous solution.
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。There is no special description in the examples, and the reaction temperature is room temperature, which is 20°C to 30°C.
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：正己烷/乙酸乙酯体系，B：二氯甲烷/甲醇体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。The monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of the column chromatography used for purifying the compound and the developing solvent system of the thin layer chromatography method include: A: n-hexane/ethyl acetate system, B: dichloromethane/methanol system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
实施例1Example 1
(±)-rel-5-((4R,12aR)-4-甲基-9-(哌嗪-1-基)-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈1(±)-rel-5-((4R,12aR)-4-methyl-9-(piperazin-1-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyridine Azino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 1
Figure PCTCN2021110197-appb-000161
Figure PCTCN2021110197-appb-000161
第一步first step
4-溴-1-(溴甲基)-2-(甲氧基甲氧基)苯1b4-Bromo-1-(bromomethyl)-2-(methoxymethoxy)benzene 1b
将化合物1a(2.0g，8.66mmol，采用公知方法“Journal of the Chemical Society.Perkin Transactions 1,2000,4231-4233”制备而得)溶于四氯化碳(50mL)，加入N-溴代丁二酰亚胺(1.8g，10.11mmol，韶远)和偶氮二异丁腈(150mg，0.92mmol)，反应在85℃搅拌3小时，将反应液冷却，加入饱和硫代硫酸钠溶液(10mL×3)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A(正己烷：乙酸乙酯＝10:1)纯化，得到标题产物1b(1.8g，产率：67.1％)。Compound 1a (2.0 g, 8.66 mmol, prepared by the well-known method "Journal of the Chemical Society. Perkin Transactions 1, 2000, 4231-4233") was dissolved in carbon tetrachloride (50 mL), and N-bromobutane was added. Diimide (1.8g, 10.11mmol, Shaoyuan) and azobisisobutyronitrile (150mg, 0.92mmol), the reaction was stirred at 85°C for 3 hours, the reaction solution was cooled, and saturated sodium thiosulfate solution (10mL) was added. ×3) washed, the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A (n-hexane:ethyl acetate=10:1) to obtain the title Product 1b (1.8 g, yield: 67.1%).
1H NMR(400MHz,CDCl 3)δ7.30-7.21(m,2H),7.17-7.05(m,1H),5.28(s,2H),4.52(s,2H),3.54(s,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.30-7.21 (m, 2H), 7.17-7.05 (m, 1H), 5.28 (s, 2H), 4.52 (s, 2H), 3.54 (s, 3H).
第二步second step
(6-甲基哌嗪-2-基)甲醇1d(6-Methylpiperazin-2-yl)methanol 1d
将化合物(1,4-二苄基-6-甲基哌嗪-2-基)甲醇1c(4.4g，14.2mmol，采用专利申请“WO2018108704A1，说明书第103页，化合物E3-E6”制备而得)溶于100mL甲醇中，加入湿钯碳(300mg，2.8mmol)，置换氢气三次，混合物在室温搅拌反应约16小时。过滤除去催化剂，滤液减压浓缩，得到标题产物1d(1.8g，产率：97.5％)，产品不经纯化直接进行下一步反应。The compound (1,4-dibenzyl-6-methylpiperazin-2-yl) methanol 1c (4.4 g, 14.2 mmol, was prepared by using the patent application "WO2018108704A1, page 103 of the specification, compound E3-E6" ) was dissolved in 100 mL of methanol, wet palladium carbon (300 mg, 2.8 mmol) was added, hydrogen was replaced three times, and the mixture was stirred and reacted at room temperature for about 16 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title product 1d (1.8 g, yield: 97.5%), which was directly subjected to the next reaction without purification.
MS m/z(ESI)：131.2[M+1]。MS m/z (ESI): 131.2 [M+1].
第三步third step
(±)-rel-5-((3R,5R)-3-(羟甲基)-5-甲基哌嗪-1-基)喹啉-8-甲腈1f(±)-rel-5-((3R,5R)-3-(hydroxymethyl)-5-methylpiperazin-1-yl)quinoline-8-carbonitrile 1f
将化合物1d(1.8g，13.8mmol)和化合物5-氟喹啉-8-甲腈1e(2.3g，13.4mmol，采用专利申请“WO2020020800A1，说明书第16页，化合物1c”制备而得)溶于20mL二甲亚砜中，然后加入N,N-二异丙基乙胺(5.2g，40.2mmol)，该混合物在100℃搅拌反应约16小时。冷却至室温后，向反应液中加入20mL水，用乙酸乙酯萃取(20mL×3)，合并有机相，依次用水(20mL)，饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B(二氯甲烷：甲醇＝20:1)纯化，得到标题产物1f(1.7g，产率：45.1％)。Compound 1d (1.8 g, 13.8 mmol) and compound 5-fluoroquinoline-8-carbonitrile 1e (2.3 g, 13.4 mmol, prepared using patent application "WO2020020800A1, page 16 of the specification, compound 1c") were dissolved in To 20 mL of dimethyl sulfoxide, N,N-diisopropylethylamine (5.2 g, 40.2 mmol) was added, and the mixture was stirred at 100° C. for about 16 hours. After cooling to room temperature, 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed successively with water (20 mL) and saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B (dichloromethane:methanol=20:1) to give the title product 1f (1.7 g, yield: 45.1%).
MS m/z(ESI)：283.0[M+1]。MS m/z (ESI): 283.0 [M+1].
第四步the fourth step
(±)-rel-5-((3R,5R)-(3-(((叔丁基二甲基硅基)氧基)甲基)-5-甲基哌嗪-1-基)喹啉-8-甲腈1g(±)-rel-5-((3R,5R)-(3-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpiperazin-1-yl)quinoline -8-carbonitrile 1g
将化合物1f(500mg，1.78mmol)溶于10mL N,N-二甲基甲酰胺中，依次加入咪唑(250mg，3.7mmol)和叔丁基二甲基氯硅烷(220mg，2.7mmol)，室温搅拌反应约16小时。向反应液中加入10mL饱和碳酸氢钠溶液，搅拌30分钟，用乙酸乙酯(10mL×3)萃取，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题产物1g(700mg产率：99.7％)，产品不经纯化直接进行下一步反应。Compound 1f (500 mg, 1.78 mmol) was dissolved in 10 mL of N,N-dimethylformamide, imidazole (250 mg, 3.7 mmol) and tert-butyldimethylsilyl chloride (220 mg, 2.7 mmol) were added successively, and the mixture was stirred at room temperature The reaction was carried out for about 16 hours. 10 mL of saturated sodium bicarbonate solution was added to the reaction solution, stirred for 30 minutes, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with water (10 mL), saturated sodium chloride solution (10 mL), and anhydrous sulfuric acid. It was dried over sodium, filtered, and the filtrate was concentrated under reduced pressure to obtain 1 g of the title product (700 mg yield: 99.7%), which was directly subjected to the next reaction without purification.
MS m/z(ESI)：397.4[M+1]。MS m/z (ESI): 397.4 [M+1].
第五步the fifth step
(±)-rel-5-((3R,5R)-4-(4-溴-2-(甲氧基甲氧基)苄基)-3-(((叔丁基二甲基硅基)氧基)甲基)-5-甲基哌嗪-1-基)喹啉-8-甲腈1h(±)-rel-5-((3R,5R)-4-(4-bromo-2-(methoxymethoxy)benzyl)-3-(((tert-butyldimethylsilyl) Oxy)methyl)-5-methylpiperazin-1-yl)quinoline-8-carbonitrile 1h
将化合物1g(700mg，1.77mmol)和化合物1b(650mg，2.1mmol)溶于20mL乙腈中，依次加入碳酸钾(750mg，5.4mmol)和碘化钾(20mg，0.12mmol)，混合物在80℃搅拌反应约3小时。冷却至室温后，向反应液中加入10mL水，用乙酸乙酯(10mL×3)萃取，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A(正己烷：乙酸乙酯＝5:1)纯化，得到标题产物1h(710mg，产率：64.3％)。Compound 1g (700 mg, 1.77 mmol) and compound 1b (650 mg, 2.1 mmol) were dissolved in 20 mL of acetonitrile, potassium carbonate (750 mg, 5.4 mmol) and potassium iodide (20 mg, 0.12 mmol) were added successively, and the mixture was stirred at 80 °C for reaction for about 3 hours. After cooling to room temperature, 10 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with water (10 mL) and saturated sodium chloride solution (10 mL) in turn, dried over anhydrous sodium sulfate, Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A (n-hexane:ethyl acetate=5:1) to give the title product 1h (710 mg, yield: 64.3%).
MS m/z(ESI)：625.0[M+1]。MS m/z (ESI): 625.0 [M+1].
第六步Step 6
(±)-rel-5-((3R,5R)-4-(4-溴-2-(羟基苄基)-3-(羟甲基)-5-甲基哌嗪-1-基)喹啉-8-甲腈1i(±)-rel-5-((3R,5R)-4-(4-bromo-2-(hydroxybenzyl)-3-(hydroxymethyl)-5-methylpiperazin-1-yl)quinoline Phosphine-8-carbonitrile 1i
将化合物1h(700mg,1.1mmol)溶于5mL二氯甲烷中，加入4M盐酸1,4-二氧六环溶液(4mL，安耐吉)，有黄色固体生成，混合物在室温继续搅拌反应约1小时。反应液减压浓缩，加入10mL饱和碳酸氢钠溶液，搅拌30分钟，用乙酸乙酯(10mL×3)萃取，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题产物1i(500mg产率：95.7％)，产品不经纯化直接进行下一步反应。Compound 1h (700 mg, 1.1 mmol) was dissolved in 5 mL of dichloromethane, 4M hydrochloric acid 1,4-dioxane solution (4 mL, Annagi) was added, a yellow solid was formed, and the mixture was stirred at room temperature for about 1 Hour. The reaction solution was concentrated under reduced pressure, 10 mL of saturated sodium bicarbonate solution was added, stirred for 30 minutes, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with water (10 mL) and saturated sodium chloride solution (10 mL) in turn. Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the title product 1i (500 mg yield: 95.7%), which is directly subjected to the next reaction without purification.
MS m/z(ESI)：466.9[M+1]。MS m/z (ESI): 466.9 [M+1].
第七步Step 7
(±)-rel-5-((4R,12aR)-9-溴-4-甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈1j(±)-rel-5-((4R,12aR)-9-bromo-4-methyl-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1- c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 1j
将粗品化合物1i(600mg，1.3mmol)溶于20mL甲苯中，加入偶氮二甲酰二哌啶(1.6g，6.3mmol)和三丁基膦(1.3g，6.4mmol)，置换氩气三次，混合物在60℃搅拌反应约1小时。冷却至室温后，反应液减压浓缩，粗产品用乙酸乙酯(10mL)打浆，所得固体过滤，滤饼用正己烷洗涤，固体干燥，得到标题产物1j(310mg产率：53.7％)。The crude compound 1i (600 mg, 1.3 mmol) was dissolved in 20 mL of toluene, azodicarbonyl dipiperidine (1.6 g, 6.3 mmol) and tributylphosphine (1.3 g, 6.4 mmol) were added, and argon was replaced three times, The mixture was stirred at 60°C for about 1 hour. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, the crude product was slurried with ethyl acetate (10 mL), the obtained solid was filtered, the filter cake was washed with n-hexane, and the solid was dried to obtain the title product 1j (310 mg yield: 53.7%).
MS m/z(ESI):449.1[M+1]。MS m/z (ESI): 449.1 [M+1].
第八步Step 8
(±)-rel-4-((4R,12aR)-2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4,12,12a-六氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-9-基)哌嗪-1-羧酸叔丁酯1k(±)-rel-4-((4R,12aR)-2-(8-cyanoquinolin-5-yl)-4-methyl-1,2,3,4,12,12a-hexahydro- 6H-Benzo[f]pyrazino[2,1-c][1,4]oxazepin-9-yl)piperazine-1-carboxylate tert-butyl ester 1k
将化合物1j(280mg，0.62mmol)和化合物哌嗪-1-羧酸叔丁酯(210mg，1.1mmol,韶远)溶于10mL1,4-二氧六环中，然后加入醋酸钯(15mg，0.067mmol，韶远)、S-(-)-1,1'-联萘-2,2'-双二苯膦(90mg，0.14mmol，毕得)和碳酸铯(700mg，2.15mmol)，置换氩气三次，混合物在100℃搅拌反应约1小时。冷却至室温后，向反应液中加入10mL水，用乙酸乙酯萃取(10mL×3)，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用高效液相色谱法(色谱柱：SharpSil T-C18，5μm，30mm*150mm；流动相1：水(含0.1％三氟乙酸)；流动相2：乙腈；25分钟梯度：25％-95％，流速：30mL/min)纯化，得到标题产物1k(160mg，产率：46.3％)。Compound 1j (280 mg, 0.62 mmol) and compound piperazine-1-carboxylate tert-butyl ester (210 mg, 1.1 mmol, Shaoyuan) were dissolved in 10 mL of 1,4-dioxane, and then palladium acetate (15 mg, 0.067 mmol, Shaoyuan), S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine (90 mg, 0.14 mmol, Bide) and cesium carbonate (700 mg, 2.15 mmol), replacing argon After gassing three times, the mixture was stirred and reacted at 100°C for about 1 hour. After cooling to room temperature, 10 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, Filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (chromatographic column: SharpSil T-C18, 5μm, 30mm*150mm; mobile phase 1: water (containing 0.1% trifluoroacetic acid); mobile phase 2: acetonitrile; 25 min gradient: 25%-95%, flow rate: 30 mL/min) purification gave the title product Ik (160 mg, yield: 46.3%).
MS m/z(ESI)：555.1[M+1]。MS m/z (ESI): 555.1 [M+1].
第九步Step 9
(±)-rel-5-((4R,12aR)-4-甲基-9-(哌嗪-1-基)-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈1(±)-rel-5-((4R,12aR)-4-methyl-9-(piperazin-1-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyridine Azino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 1
将化合物1k(100mg，0.18mmol)溶于5mL二氯甲烷中，加入5mL三氟乙酸， 混合物在室温搅拌反应约1小时。反应液减压浓缩，加入10mL饱和碳酸氢钠溶液，搅拌30分钟，用乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B(二氯甲烷：甲醇＝10:1)纯化，得到标题产物1(37mg，产率：45.1％)。Compound 1k (100 mg, 0.18 mmol) was dissolved in 5 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and the mixture was stirred and reacted at room temperature for about 1 hour. The reaction solution was concentrated under reduced pressure, 10 mL of saturated sodium bicarbonate solution was added, stirred for 30 minutes, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was washed with silica gel Purification by column chromatography with eluent system B (dichloromethane:methanol=10:1) afforded the title product 1 (37 mg, yield: 45.1%).
MS m/z(ESI)：455.0[M+1]。MS m/z (ESI): 455.0 [M+1].
1H NMR(500MHz,CDCl 3)δ9.08-9.07(m,1H),8.51-8.49(m,1H),8.03-8.01(m,1H),7.54-7.52(m,1H),7.10-7.04(m,2H),6.60-6.57(m,2H),4.25-4.22(m,1H),4.00-3.98(m,1H),3.71-3.67(m,1H),3.57-3.54(m,1H),3.36-3.32(m,2H),3.25-3.09(m,10H),2.91-2.88(m,1H),2.80-2.74(m,2H),1.32-1.31(m,3H)。 1 H NMR (500MHz, CDCl 3 ) δ 9.08-9.07(m,1H), 8.51-8.49(m,1H), 8.03-8.01(m,1H), 7.54-7.52(m,1H), 7.10-7.04 (m,2H),6.60-6.57(m,2H),4.25-4.22(m,1H),4.00-3.98(m,1H),3.71-3.67(m,1H),3.57-3.54(m,1H) , 3.36-3.32(m, 2H), 3.25-3.09(m, 10H), 2.91-2.88(m, 1H), 2.80-2.74(m, 2H), 1.32-1.31(m, 3H).
实施例1-1-a,1-1-bExample 1-1-a, 1-1-b
5-((4R,12aR)-4-甲基-9-(哌嗪-1-基)-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈1-1-a5-((4R,12aR)-4-methyl-9-(piperazin-1-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1 -c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 1-1-a
5-((4S,12aS)-4-甲基-9-(哌嗪-1-基)-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈1-1-b5-((4S,12aS)-4-methyl-9-(piperazin-1-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1 -c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 1-1-b
Figure PCTCN2021110197-appb-000162
Figure PCTCN2021110197-appb-000162
将化合物1(25mg，0.055mmol)进行手性制备(分离条件：手性制备柱Cellulose-3,5μm，21.2mm*250mm(Phenomenex)；流动相1：正己烷；流动相2：含0.1％二乙胺乙醇(80％)，流速：20mL/min)，收集其相应组分，减压浓缩，得到标题化合物1-1-a和1-1-b(5mg,5mg)。Compound 1 (25 mg, 0.055 mmol) was subjected to chiral preparation (separation conditions: chiral preparative column Cellulose-3, 5 μm, 21.2 mm*250 mm (Phenomenex); mobile phase 1: n-hexane; mobile phase 2: containing 0.1% dimethoxide Ethylamine ethanol (80%), flow rate: 20 mL/min), the corresponding fractions thereof were collected and concentrated under reduced pressure to obtain the title compounds 1-1-a and 1-1-b (5 mg, 5 mg).
单一构型化合物1-1-b(较短保留时间)：Single configuration compound 1-1-b (shorter retention time):
MS m/z(ESI)：455.0[M+1]。MS m/z (ESI): 455.0 [M+1].
手性HPLC分析：保留时间9.682分钟，手性纯度：97％(色谱柱：Phenomenex Lux Cellulose-3，150*4.6mm，5μm；流动相1：正己烷；流动相2：含0.1％二乙胺乙醇(80％)。Chiral HPLC analysis: retention time 9.682 minutes, chiral purity: 97% (chromatographic column: Phenomenex Lux Cellulose-3, 150*4.6mm, 5μm; mobile phase 1: n-hexane; mobile phase 2: containing 0.1% diethylamine Ethanol (80%).
1H NMR(500MHz,CDCl 3)δ9.08-9.07(m,1H),8.51-8.49(m,1H),8.03-8.01(m,1H),7.54-7.52(m,1H),7.10-7.04(m,2H),6.60-6.57(m,2H),4.25-4.22(m,1H),4.00-3.98(m,1H),3.71-3.67(m,1H),3.57-3.54(m,1H),3.36-3.32(m,2H),3.25-3.09(m,10H),2.91-2.88(m,1H),2.80-2.74(m,2H),1.32-1.31(m,3H)。 1 H NMR (500MHz, CDCl 3 ) δ 9.08-9.07(m,1H), 8.51-8.49(m,1H), 8.03-8.01(m,1H), 7.54-7.52(m,1H), 7.10-7.04 (m,2H),6.60-6.57(m,2H),4.25-4.22(m,1H),4.00-3.98(m,1H),3.71-3.67(m,1H),3.57-3.54(m,1H) , 3.36-3.32(m, 2H), 3.25-3.09(m, 10H), 2.91-2.88(m, 1H), 2.80-2.74(m, 2H), 1.32-1.31(m, 3H).
单一构型化合物1-1-a(较长保留时间)：Single configuration compound 1-1-a (longer retention time):
MS m/z(ESI)：455.0[M+1]。MS m/z (ESI): 455.0 [M+1].
手性HPLC分析：保留时间13.99分钟，手性纯度：97％(色谱柱：Phenomenex Lux Cellulose-3，150*4.6mm，5μm；流动相1：正己烷；流动相2：含0.1％二乙胺乙醇(80％)。Chiral HPLC analysis: retention time 13.99 minutes, chiral purity: 97% (chromatographic column: Phenomenex Lux Cellulose-3, 150*4.6mm, 5μm; mobile phase 1: n-hexane; mobile phase 2: containing 0.1% diethylamine Ethanol (80%).
1H NMR(500MHz,CDCl 3)δ9.08-9.07(m,1H),8.51-8.49(m,1H),8.03-8.01(m,1H),7.54-7.52(m,1H),7.10-7.04(m,2H),6.60-6.57(m,2H),4.25-4.22(m,1H),4.00-3.98(m,1H),3.71-3.67(m,1H),3.57-3.54(m,1H),3.36-3.32(m,2H),3.25-3.09(m,10H),2.91-2.88(m,1H),2.80-2.74(m,2H),1.32-1.31(m,3H)。 1 H NMR (500MHz, CDCl 3 ) δ 9.08-9.07(m,1H), 8.51-8.49(m,1H), 8.03-8.01(m,1H), 7.54-7.52(m,1H), 7.10-7.04 (m,2H),6.60-6.57(m,2H),4.25-4.22(m,1H),4.00-3.98(m,1H),3.71-3.67(m,1H),3.57-3.54(m,1H) , 3.36-3.32(m, 2H), 3.25-3.09(m, 10H), 2.91-2.88(m, 1H), 2.80-2.74(m, 2H), 1.32-1.31(m, 3H).
实施例2Example 2
5-((4R,12aR)-9-(3,6-二氮杂双环[3.1.1]庚-3-基)-4-甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈25-((4R,12aR)-9-(3,6-diazabicyclo[3.1.1]hept-3-yl)-4-methyl-3,4,12,12a-tetrahydro-6H- Benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 2
Figure PCTCN2021110197-appb-000163
Figure PCTCN2021110197-appb-000163
Figure PCTCN2021110197-appb-000164
Figure PCTCN2021110197-appb-000164
第一步first step
((2R,6R)-1,4-二苄基-6-甲基哌嗪-2-基)甲醇2b((2R,6R)-1,4-Dibenzyl-6-methylpiperazin-2-yl)methanol 2b
将化合物2a(7.1g,20.1436mmol采用专利申请“WO2018108704A1,说明书第103页，化合物E3-E6”制备而得)加入四氢呋喃(120mL)冰水冷却，滴加氢化铝锂(2.5M，12.1453mL)加毕，室温反应3小时，反应结束，滴加饱和食盐水淬灭反应，倒出上面澄清液，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题产物2b(5.36g,收率85.72％)。Compound 2a (7.1 g, 20.1436 mmol was prepared using patent application "WO2018108704A1, page 103 of the specification, compound E3-E6") was added to tetrahydrofuran (120 mL) for cooling with ice water, and lithium aluminum hydride (2.5 M, 12.1453 mL) was added dropwise. ) was added, reacted at room temperature for 3 hours, the reaction was over, saturated brine was added dropwise to quench the reaction, the above clear liquid was poured out, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title product 2b (5.36 g, collected rate 85.72%).
MS m/z(ESI)：311.2[M+1]。MS m/z (ESI): 311.2 [M+1].
第二步second step
((2R,6R)-6-甲基哌嗪-2-基)甲醇2c((2R,6R)-6-methylpiperazin-2-yl)methanol 2c
将化合物2b(8.3g，27.6mmol)溶于100mL甲醇中，加入湿钯碳(900mg，8.45mmol)，置换氢气三次，混合物在室温搅拌反应约16小时。过滤除去催化剂，滤液减压浓缩，得到粗品标题产物2c(3.1g，产率：89.06％)，产品不经纯化直接进行下一步反应。Compound 2b (8.3 g, 27.6 mmol) was dissolved in 100 mL of methanol, wet palladium on carbon (900 mg, 8.45 mmol) was added, hydrogen was replaced three times, and the mixture was stirred and reacted at room temperature for about 16 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the crude title product 2c (3.1 g, yield: 89.06%), which was directly subjected to the next reaction without purification.
MS m/z(ESI)：131.2[M+1]。MS m/z (ESI): 131.2 [M+1].
第三步third step
5-((3R,5R)-3-(羟甲基)-5-甲基哌嗪-1-基)喹啉-8-甲腈2d5-((3R,5R)-3-(hydroxymethyl)-5-methylpiperazin-1-yl)quinoline-8-carbonitrile 2d
将粗品化合物2c(1.48g，11.37mmol)和化合物5-氟喹啉-8-甲腈1e(1.5g，8.71mmol，采用专利申请“WO2020020800A1,说明书第16页，化合物1c”制备而得)溶于20mL二甲亚砜中，然后加入N,N-二异丙基乙胺(3.38g，26.15mmol)，该混合物在100℃搅拌反应约4小时。冷却至室温后，向反应液中加入20mL水，用乙酸乙酯萃取(20mL×3)，合并有机相，依次用水(20mL)、饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题产物2d(1.8g，产率：73.17％)。The crude compound 2c (1.48 g, 11.37 mmol) and the compound 5-fluoroquinoline-8-carbonitrile 1e (1.5 g, 8.71 mmol, prepared by using the patent application "WO2020020800A1, page 16 of the specification, compound 1c") were dissolved. In 20 mL of dimethyl sulfoxide, N,N-diisopropylethylamine (3.38 g, 26.15 mmol) was then added, and the mixture was stirred at 100°C for about 4 hours. After cooling to room temperature, 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed successively with water (20 mL) and saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title product 2d (1.8 g, yield: 73.17%).
MS m/z(ESI)：283.0[M+1]。MS m/z (ESI): 283.0 [M+1].
第四步the fourth step
5-((3R,5R)-3-((叔丁基二甲基硅基)氧基)甲基)-5-甲基哌嗪-1-基)喹啉-8-甲腈2e5-((3R,5R)-3-((tert-butyldimethylsilyl)oxy)methyl)-5-methylpiperazin-1-yl)quinoline-8-carbonitrile 2e
将化合物2d(1.8g，1.38mmol)溶于10mL N,N-二甲基甲酰胺中，依次加入咪唑(840mg，10.2mmol)和叔丁基二甲基氯硅烷(868mg，12.75mmol)，室温搅拌反应约16小时。向反应液中加入10mL饱和碳酸氢钠溶液，搅拌30分钟，用乙酸乙酯(10mL×3)萃取，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题产物2e(2.2g产率：87.01％)，产品不经纯化直接进行下一步反应。Compound 2d (1.8 g, 1.38 mmol) was dissolved in 10 mL of N,N-dimethylformamide, imidazole (840 mg, 10.2 mmol) and tert-butyldimethylsilyl chloride (868 mg, 12.75 mmol) were added successively, and the room temperature The reaction was stirred for about 16 hours. 10 mL of saturated sodium bicarbonate solution was added to the reaction solution, stirred for 30 minutes, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with water (10 mL), saturated sodium chloride solution (10 mL), and anhydrous sulfuric acid. Dry over sodium, filter, and concentrate the filtrate under reduced pressure to obtain the title product 2e (2.2 g yield: 87.01%), which is directly subjected to the next reaction without purification.
MS m/z(ESI)：397.4[M+1]。MS m/z (ESI): 397.4 [M+1].
第五步the fifth step
5-((3R,5R)-4-(4-溴-2-(甲氧基甲氧基)苄基)-3-(((叔丁基二甲基硅基)氧基)甲基)-5-甲基哌嗪-1-基)喹啉-8-甲腈2f5-((3R,5R)-4-(4-bromo-2-(methoxymethoxy)benzyl)-3-(((tert-butyldimethylsilyl)oxy)methyl) -5-Methylpiperazin-1-yl)quinoline-8-carbonitrile 2f
将化合物2e(2.2g，5.55mmol)和化合物1b(2.1g，6.77mmol)溶于50mL乙腈中，依次加入碳酸钾(2.3mg，16.64mmol)和碘化钾(20mg，0.12mmol)，混合物在80℃搅拌反应约3小时。冷却至室温后，向反应液中加入30mL水，用乙酸乙酯(30mL×3)萃取，合并有机相，依次用水(50mL)、饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化，得到标题产物2f(3.0g，产率：86.43％)。Compound 2e (2.2 g, 5.55 mmol) and compound 1b (2.1 g, 6.77 mmol) were dissolved in 50 mL of acetonitrile, potassium carbonate (2.3 mg, 16.64 mmol) and potassium iodide (20 mg, 0.12 mmol) were added in sequence, and the mixture was heated at 80 °C The reaction was stirred for about 3 hours. After cooling to room temperature, 30 mL of water was added to the reaction solution, extracted with ethyl acetate (30 mL×3), the organic phases were combined, washed with water (50 mL) and saturated sodium chloride solution (50 mL) in turn, dried over anhydrous sodium sulfate, Filtration, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system A afforded the title product 2f (3.0 g, yield: 86.43%).
MS m/z(ESI)：625.0[M+1]。MS m/z (ESI): 625.0 [M+1].
第六步Step 6
5-((3R,5R)-4-(4-溴-2-羟基苄基)-3-(羟甲基)-5-甲基哌嗪-1-基)喹啉-8-甲腈2g5-((3R,5R)-4-(4-bromo-2-hydroxybenzyl)-3-(hydroxymethyl)-5-methylpiperazin-1-yl)quinoline-8-carbonitrile 2g
将化合物2f(3.0g,4.79mmol)溶于20mL二氯甲烷中，加入4M盐酸1,4-二氧六环溶液(20mL，安耐吉)，有黄色固体生成，混合物在室温继续搅拌反应约1小时。反应液减压浓缩，加入10mL饱和碳酸氢钠溶液，搅拌30分钟，用乙酸乙酯(30mL×3)萃取，合并有机相，依次用水(50mL)、饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物2g(51.8g，产率：80.32％)，产品不经纯化直接进行下一步反应。Compound 2f (3.0 g, 4.79 mmol) was dissolved in 20 mL of dichloromethane, 4M hydrochloric acid 1,4-dioxane solution (20 mL, Annagy) was added, a yellow solid was formed, and the mixture continued to stir at room temperature to react for about 1 hour. The reaction solution was concentrated under reduced pressure, 10 mL of saturated sodium bicarbonate solution was added, stirred for 30 minutes, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with water (50 mL) and saturated sodium chloride solution (50 mL) in turn. Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 2 g of the crude title product (51.8 g, yield: 80.32%). The product is directly subjected to the next reaction without purification.
MS m/z(ESI)：466.9[M+1]。MS m/z (ESI): 466.9 [M+1].
第七步Step 7
5-((4R,12aR)-9-溴-4-甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈2h5-((4R,12aR)-9-bromo-4-methyl-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4 ]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 2h
将粗品化合物2g(2.1g,4.49mmol)溶于50mL甲苯中，加入偶氮二甲酰二哌啶(5.7g，22.59mmol)和三丁基膦(4.6g，22.73mmol)，置换氩气三次，混合物在60℃搅拌反应约1小时。冷却至室温后，反应液减压浓缩，粗产品用乙酸乙酯(10mL)打浆，所得固体过滤，滤饼用正己烷洗涤，固体干燥，得到标题产物2h(1.8g产率：89.15％)。The crude compound 2 g (2.1 g, 4.49 mmol) was dissolved in 50 mL of toluene, azodicarbonyl dipiperidine (5.7 g, 22.59 mmol) and tributylphosphine (4.6 g, 22.73 mmol) were added, and argon was replaced three times , the mixture was stirred at 60 °C for about 1 hour. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, the crude product was slurried with ethyl acetate (10 mL), the obtained solid was filtered, the filter cake was washed with n-hexane, and the solid was dried to obtain the title product 2h (1.8 g yield: 89.15%).
MS m/z(ESI)：449.1[M+1]。MS m/z (ESI): 449.1 [M+1].
第八步Step 8
3-((4R,12aR)-2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4,12,12a-六氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-9-基)-3,6-二氮杂双环[3.1.1]庚烷-6-羧酸叔丁酯2i3-((4R,12aR)-2-(8-cyanoquinolin-5-yl)-4-methyl-1,2,3,4,12,12a-hexahydro-6H-benzo[f ]pyrazino[2,1-c][1,4]oxazepin-9-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl Ester 2i
将化合物2h(50mg，0.11mmol)和化合物3,6-二氮杂双环[3.1.1]庚烷-6-羧酸叔丁酯(33mg，0.17mmol，药石)溶于10mL 1,4-二氧六环中，然后加入氯(2-二环己基膦基-2',6'-二-异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(10mg，0.011mmol，韶远)和叔丁醇钠(33mg，0.33mmol)，置换氩气三次，混合物在100℃搅拌反应约1小时。冷却至室温后，向反应液中加入10mL水，用乙酸乙酯萃取(10mL×3)，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用高效液相色谱法(色谱柱：SharpSil T-C18，5μm，30mm*150mm；流动相1：水相(含0.1％三氟乙酸)；流动相2：乙腈；25分钟梯度：25％-95％，流速：30mL/min)纯化，得到标题产物2i(30mg，产率：47.57％)。Compound 2h (50 mg, 0.11 mmol) and compound 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate tert-butyl ester (33 mg, 0.17 mmol, Yaoshi) were dissolved in 10 mL of 1,4-dicarboxylate oxane, then add chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl) Phen-2-yl)palladium(II) (10 mg, 0.011 mmol, Shaoyuan) and sodium tert-butoxide (33 mg, 0.33 mmol) were replaced with argon three times, and the mixture was stirred and reacted at 100° C. for about 1 hour. After cooling to room temperature, 10 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, Filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (chromatographic column: SharpSil T-C18, 5μm, 30mm*150mm; mobile phase 1: water phase (containing 0.1% trifluoroacetic acid); mobile phase 2: acetonitrile ; 25 min gradient: 25%-95%, flow rate: 30 mL/min) purification gave the title product 2i (30 mg, yield: 47.57%).
MS m/z(ESI)：567.1[M+1]。MS m/z (ESI): 567.1 [M+1].
第九步Step 9
5-((4R,12aR)-9-(3,6-二氮杂双环[3.1.1]庚-3-基)-4-甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈25-((4R,12aR)-9-(3,6-diazabicyclo[3.1.1]hept-3-yl)-4-methyl-3,4,12,12a-tetrahydro-6H- Benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 2
将化合物2i(30mg，0.053mmol)溶于5mL二氯甲烷中，加入5mL三氟乙酸，混合物在室温搅拌反应约1小时。反应液减压浓缩，加入10mL饱和碳酸氢钠溶液，搅拌30分钟，用乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题产物2(5mg，产率：20.2％)。Compound 2i (30 mg, 0.053 mmol) was dissolved in 5 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and the mixture was stirred and reacted at room temperature for about 1 hour. The reaction solution was concentrated under reduced pressure, 10 mL of saturated sodium bicarbonate solution was added, stirred for 30 minutes, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was washed with silica gel Purification by column chromatography with eluent system B afforded the title product 2 (5 mg, yield: 20.2%).
MS m/z(ESI)：467.2[M+1]。MS m/z (ESI): 467.2 [M+1].
1H NMR(500MHz,CDCl 3)δ9.03-9.02(m,1H),8.51-8.50(m,1H),8.03-8.01(m,1H),7.54-7.52(m,1H),7.11-7.10(m,2H),6.40-6.38(m,2H),4.39-4.38(m,1H),4.32-4.29(m,2H),4.01-3.97(m,1H),3.74-3.69(m,2H),3.63-3.61(m,2H),3.53-3.51(m,2H),3.46-3.40(m,2H),3.04-2.99(m,1H),2.88-2.85(m,2H),2.69-2.64(m,1H),2.03-1.98(m,2H),1.81-1.79(m,1H),1.25-1.21(m,3H)。 1 H NMR (500MHz, CDCl 3 ) δ 9.03-9.02 (m, 1H), 8.51-8.50 (m, 1H), 8.03-8.01 (m, 1H), 7.54-7.52 (m, 1H), 7.11-7.10 (m,2H),6.40-6.38(m,2H),4.39-4.38(m,1H),4.32-4.29(m,2H),4.01-3.97(m,1H),3.74-3.69(m,2H) ,3.63-3.61(m,2H),3.53-3.51(m,2H),3.46-3.40(m,2H),3.04-2.99(m,1H),2.88-2.85(m,2H),2.69-2.64( m, 1H), 2.03-1.98 (m, 2H), 1.81-1.79 (m, 1H), 1.25-1.21 (m, 3H).
实施例3Example 3
5-(rel-(4R,12aR)-9-(((3R,4R)-4-甲氧基吡咯烷-3-基)氨基)-4-甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈(混合物1:1)35-(rel-(4R,12aR)-9-(((3R,4R)-4-methoxypyrrolidin-3-yl)amino)-4-methyl-3,4,12,12a-tetra Hydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile (mixture 1:1 )3
Figure PCTCN2021110197-appb-000165
Figure PCTCN2021110197-appb-000165
第一步first step
(3R,4R)-3-((rel-(4R,12aR)-2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4,12,12a-六氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-9-基)氨基)-4-甲氧基吡咯烷-1-羧酸叔丁酯(混合物1:1)3a(3R,4R)-3-((rel-(4R,12aR)-2-(8-cyanoquinolin-5-yl)-4-methyl-1,2,3,4,12,12a- Hexahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-9-yl)amino)-4-methoxypyrrolidine-1-carboxy tert-Butyl acid (mixture 1:1) 3a
将化合物1j(50mg，0.11mmol)和化合物(3R,4R)-3-氨基-4-甲氧基吡咯烷-1-羧酸叔丁酯(30mg，0.14mmol，药明康德)溶于5mL 1,4-二氧六环中，然后加入甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(10mg，0.01mmol，韶远)和叔丁醇钠(30mg，0.31mmol)，置换氩气三次，混合物在80℃搅拌反应约2小时。冷却至室温后，向反应液中加入10mL水，用乙酸乙酯萃取(10mL×3)，合并有机相，依次用水(10mL)，饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化，得到标题产物3a(30mg，产率：46.1％)。Compound 1j (50 mg, 0.11 mmol) and compound (3R,4R)-3-amino-4-methoxypyrrolidine-1-carboxylate tert-butyl ester (30 mg, 0.14 mmol, WuXi AppTec) were dissolved in 5 mL of 1 ,4-dioxane, then add methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1 ,1'-biphenyl-2-yl) palladium (II) (10mg, 0.01mmol, Shaoyuan) and sodium tert-butoxide (30mg, 0.31mmol), replaced argon three times, the mixture was stirred and reacted at 80 ° C for about 2 hours . After cooling to room temperature, 10 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, Filtration, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system A afforded the title product 3a (30 mg, yield: 46.1%).
MS m/z(ESI)：585.3[M+1]。MS m/z (ESI): 585.3 [M+1].
第二步second step
5-(rel-(4R,12aR)-9-(((3R,4R)-4-甲氧基吡咯烷-3-基)氨基)-4-甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈35-(rel-(4R,12aR)-9-(((3R,4R)-4-methoxypyrrolidin-3-yl)amino)-4-methyl-3,4,12,12a-tetra Hydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 3
将化合物3a(30mg，0.051mmol)溶于5mL二氯甲烷中，加入5mL三氟乙酸，混合物在室温搅拌反应约1小时。反应液减压浓缩，加入10mL饱和碳酸氢钠溶液，搅拌30分钟，用乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用(色谱柱：SharpSil T-C18，5μm，30mm*150mm；流动相1：水相(含0.1％三氟乙酸)；流动相2：乙腈；25分钟梯度：25％-95％，流速：30mL/min)纯化，得到标题产物3(10mg，产率：40.5％)。Compound 3a (30 mg, 0.051 mmol) was dissolved in 5 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and the mixture was stirred and reacted at room temperature for about 1 hour. The reaction solution was concentrated under reduced pressure, 10 mL of saturated sodium bicarbonate solution was added, stirred for 30 minutes, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was used ( Chromatographic column: SharpSil T-C18, 5μm, 30mm*150mm; mobile phase 1: aqueous phase (containing 0.1% trifluoroacetic acid); mobile phase 2: acetonitrile; 25 minutes gradient: 25%-95%, flow rate: 30mL/min ) to give the title product 3 (10 mg, yield: 40.5%).
MS m/z(ESI)：485.2[M+1]。MS m/z (ESI): 485.2 [M+1].
1H NMR(500MHz,CD 3OD)δ9.04-9.03(m,1H),8.74-8.72(m,1H),8.20-8.18(m,1H),7.74-7.71(m,1H),7.36-7.34(m,2H),6.55-6.50(m,2H),4.73-4.70(m,1H),4.63-4.60(m,1H),4.49-4.46(m,1H),4.35-4.31(m,1H),4.20-4.17(m,1H),4.04-3.98(m,2H),3.94-3.83(m,1H),3.80-3.73(m,1H),3.73-3.62(m,2H),3.53-3.44(m,5H),3.36-3.33(m,1H),3.15-2.91(m,2H),1.73-1.60(m,3H)。 1 H NMR (500MHz, CD 3 OD) δ 9.04-9.03 (m, 1H), 8.74-8.72 (m, 1H), 8.20-8.18 (m, 1H), 7.74-7.71 (m, 1H), 7.36- 7.34(m, 2H), 6.55-6.50(m, 2H), 4.73-4.70(m, 1H), 4.63-4.60(m, 1H), 4.49-4.46(m, 1H), 4.35-4.31(m, 1H) ),4.20-4.17(m,1H),4.04-3.98(m,2H),3.94-3.83(m,1H),3.80-3.73(m,1H),3.73-3.62(m,2H),3.53-3.44 (m, 5H), 3.36-3.33 (m, 1H), 3.15-2.91 (m, 2H), 1.73-1.60 (m, 3H).
实施例4Example 4
(±)-rel-5-((4R,12aR)-4-甲基-9-(4-甲基哌嗪-1-基)-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈4(±)-rel-5-((4R,12aR)-4-methyl-9-(4-methylpiperazin-1-yl)-3,4,12,12a-tetrahydro-6H-benzo [f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 4
Figure PCTCN2021110197-appb-000166
Figure PCTCN2021110197-appb-000166
将化合物1j(50mg，0.11mmol)和化合物4-甲基哌嗪(30mg，0.30mmol,韶远)溶于5mL 1,4-二氧六环中，然后加入甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(10mg，0.01mmol，韶远)和叔丁醇钠(30 mg，0.31mmol)，置换氩气三次，混合物在80℃搅拌反应约2小时。冷却至室温后，向反应液中加入10mL水，用乙酸乙酯萃取(10mL×3)，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题产物4(12mg，产率：23.1％)。Compound 1j (50 mg, 0.11 mmol) and compound 4-methylpiperazine (30 mg, 0.30 mmol, Shaoyuan) were dissolved in 5 mL of 1,4-dioxane, and then methanesulfonic acid (2-dicyclohexyl was added) Phosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (10 mg, 0.01 mmol , Shaoyuan) and sodium tert-butoxide (30 mg, 0.31 mmol), replaced argon three times, and the mixture was stirred and reacted at 80° C. for about 2 hours. After cooling to room temperature, 10 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, Filtration, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system B afforded the title product 4 (12 mg, yield: 23.1%).
MS m/z(ESI)：469.3[M+1]。MS m/z (ESI): 469.3 [M+1].
1H NMR(500MHz,CDCl 3)δ9.09-9.08(m,1H),8.52-8.50(m,1H),8.04-8.02(m,1H),7.55-7.52(m,1H),7.09-7.05(m,2H),6.60-6.58(m,2H),4.25-4.22(m,1H),4.00-3.98(m,1H),3.71-3.67(m,1H),3.57-3.54(m,1H),3.36-3.34(m,1H),3.25-3.14(m,4H),2.94-2.85(m,1H),2.81-2.73(m,2H),2.67-2.48(m,3H),2.44-2.32(m,2H),1.66-1.55(m,4H),1.34-1.29(m,3H)。 1 H NMR (500MHz, CDCl 3 ) δ 9.09-9.08 (m, 1H), 8.52-8.50 (m, 1H), 8.04-8.02 (m, 1H), 7.55-7.52 (m, 1H), 7.09-7.05 (m,2H),6.60-6.58(m,2H),4.25-4.22(m,1H),4.00-3.98(m,1H),3.71-3.67(m,1H),3.57-3.54(m,1H) ,3.36-3.34(m,1H),3.25-3.14(m,4H),2.94-2.85(m,1H),2.81-2.73(m,2H),2.67-2.48(m,3H),2.44-2.32( m, 2H), 1.66-1.55 (m, 4H), 1.34-1.29 (m, 3H).
实施例5Example 5
(±)-rel-5-((4R,12aR)-9-(6-氨基-2-氮杂螺[3.3]庚-2-基)-4-甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈5(±)-rel-5-((4R,12aR)-9-(6-amino-2-azaspiro[3.3]hept-2-yl)-4-methyl-3,4,12,12a- Tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 5
Figure PCTCN2021110197-appb-000167
Figure PCTCN2021110197-appb-000167
化合物5的制备方法同化合物3。The preparation method of compound 5 is the same as that of compound 3.
将制备化合物3中的原料(3R,4R)-3-氨基-4-甲氧基吡咯烷-1-羧酸叔丁酯替换为化合物(2-氮杂螺[3.3]庚-6-基)氨基甲酸叔丁酯草酸盐(2:1)(毕得医药)，得到标题产物5(5mg)。The starting material (3R,4R)-3-amino-4-methoxypyrrolidine-1-carboxylic acid tert-butyl ester in the preparation of compound 3 was replaced with compound (2-azaspiro[3.3]hept-6-yl) tert-Butyl carbamate oxalate (2:1) (Pedia Pharmaceuticals) to give the title product 5 (5 mg).
MS m/z(ESI)：481.2[M+1]。MS m/z (ESI): 481.2 [M+1].
1H NMR(500MHz,CD 3OD)δ8.91-8.88(m,1H),8.59-8.56(m,1H),8.07-8.04(m,1H),7.60-7.56(m,1H),7.15-7.00(m,2H),6.10-6.02(m,2H),4.22-4.17(m,1H),4.00-3.94(m,1H),3.75-3.73(m,2H),3.65-3.63(m,2H),3.56-3.46(m,1H),3.44-3.30(m,3H),3.27-3.23(m,1H),3.14-3.03(m,1H),2.90-2.81(m,1H),2.69-2.55(m,2H),2.51-2.40(m,2H),2.09-1.91(m,2H),1.31-1.12(m,3H)。 1 H NMR (500MHz, CD 3 OD) δ 8.91-8.88 (m, 1H), 8.59-8.56 (m, 1H), 8.07-8.04 (m, 1H), 7.60-7.56 (m, 1H), 7.15- 7.00(m, 2H), 6.10-6.02(m, 2H), 4.22-4.17(m, 1H), 4.00-3.94(m, 1H), 3.75-3.73(m, 2H), 3.65-3.63(m, 2H ),3.56-3.46(m,1H),3.44-3.30(m,3H),3.27-3.23(m,1H),3.14-3.03(m,1H),2.90-2.81(m,1H),2.69-2.55 (m, 2H), 2.51-2.40 (m, 2H), 2.09-1.91 (m, 2H), 1.31-1.12 (m, 3H).
实施例6Example 6
(±)-rel-5-((4R,12aR)-9-(4-(二甲基甘氨酰基)哌嗪-1-基)-4-甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈6(±)-rel-5-((4R,12aR)-9-(4-(dimethylglycyl)piperazin-1-yl)-4-methyl-3,4,12,12a-tetra Hydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 6
Figure PCTCN2021110197-appb-000168
Figure PCTCN2021110197-appb-000168
将化合物1(20mg，0.044mmol)和化合物N,N-二甲基甘氨酸(10mg，0.097mmol，韶远)溶于5mL N,N-二甲基甲酰胺中，加入N,N-二异丙基乙胺(20mg，0.15mmol)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(40mg，0.11mmol，韶远)，混合物在室温搅拌反应约1小时。反应液加入10mL饱和氯化钠溶液，用乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题产物6(12mg，产率：50.5％)。Compound 1 (20mg, 0.044mmol) and compound N,N-dimethylglycine (10mg, 0.097mmol, Shaoyuan) were dissolved in 5mL N,N-dimethylformamide, and N,N-diisopropyl was added. Ethylethylamine (20mg, 0.15mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (40mg, 0.11mmol, Shaoyuan ), the mixture was stirred at room temperature for about 1 hour. 10 mL of saturated sodium chloride solution was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography with the eluent system B was purified to give the title product 6 (12 mg, yield: 50.5%).
MS m/z(ESI)：540.2[M+1]。MS m/z (ESI): 540.2 [M+1].
1H NMR(500MHz,MeOD-d 4)δ9.01-8.99(m,1H),8.70-8.67(m,1H),8.17-8.14(m,1H),7.69-7.66(m,1H),7.25-7.19(m,2H),6.72-6.66(m,2H),4.37-4.29(m,1H),4.13-4.04(m,1H),4.04(s,2H),3.82-3.71(m,2H),3.69-3.52(m,4H),3.49-3.43(m,1H),3.41-3.34(m,2H),3.28-3.11(m,4H),3.05-2.94(m,1H),2.89-2.65(m,5H),1.46-1.22(m,6H)。 1 H NMR (500MHz, MeOD-d 4 ) δ 9.01-8.99 (m, 1H), 8.70-8.67 (m, 1H), 8.17-8.14 (m, 1H), 7.69-7.66 (m, 1H), 7.25 -7.19(m,2H),6.72-6.66(m,2H),4.37-4.29(m,1H),4.13-4.04(m,1H),4.04(s,2H),3.82-3.71(m,2H) ,3.69-3.52(m,4H),3.49-3.43(m,1H),3.41-3.34(m,2H),3.28-3.11(m,4H),3.05-2.94(m,1H),2.89-2.65( m, 5H), 1.46-1.22 (m, 6H).
实施例7Example 7
(±)-rel-5-((6aR,10R)-(10-甲基-3-(哌嗪-1-基)-6a,7,9,10-四氢-12H-吡嗪并[2,1-c]吡啶并[3,4-f][1,4]氧杂氮杂庚环-8(6H)-基)喹啉-8-甲腈7(±)-rel-5-((6aR,10R)-(10-methyl-3-(piperazin-1-yl)-6a,7,9,10-tetrahydro-12H-pyrazino[2 ,1-c]pyrido[3,4-f][1,4]oxazepin-8(6H)-yl)quinoline-8-carbonitrile 7
Figure PCTCN2021110197-appb-000169
Figure PCTCN2021110197-appb-000169
(±)-rel-5-((3R,5R)-3-(((叔丁基二甲基硅基)氧基)甲基)-4-((4,6-二氯吡啶-3-基)甲基)-5-甲基哌嗪-1-基)喹啉-8-甲腈7b(±)-rel-5-((3R,5R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-((4,6-dichloropyridine-3- yl)methyl)-5-methylpiperazin-1-yl)quinoline-8-carbonitrile 7b
将化合物1g(200mg，0.5mmol)与化合物7a(200mg，0.83mmol，采用专利申请“WO2013064521A1，说明书第109页”制备而得)溶于乙腈(10mL)，加入碳酸钾(200mg，1.45mmol，韶远)和碘化钠(10mg，0.07mmol)，反应在80℃搅拌24小时，将反应液冷却，过滤除去固体，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化，得到标题产物7b(130mg，产率：46.3％)。Compound 1g (200mg, 0.5mmol) and compound 7a (200mg, 0.83mmol, prepared using patent application "WO2013064521A1, page 109 of the specification") were dissolved in acetonitrile (10mL), and potassium carbonate (200mg, 1.45mmol, 200g) was added. (far) and sodium iodide (10 mg, 0.07 mmol), the reaction was stirred at 80° C. for 24 hours, the reaction solution was cooled, the solid was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A, The title product 7b was obtained (130 mg, yield: 46.3%).
MS m/z(ESI)：556.1[M+1]。MS m/z (ESI): 556.1 [M+1].
第二步second step
(±)-rel-5-((3R,5R)-4-((4,6-二氯吡啶-3-基)甲基)-3-(羟甲基)-5-甲基哌嗪-1-基)喹啉-8-甲腈7c(±)-rel-5-((3R,5R)-4-((4,6-dichloropyridin-3-yl)methyl)-3-(hydroxymethyl)-5-methylpiperazine- 1-yl)quinoline-8-carbonitrile 7c
将化合物7b(130mg，0.23mmol)溶于5mL二氯甲烷中，加入4M盐酸1,4-二氧六环溶液(5mL，安耐吉)，有黄色固体生成，混合物在室温继续搅拌反应约1小时。反应液减压浓缩，加入10mL饱和碳酸氢钠溶液，搅拌30分钟，用乙酸乙酯(10mL×3)萃取，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物7c(100mg，产率：96.8％)，产品不经纯化直接进行下一步反应。Compound 7b (130 mg, 0.23 mmol) was dissolved in 5 mL of dichloromethane, 4M hydrochloric acid 1,4-dioxane solution (5 mL, Annagi) was added, a yellow solid was formed, and the mixture was stirred at room temperature for about 1 Hour. The reaction solution was concentrated under reduced pressure, 10 mL of saturated sodium bicarbonate solution was added, stirred for 30 minutes, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with water (10 mL) and saturated sodium chloride solution (10 mL) in turn. Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude title product 7c (100 mg, yield: 96.8%), which is directly subjected to the next reaction without purification.
MS m/z(ESI)：442.0[M+1]。MS m/z (ESI): 442.0 [M+1].
第三步third step
(±)-rel-5-((6aR,10R)-3-氯-10-甲基-6a,7,9,10-四氢-12H-吡嗪并[2,1-c]吡啶并[3,4-f][1,4]氧杂氮杂庚环-8(6H)基)喹啉-8-甲腈7d(±)-rel-5-((6aR,10R)-3-chloro-10-methyl-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[ 3,4-f][1,4]oxazepin-8(6H)yl)quinoline-8-carbonitrile 7d
将粗品化合物7c(50mg，0.11mmol)溶于5mL N,N-二甲基甲酰胺中，加入叔丁醇钠(22mg，0.22mmol)，混合物在室温搅拌反应约1小时，加入10mL饱和碳酸氢钠溶液，搅拌30分钟，用乙酸乙酯(10mL×3)萃取，合并有机相，依次用水(10mL)，饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化，得到标题产物7d(40mg，产率：87.2％)。The crude compound 7c (50 mg, 0.11 mmol) was dissolved in 5 mL of N,N-dimethylformamide, sodium tert-butoxide (22 mg, 0.22 mmol) was added, the mixture was stirred at room temperature for about 1 hour, and 10 mL of saturated bicarbonate was added. The sodium solution was stirred for 30 minutes, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure , the residue was purified by silica gel column chromatography with eluent system A to give the title product 7d (40 mg, yield: 87.2%).
MS m/z(ESI)：405.9[M+1]。MS m/z (ESI): 405.9 [M+1].
第四步the fourth step
(±)-rel-4-((6aR,10R)-8-(8-氰基喹啉-5-基)-10-甲基-6,6a,7,8,9,10-六氢-12H-吡嗪并[2,1-c]吡啶并[3,4-f][1,4]氧杂氮杂庚环-3-基)哌嗪-1-羧酸叔丁酯7e(±)-rel-4-((6aR,10R)-8-(8-cyanoquinolin-5-yl)-10-methyl-6,6a,7,8,9,10-hexahydro- 12H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepin-3-yl)piperazine-1-carboxylate tert-butyl ester 7e
将化合物7d(40mg，0.1mmol)和化合物哌嗪-1-羧酸叔丁酯(30mg，0.16mmol，韶远)溶于5mL1,4-二氧六环中，然后加入甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(10mg，0.01mmol，韶远)和叔丁醇钠(30mg，0.31mmol)，置换氩气三次，混合物在80℃搅拌反应约2小时。冷却至室温后，向反应液中加入10mL水，用乙酸乙酯萃取(10mL×3)，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题产物7e(30mg，产率：54.8％)。Compound 7d (40 mg, 0.1 mmol) and compound piperazine-1-carboxylate tert-butyl ester (30 mg, 0.16 mmol, Shaoyuan) were dissolved in 5 mL of 1,4-dioxane, and then methanesulfonic acid (2- Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (10 mg , 0.01 mmol, Shaoyuan) and sodium tert-butoxide (30 mg, 0.31 mmol), replaced argon three times, and the mixture was stirred at 80° C. for reaction for about 2 hours. After cooling to room temperature, 10 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title product 7e (30 mg, yield: 54.8%).
MS m/z(ESI)：556.1[M+1]。MS m/z (ESI): 556.1 [M+1].
第五步the fifth step
(±)-rel-5-((6aR,10R)-(10-甲基-3-(哌嗪-1-基)-6a,7,9,10-四氢-12H-吡嗪并[2,1-c]吡啶并[3,4-f][1,4]氧杂氮杂庚环-8(6H)-基)喹啉-8-甲腈7(±)-rel-5-((6aR,10R)-(10-methyl-3-(piperazin-1-yl)-6a,7,9,10-tetrahydro-12H-pyrazino[2 ,1-c]pyrido[3,4-f][1,4]oxazepin-8(6H)-yl)quinoline-8-carbonitrile 7
将化合物7e(30mg，0.054mmol)溶于2mL二氯甲烷中，加入2mL三氟乙酸，混合物在室温搅拌反应约1小时。反应液减压浓缩，加入10mL饱和碳酸氢钠溶液，搅拌30分钟，用乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用高效液相色谱法(色谱柱：SharpSil T-C18,5μm, 30mm*150mm；流动相1：水相(含0.1％三氟乙酸)；流动相2：乙腈；25分钟梯度：25％-95％，流速：30mL/min)纯化，得到标题产物7(20mg，产率：81.3％)。Compound 7e (30 mg, 0.054 mmol) was dissolved in 2 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred and reacted at room temperature for about 1 hour. The reaction solution was concentrated under reduced pressure, 10 mL of saturated sodium bicarbonate solution was added, stirred for 30 minutes, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was treated with high-efficiency Liquid chromatography (column: SharpSil T-C18, 5μm, 30mm*150mm; mobile phase 1: aqueous phase (containing 0.1% trifluoroacetic acid); mobile phase 2: acetonitrile; 25-minute gradient: 25%-95%, Flow rate: 30 mL/min) was purified to give the title product 7 (20 mg, yield: 81.3%).
MS m/z(ESI)：456.1[M+1]。MS m/z (ESI): 456.1 [M+1].
1H NMR(500MHz,CD 3OD)δ9.02-8.98(m,1H),8.73-8.1(m,1H),8.21-8.09(m,1H),8.04-7.95(m,1H),7.72-7.62(m,1H),7.30-7.19(m,1H),6.51-6.36(m,1H),4.44-4.34(m,1H),4.22-4.12(m,1H),3.85-3.71(m,1H),3.66-3.50(m,4H),3.49-3.36(m,2H),3.27-2.94(m,6H),2.88-2.71(m,2H),1.98-1.80(m,1H),1.37-1.21(m,3H)。 1 H NMR (500MHz, CD 3 OD) δ 9.02-8.98 (m, 1H), 8.73-8.1 (m, 1H), 8.21-8.09 (m, 1H), 8.04-7.95 (m, 1H), 7.72- 7.62(m,1H),7.30-7.19(m,1H),6.51-6.36(m,1H),4.44-4.34(m,1H),4.22-4.12(m,1H),3.85-3.71(m,1H) ), 3.66-3.50(m, 4H), 3.49-3.36(m, 2H), 3.27-2.94(m, 6H), 2.88-2.71(m, 2H), 1.98-1.80(m, 1H), 1.37-1.21 (m, 3H).
实施例8Example 8
(±)-rel-(4R,12aR)-N-(4-氨基双环[2.2.2]辛-1-基)-2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4,12,12a-六氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-9-甲酰胺8(±)-rel-(4R,12aR)-N-(4-aminobicyclo[2.2.2]oct-1-yl)-2-(8-cyanoquinolin-5-yl)-4-methyl -1,2,3,4,12,12a-Hexahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-9-carboxamide 8
Figure PCTCN2021110197-appb-000170
Figure PCTCN2021110197-appb-000170
第一步first step
(±)-rel-(4R,12aR)-2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4,12,12a-六氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-9-羧酸8a(±)-rel-(4R,12aR)-2-(8-cyanoquinolin-5-yl)-4-methyl-1,2,3,4,12,12a-hexahydro-6H-benzene Io[f]pyrazino[2,1-c][1,4]oxazepine-9-carboxylic acid 8a
将化合物1j(50mg，0.11mmol)和甲酸(40mg，0.87mmol)溶于5mL N,N-二甲基甲酰胺中，加入醋酸钯(5mg，0.02mmol)和三乙胺(25mg，0.25mmol)，然后加入二环己基碳二亚胺(45mg，0.22mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(23mg，0.04mmol，乐研)，置换氩气三次，混合物在80℃搅拌反应约4小时。冷 却至室温后，向反应液中加入10mL水，用乙酸乙酯萃取(10mL×3)，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题产物8a(20mg，产率：43.4％)。Compound 1j (50 mg, 0.11 mmol) and formic acid (40 mg, 0.87 mmol) were dissolved in 5 mL of N,N-dimethylformamide, palladium acetate (5 mg, 0.02 mmol) and triethylamine (25 mg, 0.25 mmol) were added , then added dicyclohexylcarbodiimide (45mg, 0.22mmol) and 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (23mg, 0.04mmol, Leyan), replacing argon Three times, the mixture was stirred at 80°C for about 4 hours. After cooling to room temperature, 10 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, Filtration, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system B afforded the title product 8a (20 mg, yield: 43.4%).
MS m/z(ESI)：415.1[M+1]。MS m/z (ESI): 415.1 [M+1].
第二步second step
(±)-rel-(4-((4R,12aR)-2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4,12,12a-六氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-9-甲酰氨基)双环[2.2.2]辛-1-基)氨基羧酸叔丁酯8b(±)-rel-(4-((4R,12aR)-2-(8-cyanoquinolin-5-yl)-4-methyl-1,2,3,4,12,12a-hexahydro -6H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-9-carboxamido)bicyclo[2.2.2]oct-1-yl)aminocarboxylate tert-Butyl acid 8b
将化合物8a(20mg，0.048mmol)和化合物(4-氨基双环[2.2.2]辛-1-基)氨基甲酸叔丁酯(15mg，0.062mmol，乐研)溶于5mL N,N-二甲基甲酰胺中，加入N,N-二异丙基乙胺(20mg，0.15mmol)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(30mg，0.079mmol，韶远)，混合物在室温搅拌反应约1小时。反应液加入10mL饱和氯化钠溶液，用乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题产物8b(15mg，产率：48.8％)。Compound 8a (20 mg, 0.048 mmol) and compound (4-aminobicyclo[2.2.2]oct-1-yl)carbamate tert-butyl ester (15 mg, 0.062 mmol, Leyan) were dissolved in 5 mL of N,N-dimethylformaldehyde N,N-diisopropylethylamine (20mg, 0.15mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyl amide Urea hexafluorophosphate (30 mg, 0.079 mmol, Shaoyuan), the mixture was stirred and reacted at room temperature for about 1 hour. 10 mL of saturated sodium chloride solution was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography with the eluent system B was purified to give the title product 8b (15 mg, yield: 48.8%).
MS m/z(ESI)：637.2[M+1]。MS m/z (ESI): 637.2 [M+1].
第三步third step
(±)-rel-(4R,12aR)-N-(4-氨基双环[2.2.2]辛-1-基)-2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4,12,12a-六氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-9-甲酰胺8(±)-rel-(4R,12aR)-N-(4-aminobicyclo[2.2.2]oct-1-yl)-2-(8-cyanoquinolin-5-yl)-4-methyl -1,2,3,4,12,12a-Hexahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-9-carboxamide 8
将化合物8b(15mg，0.024mmol)溶于2mL二氯甲烷中，加入2mL三氟乙酸，混合物在室温搅拌反应约1小时。反应液减压浓缩，加入5mL饱和碳酸氢钠溶液，搅拌30分钟，用乙酸乙酯(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用高效液相色谱法(色谱柱：SharpSil T-C18，5μm,30mm*150mm；流动相1：水相(含0.1％三氟乙酸)；流动相2：乙腈；25分钟梯度：25％-95％，流速：30mL/min)纯化，得到标题产物8(2mg，产率：15.8％)。Compound 8b (15 mg, 0.024 mmol) was dissolved in 2 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred and reacted at room temperature for about 1 hour. The reaction solution was concentrated under reduced pressure, 5 mL of saturated sodium bicarbonate solution was added, stirred for 30 minutes, extracted with ethyl acetate (5 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Liquid chromatography (chromatographic column: SharpSil T-C18, 5μm, 30mm*150mm; mobile phase 1: aqueous phase (containing 0.1% trifluoroacetic acid); mobile phase 2: acetonitrile; 25-minute gradient: 25%-95%, Flow rate: 30 mL/min) was purified to give the title product 8 (2 mg, yield: 15.8%).
MS m/z(ESI)：537.1[M+1]。MS m/z (ESI): 537.1 [M+1].
1H NMR(500MHz,CD 3OD)δ8.98-8.84(m,1H),8.67-8.54(m,1H),8.12-7.98(m,1H),7.74-7.53(m,1H),7.49-7.25(m,3H),7.21-7.06(m,1H),4.37-4.25(m,1H),4.17-4.07(m,1H),3.65-3.53(m,2H),3.42-3.28(m,3H),2.99-2.85(m,1H),2.75-2.58(m,2H),2.16-1.98(m,6H),1.79-1.62(m,6H),1.31-1.24(m,3H)。 1 H NMR (500MHz, CD 3 OD) δ 8.98-8.84 (m, 1H), 8.67-8.54 (m, 1H), 8.12-7.98 (m, 1H), 7.74-7.53 (m, 1H), 7.49- 7.25(m, 3H), 7.21-7.06(m, 1H), 4.37-4.25(m, 1H), 4.17-4.07(m, 1H), 3.65-3.53(m, 2H), 3.42-3.28(m, 3H ), 2.99-2.85(m, 1H), 2.75-2.58(m, 2H), 2.16-1.98(m, 6H), 1.79-1.62(m, 6H), 1.31-1.24(m, 3H).
实施例9Example 9
(±)-rel-5-((4R,12aR)-9-(氮杂环丁烷-3-基)-4-甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈9(±)-rel-5-((4R,12aR)-9-(azetidin-3-yl)-4-methyl-3,4,12,12a-tetrahydro-6H-benzo[ f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 9
Figure PCTCN2021110197-appb-000171
Figure PCTCN2021110197-appb-000171
第一步first step
(±)-rel-3-((4R,12aR)-(2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4,12,12a六氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-9-基)氮杂环丁烷-1-羧酸叔丁酯9a(±)-rel-3-((4R,12aR)-(2-(8-cyanoquinolin-5-yl)-4-methyl-1,2,3,4,12,12ahexahydro- 6H-Benzo[f]pyrazino[2,1-c][1,4]oxazepin-9-yl)azetidine-1-carboxylate tert-butyl ester 9a
将锌粉(156mg，2.38mmol)溶于5mL干燥的N,N-二甲基甲酰胺中，加入1，2-二溴乙烷(45mg，0.24mmol)和三甲基氯硅烷(26mg，0.24mmol)，混合物在60℃搅拌反应约10min，冷却至室温。加入3-碘代氮杂环丁烷-1-羧酸叔丁酯(68mg，0.24mmol，药石)，室温搅拌1小时，形成乳白色悬浊液，氮气保护。将化合物1j(50mg，0.11mmol)溶于5mL干燥的N,N-二甲基甲酰胺中，加入双三苯基磷二氯化钯(II)(10mg，0.014mmol，韶远)，加入上述悬浊液，置换氮气三次，混合物在80℃搅拌反应约4小时。冷却至室温后，向反应液中加入10mL水，用乙酸乙酯萃取(10mL×3)，合并有机相，依次用水(10mL)，饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题产物9a(20mg，产率：34.2％)。Zinc powder (156 mg, 2.38 mmol) was dissolved in 5 mL of dry N,N-dimethylformamide, 1,2-dibromoethane (45 mg, 0.24 mmol) and trimethylchlorosilane (26 mg, 0.24 mmol) were added mmol), the mixture was stirred at 60 °C for about 10 min and cooled to room temperature. Add 3-iodoazetidine-1-carboxylate tert-butyl ester (68 mg, 0.24 mmol, Yaoshi), and stir at room temperature for 1 hour to form a milky white suspension under nitrogen protection. Compound 1j (50 mg, 0.11 mmol) was dissolved in 5 mL of dry N,N-dimethylformamide, bistriphenylphosphonium palladium (II) dichloride (10 mg, 0.014 mmol, Shaoyuan) was added, and the above-mentioned The suspension was replaced with nitrogen three times, and the mixture was stirred and reacted at 80°C for about 4 hours. After cooling to room temperature, 10 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, Filtration, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system B afforded the title product 9a (20 mg, yield: 34.2%).
MS m/z(ESI)：526.1[M+1]。MS m/z (ESI): 526.1 [M+1].
第二步second step
(±)-rel-5((4R,12aR)-9-(氮杂环丁烷-3-基)-4-甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈9(±)-rel-5((4R,12aR)-9-(azetidin-3-yl)-4-methyl-3,4,12,12a-tetrahydro-6H-benzo[f ]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 9
将化合物9a(20mg，0.038mmol)溶于2mL二氯甲烷中，加入2mL三氟乙酸，混合物在室温搅拌反应约1小时。反应液减压浓缩，加入5mL饱和碳酸氢钠溶液， 搅拌30分钟，用乙酸乙酯(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用高效液相色谱法(色谱柱：SharpSil T-C18，5μm，30mm*150mm；流动相1：水相(含0.1％三氟乙酸)；流动相2：乙腈；25分钟梯度：25％-95％，流速：30mL/min)纯化，得到标题产物9(2mg，产率：12.4％)。Compound 9a (20 mg, 0.038 mmol) was dissolved in 2 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred and reacted at room temperature for about 1 hour. The reaction solution was concentrated under reduced pressure, 5 mL of saturated sodium bicarbonate solution was added, stirred for 30 minutes, extracted with ethyl acetate (5 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was treated with high-efficiency Liquid chromatography (column: SharpSil T-C18, 5μm, 30mm*150mm; mobile phase 1: aqueous phase (containing 0.1% trifluoroacetic acid); mobile phase 2: acetonitrile; 25-minute gradient: 25%-95%, Flow rate: 30 mL/min) was purified to give the title product 9 (2 mg, yield: 12.4%).
MS m/z(ESI)：426.1[M+1]。MS m/z (ESI): 426.1 [M+1].
1H NMR(500MHz,CD 3OD)δ9.02-8.95(m,1H),8.73-8.64(m,1H),8.21-8.09(m,1H),7.71-7.62(m,1H),7.47-7.37(m,1H),7.27-7.23(m,1H),7.15-7.06(m,2H),4.49-4.09(m,4H),3.92-3.76(m,2H),3.60-3.35(m,2H),3.23-3.14(m,1H),2.90-2.74(m,2H),1.45-1.33(m,4H),1.31-1.21(m,3H)。 1 H NMR (500MHz, CD 3 OD) δ 9.02-8.95 (m, 1H), 8.73-8.64 (m, 1H), 8.21-8.09 (m, 1H), 7.71-7.62 (m, 1H), 7.47- 7.37(m,1H),7.27-7.23(m,1H),7.15-7.06(m,2H),4.49-4.09(m,4H),3.92-3.76(m,2H),3.60-3.35(m,2H) ), 3.23-3.14 (m, 1H), 2.90-2.74 (m, 2H), 1.45-1.33 (m, 4H), 1.31-1.21 (m, 3H).
实施例10Example 10
5-(rel-(4R,12aR)-9-(4-(L-脯氨酰基)哌嗪-1-基)-4-甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈(混合物1:1)105-(rel-(4R,12aR)-9-(4-(L-prolyl)piperazin-1-yl)-4-methyl-3,4,12,12a-tetrahydro-6H-benzene [f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile (mixture 1:1) 10
Figure PCTCN2021110197-appb-000172
Figure PCTCN2021110197-appb-000172
化合物10的制备方法同化合物3。The preparation method of compound 10 is the same as that of compound 3.
将制备化合物3中的原料(3R,4R)-3-氨基-4-甲氧基吡咯烷-1-羧酸叔丁酯替换为化合物(2S)-2-[(哌嗪-1-基)羰基]吡咯烷-1-羧酸叔丁酯(采用公知方法“Current Organic Chemistry,2019,23(17),1867-1879”制备而得)得到标题产物10(10mg)。The starting material (3R,4R)-3-amino-4-methoxypyrrolidine-1-carboxylic acid tert-butyl ester in the preparation of compound 3 was replaced with compound (2S)-2-[(piperazin-1-yl) Carbonyl]pyrrolidine-1-carboxylate tert-butyl ester (prepared by the well-known method "Current Organic Chemistry, 2019, 23(17), 1867-1879") gave the title product 10 (10 mg).
MS m/z(ESI)：552.1[M+1]。MS m/z (ESI): 552.1 [M+1].
1H NMR(500MHz,CD 3OD)δ9.06-8.99(m,1H),8.77-8.68(m,1H),8.22-8.15(m,1H),7.77-7.67(m,1H),7.46-7.30(m,2H),6.88-6.75(m,2H),4.80-4.67(m,2H),4.69-4.20(m,3H),4.08-3.57(m,8H),3.51-3.32(m,4H),3.27-2.88(m,3H),2.60-2.47(m,1H),2.27-1.85(m,4H),1.73-1.55(m,3H)。 1 H NMR (500MHz, CD 3 OD) δ 9.06-8.99 (m, 1H), 8.77-8.68 (m, 1H), 8.22-8.15 (m, 1H), 7.77-7.67 (m, 1H), 7.46- 7.30(m,2H),6.88-6.75(m,2H),4.80-4.67(m,2H),4.69-4.20(m,3H),4.08-3.57(m,8H),3.51-3.32(m,4H ), 3.27-2.88(m, 3H), 2.60-2.47(m, 1H), 2.27-1.85(m, 4H), 1.73-1.55(m, 3H).
实施例11Example 11
(±)-rel-5-((4R,12aR)-9-(4-异丙基哌嗪-1-基)-4-甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈11(±)-rel-5-((4R,12aR)-9-(4-isopropylpiperazin-1-yl)-4-methyl-3,4,12,12a-tetrahydro-6H-benzene [f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 11
Figure PCTCN2021110197-appb-000173
Figure PCTCN2021110197-appb-000173
将化合物1(20mg，0.44mmol)溶于5mL乙腈中，加入2-碘代丙烷(15mg，0.88mmol)和碳酸钾(20mg，1.45mmol)，混合物在100℃搅拌反应约6小时。冷却至室温后，过滤，滤液减压浓缩，残余物用高效液相色谱法(色谱柱：SharpSil T-C18，5μm，30mm*150mm；流动相1：水相(含0.1％三氟乙酸)；流动相2：乙腈；25分钟梯度：25％-95％，流速：30mL/min)纯化，得到标题产物11(2mg，产率：9.2％)。Compound 1 (20 mg, 0.44 mmol) was dissolved in 5 mL of acetonitrile, 2-iodopropane (15 mg, 0.88 mmol) and potassium carbonate (20 mg, 1.45 mmol) were added, and the mixture was stirred at 100° C. for about 6 hours. After cooling to room temperature, filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (chromatographic column: SharpSil T-C18, 5μm, 30mm*150mm; mobile phase 1: water phase (containing 0.1% trifluoroacetic acid); Mobile phase 2: acetonitrile; 25 min gradient: 25%-95%, flow rate: 30 mL/min) was purified to give the title product 11 (2 mg, yield: 9.2%).
MS m/z(ESI)：497.1[M+1]。MS m/z (ESI): 497.1 [M+1].
1H NMR(500MHz,CDCl 3)δ9.09-9.08(m,1H),8.52-8.50(m,1H),8.04-8.02(m,1H),7.55-7.52(m,1H),7.09-7.05(m,2H),6.60-6.58(m,2H),4.25-4.22(m,1H),4.00-3.98(m,1H),3.71-3.67(m,1H),3.57-3.54(m,1H),3.36-3.34(m,1H),3.25-3.14(m,4H),2.91-2.88(m,1H),2.81-2.66(m,5H),1.60-1.50(m,8H),1.33-1.31(m,3H)，1.15-1.04(m,2H)。 1 H NMR (500MHz, CDCl 3 ) δ 9.09-9.08 (m, 1H), 8.52-8.50 (m, 1H), 8.04-8.02 (m, 1H), 7.55-7.52 (m, 1H), 7.09-7.05 (m,2H),6.60-6.58(m,2H),4.25-4.22(m,1H),4.00-3.98(m,1H),3.71-3.67(m,1H),3.57-3.54(m,1H) ,3.36-3.34(m,1H),3.25-3.14(m,4H),2.91-2.88(m,1H),2.81-2.66(m,5H),1.60-1.50(m,8H),1.33-1.31( m, 3H), 1.15-1.04 (m, 2H).
实施例12Example 12
5-(rel-(4R,12aR)-9-((3R,4S)-3-氨基-4-氟吡咯烷-1-基)-4-甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈(混合物1:1)125-(rel-(4R,12aR)-9-((3R,4S)-3-amino-4-fluoropyrrolidin-1-yl)-4-methyl-3,4,12,12a-tetrahydro -6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile (mixture 1:1) 12
Figure PCTCN2021110197-appb-000174
Figure PCTCN2021110197-appb-000174
化合物12的制备方法同化合物3。The preparation method of compound 12 is the same as that of compound 3.
将制备化合物3中的原料(3R,4R)-3-氨基-4-甲氧基吡咯烷-1-羧酸叔丁酯替换为化合物((3R,4S)-4-氟吡咯烷-3-基)氨基甲酸叔丁酯(乐研)得到标题产物12(20mg)。The starting material (3R,4R)-3-amino-4-methoxypyrrolidine-1-carboxylate tert-butyl ester in the preparation of compound 3 was replaced with compound ((3R,4S)-4-fluoropyrrolidine-3- base) tert-butyl carbamate (Rakuen) to give the title product 12 (20 mg).
MS m/z(ESI)：473.2[M+1]。MS m/z (ESI): 473.2 [M+1].
1H NMR(500MHz,CD 3OD)δ9.07-8.99(m,1H),8.77-8.68(m,1H),8.22-8.13(m,1H),7.77-7.67(m,1H),7.54-7.49(m,2H),7.46-7.29(m,2H),5.62-5.34(m,1H),4.80-4.27(m,4H),4.24-4.08(m,1H),4.09-3.97(m,1H),3.95-3.62(m,6H),3.49-3.39(m,1H),3.18-2.90(m,2H),1.73-1.60(m,3H)。 1 H NMR (500MHz, CD 3 OD) δ 9.07-8.99 (m, 1H), 8.77-8.68 (m, 1H), 8.22-8.13 (m, 1H), 7.77-7.67 (m, 1H), 7.54- 7.49(m, 2H), 7.46-7.29(m, 2H), 5.62-5.34(m, 1H), 4.80-4.27(m, 4H), 4.24-4.08(m, 1H), 4.09-3.97(m, 1H) ), 3.95-3.62 (m, 6H), 3.49-3.39 (m, 1H), 3.18-2.90 (m, 2H), 1.73-1.60 (m, 3H).
实施例13Example 13
5-(rel-(4R,12aR)-9-((3S,4R)-3-氨基-4-氟吡咯烷-1-基)-4-甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈(混合物1:1)135-(rel-(4R,12aR)-9-((3S,4R)-3-amino-4-fluoropyrrolidin-1-yl)-4-methyl-3,4,12,12a-tetrahydro -6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile (mixture 1:1) 13
Figure PCTCN2021110197-appb-000175
Figure PCTCN2021110197-appb-000175
化合物13的制备方法同化合物3。The preparation method of compound 13 is the same as that of compound 3.
将制备化合物3中的原料(3R,4R)-3-氨基-4-甲氧基吡咯烷-1-羧酸叔丁酯替换为((3S,4R)-4-氟吡咯烷-3-基)氨基甲酸叔丁酯(药石)得到标题产物13(10mg)。The starting material (3R,4R)-3-amino-4-methoxypyrrolidine-1-carboxylate tert-butyl ester in the preparation of compound 3 was replaced by ((3S,4R)-4-fluoropyrrolidin-3-yl ) tert-butyl carbamate (Yao Shi) to give the title product 13 (10 mg).
MS m/z(ESI)：473.0[M+1]。MS m/z (ESI): 473.0 [M+1].
1H NMR(500MHz,CD 3OD)δ9.00-8.96(m,1H),8.72-8.61(m,1H),8.18-8.07(m,1H),7.72-7.61(m,1H),7.29-7.21(m,1H),7.17-7.05(m,1H),6.32-6.17(m,2H),5.21-4.99(m,1H),4.35-4.24(m,1H),4.06-3.99(m,1H),3.75-3.40(m,6H),3.39-3.30(m,2H),3.21-3.13(m,1H),3.09-2.90(m,2H),2.80-2.66(m,2H),1.40-1.20(m,3H)。 1 H NMR (500MHz, CD 3 OD) δ 9.00-8.96 (m, 1H), 8.72-8.61 (m, 1H), 8.18-8.07 (m, 1H), 7.72-7.61 (m, 1H), 7.29- 7.21(m,1H),7.17-7.05(m,1H),6.32-6.17(m,2H),5.21-4.99(m,1H),4.35-4.24(m,1H),4.06-3.99(m,1H) ),3.75-3.40(m,6H),3.39-3.30(m,2H),3.21-3.13(m,1H),3.09-2.90(m,2H),2.80-2.66(m,2H),1.40-1.20 (m, 3H).
实施例14Example 14
(±)-rel-5-((4R,12aR)-9-(3-氨基-3-甲基氮杂环丁烷-1-基)-4-甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈14(±)-rel-5-((4R,12aR)-9-(3-amino-3-methylazetidin-1-yl)-4-methyl-3,4,12,12a- Tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 14
Figure PCTCN2021110197-appb-000176
Figure PCTCN2021110197-appb-000176
化合物14的制备方法同化合物3。The preparation method of compound 14 is the same as that of compound 3.
将制备化合物3中的原料(3R,4R)-3-氨基-4-甲氧基吡咯烷-1-羧酸叔丁酯替换为化合物(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯盐酸盐(毕得)得到标题产物14(7mg)。The starting material (3R,4R)-3-amino-4-methoxypyrrolidine-1-carboxylic acid tert-butyl ester in the preparation of compound 3 was replaced with compound (3-methylazetidin-3-yl) tert-Butyl carbamate hydrochloride (Bid) gave the title product 14 (7 mg).
MS m/z(ESI)：455.0[M+1]。MS m/z (ESI): 455.0 [M+1].
1H NMR(500MHz,CD 3OD)δ9.04-8.94(m,1H),8.72-8.62(m,1H),8.20-8.09(m,1H),7.72-7.63(m,1H),7.29-7.18(m,1H),7.17-7.06(m,1H),6.25-6.09(m,2H),4.35-4.23(m,1H),4.13-4.00(m,1H),3.84-3.68(m,2H),3.68-3.38(m,6H),3.22-3.12(m,1H),3.00-2.88(m,1H),2.82-2.67(m,2H),1.50(s,3H),1.38-1.24(m,3H)。 1 H NMR (500MHz, CD 3 OD) δ 9.04-8.94 (m, 1H), 8.72-8.62 (m, 1H), 8.20-8.09 (m, 1H), 7.72-7.63 (m, 1H), 7.29- 7.18(m,1H),7.17-7.06(m,1H),6.25-6.09(m,2H),4.35-4.23(m,1H),4.13-4.00(m,1H),3.84-3.68(m,2H ),3.68-3.38(m,6H),3.22-3.12(m,1H),3.00-2.88(m,1H),2.82-2.67(m,2H),1.50(s,3H),1.38-1.24(m , 3H).
实施例15Example 15
(±)-rel-5-((4R,12aR)-4-甲基-9-(1,2,3,6-四氢吡啶-4-基)-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈15(±)-rel-5-((4R,12aR)-4-methyl-9-(1,2,3,6-tetrahydropyridin-4-yl)-3,4,12,12a-tetrahydro -6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 15
Figure PCTCN2021110197-appb-000177
Figure PCTCN2021110197-appb-000177
Figure PCTCN2021110197-appb-000178
Figure PCTCN2021110197-appb-000178
第一步first step
(±)-rel-4-((4R,12aR)-2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4,12,12a-六氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-9-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯15a(±)-rel-4-((4R,12aR)-2-(8-cyanoquinolin-5-yl)-4-methyl-1,2,3,4,12,12a-hexahydro- 6H-Benzo[f]pyrazino[2,1-c][1,4]oxazepin-9-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tertiary Butyl ester 15a
将化合物1j(100mg，0.22mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(80mg，0.26mmol，韶远)溶于5mL1,4-二氧六环中，加入[1,1’-双(二苯基膦)二茂铁]二氯化钯(II)(10mg，0.014mmol，乐研)和碳酸钾(90mg，0.65mmol)，置换氩气三次，混合物在90℃搅拌反应约1小时。冷却至室温后，向反应液中加入10mL水，用乙酸乙酯萃取(10mL×3)，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化，得到标题产物15a(80mg，产率：65.2％)。Compound 1j (100 mg, 0.22 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,6-dihydropyridine -1(2H)-Carboxylic acid tert-butyl ester (80 mg, 0.26 mmol, Shaoyuan) was dissolved in 5 mL of 1,4-dioxane, and [1,1'-bis(diphenylphosphino)ferrocene] was added Palladium(II) chloride (10 mg, 0.014 mmol, Rakuen) and potassium carbonate (90 mg, 0.65 mmol) were replaced with argon three times, and the mixture was stirred at 90° C. for about 1 hour. After cooling to room temperature, 10 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, Filtration, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system A afforded the title product 15a (80 mg, yield: 65.2%).
MS m/z(ESI)：552.0[M+1]。MS m/z (ESI): 552.0 [M+1].
第二步second step
(±)-rel-5-((4R,12aR)-4-甲基-9-(1,2,3,6-四氢吡啶-4-基)-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈15(±)-rel-5-((4R,12aR)-4-methyl-9-(1,2,3,6-tetrahydropyridin-4-yl)-3,4,12,12a-tetrahydro -6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 15
将化合物15a(50mg，0.091mmol)溶于3mL二氯甲烷中，加入3mL三氟乙酸，混合物在室温搅拌反应约1小时。反应液减压浓缩，加入5mL饱和碳酸氢钠溶液，搅拌30分钟，用乙酸乙酯(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用高效液相色谱法(色谱柱：SharpSil T-C18，5μm，30mm*150mm；流动相1：水相(含0.1％三氟乙酸)；流动相2：乙腈；25分钟梯度：25％-95％，流速：30mL/min)纯化，得到标题产物15(30mg，产率：73.3％)。Compound 15a (50 mg, 0.091 mmol) was dissolved in 3 mL of dichloromethane, 3 mL of trifluoroacetic acid was added, and the mixture was stirred and reacted at room temperature for about 1 hour. The reaction solution was concentrated under reduced pressure, 5 mL of saturated sodium bicarbonate solution was added, stirred for 30 minutes, extracted with ethyl acetate (5 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Liquid chromatography (column: SharpSil T-C18, 5μm, 30mm*150mm; mobile phase 1: aqueous phase (containing 0.1% trifluoroacetic acid); mobile phase 2: acetonitrile; 25-minute gradient: 25%-95%, Flow rate: 30 mL/min) was purified to give the title product 15 (30 mg, yield: 73.3%).
MS m/z(ESI)：452.0[M+1]。MS m/z (ESI): 452.0 [M+1].
1H NMR(500MHz,CD 3OD)δ9.12-8.96(m,1H),8.78-8.67(m,1H),8.25-8.14(m,1H),7.78-7.62(m,1H),7.62-7.51(m,1H),7.47-7.26(m,3H),6.33-6.20(m,1H),4.79-4.46(m,2H),4.41-4.26(m,1H),4.07-3.82(m,4H),3.83-3.60(m,2H),3.57-3.42(m,2H),3.40-3.34(m,1H),3.16-2.96(m,2H),2.86-2.74(m,2H),1.80-1.53(m,3H)。 1 H NMR (500MHz, CD 3 OD) δ 9.12-8.96 (m, 1H), 8.78-8.67 (m, 1H), 8.25-8.14 (m, 1H), 7.78-7.62 (m, 1H), 7.62- 7.51(m, 1H), 7.47-7.26(m, 3H), 6.33-6.20(m, 1H), 4.79-4.46(m, 2H), 4.41-4.26(m, 1H), 4.07-3.82(m, 4H ), 3.83-3.60(m, 2H), 3.57-3.42(m, 2H), 3.40-3.34(m, 1H), 3.16-2.96(m, 2H), 2.86-2.74(m, 2H), 1.80-1.53 (m, 3H).
实施例16Example 16
(±)-rel-5-((7R,10aR)-7-甲基-2-(哌嗪-1-基)-7,8,10a,11-四氢-5H-吡嗪并[2,1-c]吡啶并[3,2-f][1,4]氧杂氮杂庚环-9(10H)-基)喹啉-8-甲腈2,2,2-三氟乙酸盐16(±)-rel-5-((7R,10aR)-7-methyl-2-(piperazin-1-yl)-7,8,10a,11-tetrahydro-5H-pyrazino[2, 1-c]pyrido[3,2-f][1,4]oxazepin-9(10H)-yl)quinoline-8-carbonitrile 2,2,2-trifluoroacetate 16
Figure PCTCN2021110197-appb-000179
Figure PCTCN2021110197-appb-000179
第一步first step
(±)-rel-5-((3R,5R)-3-((叔丁基二甲基硅基)氧基)甲基)-4-((2,6-二氯吡啶-3-基)甲基)-5-甲基哌嗪-1-基)喹啉-8-甲腈16b(±)-rel-5-((3R,5R)-3-((tert-butyldimethylsilyl)oxy)methyl)-4-((2,6-dichloropyridin-3-yl) )methyl)-5-methylpiperazin-1-yl)quinoline-8-carbonitrile 16b
将化合物1g(100mg，0.25mmol)与化合物3-(溴甲基)-2,6-二氯吡啶16a(75mg，0.32mmol，采用专利申请“WO2020097537A2,说明书第268页”制备而得)溶于乙腈(5mL)，加入碳酸钾(105mg，0.76mmol，韶远)和碘化钠(46mg，0.31mmol)，反应在80℃搅拌3小时，将反应液冷却，过滤除去固体，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化，得到标题产物16b(100mg，产率： 71.25％)。Compound 1 g (100 mg, 0.25 mmol) and compound 3-(bromomethyl)-2,6-dichloropyridine 16a (75 mg, 0.32 mmol, prepared using the patent application "WO2020097537A2, page 268 of the specification") were dissolved in Acetonitrile (5mL), potassium carbonate (105mg, 0.76mmol, Shaoyuan) and sodium iodide (46mg, 0.31mmol) were added, the reaction was stirred at 80 ° C for 3 hours, the reaction solution was cooled, filtered to remove solids, and the filtrate was concentrated under reduced pressure, The residue was purified by silica gel column chromatography with eluent system A to give the title product 16b (100 mg, yield: 71.25%).
MS m/z(ESI)：555.9[M+1]。MS m/z (ESI): 555.9 [M+1].
第二步second step
(±)-rel-5-((3R,5R)-4-((2,6-二氯吡啶-3-基)甲基)-3-(羟甲基)-5-甲基哌嗪-1-基)喹啉-8-甲腈16c(±)-rel-5-((3R,5R)-4-((2,6-dichloropyridin-3-yl)methyl)-3-(hydroxymethyl)-5-methylpiperazine- 1-yl)quinoline-8-carbonitrile 16c
将化合物16b(103mg，0.19mmol)溶于3mL二氯甲烷中，加入4M盐酸1,4-二氧六环溶液(3mL，安耐吉)，有黄色固体生成，混合物在室温继续搅拌反应约1小时。反应液减压浓缩，加入10mL饱和碳酸氢钠溶液，搅拌30分钟，用乙酸乙酯(10mL×3)萃取，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用甲醇打浆后得到标题产物16c(43mg产率：52.5％)。Compound 16b (103 mg, 0.19 mmol) was dissolved in 3 mL of dichloromethane, 4M hydrochloric acid 1,4-dioxane solution (3 mL, Annagy) was added, a yellow solid was formed, and the mixture was stirred at room temperature for about 1 Hour. The reaction solution was concentrated under reduced pressure, 10 mL of saturated sodium bicarbonate solution was added, stirred for 30 minutes, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with water (10 mL) and saturated sodium chloride solution (10 mL) in turn. Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is slurried with methanol to give the title product 16c (43 mg, yield: 52.5%).
MS m/z(ESI)：442.1[M+1]。MS m/z (ESI): 442.1 [M+1].
第三步third step
(±)-rel-5-((7R,10aR)-2-氯-7-甲基-7,8,10a,11-四氢-5H-吡嗪并[2,1-c]吡啶并[3,2-f][1,4]氧杂氮杂庚环-9(10H)-基)喹啉-8-甲腈16d(±)-rel-5-((7R,10aR)-2-chloro-7-methyl-7,8,10a,11-tetrahydro-5H-pyrazino[2,1-c]pyrido[ 3,2-f][1,4]oxazepin-9(10H)-yl)quinoline-8-carbonitrile 16d
将化合物16c(43mg，0.097mmol)溶于5mL N,N-二甲基甲酰胺中，加入氢化钠(12mg，0.31mmol)，混合物在60℃搅拌反应约16小时，加入10mL饱和碳酸氢钠溶液，搅拌30分钟，用乙酸乙酯(10mL×3)萃取，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化，得到标题产物16d(22mg，产率：55.8％)。Compound 16c (43 mg, 0.097 mmol) was dissolved in 5 mL of N,N-dimethylformamide, sodium hydride (12 mg, 0.31 mmol) was added, the mixture was stirred at 60 ° C for reaction for about 16 hours, and 10 mL of saturated sodium bicarbonate solution was added was stirred for 30 minutes, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with water (10 mL) and saturated sodium chloride solution (10 mL) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The material was purified by silica gel column chromatography with eluent system A to give the title product 16d (22 mg, yield: 55.8%).
MS m/z(ESI)：405.9[M+1]。MS m/z (ESI): 405.9 [M+1].
第四步the fourth step
(±)-rel-4-((7R,10aR)-9-(8-氰基喹啉-5-基)-7-甲基-7,8,9,10,10a,11-六氢-5H-吡嗪并[2,1-c]吡啶并[3,2-f][1,4]氧杂氮杂庚环-2-基)哌嗪-1-羧酸叔丁酯16e(±)-rel-4-((7R,10aR)-9-(8-cyanoquinolin-5-yl)-7-methyl-7,8,9,10,10a,11-hexahydro- 5H-pyrazino[2,1-c]pyrido[3,2-f][1,4]oxazepin-2-yl)piperazine-1-carboxylate tert-butyl ester 16e
将化合物16d(22mg，0.054mmol)和化合物哌嗪-1-羧酸叔丁酯(14mg，0.075mmol，韶远)溶于4mL 1,4-二氧六环中，然后加入甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(5mg，0.006mmol，韶远)和叔丁醇钠(16mg，0.17mmol)，置换氩气三次，混合物在80℃搅拌反应约2小时。冷却至室温后，向反应液中加入10mL水，用乙酸乙酯萃取(10mL×3)，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题产物16e(30mg，产率：99.6％)。Compound 16d (22 mg, 0.054 mmol) and compound piperazine-1-carboxylate tert-butyl ester (14 mg, 0.075 mmol, Shaoyuan) were dissolved in 4 mL of 1,4-dioxane, and then methanesulfonic acid (2 -Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II)( 5 mg, 0.006 mmol, Shaoyuan) and sodium tert-butoxide (16 mg, 0.17 mmol), replaced argon three times, and the mixture was stirred at 80° C. for reaction for about 2 hours. After cooling to room temperature, 10 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, Filtration, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system B afforded the title product 16e (30 mg, yield: 99.6%).
MS m/z(ESI)：556.2[M+1]。MS m/z (ESI): 556.2 [M+1].
第五步the fifth step
(±)-rel-5-((7R,10aR)-7-甲基-2-(哌嗪-1-基)-7,8,10a,11-四氢-5H-吡嗪并[2,1-c]吡啶并[3,2-f][1,4]氧杂氮杂庚环-9(10H)-基)喹啉-8-甲腈2,2,2-三氟乙酸盐16(±)-rel-5-((7R,10aR)-7-methyl-2-(piperazin-1-yl)-7,8,10a,11-tetrahydro-5H-pyrazino[2, 1-c]pyrido[3,2-f][1,4]oxazepin-9(10H)-yl)quinoline-8-carbonitrile 2,2,2-trifluoroacetate 16
将化合物16e(30mg，0.054mmol)溶于1mL二氯甲烷中，加入1mL三氟乙酸，混合物在室温搅拌反应约2小时。反应液减压浓缩，加入10mL饱和碳酸氢钠溶液，搅拌30分钟，用乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用高效液相色谱法(色谱柱：SharpSil T-C18，5μm，30mm*150mm；流动相1：水相(含0.1％三氟乙酸)；流动相2：乙腈；25分钟梯度：25％-95％，流速：30mL/min)纯化，得到标题产物16(22mg，产率：71.54％)。Compound 16e (30 mg, 0.054 mmol) was dissolved in 1 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, and the mixture was stirred and reacted at room temperature for about 2 hours. The reaction solution was concentrated under reduced pressure, 10 mL of saturated sodium bicarbonate solution was added, stirred for 30 minutes, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was treated with high-efficiency Liquid chromatography (column: SharpSil T-C18, 5μm, 30mm*150mm; mobile phase 1: aqueous phase (containing 0.1% trifluoroacetic acid); mobile phase 2: acetonitrile; 25-minute gradient: 25%-95%, Flow rate: 30 mL/min) was purified to give the title product 16 (22 mg, yield: 71.54%).
MS m/z(ESI)：456.2[M+1]。MS m/z (ESI): 456.2 [M+1].
1H NMR(500MHz,DMSO-d 6)δ9.07-9.06(m,1H),8.60-8.58(m,1H),8.26-8.25(m,1H),7.72-7.70(m,1H),7.51-7.49(m,1H),7.24-7.22(m,1H),6.45-6.44(m,1H),4.34-4.31(m,1H),3.99-3.96(m,1H),3.72-3.69(m,1H),3.41-3.37(m,6H),3.05-3.02(m,1H),2.86-2.76(m,6H),2.69-2.65(m,2H),1.20-1.18(m,3H)。 1 H NMR (500MHz, DMSO-d 6 )δ9.07-9.06(m,1H), 8.60-8.58(m,1H), 8.26-8.25(m,1H), 7.72-7.70(m,1H), 7.51 -7.49(m,1H),7.24-7.22(m,1H),6.45-6.44(m,1H),4.34-4.31(m,1H),3.99-3.96(m,1H),3.72-3.69(m, 1H), 3.41-3.37(m, 6H), 3.05-3.02(m, 1H), 2.86-2.76(m, 6H), 2.69-2.65(m, 2H), 1.20-1.18(m, 3H).
实施例16-a,16-bExample 16-a, 16-b
5-((7R,10aR)-7-甲基-2-(哌嗪-1-基)-7,8,10a,11-四氢-5H-吡嗪并[2,1-c]吡啶并[3,2-f][1,4]氧杂氮杂庚环-9(10H)-基)喹啉-8-甲腈16-a5-((7R,10aR)-7-methyl-2-(piperazin-1-yl)-7,8,10a,11-tetrahydro-5H-pyrazino[2,1-c]pyrido [3,2-f][1,4]oxazepin-9(10H)-yl)quinoline-8-carbonitrile 16-a
5-((7S,10aS)-7-甲基-2-(哌嗪-1-基)-7,8,10a,11-四氢-5H-吡嗪并[2,1-c]吡啶并[3,2-f][1,4]氧杂氮杂庚环-9(10H)-基)喹啉-8-甲腈16-b5-((7S,10aS)-7-methyl-2-(piperazin-1-yl)-7,8,10a,11-tetrahydro-5H-pyrazino[2,1-c]pyrido [3,2-f][1,4]oxazepin-9(10H)-yl)quinoline-8-carbonitrile 16-b
Figure PCTCN2021110197-appb-000180
Figure PCTCN2021110197-appb-000180
将化合物16(400mg，0.7mmol)进行手性制备(分离条件：手性制备柱Cellulose-3，5μm，21.2mm*250mm(Phenomenex)；流动相1：正己烷；流动相2：含0.1％二乙胺乙醇(80％)，流速：20mL/min)，收集其相应组分，减压浓缩，得到标题化合物(90mg,90mg)。Compound 16 (400 mg, 0.7 mmol) was subjected to chiral preparation (separation conditions: chiral preparative column Cellulose-3, 5 μm, 21.2 mm*250 mm (Phenomenex); mobile phase 1: n-hexane; mobile phase 2: containing 0.1% dimethoxide Ethylamine ethanol (80%), flow rate: 20 mL/min), the corresponding fractions were collected and concentrated under reduced pressure to give the title compound (90 mg, 90 mg).
单一构型化合物(较短保留时间)：Single configuration compound (shorter retention time):
MS m/z(ESI)：456.1[M+1]。MS m/z (ESI): 456.1 [M+1].
手性HPLC分析：保留时间9.00分钟，手性纯度：100％(色谱柱：Phenomenex Lux Cellulose-3，150*4.6mm，5μm；流动相1：正己烷；流动相2：含0.1％二乙胺乙醇(80％)。Chiral HPLC analysis: retention time 9.00 minutes, chiral purity: 100% (chromatographic column: Phenomenex Lux Cellulose-3, 150*4.6mm, 5μm; mobile phase 1: n-hexane; mobile phase 2: containing 0.1% diethylamine Ethanol (80%).
1H NMR(500MHz,CD 3OD)δ9.03-8.97(m,1H),8.75-8.51(m,1H),8.21-8.09(m,1H),7.72-7.62(m,1H),7.60-7.50(m,1H),7.30-7.19(m,1H),6.58-6.46(m,1H), 4.44-4.34(m,1H),4.17-4.02(m,1H),3.88-3.74(m,1H),3.64-3.47(m,6H),3.47-3.34(m,2H),3.24-3.16(m,1H),3.09-2.93(m,4H),2.90-2.67(m,2H),1.37-1.21(m,3H)。 1 H NMR (500MHz, CD 3 OD) δ 9.03-8.97 (m, 1H), 8.75-8.51 (m, 1H), 8.21-8.09 (m, 1H), 7.72-7.62 (m, 1H), 7.60- 7.50(m,1H), 7.30-7.19(m,1H), 6.58-6.46(m,1H), 4.44-4.34(m,1H), 4.17-4.02(m,1H), 3.88-3.74(m,1H) ),3.64-3.47(m,6H),3.47-3.34(m,2H),3.24-3.16(m,1H),3.09-2.93(m,4H),2.90-2.67(m,2H),1.37-1.21 (m, 3H).
单一构型化合物(较长保留时间)：Single configuration compound (longer retention time):
MS m/z(ESI)：456.1[M+1]。MS m/z (ESI): 456.1 [M+1].
手性HPLC分析：保留时间11.33分钟，手性纯度：96.6％(色谱柱：Phenomenex Lux Cellulose-3，150*4.6mm，5μm；流动相1：正己烷；流动相2：含0.1％二乙胺乙醇(80％)。Chiral HPLC analysis: retention time 11.33 minutes, chiral purity: 96.6% (chromatographic column: Phenomenex Lux Cellulose-3, 150*4.6mm, 5μm; mobile phase 1: n-hexane; mobile phase 2: containing 0.1% diethylamine Ethanol (80%).
1H NMR(500MHz,CD 3OD)δ9.03-8.97(m,1H),8.75-8.51(m,1H),8.21-8.09(m,1H),7.72-7.62(m,1H),7.60-7.50(m,1H),7.30-7.19(m,1H),6.58-6.46(m,1H),4.44-4.34(m,1H),4.17-4.02(m,1H),3.88-3.74(m,1H),3.64-3.47(m,6H),3.47-3.34(m,2H),3.24-3.16(m,1H),3.09-2.93(m,4H),2.90-2.67(m,2H),1.37-1.21(m,3H)。 1 H NMR (500MHz, CD 3 OD) δ 9.03-8.97 (m, 1H), 8.75-8.51 (m, 1H), 8.21-8.09 (m, 1H), 7.72-7.62 (m, 1H), 7.60- 7.50(m, 1H), 7.30-7.19(m, 1H), 6.58-6.46(m, 1H), 4.44-4.34(m, 1H), 4.17-4.02(m, 1H), 3.88-3.74(m, 1H) ),3.64-3.47(m,6H),3.47-3.34(m,2H),3.24-3.16(m,1H),3.09-2.93(m,4H),2.90-2.67(m,2H),1.37-1.21 (m, 3H).
实施例17Example 17
(±)-rel-5-((4R,12aR)-9-(4-氨基甲基)-4-甲基哌啶-1-基)-4-甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈2,2,2-三氟乙酸盐17(±)-rel-5-((4R,12aR)-9-(4-aminomethyl)-4-methylpiperidin-1-yl)-4-methyl-3,4,12,12a- Tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 2,2, 2-Trifluoroacetate 17
Figure PCTCN2021110197-appb-000181
Figure PCTCN2021110197-appb-000181
第一步first step
(±)-rel-((1-((4R,12aR)-2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4,12,12a-六氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-9-基)-4-甲基哌啶-4-基)甲基)氨基甲酸叔丁酯17a(±)-rel-((1-((4R,12aR)-2-(8-cyanoquinolin-5-yl)-4-methyl-1,2,3,4,12,12a-hexa Hydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-9-yl)-4-methylpiperidin-4-yl)methyl) tert-Butyl carbamate 17a
将化合物1j(40mg，0.089mmol)和((4-甲基哌啶-4-基)甲基)氨基甲酸叔丁酯 (26mg，0.114mmol，药石)溶于4mL1,4-二氧六环中，加入甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(8mg，0.010mmol，乐研)和叔丁醇钠(26mg，0.27mmol)，置换氩气三次，混合物在90℃搅拌反应约2小时。冷却至室温后，向反应液中加入10mL水，用乙酸乙酯萃取(10mL×3)，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题产物17a(23mg，产率：43.3％)。Compound 1j (40 mg, 0.089 mmol) and tert-butyl ((4-methylpiperidin-4-yl)methyl)carbamate (26 mg, 0.114 mmol, Yaoshi) were dissolved in 4 mL of 1,4-dioxane , adding methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2- base) palladium(II) (8 mg, 0.010 mmol, Leyan) and sodium tert-butoxide (26 mg, 0.27 mmol), replaced argon three times, and the mixture was stirred at 90° C. for about 2 hours. After cooling to room temperature, 10 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title product 17a (23 mg, yield: 43.3%).
MS m/z(ESI)：597.0[M+1]。MS m/z (ESI): 597.0 [M+1].
第二步second step
(±)-rel-5-((4R,12aR)-9-(4-氨基甲基)-4-甲基哌啶-1-基)-4-甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈2,2,2-三氟乙酸盐17(±)-rel-5-((4R,12aR)-9-(4-aminomethyl)-4-methylpiperidin-1-yl)-4-methyl-3,4,12,12a- Tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 2,2, 2-Trifluoroacetate 17
将化合物17a(23mg，0.038mmol)溶于2mL二氯甲烷中，加入2mL三氟乙酸，混合物在室温搅拌反应约6小时。反应液减压浓缩，用乙酸乙酯(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用高效液相色谱法(色谱柱：SharpSil T-C18，5μm，30mm*150mm；流动相1：水相(含0.1％三氟乙酸)；流动相2：乙腈；25分钟梯度：25％-95％，流速：30mL/min)纯化，得到标题产物17(12mg，产率：50.99％)。Compound 17a (23 mg, 0.038 mmol) was dissolved in 2 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred and reacted at room temperature for about 6 hours. The reaction solution was concentrated under reduced pressure, extracted with ethyl acetate (5 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (chromatographic column: SharpSil T-C18 , 5μm, 30mm*150mm; mobile phase 1: aqueous phase (containing 0.1% trifluoroacetic acid); mobile phase 2: acetonitrile; 25-minute gradient: 25%-95%, flow rate: 30 mL/min) purification to obtain the title product 17 (12 mg, yield: 50.99%).
MS m/z(ESI)：497.0[M+1]。MS m/z (ESI): 497.0 [M+1].
1H NMR(500MHz,CD 3OD)δ9.07-9.06(m,1H),8.76-8.74(m,1H),8.23-8.22(m，1H),7.76-7.73(m,1H),7.42-7.40(m,1H),7.38-7.36(m,1H),6.85-6.82(m,1H),6.80-6.79(m,1H),4.78-4.75(m,1H),4.65-4.62(m,1H),4.52-4.49(m,1H),4.38-4.34(m,1H),4.03-3.70(m,4H),3.54-3.47(m,3H),3.20-3.16(m,5H),2.91-2.90(m,2H),1.71-1.60(m,5H),1.16(s,3H)。 1 H NMR (500MHz, CD 3 OD) δ 9.07-9.06 (m, 1H), 8.76-8.74 (m, 1H), 8.23-8.22 (m, 1H), 7.76-7.73 (m, 1H), 7.42- 7.40(m,1H),7.38-7.36(m,1H),6.85-6.82(m,1H),6.80-6.79(m,1H),4.78-4.75(m,1H),4.65-4.62(m,1H) ), 4.52-4.49(m, 1H), 4.38-4.34(m, 1H), 4.03-3.70(m, 4H), 3.54-3.47(m, 3H), 3.20-3.16(m, 5H), 2.91-2.90 (m, 2H), 1.71-1.60 (m, 5H), 1.16 (s, 3H).
实施例18Example 18
5-((4R,12aR)-9-(4-氨基-4-甲基哌啶-1-基)-4-甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈185-((4R,12aR)-9-(4-amino-4-methylpiperidin-1-yl)-4-methyl-3,4,12,12a-tetrahydro-6H-benzo[f ]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 18
Figure PCTCN2021110197-appb-000182
Figure PCTCN2021110197-appb-000182
化合物18的制备方法同化合物2。The preparation method of compound 18 is the same as that of compound 2.
将制备化合物2中第八步的原料3,6-二氮杂双环[3.1.1]庚烷-6-羧酸叔丁酯替换为(4-甲基哌啶-4-基)氨基甲酸叔丁酯(毕得)得到标题产物18(20mg)。The raw material 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester in the eighth step in the preparation of compound 2 was replaced by (4-methylpiperidin-4-yl)carbamic acid tertiary Butyl ester (Bid) gave the title product 18 (20 mg).
MS m/z(ESI)：483.2[M+1]。MS m/z (ESI): 483.2 [M+1].
1H NMR(500MHz,CD 3OD)δ9.02-8.96(m,1H),8.70-8.63(m,1H),8.17-8.09(m,1H),7.70-7.62(m,1H),7.27-7.20(m,1H),7.18-7.10(m,1H),6.72-6.58(m,2H),4.36-4.24(m,1H),4.13-4.03(m,1H),3.70-3.40(m,3H),3.40-3.33(m,2H),3.22-3.04(m,4H),3.00-2.90(m,1H),2.81-2.64(m,2H),1.80-1.60(m,4H),1.38-1.27(m,3H),1.25-1.15(m,3H)。 1 H NMR (500MHz, CD 3 OD) δ 9.02-8.96 (m, 1H), 8.70-8.63 (m, 1H), 8.17-8.09 (m, 1H), 7.70-7.62 (m, 1H), 7.27- 7.20(m, 1H), 7.18-7.10(m, 1H), 6.72-6.58(m, 2H), 4.36-4.24(m, 1H), 4.13-4.03(m, 1H), 3.70-3.40(m, 3H ),3.40-3.33(m,2H),3.22-3.04(m,4H),3.00-2.90(m,1H),2.81-2.64(m,2H),1.80-1.60(m,4H),1.38-1.27 (m, 3H), 1.25-1.15 (m, 3H).
实施例19Example 19
(±)-rel-5-((4R,12aR)-9-(4-氨基-4-甲基哌啶-1-基)-4-甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈2,2,2-三氟乙酸盐19(±)-rel-5-((4R,12aR)-9-(4-amino-4-methylpiperidin-1-yl)-4-methyl-3,4,12,12a-tetrahydro- 6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 2,2,2-tri Fluoroacetate 19
Figure PCTCN2021110197-appb-000183
Figure PCTCN2021110197-appb-000183
第一步first step
(±)-rel-(1-((4R,12aR)-2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4,12,12a-六氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-9-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯19a(±)-rel-(1-((4R,12aR)-2-(8-cyanoquinolin-5-yl)-4-methyl-1,2,3,4,12,12a-hexahydro -6H-Benzo[f]pyrazino[2,1-c][1,4]oxazepin-9-yl)-4-methylpiperidin-4-yl)carbamic acid tert-butyl Ester 19a
将化合物1j(40mg，0.089mmol)和(4-甲基哌啶-4-基)氨基甲酸叔丁酯(25mg，0.117mmol，药石)溶于4mL1,4-二氧六环中，加入甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(8mg，0.010mmol，乐研)和叔丁醇钠(26mg，0.27mmol)，置换氩气三次，混合物在90℃搅拌反应约2小时。冷 却至室温后，向反应液中加入10mL水，用乙酸乙酯萃取(10mL×3)，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物19a(51mg，产率：98.3％)，产品不经纯化直接用于下一步反应。Compound 1j (40 mg, 0.089 mmol) and tert-butyl (4-methylpiperidin-4-yl)carbamate (25 mg, 0.117 mmol, Yaoshi) were dissolved in 4 mL of 1,4-dioxane, and methanesulfonic acid was added. Acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium ( II) (8 mg, 0.010 mmol, Rakuen) and sodium tert-butoxide (26 mg, 0.27 mmol), replaced argon three times, and the mixture was stirred at 90° C. for reaction for about 2 hours. After cooling to room temperature, 10 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, Filtration and concentration of the filtrate under reduced pressure gave the crude title product 19a (51 mg, yield: 98.3%), which was used in the next reaction without purification.
MS m/z(ESI)：583.2[M+1]。MS m/z (ESI): 583.2 [M+1].
第二步second step
(±)-rel-5-((4R,12aR)-9-(4-氨基-4-甲基哌啶-1-基)-4-甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈2,2,2-三氟乙酸盐19(±)-rel-5-((4R,12aR)-9-(4-amino-4-methylpiperidin-1-yl)-4-methyl-3,4,12,12a-tetrahydro- 6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 2,2,2-tri Fluoroacetate 19
将化合物19a(51mg，0.088mmol)溶于2mL二氯甲烷中，加入2mL三氟乙酸，混合物在室温搅拌反应约6小时。反应液减压浓缩，用乙酸乙酯(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用高效液相色谱法(色谱柱：SharpSil T-C18，5μm，30mm*150mm；流动相1：水相(含0.1％三氟乙酸)；流动相2：乙腈；25分钟梯度：25％-95％，流速：30mL/min)纯化，得到标题产物19(12mg，产率：28.4％)。Compound 19a (51 mg, 0.088 mmol) was dissolved in 2 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred and reacted at room temperature for about 6 hours. The reaction solution was concentrated under reduced pressure, extracted with ethyl acetate (5 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (chromatographic column: SharpSil T-C18 , 5μm, 30mm*150mm; mobile phase 1: aqueous phase (containing 0.1% trifluoroacetic acid); mobile phase 2: acetonitrile; 25-minute gradient: 25%-95%, flow rate: 30 mL/min) purification to obtain the title product 19 (12 mg, yield: 28.4%).
MS m/z(ESI)：483.0[M+1]。MS m/z (ESI): 483.0 [M+1].
1H NMR(500MHz,CD 3OD)δ9.06-9.05(m,1H),8.76-8.74(m,1H),8.23-8.21(m,1H),7.76-7.73(m,1H),7.43-7.42(m,1H),7.38-7.36(m,1H),6.87-6.84(m,1H),6.82-6.81(m,1H),4.76-4.75(m,1H),4.65-4.62(m,1H),4.51-4.48(m,1H),4.38-4.34(m,1H),4.03-3.77(m,4H),3.72-3.64(m,3H),3.21-3.14(m,2H),3.11-3.00(m,2H),1.96-1.89(m,4H),1.69-1.68(m,3H),1.48(s,3H)。 1 H NMR (500MHz, CD 3 OD) δ 9.06-9.05 (m, 1H), 8.76-8.74 (m, 1H), 8.23-8.21 (m, 1H), 7.76-7.73 (m, 1H), 7.43- 7.42(m,1H),7.38-7.36(m,1H),6.87-6.84(m,1H),6.82-6.81(m,1H),4.76-4.75(m,1H),4.65-4.62(m,1H) ), 4.51-4.48(m, 1H), 4.38-4.34(m, 1H), 4.03-3.77(m, 4H), 3.72-3.64(m, 3H), 3.21-3.14(m, 2H), 3.11-3.00 (m, 2H), 1.96-1.89 (m, 4H), 1.69-1.68 (m, 3H), 1.48 (s, 3H).
实施例20Example 20
(±)-rel-5-((4R,12aR)-9-(2,5-二氮杂双环[2.2.1]庚-2-基)-4-甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈20(±)-rel-5-((4R,12aR)-9-(2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-methyl-3,4,12,12a -Tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 20
Figure PCTCN2021110197-appb-000184
Figure PCTCN2021110197-appb-000184
Figure PCTCN2021110197-appb-000185
Figure PCTCN2021110197-appb-000185
第一步first step
(±)-rel-5-((4R,12aR)-2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4,12,12a-六氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-9-基)-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯20a(±)-rel-5-((4R,12aR)-2-(8-cyanoquinolin-5-yl)-4-methyl-1,2,3,4,12,12a-hexahydro- 6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-9-yl)-2,5-diazabicyclo[2.2.1]heptane- 2-Carboxylic acid tert-butyl ester 20a
将化合物1j(34mg，0.076mmol)和2,5-氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯(20mg，0.10mmol，乐妍)溶于4mL 1,4-二氧六环中，加入甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(8mg，0.010mmol,乐研)和叔丁醇钠(23mg，0.24mmol)，置换氩气三次，混合物在90℃搅拌反应约2小时。冷却至室温后，向反应液中加入10mL水，用乙酸乙酯萃取(10mL×3)，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化，得到标题产物20a(30mg，产率：69.9％)。Compound 1j (34 mg, 0.076 mmol) and tert-butyl 2,5-azabicyclo[2.2.1]heptane-2-carboxylate (20 mg, 0.10 mmol, Leyan) were dissolved in 4 mL of 1,4-dioxane In the six rings, add methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl) -2-yl)palladium(II) (8 mg, 0.010 mmol, Leyan) and sodium tert-butoxide (23 mg, 0.24 mmol), argon was replaced three times, and the mixture was stirred at 90° C. for reaction for about 2 hours. After cooling to room temperature, 10 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title product 20a (30 mg, yield: 69.9%).
MS m/z(ESI)：567.0[M+1]。MS m/z (ESI): 567.0 [M+1].
第二步second step
(±)-rel-5-((4R,12aR)-9-(2,5-二氮杂双环[2.2.1]庚-2-基)-4-甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈20(±)-rel-5-((4R,12aR)-9-(2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-methyl-3,4,12,12a -Tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 20
将化合物20a(30mg，0.053mmol)溶于2mL二氯甲烷中，加入2mL三氟乙酸，混合物在室温搅拌反应约1小时。反应液减压浓缩，加入5mL饱和碳酸氢钠溶液，搅拌30分钟，用乙酸乙酯(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用高效液相色谱法(色谱柱：SharpSil T-C18，5μm，30mm*150mm；流动相1：水相(含0.1％三氟乙酸)；流动相2：乙腈；25分钟梯度：25％-95％，流速：30mL/min)纯化，得到标题产物20(22mg，产率：71.6％)。Compound 20a (30 mg, 0.053 mmol) was dissolved in 2 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred and reacted at room temperature for about 1 hour. The reaction solution was concentrated under reduced pressure, 5 mL of saturated sodium bicarbonate solution was added, stirred for 30 minutes, extracted with ethyl acetate (5 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Liquid chromatography (column: SharpSil T-C18, 5μm, 30mm*150mm; mobile phase 1: aqueous phase (containing 0.1% trifluoroacetic acid); mobile phase 2: acetonitrile; 25-minute gradient: 25%-95%, Flow rate: 30 mL/min) was purified to give the title product 20 (22 mg, yield: 71.6%).
MS m/z(ESI)：467.2[M+1]。MS m/z (ESI): 467.2 [M+1].
1H NMR(500MHz,DMSO-d 6)δ9.17-9.10(m,1H),8.70-8.68(m,1H),8.33-8.32(m,1H),7.78-7.75(m,1H),7.46-7.45(m,1H),7.35-7.33(m,1H),6.50-6.48(m,2H),4.70-4.61(m,3H),4.50-4.30(m,4H),3.95-3.94(m,1H),3.80-3.70(m,3H),3.62-3.58(m,1H),3.30-3.24(m,2H),3.09-2.91(m,3H),3.09-3.04(m,1H),2.96-2.91(m,1H),1.58-1.57(m,3H)。 1 H NMR (500MHz, DMSO-d 6 )δ9.17-9.10(m,1H), 8.70-8.68(m,1H), 8.33-8.32(m,1H), 7.78-7.75(m,1H), 7.46 -7.45(m, 1H), 7.35-7.33(m, 1H), 6.50-6.48(m, 2H), 4.70-4.61(m, 3H), 4.50-4.30(m, 4H), 3.95-3.94(m, 1H), 3.80-3.70(m, 3H), 3.62-3.58(m, 1H), 3.30-3.24(m, 2H), 3.09-2.91(m, 3H), 3.09-3.04(m, 1H), 2.96- 2.91 (m, 1H), 1.58-1.57 (m, 3H).
实施例21Example 21
5-((4R,12aR)-4-甲基-9-(4-(2-(甲基氨基)乙基)哌嗪-1-基)-3,4,12,12a-四氢-1H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(6H)-基)喹啉-8-甲腈215-((4R,12aR)-4-methyl-9-(4-(2-(methylamino)ethyl)piperazin-1-yl)-3,4,12,12a-tetrahydro-1H -Benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(6H)-yl)quinoline-8-carbonitrile 21
Figure PCTCN2021110197-appb-000186
Figure PCTCN2021110197-appb-000186
第一步first step
(2-(4-((4R,12aR)-2-(8-氰基喹啉-5-基)-4-甲基-2,3,4,6,12,12a-六氢-1H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-9-基)哌嗪-1-基)乙基)(甲基)氨基羧酸叔丁酯21a(2-(4-((4R,12aR)-2-(8-cyanoquinolin-5-yl)-4-methyl-2,3,4,6,12,12a-hexahydro-1H- Benzo[f]pyrazino[2,1-c][1,4]oxazepan-9-yl)piperazin-1-yl)ethyl)(methyl)aminocarboxylate tert-butyl Ester 21a
将化合物1-1-a(50mg，0.11mmol)和甲基(2-氧代乙基)氨基甲酸叔丁酯(38mg，0.22mmol，乐研)溶于5mL二氯甲烷和5mL甲醇的混合溶剂中，加入乙酸钠(20mg，0.24mmol，乐研)，混合物在室温搅拌反应约16小时。向反应液中加入氰基硼氢化钠(20mg，0.33mmol，韶远)，在室温继续搅拌反应约2小时。反应液减压浓缩，加入10mL饱和氯化钠溶液，用乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化，得到标题产物21a(45mg，产率：66.9％)。Compound 1-1-a (50 mg, 0.11 mmol) and tert-butyl methyl(2-oxoethyl)carbamate (38 mg, 0.22 mmol, Leyan) were dissolved in a mixed solvent of 5 mL of dichloromethane and 5 mL of methanol To this, sodium acetate (20 mg, 0.24 mmol, Rakuen) was added, and the mixture was stirred at room temperature for about 16 hours. Sodium cyanoborohydride (20 mg, 0.33 mmol, Shaoyuan) was added to the reaction solution, and the reaction was continued to stir at room temperature for about 2 hours. The reaction solution was concentrated under reduced pressure, 10 mL of saturated sodium chloride solution was added, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography Purification with eluent system A afforded the title product 21a (45 mg, yield: 66.9%).
MS m/z(ESI)：612.1[M+1]。MS m/z (ESI): 612.1 [M+1].
第二步second step
5-((4R,12aR)-4-甲基-9-(4-(2-(甲基氨基)乙基)哌嗪-1-基)-3,4,12,12a-四氢-1H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(6H)-基)喹啉-8-甲腈215-((4R,12aR)-4-methyl-9-(4-(2-(methylamino)ethyl)piperazin-1-yl)-3,4,12,12a-tetrahydro-1H -Benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(6H)-yl)quinoline-8-carbonitrile 21
将化合物21a(45mg，0.074mmol)溶于5mL二氯甲烷中，加入5mL三氟乙酸，混合物在室温搅拌反应约1小时。反应液减压浓缩，加入10mL饱和碳酸氢钠溶液，搅拌30分钟，用乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干 燥，过滤，滤液减压浓缩，残余物用高效液相色谱法(色谱柱：SharpSil T-C18，5μm，30mm*150mm；流动相1：水相(含0.1％三氟乙酸)；流动相2：乙腈；25分钟梯度：25％-95％，流速：30mL/min)纯化，得到标题产物21(40mg，产率：86.9％)。Compound 21a (45 mg, 0.074 mmol) was dissolved in 5 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and the mixture was stirred and reacted at room temperature for about 1 hour. The reaction solution was concentrated under reduced pressure, 10 mL of saturated sodium bicarbonate solution was added, stirred for 30 minutes, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was treated with high-efficiency Liquid chromatography (column: SharpSil T-C18, 5μm, 30mm*150mm; mobile phase 1: aqueous phase (containing 0.1% trifluoroacetic acid); mobile phase 2: acetonitrile; 25-minute gradient: 25%-95%, Flow rate: 30 mL/min) was purified to give the title product 21 (40 mg, yield: 86.9%).
MS m/z(ESI)：512.2[M+1]。MS m/z (ESI): 512.2 [M+1].
1H NMR(500MHz,CD 3OD)δ9.05-8.99(m,1H),8.77-8.68(m,1H),8.24-8.13(m,1H),7.77-7.69(m,1H),7.47-7.29(m,2H),6.89-6.73(m,2H),4.80-4.24(m,4H),4.10-3.83(m,2H),3.84-3.62(m,2H),3.54-3.37(m,6H),3.15-2.88(m,7H),2.80-2.68(m,4H),1.74-1.60(m,3H)。 1 H NMR (500MHz, CD 3 OD) δ 9.05-8.99 (m, 1H), 8.77-8.68 (m, 1H), 8.24-8.13 (m, 1H), 7.77-7.69 (m, 1H), 7.47- 7.29(m,2H),6.89-6.73(m,2H),4.80-4.24(m,4H),4.10-3.83(m,2H),3.84-3.62(m,2H),3.54-3.37(m,6H ), 3.15-2.88(m, 7H), 2.80-2.68(m, 4H), 1.74-1.60(m, 3H).
实施例22Example 22
(±)-rel-5-((4R,12aR)-4,7-二甲基-9-(哌嗪-1-基)-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈22(±)-rel-5-((4R,12aR)-4,7-dimethyl-9-(piperazin-1-yl)-3,4,12,12a-tetrahydro-6H-benzo[ f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 22
Figure PCTCN2021110197-appb-000187
Figure PCTCN2021110197-appb-000187
第一步first step
4-溴-2-(甲氧基甲氧基)-6-甲基苯甲醛22b4-Bromo-2-(methoxymethoxy)-6-methylbenzaldehyde 22b
将化合物4-溴-2-羟基-6-甲基苯甲醛22a(500mg，2.33mmol，采用公知方法“Organic Letters,2017,vol.19,no.23,p.6280-6283”制备而得)溶于乙腈(20mL)，加入无水碳酸钾(1.0g，3.11mmol，国药)和溴甲基甲醚(350mg，2.80mmol)，反应在室温搅拌3小时，将反应液过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化，得到标题产物22b(230mg，产率：38.18％)。The compound 4-bromo-2-hydroxy-6-methylbenzaldehyde 22a (500 mg, 2.33 mmol, prepared by a known method "Organic Letters, 2017, vol.19, no.23, p.6280-6283") It was dissolved in acetonitrile (20 mL), anhydrous potassium carbonate (1.0 g, 3.11 mmol, Chinese medicine) and bromomethyl methyl ether (350 mg, 2.80 mmol) were added, the reaction was stirred at room temperature for 3 hours, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure , the residue was purified by silica gel column chromatography with eluent system A to give the title product 22b (230 mg, yield: 38.18%).
第二步second step
(4-溴-2-(甲氧基甲氧基)-6-甲基苯基)甲醇22c(4-Bromo-2-(methoxymethoxy)-6-methylphenyl)methanol 22c
将化合物22b(230mg，0.89mmol)溶于10mL甲醇中，冰水冷却，加入硼氢化钠(68mg，1.8mmol)，加毕，室温反应过夜，反应结束，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题产物22c(220mg，产率：94.9％)。Compound 22b (230 mg, 0.89 mmol) was dissolved in 10 mL of methanol, cooled with ice water, sodium borohydride (68 mg, 1.8 mmol) was added, the addition was completed, the reaction was performed at room temperature overnight, the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was washed with silica gel Purification by column chromatography with eluent system A afforded the title product 22c (220 mg, yield: 94.9%).
第三步third step
4-溴-2-(甲氧基甲氧基)-6-甲基苄基甲烷磺酸酯22d4-Bromo-2-(methoxymethoxy)-6-methylbenzylmethanesulfonate 22d
将化合物22c(220mg，0.8mmol)溶于10mL二氯甲烷中，冰水冷却，加入N,N-二异丙基乙胺(330mg，2.55mmol)，滴加甲烷磺酰氯(145mg，1.26mmol)，加毕，室温反应2小时，加入10mL水，二氯甲烷萃取(20mL×3)，饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化，得到标题产物22d(250mg，产率：87.47％)。Compound 22c (220 mg, 0.8 mmol) was dissolved in 10 mL of dichloromethane, cooled with ice water, N,N-diisopropylethylamine (330 mg, 2.55 mmol) was added, and methanesulfonyl chloride (145 mg, 1.26 mmol) was added dropwise , the addition was completed, the reaction was carried out at room temperature for 2 hours, 10 mL of water was added, extracted with dichloromethane (20 mL×3), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was washed with silica gel Purification by column chromatography with eluent system A afforded the title product 22d (250 mg, yield: 87.47%).
第四步the fourth step
(±)-rel-5-((3R,5R)-4-(4-溴-2-(甲氧基甲氧基)-6-甲基苄基)-3-(((叔丁基二甲基硅基)氧基)甲基)-5-甲基哌嗪-1-基)喹啉-8-甲腈22e(±)-rel-5-((3R,5R)-4-(4-bromo-2-(methoxymethoxy)-6-methylbenzyl)-3-(((tert-butyldi Methylsilyl)oxy)methyl)-5-methylpiperazin-1-yl)quinoline-8-carbonitrile 22e
将化合物1g(260mg，0.66mmol)和化合物22d(250mg，20.74mmol)溶于10mL乙腈中，依次加入碳酸钾(306mg，2.21mmol)和碘化钾(20mg，0.12mmol)，混合物在80℃搅拌反应约3小时。冷却至室温后，向反应液中加入10mL水，用乙酸乙酯(10mL×3)萃取，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化，得到标题产物22e(212mg，产率：44.97％)。Compound 1g (260 mg, 0.66 mmol) and compound 22d (250 mg, 20.74 mmol) were dissolved in 10 mL of acetonitrile, potassium carbonate (306 mg, 2.21 mmol) and potassium iodide (20 mg, 0.12 mmol) were added successively, and the mixture was stirred at 80 °C for reaction about 3 hours. After cooling to room temperature, 10 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with water (10 mL) and saturated sodium chloride solution (10 mL) in turn, dried over anhydrous sodium sulfate, Filtration, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system A afforded the title product 22e (212 mg, yield: 44.97%).
MS m/z(ESI)：639.1[M+1]。MS m/z (ESI): 639.1 [M+1].
第五步the fifth step
(±)-rel-5-((3R,5R)-4-(4-溴-2-羟基-6-甲基苄基)-3-(羟甲基)-5-甲基哌嗪-1-基)喹啉-8-甲腈22f(±)-rel-5-((3R,5R)-4-(4-bromo-2-hydroxy-6-methylbenzyl)-3-(hydroxymethyl)-5-methylpiperazine-1 -yl)quinoline-8-carbonitrile 22f
将化合物22e(200mg，0.31mmol)溶于5mL二氯甲烷中，加入4M盐酸1,4-二氧六环溶液(4mL，安耐吉)，有黄色固体生成，混合物在室温继续搅拌反应约1小时。反应液减压浓缩，加入10mL饱和碳酸氢钠溶液，搅拌30分钟，用乙酸乙酯(10mL×3)萃取，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤， 无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物22f(200mg)，产品不经纯化直接进行下一步反应。Compound 22e (200 mg, 0.31 mmol) was dissolved in 5 mL of dichloromethane, 4M hydrochloric acid 1,4-dioxane solution (4 mL, Annagi) was added, a yellow solid was formed, and the mixture was stirred at room temperature for about 1 Hour. The reaction solution was concentrated under reduced pressure, 10 mL of saturated sodium bicarbonate solution was added, stirred for 30 minutes, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with water (10 mL) and saturated sodium chloride solution (10 mL) in turn, no Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude title product 22f (200 mg), which is directly subjected to the next reaction without purification.
MS m/z(ESI)：481.0[M+1]。MS m/z (ESI): 481.0 [M+1].
第六步Step 6
(±)-rel-5-((4R,12aR)-9-溴-4,7-二甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈22g(±)-rel-5-((4R,12aR)-9-bromo-4,7-dimethyl-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2 ,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 22g
将粗品化合物22f(200mg，0.42mmol)溶于10mL甲苯中，加入偶氮二甲酰二哌啶(525mg，2.08mmol)和三丁基膦(420mg，2.08mmol)，置换氩气三次，混合物在60℃搅拌反应约1小时。冷却至室温后，反应液减压浓缩，粗产品用乙酸乙酯(10mL)打浆，所得固体过滤，滤饼用正己烷洗涤，固体干燥，得到标题产物22g(102mg产率：52.98％)。The crude compound 22f (200 mg, 0.42 mmol) was dissolved in 10 mL of toluene, azodicarbonyl dipiperidine (525 mg, 2.08 mmol) and tributylphosphine (420 mg, 2.08 mmol) were added, and the argon was replaced three times. The reaction was stirred at 60°C for about 1 hour. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, the crude product was slurried with ethyl acetate (10 mL), the obtained solid was filtered, the filter cake was washed with n-hexane, and the solid was dried to obtain 22 g of the title product (102 mg yield: 52.98%).
MS m/z(ESI):463.1[M+1]。MS m/z(ESI): 463.1[M+1].
第七步Step 7
(±)-rel-4-((4R,12aR)-2-(8-氰基喹啉-5-基)-4,7-二甲基-1,2,3,4,12,12a-六氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-9-基)哌嗪-1-羧酸叔丁酯22h(±)-rel-4-((4R,12aR)-2-(8-cyanoquinolin-5-yl)-4,7-dimethyl-1,2,3,4,12,12a- Hexahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-9-yl)piperazine-1-carboxylate tert-butyl ester 22h
将化合物22g(100mg，0.22mmol)和化合物哌嗪-1-羧酸叔丁酯(82mg，0.44mmol，韶远)溶于10mL1,4-二氧六环中，然后加入甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(19mg，0.022mmol，乐研)、叔丁醇钠(65mg，0.68mmol)，置换氩气三次，混合物在100℃搅拌反应约1小时。冷却至室温后，向反应液中加入10mL水，用乙酸乙酯萃取(10mL×3)，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用高效液相色谱法(色谱柱：SharpSil T-C18，5μm，30mm*150mm；流动相1：水相(含0.1％三氟乙酸)；流动相2：乙腈；25分钟梯度：25％-95％，流速：30mL/min)纯化，得到标题产物22h(51mg，产率：41.55％)。Compound 22g (100mg, 0.22mmol) and compound piperazine-1-carboxylate tert-butyl ester (82mg, 0.44mmol, Shaoyuan) were dissolved in 10mL of 1,4-dioxane, and then methanesulfonic acid (2- Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (19 mg , 0.022 mmol, Leyan), sodium tert-butoxide (65 mg, 0.68 mmol), replaced argon three times, and the mixture was stirred at 100° C. for reaction for about 1 hour. After cooling to room temperature, 10 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, Filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (chromatographic column: SharpSil T-C18, 5μm, 30mm*150mm; mobile phase 1: water phase (containing 0.1% trifluoroacetic acid); mobile phase 2: acetonitrile ; 25 min gradient: 25%-95%, flow rate: 30 mL/min) purification gave the title product 22h (51 mg, yield: 41.55%).
MS m/z(ESI)：569.0[M+1]。MS m/z (ESI): 569.0 [M+1].
第八步Step 8
(±)-rel-5-((4R,12aR)-4,7-二甲基-9-(哌嗪-1-基)-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈22(±)-rel-5-((4R,12aR)-4,7-dimethyl-9-(piperazin-1-yl)-3,4,12,12a-tetrahydro-6H-benzo[ f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 22
将化合物22h(50mg，0.088mmol)溶于5mL二氯甲烷中，加入5mL三氟乙酸，混合物在室温搅拌反应约1小时。反应液减压浓缩，加入10mL饱和碳酸氢钠溶液，搅拌30分钟，用乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题产物22(12mg，产率：29.12％)。Compound 22h (50 mg, 0.088 mmol) was dissolved in 5 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and the mixture was stirred and reacted at room temperature for about 1 hour. The reaction solution was concentrated under reduced pressure, 10 mL of saturated sodium bicarbonate solution was added, stirred for 30 minutes, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was washed with silica gel Purification by column chromatography with eluent system B afforded the title product 22 (12 mg, yield: 29.12%).
MS m/z(ESI)：469.2[M+1]。MS m/z (ESI): 469.2 [M+1].
1H NMR(500MHz,CDCl 3)δ9.07-9.06(m,1H),8.60-8.59(m,1H),8.26-8.25(m,1H),7.71-7.70(m,1H),7.21-7.19(m,2H),5.52-5.41(m,2H),4.39-4.38(m,1H), 4.32-4.29(m,2H),4.01-3.97(m,1H),3.74-3.69(m,2H),3.63-3.61(m,2H),3.53-3.51(m,2H),3.46-3.40(m,2H),3.04-2.99(m,1H),2.88-2.85(m,2H),2.69-2.64(m,1H),2.03-1.98(m,2H)1.81-1.79(m,1H),1.25-1.21(m,4H)。 1 H NMR (500MHz, CDCl 3 ) δ 9.07-9.06 (m, 1H), 8.60-8.59 (m, 1H), 8.26-8.25 (m, 1H), 7.71-7.70 (m, 1H), 7.21-7.19 (m,2H),5.52-5.41(m,2H),4.39-4.38(m,1H), 4.32-4.29(m,2H),4.01-3.97(m,1H),3.74-3.69(m,2H) ,3.63-3.61(m,2H),3.53-3.51(m,2H),3.46-3.40(m,2H),3.04-2.99(m,1H),2.88-2.85(m,2H),2.69-2.64( m, 1H), 2.03-1.98 (m, 2H) 1.81-1.79 (m, 1H), 1.25-1.21 (m, 4H).
实施例23Example 23
(±)-rel-5-((4R,12aR)-4,8-二甲基-9-(哌嗪-1-基)-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈23(±)-rel-5-((4R,12aR)-4,8-dimethyl-9-(piperazin-1-yl)-3,4,12,12a-tetrahydro-6H-benzo[ f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 23
Figure PCTCN2021110197-appb-000188
Figure PCTCN2021110197-appb-000188
第一步first step
4-溴-2-(甲氧基甲氧基)-5-甲基苯甲醛23b4-Bromo-2-(methoxymethoxy)-5-methylbenzaldehyde 23b
将化合物4-溴-2-羟基-5-甲基苯甲醛23a(500mg，2.33mmol，采用公知方法“Organic Letters,2017,vol.19,no.23,p.6280-6283”制备而得)溶于乙腈(20mL)，加入无水碳酸钾(1.0g，3.11mmol，国药)和溴甲基甲醚(350mg，2.80mmol)，反应在室温搅拌3小时，将反应液过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化，得到标题产物23b(250mg，产率：24.89％)。The compound 4-bromo-2-hydroxy-5-methylbenzaldehyde 23a (500 mg, 2.33 mmol, prepared by a known method "Organic Letters, 2017, vol.19, no.23, p.6280-6283") It was dissolved in acetonitrile (20 mL), anhydrous potassium carbonate (1.0 g, 3.11 mmol, Chinese medicine) and bromomethyl methyl ether (350 mg, 2.80 mmol) were added, the reaction was stirred at room temperature for 3 hours, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure , the residue was purified by silica gel column chromatography with eluent system A to give the title product 23b (250 mg, yield: 24.89%).
第二步second step
(4-溴-2-(甲氧基甲氧基)-5-甲基苯基)甲醇23c(4-Bromo-2-(methoxymethoxy)-5-methylphenyl)methanol 23c
将化合物23b(150mg，0.58mmol)溶于10mL甲醇中，冰水冷却，加入硼氢化钠(44mg，1.16mmol)，加毕，室温反应过夜，反应结束，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题产物23c(120mg，产率：79.38％)。Compound 23b (150 mg, 0.58 mmol) was dissolved in 10 mL of methanol, cooled with ice water, sodium borohydride (44 mg, 1.16 mmol) was added, the addition was completed, the reaction was performed at room temperature overnight, the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was washed with silica gel Purification by column chromatography with eluent system A afforded the title product 23c (120 mg, yield: 79.38%).
第三步third step
4-溴-2-(甲氧基甲氧基)-5-甲基苄基甲烷磺酸酯23d4-Bromo-2-(methoxymethoxy)-5-methylbenzylmethanesulfonate 23d
将化合物23c(120mg，0.46mmol)溶于10ml二氯甲烷中，冰水冷却，加入N,N-二异丙基乙胺(178mg，1.38mmol)，滴加甲烷磺酰氯(80mg，0.70mmol)，加毕，室温反应2小时，加入10mL水，二氯甲烷萃取(20mL×3)，饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化，得到标题产物23d(140mg，产率：89.8％)。Compound 23c (120 mg, 0.46 mmol) was dissolved in 10 ml of dichloromethane, cooled with ice water, N,N-diisopropylethylamine (178 mg, 1.38 mmol) was added, and methanesulfonyl chloride (80 mg, 0.70 mmol) was added dropwise. , the addition was completed, the reaction was carried out at room temperature for 2 hours, 10 mL of water was added, extracted with dichloromethane (20 mL×3), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was washed with silica gel Purification by column chromatography with eluent system A afforded the title product 23d (140 mg, yield: 89.8%).
第四步the fourth step
(±)-rel-5-((3R,5R)-4-(4-溴-2-(甲氧基甲氧基)-5-甲基苄基)-3-(((叔丁基二甲基硅基)氧基)甲基)-5-甲基哌嗪-1-基)喹啉-8-甲腈23e(±)-rel-5-((3R,5R)-4-(4-bromo-2-(methoxymethoxy)-5-methylbenzyl)-3-(((tert-butyldi Methylsilyl)oxy)methyl)-5-methylpiperazin-1-yl)quinoline-8-carbonitrile 23e
将化合物1g(150mg，0.38mmol)和化合物23d(140mg，0.41mmol)溶于10mL乙腈中，依次加入碳酸钾(306mg，2.21mmol)和碘化钾(20mg，0.12mmol)，混合物在80℃搅拌反应约3小时。冷却至室温后，向反应液中加入10mL水，用乙酸乙酯(10mL×3)萃取，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化，得到标题产物23e(160mg，产率：60.6％)。Compound 1g (150 mg, 0.38 mmol) and compound 23d (140 mg, 0.41 mmol) were dissolved in 10 mL of acetonitrile, potassium carbonate (306 mg, 2.21 mmol) and potassium iodide (20 mg, 0.12 mmol) were added in sequence, and the mixture was stirred at 80 °C for reaction for about 3 hours. After cooling to room temperature, 10 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with water (10 mL) and saturated sodium chloride solution (10 mL) in turn, dried over anhydrous sodium sulfate, Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title product 23e (160 mg, yield: 60.6%).
MS m/z(ESI)：639.2[M+1]。MS m/z (ESI): 639.2 [M+1].
第五步the fifth step
(±)-rel-5-((3R,5R)-4-(4-溴-2-羟基-5-甲基苄基)-3-(羟甲基)-5-甲基哌嗪-1-基)喹啉-8-甲腈23f(±)-rel-5-((3R,5R)-4-(4-bromo-2-hydroxy-5-methylbenzyl)-3-(hydroxymethyl)-5-methylpiperazine-1 -yl)quinoline-8-carbonitrile 23f
将化合物23e(160mg，0.25mmol)溶于5mL二氯甲烷中，加入4M盐酸1,4-二氧六环溶液(4mL，安耐吉)，有黄色固体生成，混合物在室温继续搅拌反应约1小时。反应液减压浓缩，加入10mL饱和碳酸氢钠溶液，搅拌30分钟，用乙酸乙酯(10mL×3)萃取，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物23f(98mg产率：81.39％)， 产品不经纯化直接进行下一步反应。Compound 23e (160 mg, 0.25 mmol) was dissolved in 5 mL of dichloromethane, 4M hydrochloric acid 1,4-dioxane solution (4 mL, Annagy) was added, a yellow solid was formed, and the mixture was stirred at room temperature for about 1 Hour. The reaction solution was concentrated under reduced pressure, 10 mL of saturated sodium bicarbonate solution was added, stirred for 30 minutes, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with water (10 mL) and saturated sodium chloride solution (10 mL) in turn. It was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title product 23f (98 mg yield: 81.39%), which was directly subjected to the next reaction without purification.
MS m/z(ESI):481.0[M+1]。MS m/z (ESI): 481.0 [M+1].
第六步Step 6
(±)-rel-5-((4R,12aR)-9-溴-4,8-二甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈23g(±)-rel-5-((4R,12aR)-9-bromo-4,8-dimethyl-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2 ,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 23g
将粗品化合物23f(140mg，0.29mmol)溶于10mL甲苯中，加入偶氮二甲酰二哌啶(367mg，1.45mmol)和三丁基膦(295mg，1.45mmol)，置换氩气三次，混合物在60℃搅拌反应约1小时。冷却至室温后，反应液减压浓缩，粗产品用乙酸乙酯(10mL)打浆，所得固体过滤，滤饼用正己烷洗涤，固体干燥，得到标题产物23g(80mg产率：59.36％)。The crude compound 23f (140 mg, 0.29 mmol) was dissolved in 10 mL of toluene, azodicarbonyl dipiperidine (367 mg, 1.45 mmol) and tributylphosphine (295 mg, 1.45 mmol) were added, argon was replaced three times, and the mixture was The reaction was stirred at 60°C for about 1 hour. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, the crude product was slurried with ethyl acetate (10 mL), the obtained solid was filtered, the filter cake was washed with n-hexane, and the solid was dried to obtain 23 g of the title product (80 mg yield: 59.36%).
MS m/z(ESI)：463.1[M+1]。MS m/z (ESI): 463.1 [M+1].
第七步Step 7
(±)-rel-4-((4R,12aR)-2-(8-氰基喹啉-5-基)-4,8-二甲基-1,2,3,4,12,12a-六氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-9-基)哌嗪-1-羧酸叔丁酯23h(±)-rel-4-((4R,12aR)-2-(8-cyanoquinolin-5-yl)-4,8-dimethyl-1,2,3,4,12,12a- Hexahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-9-yl)piperazine-1-carboxylate tert-butyl ester 23h
将化合物23g(80mg，0.20mmol)和化合物哌嗪-1-羧酸叔丁酯(88mg，0.47mmol，韶远)溶于10mL1,4-二氧六环中，然后加入甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(19mg，0.022mmol，乐研)、叔丁醇钠(65mg，0.68mmol)，置换氩气三次，混合物在100℃搅拌反应约1小时。冷却至室温后，向反应液中加入10mL水，用乙酸乙酯萃取(10mL×3)，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用高效液相色谱法(色谱柱：SharpSil T-C18，5μm，30mm*150mm；流动相1：水相(含0.1％三氟乙酸)；流动相2：乙腈；25分钟梯度：25％-95％，流速：30mL/min)纯化，得到标题产物23h(80mg，产率：59.25％)。Compound 23g (80mg, 0.20mmol) and compound piperazine-1-carboxylate tert-butyl ester (88mg, 0.47mmol, Shaoyuan) were dissolved in 10mL of 1,4-dioxane, and then methanesulfonic acid (2- Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (19 mg , 0.022 mmol, Leyan), sodium tert-butoxide (65 mg, 0.68 mmol), replaced argon three times, and the mixture was stirred and reacted at 100° C. for about 1 hour. After cooling to room temperature, 10 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, Filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (chromatographic column: SharpSil T-C18, 5μm, 30mm*150mm; mobile phase 1: water phase (containing 0.1% trifluoroacetic acid); mobile phase 2: acetonitrile ; 25 min gradient: 25%-95%, flow rate: 30 mL/min) purification gave the title product 23h (80 mg, yield: 59.25%).
MS m/z(ESI)：569.0[M+1]。MS m/z (ESI): 569.0 [M+1].
第八步Step 8
(±)-rel-5-((4R,12aR)-4,8-二甲基-9-(哌嗪-1-基)-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈23(±)-rel-5-((4R,12aR)-4,8-dimethyl-9-(piperazin-1-yl)-3,4,12,12a-tetrahydro-6H-benzo[ f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 23
将化合物23h(50mg，0.088mmol)溶于5mL二氯甲烷中，加入5mL三氟乙酸，混合物在室温搅拌反应约1小时。反应液减压浓缩，加入10mL饱和碳酸氢钠溶液，搅拌30分钟，用乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题产物23(12mg，产率：29.12％)。Compound 23h (50 mg, 0.088 mmol) was dissolved in 5 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and the mixture was stirred and reacted at room temperature for about 1 hour. The reaction solution was concentrated under reduced pressure, 10 mL of saturated sodium bicarbonate solution was added, stirred for 30 minutes, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was washed with silica gel Purification by column chromatography with eluent system B afforded the title product 23 (12 mg, yield: 29.12%).
MS m/z(ESI)：469.2[M+1]。MS m/z (ESI): 469.2 [M+1].
1H NMR(500MHz,CDCl 3)δ9.07-9.06(m,1H),8.60-8.58(m,1H),8.26-8.24(m,1H),7.72-7.70(m,1H),7.22-7.20(m,1H),7.05-7.04(m,1H),6.60-6.58(m,1H),4.30-4.27(m,1H),3.98-3.94(m,1H),3.63-3.55(m,2H),3.43-3.36(m,4H),3.10-3.05 (m,4H),2.91-2.87(m,4H),2.63-2.51(m,2H),2.16(m,3H),1.23-1.16(m,4H)。 1 H NMR (500MHz, CDCl 3 ) δ 9.07-9.06 (m, 1H), 8.60-8.58 (m, 1H), 8.26-8.24 (m, 1H), 7.72-7.70 (m, 1H), 7.22-7.20 (m,1H),7.05-7.04(m,1H),6.60-6.58(m,1H),4.30-4.27(m,1H),3.98-3.94(m,1H),3.63-3.55(m,2H) ,3.43-3.36(m,4H),3.10-3.05(m,4H),2.91-2.87(m,4H),2.63-2.51(m,2H),2.16(m,3H),1.23-1.16(m, 4H).
实施例24Example 24
(±)-rel-5-((4R,12aR)-4,10-二甲基-9-(哌嗪-1-基)-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈24(±)-rel-5-((4R,12aR)-4,10-dimethyl-9-(piperazin-1-yl)-3,4,12,12a-tetrahydro-6H-benzo[ f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 24
Figure PCTCN2021110197-appb-000189
Figure PCTCN2021110197-appb-000189
第一步first step
4-溴-2-羟基-3-甲基苯甲酸甲酯24bMethyl 4-bromo-2-hydroxy-3-methylbenzoate 24b
将2-氨基-4-溴-3甲基苯甲酸甲酯24a(680mg，2.7859mmol)溶于25％的硫酸 溶液10mL中，冰水冷却，滴加亚硝酸钠(290mg，4.2032mmol)的1mL水溶液，加毕，0℃反应2小时。反应结束，加入5％的硫酸溶液10mL，回流反应2小时，反应结束，冷却至室温，二氯甲烷萃取(30mL×3)，饱和食盐水洗涤(50mL×1)，硫酸镁干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到24b(390mg,产率：57.1％)。Methyl 2-amino-4-bromo-3-methylbenzoate 24a (680 mg, 2.7859 mmol) was dissolved in 10 mL of a 25% sulfuric acid solution, cooled with ice water, and 1 mL of sodium nitrite (290 mg, 4.2032 mmol) was added dropwise Aqueous solution, the addition was completed, and the reaction was carried out at 0°C for 2 hours. After the reaction was completed, 10 mL of 5% sulfuric acid solution was added, the reaction was refluxed for 2 hours, the reaction was completed, cooled to room temperature, extracted with dichloromethane (30 mL×3), washed with saturated brine (50 mL×1), dried over magnesium sulfate, filtered, and the filtrate was It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give 24b (390 mg, yield: 57.1%).
第二步second step
4-溴-2-(甲氧基甲氧基)-3-甲基苯甲酸甲酯24cMethyl 4-bromo-2-(methoxymethoxy)-3-methylbenzoate 24c
将化合物24b(380mg，1.5506mmol)溶于乙腈(20mL)，加入无水碳酸钾(643mg，4.65mmol，国药)和溴甲基甲醚(388mg，3.10mmol)，反应在室温搅拌3小时，将反应液过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化，得到标题产物24c(360mg，产率：80.30％)。Compound 24b (380 mg, 1.5506 mmol) was dissolved in acetonitrile (20 mL), anhydrous potassium carbonate (643 mg, 4.65 mmol, Chinese medicine) and bromomethyl methyl ether (388 mg, 3.10 mmol) were added, the reaction was stirred at room temperature for 3 hours, The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 24c (360 mg, yield: 80.30%).
第三步third step
(4-溴-2-(甲氧基甲氧基)-3-甲基苯基)甲醇24d(4-Bromo-2-(methoxymethoxy)-3-methylphenyl)methanol 24d
将化合物24c(380mg，1.31mmol)溶于10mL甲醇中，冰水冷却，加入硼氢化锂(145mg，6.55mmol)，加毕，室温反应过夜，反应结束，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题产物24d(300mg，产率：87.41％)。Compound 24c (380 mg, 1.31 mmol) was dissolved in 10 mL of methanol, cooled with ice water, lithium borohydride (145 mg, 6.55 mmol) was added, the addition was completed, the reaction was performed at room temperature overnight, the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was washed with silica gel Purification by column chromatography with eluent system A afforded the title product 24d (300 mg, yield: 87.41%).
第四步the fourth step
4-溴-2-(甲氧基甲氧基)-3-甲基苄基甲烷磺酸酯24e4-Bromo-2-(methoxymethoxy)-3-methylbenzylmethanesulfonate 24e
将化合物24d(300mg，1.15mmol)溶于10mL二氯甲烷中，冰水冷却，加入N,N-二异丙基乙胺(446mg，3.45mmol)，滴加甲烷磺酰氯(264mg，2.30mmol)，加毕，室温反应2小时，加入10mL水，二氯甲烷萃取(20ml×3)，饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化，得到标题产物24e(321mg,产率：82.4％)。Compound 24d (300 mg, 1.15 mmol) was dissolved in 10 mL of dichloromethane, cooled with ice water, N,N-diisopropylethylamine (446 mg, 3.45 mmol) was added, and methanesulfonyl chloride (264 mg, 2.30 mmol) was added dropwise. , the addition was completed, the reaction was carried out at room temperature for 2 hours, 10 mL of water was added, extracted with dichloromethane (20 mL×3), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was washed with silica gel Purification by column chromatography with eluent system A afforded the title product 24e (321 mg, yield: 82.4%).
第五步the fifth step
(±)-rel-5-((3R,5R)-4-(4-溴-2-(甲氧基甲氧基)-3-甲基苄基)-3-(((叔丁基二甲基硅基)氧基)甲基)-5-甲基哌嗪-1-基)喹啉-8-甲腈24f(±)-rel-5-((3R,5R)-4-(4-bromo-2-(methoxymethoxy)-3-methylbenzyl)-3-(((tert-butyldi Methylsilyl)oxy)methyl)-5-methylpiperazin-1-yl)quinoline-8-carbonitrile 24f
将化合物1g(300mg，0.76mol)和化合物24e(308mg，0.91mol)溶于10mL乙腈中，依次加入碳酸钾(315mg，2.2792mmol)和碘化钾(20mg，0.12mmol)，混合物在80℃搅拌反应约3小时。冷却至室温后，向反应液中加入10mL水，用乙酸乙酯(10mL×3)萃取，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化，得到标题产物24f(298mg，产率：61.58％)。Compound 1g (300 mg, 0.76 mol) and compound 24e (308 mg, 0.91 mol) were dissolved in 10 mL of acetonitrile, potassium carbonate (315 mg, 2.2792 mmol) and potassium iodide (20 mg, 0.12 mmol) were added in sequence, and the mixture was stirred at 80 °C for reaction for about 3 hours. After cooling to room temperature, 10 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with water (10 mL) and saturated sodium chloride solution (10 mL) in turn, dried over anhydrous sodium sulfate, Filtration, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system A afforded the title product 24f (298 mg, yield: 61.58%).
MS m/z(ESI)：639.2[M+1]。MS m/z (ESI): 639.2 [M+1].
第六步Step 6
(±)-rel-5-((3R,5R)-4-(4-溴-2-羟基-3-甲基苄基)-3-(羟甲基)-5-甲基哌嗪-1-基)喹啉-8- 甲腈24g(±)-rel-5-((3R,5R)-4-(4-bromo-2-hydroxy-3-methylbenzyl)-3-(hydroxymethyl)-5-methylpiperazine-1 -yl)quinoline-8-carbonitrile 24g
将化合物24f(260mg，0.41mol)溶于5mL二氯甲烷中，加入4M盐酸1,4-二氧六环溶液(4mL，安耐吉)，有黄色固体生成，混合物在室温继续搅拌反应约1小时。反应液减压浓缩，加入10mL饱和碳酸氢钠溶液，搅拌30分钟，用乙酸乙酯(10mL×3)萃取，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物24g(150mg，产率：76.66％)，产品不经纯化直接进行下一步反应。Compound 24f (260 mg, 0.41 mol) was dissolved in 5 mL of dichloromethane, 4M hydrochloric acid 1,4-dioxane solution (4 mL, Annagy) was added, a yellow solid was formed, and the mixture was stirred at room temperature for about 1 Hour. The reaction solution was concentrated under reduced pressure, 10 mL of saturated sodium bicarbonate solution was added, stirred for 30 minutes, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with water (10 mL) and saturated sodium chloride solution (10 mL) in turn. Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 24 g of the crude title product (150 mg, yield: 76.66%). The product is directly subjected to the next reaction without purification.
MS m/z(ESI)：481.0[M+1]。MS m/z (ESI): 481.0 [M+1].
第七步Step 7
(±)-rel-5-((4R,12aR)-9-溴-4,10-二甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈24h(±)-rel-5-((4R,12aR)-9-bromo-4,10-dimethyl-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2 ,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 24h
将粗品化合物24g(150mg，0.31mmol)溶于10mL甲苯中，加入偶氮二甲酰二哌啶(367mg，1.45mmol)和三丁基膦(295mg，1.45mmol)，置换氩气三次，混合物在60℃搅拌反应约1小时。冷却至室温后，反应液减压浓缩，粗产品用乙酸乙酯(10mL)打浆，所得固体过滤，滤饼用正己烷洗涤，固体干燥，得到标题产物24h(100mg产率：69.25％)。The crude compound 24g (150mg, 0.31mmol) was dissolved in 10mL of toluene, azodicarbonyl dipiperidine (367mg, 1.45mmol) and tributylphosphine (295mg, 1.45mmol) were added, and the argon was replaced three times, and the mixture was The reaction was stirred at 60°C for about 1 hour. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, the crude product was slurried with ethyl acetate (10 mL), the obtained solid was filtered, the filter cake was washed with n-hexane, and the solid was dried to obtain the title product 24h (100 mg yield: 69.25%).
MS m/z(ESI)：462.1[M+1]。MS m/z (ESI): 462.1 [M+1].
第八步Step 8
(±)-rel-4-((4R,12aR)-2-(8-氰基喹啉-5-基)-4,10-二甲基-1,2,3,4,12,12a-六氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-9-基)哌嗪-1-羧酸叔丁酯24i(±)-rel-4-((4R,12aR)-2-(8-cyanoquinolin-5-yl)-4,10-dimethyl-1,2,3,4,12,12a- Hexahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-9-yl)piperazine-1-carboxylate tert-butyl ester 24i
将化合物24h(90mg，0.19mmol)和化合物哌嗪-1-羧酸叔丁酯(53mg，0.28mmol，韶远)溶于10mL 1,4-二氧六环中，然后加入甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(19mg，0.022mmol，乐研)、叔丁醇钠(56mg，0.58mmol)，置换氩气三次，混合物在100℃搅拌反应约1小时。冷却至室温后，向反应液中加入10mL水，用乙酸乙酯萃取(10mL×3)，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用高效液相色谱法(色谱柱：SharpSil T-C18，5μm，30mm*150mm；流动相1：水相(含0.1％三氟乙酸)；流动相2：乙腈；25分钟梯度：25％-95％，流速：30mL/min)纯化，得到标题产物24i(65mg，产率：58.84％)。Compound 24h (90 mg, 0.19 mmol) and compound piperazine-1-carboxylate tert-butyl ester (53 mg, 0.28 mmol, Shaoyuan) were dissolved in 10 mL of 1,4-dioxane, and then methanesulfonic acid (2 -Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II)( 19 mg, 0.022 mmol, Leyan), sodium tert-butoxide (56 mg, 0.58 mmol), replaced argon three times, and the mixture was stirred and reacted at 100° C. for about 1 hour. After cooling to room temperature, 10 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, Filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (chromatographic column: SharpSil T-C18, 5μm, 30mm*150mm; mobile phase 1: water phase (containing 0.1% trifluoroacetic acid); mobile phase 2: acetonitrile ; 25 min gradient: 25%-95%, flow rate: 30 mL/min) purification gave the title product 24i (65 mg, yield: 58.84%).
MS m/z(ESI)：569.0[M+1]。MS m/z (ESI): 569.0 [M+1].
第九步Step 9
(±)-rel-5-((4R,12aR)-4,10-二甲基-9-(哌嗪-1-基)-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈24(±)-rel-5-((4R,12aR)-4,10-dimethyl-9-(piperazin-1-yl)-3,4,12,12a-tetrahydro-6H-benzo[ f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 24
将化合物24i(50mg，0.088mmol)溶于5mL二氯甲烷中，加入5mL三氟乙酸，混合物在室温搅拌反应约1小时。反应液减压浓缩，加入10mL饱和碳酸氢钠溶液，搅拌30分钟，用乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥， 过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题产物24(8mg，产率：19.40％)。Compound 24i (50 mg, 0.088 mmol) was dissolved in 5 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and the mixture was stirred and reacted at room temperature for about 1 hour. The reaction solution was concentrated under reduced pressure, 10 mL of saturated sodium bicarbonate solution was added, stirred for 30 minutes, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was washed with silica gel Purification by column chromatography with eluent system B afforded the title product 24 (8 mg, yield: 19.40%).
MS m/z(ESI)：469.2.[M+1]。MS m/z (ESI): 469.2.[M+1].
1H NMR(500MHz,CDCl 3)δ9.07-9.06(m,1H),8.61-8.59(m,1H),8.26-8.24(m,1H),7.73-7.70(m,1H),7.22-7.20(m,1H),6.53-6.51(m,1H),6.63-6.39(m,1H),4.30-4.27(m,1H),4.13-4.10(m,1H),3.61-3.52(m,2H),3.40-3.36(m,2H),3.27-3.24(m,4H),3.20-3.18(m,4H),3.07-3.05(m,1H),2.68-2.62(m,2H),2.30(m,3H),1.48-1.43(m,5H)。 1 H NMR (500MHz, CDCl 3 ) δ 9.07-9.06 (m, 1H), 8.61-8.59 (m, 1H), 8.26-8.24 (m, 1H), 7.73-7.70 (m, 1H), 7.22-7.20 (m,1H),6.53-6.51(m,1H),6.63-6.39(m,1H),4.30-4.27(m,1H),4.13-4.10(m,1H),3.61-3.52(m,2H) ,3.40-3.36(m,2H),3.27-3.24(m,4H),3.20-3.18(m,4H),3.07-3.05(m,1H),2.68-2.62(m,2H),2.30(m, 3H), 1.48-1.43 (m, 5H).
实施例25Example 25
(±)-rel-5-((4R,12aR)-4-甲基-10-(哌嗪-1-基)-3,4,12,12a-四氢-1H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(6H)-基)喹啉-8-甲腈25(±)-rel-5-((4R,12aR)-4-methyl-10-(piperazin-1-yl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyridine Azino[2,1-c][1,4]oxazepin-2(6H)-yl)quinoline-8-carbonitrile 25
Figure PCTCN2021110197-appb-000190
Figure PCTCN2021110197-appb-000190
第一步first step
1-溴-3-(溴甲基)-2-(甲氧基甲氧基)苯25b1-Bromo-3-(bromomethyl)-2-(methoxymethoxy)benzene 25b
将1-溴-2-(甲氧基甲氧基)-3-甲基苯25a(1.0g，4.33mmol，采用公知方法“Journal of Chemical Sciences,2021,133,28”的3/34页公开的4b的合成方法制备)溶于四氯化碳20mL中，冰水冷却，加入N-溴代丁二酰亚胺(920mg，5.17mmol， 韶远)，加毕，85℃反应3小时，反应结束，冷却至室温，加入饱和碳酸氢钠溶液50mL搅拌，二氯甲烷萃取(30mL×3)，饱和食盐水洗涤(50mL×1)，有机相用无水硫酸镁干燥，过滤旋干拌样，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到25b(2.0g，产率：80.9％)。1-Bromo-2-(methoxymethoxy)-3-methylbenzene 25a (1.0 g, 4.33 mmol, was disclosed on page 3/34 of "Journal of Chemical Sciences, 2021, 133, 28" using a well-known method 4b) was dissolved in 20 mL of carbon tetrachloride, cooled with ice water, N-bromosuccinimide (920 mg, 5.17 mmol, Shaoyuan) was added, the addition was completed, and the reaction was carried out at 85 °C for 3 hours. After completion, cooled to room temperature, 50 mL of saturated sodium bicarbonate solution was added and stirred, extracted with dichloromethane (30 mL×3), washed with saturated brine (50 mL×1), the organic phase was dried over anhydrous magnesium sulfate, filtered and spin-dried and mixed. The residue was purified by silica gel column chromatography with eluent system A to give 25b (2.0 g, yield: 80.9%).
1H NMR(500MHz,CDCl 3)δ7.53-7.51(m,1H),7.38-7.36(m,1H),7.02-6.99(m,1H),5.20(s,2H),4.61(s,2H),3.70(s,3H)。 1 H NMR (500MHz, CDCl 3 ) δ 7.53-7.51 (m, 1H), 7.38-7.36 (m, 1H), 7.02-6.99 (m, 1H), 5.20 (s, 2H), 4.61 (s, 2H) ), 3.70(s, 3H).
第二步second step
(±)-rel-5-((3R,5R)-4-(3-溴-2-(甲氧基甲氧基)苄基)-3-(((叔丁基二甲基硅基)氧基)甲基)-5-甲基哌嗪-1-基)喹啉-8-甲腈25c(±)-rel-5-((3R,5R)-4-(3-bromo-2-(methoxymethoxy)benzyl)-3-(((tert-butyldimethylsilyl) Oxy)methyl)-5-methylpiperazin-1-yl)quinoline-8-carbonitrile 25c
将化合物25b(300mg，0.97mmol)和化合物1g(250mg，0.63mmol)溶于乙腈(20mL)，加入碳酸铯(600mg，1.84mmol，国药)，反应在80℃搅拌3小时，反应结束，冷却至室温，将反应液过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化，得到标题产物25c(220mg，产率：55.7％)。Compound 25b (300 mg, 0.97 mmol) and compound 1 g (250 mg, 0.63 mmol) were dissolved in acetonitrile (20 mL), cesium carbonate (600 mg, 1.84 mmol, Chinese medicine) was added, and the reaction was stirred at 80° C. for 3 hours. After the reaction was completed, it was cooled to At room temperature, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title product 25c (220 mg, yield: 55.7%).
MS m/z(ESI)：625.2[M+1]。MS m/z (ESI): 625.2 [M+1].
第三步third step
(±)-rel-5-((3R,5R)-4-(3-溴-2-羟基苄基)-3-(羟甲基)-5-甲基哌嗪-1-基)喹啉-8-甲腈25d(±)-rel-5-((3R,5R)-4-(3-bromo-2-hydroxybenzyl)-3-(hydroxymethyl)-5-methylpiperazin-1-yl)quinoline -8-carbonitrile 25d
将化合物25c(220mg，0.35mol)溶于5mL二氯甲烷中，加入4M盐酸1,4-二氧六环溶液(4mL，安耐吉)，有黄色固体生成，混合物在室温继续搅拌反应约1小时。反应液减压浓缩，加入10mL饱和碳酸氢钠溶液，搅拌30分钟，用乙酸乙酯(10mL×3)萃取，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物25d(150mg，产率：91.7％)，产品不经纯化直接进行下一步反应。Compound 25c (220 mg, 0.35 mol) was dissolved in 5 mL of dichloromethane, 4M hydrochloric acid 1,4-dioxane solution (4 mL, Annagy) was added, a yellow solid was formed, and the mixture was stirred at room temperature for about 1 Hour. The reaction solution was concentrated under reduced pressure, 10 mL of saturated sodium bicarbonate solution was added, stirred for 30 minutes, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with water (10 mL) and saturated sodium chloride solution (10 mL) in turn. Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude title product 25d (150 mg, yield: 91.7%), which is directly subjected to the next reaction without purification.
MS m/z(ESI)：467.0[M+1]。MS m/z (ESI): 467.0 [M+1].
第四步the fourth step
(±)-rel-5-((4R,12aR)-10-溴-4-甲基-3,4,12,12a-四氢-1H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(6H)-基)喹啉-8-甲腈25e(±)-rel-5-((4R,12aR)-10-bromo-4-methyl-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1- c][1,4]oxazepin-2(6H)-yl)quinoline-8-carbonitrile 25e
将粗品化合物25d(110mg，0.24mmol)溶于10mL甲苯中，加入偶氮二甲酰二哌啶(240mg，1.18mmol)和三丁基膦(300mg，1.19mmol)，置换氩气三次，混合物在60℃搅拌反应约1小时。冷却至室温后，反应液减压浓缩，粗产品用乙酸乙酯10mL)打浆，所得固体过滤，滤饼用正己烷洗涤，固体干燥，得到标题产物25e(90mg产率：85.1％)。The crude compound 25d (110 mg, 0.24 mmol) was dissolved in 10 mL of toluene, azodicarbonyldipiperidine (240 mg, 1.18 mmol) and tributylphosphine (300 mg, 1.19 mmol) were added, and the argon was replaced three times. The reaction was stirred at 60°C for about 1 hour. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, the crude product was slurried with ethyl acetate (10 mL), the obtained solid was filtered, the filter cake was washed with n-hexane, and the solid was dried to obtain the title product 25e (90 mg yield: 85.1%).
MS m/z(ESI)：449.9[M+1]。MS m/z (ESI): 449.9 [M+1].
第五步the fifth step
(±)-rel-4-((4R,12aR)-2-(8-氰基喹啉-5-基)-4-甲基-2,3,4,6,12,12a-六氢-1H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-10-基)哌嗪-1-羧酸叔丁酯25f(±)-rel-4-((4R,12aR)-2-(8-cyanoquinolin-5-yl)-4-methyl-2,3,4,6,12,12a-hexahydro- 1H-Benzo[f]pyrazino[2,1-c][1,4]oxazepin-10-yl)piperazine-1-carboxylate tert-butyl ester 25f
将化合物25e(50mg，0.11mmol)和化合物哌嗪-1-羧酸叔丁酯(40mg，0.21mmol，韶远)溶于10mL甲苯中，然后加入三(二亚苄基丙酮)二钯(10mg，0.011mmol，韶远)、S-(-)-1,1'-联萘-2,2'-双二苯膦(15mg，0.024mmol，毕得)、叔丁醇钠(32mg，0.33mmol)，置换氩气三次，混合物在100℃搅拌反应约1小时。冷却至室温后，向反应液中加入10mL水，用乙酸乙酯萃取(10mL×3)，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用高效液相色谱法(色谱柱：SharpSil T-C18，5μm，30mm*150mm；流动相1：水相(含0.1％三氟乙酸)；流动相2：乙腈；25分钟梯度：25％-95％，流速：30mL/min)纯化，得到标题产物25f(35mg，产率：56.7％)。Compound 25e (50 mg, 0.11 mmol) and compound piperazine-1-carboxylate tert-butyl ester (40 mg, 0.21 mmol, Shaoyuan) were dissolved in 10 mL of toluene, and then tris(dibenzylideneacetone)dipalladium (10 mg) was added. , 0.011mmol, Shaoyuan), S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine (15mg, 0.024mmol, Bi De), sodium tert-butoxide (32mg, 0.33mmol ), replaced argon three times, and the mixture was stirred at 100 °C for about 1 hour. After cooling to room temperature, 10 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, Filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (chromatographic column: SharpSil T-C18, 5μm, 30mm*150mm; mobile phase 1: water phase (containing 0.1% trifluoroacetic acid); mobile phase 2: acetonitrile ; 25 min gradient: 25%-95%, flow rate: 30 mL/min) purification gave the title product 25f (35 mg, yield: 56.7%).
MS m/z(ESI)：555.2[M+1]。MS m/z (ESI): 555.2 [M+1].
第六步Step 6
(±)-rel-5-((4R,12aR)-4-甲基-10-(哌嗪-1-基)-3,4,12,12a-四氢-1H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(6H)-基)喹啉-8-甲腈25(±)-rel-5-((4R,12aR)-4-methyl-10-(piperazin-1-yl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyridine Azino[2,1-c][1,4]oxazepin-2(6H)-yl)quinoline-8-carbonitrile 25
将化合物25f(35mg，0.063mmol)溶于5mL二氯甲烷中，加入5mL三氟乙酸，混合物在室温搅拌反应约1小时。反应液减压浓缩，加入10mL饱和碳酸氢钠溶液，搅拌30分钟，用乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题产物25(10mg，产率：27.9％)。Compound 25f (35 mg, 0.063 mmol) was dissolved in 5 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and the mixture was stirred and reacted at room temperature for about 1 hour. The reaction solution was concentrated under reduced pressure, 10 mL of saturated sodium bicarbonate solution was added, stirred for 30 minutes, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was washed with silica gel Purification by column chromatography with eluent system B afforded the title product 25 (10 mg, yield: 27.9%).
MS m/z(ESI)：455.2[M+1]。MS m/z (ESI): 455.2 [M+1].
1H NMR(500MHz,CD 3OD)δ9.04-9.02(m,1H),8.79-8.69(m,1H),8.23-8.17(m,1H),7.77-7.66(m,1H),7.39-7.30(m,1H),7.30-7.10(m,3H),4.86-4.75(m,2H),4.65-4.45(m,1H),4.41-4.30(m,1H),4.09-3.80(m,2H),3.80-3.62(m,2H),3.56-3.44(m,2H),3.44-3.32(m,4H),3.28-3.91(m,4H),1.76-1.57(m,3H)。 1 H NMR (500MHz, CD 3 OD) δ 9.04-9.02 (m, 1H), 8.79-8.69 (m, 1H), 8.23-8.17 (m, 1H), 7.77-7.66 (m, 1H), 7.39- 7.30(m, 1H), 7.30-7.10(m, 3H), 4.86-4.75(m, 2H), 4.65-4.45(m, 1H), 4.41-4.30(m, 1H), 4.09-3.80(m, 2H ), 3.80-3.62(m, 2H), 3.56-3.44(m, 2H), 3.44-3.32(m, 4H), 3.28-3.91(m, 4H), 1.76-1.57(m, 3H).
实施例26Example 26
5-((4R,12aR)-9-((1R,4R)-2,5-二氮杂双环[2.2.1]庚-2-基)-4-甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈265-((4R,12aR)-9-((1R,4R)-2,5-diazabicyclo[2.2.1]hept-2-yl)-4-methyl-3,4,12,12a -Tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 26
Figure PCTCN2021110197-appb-000191
Figure PCTCN2021110197-appb-000191
化合物26的制备方法同化合物2。The preparation method of compound 26 is the same as that of compound 2.
将制备化合物2中第八步的原料3,6-二氮杂双环[3.1.1]庚烷-6-羧酸叔丁酯替换为(1R,4R)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯(药石)得到标题产物26(20mg)。Substitute (1R,4R)-2,5-diazabicyclo[ 2.2.1] Heptane-2-carboxylate tert-butyl ester (Yoshishi) to give the title product 26 (20 mg).
MS m/z(ESI)：467.2[M+1]。MS m/z (ESI): 467.2 [M+1].
1H NMR(500MHz,CD 3OD)δ9.02-8.92(m,1H),8.70-8.60(m,1H),8.18-8.05(m,1H),7.72-7.60(m,1H),7.29-7.19(m,1H),7.13-7.05(m,1H),6.37-6.23(m,2H),4.44-4.34(m,1H),4.33-4.21(m,1H),4.10-3.96(m,1H),3.84-3.75(m,1H),3.68-3.32(m,5H),3.22-3.10(m,1H),3.07-2.88(m,4H),2.80-2.65(m,2H),2.03-1.91(m,1H),1.84-1.74(m,1H),1.40-1.25(m,3H)。 1 H NMR (500MHz, CD 3 OD) δ 9.02-8.92 (m, 1H), 8.70-8.60 (m, 1H), 8.18-8.05 (m, 1H), 7.72-7.60 (m, 1H), 7.29- 7.19(m,1H),7.13-7.05(m,1H),6.37-6.23(m,2H),4.44-4.34(m,1H),4.33-4.21(m,1H),4.10-3.96(m,1H) ), 3.84-3.75(m, 1H), 3.68-3.32(m, 5H), 3.22-3.10(m, 1H), 3.07-2.88(m, 4H), 2.80-2.65(m, 2H), 2.03-1.91 (m, 1H), 1.84-1.74 (m, 1H), 1.40-1.25 (m, 3H).
实施例27Example 27
5-((4R,12aR)-9-((1S,4S)-2,5-二氮杂双环[2.2.1]庚-2-基)-4-甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈275-((4R,12aR)-9-((1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl)-4-methyl-3,4,12,12a -Tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 27
Figure PCTCN2021110197-appb-000192
Figure PCTCN2021110197-appb-000192
第一步first step
(1S,4S)-5-((4R,12aR)-2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4,12,12a-六氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-9-基)-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯27b(1S,4S)-5-((4R,12aR)-2-(8-cyanoquinolin-5-yl)-4-methyl-1,2,3,4,12,12a-hexahydro- 6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-9-yl)-2,5-diazabicyclo[2.2.1]heptane- 2-Carboxylic acid tert-butyl ester 27b
将化合物2h(100mg，0.22mmol)和化合物(1S,4S)-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯27a(66mg，0.33mmol，书亚)溶于10mL 1,4-二氧六环中，然后加 入氯(2-二环己基膦基-2',6'-二-异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(19mg，0.023mmol，韶远)和叔丁醇钠(65mg，0.68mmol)，置换氩气三次，混合物在100℃搅拌反应约1小时。冷却至室温后，向反应液中加入10mL水，用乙酸乙酯萃取(10mL×3)，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用高效液相色谱法(色谱柱：SharpSil T-C18，5μm，30mm*150mm；流动相1：水相(含0.1％三氟乙酸)；流动相2：乙腈；25分钟梯度：25％-95％，流速：30mL/min)纯化，得到标题产物27b(65mg，产率：51.54％)。Compound 2h (100 mg, 0.22 mmol) and compound (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl ester 27a (66 mg, 0.33 mmol, Shua) were combined Dissolve in 10 mL 1,4-dioxane, then add chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2- Amino-1,1'-biphenyl-2-yl)palladium(II) (19 mg, 0.023 mmol, Shaoyuan) and sodium tert-butoxide (65 mg, 0.68 mmol), replaced with argon three times, the mixture was stirred at 100 °C for reaction about 1 hour. After cooling to room temperature, 10 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, Filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (chromatographic column: SharpSil T-C18, 5μm, 30mm*150mm; mobile phase 1: water phase (containing 0.1% trifluoroacetic acid); mobile phase 2: acetonitrile ; 25 min gradient: 25%-95%, flow rate: 30 mL/min) purification gave the title product 27b (65 mg, yield: 51.54%).
MS m/z(ESI)：567.1[M+1]。MS m/z (ESI): 567.1 [M+1].
第二步second step
5-((4R,12aR)-9-((1S,4S)-2,5-二氮杂双环[2.2.1]庚-2-基)-4-甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈275-((4R,12aR)-9-((1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl)-4-methyl-3,4,12,12a -Tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 27
将化合物27b(65mg，0.11mmol)溶于5mL二氯甲烷中，加入5mL三氟乙酸，混合物在室温搅拌反应约1小时。反应液减压浓缩，加入10mL饱和碳酸氢钠溶液，搅拌30分钟，用乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题产物27(40mg，产率：74.74％)。Compound 27b (65 mg, 0.11 mmol) was dissolved in 5 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and the mixture was stirred and reacted at room temperature for about 1 hour. The reaction solution was concentrated under reduced pressure, 10 mL of saturated sodium bicarbonate solution was added, stirred for 30 minutes, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was washed with silica gel Purification by column chromatography with eluent system B afforded the title product 27 (40 mg, yield: 74.74%).
MS m/z(ESI)：467.1[M+1]。MS m/z (ESI): 467.1 [M+1].
1H NMR(500MHz,DMSO-d 6)δ9.07-9.06(m,1H),8.60-8.59(m,1H),8.26-8.24(m,1H),7.72-7.70(m,1H),7.22-7.21(m,1H),7.11-7.10(m,2H),6.30-6.28(m,2H),4.56(s,1H),4.36(s,1H),4.30-4.27(m,1H),3.98-3.95(m,1H),3.57-3.52(m,2H),3.42-3.38(m,2H),3.24-3.20(m,2H),3.11.3.08(m,1H),3.03-3.01(m,1H),2.68-2.63(m,2H),2.55(s,1H),2.09-2.07(m,1H),2.03-2.00(m,1H),1.97-1.89(m,1H),1.26-1.21(m,3H)。 1 H NMR (500MHz, DMSO-d 6 )δ9.07-9.06(m,1H), 8.60-8.59(m,1H), 8.26-8.24(m,1H), 7.72-7.70(m,1H), 7.22 -7.21(m,1H),7.11-7.10(m,2H),6.30-6.28(m,2H),4.56(s,1H),4.36(s,1H),4.30-4.27(m,1H),3.98 -3.95(m, 1H), 3.57-3.52(m, 2H), 3.42-3.38(m, 2H), 3.24-3.20(m, 2H), 3.11.3.08(m, 1H), 3.03-3.01(m, 1H), 2.68-2.63(m, 2H), 2.55(s, 1H), 2.09-2.07(m, 1H), 2.03-2.00(m, 1H), 1.97-1.89(m, 1H), 1.26-1.21( m, 3H).
实施例28Example 28
5-(rel-(4R,12aR)-9-((S)-3-氨基-3-甲基吡咯烷-1-基)-4-甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈(混合物1:1)285-(rel-(4R,12aR)-9-((S)-3-amino-3-methylpyrrolidin-1-yl)-4-methyl-3,4,12,12a-tetrahydro- 6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile (mixture 1:1) 28
Figure PCTCN2021110197-appb-000193
Figure PCTCN2021110197-appb-000193
Figure PCTCN2021110197-appb-000194
Figure PCTCN2021110197-appb-000194
第一步first step
((S)-1-(rel-((4R,12aR))-2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4,12,12a-六氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-9-基)-3-甲基吡咯烷-3-基)氨基甲酸叔丁酯(混合物1:1)28b((S)-1-(rel-((4R,12aR))-2-(8-cyanoquinolin-5-yl)-4-methyl-1,2,3,4,12,12a- Hexahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-9-yl)-3-methylpyrrolidin-3-yl)carbamic acid tert-Butyl ester (mixture 1:1) 28b
将化合物1j(50mg，0.11mmol)和化合物(S)-(3-甲基吡咯烷-3-基)氨基甲酸叔丁酯28a(34mg，0.17mmol，药石)溶于10mL1,4-二氧六环中，然后加入氯(2-二环己基膦基-2',6'-二-异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(10mg，0.011mmol，韶远)和叔丁醇钠(33mg，0.33mmol)，置换氩气三次，混合物在100℃搅拌反应约1小时。冷却至室温后，向反应液中加入10mL水，用乙酸乙酯萃取(10mL×3)，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用高效液相色谱法(色谱柱：SharpSil T-C18，5μm，30mm*150mm；流动相1：水相(含0.1％三氟乙酸)；流动相2：乙腈；25分钟梯度：25％-95％，流速：30mL/min)纯化，得到标题产物28b(30mg，产率：47.40％)。Compound 1j (50 mg, 0.11 mmol) and compound (S)-(3-methylpyrrolidin-3-yl)carbamate tert-butyl ester 28a (34 mg, 0.17 mmol, Yaoshi) were dissolved in 10 mL of 1,4-dioxane ring, then add chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl- 2-yl) palladium (II) (10 mg, 0.011 mmol, Shaoyuan) and sodium tert-butoxide (33 mg, 0.33 mmol), replaced argon three times, and the mixture was stirred at 100 °C for about 1 hour. After cooling to room temperature, 10 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, Filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (chromatographic column: SharpSil T-C18, 5μm, 30mm*150mm; mobile phase 1: water phase (containing 0.1% trifluoroacetic acid); mobile phase 2: acetonitrile ; 25 min gradient: 25%-95%, flow rate: 30 mL/min) purification gave the title product 28b (30 mg, yield: 47.40%).
MS m/z(ESI)：569.1[M+1]。MS m/z (ESI): 569.1 [M+1].
第二步second step
5-(rel-(4R,12aR)-9-((S)-3-氨基-3-甲基吡咯烷-1-基)-4-甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈285-(rel-(4R,12aR)-9-((S)-3-amino-3-methylpyrrolidin-1-yl)-4-methyl-3,4,12,12a-tetrahydro- 6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 28
将化合物28b(30mg，0.053mmol)溶于5mL二氯甲烷中，加入5mL三氟乙酸，混合物在室温搅拌反应约1小时。反应液减压浓缩，加入10mL饱和碳酸氢钠溶液，搅拌30分钟，用乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题产物28(10mg，产率：40.46％)。Compound 28b (30 mg, 0.053 mmol) was dissolved in 5 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and the mixture was stirred and reacted at room temperature for about 1 hour. The reaction solution was concentrated under reduced pressure, 10 mL of saturated sodium bicarbonate solution was added, stirred for 30 minutes, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was washed with silica gel Purification by column chromatography with eluent system B afforded the title product 28 (10 mg, yield: 40.46%).
MS m/z(ESI)：469.1[M+1]。MS m/z (ESI): 469.1 [M+1].
1H NMR(500MHz,DMSO-d 6)δ9.11-9.10(m,1H),8.68-8.65(m,1H),8.30-8.25(m,3H),7.75-7.73(m,1H),7.43-7.40(m,1H),6.38-6.32(m,1H),4.46-4.44(m,1H),4.40-4.30(m,2H),3.94-3.73(m,2H),3.51-3.45(m,4H),3.04-2.95(m,2H),8.85-2.81(m,1H),2.19-2.10(m,2H),2..02-1.99(m,1H),1.60-1.58(m,2H),1.46(s,3H), 1.26-1.24(m,3H),0.90-0.85(m,1H)。 1 H NMR (500MHz, DMSO-d 6 )δ9.11-9.10(m,1H), 8.68-8.65(m,1H), 8.30-8.25(m,3H), 7.75-7.73(m,1H), 7.43 -7.40(m,1H),6.38-6.32(m,1H),4.46-4.44(m,1H),4.40-4.30(m,2H),3.94-3.73(m,2H),3.51-3.45(m, 4H), 3.04-2.95(m, 2H), 8.85-2.81(m, 1H), 2.19-2.10(m, 2H), 2..02-1.99(m, 1H), 1.60-1.58(m, 2H) , 1.46(s, 3H), 1.26-1.24(m, 3H), 0.90-0.85(m, 1H).
实施例29Example 29
(±)-rel-5-((4R,12aR)-9-(4-氨基哌啶-1-基)-4-甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈29(±)-rel-5-((4R,12aR)-9-(4-aminopiperidin-1-yl)-4-methyl-3,4,12,12a-tetrahydro-6H-benzo[ f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 29
Figure PCTCN2021110197-appb-000195
Figure PCTCN2021110197-appb-000195
第一步first step
(±)-rel-(1-((4R,12aR)-2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4,12,12a-六氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-9-基)哌啶-4-基)氨基甲酸叔丁酯29b(±)-rel-(1-((4R,12aR)-2-(8-cyanoquinolin-5-yl)-4-methyl-1,2,3,4,12,12a-hexahydro -6H-Benzo[f]pyrazino[2,1-c][1,4]oxazepin-9-yl)piperidin-4-yl)carbamate tert-butyl ester 29b
将化合物1j(60mg，0.13mmol)和化合物哌啶-4-基氨基甲酸叔丁酯29a(41mg，0.20mmol，药石)溶于10mL1,4-二氧六环中，然后加入氯(2-二环己基膦基-2',6'-二-异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(12mg，0.014mmol，韶远)和叔丁醇钠(38mg，0.40mmol)，置换氩气三次，混合物在100℃搅拌反应约1小时。冷却至室温后，向反应液中加入10mL水，用乙酸乙酯萃取(10mL×3)，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用高效液相色谱法(色谱柱：SharpSil T-C18，5μm，30mm*150mm；流动相1：水相(含0.1％三氟乙酸)；流动相2：乙腈；25分钟梯度：25％-95％，流速：30mL/min)纯化，得到标题产物29b(30mg，产率：39.50％)。Compound 1j (60 mg, 0.13 mmol) and compound tert-butyl piperidin-4-ylcarbamate 29a (41 mg, 0.20 mmol, Yaoshi) were dissolved in 10 mL of 1,4-dioxane, and then chloro (2-dioxane) was added. Cyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (12mg , 0.014 mmol, Shaoyuan) and sodium tert-butoxide (38 mg, 0.40 mmol), replaced argon three times, and the mixture was stirred and reacted at 100° C. for about 1 hour. After cooling to room temperature, 10 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, Filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (chromatographic column: SharpSil T-C18, 5μm, 30mm*150mm; mobile phase 1: water phase (containing 0.1% trifluoroacetic acid); mobile phase 2: acetonitrile ; 25 min gradient: 25%-95%, flow rate: 30 mL/min) purification gave the title product 29b (30 mg, yield: 39.50%).
MS m/z(ESI)：569.1[M+1]。MS m/z (ESI): 569.1 [M+1].
第二步second step
(±)-rel-5-((4R,12aR)-9-(4-氨基哌啶-1-基)-4-甲基-3,4,12,12a-四氢-6H-苯并[f]吡嗪 并[2,1-c][1,4]氧杂氮杂庚环-2(1H)-基)喹啉-8-甲腈29(±)-rel-5-((4R,12aR)-9-(4-aminopiperidin-1-yl)-4-methyl-3,4,12,12a-tetrahydro-6H-benzo[ f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)quinoline-8-carbonitrile 29
将化合物29b(30mg，0.052mmol)溶于5mL二氯甲烷中，加入5mL三氟乙酸，混合物在室温搅拌反应约1小时。反应液减压浓缩，加入10mL饱和碳酸氢钠溶液，搅拌30分钟，用乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题产物29(8mg，产率：32.36％)。Compound 29b (30 mg, 0.052 mmol) was dissolved in 5 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and the mixture was stirred and reacted at room temperature for about 1 hour. The reaction solution was concentrated under reduced pressure, 10 mL of saturated sodium bicarbonate solution was added, stirred for 30 minutes, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was washed with silica gel Purification by column chromatography with eluent system B afforded the title product 29 (8 mg, yield: 32.36%).
MS m/z(ESI)：469.1[M+1]。MS m/z (ESI): 469.1 [M+1].
1H NMR(500MHz,DMSO-d 6)δ9.11-9.10(m,1H),8.68-8.67(m,1H),8.32-8.31(m,1H),7.98-7.97(m,2H),7.76-7.74(m,1H),7.46-7.45(m,1H),3.78-3.72(m,1H),4.66-4.62(m,2H),4.42-4.30(m,2H),3.82-3.72(m,5H),3.24(s,2H),3.06-3.00(m,2H),2.81-2.78(m,2H),1.94-1.92(m,2H),1.59-1.54(m,4H),1.28-1.24(m,3H)。 1 H NMR (500MHz, DMSO-d 6 )δ9.11-9.10(m,1H), 8.68-8.67(m,1H), 8.32-8.31(m,1H), 7.98-7.97(m,2H), 7.76 -7.74(m,1H),7.46-7.45(m,1H),3.78-3.72(m,1H),4.66-4.62(m,2H),4.42-4.30(m,2H),3.82-3.72(m, 5H), 3.24(s, 2H), 3.06-3.00(m, 2H), 2.81-2.78(m, 2H), 1.94-1.92(m, 2H), 1.59-1.54(m, 4H), 1.28-1.24( m, 3H).
实施例30Example 30
(±)-rel-5-((4R,12aR)-9-(4-异丁基哌嗪-1-基)-4-甲基-3,4,12,12a-四氢-1H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(6H)-基)喹啉-8-甲腈30(±)-rel-5-((4R,12aR)-9-(4-isobutylpiperazin-1-yl)-4-methyl-3,4,12,12a-tetrahydro-1H-benzene Io[f]pyrazino[2,1-c][1,4]oxazepin-2(6H)-yl)quinoline-8-carbonitrile 30
Figure PCTCN2021110197-appb-000196
Figure PCTCN2021110197-appb-000196
将化合物1j(20mg，0.045mmol)和化合物N-异丁基哌嗪(20mg，0.14mmol,韶远)溶于5mL 1,4-二氧六环中，然后加入甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(10mg，0.01mmol，韶远)和叔丁醇钠 (30mg，0.31mmol)，置换氩气三次，混合物在80℃搅拌反应约2小时。冷却至室温后，向反应液中加入10mL水，用乙酸乙酯萃取(10mL×3)，合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题产物30(10mg，产率：44.1％)。Compound 1j (20 mg, 0.045 mmol) and compound N-isobutylpiperazine (20 mg, 0.14 mmol, Shaoyuan) were dissolved in 5 mL of 1,4-dioxane, and then methanesulfonic acid (2-bicyclo) was added. Hexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (10 mg, 0.01 mmol, Shaoyuan) and sodium tert-butoxide (30 mg, 0.31 mmol), replaced argon three times, and the mixture was stirred at 80° C. for reaction for about 2 hours. After cooling to room temperature, 10 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title product 30 (10 mg, yield: 44.1%).
MS m/z(ESI)：511.2[M+1]。MS m/z (ESI): 511.2 [M+1].
1H NMR(500MHz,CD3OD)δ9.02-8.96(m,1H),8.70-8.63(m,1H),8.17-8.09(m,1H),7.70-7.62(m,1H),7.27-7.20(m,1H),7.18-7.10(m,1H),6.72-6.58(m,2H),4.16-3.80(m,4H),3.84-3.60(m,4H),3.25-3.13(m,2H),3.13-3.04(m,3H),3.02-2.89(m,1H),2.29-2.16(m,1H),2.81-2.64(m,2H),1.80-1.60(m,4H),1.38-1.27(m,3H),1.15-1.05(m,6H)。 1 H NMR(500MHz, CD3OD)δ9.02-8.96(m,1H),8.70-8.63(m,1H),8.17-8.09(m,1H),7.70-7.62(m,1H),7.27-7.20( m,1H),7.18-7.10(m,1H),6.72-6.58(m,2H),4.16-3.80(m,4H),3.84-3.60(m,4H),3.25-3.13(m,2H), 3.13-3.04(m, 3H), 3.02-2.89(m, 1H), 2.29-2.16(m, 1H), 2.81-2.64(m, 2H), 1.80-1.60(m, 4H), 1.38-1.27(m , 3H), 1.15-1.05 (m, 6H).
实施例31Example 31
(±)-rel-5-((4R,12aR)-9-(4-环丙基哌嗪-1-基)-4-甲基-3,4,12,12a-四氢-1H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(6H)-基)喹啉-8-甲腈31(±)-rel-5-((4R,12aR)-9-(4-cyclopropylpiperazin-1-yl)-4-methyl-3,4,12,12a-tetrahydro-1H-benzene [f]pyrazino[2,1-c][1,4]oxazepin-2(6H)-yl)quinoline-8-carbonitrile 31
Figure PCTCN2021110197-appb-000197
Figure PCTCN2021110197-appb-000197
将化合物1j(50mg，0.11mmol)和化合物1-环丙基哌嗪(30mg，0.24mmol,韶远)溶于5mL 1,4-二氧六环中，然后加入甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(10mg，0.01mmol，韶远)和叔丁醇钠(30mg，0.31mmol)，置换氩气三次，混合物在80℃搅拌反应约2小时。冷却至室 温后，向反应液中加入10mL水，用乙酸乙酯萃取(10mL×3)，合并有机相，依次用水(10mL)，饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题产物31(12mg，产率：21.8％)。Compound 1j (50 mg, 0.11 mmol) and compound 1-cyclopropylpiperazine (30 mg, 0.24 mmol, Shaoyuan) were dissolved in 5 mL of 1,4-dioxane, and then methanesulfonic acid (2-bicyclo) was added. Hexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (10 mg, 0.01 mmol, Shaoyuan) and sodium tert-butoxide (30 mg, 0.31 mmol), replaced argon three times, and the mixture was stirred at 80° C. for reaction for about 2 hours. After cooling to room temperature, 10 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title product 31 (12 mg, yield: 21.8%).
MS m/z(ESI)：495.2[M+1]。MS m/z (ESI): 495.2 [M+1].
1H NMR(500MHz,CDCl 3)δ9.09-9.08(m,1H),8.56-8.44(m,1H),8.10-8.01(m,1H),7.60-7.50(m,1H),7.16-6.97(m,2H),6.65-6.50(m,2H),4.24-4.22(m,1H),4.05-3.98(m,1H),3.75-3.64(m,1H),3.60-3.51(m,1H),3.36-3.29(m,1H),3.27-3.05(m,4H),2.94-2.85(m,1H),2.84-2.67(m,4H),1.80-1.63(m,2H),1.39-1.24(m,3H),1.21-0.82(m,3H),0.62-0.31(m,4H)。 1 H NMR (500MHz, CDCl 3 ) δ 9.09-9.08 (m, 1H), 8.56-8.44 (m, 1H), 8.10-8.01 (m, 1H), 7.60-7.50 (m, 1H), 7.16-6.97 (m,2H),6.65-6.50(m,2H),4.24-4.22(m,1H),4.05-3.98(m,1H),3.75-3.64(m,1H),3.60-3.51(m,1H) ,3.36-3.29(m,1H),3.27-3.05(m,4H),2.94-2.85(m,1H),2.84-2.67(m,4H),1.80-1.63(m,2H),1.39-1.24( m, 3H), 1.21-0.82 (m, 3H), 0.62-0.31 (m, 4H).
实施例32Example 32
(±)-rel-5-((4R,12aR)-9-(氮杂环丁烷-3-基氨基)-4-甲基-3,4,12,12a-四氢-1H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(6H)-基)喹啉-8-甲腈32(±)-rel-5-((4R,12aR)-9-(azetidin-3-ylamino)-4-methyl-3,4,12,12a-tetrahydro-1H-benzo [f]pyrazino[2,1-c][1,4]oxazepin-2(6H)-yl)quinoline-8-carbonitrile 32
Figure PCTCN2021110197-appb-000198
Figure PCTCN2021110197-appb-000198
第一步first step
(±)-rel-3-(((4R,12aR)-2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4,12,12a-六氢-6H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-9-基)氨基)氮杂环丁烷-1-甲酸叔丁酯32b(±)-rel-3-(((4R,12aR)-2-(8-cyanoquinolin-5-yl)-4-methyl-1,2,3,4,12,12a-hexahydro -6H-Benzo[f]pyrazino[2,1-c][1,4]oxazepin-9-yl)amino)azetidine-1-carboxylate tert-butyl ester 32b
将化合物1j(50mg，0.11mmol)和化合物1-叔丁氧羰基-3-胺基环丁胺32a(30mg，0.17mmol，药石)溶于10mL1,4-二氧六环中，然后加入甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(10mg，0.01mmol，韶远)和叔丁醇钠(30mg，0.31mmol)，置换氩气三次，混合物在100℃搅拌反应约1小时。冷却至室温后，向反应液中加入10mL水，用乙酸乙酯萃取(10mL×3)， 合并有机相，依次用水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题产物32b(33mg，产率：54.9％)。Compound 1j (50 mg, 0.11 mmol) and compound 1-tert-butoxycarbonyl-3-aminocyclobutanamine 32a (30 mg, 0.17 mmol, Yaoshi) were dissolved in 10 mL of 1,4-dioxane, followed by the addition of methanesulfonic acid Acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium ( II) (10 mg, 0.01 mmol, Shaoyuan) and sodium tert-butoxide (30 mg, 0.31 mmol), replaced argon three times, and the mixture was stirred at 100° C. for reaction for about 1 hour. After cooling to room temperature, 10 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, Filtration, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system B afforded the title product 32b (33 mg, yield: 54.9%).
MS m/z(ESI)：541.2[M+1]。MS m/z (ESI): 541.2 [M+1].
第二步second step
(±)-rel-5-((4R,12aR)-9-(氮杂环丁烷-3-基氨基)-4-甲基-3,4,12,12a-四氢-1H-苯并[f]吡嗪并[2,1-c][1,4]氧杂氮杂庚环-2(6H)-基)喹啉-8-甲腈32(±)-rel-5-((4R,12aR)-9-(azetidin-3-ylamino)-4-methyl-3,4,12,12a-tetrahydro-1H-benzo [f]pyrazino[2,1-c][1,4]oxazepin-2(6H)-yl)quinoline-8-carbonitrile 32
将化合物32b(33mg，0.054mmol)溶于5mL二氯甲烷中，加入5mL三氟乙酸，混合物在室温搅拌反应约1小时。反应液减压浓缩，加入10mL饱和碳酸氢钠溶液，搅拌30分钟，用乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题产物32(20mg，产率：59.1％)。Compound 32b (33 mg, 0.054 mmol) was dissolved in 5 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and the mixture was stirred and reacted at room temperature for about 1 hour. The reaction solution was concentrated under reduced pressure, 10 mL of saturated sodium bicarbonate solution was added, stirred for 30 minutes, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was washed with silica gel Purification by column chromatography with eluent system B afforded the title product 32 (20 mg, yield: 59.1%).
MS m/z(ESI)：441.2[M+1]。MS m/z (ESI): 441.2 [M+1].
1H NMR(500MHz,CD 3OD)δ9.06-8.96(m,1H),8.80-8.66(m,1H),8.27-8.15(m,1H),7.80-7.66(m,1H),7.40-7.25(m,2H),6.52-6.34(m,2H),4.81-4.24(m,6H),4.09-3.91(m,3H),3.90-3.60(m,2H),3.13-2.85(m,2H),1.84-1.70(m,2H),1.70-1.46(m,3H)。 1 H NMR (500MHz, CD 3 OD) δ 9.06-8.96 (m, 1H), 8.80-8.66 (m, 1H), 8.27-8.15 (m, 1H), 7.80-7.66 (m, 1H), 7.40- 7.25(m, 2H), 6.52-6.34(m, 2H), 4.81-4.24(m, 6H), 4.09-3.91(m, 3H), 3.90-3.60(m, 2H), 3.13-2.85(m, 2H ), 1.84-1.70 (m, 2H), 1.70-1.46 (m, 3H).
生物学评价Biological evaluation
以下结合测试例进一步描述解释本公开，但这些实施例并非意味着限制本公开的范围。The present disclosure is further described and explained below in conjunction with test examples, but these examples are not meant to limit the scope of the present disclosure.
测试例1：本公开化合物对人TLR7激活通路的抑制作用Test Example 1: Inhibitory effect of compounds of the present disclosure on human TLR7 activation pathway
一、实验材料及仪器1. Experimental materials and instruments
1.HEK-Blue TM hTLR7细胞(Invivogen) 1. HEK-Blue ™ hTLR7 cells (Invivogen)
2.雷西莫特(R848/Resiquimod，Invivogen)2. Resiquimod (R848/Resiquimod, Invivogen)
3.碱性磷酸酶检测培养基(Quanti-Blue Detection，Invivogen)3. Alkaline phosphatase detection medium (Quanti-Blue Detection, Invivogen)
4.杀稻瘟菌素(Blasticidin，Invivogen)4. Blasticidin (Invivogen)
5.博莱霉素(Zeocin，Invivogen)5. Bleomycin (Zeocin, Invivogen)
6.新霉素(Normocin，Invivogen)6. Neomycin (Normocin, Invivogen)
7.DMEM高糖培养基(DMEM/HIGH Glucose，GE Healthcare)7. DMEM high glucose medium (DMEM/HIGH Glucose, GE Healthcare)
8.胎牛血清(FBS，Gibco)8. Fetal bovine serum (FBS, Gibco)
9.磷酸盐缓冲液(上海源培生物科技有限公司)9. Phosphate buffer (Shanghai Yuanpei Biotechnology Co., Ltd.)
10.无菌水(上海恒瑞自制)10. Sterile water (made by Shanghai Hengrui)
11. 15ml离心管(Corning)11. 15ml centrifuge tube (Corning)
12. 96孔配药板(Corning)12. 96-well dispensing plate (Corning)
13. 96孔平底细胞培养板(Corning)13. 96-well flat-bottom cell culture plate (Corning)
14.恒温细胞培养箱(Thermo scientific)14. Constant temperature cell incubator (Thermo scientific)
15.恒温箱(上海一恒科学仪器有限公司)15. Incubator (Shanghai Yiheng Scientific Instrument Co., Ltd.)
16.PHERAstar FS酶标仪(BMG Labtech)16. PHERAstar FS microplate reader (BMG Labtech)
二、实验步骤2. Experimental steps
在Invivogen购得HEK-Blue TM hTLR7细胞，此细胞是将人Toll样受体7(TLR7)基因和含分泌型碱性磷酸酶报告基因(SEAP)共转染到HEK293细胞，碱性磷酸酶报告基因(SEAP)处于含5个NF-kB和AP-1结合位点的IFN-β最小启动子的调控下，当用激动剂激活TLR7后，通过下游NF-kB和AP-1引起SEAP分泌，加入拮抗化合物后，上述通路被抑制，SEAP分泌降低，通过SEAP底物测定OD620，从而评估化合物对TLR7通路的活性。 HEK-Blue TM hTLR7 cells were purchased from Invivogen. This cell was co-transfected with human Toll-like receptor 7 (TLR7) gene and secreted alkaline phosphatase reporter gene (SEAP) into HEK293 cells, and alkaline phosphatase reporter The gene (SEAP) is under the regulation of the IFN-β minimal promoter containing 5 NF-kB and AP-1 binding sites, and upon activation of TLR7 with an agonist, SEAP secretion is induced through downstream NF-kB and AP-1, After the addition of antagonistic compounds, the above-mentioned pathways were inhibited and SEAP secretion was reduced, and OD620 was measured by SEAP substrates to assess the activity of the compounds on the TLR7 pathway.
将溶于100％DMSO的20mM受试化合物用100％DMSO系列稀释至2000、400、80、16、3.2、0.64、0.128、0.0256μM，空白孔为100％DMSO，再20倍稀释于含10％灭活FBS的DMEM高糖培养基(完全培养基)中。用无菌水将R848稀释至10μM。在96孔细胞培养板中加入20μL/孔无菌水稀释的10μM R848，再将上述稀释于完全培养基的化合物和100％DMSO按每孔20μL加入到含有R848的孔中；阴性对照孔加入20μL无菌水和20μL稀释于完全培养基的100％DMSO。The 20 mM test compound dissolved in 100% DMSO was serially diluted with 100% DMSO to 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256 μM, the blank well was 100% DMSO, and then diluted 20 times in 10% DMSO. FBS-inactivated DMEM high-glucose medium (complete medium). R848 was diluted to 10 μM with sterile water. Add 20 μL/well of 10 μM R848 diluted in sterile water to a 96-well cell culture plate, then add the above compound diluted in complete medium and 100% DMSO to the wells containing R848 at 20 μL per well; add 20 μL to the negative control wells Sterile water and 20 μL of 100% DMSO diluted in complete medium.
HEK-Blue TM hTLR7细胞培养于含10％灭活FBS、100μg/mL新霉素、10μg/mL杀稻瘟菌素和100μg/mL博莱霉素的DMEM高糖培养基中。取生长良好，生长至70％-80％的细胞，弃去生长培养基，加5-10mL 37℃预热的PBS洗细胞一次，再加入2-5mL预热的PBS置于37℃培养1-2分钟，用移液器吹散细胞，转移细胞至15mL离心管，计数细胞，用完全培养基调整细胞密度到4.8×10 5/mL。加160μL调整密度后细胞悬液到上述96孔细胞培养板中，最终每孔细胞数为76500/孔，R848终浓度为1μM，受试化合物终浓度分别为10000、2000、400、80、16、3.2、0.64、0.128nM。将细胞置于37℃，5％CO 2培养箱中培养20小时，随后取上清20μL，加入180μL配制好的Quanti-Blue，于37℃恒温箱避光孵育120分钟后，酶标仪读取OD620吸光值。使用以下公式计算抑制率：抑制率＝{1-(OD受试化合物-OD阴性对照孔)/(OD空白孔-OD阴性对照孔)}×100％，用Graphpad Prism软件根据化合物各浓度与相应的抑制率绘出抑制曲线，并计算抑制率达到50％时化合物的浓度，即IC 50值见表1。 HEK-Blue ™ hTLR7 cells were cultured in DMEM high glucose medium containing 10% inactivated FBS, 100 μg/mL neomycin, 10 μg/mL blasticidin and 100 μg/mL bleomycin. Take the well-grown cells that have grown to 70%-80%, discard the growth medium, add 5-10mL of pre-warmed PBS at 37°C to wash the cells once, then add 2-5mL of pre-warmed PBS and incubate at 37°C for 1- For 2 minutes, blow off the cells with a pipette, transfer the cells to a 15 mL centrifuge tube, count the cells, and adjust the cell density to 4.8×10 5 /mL with complete medium. Add 160 μL of the density-adjusted cell suspension to the above 96-well cell culture plate, the final number of cells per well is 76500/well, the final concentration of R848 is 1 μM, and the final concentration of the test compound is 10000, 2000, 400, 80, 16, 3.2, 0.64, 0.128 nM. The cells were placed in a 37°C, 5% CO2 incubator for 20 hours, then 20 μL of the supernatant was taken, 180 μL of prepared Quanti-Blue was added, and the cells were incubated for 120 minutes in a 37°C incubator away from light, and read by a microplate reader. OD620 absorbance value. Use the following formula to calculate the inhibition rate: inhibition rate={1-(OD test compound-OD negative control well)/(OD blank well-OD negative control well)}×100%, use Graphpad Prism software according to the corresponding compound concentrations and corresponding The inhibition rate was drawn and the inhibition curve was drawn, and the concentration of the compound when the inhibition rate reached 50% was calculated, that is, the IC 50 value is shown in Table 1.
表1本公开化合物通过对人TLR7通路测得的IC 50值 Table 1 IC50 values of compounds of the present disclosure measured by the human TLR7 pathway
实施例编号Example number IC 50(nM) IC50 (nM)
11 1515
1-1-b1-1-b 4242
1-1-a1-1-a 1111
22 8989
33 4141
44 3535
55 5757
66 1919
77 1111
88 5252
99 7373
1010 3131
1111 2020
1212 8080
1313 2525
1414 1919
1515 1616
1616 88
16-a和16-b中保留时间11.33对应的化合物Compounds corresponding to retention time 11.33 in 16-a and 16-b 1010
16-a和16-b中保留时间9.00对应的化合物Compounds corresponding to retention time 9.00 in 16-a and 16-b 1717
1717 3232
1818 1212
1919 1212
2020 1919
21twenty one 2525
22twenty two 3131
23twenty three 1111
24twenty four 3434
2525 161161
2626 1616
2727 23twenty three
2828 2525
2929 2828
3030 110110
3131 125125
3232 119119
结论：本公开化合物对TLR7通路具有很好的抑制作用。Conclusion: The disclosed compounds have a good inhibitory effect on the TLR7 pathway.
测试例2：本公开化合物对人TLR8激活通路的抑制作用一、实验材料及仪器Test Example 2: Inhibitory effect of the compounds of the present disclosure on human TLR8 activation pathway 1. Experimental materials and instruments
1.HEK-Blue TM hTLR8细胞(Invivogen) 1. HEK-Blue ™ hTLR8 cells (Invivogen)
2.雷西莫特(R848/Resiquimod，Invivogen)2. Resiquimod (R848/Resiquimod, Invivogen)
3.碱性磷酸酶检测培养基(Quanti-Blue Detection，Invivogen)3. Alkaline phosphatase detection medium (Quanti-Blue Detection, Invivogen)
4.杀稻瘟菌素(Blasticidin，Invivogen)4. Blasticidin (Invivogen)
5.博莱霉素(Zeocin，Invivogen)5. Bleomycin (Zeocin, Invivogen)
6.新霉素(Normocin，Invivogen)6. Neomycin (Normocin, Invivogen)
7.DMEM高糖培养基(DMEM/HIGH Glucose，GE Healthcare)7. DMEM high glucose medium (DMEM/HIGH Glucose, GE Healthcare)
8.胎牛血清(Gibco)8. Fetal Bovine Serum (Gibco)
9.磷酸盐缓冲液(上海源培生物科技有限公司)9. Phosphate buffer (Shanghai Yuanpei Biotechnology Co., Ltd.)
10.无菌纯水(上海恒瑞自制)10. Sterile pure water (made by Shanghai Hengrui)
11. 15ml离心管(Corning)11. 15ml centrifuge tube (Corning)
12. 96孔配药板(Corning)12. 96-well dispensing plate (Corning)
13. 96孔平底细胞培养板(Corning)13. 96-well flat-bottom cell culture plate (Corning)
14.恒温细胞培养箱(Thermo scientific)14. Constant temperature cell incubator (Thermo scientific)
15.恒温箱(上海一恒科学仪器有限公司)15. Incubator (Shanghai Yiheng Scientific Instrument Co., Ltd.)
16.PHERAstar FS酶标仪(BMG Labtech)16. PHERAstar FS microplate reader (BMG Labtech)
二、实验步骤2. Experimental steps
在Invivogen购得HEK-Blue TM hTLR8细胞，此细胞是将人Toll样受体8(TLR8)基因和含分泌型碱性磷酸酶报告基因(SEAP)共转染到HEK293细胞，碱性磷酸酶报告基因(SEAP)处于含5个NF-kB和AP-1结合位点的IFN-β最小启动子的调控下，当用激动剂激活TLR8后，通过下游NF-kB和AP-1引起SEAP分泌，加入拮抗化合物后，上述通路被抑制，SEAP分泌降低，通过SEAP底物测定OD620，从而评估化合物对TLR8通路的活性。 HEK-Blue TM hTLR8 cells were purchased from Invivogen. The cells were co-transfected with human Toll-like receptor 8 (TLR8) gene and secreted alkaline phosphatase reporter gene (SEAP) into HEK293 cells, and alkaline phosphatase reporter The gene (SEAP) is under the regulation of the IFN-β minimal promoter containing 5 NF-kB and AP-1 binding sites, and upon activation of TLR8 with an agonist, SEAP secretion is induced through downstream NF-kB and AP-1, After the addition of antagonistic compounds, the above pathways were inhibited and SEAP secretion was reduced, and OD620 was measured by SEAP substrates to assess the activity of the compounds on the TLR8 pathway.
将溶于100％DMSO的20mM受试化合物用100％DMSO系列稀释至2000、400、80、16、3.2、0.64、0.128、0.0256μM，空白孔为100％DMSO，再20倍稀释于含10％灭活FBS的DMEM高糖培养基(完全培养基)中。用无菌水将R848稀释至60μM。在96孔细胞培养板中加入20μL/孔无菌水稀释的60μM R848，再将上述稀释于完全培养基的化合物和100％DMSO按每孔20μL加入到含有R848的孔中。阴性对照孔加入20μL无菌水和20μL稀释于完全培养基的100％DMSO。The 20 mM test compound dissolved in 100% DMSO was serially diluted with 100% DMSO to 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256 μM, the blank well was 100% DMSO, and then diluted 20 times in 10% DMSO. FBS-inactivated DMEM high-glucose medium (complete medium). Dilute R848 to 60 μM with sterile water. Add 20 μL/well of 60 μM R848 diluted in sterile water to a 96-well cell culture plate, and then add the above-mentioned compound diluted in complete medium and 100% DMSO to the wells containing R848 at 20 μL per well. Negative control wells were added with 20 μL sterile water and 20 μL 100% DMSO diluted in complete medium.
HEK-Blue TM hTLR8细胞培养于含10％灭活FBS、100μg/mL新霉素、10μg/mL杀稻瘟菌素和100μg/mL博莱霉素的DMEM高糖培养基中。取生长良好，生长至70％-80％的细胞，弃去生长培养基，加5-10mL 37℃预热的PBS洗细胞一次，再加2-5mL预热的PBS置于37℃培养1-2分钟，用移液器吹散细胞，转移细胞至15mL离心管，计数细胞，用完全培养基调整细胞密度到4.8×10 5/mL。加160μL调整密度后细胞悬液到上述96孔细胞培养板中，最终每孔细胞数为76500/孔，R848终浓度为6μM，受试化合物终浓度分别为10000、2000、400、80、16、3.2、0.64、0.128nM。将细胞置于37℃，5％CO 2培养箱中培养20小时，随后取上清20μL，加入180μL配制好的Quanti-Blue，于37℃恒温箱避光孵育120分钟，酶标仪读取OD620吸光值。使用以下公式计算抑制率：抑制率＝{1-(OD受试化合物-OD阴性对照孔)/(OD空白孔-OD阴性对照孔)}×100％，用Graphpad Prism软件根据化合物各浓度与相应的抑制率绘出抑制曲线，并计算抑制率达到50％时化合物的浓 度，即IC 50值见表2。 HEK-Blue ™ hTLR8 cells were cultured in DMEM high glucose medium containing 10% inactivated FBS, 100 μg/mL neomycin, 10 μg/mL blasticidin and 100 μg/mL bleomycin. Take the well-grown cells that have grown to 70%-80%, discard the growth medium, add 5-10 mL of pre-warmed PBS at 37°C to wash the cells once, and add 2-5 mL of pre-warmed PBS to culture at 37°C for 1- For 2 minutes, blow off the cells with a pipette, transfer the cells to a 15 mL centrifuge tube, count the cells, and adjust the cell density to 4.8×10 5 /mL with complete medium. Add 160 μL of the cell suspension after adjusting the density to the above 96-well cell culture plate, the final number of cells per well is 76500/well, the final concentration of R848 is 6 μM, and the final concentration of the test compound is 10000, 2000, 400, 80, 16, 3.2, 0.64, 0.128 nM. The cells were placed in a 37°C, 5% CO2 incubator for 20 hours, then 20 μL of the supernatant was taken, 180 μL of prepared Quanti-Blue was added, and the cells were incubated at 37°C in the dark for 120 minutes, and the OD620 was read by a microplate reader. absorbance value. Use the following formula to calculate the inhibition rate: inhibition rate={1-(OD test compound-OD negative control well)/(OD blank well-OD negative control well)}×100%, use Graphpad Prism software according to the corresponding compound concentrations and corresponding The inhibition rate was drawn and the inhibition curve was drawn, and the concentration of the compound when the inhibition rate reached 50% was calculated, that is, the IC 50 value is shown in Table 2.
表2本公开化合物通过对人TLR8通路测得的IC 50值 Table 2 IC50 values of compounds of the present disclosure measured by the human TLR8 pathway
实施例编号Example number IC 50(nM) IC50 (nM)
11 66
1-1-b1-1-b 3232
1-1-a1-1-a 55
22 2929
33 2020
44 1313
55 1818
66 1010
77 66
88 5151
99 2525
1010 1818
1111 77
1212 3131
1313 1616
1414 55
1515 1313
1616 99
16-a和16-b中保留时间11.33对应的化合物Compounds corresponding to retention time 11.33 in 16-a and 16-b 55
16-a和16-b中保留时间9.00对应的化合物Compounds corresponding to retention time 9.00 in 16-a and 16-b 3232
1717 1717
1818 66
1919 66
2020 66
21twenty one 88
22twenty two 1010
23twenty three 1515
24twenty four 99
2525 22twenty two
2626 33
2727 44
2828 99
2929 1212
3030 1919
3131 2020
3232 7474
结论：本公开化合物对TLR8通路具有很好的抑制作用。Conclusion: The disclosed compounds have a good inhibitory effect on the TLR8 pathway.
测试例3：本公开化合物对人TLR9激活通路的抑制作用Test Example 3: Inhibitory effect of compounds of the present disclosure on human TLR9 activation pathway
一、实验材料及仪器1. Experimental materials and instruments
1.HEK-Blue TM hTLR9细胞(Invivogen) 1. HEK-Blue ™ hTLR9 cells (Invivogen)
2.CpG ODN2006(Invivogen)2. CpG ODN2006 (Invivogen)
3.碱性磷酸酶检测培养基(Quanti-Blue Detection，Invivogen)3. Alkaline phosphatase detection medium (Quanti-Blue Detection, Invivogen)
4.杀稻瘟菌素(Blasticidin，Invivogen)4. Blasticidin (Invivogen)
5.博莱霉素(Zeocin，Invivogen)5. Bleomycin (Zeocin, Invivogen)
6.新霉素(Normocin，Invivogen)6. Neomycin (Normocin, Invivogen)
7.DMEM高糖培养基(DMEM/HIGH Glucose，GE Healthcare)7. DMEM high glucose medium (DMEM/HIGH Glucose, GE Healthcare)
8.胎牛血清(Gibco)8. Fetal Bovine Serum (Gibco)
9.磷酸盐缓冲液(上海源培生物科技有限公司)9. Phosphate buffer (Shanghai Yuanpei Biotechnology Co., Ltd.)
10.无菌纯水(上海恒瑞自制)10. Sterile pure water (made by Shanghai Hengrui)
11. 15ml离心管(Corning)11. 15ml centrifuge tube (Corning)
12. 96孔配药板(Corning)12. 96-well dispensing plate (Corning)
13. 96孔平底细胞培养板(Corning)13. 96-well flat-bottom cell culture plate (Corning)
14.恒温细胞培养箱(Thermo scientific)14. Constant temperature cell incubator (Thermo scientific)
15.恒温箱(上海一恒科学仪器有限公司)15. Incubator (Shanghai Yiheng Scientific Instrument Co., Ltd.)
16.PHERAstar FS酶标仪(BMG Labtech)16. PHERAstar FS microplate reader (BMG Labtech)
二、实验步骤2. Experimental steps
在Invivogen购得HEK-Blue TM hTLR9细胞，此细胞是将人Toll样受体9(TLR9)基因和含分泌型碱性磷酸酶报告基因(SEAP)共转染到HEK293细胞，碱性磷酸酶报告基因(SEAP)处于含5个NF-kB和AP-1结合位点的IFN-β最小启动子的调控下，当用激动剂激活TLR9后，通过下游NF-kB和AP-1引起SEAP分泌，加入拮抗化合物后，上述通路被抑制，SEAP分泌降低，通过SEAP底物测定OD620，从而评估化合物对TLR9通路的活性。 HEK-Blue TM hTLR9 cells were purchased from Invivogen. The cells were co-transfected with human Toll-like receptor 9 (TLR9) gene and secreted alkaline phosphatase reporter gene (SEAP) into HEK293 cells, and alkaline phosphatase reporter The gene (SEAP) is under the regulation of an IFN-β minimal promoter containing 5 NF-kB and AP-1 binding sites, and upon activation of TLR9 with an agonist, SEAP secretion is induced through downstream NF-kB and AP-1, After the addition of antagonistic compounds, the above pathways were inhibited and SEAP secretion was reduced, and OD620 was measured by SEAP substrates to assess the activity of the compounds on the TLR9 pathway.
将溶于100％DMSO的20mM受试化合物用100％DMSO系列稀释至2000、400、80、16、3.2、0.64、0.128、0.0256μM，空白孔为100％DMSO，再20倍稀释于含10％灭活FBS的DMEM高糖培养基(完全培养基)中。用无菌水将ODN2006稀释至10μM。在96孔细胞培养板中加入20μL/孔无菌水稀释的10μM ODN2006，再将上述稀释于完全培养基的化合物和100％DMSO按每孔20μL加入到含有ODN2006的孔中。阴性对照孔加入20μL无菌水和20μL稀释于完全培养基的100％DMSO。The 20 mM test compound dissolved in 100% DMSO was serially diluted with 100% DMSO to 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256 μM, the blank well was 100% DMSO, and then diluted 20 times in 10% DMSO. FBS-inactivated DMEM high-glucose medium (complete medium). Dilute ODN2006 to 10 μM with sterile water. Add 20 μL/well of 10 μM ODN2006 diluted in sterile water to a 96-well cell culture plate, and then add the above-mentioned compounds diluted in complete medium and 100% DMSO into the wells containing ODN2006 at 20 μL per well. Negative control wells were added with 20 μL sterile water and 20 μL 100% DMSO diluted in complete medium.
HEK-Blue TM hTLR9细胞培养于含10％FBS、100μg/mL新霉素、10μg/mL杀稻瘟菌素和100μg/mL博莱霉素的DMEM/高糖培养基中。取生长良好，生长至70％-80％的细胞，弃去生长培养基，加5-10mL 37℃预热的PBS洗细胞一次，再加2-5mL 预热的PBS置于37℃培养1-2分钟，用移液器吹散细胞，转移细胞至15mL离心管，计数细胞，用完全培养基调整细胞密度到4.8×10 5/mL。加160μL调整密度后细胞悬液到上述96孔细胞培养板中，最终每孔细胞数为76500/孔，ODN2006终浓度为1μM，受试化合物终浓度分别为10000、2000、400、80、16、3.2、0.64、0.128nM。将细胞置于37℃，5％CO 2培养箱中培养20小时，随后取上清20μL，加入180μL配制好的Quanti-Blue，于37℃恒温箱避光孵育15分钟后，酶标仪读取OD620吸光值。使用以下公式计算抑制率：抑制率＝{1-(OD受试化合物-OD阴性对照孔)/(OD空白孔-OD阴性对照孔)}×100％，用Graphpad Prism软件根据化合物各浓度与相应的抑制率绘出抑制曲线，并计算抑制率达到50％时化合物的浓度，即IC 50值见表3。 HEK-Blue ™ hTLR9 cells were cultured in DMEM/high glucose medium containing 10% FBS, 100 μg/mL neomycin, 10 μg/mL blasticidin and 100 μg/mL bleomycin. Take the well-grown cells that have grown to 70%-80%, discard the growth medium, add 5-10mL of pre-warmed PBS at 37°C to wash the cells once, and add 2-5mL of pre-warmed PBS and incubate at 37°C for 1- For 2 minutes, blow off the cells with a pipette, transfer the cells to a 15 mL centrifuge tube, count the cells, and adjust the cell density to 4.8×10 5 /mL with complete medium. Add 160 μL of the density-adjusted cell suspension to the above 96-well cell culture plate, the final number of cells per well is 76500/well, the final concentration of ODN2006 is 1 μM, and the final concentration of the test compound is 10000, 2000, 400, 80, 16, 3.2, 0.64, 0.128 nM. The cells were cultured in a 37°C, 5% CO2 incubator for 20 hours, then 20 μL of the supernatant was taken, 180 μL of prepared Quanti-Blue was added, and the cells were incubated in a 37°C incubator for 15 minutes in the dark, and read by a microplate reader. OD620 absorbance value. Use the following formula to calculate the inhibition rate: inhibition rate={1-(OD test compound-OD negative control well)/(OD blank well-OD negative control well)}×100%, use Graphpad Prism software according to the corresponding compound concentrations and corresponding The inhibition rate was drawn and the inhibition curve was drawn, and the concentration of the compound when the inhibition rate reached 50% was calculated, that is, the IC 50 value is shown in Table 3.
表3本公开化合物通过对人TLR9通路测得的IC 50值 Table 3 IC50 values of compounds of the present disclosure measured by the human TLR9 pathway
实施例编号Example number IC 50(nM) IC50 (nM)
11 568568
1-1-b1-1-b 598598
1-1-a1-1-a 690690
22 797797
33 501501
44 807807
55 849849
66 380380
1010 375375
1111 498498
1313 591591
1414 553553
1515 633633
1616 551551
16-a和16-b中保留时间11.33对应的化合物Compounds corresponding to retention time 11.33 in 16-a and 16-b 650650
16-a和16-b中保留时间9.00对应的化合物Compounds corresponding to retention time 9.00 in 16-a and 16-b 835835
1717 376376
1818 318318
1919 192192
2020 240240
21twenty one 443443
22twenty two 413413
23twenty three 442442
24twenty four 376376
2626 279279
2727 417417
2828 210210
2929 486486
3232 413413
结论：本公开化合物对TLR9通路具有抑制作用。Conclusion: The disclosed compounds have inhibitory effect on TLR9 pathway.

Claims (25)

  1. 一种通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：A compound represented by the general formula (I) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2021110197-appb-100001
    Figure PCTCN2021110197-appb-100001
    其中：in:
    环A选自以下基团中的一种：Ring A is selected from one of the following groups:
    Figure PCTCN2021110197-appb-100002
    Figure PCTCN2021110197-appb-100002
    其中，R 1和R 2相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、烯基、炔基、烷氧基、卤代烷氧基、卤素、氰基、氨基、硝基、羟基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； wherein, R 1 and R 2 are the same or different, and are independently selected from hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkoxy groups group, halogen, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein, the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heteroalkyl substituted with one or more substituents in cyclic, aryl and heteroaryl;
    R 3和R 4相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、烯基、炔基、烷氧基、卤代烷氧基、氧代基、卤素、氰基、 氨基、硝基、羟基、醛基和羧基； R 3 and R 4 are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, oxo, halogen, cyano, amino, nitro, hydroxyl, aldehyde and carboxyl;
    Z选自CH 2、CR 7aR 7b、NR 8a和氧原子； Z is selected from CH 2 , CR 7a R 7b , NR 8a and oxygen atoms;
    L 1和L 2相同或不同，且各自独立地选自化学键、CH 2、CR 7cR 7d和C(O)； L 1 and L 2 are the same or different, and are each independently selected from a chemical bond, CH 2 , CR 7c R 7d and C(O);
    L 3选自化学键、CH 2、CR 7eR 7f、NH、C(O)NR 8b、NR 8b(CH 2) m和C(O)； L 3 is selected from chemical bonds, CH 2 , CR 7e R 7f , NH, C(O)NR 8b , NR 8b (CH 2 ) m and C(O);
    X和Y相同或不同，且各自独立地为CR 5a或氮原子； X and Y are the same or different, and are each independently a CR 5a or a nitrogen atom;
    W 1、W 2、W 3和W 4之一为碳原子，其余三个相同或不同，且各自独立地为CR 5b或氮原子； One of W 1 , W 2 , W 3 and W 4 is a carbon atom, and the other three are the same or different, and each independently is a CR 5b or a nitrogen atom;
    R 5a选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、烯基、炔基、烷氧基、卤代烷氧基、卤素、氰基、氨基、硝基、羟基、醛基和羧基； R 5a is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, halogen, cyano, amino, nitro, hydroxyl , aldehyde group and carboxyl group;
    R 5b选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、烯基、炔基、卤素、氰基、氨基、-NR 9aR 9b、-COR 10、-C(O)OR 11、-OR 12、硝基、羟基、醛基、羧基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、烷氧基烷基、卤代烷基、卤代烷氧基、氰基、氨基、-(CH 2) sNR 13aR 13b、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R 5b is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, halogen, cyano, amino, -NR 9a R 9b , -COR 10 , -C (O) OR 11 , -OR 12 , nitro group, hydroxyl group, aldehyde group, carboxyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group; wherein, the alkyl group, cycloalkyl group, heterocyclic group , aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy, cyano, amino, -( CH 2 ) s NR 13a R 13b , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted with one or more substituents;
    环B选自环烷基、杂环基、芳基和杂芳基；Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
    R 6相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、烯基、炔基、氧代基、卤素、氰基、氨基、-NR 9aR 9b、-COR 10、-C(O)OR 11、-OR 12、-(CH 2) sNR 13aR 13b、-CO(CH 2) sNR 13aR 13b、硝基、羟基、醛基、羧基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、烷氧基烷基、卤代烷基、卤代烷氧基、氰基、氨基、-(CH 2) sNR 13aR 13b、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R 6 are the same or different, and each is independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an oxo group, a halogen group, a cyano group, an amino group, -NR 9a R 9b , -COR 10 , -C(O)OR 11 , -OR 12 , -(CH 2 ) s NR 13a R 13b , -CO(CH 2 ) s NR 13a R 13b , nitro, hydroxyl, Aldehyde, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy, cyano, amino, -(CH 2 ) s NR 13a R 13b , nitro, hydroxy, hydroxy substituted with one or more substituents of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
    R 7a、R 7b、R 7c、R 7d、R 7e和R 7f相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、烯基、炔基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基和杂芳基； R 7a , R 7b , R 7c , R 7d , R 7e and R 7f are the same or different, and are each independently selected from hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkenyl groups , alkynyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
    R 8a和R 8b相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基； R 8a and R 8b are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group ;
    R 9a和R 9b相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、-(CH 2) sNR 13aR 13b、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R 9a and R 9b are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group ; wherein, the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkane One or more substituents of oxy, cyano, amino, -(CH 2 ) s NR 13a R 13b , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl replaced;
    R 10选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨 基、-(CH 2) sNR 13aR 13b、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R 10 is selected from hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group; wherein, the alkyl group, cycloalkyl group, heterocyclic group , aryl, and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -( CH2 ) sNR 13a R 13b , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted with one or more substituents;
    R 11和R 12相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、-(CH 2) sNR 13aR 13b、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R 11 and R 12 are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group ; wherein, the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkane One or more substituents of oxy, cyano, amino, -(CH 2 ) s NR 13a R 13b , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl replaced;
    R 13a和R 13b相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基和羟烷基； R 13a and R 13b are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, and a hydroxyalkyl group;
    n为0、1、2、3；n is 0, 1, 2, 3;
    p为0、1、2、3；p is 0, 1, 2, 3;
    q为0、1、2、3；q is 0, 1, 2, 3;
    t为0、1、2、3、4、5；t is 0, 1, 2, 3, 4, 5;
    s为0、1、2、3、4、5、6；s is 0, 1, 2, 3, 4, 5, 6;
    m为0、1、2、3、4、5、6。m is 0, 1, 2, 3, 4, 5, 6.
  2. 根据权利要求1所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(I-1)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：The compound represented by the general formula (I) according to claim 1 or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or its A pharmaceutically acceptable salt, which is the compound represented by the general formula (I-1) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or Its pharmaceutically acceptable salts:
    Figure PCTCN2021110197-appb-100003
    Figure PCTCN2021110197-appb-100003
    其中：in:
    环B为至少含有1个N原子的4至12元杂环基；Ring B is a 4- to 12-membered heterocyclic group containing at least 1 N atom;
    R 6a选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、烯基、炔基、-NR 9aR 9b、-COR 10、-C(O)OR 11、-OR 12、-(CH 2) sNR 13aR 13b、-CO(CH 2) sNR 13aR 13b和环烷基； R 6a is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, -NR 9a R 9b , -COR 10 , -C(O)OR 11 , - OR 12 , -(CH 2 ) s NR 13a R 13b , -CO(CH 2 ) s NR 13a R 13b and cycloalkyl;
    t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
    环A、X、Y、Z、L 1、L 2、L 3、W 1至W 4、R 3、R 4、R 6、R 9a、R 9b、R 10至R 12、 R 13a、R 13b、s和n如权利要求1中所定义。 Ring A, X, Y, Z, L 1 , L 2 , L 3 , W 1 to W 4 , R 3 , R 4 , R 6 , R 9a , R 9b , R 10 to R 12 , R 13a , R 13b , s and n are as defined in claim 1 .
  3. 根据权利要求1所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(II)所示的化合物，或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：The compound represented by the general formula (I) according to claim 1 or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or its A pharmaceutically acceptable salt, which is the compound represented by the general formula (II), or its tautomer, racemate, enantiomer, diastereomer, or its mixture form, or its Medicinal salts:
    Figure PCTCN2021110197-appb-100004
    Figure PCTCN2021110197-appb-100004
    其中：in:
    环B、X、Y、Z、L 1、L 2、L 3、W 1至W 4、R 1至R 4、R 6、q、n和t如权利要求1中所定义。 Rings B, X, Y, Z, L 1 , L 2 , L 3 , W 1 to W 4 , R 1 to R 4 , R 6 , q, n and t are as defined in claim 1 .
  4. 根据权利要求1至3中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中Z为氧原子。The compound represented by the general formula (I) according to any one of claims 1 to 3 or its tautomer, racemate, enantiomer, diastereomer, or its tautomer, racemate, enantiomer, or diastereomer In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein Z is an oxygen atom.
  5. 根据权利要求1至4中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中X和Y相同，为氮原子。The compound represented by the general formula (I) according to any one of claims 1 to 4 or its tautomer, racemate, enantiomer, diastereomer, or its tautomer, racemate, enantiomer, or diastereomer In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein X and Y are the same and are nitrogen atoms.
  6. 根据权利要求1至5中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中W 1、W 2和W 4为CR 5b，W 3为碳原子；或者W 1和W 4为CR 5b，W 2为氮原子，W 3为碳原子；或者W 1和W 2为CR 5b，W 3为碳原子，W 4为氮原子；其中R 5b为氢原子或C 1-6烷基。 The compound represented by the general formula (I) according to any one of claims 1 to 5 or its tautomer, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein W 1 , W 2 and W 4 are CR 5b , W 3 is a carbon atom; or W 1 and W 4 are CR 5b , W 2 is a nitrogen atom, and W 3 is a carbon atom or W 1 and W 2 are CR 5b , W 3 is a carbon atom, and W 4 is a nitrogen atom; wherein R 5b is a hydrogen atom or a C 1-6 alkyl group.
  7. 根据权利要求1、3至6中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构 体、或其混合物形式、或其可药用的盐：The compound represented by the general formula (I) according to any one of claims 1, 3 to 6 or its tautomer, racemate, enantiomer, diastereomer, Or its mixture form, or its pharmaceutically acceptable salt, which is the compound represented by general formula (III) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2021110197-appb-100005
    Figure PCTCN2021110197-appb-100005
    其中：in:
    环B、L 1至L 3、R 1至R 4、R 6、q、n和t如权利要求1中所定义。 Ring B, L 1 to L 3 , R 1 to R 4 , R 6 , q, n and t are as defined in claim 1 .
  8. 根据权利要求1至7中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中L 1为CH 2，L 2为化学键。 The compound represented by the general formula (I) according to any one of claims 1 to 7 or its tautomer, racemate, enantiomer, diastereomer, or its tautomer, racemate, enantiomer, or diastereomer In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein L 1 is CH 2 and L 2 is a chemical bond.
  9. 根据权利要求1、3至8中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(IV)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：The compound represented by the general formula (I) according to any one of claims 1, 3 to 8 or its tautomer, racemate, enantiomer, diastereomer, Or its mixture form, or its pharmaceutically acceptable salt, which is the compound represented by general formula (IV) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2021110197-appb-100006
    Figure PCTCN2021110197-appb-100006
    其中：in:
    环B、L 3、R 1至R 3、R 6、q和t如权利要求1中所定义。 Rings B, L 3 , R 1 to R 3 , R 6 , q and t are as defined in claim 1 .
  10. 根据权利要求1、3至9中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中环B选自3至8元环烷基、3至12元杂环基、6至10元芳基和5至10 元杂芳基；优选地，环B为3至8元环烷基或至少含有1个N原子的4至8元杂环基；更优选地，环B选自哌嗪基、双环[2.2.2]辛-1-基、吡咯烷基、氮杂螺[3.3]庚烷基、双环[2.2.2]辛烷基、氮杂环丁烷基、1,2,3,6-四氢吡啶基、哌啶基、2,5-二氮杂二环[2.2.1]庚基和3,6-二氮杂二环[3.1.1]庚基。The compound represented by the general formula (I) according to any one of claims 1, 3 to 9 or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from 3 to 8 membered cycloalkyl, 3 to 12 membered heterocyclyl, 6 to 10 membered aryl, and 5 to 10 membered heteroaryl; preferably Preferably, Ring B is a 3- to 8-membered cycloalkyl group or a 4- to 8-membered heterocyclic group containing at least 1 N atom; more preferably, Ring B is selected from piperazinyl, bicyclo[2.2.2]octane-1- base, pyrrolidinyl, azaspiro[3.3]heptyl, bicyclo[2.2.2]octyl, azetidinyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, 2,5-diazabicyclo[2.2.1]heptyl and 3,6-diazabicyclo[3.1.1]heptyl.
  11. 根据权利要求1至10中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中L 3选自化学键、NH和C(O)NR 8b，其中R 8b为氢原子。 The compound represented by the general formula (I) according to any one of claims 1 to 10 or its tautomer, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein L 3 is selected from a bond, NH and C(O)NR 8b , wherein R 8b is a hydrogen atom.
  12. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 1为氰基。 The compound represented by the general formula (I) according to any one of claims 1 to 11 or its tautomer, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein R 1 is cyano.
  13. 根据权利要求1至12中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 2为氢原子。 The compound represented by the general formula (I) according to any one of claims 1 to 12 or its tautomer, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein R 2 is a hydrogen atom.
  14. 根据权利要求1至13中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 3为C 1-6烷基。 The compound represented by the general formula (I) according to any one of claims 1 to 13 or its tautomer, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein R 3 is C 1-6 alkyl.
  15. 根据权利要求1至8、10至14中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 4为氢原子。 The compound represented by the general formula (I) according to any one of claims 1 to 8 and 10 to 14 or its tautomer, racemate, enantiomer, and diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is a hydrogen atom.
  16. 根据权利要求1至15中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 6选自氢原子、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、卤素、-COR 10、-(CH 2) sNR 13aR 13b、-CO(CH 2) sNR 13aR 13b和3至8元环烷基；其中R 10选自氢原子、C 1-6烷基、3至8元环烷基和3至12元杂环基；R 13a和R 13b相同或不同，且各自独立地为氢原子或C 1-6烷基；s为0、1或2。 The compound represented by the general formula (I) according to any one of claims 1 to 15 or its tautomer, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, halogen, -COR 10 , -(CH 2 ) s NR 13a R 13b , -CO(CH 2 ) s NR 13a R 13b and 3- to 8-membered cycloalkyl; wherein R 10 is selected from hydrogen atom, C 1-6 alkyl, 3- to 8-membered cycloalkyl and a 3- to 12-membered heterocyclic group; R 13a and R 13b are the same or different, and are each independently a hydrogen atom or a C 1-6 alkyl group; s is 0, 1 or 2.
  17. 根据权利要求1至16中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其选自以下化合物：The compound represented by the general formula (I) according to any one of claims 1 to 16 or its tautomer, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof, selected from the following compounds:
    Figure PCTCN2021110197-appb-100007
    Figure PCTCN2021110197-appb-100007
    Figure PCTCN2021110197-appb-100008
    Figure PCTCN2021110197-appb-100008
    Figure PCTCN2021110197-appb-100009
    Figure PCTCN2021110197-appb-100009
    Figure PCTCN2021110197-appb-100010
    Figure PCTCN2021110197-appb-100010
    Figure PCTCN2021110197-appb-100011
    Figure PCTCN2021110197-appb-100011
    Figure PCTCN2021110197-appb-100012
    Figure PCTCN2021110197-appb-100012
    Figure PCTCN2021110197-appb-100013
    Figure PCTCN2021110197-appb-100013
    Figure PCTCN2021110197-appb-100014
    Figure PCTCN2021110197-appb-100014
    Figure PCTCN2021110197-appb-100015
    Figure PCTCN2021110197-appb-100015
    Figure PCTCN2021110197-appb-100016
    Figure PCTCN2021110197-appb-100016
    Figure PCTCN2021110197-appb-100017
    Figure PCTCN2021110197-appb-100017
    Figure PCTCN2021110197-appb-100018
    Figure PCTCN2021110197-appb-100018
    Figure PCTCN2021110197-appb-100019
    Figure PCTCN2021110197-appb-100019
  18. 一种通式(I-1a)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：A compound represented by the general formula (I-1a) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable form thereof Salt:
    Figure PCTCN2021110197-appb-100020
    Figure PCTCN2021110197-appb-100020
    其中：in:
    R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
    环B为至少含有1个N原子的4至12元杂环基；Ring B is a 4- to 12-membered heterocyclic group containing at least 1 N atom;
    t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
    环A、X、Y、Z、L 1、L 2、L 3、W 1至W 4、R 3、R 4、R 6和n如权利要求2中所定义。 Rings A, X, Y, Z, L 1 , L 2 , L 3 , W 1 to W 4 , R 3 , R 4 , R 6 and n are as defined in claim 2 .
  19. 一种化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其选自如下化合物：A compound or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
    Figure PCTCN2021110197-appb-100021
    Figure PCTCN2021110197-appb-100021
    Figure PCTCN2021110197-appb-100022
    Figure PCTCN2021110197-appb-100022
    Figure PCTCN2021110197-appb-100023
    Figure PCTCN2021110197-appb-100023
    Figure PCTCN2021110197-appb-100024
    Figure PCTCN2021110197-appb-100024
    Figure PCTCN2021110197-appb-100025
    Figure PCTCN2021110197-appb-100025
    Figure PCTCN2021110197-appb-100026
    Figure PCTCN2021110197-appb-100026
  20. 一种制备通式(I-1)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括：A preparation of the compound represented by the general formula (I-1) or its tautomer, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable The salt method, which includes:
    Figure PCTCN2021110197-appb-100027
    Figure PCTCN2021110197-appb-100027
    通式(I-1a)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐脱去保护基R W，得到通式(I-1)的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐， Deprotection of a compound of general formula (I-1a) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof group R W to obtain the compound of general formula (I-1) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or its pharmaceutically acceptable of salt,
    其中：in:
    R W为保护基；优选地，R W为氨基保护基；更优选地，R W为叔丁氧羰基； R W is a protecting group; preferably, R W is an amino protecting group; more preferably, R W is tert-butoxycarbonyl;
    R 6a为氢原子； R 6a is a hydrogen atom;
    环B为至少含有1个N原子的4至12元杂环基；Ring B is a 4- to 12-membered heterocyclic group containing at least 1 N atom;
    t为1、2、3、4、5；t is 1, 2, 3, 4, 5;
    环A、X、Y、Z、L 1、L 2、L 3、W 1至W 4、R 3、R 4、R 6和n如权利要求2中所定义。 Rings A, X, Y, Z, L 1 , L 2 , L 3 , W 1 to W 4 , R 3 , R 4 , R 6 and n are as defined in claim 2 .
  21. 一种药物组合物，所述药物组合物含有根据权利要求1～17中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。A pharmaceutical composition comprising the compound represented by the general formula (I) according to any one of claims 1 to 17 or its tautomer, racemate, enantiomer isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  22. 根据权利要求1～17中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或根据权利要求21所述的药物组合物在制备用于抑制TLR7、TLR8和TLR9的药物中的用途。The compound represented by the general formula (I) according to any one of claims 1 to 17, or a tautomer, racemate, enantiomer, diastereomer, or its tautomer, racemate, enantiomer, or Use of a mixture form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21 in the manufacture of a medicament for inhibiting TLR7, TLR8 and TLR9.
  23. 根据权利要求1～17中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或根据权利要求21所述的药物组合物在制备用于抑制TLR7、TLR8或TLR9的药物中的用途；优选在制备用于抑制TLR7和TLR8的药物中的用途，或在制备用于抑制TLR7和TLR9的药物中的用途。The compound represented by the general formula (I) according to any one of claims 1 to 17, or a tautomer, racemate, enantiomer, diastereomer, or its tautomer, racemate, enantiomer, or Mixture form or its pharmaceutically acceptable salt or the purposes of pharmaceutical composition according to claim 21 in the preparation of medicine for inhibiting TLR7, TLR8 or TLR9; preferably in the preparation of medicine for inhibiting TLR7 and TLR8 purposes, or in the preparation of drugs for inhibiting TLR7 and TLR9.
  24. 根据权利要求1～17中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或根据权利要求21所述的药物组合物在制备用于治疗和/或预防炎性或自身免疫性疾病的药物中的用途。The compound represented by the general formula (I) according to any one of claims 1 to 17 or a tautomer, racemate, enantiomer, diastereomer, or its tautomer, racemate, enantiomer, or Use of a mixture form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21 in the manufacture of a medicament for the treatment and/or prevention of inflammatory or autoimmune diseases.
  25. 根据权利要求24所述的用途，其中所述的炎性或自身免疫性疾病选自系统性红斑狼疮(SLE)、类风湿性关节炎、多发性硬化(MS)和肖格伦综合症。The use according to claim 24, wherein the inflammatory or autoimmune disease is selected from the group consisting of systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS) and Shoghren's syndrome.
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