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WO2025195327A1 - Spiro/bridged polycyclic compounds as well as preparation method therefor and use thereof - Google Patents

Spiro/bridged polycyclic compounds as well as preparation method therefor and use thereof

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Publication number
WO2025195327A1
WO2025195327A1 PCT/CN2025/082933 CN2025082933W WO2025195327A1 WO 2025195327 A1 WO2025195327 A1 WO 2025195327A1 CN 2025082933 W CN2025082933 W CN 2025082933W WO 2025195327 A1 WO2025195327 A1 WO 2025195327A1
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WO
WIPO (PCT)
Prior art keywords
group
membered
alkyl
heteroatoms selected
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/082933
Other languages
French (fr)
Chinese (zh)
Inventor
薛海
石和鹏
张培龙
李祥秋
兰文丽
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beijing Avistone Biotechnology Co Ltd
Original Assignee
Beijing Avistone Biotechnology Co Ltd
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Filing date
Publication date
Application filed by Beijing Avistone Biotechnology Co Ltd filed Critical Beijing Avistone Biotechnology Co Ltd
Publication of WO2025195327A1 publication Critical patent/WO2025195327A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • 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

Definitions

  • the present invention belongs to the field of medical technology, and in particular relates to a spiro/bridged ring compound and a preparation method and application thereof.
  • the epidermal growth factor receptor 2 (HER2, ErbB2) gene is located on the long arm of chromosome 17 (17q21). It is one of the four members of the ErbB family (EGFR/HER1/ErbB1, HER2/ErbB2, HER3/ErbB31, and HER4/ErbB4) and possesses tyrosine kinase activity. Currently, no ligand has been found that can directly interact with HER2. HER2 can form heterodimers with other members of the ErbB family, activating the downstream MEK/ERK/MAPK pathway and the PI3K/AKT bypass pathway for signal transduction, ultimately promoting cell growth, proliferation, and division.
  • Overexpression (upregulation) or overactivity (amplification or mutation) of HER2 has been linked to numerous cancers, including breast, colorectal, gastric, non-small cell lung, head and neck, ovarian, cervical, bladder, esophageal, endometrial, and glioblastoma.
  • the prevalence of HER2 overexpression in lung, breast, gastric, bile duct, ovarian, and endometrial cancers is approximately 2.5%, 15% to 25%, 20%, 20%, 27%, and 18% to 80%, respectively.
  • HER2 mutations in non-small cell lung cancer are approximately 2%-4%, of which exon 20 insertion mutations account for 71% of HER2 mutations, including common subtypes such as A772_G775dup (55.0%), G776delinsVC (8.3%), G778_P780dup (5.6%), and G776delinsLC (2.1%).
  • Other HER2 mutations include exon 19 mutation L755P (1.9%), exon 21 mutation V842I (0.7%), transmembrane domain mutations V659E (4.1%) and G660D (0.9%), and extracellular region mutations D277Y (1.9%), S310F (7.7%), S310Y (1.9%), and A466V (1.4%).
  • mAbs monoclonal antibodies
  • TKIs small molecule tyrosine kinase inhibitors
  • ADCs antibody-drug conjugates
  • Monoclonal antibodies and antibody-drug conjugates have poor selectivity for wild-type EGFR. Furthermore, as large molecules, these drugs are not easily able to cross the blood-brain barrier. Furthermore, some patients develop resistance or relapse after a period of monoclonal antibody (mAb) use. Furthermore, antibody-drug conjugates, such as trastuzumab, have a 12.9% incidence of grade 3 or higher interstitial pneumonitis at the approved dose of 5.4 mg/kg.
  • TKIs are divided into selective TKIs (tucatinib) and non-selective TKIs (lapatinib, neratinib, and pyrotinib).
  • TKIs exhibit moderate antitumor activity against wild-type HER2, but are less effective against the most common HER2 exon 20 insertion mutations, with clinical objective response rates (ORRs) ranging from 0-30%.
  • ORRs clinical objective response rates
  • non-selective TKIs have poor selectivity for wild-type EGFR and are prone to adverse reactions such as rash and diarrhea. Therefore, the development of HER2 inhibitors that are selective, can cross the blood-brain barrier, and have potential inhibitory effects against HER2 exon 20 insertion mutations is of great significance.
  • the present invention aims to provide a spiro/bridged ring compound and its preparation method and application.
  • the spiro/bridged ring compound of the present invention has good activity in inhibiting HER2 exon 20 insertion mutation, has high selectivity for wild-type EGFR, can pass through the blood-brain barrier, and can be used as a treatment for diseases related to HER2 abnormality induction, especially for the treatment of cancer diseases.
  • the present invention is achieved through the following technical solutions.
  • the E ring is a 6-10 membered aryl group or a 5-10 membered heteroaryl group containing one or more heteroatoms selected from N, O, and S;
  • Q 1 is absent or is a 6-12 membered aryl group or a 5-12 membered heteroaryl group containing one or more heteroatoms selected from N, O, and S, and the 6-12 membered aryl group or the 5-12 membered heteroaryl group containing one or more heteroatoms selected from N, O, and S is optionally substituted by one or more R';
  • L 3 is NR 4 , O, CR 5 R 6 , S, S(O) or S(O) 2 ;
  • L 4 is absent or is a chemical bond, O, NR 4 , CR 5 R 6 , C( ⁇ O), S, S(O) or S(O) 2 ;
  • Y1 is N or CR a ;
  • Y 2 is N or CR b ;
  • Y 3 is N or CR c ;
  • Y 4 is N or CR d ;
  • Y 5 is N, CR e or C; when L 2 is a chemical bond, Y 5 is N; when L 2 is O or NR 4 , Y 5 is CR e or C;
  • R7 is C1-6 alkylene, C2-4 alkenylene, halogenated C1-6 alkylene, deuterated C1-6 alkylene or halogenated C2-4 alkenylene;
  • R b together with R 2 and the atoms to which they are attached form a 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S ⁇ O, S(O) 2 , or a 5-6 membered heteroaryl containing one, two, three, or four heteroatoms selected from N, O, and S, and the 3-12 membered cycloalkyl, the 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S ⁇ O, S(O) 2 , or a 5-6 membered heteroaryl containing one, two, three, or four heteroatoms selected from N, O, and S are optionally substituted with one or more R ′;
  • R c is a hydrogen atom, a deuterium atom, a halogen, a cyano group, an amino group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkylthio group, a C 1-6 alkylamino group or a di(C 1-6 alkyl)amino group, wherein the amino group, the C 1-6 alkyl group, the C 1-6 alkoxy group, the C 1-6 alkylthio group, the C 1-6 alkylamino group or the di(C 1-6 alkyl)amino group is optionally substituted with one or more R ′;
  • R d is absent or is a hydrogen atom, a deuterium atom, a halogen, a cyano group, an amino group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkylthio group or a C 1-6 alkylamino group, wherein the amino group, the C 1-6 alkyl group, the C 1-6 alkoxy group, the C 1-6 alkylthio group or the C 1-6 alkylamino group is optionally substituted with one or more R′;
  • R b and R d together with the atoms to which they are attached form a 3-12 membered cycloalkyl group, a 3-12 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S ⁇ O, S(O) 2 , or a 5-6 membered heteroaryl group containing one, two, three, or four heteroatoms selected from N, O, and S, and the 3-12 membered cycloalkyl group, the 3-12 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S ⁇ O, S(O) 2 , or the 5-6 membered heteroaryl group containing one, two, three, or four heteroatoms selected from N, O, and S are optionally substituted with one or more R ′;
  • R e and R f are each independently a hydrogen atom, a deuterium atom, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, a 3-12 membered cycloalkyl group, or a 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S ⁇ O, and S(O) 2 ;
  • Re and Rf in NR e R f together with the attached N atom form a 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S ⁇ O, and S(O) 2 ;
  • R a1 is a hydrogen atom, a C 1-6 alkyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S ⁇ O, and S(O) 2 , a 3-12-membered cycloalkyl-C 1-6 alkyl group, or a 3-12-membered heterocyclyl-C 1-6 alkyl group containing one or more heteroatoms selected from N, O, S, S ⁇ O, and S(O) 2 , wherein the C 1-6 alkyl group, the 3-12-membered cycloalkyl group, the 3-12-membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S ⁇ O, and S(O) 2 , the 3-12-membered cycloalkyl-C 1-6 alkyl group, or the 3-12-membered heterocyclyl-C 1-6
  • R′ is each independently a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a halogenated C 1-4 alkyl group, a deuterated C 1-6 alkyl group, a 3-12 membered cycloalkyl group, a 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S ⁇ O, and S(O) 2 , a C 1-4 alkylamino group, a di(C 1-4 alkyl)amino group, a C 1-6 alkoxy group, a C 1-6 alkoxy-C 1-6 alkyl group, a halogenated C 1-6 alkoxy group, or an oxo( ⁇ O);
  • n are each independently 0, 1, 2, 3, 4 or 5;
  • any one of R d or R 2 and any one of R a or R b together with the atoms to which they are attached must form one and only one ring, said ring being a 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S ⁇ O, S(O) 2, or a 5-6 membered heteroaryl containing one, two, three or four heteroatoms selected from N, O, S, said 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S ⁇ O, S(O) 2 , or a 5-6 membered heteroaryl containing one, two, three or four heteroatoms selected from N, O, S, and said 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S ⁇ O
  • the compound of formula I further has a structure as shown in formula II or formula III,
  • W is N, C or CR a ;
  • t 0, 1, 2, 3, 4, or 5.
  • Ring A is piperidinyl, azetidinyl, pyrrolidinyl, piperazinyl, homopiperidine, homopiperazine, 1,4-azaoxepane, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-azabicyclo[2.2.2]octane, 2-azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.2]octane or 2,5-diazabicyclo[2.2.1]heptane.
  • the E ring is phenyl or a 5-6 membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O, and S;
  • the E ring is phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene or pyrazole.
  • Q is Said place optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy;
  • Ring B is pyrrole, imidazole, pyrazole, thiazole, oxazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine or triazine;
  • X a , X b , and X c are each independently N or CH;
  • X 2 is N, CH, CH 2 , O, S, S(O) or S(O) 2 ;
  • X 3 and X 4 are each independently N or C, and X 3 and X 4 are not N at the same time, and X 1 , X 2 and X 3 are not N at the same time;
  • X 5 is a chemical bond, N, CH, CH 2 , O or S;
  • X6 is N, O, S or CH;
  • Q 1 is selected from the following groups: said Q 1 is optionally substituted by one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, deuterated methyl, ethyl, isopropyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy;
  • Q 1 is selected from the following groups:
  • R 5 and R 6 are each independently a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a 3-6 membered cycloalkyl group, a C 1-6 alkoxy group, a halogenated C 1-6 alkoxy group, a 3-12 membered cycloalkyloxy group, a C 1-6 alkylamino group, or a di(C 1-6 alkyl)amino group;
  • R 5 and R 6 together with the attached C atom form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group is optionally substituted with one or more methyl, ethyl, halogen, deuterium atom or cyclopropyl group;
  • R7 is methylene, ethylene or propylene
  • R4 is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a 1,2-dihydroxypropan-3-yl group, an acetyl group, a methoxyethyl group, an acetylcyano group, a deuterated methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a propenyl group or a propynyl group;
  • R 5 and R 6 are each independently a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, a deuterated methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a cyclopropyl group, a methylamino group, a dimethylamino group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a propenyl group, or a propynyl group;
  • R 5 and R 6 together with the attached C atom form a cyclopropyl or cyclobutyl group, wherein the cyclopropyl or cyclobutyl group is optionally substituted with one or more methyl groups, ethyl groups, halogen groups, deuterium atoms or cyclopropyl groups;
  • R7 is a methylene group.
  • L 2 is a chemical bond or NR 4 ;
  • L 2 is a chemical bond or NR 4 ;
  • R 4 is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a 1,2-dihydroxyprop-3-yl group, an acetyl group, a methoxyethyl group, an acetylcyano group, a deuterated methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a propenyl group or a propynyl group.
  • L 3 is NR 4 ;
  • L 3 is NR 4 ;
  • R 4 is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a 1,2-dihydroxyprop-3-yl group, an acetyl group, a methoxyethyl group, an acetylcyano group, a deuterated methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a propenyl group or a propynyl group.
  • L 4 is O or CR 5 R 6 ;
  • R 5 and R 6 are each independently a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a 3-6 membered cycloalkyl group, a C 1-6 alkoxy group, a halogenated C 1-6 alkoxy group, a 3-12 membered cycloalkyloxy group, a C 1-6 alkylamino group, or a di(C 1-6 alkyl)amino group;
  • R 5 and R 6 together with the attached C atom form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group is optionally substituted with one or more methyl, ethyl, halogen, deuterium atom or cyclopropyl group;
  • L 4 is O or CR 5 R 6 ;
  • R 5 and R 6 are each independently a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, a deuterated methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a cyclopropyl group, a methylamino group, a dimethylamino group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a propenyl group, or a propynyl group;
  • R 5 and R 6 together with the attached C atom form a cyclopropyl or cyclobutyl group, which is optionally substituted with one or more methyl, ethyl, halogen, deuterium atoms or cyclopropyl groups.
  • Y 1 is N or CR a ;
  • R a is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a 4-10 membered heterocyclic group, OR a1 , SR a1 or NR a1 , wherein the C 1-6 alkyl group, the C 2-4 alkenyl group, the C 2-4 alkynyl group or the 4-10 membered heterocyclic group is optionally substituted by one or more R′;
  • R a1 is a hydrogen atom, a C 1-4 alkyl group, a 3-6 membered cycloalkyl group, a 3-6 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S ⁇ O, and S(O) 2 , a 3-6 membered cycloalkyl-C 1-6 alkyl group, or a 3-6 membered heterocyclyl-C 1-6 alkyl group containing one or more heteroatoms selected from N, O, S, S ⁇ O, and S(O) 2 , wherein the C 1-4 alkyl group, the 3-6 membered cycloalkyl group, the 3-6 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S ⁇ O, and S(O) 2 , the 3-6 membered cycloalkyl-C 1-6 alkyl group, or the 3-6 membered heterocyclyl-C 1-6 alkyl group containing one or
  • R′ is a deuterium atom, F, Cl, cyano, hydroxy, amino, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, methoxy, pyrrolidinyl, 1-methylpyrrolidin-3-yl, or oxo ( ⁇ O);
  • Y 1 is N or CR a ;
  • Ra is a hydrogen atom, a deuterium atom, F, Cl, Br, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a difluoromethyl group, a trifluoromethyl group, an ethynyl group, a 2-(1,3-dimethylpyrrolidin-3-yl)ethynyl group, an acetylcyano group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a hydroxyethoxy group, an N',N'-dimethylaminoethoxy group, an N'-methylaminoethoxy group, a morpholinyl group, a 2-oxa-6-azaspiro[
  • R b is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a 4-10 membered heterocyclic group, OR a1 , SR a1 or NR a1 , wherein the C 1-6 alkyl group, the C 2-4 alkenyl group, the C 2-4 alkynyl group or the 4-10 membered heterocyclic group is optionally substituted by one or more R′;
  • R a1 is a hydrogen atom, a C 1-4 alkyl group, a 3-6 membered cycloalkyl group, a 3-6 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S ⁇ O, and S(O) 2 , a 3-6 membered cycloalkyl-C 1-6 alkyl group, or a 3-6 membered heterocyclyl-C 1-6 alkyl group containing one or more heteroatoms selected from N, O, S, S ⁇ O, and S(O) 2 , wherein the C 1-4 alkyl group, the 3-6 membered cycloalkyl group, the 3-6 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S ⁇ O, and S(O) 2 , the 3-6 membered cycloalkyl-C 1-6 alkyl group, or the 3-6 membered heterocyclyl-C 1-6 alkyl group containing one or
  • R b and R d together with the atoms to which they are attached form a 4-7 membered cycloalkyl group or a 5-7 membered heterocyclyl group containing 1 or 2 heteroatoms selected from N, O, S, S ⁇ O, S(O) 2 , wherein the 4-7 membered cycloalkyl group or the 5-7 membered heterocyclyl group containing 1 or 2 heteroatoms selected from N, O, S, S ⁇ O, S(O) 2 are optionally substituted with one or more R ′;
  • R′ is a deuterium atom, F, Cl, cyano, hydroxy, amino, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, methoxy, pyrrolidinyl, 1-methylpyrrolidin-3-yl, or oxo ( ⁇ O);
  • Y 2 is N or CR b ;
  • R b is a hydrogen atom, a deuterium atom, F, Cl, Br, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a difluoromethyl group, a trifluoromethyl group, an ethynyl group, a 2-(1,3-dimethylpyrrolidin-3-yl)ethynyl group, an acetylcyano group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a hydroxyethoxy group, an N',N'-dimethylaminoethoxy group, an N'-methylaminoethoxy group, a morpholinyl group, a 2-oxa-6-azaspir
  • Rb and Rd together with the atoms to which they are attached, form a morpholinyl, tetrahydrofuranyl, dihydroimidazolyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide or hexahydro-1,4-thiazepinyl-1,1-dioxide, wherein the morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxa
  • Y 3 is N or CR c ;
  • R c is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group, wherein the amino group, the methyl group, the isopropyl group, the ethyl group, the cyclopropyl group, the methoxy group and the cyclopropyloxy group are optionally substituted by one or more R ′;
  • R′ is a deuterium atom, F, Cl, cyano, hydroxy, amino, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, methoxy, pyrrolidinyl, 1-methylpyrrolidin-3-yl, or oxo ( ⁇ O);
  • Y 3 is N or CR c ;
  • R c is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group.
  • Y 4 is N or CR d ;
  • R d is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group, wherein the amino group, the methyl group, the isopropyl group, the ethyl group, the cyclopropyl group, the methoxy group and the cyclopropyloxy group are optionally substituted by one or more R's;
  • R′ is a deuterium atom, F, Cl, cyano, hydroxy, amino, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, methoxy, pyrrolidinyl, 1-methylpyrrolidin-3-yl, or oxo ( ⁇ O);
  • Y 4 is N or CR d ;
  • Rb and Rd together with the atoms to which they are attached form a morpholinyl, tetrahydrofuranyl, dihydroimidazolyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide or hexahydro-1,4-thiazepinyl-1,1-dioxide, wherein the morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxazepinyl,
  • Y 5 is N, CR e or C; when L 2 is a chemical bond, Y 5 is N; when L 2 is O or NR 4 , Y 5 is CR e or C;
  • Y 5 is N, CH or C; when L 2 is a chemical bond, Y 5 is N; when L 2 is O or NR 4 , Y 5 is CH or C.
  • R 1 is a halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, oxetyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl group, wherein the halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, oxetyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl group is optionally substituted with one or more F, Cl, methyl, ethyl, cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetyl, butylene oxide, a deuterium atom, a phenyl, pyridinyl, or NR x R y , wherein the methyl, ethyl, cyclomethyl, vinyl
  • R x and R y are each independently a hydrogen atom, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, azetidinylmethyl or azetidinylethyl, and the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, azetidinylmethyl or azetidinylethyl is optionally substituted with one or more R′;
  • R in NRxRy is taken together with Ry and the nitrogen atom to which it is attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1] heptanyl , 9-azabicyclo[3.3.1]nonanyl, 2-azabicyclo[4.1.0]heptanyl, or 2-azabicyclo[3.1.0]hexanyl, said azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptanyl, 9-azabicyclo[3.3.1]nonanyl, 2-azabicyclo[4.1.0]heptanyl, or 2-azabicyclo[3.1.0]hexanyl being optionally substitute
  • R′ is a deuterium atom, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, vinyl, ethynyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, or oxo ( ⁇ O)
  • R 1 is selected from the following groups:
  • R 2 is a hydrogen atom, a deuterium atom, F, Cl, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a cyclopropyl group, a cyclobutyl group, a deuterated methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a vinyl group, a propenyl group, an ethynyl group, a propynyl group, a cyano group, a difluoromethoxy group, a trifluoromethoxy group, a methoxy group, a methoxymethyl group or an oxo group ( ⁇ O);
  • Rb together with R2 and the atoms to which they are attached form a morpholinyl, tetrahydrofuranyl, dihydroimidazolyl, thiomorpholinyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide or hexahydro-1,4-thiazepinyl-1,1-dioxide, wherein the morpholinyl, thiomorpholinyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, 4-thiomorpholinyl-1,1-di
  • 1-dioxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide or hexahydro-1,4-thiazepinyl-1,1-dioxide is optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, dimethylaminoalkyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy.
  • R 3 is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a nitro group, a C 1-4 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a 3-6 membered saturated or unsaturated cycloalkyl group, a 3-6 membered saturated or unsaturated heterocyclic group containing one or more heteroatoms selected from N, O, S, S ⁇ O, and S(O) 2 , a halogenated C 1-4 alkyl group, a halogenated C 1-4 alkoxy group, OR e , SOR e , S(O) 2 R e , C( ⁇ O)R e , C( ⁇ O)NR e , NRe R f , NRe C( ⁇ O)R f , S(O) 2 NRe , P(O)(R e ) 2 , wherein the C
  • R e and R f are each independently a hydrogen atom, a deuterium atom, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, or a 3-12 membered cycloalkyl group;
  • Re and Rf in NR e R f together with the attached N atom form a 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S ⁇ O, and S(O) 2 ;
  • R 3 is a hydrogen atom, a deuterium atom, F, Cl, a cyano group, a nitro group, a methyl group, an ethyl group, an isopropyl group, an ethylene group, an acetylene group, a cyclopropyl group, a cyclobutyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a hydroxyl group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a methylamino group, an ethylamino group, SOCH 3 , S(O) 2 CH 3 , C( ⁇ O)CH 3 , C( ⁇ O)NCH 3 , NHC( ⁇ O)CH 3 , S(O) 2 NCH 3 , P(O)(CH 3 , S
  • R b and R d together with the atoms to which they are attached form a G ring, wherein the G ring is a 4-7 membered cycloalkyl group, a 4-7 membered heterocyclyl group containing 1 or 2 heteroatoms selected from N, O, S, S ⁇ O, S(O) 2 , and the 4-7 membered cycloalkyl group, the 4-7 membered heterocyclyl group containing 1 or 2 heteroatoms selected from N, O, S, S ⁇ O, S(O) 2 are optionally substituted with one or more R ′;
  • R b and R 2 together with the atoms to which they are attached form a G ring, wherein the G ring is a 4-7 membered cycloalkyl group, a 4-7 membered heterocyclyl group containing 1 or 2 heteroatoms selected from N, O, S, S ⁇ O, S(O) 2 , and the 4-7 membered cycloalkyl group, the 4-7 membered heterocyclyl group containing 1 or 2 heteroatoms selected from N, O, S, S ⁇ O, S(O) 2 are optionally substituted with one or more R ′;
  • the G ring is morpholinyl, tetrahydrofuranyl, dihydroimidazolyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide or hexahydro-1,4-thiazepinyl-1,1-dioxide, the morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxazepinyl , hexahydro-1,4-thiazepiny
  • the compound of formula I further has a structure as shown in formula II,
  • Ring E is phenyl or a 5-6 membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O and S;
  • Q1 is Said place optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy;
  • L 2 is a chemical bond or NR 4 ;
  • L 3 is NR 4 ;
  • L 4 is O or CR 5 R 6 ;
  • Y1 is N or CR a ;
  • Y 3 is N or CR c ;
  • Y 5 is N, CH or C; when L 2 is a chemical bond, Y 5 is N; when L 2 is O or NR 4 , Y 5 is CH or C;
  • R 1 is a halomethyl group, vinyl group, propenyl group, ethynyl group, propynyl group, butynyl group, oxetyl group, cyclobutenyl group, cyclopentenyl group or cyclohexenyl group, wherein the halomethyl group, vinyl group, propenyl group, ethynyl group, propynyl group, butynyl group, oxetyl group, cyclobutenyl group, cyclopentenyl group or cyclohexenyl group is optionally substituted with one or more F, Cl, methyl group, ethyl group, cyclopropyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, oxetyl group, butylene oxide group, deuterium atom, phenyl group, pyridinyl group or NR x R
  • R4 is a hydrogen atom, a C1-6 alkyl group, a halogenated C1-6 alkyl group, a deuterated C1-6 alkyl group, a C2-4 alkenyl group, a C2-4 alkynyl group or a 3-12 membered cycloalkyl group, wherein the C1-6 alkyl group, the halogenated C1-6 alkyl group, the deuterated C1-6 alkyl group, the C2-4 alkenyl group, the C2-4 alkynyl group or the 3-12 membered cycloalkyl group is optionally substituted with one or more methyl groups, ethyl groups, halogen groups, deuterium atoms, cyano groups, hydroxyl groups, methoxy groups or cyclopropyl groups;
  • R 5 and R 6 are each independently a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a 3-6 membered cycloalkyl group, a C 1-6 alkoxy group, a halogenated C 1-6 alkoxy group, a 3-12 membered cycloalkyloxy group, a C 1-6 alkylamino group, or a di(C 1-6 alkyl)amino group;
  • R 5 and R 6 together with the attached C atom form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group is optionally substituted with one or more methyl, ethyl, halogen, deuterium atom or cyclopropyl group;
  • R7 is methylene, ethylene or propylene
  • R a is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a 4-10 membered heterocyclic group, OR a1 , SR a1 or NR a1 , wherein the C 1-6 alkyl group, the C 2-4 alkenyl group, the C 2-4 alkynyl group or the 4-10 membered heterocyclic group is optionally substituted by one or more R′;
  • R a1 is a hydrogen atom, a C 1-4 alkyl group, a 3-6 membered cycloalkyl group, a 3-6 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S ⁇ O, and S(O) 2 , a 3-6 membered cycloalkyl-C 1-6 alkyl group, or a 3-6 membered heterocyclyl-C 1-6 alkyl group containing one or more heteroatoms selected from N, O, S, S ⁇ O, and S(O) 2 , wherein the C 1-4 alkyl group, the 3-6 membered cycloalkyl group, the 3-6 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S ⁇ O, and S(O) 2 , the 3-6 membered cycloalkyl-C 1-6 alkyl group, or the 3-6 membered heterocyclyl-C 1-6 alkyl group containing one or
  • R c is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group, wherein the amino group, the methyl group, the isopropyl group, the ethyl group, the cyclopropyl group, the methoxy group and the cyclopropyloxy group are optionally substituted by one or more R ′;
  • R x and R y are each independently a hydrogen atom, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, azetidinylmethyl or azetidinylethyl, and the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, azetidinylmethyl or azetidinylethyl is optionally substituted with one or more R′;
  • R in NRxRy is taken together with Ry and the nitrogen atom to which it is attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1] heptanyl , 9-azabicyclo[3.3.1]nonanyl, 2-azabicyclo[4.1.0]heptanyl, or 2-azabicyclo[3.1.0]hexanyl, said azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptanyl, 9-azabicyclo[3.3.1]nonanyl, 2-azabicyclo[4.1.0]heptanyl, or 2-azabicyclo[3.1.0]hexanyl being optionally substitute
  • Re and Rf in NR e R f together with the attached N atom form a 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S ⁇ O, and S(O) 2 ;
  • Ring B is pyrrole, imidazole, pyrazole, thiazole, oxazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine or triazine;
  • X a , X b , and X c are each independently N or CH;
  • X 1 is a chemical bond, N, CH, CH 2 , S, O, S(O) or S(O) 2 ;
  • X 2 is N, CH, CH 2 , O, S, S(O) or S(O) 2 ;
  • X 3 and X 4 are each independently N or C, and X 3 and X 4 are not N at the same time, and X 1 , X 2 and X 3 are not N at the same time;
  • X 5 is a chemical bond, N, CH, CH 2 , O or S;
  • X6 is N, O, S or CH;
  • R′ is each independently a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a halogenated C 1-4 alkyl group, a deuterated C 1-6 alkyl group, a 3-12 membered cycloalkyl group, a 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S ⁇ O, and S(O) 2 , a C 1-4 alkylamino group, a di(C 1-4 alkyl)amino group, a C 1-6 alkoxy group, a C 1-6 alkoxy-C 1-6 alkyl group, a halogenated C 1-6 alkoxy group, or an oxo( ⁇ O);
  • n, and t are each independently 0, 1, 2, 3, 4, or 5.
  • the compound of formula I further has a structure of formula III,
  • Ring E is phenyl or a 5-6 membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O and S;
  • W is N, C or CR a ;
  • Q1 is Said place optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy;
  • L 2 is a chemical bond or NR 4 ;
  • L 3 is NR 4 ;
  • L 4 is O or CR 5 R 6 ;
  • Y1 is N or CR a ;
  • Y 3 is N or CR c ;
  • Y 4 is N or CR d ;
  • Y 5 is N, CH or C; when L 2 is a chemical bond, Y 5 is N; when L 2 is O or NR 4 , Y 5 is CH or C;
  • R 1 is a halomethyl group, vinyl group, propenyl group, ethynyl group, propynyl group, butynyl group, oxetyl group, cyclobutenyl group, cyclopentenyl group or cyclohexenyl group, wherein the halomethyl group, vinyl group, propenyl group, ethynyl group, propynyl group, butynyl group, oxetyl group, cyclobutenyl group, cyclopentenyl group or cyclohexenyl group is optionally substituted with one or more F, Cl, methyl group, ethyl group, cyclopropyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, oxetyl group, butylene oxide group, deuterium atom, phenyl group, pyridinyl group or NR x R
  • R a is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a 4-10 membered heterocyclic group, OR a1 , SR a1 or NR a1 , wherein the C 1-6 alkyl group, the C 2-4 alkenyl group, the C 2-4 alkynyl group or the 4-10 membered heterocyclic group is optionally substituted by one or more R′;
  • R c is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group, wherein the amino group, the methyl group, the isopropyl group, the ethyl group, the cyclopropyl group, the methoxy group and the cyclopropyloxy group are optionally substituted by one or more R ′;
  • R x and R y are each independently a hydrogen atom, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, azetidinylmethyl or azetidinylethyl, and the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, azetidinylmethyl or azetidinylethyl is optionally substituted with one or more R′;
  • R in NRxRy is taken together with Ry and the nitrogen atom to which it is attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1] heptanyl , 9-azabicyclo[3.3.1]nonanyl, 2-azabicyclo[4.1.0]heptanyl, or 2-azabicyclo[3.1.0]hexanyl, said azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptanyl, 9-azabicyclo[3.3.1]nonanyl, 2-azabicyclo[4.1.0]heptanyl, or 2-azabicyclo[3.1.0]hexanyl being optionally substitute
  • R e and R f are each independently a hydrogen atom, a deuterium atom, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, or a 3-12 membered cycloalkyl group;
  • Re and Rf in NR e R f together with the attached N atom form a 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S ⁇ O, and S(O) 2 ;
  • Ring B is pyrrole, imidazole, pyrazole, thiazole, oxazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine or triazine;
  • X a , X b , and X c are each independently N or CH;
  • X 1 is a chemical bond, N, CH, CH 2 , S, O, S(O) or S(O) 2 ;
  • X 2 is N, CH, CH 2 , O, S, S(O) or S(O) 2 ;
  • X 3 and X 4 are each independently N or C, and X 3 and X 4 are not N at the same time, and X 1 , X 2 and X 3 are not N at the same time;
  • X 5 is a chemical bond, N, CH, CH 2 , O or S;
  • X6 is N, O, S or CH;
  • R′ is each independently a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a halogenated C 1-4 alkyl group, a deuterated C 1-6 alkyl group, a 3-12 membered cycloalkyl group, a 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S ⁇ O, and S(O) 2 , a C 1-4 alkylamino group, a di(C 1-4 alkyl)amino group, a C 1-6 alkoxy group, a C 1-6 alkoxy-C 1-6 alkyl group, a halogenated C 1-6 alkoxy group, or an oxo( ⁇ O);
  • R′ is each independently a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-4 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a halo-substituted C 1-4 alkyl group, a deuterated C 1-4 alkyl group, a 3-10 membered cycloalkyl group, a 3-10 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S ⁇ O, and S(O) 2 , a C 1-4 alkylamino group, a di(C 1-4 alkyl)amino group, a C 1-6 alkoxy group, a C 1-6 alkoxy-C 1-6 alkyl group, a halo-substituted C 1-6 alkoxy group, or an oxo( ⁇ O);
  • R′ is each independently a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-4 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a halogenated C 1-4 alkyl group, a deuterated C 1-4 alkyl group, a 3-6 membered cycloalkyl group, a 4-7 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S ⁇ O, and S(O) 2 , a C 1-4 alkylamino group, a di(C 1-4 alkyl)amino group, a C 1-4 alkoxy group, a C 1-4 alkoxy-C 1-4 alkyl group, a halogenated C 1-4 alkoxy group, or an oxo( ⁇ O) group;
  • R′ is a deuterium atom, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, vinyl, ethynyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy or oxo ( ⁇ O).
  • Ring E is phenyl or a 5-6 membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O and S;
  • Q1 is Said place optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy;
  • L 2 is a chemical bond or NR 4 ;
  • L 3 is NR 4 ;
  • L 4 is O or CR 5 R 6 ;
  • Y1 is N or CR a ;
  • Y 2 is N or CR b ;
  • Y 4 is N or CR d ;
  • Y 5 is N, CH or C; when L 2 is a chemical bond, Y 5 is N; when L 2 is O or NR 4 , Y 5 is CH or C;
  • R 1 is a halomethyl group, vinyl group, propenyl group, ethynyl group, propynyl group, butynyl group, oxetyl group, cyclobutenyl group, cyclopentenyl group or cyclohexenyl group, wherein the halomethyl group, vinyl group, propenyl group, ethynyl group, propynyl group, butynyl group, oxetyl group, cyclobutenyl group, cyclopentenyl group or cyclohexenyl group is optionally substituted with one or more F, Cl, methyl group, ethyl group, cyclopropyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, oxetyl group, butylene oxide group, deuterium atom, phenyl group, pyridinyl group or NR x R
  • R4 is a hydrogen atom, a C1-6 alkyl group, a halogenated C1-6 alkyl group, a deuterated C1-6 alkyl group, a C2-4 alkenyl group, a C2-4 alkynyl group or a 3-12 membered cycloalkyl group, wherein the C1-6 alkyl group, the halogenated C1-6 alkyl group, the deuterated C1-6 alkyl group, the C2-4 alkenyl group, the C2-4 alkynyl group or the 3-12 membered cycloalkyl group is optionally substituted with one or more methyl groups, ethyl groups, halogen groups, deuterium atoms, cyano groups, hydroxyl groups, methoxy groups or cyclopropyl groups;
  • R 5 and R 6 are each independently a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a 3-6 membered cycloalkyl group, a C 1-6 alkoxy group, a halogenated C 1-6 alkoxy group, a 3-12 membered cycloalkyloxy group, a C 1-6 alkylamino group, or a di(C 1-6 alkyl)amino group;
  • R7 is methylene, ethylene or propylene
  • W is N, C or CR a ;
  • R a and R b are each independently a hydrogen atom, a deuterium atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a 4-10 membered heterocyclic group, OR a1 , SR a1 or NR a1 , wherein the C 1-6 alkyl group, the C 2-4 alkenyl group, the C 2-4 alkynyl group or the 4-10 membered heterocyclic group is optionally substituted by one or more R′;
  • R c is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group, wherein the amino group, the methyl group, the isopropyl group, the ethyl group, the cyclopropyl group, the methoxy group and the cyclopropyloxy group are optionally substituted by one or more R ′;
  • R d is absent or is a hydrogen atom, a deuterium atom, a halogen, a cyano group, an amino group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkylthio group or a C 1-6 alkylamino group, wherein the amino group, the C 1-6 alkyl group, the C 1-6 alkoxy group, the C 1-6 alkylthio group or the C 1-6 alkylamino group is optionally substituted with one or more R′;
  • R e and R f are each independently a hydrogen atom, a deuterium atom, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, or a 3-12 membered cycloalkyl group;
  • Re and Rf in NR e R f together with the attached N atom form a 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S ⁇ O, and S(O) 2 ;
  • R x and R y are each independently a hydrogen atom, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, azetidinylmethyl or azetidinylethyl, and the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, azetidinylmethyl or azetidinylethyl is optionally substituted with one or more R′;
  • R in NRxRy is taken together with Ry and the nitrogen atom to which it is attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1] heptanyl , 9-azabicyclo[3.3.1]nonanyl, 2-azabicyclo[4.1.0]heptanyl, or 2-azabicyclo[3.1.0]hexanyl, said azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptanyl, 9-azabicyclo[3.3.1]nonanyl, 2-azabicyclo[4.1.0]heptanyl, or 2-azabicyclo[3.1.0]hexanyl being optionally substitute
  • R a1 is a hydrogen atom, a C 1-4 alkyl group, a 3-6 membered cycloalkyl group, a 3-6 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S ⁇ O, and S(O) 2 , a 3-6 membered cycloalkyl-C 1-6 alkyl group, or a 3-6 membered heterocyclyl-C 1-6 alkyl group containing one or more heteroatoms selected from N, O, S, S ⁇ O, and S(O) 2 , wherein the C 1-4 alkyl group, the 3-6 membered cycloalkyl group, the 3-6 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S ⁇ O, and S(O) 2 , the 3-6 membered cycloalkyl-C 1-6 alkyl group, or the 3-6 membered heterocyclyl-C 1-6 alkyl group containing one or
  • Ring B is pyrrole, imidazole, pyrazole, thiazole, oxazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine or triazine;
  • X a , X b , and X c are each independently N or CH;
  • X 1 is a chemical bond, N, CH, CH 2 , S, O, S(O) or S(O) 2 ;
  • X 2 is N, CH, CH 2 , O, S, S(O) or S(O) 2 ;
  • X 3 and X 4 are each independently N or C, and X 3 and X 4 are not N at the same time, and X 1 , X 2 and X 3 are not N at the same time;
  • X 5 is a chemical bond, N, CH, CH 2 , O or S;
  • n, and t are each independently 0, 1, 2, or 3.
  • Ring A is piperidinyl, azetidinyl, pyrrolidinyl, piperazinyl, homopiperidine, homopiperazine, 1,4-azaoxepane, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-azabicyclo[2.2.2]octane, 2-azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.2]octane, 2,5-diazabicyclo[2.2.1]heptane, 8-azabicyclo[3.2.1]octane, 6-azabicyclo[3.1.1]heptane or 7-azabicyclo[2.2.1]heptane;
  • Ring E is phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene or pyrazole;
  • Q1 is selected from the following groups: said Q 1 is optionally substituted by one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, deuterated methyl, ethyl, isopropyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy;
  • L 2 is a chemical bond or NR 4 ;
  • L 3 is NR 4 ;
  • L 4 is O or CR 5 R 6 ;
  • R4 is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a 1,2-dihydroxypropan-3-yl group, an acetyl group, a methoxyethyl group, an acetylcyano group, a deuterated methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a propenyl group or a propynyl group;
  • R 5 and R 6 together with the attached C atom form a cyclopropyl or cyclobutyl group, wherein the cyclopropyl or cyclobutyl group is optionally substituted with one or more methyl groups, ethyl groups, halogen groups, deuterium atoms or cyclopropyl groups;
  • R7 is methylene
  • Y1 is N or CR a ;
  • Y 2 is N or CR b ;
  • Y 3 is N or CR c ;
  • Y 4 is N or CR d ;
  • Y 5 is N, CH or C; when L 2 is a chemical bond, Y 5 is N; when L 2 is O or NR 4 , Y 5 is CH or C;
  • Ra is a hydrogen atom, a deuterium atom, F, Cl, Br, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a difluoromethyl group, a trifluoromethyl group, an ethynyl group, a 2-(1,3-dimethylpyrrolidin-3-yl)ethynyl group, an acetylcyano group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a hydroxyethoxy group, an N',N'-dimethylaminoethoxy group, an N'-methylaminoethoxy group, a morpholinyl group, a 2-oxa-6-azaspiro[
  • R c is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group;
  • Rb and Rd together with the atoms to which they are attached form a morpholinyl, tetrahydrofuranyl, dihydroimidazolyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide or hexahydro-1,4-thiazepinyl-1,1-dioxide, wherein the morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxazepinyl,
  • R1 is selected from the following groups:
  • Rb together with R2 and the atoms to which they are attached form a morpholinyl, tetrahydrofuranyl, dihydroimidazolyl, thiomorpholinyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide or hexahydro-1,4-thiazepinyl-1,1-dioxide, wherein the morpholinyl, thiomorpholinyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, 4-thiomorpholinyl-1,1-di
  • 1-dioxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide, or hexahydro-1,4-thiazepinyl-1,1-dioxide is optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, dimethylaminoalkyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy;
  • R 3 is a hydrogen atom, a deuterium atom, F, Cl, a cyano group, a nitro group, a methyl group, an ethyl group, an isopropyl group, an ethylene group, an acetylene group, a cyclopropyl group, a cyclobutyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a hydroxyl group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a methylamino group, an ethylamino group, SOCH 3 , S(O) 2 CH 3 , C( ⁇ O)CH 3 , C( ⁇ O)NCH 3 , NHC( ⁇ O)CH 3 , S(O) 2 NCH 3 , P(O)(CH 3 ) 2
  • Ring G is morpholinyl, tetrahydrofuranyl, dihydroimidazolyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide or hexahydro-1,4-thiazepinyl-1,1-dioxide, and the morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl,
  • W is C or CH
  • n, and t are each independently 0, 1, 2, or 3.
  • Ring A is piperidinyl, azetidinyl, pyrrolidinyl, piperazinyl, homopiperazine, 1,4-azaoxepane, cyclopentyl, cyclohexyl, or 8-azabicyclo[3.2.1]octane;
  • Ring E is phenyl
  • Q1 is selected from the following groups:
  • L 1 is a chemical bond, O, NR 4 , CR 5 R 6 or C( ⁇ O);
  • L 2 is a chemical bond or NH
  • L 3 is NH
  • L 4 is O or CR 5 R 6 ;
  • R4 is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a 1,2-dihydroxypropan-3-yl group, an acetyl group, a methoxyethyl group, an acetylcyano group, a deuterated methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a propenyl group or a propynyl group;
  • R 5 and R 6 are each independently a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, a deuterated methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a cyclopropyl group, a methylamino group, a dimethylamino group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a propenyl group, or a propynyl group;
  • R 5 and R 6 together with the attached C atom form a cyclopropyl or cyclobutyl group, wherein the cyclopropyl or cyclobutyl group is optionally substituted with one or more methyl groups, ethyl groups, halogen groups, deuterium atoms or cyclopropyl groups;
  • Y1 is N or CR a ;
  • Y 2 is N or CR b ;
  • Y 3 is N
  • Y 4 is N or CR d ;
  • Y 5 is N, CH or C; when L 2 is a chemical bond, Y 5 is N; when L 2 is O or NR 4 , Y 5 is CH or C;
  • Ra is a hydrogen atom, a deuterium atom, F, Cl, Br, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a difluoromethyl group, a trifluoromethyl group, an ethynyl group, a 2-(1,3-dimethylpyrrolidin-3-yl)ethynyl group, an acetylcyano group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a hydroxyethoxy group, an N',N'-dimethylaminoethoxy group, an N'-methylaminoethoxy group, a morpholinyl group, a 2-oxa-6-azaspiro[
  • Rb and Rd together with the atoms to which they are attached form a morpholinyl, tetrahydrofuranyl, dihydroimidazolyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide or hexahydro-1,4-thiazepinyl-1,1-dioxide, wherein the morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxazepinyl,
  • R1 is selected from the following groups:
  • Rb together with R2 and the atoms to which they are attached form a morpholinyl, tetrahydrofuranyl, dihydroimidazolyl, thiomorpholinyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide or hexahydro-1,4-thiazepinyl-1,1-dioxide, wherein the morpholinyl, thiomorpholinyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, 4-thiomorpholinyl-1,1-di
  • 1-dioxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide, or hexahydro-1,4-thiazepinyl-1,1-dioxide is optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, dimethylaminoalkyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy;
  • R3 is a hydrogen atom, a deuterium atom, F, Cl, a cyano group, a nitro group, a methyl group, an ethyl group, an isopropyl group, an ethylene group, an acetylene group, a cyclopropyl group, a cyclobutyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a hydroxyl group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a methylamino group, an ethylamino group, and the methyl group, ethyl group, isopropyl group, an ethylene group, an acetylene group, a cyclopropyl group, a cyclobutyl group, a difluoroethyl
  • Ring G is morpholinyl, tetrahydrofuranyl, dihydroimidazolyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxazepinyl, wherein the morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxazepinyl is optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, dimethylaminoalkyl, methoxy, ethoxy, difluorome
  • W is C or CH
  • n, and t are each independently 0, 1, 2, or 3.
  • the compound represented by formula I is selected from the following compounds:
  • the present invention provides a method for preparing a compound of formula II, comprising the following reaction steps:
  • Compound II-3 undergoes a reduction reaction to form Compound II-5; or Compound II-3 undergoes a halogenation reaction to form Compound II-4, and Compound II-4 then undergoes a coupling reaction to form Compound II-5;
  • the present invention provides a method for preparing a compound of formula III, comprising the following reaction steps:
  • Compound III-3 undergoes a reduction reaction to form Compound III-5; or Compound III-3 undergoes a halogenation reaction to form Compound III-4, and Compound III-4 then undergoes a coupling reaction to form Compound III-5;
  • A, E, Q 1 , M, Y 1 , Y 3 , Y 4 , Y 5 , L 1 , L 2 , L 3 , L 4 , R 1 , R 2 , R 3 , R ' , G, W, m, n, and t are as defined above;
  • X' is NO 2 or H;
  • X" is a halogen; and Boc is tert-butyloxycarbonyl.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof and a pharmaceutically acceptable carrier or excipient;
  • the pharmaceutical composition is in the form of tablets, capsules, pills, granules, powders, suppositories, injections, solutions, suspensions, ointments, patches, lotions, drops, liniments, or sprays.
  • the present invention provides the use of the aforementioned compound or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate, or a pharmaceutical composition comprising the aforementioned compound or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate and a pharmaceutically acceptable carrier or excipient in the preparation of a pharmaceutical composition for treating diseases mediated by abnormal HER2;
  • the disease is a tumor disease
  • the tumor disease includes: head and neck cancer, nasopharyngeal cancer, melanoma, bladder cancer, esophageal cancer, kidney cancer, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, pancreatic cancer, glioma, prostate cancer, leukemia, lymphoma, gastric cancer, lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, squamous cell carcinoma, bile duct cancer, endometrial cancer, multiple myeloma or mesothelioma, atherosclerosis or pulmonary fibrosis.
  • the present invention provides a method for treating diseases mediated by abnormal HER2, which comprises administering to a patient in need thereof a therapeutically effective amount of the above-mentioned compound or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate or pharmaceutical composition.
  • the disease is a tumor disease
  • the tumor disease includes: head and neck cancer, nasopharyngeal cancer, melanoma, bladder cancer, esophageal cancer, kidney cancer, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, pancreatic cancer, glioma, prostate cancer, leukemia, lymphoma, gastric cancer, lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, squamous cell carcinoma, bile duct cancer, endometrial cancer, multiple myeloma or mesothelioma, atherosclerosis or pulmonary fibrosis.
  • the present invention provides a method for treating tumors, which comprises administering to a patient in need thereof a therapeutically effective amount of the above-mentioned compound or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate or pharmaceutical composition.
  • the patient is preferably a mammal, and the mammal is preferably a human.
  • the administration routes include oral, mucosal, sublingual, ocular, topical, parenteral, rectal, intracisternal, vaginal, peritoneal, bladder, and nasal administration.
  • the tumor comprises: head and neck cancer, melanoma, bladder cancer, esophageal cancer, anaplastic large cell lymphoma, renal cell carcinoma, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, pancreatic cancer, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, non-Hodgkin lymphoma, gastric cancer, lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, squamous cell carcinoma, bile duct cancer, endometrial cancer, multiple myeloma, or mesothelioma.
  • the compounds of the present invention or their pharmaceutically acceptable salts, stereoisomers, racemates, tautomers, isotope-labeled substances, deuterated substances, N-oxides, prodrug molecules, hydrates or solvates or pharmaceutical compositions can be introduced into the body through any suitable route, such as oral administration, intravenous injection, intranasal administration, external application, intramuscular injection, intradermal injection, transdermal administration or subcutaneous administration.
  • the compounds provided herein, or pharmaceutically acceptable salts, stereoisomers, racemates, tautomers, isotopically labeled substances, deuterated substances, N-oxides, prodrug molecules, hydrates or solvates thereof, or pharmaceutical compositions thereof can be formulated into dosage forms suitable for drug release and administered by injection (e.g., subcutaneous, intravenous, intramuscular, arterial, intrathecal, intracapsular, intrathecal, intracardial, intradermal, intraperitoneal, transtracheal, epidermal, intraarticular, subcapsular, subarachnoid, intraspinal, intrasternal, and/or infusion) and non-injection routes of administration (e.g., oral, enteral, buccal, nasal, intranasal, mucosal, epidermal, patch, dermal, ophthalmic, pulmonary, sublingual, rectal, vaginal or epidermal topical administration).
  • injection e.g., subcutaneous, intravenous, intramuscular, arterial, intrat
  • Suitable dosage forms include, but are not limited to, dosage forms for injection such as emulsions, solutions and suspensions, dosage forms for oral administration such as tablets, capsules, pills, dragees, powders and granules, dosage forms for topical or transdermal administration such as sprays, ointments, pastes, creams, lotions, gels, solutions, drug patches and inhalants, and dosage forms for vaginal or rectal administration such as suppositories.
  • dosage forms for injection such as emulsions, solutions and suspensions
  • dosage forms for oral administration such as tablets, capsules, pills, dragees, powders and granules
  • dosage forms for topical or transdermal administration such as sprays, ointments, pastes, creams, lotions, gels, solutions, drug patches and inhalants
  • dosage forms for vaginal or rectal administration such as suppositories.
  • HER2 abnormality refers to HER2 gene mutation, HER2 amplification, or HER2 overexpression
  • the HER2 gene mutation includes mutations in exons 18-21, transmembrane domain mutations, and extracellular region mutations; the mutations include point mutations (e.g., exon 20 point mutations), deletion mutations, and insertion mutations (e.g., exon 20 insertion mutations);
  • the exon 20 insertion mutations include Y772_A775dup, G776delinsVC, G778_P780dup, G776delinsLC, E770delinsEAYVM, E770_A771insAYVM, Y772_V773insMMAY, M774delinsWLV, A775_G776insYVMS, A775_G776insVVMA, A775_G776insSVMA, A775_G776insTVMA, A775_G776insC, G776delinsAVGC, G776 76delinsVV, G776delinsVG, G776_V777delinsCVC, G776_V777delinsVC, G776delinsIC, V777delinsAPL, V777_G778insC, G778insGSP, G778_S779insCPG; point mutations in ex
  • the compounds or pharmaceutical compositions of the present invention can be administered simultaneously with one or more other pharmacologically active substances, thereby achieving additive or even synergistic effects in vivo.
  • the compounds of the present invention can be combined with other pharmacologically active substances to form a single pharmaceutical composition, or administered simultaneously as separate compositions, or administered sequentially as separate compositions.
  • Additional pharmacologically active substances that can be administered concurrently with the compounds of the present invention for the treatment of cancer include, but are not limited to: 1) EGFR family inhibitors, monoclonal/diabodies, or ADCs, such as osimertinib, ametinib, vumetinib, befortinib, rizitinib, riertinib, liertinib, olmutinib, lazertinib, PLB1004, afatinib, dacomitinib, erlotinib, gefitinib, icotinib, cetuximab, panitumumab, amivantamab, lapatinib, neratinib, tucatinib, trastuzumab, pertuzumab, margetuximab, emtansinetrastuzumab, denatinib, and the like; 2) monoclonal/d
  • Anti-angiogenic drugs such as bevacizumab, aflibercept, ramucirumab, nintedanib, etc.
  • Apoptosis inducers such as Bcl-2), such as obatoclax, venetoclax, etc.
  • Chemotherapeutic drugs such as fluorouracil, doxorubicin, daunorubicin, tamoxifen, leuprorelin, goserelin, flutamide, nilutamide, finasteride, dexamethasone, aminoglutethimide, amsacrine, anastrozole, asparaginase, BCG, bicalutamide, bleomycin, busulfan, camptothecin, capecitabine, carboplatin, cisplatin, carboplatin, Mustine, chlorambucil, cladribine, colchicine, cyclophosphamide, cyproterone
  • the compounds provided herein can be used concurrently with immunotherapeutic agents.
  • immunotherapeutic agents include: PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, such as durvalumab; agents that reverse multidrug resistance in tumor cells (such as verapamil), mycophenolate mofetil, thalidomide, cyclosporine, and monoclonal antibodies.
  • the compounds provided herein can be used concurrently with non-chemical methods for cancer treatment. In certain embodiments, the compounds provided herein can be used concurrently with radiotherapy. In certain embodiments, the compounds provided herein can be used in combination with surgery, tumor thermal therapy, focused ultrasound therapy, cryotherapy, or a combination of these therapies.
  • the present invention was carried out under conventional conditions or those recommended by the manufacturer.
  • the raw materials or excipients, as well as the reagents or instruments used, for which the manufacturer is not specified, are all conventional products that can be purchased commercially.
  • the minimum and maximum carbon atom content of a hydrocarbon group is indicated by a prefix.
  • the prefix (C ab )alkyl represents any alkyl group containing from “a” to "b” carbon atoms.
  • C 1-6 alkyl refers to an alkyl group containing from 1 to 6 carbon atoms.
  • the alkyl group can be branched or straight chain.
  • the atoms described in the compounds of the present invention include their isotopes, for example, hydrogen may be deuterium or tritium.
  • “Bridged ring” refers to a polycyclic group in which any two rings share two atoms that are directly or indirectly connected. It may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system.
  • the ring atoms may be all carbon atoms or one or more of the ring atoms may be selected from N, O, S, SO or S(O) 2. 7-10 rings are preferred.
  • Spirocyclic refers to a polycyclic group in which any two rings share a common carbon atom, may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system, and the ring atoms may be all carbon atoms or one or more of the ring atoms may be selected from N, O, S, SO or S(O) 2. Preferably, the ring has 5-10 rings.
  • Fused ring refers to a polycyclic group in which each ring shares two adjacent atoms with other rings in the system. It may contain one or more double bonds or have a completely conjugated ⁇ -electron system.
  • the ring atoms may be all carbon atoms or one or more ring atoms may be selected from N, O, S, SO, or S(O) 2 . It preferably has 5-10 rings.
  • Linked ring refers to any two or more rings connected by chemical bonds.
  • the number of constituent rings it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group.
  • a cyclic group can be bonded to another group in a variety of ways. If the bonding method is not specified, all possible methods are included. For example, “pyridyl” includes 2-, 3-, or 4-pyridyl, and “thienyl” includes 2- or 3-thienyl.
  • Alkyl refers to a linear or branched, monovalent, saturated hydrocarbon group, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and other similar groups.
  • it is a C 1-8 alkyl group. More preferably, it is a C 1-6 alkyl group. More preferably, it is a C 1-4 alkyl group.
  • the alkyl group may be substituted or unsubstituted with one or more substituents. When substituted, the substituents may be substituted at any point of attachment.
  • the substituents are preferably the following groups:
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, which can be combined with other groups.
  • Monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 3-8 membered cycloalkyl groups are preferred. 4-7 membered cycloalkyl groups are preferred. 3-6 membered cycloalkyl groups are more preferred.
  • the partially unsaturated monocyclic or polycyclic hydrocarbon group refers to a cycloalkenyl group.
  • Polycyclic hydrocarbon groups include linked, spirocyclic, fused, or bridged ring cyclic aliphatic hydrocarbon groups, including but not limited to the following groups:
  • Cycloalkenyl refers to a partially unsaturated monocyclic or polycyclic hydrocarbon ring having at least one carbon-carbon double bond, but does not form a completely conjugated ⁇ electron system and can be combined with other groups.
  • Monocyclic cycloalkenyls include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptatrienyl, cyclooctenyl, etc.
  • a 3-8 membered cycloalkenyl More preferably, a 3-6 membered cycloalkenyl.
  • Polycyclic cycloalkenyls include linked rings, spiro rings, fused rings, or bridged ring cycloalkenyls. Including but not limited to the following groups:
  • the cycloalkyl or cycloalkenyl group may be fused with an aryl, heteroaryl or heterocyclic group, including but not limited to tetrahydronaphthyl, benzocycloheptyl and the like.
  • Alkenyl refers to a linear, branched, or cyclic hydrocarbon group containing one or more carbon-carbon double bonds, including but not limited to ethenyl, propenyl, (E)-2-methylethenyl, (Z)-2-methylethenyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, and (Z)-but-1-enyl.
  • it is a C2-6 alkenyl group. More preferably, it is a C2-4 alkenyl group.
  • Alkynyl refers to a linear, branched, or cyclic hydrocarbon group containing one or more carbon-carbon triple bonds, including but not limited to ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, and but-3-ynyl. Preferably, it is a C2-6 alkynyl group. More preferably, it is a C2-4 alkynyl group.
  • Alkylene refers to a straight or branched, divalent saturated hydrocarbon group, i.e., one hydrogen atom of the alkyl group is further substituted, including but not limited to “methylene” refers to -CH2- , “ethylene” refers to -CH2CH2- , “propylene” refers to -CH2CH2CH2- , and “butylene” refers to -CH2CH2CH2CH2- or -CH2CH ( CH3 ) CH2- .
  • Halogen refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
  • Haloalkyl refers to an alkyl group as defined herein, wherein one or more hydrogen atoms have been replaced by the same or different halogen atoms, including but not limited to -CH2Cl , -CHF2 , -CH2CF3 , -CH2CCl3 , perfluoroalkyl (e.g., -CF3 ), and the like.
  • Alkylamino refers to NH 3 substituted by an alkyl group, including but not limited to methylamino, ethylamino, propylamino, isopropylamino, and the like.
  • Dialkylamino refers to a group having the structure N( C1-6alkyl ) 2 , including but not limited to dimethylamino, diethylamino, methyl(ethyl)amino, dipropylamino, diisopropylamino, and the like.
  • Aryl refers to a monocyclic or polycyclic carbocyclic ring system having one or more fused or unfused aromatic rings, including but not limited to phenyl, naphthyl, and indenyl. A 6-10 membered monocyclic or bicyclic aromatic group is preferred. Phenyl or naphthyl is more preferred. Phenyl is most preferred.
  • Polycyclic ring systems include fused, bridged or spiro ring systems.
  • monocyclic heterocyclic moieties include, but are not limited to, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, oxopiperidinyl, oxopiperazinyl, oxohomopiperazinyl, tetrahydrofuranyl, imidazolinyl, morpholinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, quinuclidinyl, thiadiazolidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, etc.
  • polycyclic heterocyclyl moieties include, but are not limited to, 2-azabicyclo[2.2.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 1-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2.1]octyl, 6-oxa-2-azabicyclo[3.2.1]octyl, 6-oxa-3-azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2 .1]octyl, 8-azabicyclo[3.2.1]octyl, 8-azabicyclo[5.1.0]o
  • the heterocyclic group may be fused to an aryl group, a heteroaryl group or a cycloalkyl group, including but not limited to the following groups:
  • the heterocyclic group is optionally substituted or unsubstituted, and the substituted substituents are preferably one or more of the following groups: a deuterium atom, a halogen, CN, a nitro group, a hydroxyl group, an azido group, a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, a C 2-6 heteroalkenyl group, a 3-12 membered saturated or unsaturated cycloalkyl group, a 3-12 membered saturated or unsaturated heterocyclic group, a halogenated C 1-10 alkyl group, a C 1-10 alkoxy group, a halogenated C 1-10 alkoxy group, a deuterated C 1-10 alkyl group, a deuterated C 1-10 alkoxy group, a 6-10 membered aryl group, a 5-10 membered heteroaryl group, and an oxo ( ⁇ O) group.
  • heteroaryl moieties include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiadiazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, or benzothiazolyl.
  • the heteroaryl group may be fused to an aryl group, a heterocyclic group or a cycloalkyl group, including but not limited to the following groups:
  • Alkoxy refers to a linear or branched, monovalent, saturated alkyl group bonded to an oxygen atom, including but not limited to methoxy, ethoxy, propoxy, butoxy, isobutoxy, tert-butoxy, and similar groups. Preferably, it is a C1-8 alkoxy group. More preferably, it is a C1-6 alkoxy group. More preferably, it is a C1-4 alkoxy group.
  • Cycloalkoxy refers to an -O-cycloalkyl group, wherein the cycloalkyl group is as described above. Preferably, a C 3-8 cycloalkoxy group is included. Examples include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and other similar groups.
  • Heterocyclyloxy refers to an -O-heterocyclyl group, wherein the heterocyclyl group is as defined above, including but not limited to azetidinyloxy, oxetanyloxy, pyrrolidinyloxy, oxhexyloxy, piperidinyloxy and other similar groups.
  • “Pharmaceutically acceptable salt” refers to conventional acid addition salts or base addition salts that retain the biological effectiveness and properties of the compound of Formula I and are formed by suitable non-toxic organic or inorganic acids or organic or inorganic bases.
  • acid addition salts include those derived from inorganic acids and those derived from organic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid.
  • organic acids include acetic acid, propionic acid, glycolic acid, oxalic acid, stearic acid, ascorbic acid, p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, oxalic acid, succinic acid, citric acid, maleic acid, hydroxymaleic acid, lactic acid, fumaric acid, tartaric acid, malic acid, isethionic acid, benzenesulfonic acid, trifluoroacetic acid, mandelic acid, etc.
  • base addition salts include those derived from inorganic acids and those derived from organic acids, such as ammonium salts, calcium salts, iron salts, aluminum salts, sodium salts, potassium salts, zinc salts, and magnesium salts.
  • the organic bases include salts of primary, secondary and tertiary amines, such as trimethylamine, triethylamine, tripropylamine, diethanolamine, ethylenediamine, ethanolamine, etc.
  • Chemical modification of pharmaceutical compounds (i.e., drugs) into salts is a technique well known to pharmacists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of the compounds.
  • Prodrug molecule refers to a prodrug that can be converted into a compound of the present invention and a pharmaceutically acceptable salt thereof in vivo.
  • N-oxide means that when a compound contains an amine functional group or a heteroaryl compound containing a N atom, one or more N atoms can be oxidized to form a compound containing N + , preferably an N-oxide of a tertiary amine or an N-oxide of a heteroaryl compound containing N.
  • Hydrophillipate refers to an association formed with a certain amount of water.
  • Solvents that form solvates include, but are not limited to, methanol, ethanol, isopropanol, ethyl acetate, acetic acid, and the like.
  • a “pharmaceutical composition” refers to a mixture of one or more of the compounds of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, with other chemical components, such as a pharmaceutically acceptable carrier, excipient, or diluent.
  • a pharmaceutical composition is to facilitate administration to an animal.
  • Pharmaceutical compositions may include pharmaceutically acceptable excipients to simulate physiological conditions, such as pH adjusting and buffering agents, toxicity modifiers, and the like, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, and sodium lactate.
  • “Pharmaceutically acceptable carrier” means a pharmaceutically acceptable substance, ingredient, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that participates in carrying or delivering a compound of the invention from one location, body fluid, tissue, organ (internal or external), or body part to another location, body fluid, organ (internal or external), or body part.
  • a pharmaceutically acceptable carrier can be a medium, diluent, excipient, or other material that is not unduly toxic or has adverse effects and is suitable for use in contact with animal tissue.
  • Some pharmaceutically acceptable carrier substances include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) tragacanth; (5) maltose; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) Glycols, such as propylene glycol; (11) Polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) Lipids, such as ethyl oleate and ethyl laurate; (13) Agarose; (14) Buffers, such as magnesium hydroxide and aluminum hydroxide; (15) Algin
  • Each pharmaceutically acceptable carrier should be compatible with the other components, for example, forming a formulation with the compound provided in the present invention, without excessive toxicity, irritation, allergic reaction, immunogenicity or other problems or complications to living tissues or organs, and with a reasonable benefit-risk ratio.
  • the pharmaceutical composition can be prepared into any suitable dosage form, such as solid dosage forms (e.g., tablets, capsules, powders, granules, etc.) and liquid dosage forms (e.g., aqueous solutions, emulsions, elixirs, syrups, etc.).
  • solid dosage forms e.g., tablets, capsules, powders, granules, etc.
  • liquid dosage forms e.g., aqueous solutions, emulsions, elixirs, syrups, etc.
  • the preparation methods and processes of pharmaceutical compositions are well known and can be prepared according to conventional techniques, such as those provided in Remington, The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2003).
  • Figure 1 is a reaction scheme for preparing the compound of formula II
  • Figure 2 is a reaction scheme for preparing the compound of formula III.
  • the first group of preparation examples intermediate preparation
  • Step 1 Dissolve methyl 4-aminopicolinate (10.0 g, 65.72 mmol) in dichloromethane (100 mL). Add dimethylaminopyridine (0.8 g, 6.57 mmol) and triethylamine (10.0 g, 98.59 mmol) sequentially. Cool to 0°C, then slowly add di-tert-butyl dicarbonate (15.8 g, 72.30 mmol) dropwise. Stir at room temperature for 4 h. After the reaction is complete, add water (50 mL) to the reaction solution, extract with ethyl acetate (60 mL x 3).
  • Step 2 Under nitrogen, methyl 4-((tert-butoxycarbonyl)amino)picolinate (11.7 g, 46.38 mmol) was dissolved in acetic acid (100 mL). Platinum dioxide (5.3 g, 23.19 mmol) was added to displace the hydrogen atmosphere. The mixture was heated to 60°C and stirred overnight. After completion of the reaction, the mixture was cooled to room temperature and filtered. The filtrate was adjusted to a basic pH by adding sodium bicarbonate solution. The mixture was extracted with dichloromethane/methanol (10/1, 50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product.
  • Step 3 Under nitrogen, dissolve methyl 4-((tert-butoxycarbonyl)amino)piperidine-2-carboxylate (8.3 g, 32.13 mmol) in tetrahydrofuran (60 mL), cool to 0°C, slowly add lithium borohydride (2.1 g, 96.39 mmol), and stir at room temperature overnight. After the reaction is complete, cool to room temperature, add methanol (30 mL), and concentrate under reduced pressure to obtain the crude product.
  • Step 1 Under nitrogen, 5-chloro-2,3-difluoropyridine (15.0 g, 0.10 mol) was dissolved in tetrahydrofuran (150 mL), cooled to -78°C, and lithium diisopropylamide (2 M, 60.2 mL, 0.12 mol) was added. The mixture was stirred at -78°C for 1 hour. Solid dry ice (15.0 g, 0.34 mol) was added, and the mixture was slowly warmed to room temperature and stirred for 2 hours. After the reaction was complete, it was concentrated under reduced pressure. The residue was diluted with dichloromethane (100 mL) and sodium hydroxide solution (100 mL).
  • the mixture was extracted with dichloromethane (100 mL ⁇ 3).
  • the aqueous phase was adjusted to pH 1 with hydrochloric acid solution and extracted with ethyl acetate (100 mL ⁇ 3).
  • the combined organic phases were washed with saturated brine (100 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield 5-chloro-2,3-difluoroisonicotinic acid (pale yellow solid, 14 g, crude product).
  • Step 2 Dissolve 5-chloro-2,3-difluoroisonicotinic acid (14.0 g, 72.34 mmol) in N,N-dimethylformamide (140 mL), cool to 0°C, and sequentially add HATU (41.2 g, 108.5 mmol), ammonium chloride (3.9 g, 72.34 mmol), and N,N-diisopropylethylamine (28.0 g, 217.02 mmol). Stir at room temperature for 1 h.
  • Step 3 Dissolve 5-chloro-2,3-difluoroisonicotinamide (7.8 g, 40.51 mmol) in dichloromethane (120 mL), cool to 0°C, add triethylamine (12.3 g, 121.52 mmol), and then add trifluoroacetic anhydride (12.8 g, 60.76 mmol) dropwise. Stir at room temperature for 2 h. After the reaction is complete, add water (100 mL) to the reaction solution, extract with dichloromethane (100 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product.
  • the crude product is isolated and purified by silica gel column chromatography using ethyl acetate/petroleum ether (14%) as the eluent to obtain 5-chloro-2,3-difluoroisonicotinonitrile (5.3 g, 75.1%) as a pale yellow oil.
  • Step 1 Under nitrogen, 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (2.0 g, 9.39 mmol) was dissolved in acetonitrile (50 mL). Copper chloride (1.9 g, 14.08 mmol) was added, and the temperature was cooled to 0°C. Tert-butyl nitrite (1.5 g, 14.08 mmol) was added, and the temperature was raised to 90°C with stirring for 1 h. After the reaction was complete, the mixture was cooled to room temperature, and water (50 mL) was added. The mixture was filtered, and the filtrate was extracted with ethyl acetate (30 mL x 3).
  • Step 2 Under nitrogen protection, 7-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (1.4 g, 6.02 mmol) was dissolved in 1,4-dioxane (20 mL), and pinacol diboron (2.3 g, 9.03 mmol), potassium acetate (2.1 g, 21.08 mmol) and Pd(dppf)Cl 2 (0.4 g, 0.60 mmol) were added in sequence. The temperature was raised to 100°C and stirred for 1 h. After the reaction was complete, the mixture was cooled to room temperature, and water (50 mL) was added to the reaction mixture.
  • Step 3 Dissolve 2-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (1.5 g, 5.37 mmol) in tetrahydrofuran (20 mL), cool to 0°C, add sodium hydroxide (1 M, 16.1 mL, 16.10 mmol) and hydrogen peroxide (30%, 1.6 mL, 16.10 mmol) in sequence, return to room temperature and stir for 1 h. After the reaction was complete, the reaction solution was extracted with ethyl acetate (20 mL x 3).
  • Step 1 Under nitrogen, dissolve 4-bromo-3-fluoro-1,2-phenylenediamine (2g, 9.76mmol) in anhydrous ethanol (20mL). Add sodium carbonate (2.70g, 19.51mmol) and glyoxal (0.68g, 11.70mmol) sequentially, and stir at room temperature for 2h. After completion of the reaction, concentrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-100%) to afford 6-bromo-5-fluoroquinoxaline (yellow solid, 2.2g, 99.3%).
  • Step 2 Under nitrogen, 6-bromo-5-fluoroquinoxaline (1.8 g, 7.93 mmol) was dissolved in a mixture of 1,4-dioxane and water (15 mL, 2/1, v/v). Pd 2 (dba) 3 (0.36 g, 0.40 mmol), t-Buxphos (0.17 g, 0.40 mmol), and potassium hydroxide (4.5 g, 79.28 mmol) were added. The mixture was heated to 100°C and stirred for 5 h. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product.
  • 8-Fluoroquinoxalin-6-ol was prepared using 5-bromo-3-fluoro-1,2-phenylenediamine and glyoxal as raw materials according to the method for synthesizing 5-fluoroquinoxalin-6-ol.
  • MS (ESI + ) m/z 165.1 [M+H] + .
  • Step 1 Under nitrogen, 4-benzyloxypyridine N-oxide (3.0 g, 14.91 mmol) was dissolved in pyridine (2.5 mL). Diphenoxyphosphoryl azide (8.2 g, 29.83 mmol) was added, and the mixture was heated to 100°C and stirred for 12 h. After the reaction was complete, the mixture was cooled to room temperature and water (150 mL) was added. The mixture was extracted with ethyl acetate (100 mL ⁇ 3). The combined organic phases were washed with saturated brine (100 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 1 Under nitrogen, 4-(benzyloxy)pyridin-2(1H)-one (1 g, 4.97 mmol) was dissolved in N,N-dimethylformamide (15 mL). Potassium carbonate (1.4 g, 9.95 mmol) and ethyl bromide (1.2 g, 10.94 mmol) were added sequentially. The mixture was heated to 80°C and stirred for 2 h. After the reaction was complete, it was cooled to room temperature. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 1 Under nitrogen, 4-(benzyloxy)pyridin-2(1H)-one (1 g, 4.97 mmol) was dissolved in N,N-dimethylformamide (15 mL). Cesium carbonate (3.2 g, 9.95 mmol) and 2-iodopropane (1.86 g, 10.94 mmol) were added sequentially. The mixture was heated to 80°C and stirred for 2 h. After the reaction was complete, it was cooled to room temperature. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 1 Under nitrogen protection, dissolve 4-(benzyloxy)pyridin-2(1H)-one (2.0 g, 9.94 mmol) in 1,2-dichloroethane (70 mL), and add sodium carbonate (2.4 g, 22.86 mmol), copper acetate (1.9 g, 10.64 mmol), 2,2'-bipyridine (1.7 g, 10.88 mmol) and cyclopropylboronic acid (1.9 g, 22.9 mmol) in sequence. Heat to 70°C and stir overnight. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure.
  • Step 1 Dissolve tert-butyl 3-(hydroxymethyl)-3-methylpyrrolidine-1-carboxylate (1 g, 4.65 mmol) in dichloromethane (10 mL) in a 100 mL eggplant-shaped flask. Cool to 0°C, add Dess-Martin periodinane (2.4 g, 5.57 mmol), and stir at room temperature for 2 h. After the reaction is complete, add water (5 mL), extract the mixture with dichloromethane (30 mL x 3), and combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • Step 2 In a 100 mL eggplant-shaped flask, tert-butyl 3-formyl-3-methylpyrrolidine-1-carboxylate (670 mg, 3.14 mmol) was dissolved in anhydrous methanol (15 mL). Potassium carbonate (868.3 mg, 6.28 mmol) was added, the temperature was cooled to 0°C, and dimethyl p-(diazomethyl)phosphate (905.3 mg, 4.71 mmol) was slowly added dropwise. The mixture was returned to room temperature and stirred for 20 min. After the reaction was complete, water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 3).
  • Step 4 In a 100 mL eggplant-shaped flask, 3-ethynyl-3-methylpyrrolidine (747 mg, 6.84 mmol) was dissolved in anhydrous methanol (20 mL). 20% aqueous formaldehyde (2.1 g, 13.68 mmol) was slowly added dropwise and stirred until uniform. Acetic acid (41.1 mg, 0.68 mmol) was then added dropwise. The temperature was lowered to 0°C, and sodium cyanoborohydride (860.0 mg, 13.68 mmol) was added. The mixture was returned to room temperature and stirred for 1 hour.
  • Step 1 Under nitrogen, 4-chloro-2-fluorobenzoic acid (10.0 g, 57.29 mmol) was dissolved in tetrahydrofuran (150 mL). The temperature was lowered to 0°C, and lithium aluminum hydride (3.6 g, 85.93 mmol) was slowly added portionwise. After addition, the temperature was raised to 70°C and stirred for 12 h. After the reaction was complete, the mixture was cooled to room temperature and water (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 2 Under nitrogen, (4-chloro-2-fluorophenyl)methane-d 2 -ol (4.5 g, 27.68 mmol) was dissolved in dichloromethane (60 mL), cooled to 0°C, and phosphorus tribromide (11.2 g, 41.52 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 1 Under nitrogen, dissolve 4-bromo-2-chloro-6-fluoro-benzaldehyde (2.8 g, 11.79 mmol) in methanol (40 mL), cool to 0°C, add sodium borohydride (892.2 mg, 23.58 mmol), and stir at 0°C for 1 hour. After the reaction is complete, return to room temperature, add water (50 mL), and extract the mixture with dichloromethane (50 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure.
  • Step 2 Under nitrogen, (4-bromo-2-chloro-6-fluorophenyl)methanol (2.6 g, 10.86 mmol) was dissolved in a mixture of dichloromethane and tetrahydrofuran (1/1 v/v, 30 mL). The temperature was cooled to 0°C, and phosphorus tribromide (4.4 g, 16.29 mmol) was added. Stirring was continued at room temperature for 1 hour.
  • Step 1 Under nitrogen, 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (2.0 g, 9.38 mmol) was dissolved in acetonitrile (50.0 mL). Copper chloride (1.9 g, 14.08 mmol) was added with stirring. The temperature was lowered to 0°C, and tert-butyl nitrite (1.4 g, 14.08 mmol) was added. The temperature was raised to 90°C and stirred for 1 h. After the reaction was complete, the mixture was returned to room temperature. Water (50 mL) was added to the reaction mixture, and the mixture was filtered. The filtrate was extracted with ethyl acetate (50 mL x 3).
  • Step 2 Under nitrogen protection, 7-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (1.4 g, 6.02 mmol) was dissolved in dioxane (20.00 mL), and pinacol diboron (2.3 g, 9.03 mmol), Pd(dppf)Cl 2 (0.4 g, 0.60 mmol) and potassium acetate (2.1 g, 21.08 mmol) were added in sequence. The temperature was raised to 100°C and stirred for 1 h. After the reaction was complete, the reaction mixture was returned to room temperature and water (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL x 3).
  • Step 3 Dissolve 2-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (1.5 g, 5.36 mmol) in tetrahydrofuran (20 mL), cool to 0°C, add sodium hydroxide (16.1 mL, 1 M, 16.08 mmol) and hydrogen peroxide (30%, 1.8 mL, 16.08 mmol), return to room temperature and stir for 1 hour. Extract with ethyl acetate (20 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • Step 1 Dissolve 2,3-difluoro-6-nitrobenzonitrile (1.0 g, 5.43 mmol) in N,N-dimethylformamide (20 mL), add tert-butyl 4-amino-4-hydroxymethylpiperidine-1-carboxylate (1.3 g, 5.43 mmol) and N,N-diisopropylethylamine (1.4 g, 10.86 mmol) in sequence, and heat to 70 ° C and stir for 10 h. After the reaction was complete, the mixture was cooled to room temperature, and water (20 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (20 mL x 3).
  • Step 2 Dissolve tert-butyl 4-((3-cyano-2-fluoro-4-nitrophenyl)amino)-4-(hydroxymethyl)piperidine-1-carboxylate (1.1 g, 2.74 mmol) in N,N-dimethylformamide (20 mL), cool to 0°C, add NaH (0.1 g, 4.11 mmol), and stir at room temperature for 2 h. After the reaction is complete, add water (30 mL) and extract with ethyl acetate (30 mL x 3). The combined organic phases are dried over saturated anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain the crude product.
  • intermediate A5 (240.0 mg, 0.53 mmol) was dissolved in 1,4-dioxane/water (10/1,5 mL), and methylboric acid (34.9 mg, 0.58 mmol), Pd(dppf)Cl 2 (38.7 mg, 0.053 mmol) and potassium carbonate (182.9 mg, 1.32 mmol) were added in sequence.
  • the temperature was raised to 90°C and stirred for 2 h. After the reaction was complete, the mixture was cooled to room temperature, and water (20 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (20 mL x 3).
  • Steps 1 and 2 Using 2,3-difluoro-6-nitrobenzonitrile and tert-butyl 3-amino-3-(hydroxymethyl)piperidine-1-carboxylate as starting materials, prepare tert-butyl 8-cyano-7-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,3'-piperidine]-1'-carboxylate (yellow solid) according to the method for synthesizing Intermediate A1.
  • MS (ESI + ) m/z 375.1 [M+H] + .
  • Step 1 Under nitrogen protection, dissolve 2,3-difluoroisonicotinonitrile (1.0 g, 7.14 mmol) in N,N-dimethylformamide (50 mL), add tert-butyl 4-amino-4-(hydroxymethyl)piperidine-1-carboxylate (1.6 g, 7.14 mmol) and cesium carbonate (4.7 g, 14.28 mmol), and heat to 80°C and stir for 1 h. After the reaction was complete, the mixture was cooled to room temperature, and water (50 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (100 mL ⁇ 3).
  • Step 2 Dissolve tert-butyl 8'-cyano-2'H,4'H-spiro[piperidine-4,3'-pyrido[3,2-b][1,4]oxazine]-1-carboxylate (600.0 mg, 1.82 mmol) in N,N-dimethylformamide (6 mL), add N-bromosuccinimide (323.2 mg, 1.82 mmol), and stir at room temperature for 1 h. After the reaction was complete, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL ⁇ 3).
  • Step 1 Under nitrogen protection, dissolve tert-butyl (2-(hydroxymethyl)piperidin-4-yl)carbamate (1.0 g, 4.34 mmol) in tetrahydrofuran (10 mL), cool to 0°C, slowly add sodium bis(trimethylsilyl)amide (1.6 g, 8.68 mmol) dropwise, stir at 0°C for 20 min, then slowly add 2,3-difluoroisonicotinonitrile (0.6 g, 4.34 mmol) dropwise, and stir at 0°C for 2 h. After the reaction was complete, the reaction mixture was returned to room temperature and ammonium chloride solution (10 mL) was added.
  • Steps 1 and 2 Using 2,3-difluoro-6-nitrobenzonitrile and tert-butyl (3R)-3-(hydroxymethyl)piperazine-1-carboxylate as starting materials, prepare tert-butyl (R)-7-cyano-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate according to the synthetic method of Intermediate A1.
  • MS (ESI + ) m/z 361.2 [M+H] + .
  • Intermediates A23-A24 were prepared using intermediate A13 and iodoethane or deuterated iodomethane as raw materials according to the method for synthesizing intermediate A22, as shown in Table 1.
  • Step 1 Dissolve (5-chloro-3-fluoropyridin-2-yl)methanol (20 g, 123.79 mmol) in dichloromethane (200 mL), add dichlorothionyl (29.5 g, 247.59 mmol) at 0°C, return to room temperature and stir for 4 hours. After the reaction is complete, concentrate under reduced pressure, add saturated aqueous sodium bicarbonate solution (25 mL) to the residue, and extract the mixture with dichloromethane (30 mL ⁇ 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give 5-chloro-2-chloromethyl-3-fluoropyridine (brown oil, crude product).
  • Step 2 Under nitrogen protection, 1-tert-butyl 4-methylpiperidine-1,4-dicarboxylate (27.3 g, 112.22 mmol) was dissolved in tetrahydrofuran (200 mL), cooled to -78 ° C, and a tetrahydrofuran solution of LDA (77 mL, 2 M) was slowly added. The mixture was stirred at -78 ° C for 2 h, and then 5-chloro-2-chloromethyl-3-fluoropyridine (20.2 g, 112.22 mmol) was added. The mixture was stirred at -78 ° C for 2 h. After the reaction was complete, the mixture was added to the reaction mixture.
  • Step 3 Under nitrogen protection, tert-butyl 4-methoxycarbonyl-4-((5-chloro-3-fluoropyridin-2-yl)methyl)piperidine-1-carboxylate (34.2 g, 88.40 mmol) was dissolved in tetrahydrofuran (300 mL), cooled to 0°C, and a tetrahydrofuran solution of lithium aluminum hydroxide (36 mL, 2.5 M, 88.40 mmol) was added. The mixture was returned to room temperature and stirred for 3 h. After the reaction was complete, an aqueous solution of sodium tartrate was added to the reaction solution.
  • Step 4 Under nitrogen protection, tert-butyl 4-((5-chloro-3-fluoropyridin-2-yl)methyl)-4-(hydroxymethyl)piperidine-1-carboxylate (23 g, 64.10 mmol) was dissolved in N,N-dimethylformamide (200 mL), cooled to 0 ° C, imidazole (13.1 g, 192.29 mmol) was added in batches, and then tert-butyldimethylsilyl chloride N,N-dimethylformamide solution (14.5 g, 96.14 mmol, 30 mL) was added dropwise. Stir at room temperature for 5 h. After the reaction was complete, cool to room temperature and add the reaction mixture.
  • Step 5 Under nitrogen protection, diisopropylamine (12 mL) was dissolved in tetrahydrofuran (230 mL), cooled to -78 ° C, and n-butyl lithium (29 mL, 2.5 M) was slowly added dropwise. The temperature was raised to 0 ° C and stirred for 1 h.
  • Step 6 Dissolve 2-((1-(tert-butyloxycarbonyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)piperidin-4-yl)methyl)-5-chloro-3-fluoroisonicotinic acid (25 g, 48.35 mmol) in N,N-dimethylformamide (250 mL), cool to 0°C, add HOBT (9.8 g, 72.52 mmol), EDCI (11.3 g, 72.52 mmol) and ammonium chloride (7.8 g, 145.04 mmol) in sequence, stir at room temperature for 2 h, and after the reaction is complete, add The mixture was added to a flask of water (150 mL), extracted with ethyl acetate (300 mL ⁇ 3), and the combined organic phases were washed with saturated brine (100 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and the filtr
  • Step 7 Under nitrogen protection, tert-butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-((4-carbamoyl-5-chloro-3-fluoropyridin-2-yl)methyl)piperidine-1-carboxylate (18 g, 34.88 mmol) was dissolved in dichloromethane (200 mL), cooled to 0°C, and triethylamine (10.6 g, 104.63 mmol) and trifluoroacetic anhydride (11.0 g, 52.31 mmol) were added dropwise in sequence, and stirred at room temperature for 2 h.
  • Step 8 Under nitrogen protection, tert-butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-((5-chloro-4-cyano-3-fluoropyridin-2-yl)methyl)piperidine-1-carboxylate (14 g, 28.11 mmol) was dissolved in tetrahydrofuran (45 mL), triethylamine trihydrofluoride (90 mL) was added, and the temperature was raised to 65 ° C and stirred for 5 h. After the reaction was complete, the mixture was cooled to room temperature and saturated brine (80 mL) was added. The mixture was extracted with ethyl acetate (150 mL x 3).
  • Step 9 Under nitrogen, tert-butyl 4-((5-chloro-4-cyano-3-fluoropyridin-2-yl)methyl)-4-(hydroxymethyl)piperidine-1-carboxylate (10.2 g, 26.57 mmol) was dissolved in 1,4-dioxane (500 mL), and cesium carbonate (43.3 g, 132.87 mmol) was added. The mixture was heated to 120°C and stirred for 3 h. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure.
  • Step 1 Under nitrogen protection, potassium tert-butoxide (4.0 g, 35.17 mmol) was dissolved in tetrahydrofuran (70 mL), cooled to -30 ° C, and a tetrahydrofuran solution (10 mL) of 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde (5.0 g, 23.44 mmol) was added, stirred at -30 ° C for 0.5 h, and then a tetrahydrofuran solution (10 mL) of 1-(bromomethyl)-4-chloro-2-fluorobenzene (6.3 g, 28.13 mmol) was added dropwise, and the mixture was stirred at -30 ° C for 0.5 h.
  • Step 7 Under nitrogen protection, tert-butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-((4-chloro-3-cyano-2-fluoropyridin-2-yl)methyl)piperidine-1-carboxylate (4.8 g, 9.7 mmol) was dissolved in tetrahydrofuran (50 mL), and a tetrahydrofuran solution of TBAF (1 M, 19.3 mL, 19.3 mmol) was added and stirred at room temperature for 1 h. After the reaction was complete, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 3).
  • Step 1 Dissolve 2,3-difluoro-6-nitroaniline (10 g, 57.44 mmol) in N,N-dimethylformamide (100 mL), cool to 0°C, slowly add N-chlorosuccinimide (15.3 g, 114.87 mmol), and heat to 80°C with stirring overnight. After the reaction is complete, cool to room temperature, add water (30 mL), and extract the mixture with ethyl acetate (50 mL). The combined organic phases are washed with water (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure.
  • Step 2 Under nitrogen, 4-chloro-2,3-difluoro-6-nitroaniline (6.7 g, 32.13 mmol) was dissolved in acetonitrile (70 mL). Copper bromide (1.1 g, 48.19 mmol) was added. The temperature was cooled to 0°C, and tert-butyl nitrite (6.6 g, 64.25 mmol) was slowly added dropwise. The mixture was returned to room temperature and stirred for 30 minutes. The temperature was then raised to 60°C and stirred overnight. After the reaction was complete, the mixture was cooled to room temperature and poured into ice water (50 mL).
  • Step 3 Under nitrogen, 2-bromo-5-chloro-3,4-difluoro-1-nitrobenzene (5.2 g, 19.09 mmol) was dissolved in N,N-dimethylformamide (50 mL). Cuprous cyanide (3.4 g, 38.17 mmol) was added and the mixture was heated to 120°C and stirred for 6 h. After the reaction was complete, the mixture was cooled to room temperature and water (20 mL) was added. The mixture was extracted with ethyl acetate (50 mL). The combined organic phases were washed with water (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 4 Dissolve 4-chloro-2,3-difluoro-6-nitrobenzonitrile (2.5 g, 11.44 mmol) in 1,4-dioxane (30 mL), add cesium carbonate (18.6 g, 57.20 mmol) and tert-butyl 4-hydroxy-4-(hydroxymethyl)piperidine-1-carboxylate (2.7 g, 11.44 mmol) in sequence, and heat to 120 ° C and stir for 1 h. After the reaction was complete, the mixture was cooled to room temperature and water (20 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3).
  • Step 1 Under nitrogen protection, dissolve methyl N-Boc-4-piperidincarboxylate (7.0 g, 28.77 mmol) in tetrahydrofuran (100 mL), cool to -78 ° C, add LDA solution in tetrahydrofuran (2 M, 21.6 mL, 43.16 mmol) dropwise, stir at -78 ° C for 1 h, then add 5-chloro-3-fluoropyridine-2-carboxaldehyde (5.0 g, 31.65 mmol) in tetrahydrofuran (20 mL) dropwise, and continue stirring for 1 h.
  • Step 2 Under nitrogen, ethyl N-Boc-4-((5-chloro-3-fluoropyridin-2-yl)(hydroxy)methyl)piperidine-4-carboxylate (9.0 g, 22.34 mmol) was dissolved in tetrahydrofuran (150 mL). The temperature was lowered to 0°C, and a 2M solution of lithium borohydride in tetrahydrofuran (44.7 mL, 89.36 mmol) was slowly added. The mixture was stirred at room temperature for 1 h. After the reaction was complete, ice water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 3).
  • Step 3 Dissolve tert-butyl 4-((5-chloro-3-fluoropyridin-2-yl)(hydroxy)methyl)-4-(hydroxymethyl)piperidine-1-carboxylate (7.0 g, 18.67 mmol) in DMF (100 mL), add imidazole (3.8 g, 56.02 mmol), cool to 0°C, slowly add TBSCl (5.6 g, 37.35 mmol), and stir at room temperature for 16 h. After the reaction was complete, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL ⁇ 3).
  • Step 4 Under nitrogen, dissolve tert-butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-((5-chloro-3-fluoropyridin-2-yl)(hydroxy)methyl)piperidine-1-carboxylate (8.0 g, 16.36 mmol) in tetrahydrofuran (150 mL), cool to -78°C, add LDA solution in tetrahydrofuran (2 M, 12.3 mL, 24.54 mmol) dropwise, and stir at -78°C for 4 h. Then, slowly add dry ice and stir for 1 h. After the reaction was complete, the temperature was restored to room temperature.
  • Step 5 Under nitrogen protection, 2-((1-(tert-butoxycarbonyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)piperidin-4-yl)(hydroxy)methyl)-5-chloro-3-fluoroisonicotinic acid (6.5 g, 12.19 mmol) was dissolved in DMF (100 mL), and HOBT (2.5 g, 18.29 mmol) and EDCI (3.5 g, 18.29 mmol) were added in sequence. The mixture was stirred at room temperature for 0.5 h, and then ammonium chloride (3.3 g, 60.97 mmol) was slowly added and stirred at room temperature for 1 h.
  • HOBT 2.5 g, 18.29 mmol
  • EDCI 3.5 g, 18.29 mmol
  • Step 6 Under nitrogen protection, tert-butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-((4-carbamoyl-5-chloro-3-fluoropyridin-2-yl)(hydroxy)methyl)piperidine-1-carboxylate (4.1 g, 7.71 mmol) was dissolved in dichloromethane (80 mL), triethylamine (7.8 g, 77.05 mmol) was added, the temperature was lowered to 0°C, trifluoroacetic anhydride (8.1 g, 38.53 mmol) was slowly added, and the mixture was stirred at room temperature for 1 h.
  • Step 7 Under nitrogen protection, tert-butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-((5-chloro-4-cyano-3-fluoropyridin-2-yl)(hydroxy)methyl)piperidine-1-carboxylate (2.7 g, 5.25 mmol) was dissolved in tetrahydrofuran (40 mL), and a tetrahydrofuran solution of TBAF (1 M, 10.5 mL, 10.51 mmol) was added and stirred at room temperature for 1 h. After the reaction was complete, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 3).
  • Step 8 Dissolve tert-butyl 7'-chloro-8'-cyano-4'-hydroxy-2'H,4'H-spiro[piperidine-4,3'-pyrano[3,2-b]pyridine]-1-carboxylate (400.0 mg, 1.05 mmol) in chloroform (5 mL). Add manganese dioxide (915.5 mg, 10.53 mmol). Heat to 60°C and stir for 1 hour.
  • Step 1 Under nitrogen, dissolve methyltriphenylphosphonium bromide (23.8 g, 66.58 mmol) in tetrahydrofuran (50 mL), cool to 0°C, add n-butyllithium in n-hexane (2.5 M, 26.6 mL, 66.58 mmol), and stir at 0°C for 1 h. Add N-tert-butyloxycarbonylnortropinone (5.0 g, 22.19 mmol), and stir at 0°C for 2 h.
  • Step 2 Under nitrogen, tert-butyl 3-methylene-8-azabicyclo[3.2.1]octane-8-carboxylate (2.1 g, 9.41 mmol) was dissolved in a mixture of tetrahydrofuran and water (4/1 v/v, 25 mL). The mixture was cooled to 0°C, and N-methylmorpholine oxide (3.3 g, 28.25 mmol) and 2% osmium tetroxide in tert-butyl alcohol (3 mL) were added sequentially. The mixture was allowed to return to room temperature and stirred for 16 h.
  • N-methylmorpholine oxide 3.3 g, 28.25 mmol
  • 2% osmium tetroxide in tert-butyl alcohol
  • Intermediates A33 and A34 were prepared using commercially available or prepared fluorobenzene compounds and commercially available tert-butyl 4-formylpiperidine-1-carboxylate as raw materials according to the method for synthesizing intermediate A27, as shown in Table 2.
  • tert-butyl 7'-chloro-8'-cyano-4'-oxo-2'H,4'H-spiro[piperidine-4,3'-pyrano[3,2-b]pyridine]-1-carboxylate (Intermediate A31, 300.0 mg, 0.79 mmol) was dissolved in BAST (5 mL) and stirred at room temperature for 3 h. After the reaction was complete, aqueous sodium bicarbonate (10 mL) was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 2 Under nitrogen, methyl N-Boc-4-((4-chloro-3-cyano-2-fluorophenyl)(hydroxy)methyl)piperidine-4-carboxylate (3.0 g, 7.03 mmol) was dissolved in tetrahydrofuran (50 mL), cooled to 0°C, and lithium aluminum hydride (1.1 g, 28.11 mmol) was added. After addition, the mixture was returned to room temperature and stirred for 2 h. After the reaction was complete, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 3).
  • Step 3 Dissolve tert-butyl 4-((4-chloro-3-cyano-2-fluorophenyl)(hydroxy)methyl)-4-(hydroxymethyl)piperidine-1-carboxylate (2.0 g, 5.01 mmol) in 1,4-dioxane (30 mL), add cesium carbonate (3.3 g, 10.04 mmol), and heat to 120°C with stirring for 4 h. After the reaction is complete, cool to room temperature, add water (50 mL), and extract the mixture with ethyl acetate (50 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure.
  • Step 1 Dissolve 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene (1.0 g, 5.40 mmol) in N,N-dimethylformamide (30 mL). Add 1-methyl-1H-benzo[d]imidazol-5-ol (1.2 g, 8.10 mmol) and cesium carbonate (5.3 g, 16.20 mmol). Heat to 120°C and stir for 3 h. After completion, cool to room temperature and concentrate under reduced pressure to obtain the crude product.
  • Step 2 Dissolve 5-(5-methoxy-2-methyl-4-nitrophenoxy)-1-methyl-1H-benzo[d]imidazole (1.5 g, 4.79 mmol) in N,N-dimethylformamide (30 mL). Cool to 0°C, add tetrahydroxydiborane (2.1 g, 23.94 mmol) and 4,4'-bipyridine (3.7 mg, 0.024 mmol), and stir at room temperature for 10 min. After the reaction is complete, extract with methanol/dichloromethane (1/10, 30 mL x 3).
  • the first substitution reaction can also be prepared by the following conditions: Na 2 CO 3 /K 2 CO 3 , DMF, 80°C; K 2 CO 3 , DMSO, 100°C.
  • the second reduction reaction conditions can also be prepared by the following conditions: ammonium chloride and iron powder, ethanol/water, 80°C to 90°C; ammonium chloride and iron powder, methanol/water, 60°C to 80°C; palladium carbon (50%) and hydrogen, methanol, rt.
  • Step 1 Under nitrogen protection, 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (1 g, 4.08 mmol) was dissolved in a mixture of 1,4-dioxane and water (21 mL, 6/1, v/v). 1-Bromomethyl-2-methyl-4-nitrobenzene (1.1 g, 4.90 mmol), potassium carbonate (1.7 g, 12.24 mmol) and Pd(DTBPF)Cl 2 were added in sequence. The reaction mixture was heated to 60°C and stirred for 1 hour. After the reaction was complete, the mixture was cooled to room temperature and water (30 mL) was added.
  • Step 2 Dissolve 7-(2-methyl-4-nitrobenzyl)-[1,2,4]triazolo[1,5-a]pyridine (300 mg, 1.12 mmol) in N,N-dimethylformamide (5 mL), add 4,4-bipyridine (8.7 mg, 0.06 mmol), cool to 0°C, then add tetrahydroxydiboron (300.7 mg, 3.35 mmol), stir at 0°C for 30 min, and return to room temperature after the reaction is complete. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3).
  • Step 1 Under nitrogen protection, 7-bromoimidazole [1,2-a] pyridine (2 g, 10.2 mmol) was dissolved in a mixed solution of dimethyl sulfoxide/water (30 mL, 4/1 v/v), and lithium hydroxide monohydrate (899.6 mg, 21.4 mmol), N, N'-bis (4-hydroxy-2,6-dimethylphenyl) oxamide (66.9 mg, 0.2 mmol) and copper acetylacetonate (53.2 mg, 0.2 mmol) were added in sequence. The mixture was heated to 80 ° C and stirred for 2 h. After the reaction was complete, the mixture was cooled to room temperature and water (10 mL) was added.
  • Step 2 Dissolve imidazo[1,2-a]pyridin-7-ol (1.0 g, 7.45 mmol) in N,N-dimethylformamide (20 mL). Add cesium carbonate (4.9 g, 14.91 mmol) and 1-fluoro-2-methyl-4-nitrobenzene (1.2 g, 7.45 mmol) sequentially. Heat to 80°C and stir for 3 h. After the reaction is complete, cool to room temperature and add water (30 mL). The mixture is extracted with ethyl acetate (30 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure.
  • Step 3 Dissolve 7-(2-methyl-4-nitrophenoxy)imidazo[1,2-a]pyridine (1.0 g, 3.71 mmol) in acetonitrile (15 mL), add N-chlorosuccinimide (595.1 mg, 4.46 mmol), and stir at room temperature for 16 hours. After the reaction is complete, add water (30 mL) to the reaction mixture, extract with ethyl acetate (40 mL x 3), dry the combined organic phases over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • Step 1 Under nitrogen protection, 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (1 g, 4.08 mmol) was dissolved in a mixture of 1,4-dioxane/water (6/1 v/v, 21 mL). 1-(bromomethyl)-2-methyl-4-nitrobenzene (1.1 g, 4.90 mmol), potassium carbonate (1.7 g, 12.24 mmol) and Pd(dtbpf)Cl 2 were added in sequence. The mixture was heated to 60°C and stirred for 1 hour. After the reaction was complete, it was cooled to room temperature.
  • Step 2 Dissolve 7-(2-methyl-4-nitrobenzyl)-[1,2,4]triazolo[1,5-a]pyridine (300 mg, 1.12 mmol) in N,N-dimethylformamide (5 mL), add 4,4'-bipyridine (8.7 mg, 0.06 mmol), cool to 0°C, add tetrahydroxydiboron (300.7 mg, 3.35 mmol), stir at 0°C for 30 min, and after the reaction is complete, reverse the reaction. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3).
  • Step 1 Intermediate A1 (100.0 mg, 0.27 mmol) was dissolved in ethanol/water (3/1, 4 mL). Iron powder (149.2 mg, 2.67 mmol) and ammonium chloride (142.9 mg, 2.67 mmol) were added sequentially. The mixture was heated to 70°C and stirred for 1 h. After the reaction was complete, the mixture was cooled to room temperature and filtered. Water (10 mL) was added to the filtrate, which was then extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford the crude product.
  • Step 2 Dissolve tert-butyl 7-amino-8-cyano-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidine]-1'-carboxylate (100.0 mg, 0.29 mmol) in N,N-dimethylformamide dimethyl acetal (5 mL), heat to 100°C, and stir for 1 hour.
  • Step 1 Under nitrogen protection, intermediate A13 (450.0 mg, 1.10 mmol) was dissolved in 1,4-dioxane (5 mL), and tert-butyl carbamate (154.6 mg, 1.32 mmol), Pd 2 (dba) 3 (100.7 mg, 0.11 mmol), XantPhos (63.6 mg, 0.11 mmol) and cesium carbonate (716.5 mg, 2.20 mmol) were added in sequence. The temperature was raised to 90°C and stirred for 1 h. After the reaction was complete, the mixture was cooled to room temperature, and water (50 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (50 mL x 3).
  • Step 2 Dissolve tert-butyl 7'-((tert-Butyloxycarbonyl)amino)-8'-cyano-2'H,4'H-spiro[piperidine-4,3'-pyrido[3,2-b][1,4]oxazine]-1-carboxylate (350.0 mg, 0.79 mmol) in dichloromethane (3 mL). Add trifluoroacetic acid (1 mL) and stir at room temperature for 1 hour. After the reaction is complete, the reaction mixture is dried with nitrogen.
  • Step 3 Under nitrogen protection, 7'-amino-2'H, 4'H-spiro[piperidine-4,3'-pyrido[3,2-b][1,4]oxazine]-8'-carbonitrile (350.0 mg, 1.43 mmol) was dissolved in tetrahydrofuran (2 mL) and water (2 mL), cooled to 0°C, and sodium bicarbonate (359.6 mg, 4.28 mmol) and di-tert-butyl dicarbonate (311.4 mg, 1.43 mmol) were added in sequence, and stirred at room temperature for 1 h. After the reaction was complete, the reaction solution was extracted with ethyl acetate (30 mL x 3).
  • Intermediates C25-C31, C36-C38, and C45 were prepared using intermediates A22-A27, A33-A36, and A37 or commercially available compounds as starting materials, following the method for synthesizing intermediate C12 (the second and third steps can be used to synthesize tert-butyl 7'-amino-8'-cyano-2'H,4'H-spiro[piperidine-4,3'-pyrido[3,2-b][1,4]oxazine]-1-carboxylate in a single step under the following conditions: TABF, THF, 60°C). See Table 5.
  • Step 1 Under nitrogen protection, intermediate A12 (1.0 g, 2.73 mmol) was dissolved in 1,4-dioxane (10 mL). Tert-butyl carbamate (480.4 mg, 4.10 mmol), EPhos Pd G4 (251.1 mg, 0.27 mmol), EPhos (146.2 mg, 0.27 mmol) and cesium carbonate (1.8 g, 5.47 mmol) were added in sequence. The temperature was raised to 100°C and stirred overnight. After the reaction was complete, the mixture was cooled to room temperature, and water (50 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (30 mL x 3).
  • Step 1 Under nitrogen protection, intermediate A14 (900.0 mg, 2.28 mmol) was dissolved in dimethyl sulfoxide (12 mL). Cuprous iodide (86.7 mg, 0.46 mmol), potassium carbonate (944.0 mg, 6.83 mmol), L-proline (104.9 mg, 0.91 mmol) and aqueous ammonia (25%, 239.4 mg, 6.83 mmol) were added in sequence. The mixture was heated to 90°C and stirred for 18 h. After the reaction was complete, the mixture was cooled to room temperature. Saturated brine (25 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (35 mL ⁇ 3).
  • Step 2 Intermediate C14 (brown oil, 600 mg, crude) was prepared using tert-butyl (R)-3-amino-4-cyano-6a,7,9,10-tetrahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine-8-carboxylate according to the procedure for Intermediate C1, Step 2.
  • MS (ESI + ) m/z 387.2 [M+H] + .
  • Intermediates A15-A17 were used as raw materials and intermediates C15-C17 were prepared according to the method for synthesizing intermediate C14, as shown in Table 6.
  • tert-butyl (E)-8-chloro-5-cyano-6-(((dimethylamino)methylene)amino)-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-1'-carboxylate (Intermediate C23, 150 mg, 0.35 mmol) was dissolved in methanol (8 mL), and t-BuBrettPhos Pd G3 (32.8 mg, 0.03 mmol), t-BuBrettPhos (16.7 mg, 0.03 mmol), and cesium carbonate (450.2 mg, 1.38 mmol) were heated to 100°C and stirred for 1 hour.
  • Step 1 Under nitrogen protection, tert-butyl 7'-chloro-8'-cyano-4'-oxo-2'H,4'H-spiro[piperidine-4,3'-pyrano[3,2-b]pyridine]-1-carboxylate (Intermediate A31, 200.0 mg, 0.53 mmol) was dissolved in DMF (5 mL). Sodium azide (68.8 mg, 1.06 mmol) was slowly added, and the temperature was raised to 100°C and stirred for 1 h. After the reaction was complete, the mixture was cooled to room temperature. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL ⁇ 3).
  • tert-butyl 5-chloro-8-cyano-7-(((dimethylamino)methylene)amino)-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidine]-1'-carboxylate (Intermediate C7, 200.0 mg, 0.46 mmol) was dissolved in DMF (4 mL), cooled to 0°C, and sodium hydroxide (60%, 50.5 mg, 1.36 mmol) was added. The mixture was stirred at 0°C for 15 min. Methyl iodide (196.3 mg, 1.38 mmol) was added. After the addition was complete, the mixture was heated to 60°C and stirred for 1 h.
  • Step 1 Under nitrogen, 6-amino-3-bromo-2-fluorobenzonitrile (10.0 g, 46.51 mmol) was dissolved in tetrahydrofuran (100 mL). Sodium methoxide (7.5 g, 0.14 mol) was added and the mixture was stirred at reflux for 6 h. After the reaction was complete, the mixture was cooled to room temperature and ice water (100 mL) was added. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 3 Under nitrogen protection, N'-(4-bromo-2-cyano-3-methoxyphenyl)-N,N-dimethylformamidine (6.0 g, 21.27 mmol) was dissolved in a mixture of 1,4-dioxane and water (66 mL, 10/1 v/v). KOH (3.6 g, 63.80 mmol) and Brettphos Pd G3 (1.9 g, 2.13 mmol) were added in sequence. The temperature was raised to 100 ° C and stirred for 4 h. After the reaction was complete, the mixture was cooled to room temperature and water (50 mL) was added. The mixture was back-extracted with ethyl acetate (50 mL).
  • Step 1 Dissolve intermediate C1 (110.0 mg, 0.28 mmol) in methyl tert-butyl ether/acetic acid (4 mL, 1/1 v/v), add intermediate B7 (83.7 mg, 0.33 mmol), and heat to 70°C and stir for 10 h. After the reaction was complete, the mixture was cooled to room temperature. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • Step 2 Dissolve tert-butyl 10'-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-2'H,4'H-spiro[piperidin-4,3'-[1,4]oxazino[2,3-f]quinazoline]-1-carboxylate (70.0 mg, 0.12 mmol) in dichloromethane/trifluoroacetic acid (4 mL, 3/1 v/v) and stir at room temperature for 0.5 h.
  • Step 3 Dissolve N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-2'H,4'H-spiro[piperidine-4,3'-[1,4]oxazino[2,3-f]quinazoline]-10'-amine (110.0 mg, 0.22 mmol) in tetrahydrofuran (5 mL), add triethylamine (65.8 mg, 0.65 mmol) dropwise to adjust the pH to >7, then add acrylic anhydride (13.7 mg, 0.11 mmol) dropwise and stir at room temperature for 15 min.
  • Example 2-130 Preparation of final products 2-4, 6-11, 15-23, 25-37, 39-48, 50-60, 62-63, 73-75, 77-90, 92-99, 101-109, 113-116, 120-125, 127-128, 130-133, 135, 137-141, 145-147, 149-151, 154, 159, 177-187
  • the preparation method of the final product 1 is adopted (the third step condensation reaction can also be prepared under the following conditions: acrylic acid or (E)-4-(dimethylamino)but-2-enoic acid or 2-butynoic acid, EDCI, pyridine, room temperature; acryloyl chloride, sodium bicarbonate solution, THF, room temperature), and the final products 2-4, 6-11, 15-23, 25-37, 39-48, 50-60, 62-63, 73-75, 77-90, 92-99, 101-109, 113-116, 120-125, 127-128, 130-133, 135, 137-141, 145-147, 149-151, 154, 159, and 177-187 are prepared using intermediates B1-B49 or commercially available substituted aniline compounds, intermediates C1-C44, and acrylic anhydride as raw materials. As shown in Table 8.
  • Example 131 Preparation of 1-(5'-methoxy-10'-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-2'H,4'H-spiro[piperidin-4,3'-[1,4]oxazino[2,3-f]quinazoline]-1-yl)prop-2-en-1-one (Final Product 12)
  • Step 2 Under nitrogen protection, tert-butyl 5'-bromo-10'-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-2'H,4'H-spiro[piperidine-4,3'-[1,4]oxazino[2,3-f]quinazoline]-1-carboxylate (120.0 mg, 0.17 mmol), t-BuBrettPhos Pd G3 (33.2 mg, 0.035 mmol), t-BuBrettPhos (16.9 mg, 0.035 mmol) and cesium carbonate (227.8 mg, 0.70 mmol) were dissolved in methanol (5 mL), heated to 100 ° C and stirred for 2 h.
  • Step 3 and Step 4 Using 5'-methoxy-10'-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-2'H,4'H-spiro[piperidine-4,3'-[1,4]oxazino[2,3-f]quinazoline]-1-carboxylic acid tert-butyl ester as raw material, the final product 12 was prepared according to the methods of Step 2 and Step 3 of Example 1.
  • Example 132 Preparation of 1-(4'-fluoro-10'-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-2'H,4'H-spiro[piperidin-4,3'-pyrano[2,3-f]quinazoline]-1-yl)prop-2-en-1-one (Final Product 117)
  • Step 1 From tert-butyl 8-cyano-7-(((dimethylamino)methylene)amino)-4-oxospiro[chromane-3,4'-piperidine]-1'-carboxylate (Intermediate C38, 150.0 mg, 0.36 mmol) and 3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline (Intermediate B7, 110.5 mg, 0.44 mmol), tert-butyl 10'-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-4'-oxo-2'H,4'H-spiro[piperidine-4,3'-pyrano[2,3-f]quinazoline]-1-carboxylate (pale yellow solid, 110 mg, 48.7%) was prepared according to the procedure for the first step of the synthesis of final product 1. MS(
  • Step 2 Dissolve tert-butyl 10'-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-4'-oxo-2'H,4'H-spiro[piperidine-4,3'-pyrano[2,3-f]quinazoline]-1-carboxylate (120.0 mg, 0.19 mmol) in methanol (5 mL), cool to 0°C, add sodium borohydride (14.6 mg, 0.39 mmol), and after addition, return to room temperature and stir for 2 h.
  • Step 3 Dissolve tert-butyl 4'-hydroxy-10'-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-2'H,4'H-spiro[piperidine-4,3'-pyrano[2,3-f]quinazoline]-1-carboxylate (140.0 mg, 0.23 mmol) in BAST (3 mL) and stir at room temperature for 12 h. After the reaction was complete, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL ⁇ 3).
  • Step 4 and Step 5 Using tert-butyl 4'-fluoro-10'-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-2'H,4'H-spiro[piperidin-4,3'-pyrano[2,3-f]quinazoline]-1-carboxylate and acrylic anhydride as raw materials, 1-(4'-fluoro-10'-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-2'H,4'H-spiro[piperidin-4,3'-pyrano[2,3-f]quinazoline]-1-yl)prop-2-en-1-one was prepared according to the method of Step 2 and Step 3 for synthesizing the final product 1.
  • Final product 126 was prepared using tert-butyl 8-cyano-7-(((dimethylamino)methylene)amino)-4-oxospiro[chromane-3,4'-piperidine]-1'-carboxylate (Intermediate C38) and 3-methyl-4-(quinoxalin-6-yloxy)aniline (Intermediate B3) as starting materials, following the method for synthesizing final product 117. Table 9 shows the reaction.
  • Example 134 Preparation of 1-(10'-((3-ethynyl-4-(quinoxalin-6-yloxy)phenyl)amino)-2'H-spiro[piperidin-4,3'-[1,4]dioxane[2,3-f]quinazolin]-1-yl)prop-2-en-1-one (Final Product 129)
  • Step 2 Under nitrogen protection, tert-butyl 10'-((3-bromo-4-(quinoxalin-6-yloxy)phenyl)amino)-2'H-spiro[piperidine-4,3'-[1,4]dioxane[2,3-f]quinazoline]-1-carboxylate (400.0 mg, 0.60 mmol) was dissolved in DMF (6 mL), and N-methyldicyclohexylamine (581.8 mg, 2.98 mmol), cataCXium A Pd G3 (43.5 mg, 0.060 mmol) and trimethylsilylacetylene (877.6 mg, 8.93 mmol) were added in sequence, and the temperature was raised to 90 ° C and stirred for 3 h.
  • Step 3 Dissolve tert-butyl 10'-((4-(quinoxalin-6-yloxy)-3-((trimethylsilyl)ethynyl)phenyl)amino)-2'H-spiro[piperidine-4,3'-[1,4]dioxane[2,3-f]quinazoline]-1-carboxylate (270.0 mg, 0.39 mmol) in tetrahydrofuran (4 mL), add triethylamine hydrofluoride (631.9 mg, 3.92 mmol), and stir at room temperature for 1 h. After the reaction was complete, water (15 mL) was added to the reaction solution, and the pH was adjusted to >7 with sodium bicarbonate.
  • Step 4 and Step 5 Using tert-butyl 10'-((3-ethynyl-4-(quinoxalin-6-yloxy)phenyl)amino)-2'H-spiro[piperidine-4,3'-[1,4]dioxane[2,3-f]quinazoline]-1-carboxylate as raw material, prepare 1-(10'-((3-ethynyl-4-(quinoxalin-6-yloxy)phenyl)amino)-2'H-spiro[piperidine-4,3'-[1,4]dioxane[2,3-f]quinazoline]-1-yl)prop-2-en-1-one according to the method of the second and third steps of the synthesis of the final product 1.
  • Step 1 Under nitrogen, N'-(2-cyano-4-hydroxy-3-methoxyphenyl)-N,N-dimethylformamidine (Intermediate C44, 1.0 g, 4.65 mmol) was dissolved in a mixture of toluene and acetic acid (10 mL, 1/1 v/v). 3-Chloro-4-(quinoxalin-6-yloxy)aniline (Intermediate B18, 1.2 g, 4.56 mmol) was added and the mixture was heated to 100°C and stirred for 4 h. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure.
  • Step 2 Dissolve 4-((3-chloro-4-(quinoxalin-6-yloxy)phenyl)amino)-5-methoxyquinazolin-6-ol (1.2 g, 2.69 mmol) in tetrahydrofuran (15 mL), add N-Boc-4-hydroxypiperidine (812.6 mg, 4.04 mmol) and triphenylphosphine (776.5 mg, 2.96 mmol) in sequence, cool to 0°C, and slowly add DEAD (562.5 mg, 3.23 mmol) dropwise. After the addition is complete, return to room temperature and stir for 2 h.
  • Step 3 Dissolve tert-butyl 4-((4-((3-chloro-4-(quinoxalin-6-yloxy)phenyl)amino)-5-methoxyquinazolin-6-yl)oxy)piperidine-1-carboxylate (150.0 mg, 0.24 mmol) in a mixture of dichloromethane and trifluoroacetic acid (1/1 v/v, 4 mL) and stir at room temperature for 1 hour.
  • Step 4 Dissolve N-(3-chloro-4-(quinoxalin-6-yloxy)phenyl)-5-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine (150.0 mg, 0.28 mmol) in tetrahydrofuran (2 mL), add saturated sodium bicarbonate solution (2 mL), cool to 0°C, add a solution of acryloyl chloride (12.8 mg, 0.14 mmol) in tetrahydrofuran (2 mL), and stir at 0°C for 0.5 h.
  • Example 136 Preparation of 8-acryloyl-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-6,6a,7,8,9,10-hexahydropyrazino[1',2':4,5][1,4]oxazino[2,3-f]quinazoline-12-carbonitrile (Final Product 162)
  • Step 1 Dissolve tert-butyl 10-bromo-7-cyano-8-(((dimethylamino)methylene)amino)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate (Intermediate C19, 955.0 mg, 2.06 mmol) in acetic acid (15 mL). Add 3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline (Intermediate B7, 625.1 mg, 2.47 mmol) in the mixture and heat to 60°C with stirring for 3 h.
  • Step 2 Under nitrogen protection, tert-butyl 12-bromo-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-6a,7,9,10-tetrahydropyrazino[1',2':4,5][1,4]oxazino[2,3-f]quinazoline-8(6H)-carboxylate (100.0 mg, 0.15 mmol) was dissolved in DMF (5 mL), and RuPhos Pd G3 (12.5 mg, 0.015 mmol), RuPhos (6.9 mg, 0.015 mmol) and zinc cyanide (21.0 mg, 0.18 mmol) were added in sequence.
  • Step 3 and Step 4 Using 12-cyano-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-6a,7,9,10-tetrahydropyrazino[1',2':4,5][1,4]oxazino[2,3-f]quinazoline-8(6H)-carboxylic acid tert-butyl ester as raw material, 8-acryloyl-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-6,6a,7,8,9,10-hexahydropyrazino[1',2':4,5][1,4]oxazino[2,3-f]quinazoline-12-carbonitrile was prepared according to the method of Step 2 and Step 3 of the synthesis of the final product 1.
  • Example 137 Preparation of 1-(12-ethynyl-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-6a,7,9,10-tetrahydropyrazino[1',2':4,5][1,4]oxazino[2,3-f]quinazolin-8(6H)-yl)prop-2-en-1-one (Final Product 163)
  • Step 1 Dissolve tert-butyl 10-bromo-7-cyano-8-(((dimethylamino)methylene)amino)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate (Intermediate C19, 955 mg, 2.06 mmol) in acetic acid (15 mL), add 3-methyl-4-[(1-methyl-1,3-benzodiazol-5-yl)oxy]aniline (Intermediate B7, 625.1 mg, 2.47 mmol), heat to 60°C and stir for 3 h. After completion of the reaction, the product was cooled to room temperature and concentrated under reduced pressure.
  • Step 2 Under nitrogen protection, tert-butyl 12-bromo-4-((3-methyl-4-)(((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-6a,7,9,10-tetrahydropyrazino[1',2':4,5][1,4]oxazolo[2,3-f]quinazoline-8(6H)-carboxylate (500 mg, 0.75 mmol) was dissolved in tetrahydrofuran (8 mL), and trimethylsilylacetyl (109.5 mg, 1.10 mmol), DBU (339.5 mg, 2.25 mmol), cuprous iodide (28.5 mg, 0.15 mmol) and Pd(PPh 3 ) 2 Cl 2 were added in sequence.
  • Step 3 Dissolve tert-butyl 12-ethynyl-4-((3-methyl-4-)(((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-6a,7,9,10-tetrahydropyrazino[1',2':4,5][1,4]oxazolo[2,3-f]quinazoline-8(6H)-carboxylate (200 mg, 0.29 mmol) in tetrahydrofuran (5 mL), add triethylamine trihydrofluoride (280.4 mg, 1.74 mmol), stir at room temperature for 1 h, and after the reaction is complete, add ...
  • Step 4 tert-Butyl 4-((3-methyl-4-)((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-12-((trimethylsilyl)ethynyl)-6a,7,9,10-tetrahydropyrazino[1',2':4,5][1,4]oxazolo[2,3-f]quinazoline-8(6H)-carboxylate (150 mg, 0.24 mmol) was dissolved in dichloromethane (3 ml) To the reaction mixture was added 1 mL of trifluoroacetic acid (1 mL), stirred at room temperature for 20 min, and concentrated under reduced pressure to afford 12-ethynyl-N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-6,6a,7,8,9,10-hexahydropyrazinyl[1
  • Step 5 12-Ethynyl-N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-6,6a,7,8,9,10-hexahydropyrazinyl[1',2':4,5][1,4]oxazolo[2,3-f]quinazolin-4-amine (260 mg, 0.50 mmol) was dissolved in tetrahydrofuran (5 mL), triethylamine (152.5 mg, 1.51 mmol) was added, the pH was adjusted to >7, acrylic anhydride (31.7 mg, 0.25 mmol) was added, and the mixture was stirred at room temperature for 20 min.
  • intermediates B7-B8 Using intermediates B7-B8, intermediates C18-C20, C22 or C24, intermediate alkyne compounds or commercially available alkyne compounds as raw materials, final products 91, 164-167, and 171 were prepared using the method for synthesizing final product 163, as shown in Table 10.
  • Example 144 Preparation of 1-(4-((3-methyl-4-)((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-12-morpholino-6a,7,9,10-tetrahydropyrazino[1',2':4,5][1,4]oxazolyl[2,3-f]quinazolin-8(6H)-yl)prop-2-en-1-one (final product 169)
  • Step 1 Under nitrogen protection, 12-bromo-4-((3-methyl-4-)(((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-6a,7,9,10-tetrahydropyrazino[1',2':4,5][1,4]oxazolo[2,3-f]quinazoline-8(6H)-carboxylic acid tert-butyl ester (prepared by intermediate C19 and intermediate B7 according to the first step of Example 1) (100 mg, 0.145 mmol) was dissolved in 1,4-dioxane (5 mL), and morpholine (19.4 mg, 0.22 mmol), potassium tert-butoxide (50.1 mg, 0.45 mmol) and (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2
  • Step 2 tert-Butyl 4-((3-methyl-4-)((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-12-morpholino-6a,7,9,10-tetrahydropyrazino[1',2':4,5][1,4]oxazolo[2,3-f]quinazoline-8(6H)-carboxylate (85 mg, 0.125 mmol) was dissolved in dichloromethane (3 mL) and trifluoromethane was added. Acetic acid (1 mL) was added and stirred at room temperature for 30 minutes.
  • Step 3 N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-12-morpholino-6,6a,7,8,9,10-hexahydropyrazino[1',2':4,5][1,4]oxazolo[2,3-f]quinazolin-4-amine (170 mg, 0.294 mmol) was dissolved in tetrahydrofuran (5 mL), and triethylamine (89.18 mg, 0.882 mmol) was added dropwise to adjust the pH to >7, and then acrylic anhydride (18.52 mg, 0.147 mmol) was added dropwise. The mixture was stirred at room temperature for 15 min.
  • Comparative compound A was prepared using intermediate B8 and intermediate M (prepared using (R)-7-cyano-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester as a raw material according to the method for synthesizing intermediate C18) as raw materials and following the method for synthesizing final product 1.
  • the CellTiter-Glo TM Live Cell Assay Kit uses luciferase as a detector. Luciferase requires ATP to produce luminescence. CellTiter-Glo TM reagent is added to the cell culture medium and luminescence is measured. The light signal is proportional to the amount of ATP in the system, which in turn is positively correlated with the number of viable cells. Therefore, by measuring ATP levels using the CellTiter-Glo Kit, cell proliferation can be monitored.
  • the Celltiter-Glo (CTG) method was used to measure the proliferation inhibitory effect of the aforementioned compounds in the tumor cell line HER2 775-776insYVMA Ba/F3 cell line, and the 50% inhibitory concentration IC 50 was calculated.
  • Cell culture medium RPMI 1640, 10% FBS, 1% P/S. Adjust the cell concentration and add 95 ⁇ L or 90 ⁇ L of cell suspension to a 96-well plate.
  • Cell culture environment cultured at 37°C, 5% CO 2 , and 95% humidity.
  • Drug storage solution The drug was dissolved in DMSO to prepare a 10 mM DMSO storage solution.
  • DMSO stock solutions of drugs were stored in a desiccator at room temperature for short-term storage (up to 3 months). The remaining drugs were stored at -20°C for longer periods.
  • the cells in the drug-added 96-well plate were cultured at 37°C, 5% CO 2 , and 95% humidity for 72 hours before CTG analysis.
  • Inhibition rate (Inh%) 100-(RLU compound -RLU blank )/(RLU control -RLU blank )*100%.
  • the compounds of the present invention have good proliferation inhibition activity against HER2 775-776insYVMA Ba/F3 cell line (expressing HER2 exon 20 insertion mutation), and the inhibition IC 50 value reaches nanomolar concentration.
  • Cell culture medium DMEM, 10% FBS, 1% Glutamax, and 1% P/S. Adjust the cell concentration and add 40 ⁇ L of the cell suspension to each well of a 384-well plate. Centrifuge at 1000 rpm for 30 seconds and incubate for 4 hours.
  • Drug storage solution The drug was dissolved in DMSO to prepare a 10 mM DMSO storage solution.
  • DMSO stock solutions of drugs were stored in a desiccator at room temperature for short-term storage (up to 3 months). The remaining drugs were stored at -20°C for longer periods.
  • the cells in the drug-added 384-well plate were cultured at 37°C, 5% CO 2 , and 95% humidity for 30 minutes.
  • Inhibition rate (Inh%) 100-(Signal compound -Signal Ave_PC )/(Signal Ave_VC -Signal Ave_PC )*100%.
  • SignalAve_PC Average signal value of the positive control on the entire plate
  • Signal Ave_VC Average signal value of negative control in the whole plate
  • the compounds of the present invention have weak inhibition on wild-type EGFR and have good selectivity for wild-type EGFR.
  • MDCKII-MDR1 cells were cultured in T-75 cell culture flasks in an incubator set at 37°C, 5% CO 2 , and a relative humidity of 95%. Cells were seeded in Transwell plates when they reached 70-90% confluence.
  • MDCKII-MDR1 and MDCKII should be fully confluent and differentiated. At this point, they can be used for penetration assays.
  • the hole cannot be used for penetration testing.
  • the integrity of the cell monolayer membrane was evaluated by leakage of fluorescein yellow after 2 hours of incubation.
  • the fluorescein yellow stock solution was diluted with HBSS (10mM HEPES, pH 7.4) to a final concentration of 100 ⁇ M.
  • 100 ⁇ L of fluorescein yellow solution was added to each well of the upper Transwell insert, and 300 ⁇ L of HBSS (10mM HEPES, pH 7.4) was added to each well of the lower receiving plate. After incubation at 37°C for 30 minutes, 80 ⁇ L of solution was aspirated from the upper and lower layers of each well into a new 96-well plate. Fluorescence was measured using a microplate reader with an excitation wavelength of 485nm and an emission wavelength of 530nm.
  • the membrane area in the formula is the membrane area of the Transwell-96 plate (0.143 cm 2 ); the incubation time is in seconds (s).
  • the efflux rate is calculated using the following formula:
  • Drug preparation The compounds were prepared into clear solutions with 10% DMSO + 10% Solutol HS15 + 5% Cremophor EL + 20% PEG400 + 55% (20% Captisol aqueous solution) as solvents for PO administration.
  • the administration method was cassette dosing.
  • the dosage of the compound was 10 mg/kg.
  • the pharmacokinetic parameters are shown in Table 14.
  • the compounds of the present invention have good exposure.
  • the quinazoline 7-position is N (such as compounds 135 and 146) or when the 7-position CH is substituted with a substituent (such as compounds 164 and 166), good exposure is shown.

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Abstract

The present invention relates to spiro/bridged polycyclic compounds as well as a preparation method therefor and the use thereof, the structure of the spiro/bridged polycyclic compounds being shown as formula I: <img file="PCTCN2025082933-isre-I000001.jpg" he="28.08" img-content="drawing" img-format="jpg" inline="yes" orientation="portrait" wi="60.34"/>. The spiro/bridged polycyclic compounds have inhibitory effect on epidermal growth factor receptor 2 (HER2), and thus are used for treating HER2 abnormality-induced related diseases, especially treating cancer diseases.

Description

螺环/桥环化合物及其制备方法和应用Spirocyclic/bridged ring compounds and their preparation methods and applications 技术领域Technical Field

本发明属于医药技术领域，具体涉及一种螺环/桥环化合物及其制备方法和应用。The present invention belongs to the field of medical technology, and in particular relates to a spiro/bridged ring compound and a preparation method and application thereof.

背景技术Background Art

表皮生长因子受体2(HER2,ErbB2)基因位于17号染色体长臂(17q21)，是ErbB家族四个成员(EGFR/HER1/ErbB1、HER2/ErbB2、HER3/ErbB31和HER4/ErbB4)之一，具有酪氨酸激酶活性。目前尚未发现能与HER2直接作用的配体，HER2可通过与ErbB家族的其他成员组成异源二聚体，激活下游MEK/ERK/MAPK通路和PI3K/AKT旁路进行信号传导，最终促进细胞生长、增殖和分裂等。The epidermal growth factor receptor 2 (HER2, ErbB2) gene is located on the long arm of chromosome 17 (17q21). It is one of the four members of the ErbB family (EGFR/HER1/ErbB1, HER2/ErbB2, HER3/ErbB31, and HER4/ErbB4) and possesses tyrosine kinase activity. Currently, no ligand has been found that can directly interact with HER2. HER2 can form heterodimers with other members of the ErbB family, activating the downstream MEK/ERK/MAPK pathway and the PI3K/AKT bypass pathway for signal transduction, ultimately promoting cell growth, proliferation, and division.

HER2的过度表达(上调)或过度活动(扩增或突变)已证实与许多癌症相关，包括乳腺癌、结肠直肠癌、胃癌、非小细胞肺癌、头颈部癌、卵巢癌、宫颈癌、膀胱癌、食道癌、子宫内膜癌和胶质母细胞瘤。HER2过表达在肺癌、乳腺癌、胃癌、胆管癌、卵巢癌和子宫内膜癌中的检出率分别约为2.5％，15％～25％，20％，20％，27％，18％～80％。Overexpression (upregulation) or overactivity (amplification or mutation) of HER2 has been linked to numerous cancers, including breast, colorectal, gastric, non-small cell lung, head and neck, ovarian, cervical, bladder, esophageal, endometrial, and glioblastoma. The prevalence of HER2 overexpression in lung, breast, gastric, bile duct, ovarian, and endometrial cancers is approximately 2.5%, 15% to 25%, 20%, 20%, 27%, and 18% to 80%, respectively.

HER2突变在非小细胞肺癌中检出率大约为2％-4％，其中20号外显子插入突变占HER2突变的71％，包括A772_G775dup(55.0％)、G776delinsVC(8.3％)、G778_P780dup(5.6％)和G776delinsLC(2.1％)等常见亚型。其他HER2突变包括19号外显子突变L755P(1.9％)、21号外显子突变V842I(0.7％)、跨膜结构域突变V659E(4.1％)和G660D(0.9％)以及胞外区域突变D277Y(1.9％)、S310F(7.7％)、S310Y(1.9％)和A466V(1.4％)。此外，研究显示携带HER2异常癌症患者在疾病过程中更易发生中枢神经系统转移，大约有47％ HER2突变的非小细胞肺癌患者发生脑转移，且与不良预后有关。The detection rate of HER2 mutations in non-small cell lung cancer is approximately 2%-4%, of which exon 20 insertion mutations account for 71% of HER2 mutations, including common subtypes such as A772_G775dup (55.0%), G776delinsVC (8.3%), G778_P780dup (5.6%), and G776delinsLC (2.1%). Other HER2 mutations include exon 19 mutation L755P (1.9%), exon 21 mutation V842I (0.7%), transmembrane domain mutations V659E (4.1%) and G660D (0.9%), and extracellular region mutations D277Y (1.9%), S310F (7.7%), S310Y (1.9%), and A466V (1.4%). In addition, studies have shown that patients with HER2-abnormal cancer are more likely to develop central nervous system metastasis during the course of the disease. Approximately 47% of patients with HER2-mutated non-small cell lung cancer develop brain metastasis, which is associated with poor prognosis.

目前临床上批准用于治疗HER2异常的药物包括单克隆抗体(mAbs)(曲妥珠单抗、帕妥珠单抗等)、小分子酪氨酸激酶抑制剂(TKIs)(拉帕替尼、图卡替尼、那来替尼、吡咯替尼等)和抗体偶联药物(ADCs)(恩美曲妥珠单抗、德曲妥珠单抗)。Currently, clinically approved drugs for the treatment of HER2 abnormalities include monoclonal antibodies (mAbs) (trastuzumab, pertuzumab, etc.), small molecule tyrosine kinase inhibitors (TKIs) (lapatinib, tucatinib, neratinib, pyrotinib, etc.) and antibody-drug conjugates (ADCs) (enmetazocine, trastuzumab dextromethorphan).

单克隆抗体和抗体偶联药物对野生型EGFR选择性差，且单克隆抗体和抗体偶联药物为大分子药物，不易透过血脑屏障，而且一部分患者使用单克隆抗体(mAbs)一段时间后会产生耐药或复发。此外，抗体偶联药物如德曲妥珠单抗，在批准剂量5.4mg/kg下，发生3级及以上间质性肺炎的比例达到12.9％。TKIs分为有选择性TKI(图卡替尼)和非选择性TKIs(拉帕替尼、那来替尼和吡咯替尼)，它们对野生型HER2显示出中等的抗肿瘤活性，但对最常见的HER2外显子20插入突变效果较差，临床客观响应率ORR为0-30％。另外，非选择性TKIs对野生型EGFR选择性差，易发生皮疹、腹泻等不良反应。因此，开发具有选择性、能透过血脑屏障且对HER2外显子20插入突变有潜在抑制作用的HER2抑制剂的具有重要意义。Monoclonal antibodies and antibody-drug conjugates have poor selectivity for wild-type EGFR. Furthermore, as large molecules, these drugs are not easily able to cross the blood-brain barrier. Furthermore, some patients develop resistance or relapse after a period of monoclonal antibody (mAb) use. Furthermore, antibody-drug conjugates, such as trastuzumab, have a 12.9% incidence of grade 3 or higher interstitial pneumonitis at the approved dose of 5.4 mg/kg. TKIs are divided into selective TKIs (tucatinib) and non-selective TKIs (lapatinib, neratinib, and pyrotinib). These TKIs exhibit moderate antitumor activity against wild-type HER2, but are less effective against the most common HER2 exon 20 insertion mutations, with clinical objective response rates (ORRs) ranging from 0-30%. Furthermore, non-selective TKIs have poor selectivity for wild-type EGFR and are prone to adverse reactions such as rash and diarrhea. Therefore, the development of HER2 inhibitors that are selective, can cross the blood-brain barrier, and have potential inhibitory effects against HER2 exon 20 insertion mutations is of great significance.

发明内容Summary of the Invention

为了解决现有技术的缺陷，本发明旨在提供一种螺环/桥环化合物及其制备方法和应用，本发明的螺环/桥环化合物具有良好的抑制HER2 20号外显子插入突变活性，且对野生型EGFR选择性较高，能透过血脑屏障，特别是能够作为HER2异常诱导的相关疾病治疗，尤其是癌症疾病方面的治疗。In order to address the defects of the prior art, the present invention aims to provide a spiro/bridged ring compound and its preparation method and application. The spiro/bridged ring compound of the present invention has good activity in inhibiting HER2 exon 20 insertion mutation, has high selectivity for wild-type EGFR, can pass through the blood-brain barrier, and can be used as a treatment for diseases related to HER2 abnormality induction, especially for the treatment of cancer diseases.

本发明是通过以下技术方案来实现的。The present invention is achieved through the following technical solutions.

第一方面，本发明提供具有如下式I所示结构的化合物或其药学上可接受的盐、立体异构体、消旋体、互变异构体、同位素标记物、氘代物、N-氧化物、前药分子、水合物或溶剂化物：
In a first aspect, the present invention provides a compound having a structure as shown in Formula I below, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof:

其中，在式I中，Wherein, in Formula I,

A环为含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基、3-12元环烷基；Ring A is a 3-12 membered heterocyclic group or a 3-12 membered cycloalkyl group containing one or more heteroatoms selected from N, O, S, S=O, and S(O) 2 ;

E环为6-10元芳基或含有1个或多个选自N、O、S杂原子的5-10元杂芳基；The E ring is a 6-10 membered aryl group or a 5-10 membered heteroaryl group containing one or more heteroatoms selected from N, O, and S;

Q1不存在或为6-12元芳基或含有1个或多个选自N、O、S杂原子的5-12元杂芳基，所述6-12元芳基或含有1个或多个选自N、O、S杂原子的5-12元杂芳基任选地被一个或者多个R′取代；Q 1 is absent or is a 6-12 membered aryl group or a 5-12 membered heteroaryl group containing one or more heteroatoms selected from N, O, and S, and the 6-12 membered aryl group or the 5-12 membered heteroaryl group containing one or more heteroatoms selected from N, O, and S is optionally substituted by one or more R';

L1为化学键、O、NR4、CR5R6、-OR7-、C(＝O)、S、S(O)或S(O)2；L 1 is a chemical bond, O, NR 4 , CR 5 R 6 , -OR 7 -, C(=O), S, S(O) or S(O) 2 ;

L2为化学键、O或NR4；L 2 is a chemical bond, O or NR 4 ;

L3为NR4、O、CR5R6、S、S(O)或S(O)2；L 3 is NR 4 , O, CR 5 R 6 , S, S(O) or S(O) 2 ;

L4不存在或为化学键、O、NR4、CR5R6、C(＝O)、S、S(O)或S(O)2；L 4 is absent or is a chemical bond, O, NR 4 , CR 5 R 6 , C(═O), S, S(O) or S(O) 2 ;

M为C＝O或S(＝O)2；M is C=O or S(=O) 2 ;

Y1为N或CRa； Y1 is N or CR a ;

Y2为N或CRb；Y 2 is N or CR b ;

Y3为N或CRc；Y 3 is N or CR c ;

Y4为N或CRd；Y 4 is N or CR d ;

Y5为N、CRe或C；当L2为化学键，Y5为N；当L2为O或NR4时，Y5为CRe或C；Y 5 is N, CR e or C; when L 2 is a chemical bond, Y 5 is N; when L 2 is O or NR 4 , Y 5 is CR e or C;

R1为卤代甲基、C2-4烯基、C2-4炔基、环氧丙烷基或C4-6环烯基，所述C2-4烯基、C2-4炔基、环氧丙烷基或C4-6环烯基任选地被一个或者多个卤素、氰基、C1-4烷基、卤代C1-4烷基、3-12元环烷基、氘原子、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基、含有1个或多个选自N、O、S杂原子的5-12元杂芳基、6-12元芳基、C1-3烷氧基-C1-3烷基-或NRxRy取代，所述C1-4烷基、卤代C1-4烷基、3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基、含有1个或多个选自N、O、S杂原子的5-12元杂芳基、6-12元芳基或C1-3烷氧基-C1-3烷基-任选被一个或者多个R′取代；R 1 is a halomethyl, C 2-4 alkenyl, C 2-4 alkynyl, propylene oxide or C 4-6 cycloalkenyl group, wherein the C 2-4 alkenyl, C 2-4 alkynyl, propylene oxide or C 4-6 cycloalkenyl group is optionally substituted by one or more halogen, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, 3-12 membered cycloalkyl, deuterium atom, 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S=O, S(O) 2 , 5-12 membered heteroaryl containing one or more heteroatoms selected from N, O, S, 6-12 membered aryl, C 1-3 alkoxy-C 1-3 alkyl- or NR x R y , wherein the C 1-4 alkyl, halogenated C 1-4 alkyl, 3-12 membered cycloalkyl, containing one or more heteroatoms selected from N, O, S, S=O, S(O) 2 2 heteroatoms, 3-12 membered heterocyclyl, 5-12 membered heteroaryl containing one or more heteroatoms selected from N, O, S, 6-12 membered aryl or C 1-3 alkoxy-C 1-3 alkyl-optionally substituted by one or more R';

R2为氢原子、氘原子、卤素、氰基、羟基、氨基、C1-6烷基、C2-6烯基、C2-6炔基、卤代C1-4烷基、氘代C1-6烷基、3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基、C1-4烷基氨基、二(C1-4烷基)氨基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、卤代C1-6烷氧基或氧代(＝O)，所述羟基、氨基、C1-6烷基、C2-6烯基、C2-6炔基、卤代C1-4烷基、氘代C1-6烷基、3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基、C1-4烷基氨基、二(C1-4烷基)氨基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、卤代C1-6烷氧基任选地被一个或者多个R′取代；R 2 is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a halogenated C 1-4 alkyl group, a deuterated C 1-6 alkyl group, a 3-12 membered cycloalkyl group, a 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, and S(O) 2 , a C 1-4 alkylamino group, a di(C 1-4 alkyl)amino group, a C 1-6 alkoxy group, a C 1-6 alkoxy -C 1-6 alkyl group, a halogenated C 1-6 alkoxy group, or an oxo(=O) group, wherein the hydroxyl group, the amino group, the C 1-6 alkyl group, the C 2-6 alkenyl group, the C 2-6 alkynyl group, the halogenated C 1-4 alkyl group, the deuterated C 1-6 alkyl group, the 3-12 membered cycloalkyl group, the 3-12 membered cycloalkyl group, the 2 heteroatoms, 3-12 membered heterocyclyl, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, halogenated C 1-6 alkoxy, optionally substituted by one or more R′;

R3为氢原子、氘原子、卤素、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、3-12元饱和或不饱和环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元饱和或不饱和杂环基、卤代C1- 6烷基、卤代C1-6烷氧基、ORe、SRe、SORe、S(O)2Re、C(＝O)Re、C(＝O)NRe、C(＝O)ORe、NReRf、NReC(＝O)Rf、OC(＝O)Re、SONRf、S(O)2NRe、NHS(O)2Re、NHS(O)Re、NReC(＝O)ORf、NReC(＝O)NRf、-(O)(ORe)2或P(O)(Re)2，所述C1-6烷基、C2-6烯基、C2-6炔基、C2-6杂炔基、3-12元饱和或不饱和环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元饱和或不饱和杂环基、卤代C1-6烷基或卤代C1-6烷氧基任选地被一个或者多个R′取代； R3 is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a nitro group, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a 3-12-membered saturated or unsaturated cycloalkyl group, a 3-12-membered saturated or unsaturated heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, and S(O) 2 , a halogenated C1-6 alkyl group, a halogenated C1-6 alkoxy group, ORe , SRe , SORe , S(O) 2Re , C(=O) Re , C (=O) NRe , C(=O) ORe , NReRf , NReC (=O) Rf , OC(=O) Re , SONRf , S (O) 2NRe , NHS(O) 2Re , NHS(O) Re , NReC (=O) ORf , NReC (=O) NRf , -(O)(OR e ) 2 or P(O)(R e ) 2 , the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 heteroalkynyl, 3-12 membered saturated or unsaturated cycloalkyl, 3-12 membered saturated or unsaturated heterocyclic group containing one or more heteroatoms selected from N, O, S, S═O, S(O) 2 , halogenated C 1-6 alkyl or halogenated C 1-6 alkoxy is optionally substituted by one or more R′;

R4为氢原子、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、氰基-C1-6烷基-、羟基C1-6烷基、C2-4烯基、C2-4炔基、C(＝O)Re或3-12元环烷基，所述C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、氰基-C1-6烷基-、羟基C1-6烷基、C2-4烯基、C2-4炔基或3-12元环烷基任选地被一个或者多个R′取代； R4 is a hydrogen atom, a C1-6 alkyl group, a halogenated C1-6 alkyl group, a deuterated C1-6 alkyl group, a cyano- C1-6 alkyl group, a hydroxy C1-6 alkyl group, a C2-4 alkenyl group, a C2-4 alkynyl group, C(=O) Re , or a 3-12-membered cycloalkyl group, wherein the C1-6 alkyl group, the halogenated C1-6 alkyl group, the deuterated C1-6 alkyl group, the cyano- C1-6 alkyl group, the hydroxy C1-6 alkyl group, the C2-4 alkenyl group, the C2-4 alkynyl group, or the 3-12-membered cycloalkyl group is optionally substituted by one or more R's;

R5、R6各自独立地为氢原子、氘原子、卤素、氰基、羟基、氨基、C1-6烷基、卤代C1-6烷基、C2- 4烯基、C2-4炔基、3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基、C1-6烷氧基、卤代C1-6烷氧基、3-12元环烷基氧基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基氧基、C1-6烷基巯基、C1-6烷基氨基、二(C1-6烷基)氨基、氰基-C1-6烷基-、C1- 6烷氧基-C1-6烷基-、3-12元环烷基-C1-6烷基-或含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基-C1-6烷基-，所述羟基、氨基、C1-6烷基、卤代C1-6烷基、C2-4烯基、C2-4炔基、3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基、C1-6烷氧基、卤代C1- 6烷氧基、3-12元环烷基氧基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基氧基、C1-6烷基巯基、C1-6烷基氨基、二(C1-6烷基)氨基、氰基-C1-6烷基-、C1-6烷氧基-C1-6烷基-、3-12元环烷基-C1-6烷基-或含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基-C1-6烷基-任选地被一个或者多个R′取代；R 5 and R 6 are each independently a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S=O, and S(O) 2 , a C 1-6 alkoxy group, a halogenated C 1-6 alkoxy group, a 3-12-membered cycloalkyloxy group, a 3-12-membered heterocyclyloxy group containing one or more heteroatoms selected from N, O, S, S=O, and S(O) 2 , a C 1-6 alkylthiol group, a C 1-6 alkylamino group, a di(C 1-6 alkyl)amino group, a cyano-C 1-6 alkyl-, a C 1-6 alkoxy-C 1-6 alkyl-, a 3-12 - membered cycloalkyl-C C 1-6 alkyl- or a 3-12 membered heterocyclyl-C 1-6 alkyl-containing one or more heteroatoms selected from N, O, S, S=O, S(O) 2 , the hydroxyl, amino, C 1-6 alkyl, a halogenated C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, a 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S=O, S(O) 2 , a C 1-6 alkoxy, a halogenated C 1-6 alkoxy, a 3-12 membered cycloalkyloxy, a 3-12 membered heterocyclyloxy containing one or more heteroatoms selected from N, O, S, S=O, S(O) 2 , a C 1-6 alkylthiol, a C 1-6 alkylamino, a di(C 1-6 alkyl)amino, a cyano-C 1-6 alkyl-, a C 1-6 alkoxy-C 1-6 alkyl-, 3-12 membered cycloalkyl-C 1-6 alkyl- or 3-12 membered heterocyclyl-C 1-6 alkyl- containing 1 or more heteroatoms selected from N, O, S, S=O, S(O) 2 , optionally substituted with one or more R′;

或R5与R6和所连接的C原子一起形成3-6元环烷基或含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基，所述3-6元环烷基或含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基任选地被一个或者多个R′取代；or R 5 together with R 6 and the C atom to which they are attached form a 3-6 membered cycloalkyl group or a 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O) 2 , which is optionally substituted by one or more R′ ;

R7为C1-6亚烷基、C2-4亚烯基、卤代C1-6亚烷基、氘代C1-6亚烷基或卤代C2-4亚烯基； R7 is C1-6 alkylene, C2-4 alkenylene, halogenated C1-6 alkylene, deuterated C1-6 alkylene or halogenated C2-4 alkenylene;

Ra、Rb各自独立为氢原子、氘原子、卤素、氰基、C1-6烷基、C2-4烯基、C2-4炔基、3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基、ORa1、SRa1、NRa1、S(＝O)Ra1或S(＝O)2Ra1，所述C1-6烷基、C2-4烯基、C2-4炔基、3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基任选地被一个或者多个R′取代；R a and R b are each independently a hydrogen atom, a deuterium atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , OR a1 , SR a1 , NR a1 , S(═O)R a1 or S(═O) 2 R a1 , and the C 1-6 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, a 3-12-membered cycloalkyl group, or a 3-12-membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 are optionally substituted by one or more R′;

或者，Ra与R2和所连接的原子一起形成3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基或含有1、2、3、4个选自N、O、S杂原子的5-6元杂芳基，所述3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基或含有1、2、3、4个选自N、O、S杂原子的5-6元杂芳基任选地被一个或者多个R′取代；Alternatively, Ra , R2 and the atoms to which they are attached form a 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S=O, S(O) 2 , or a 5-6 membered heteroaryl containing one, two, three, or four heteroatoms selected from N, O, and S, and the 3-12 membered cycloalkyl, the 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S=O, S(O) 2 , or the 5-6 membered heteroaryl containing one, two, three, or four heteroatoms selected from N, O, and S are optionally substituted with one or more R';

或者，Rb与R2和所连接的原子一起形成3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基或含有1、2、3、4个选自N、O、S杂原子的5-6元杂芳基，所述3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基或含有1、2、3、4个选自N、O、S杂原子的5-6元杂芳基任选地被一个或者多个R′取代；Alternatively, R b together with R 2 and the atoms to which they are attached form a 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S═O, S(O) 2 , or a 5-6 membered heteroaryl containing one, two, three, or four heteroatoms selected from N, O, and S, and the 3-12 membered cycloalkyl, the 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S═O, S(O) 2 , or a 5-6 membered heteroaryl containing one, two, three, or four heteroatoms selected from N, O, and S are optionally substituted with one or more R ′;

Rc为氢原子、氘原子、卤素、氰基、氨基、C1-6烷基、C1-6烷氧基、C1-6烷基巯基、C1-6烷基氨基或二(C1-6烷基)氨基，所述氨基、C1-6烷基、C1-6烷氧基、C1-6烷基巯基、C1-6烷基氨基或二(C1-6烷基)氨基任选地被一个或者多个R′取代；R c is a hydrogen atom, a deuterium atom, a halogen, a cyano group, an amino group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkylthio group, a C 1-6 alkylamino group or a di(C 1-6 alkyl)amino group, wherein the amino group, the C 1-6 alkyl group, the C 1-6 alkoxy group, the C 1-6 alkylthio group, the C 1-6 alkylamino group or the di(C 1-6 alkyl)amino group is optionally substituted with one or more R ′;

Rd不存在或为氢原子、氘原子、卤素、氰基、氨基、C1-6烷基、C1-6烷氧基、C1-6烷基巯基或C1- 6烷基氨基，所述氨基、C1-6烷基、C1-6烷氧基、C1-6烷基巯基或C1-6烷基氨基任选地被一个或者多个R′取代；R d is absent or is a hydrogen atom, a deuterium atom, a halogen, a cyano group, an amino group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkylthio group or a C 1-6 alkylamino group, wherein the amino group, the C 1-6 alkyl group, the C 1-6 alkoxy group, the C 1-6 alkylthio group or the C 1-6 alkylamino group is optionally substituted with one or more R′;

或者，Rb与Rd和所连接的原子一起形成3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基或含有1、2、3、4个选自N、O、S杂原子的5-6元杂芳基，所述3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基或含有1、2、3、4个选自N、O、S杂原子的5-6元杂芳基任选地被一个或者多个R′取代；Alternatively, R b and R d together with the atoms to which they are attached form a 3-12 membered cycloalkyl group, a 3-12 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S═O, S(O) 2 , or a 5-6 membered heteroaryl group containing one, two, three, or four heteroatoms selected from N, O, and S, and the 3-12 membered cycloalkyl group, the 3-12 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S═O, S(O) 2 , or the 5-6 membered heteroaryl group containing one, two, three, or four heteroatoms selected from N, O, and S are optionally substituted with one or more R ′;

或者，Ra与Rd和所连接的原子一起形成3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基或含有1、2、3、4个选自N、O、S杂原子的5-6元杂芳基，所述3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基或含有1、2、3、4个选自N、O、S杂原子的5-6元杂芳基任选地被一个或者多个R′取代；Alternatively, Ra and Rd , together with the atoms to which they are attached, form a 3-12 membered cycloalkyl group, a 3-12 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S=O, or S(O) 2 , or a 5-6 membered heteroaryl group containing one, two, three, or four heteroatoms selected from N, O, or S, and the 3-12 membered cycloalkyl group, the 3-12 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S=O, or S(O) 2 , or the 5-6 membered heteroaryl group containing one, two, three, or four heteroatoms selected from N, O, or S are optionally substituted with one or more R';

Re、Rf各自独立地为氢原子、氘原子、C1-4烷基、卤代C1-4烷基、3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基；R e and R f are each independently a hydrogen atom, a deuterium atom, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, a 3-12 membered cycloalkyl group, or a 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 ;

或者，NReRf中Re和Rf与连接的N原子一起形成含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基；Alternatively, Re and Rf in NR e R f together with the attached N atom form a 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 ;

Ra1为氢原子、C1-6烷基、3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基、3-12元环烷基-C1-6烷基或含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基-C1-6烷基，所述C1-6烷基、3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基、3-12元环烷基-C1-6烷基或含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基-C1-6烷基任选地被一个或者多个R′取代；R a1 is a hydrogen atom, a C 1-6 alkyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , a 3-12-membered cycloalkyl-C 1-6 alkyl group, or a 3-12-membered heterocyclyl-C 1-6 alkyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , wherein the C 1-6 alkyl group, the 3-12-membered cycloalkyl group, the 3-12-membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , the 3-12-membered cycloalkyl-C 1-6 alkyl group, or the 3-12-membered heterocyclyl-C 1-6 alkyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 are optionally substituted with one or more R′;

Rx、Ry各自独立地为氢原子、C1-4烷基、卤代C1-4烷基、3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基、3-12元环烷基-C1-4烷基-、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基-C1-4烷基-、C1-4烷氧基-C1-4烷基-或氘代C1-4烷基，所述C1-4烷基、卤代C1-4烷基、3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基、3-12元环烷基-C1-4烷基-、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基-C1-4烷基-、C1-4烷氧基-C1-4烷基-或氘代C1-4烷基任选地被一个或者多个R′取代； Rx and Ry are each independently a hydrogen atom, a C1-4 alkyl group, a halogenated C1-4 alkyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S=O, and S(O) 2 , a 3-12-membered cycloalkyl- C1-4 alkyl-, a 3-12-membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S=O, and S(O) 2 , a C1-4 alkoxy- C1-4 alkyl-, or a deuterated C1-4 alkyl group, wherein the C1-4 alkyl group, the halogenated C1-4 alkyl group, the 3-12-membered cycloalkyl group, the 3-12-membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S=O, and S(O) 2 , the 3-12-membered cycloalkyl-C1-4 alkyl- 1-4 alkyl-, 3-12 membered heterocyclyl-C 1-4 alkyl- containing 1 or more heteroatoms selected from N, O, S, S=O, S(O) 2 , C 1-4 alkoxy-C 1-4 alkyl- or deuterated C 1-4 alkyl, optionally substituted by one or more R′;

或NRxRy中Rx与Ry和所连接的N原子一起形成含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基，所述含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基任选地被一个或者多个R′取代；or in NRxRy , Rx and Ry together with the nitrogen atom to which they are attached form a 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, and S(O) 2 , wherein the 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, and S(O) 2 is optionally substituted by one or more R';

R′各自独立地为氘原子、卤素、氰基、羟基、氨基、C1-6烷基、C2-6烯基、C2-6炔基、卤代C1-4烷基、氘代C1-6烷基、3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基、C1-4烷基氨基、二(C1-4烷基)氨基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、卤代C1-6烷氧基或氧代(＝O)；R′ is each independently a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a halogenated C 1-4 alkyl group, a deuterated C 1-6 alkyl group, a 3-12 membered cycloalkyl group, a 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , a C 1-4 alkylamino group, a di(C 1-4 alkyl)amino group, a C 1-6 alkoxy group, a C 1-6 alkoxy-C 1-6 alkyl group, a halogenated C 1-6 alkoxy group, or an oxo(═O);

m、n各自独立地为0、1、2、3、4或5；m and n are each independently 0, 1, 2, 3, 4 or 5;

条件是，1)Rd或R2任意一个基团与Ra或Rb任意一个基团和它们所连接的原子一起必须形成一个且只有一个环，所述环为3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基或含有1、2、3或4个选自N、O、S杂原子的5-6元杂芳基，所述3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基或含有1、2、3或4个选自N、O、S杂原子的5-6元杂芳基任选地被一个或者多个R′取代；Provided that 1) any one of R d or R 2 and any one of R a or R b together with the atoms to which they are attached must form one and only one ring, said ring being a 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S═O, S(O) 2, or a 5-6 membered heteroaryl containing one, two, three or four heteroatoms selected from N, O, S, said 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S═O, S(O) 2 , or a 5-6 membered heteroaryl containing one, two, three or four heteroatoms selected from N, O, S, and said 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S═O, S(O) 2 , or a 5-6 membered heteroaryl containing one, two, three or four heteroatoms selected from N, O, S, and said 5-6 membered heteroaryl is optionally substituted with one or more R′;

2)当R2与Rb和它们所连接的原子一起形成吗啉环，且Y1为CH时，Q1不为 2) When R 2 and R b together with the atoms to which they are attached form a morpholine ring, and Y 1 is CH, Q 1 is not

在某些实施方式中，所述式I化合物进一步具有如式II或式III所示的结构，
In certain embodiments, the compound of formula I further has a structure as shown in formula II or formula III,

其中，in,

G环为3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基或含有1、2、3或4个选自N、O、S杂原子的5-6元杂芳基；Ring G is a 3-12 membered cycloalkyl group, a 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O) 2 , or a 5-6 membered heteroaryl group containing one, two, three or four heteroatoms selected from N, O, and S;

W为N、C或CRa；W is N, C or CR a ;

t为0、1、2、3、4或5。t is 0, 1, 2, 3, 4, or 5.

在某些实施方式中，A环为含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的4-7元杂环基、3-6元环烷基；In certain embodiments, ring A is a 4-7 membered heterocyclyl or a 3-6 membered cycloalkyl group containing 1 or 2 heteroatoms selected from N, O, S, S=O, and S(O) 2 ;

优选地，A环为哌啶基、吖丁啶基、吡咯烷基、哌嗪基、高哌啶、高哌嗪、1,4-氮杂氧杂环庚烷、环丙基、环丁基、环戊基、环己基、2-氮杂二环[2.2.2]辛烷、2-氮杂二环[2.2.1]庚烷、2,5-二氮杂二环[2.2.2]辛烷或2,5-二氮杂二环[2.2.1]庚烷。Preferably, Ring A is piperidinyl, azetidinyl, pyrrolidinyl, piperazinyl, homopiperidine, homopiperazine, 1,4-azaoxepane, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-azabicyclo[2.2.2]octane, 2-azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.2]octane or 2,5-diazabicyclo[2.2.1]heptane.

在某些实施方式中，A环为含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的4-9元杂环基；In certain embodiments, ring A is a 4-9 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, S=O, S(O) 2 ;

优选地，A环为哌啶基、吖丁啶基、吡咯烷基、哌嗪基、高哌啶、高哌嗪、1,4-氮杂氧杂环庚烷、环丙基、环丁基、环戊基、环己基、2-氮杂二环[2.2.2]辛烷、2-氮杂二环[2.2.1]庚烷、2,5-二氮杂二环[2.2.2]辛烷、2,5-二氮杂二环[2.2.1]庚烷、8-氮杂双环[3.2.1]辛烷、6-氮杂双环[3.1.1]庚烷或7-氮杂双环[2.2.1]庚烷。Preferably, Ring A is piperidinyl, azetidinyl, pyrrolidinyl, piperazinyl, homopiperidine, homopiperazine, 1,4-azaoxepane, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-azabicyclo[2.2.2]octane, 2-azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.2]octane, 2,5-diazabicyclo[2.2.1]heptane, 8-azabicyclo[3.2.1]octane, 6-azabicyclo[3.1.1]heptane or 7-azabicyclo[2.2.1]heptane.

在某些实施方式中，E环为苯基或含有1、2、3或4个选自N、O、S杂原子的5-6元杂芳基；In certain embodiments, the E ring is phenyl or a 5-6 membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O, and S;

优选地，E环为苯基、吡啶基、嘧啶、哒嗪、吡嗪、噻吩或吡唑。Preferably, the E ring is phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene or pyrazole.

在某些实施方式中，Q1为所述地 任选地被一个或多个氘原子、F、Cl、氰基、羟基、氨基、甲基、乙基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、甲氨基、二甲氨基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基或三氟乙氧基取代；In certain embodiments, Q is Said place optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy;

--/---为无或化学键；--/--- is none or chemical bond;

B环为吡咯、咪唑、吡唑、噻唑、噁唑、噁二唑、三氮唑、四氮唑、吡啶、嘧啶、哒嗪、吡嗪或三嗪；Ring B is pyrrole, imidazole, pyrazole, thiazole, oxazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine or triazine;

Xa、Xb、Xc各自独立地为N或CH；X a , X b , and X c are each independently N or CH;

X1为化学键、N、CH、CH2、S、O、S(O)或S(O)2；X 1 is a chemical bond, N, CH, CH 2 , S, O, S(O) or S(O) 2 ;

X2为N、CH、CH2、O、S、S(O)或S(O)2；X 2 is N, CH, CH 2 , O, S, S(O) or S(O) 2 ;

X3、X4各自独立地为N或C，且X3和X4不同时为N，X1、X2和X3不同时为N；X 3 and X 4 are each independently N or C, and X 3 and X 4 are not N at the same time, and X 1 , X 2 and X 3 are not N at the same time;

X5为化学键、N、CH、CH2、O或S；X 5 is a chemical bond, N, CH, CH 2 , O or S;

X6为N、O、S或CH； X6 is N, O, S or CH;

优选地，Q1选自以下基团：
所述Q1任选地被一个或多个氘原子、F、Cl、氰基、羟基、氨基、甲基、氘代甲基、乙基、异丙基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、甲氨基、二甲氨基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基或三氟乙氧基取代；Preferably, Q 1 is selected from the following groups:
said Q 1 is optionally substituted by one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, deuterated methyl, ethyl, isopropyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy;

更优选地，Q1选自以下基团：

More preferably, Q 1 is selected from the following groups:

在某些实施方式中，L1为化学键、O、NR4、CR5R6、-OR7-或C(＝O)；In certain embodiments, L 1 is a bond, O, NR 4 , CR 5 R 6 , -OR 7 -, or C(=O);

R4为氢原子、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C2-4烯基、C2-4炔基或3-12元环烷基，所述C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C2-4烯基、C2-4炔基或3-12元环烷基任选地被一个或者多个甲基、乙基、卤素、氘原子、氰基、羟基、甲氧基、环丙基或氧代(＝O)取代； R4 is a hydrogen atom, a C1-6 alkyl group, a halogenated C1-6 alkyl group, a deuterated C1-6 alkyl group, a C2-4 alkenyl group, a C2-4 alkynyl group or a 3-12 membered cycloalkyl group, wherein the C1-6 alkyl group, the halogenated C1-6 alkyl group, the deuterated C1-6 alkyl group, the C2-4 alkenyl group, the C2-4 alkynyl group or the 3-12 membered cycloalkyl group is optionally substituted with one or more methyl groups, ethyl groups, halogen groups, deuterium atoms, cyano groups, hydroxyl groups, methoxy groups, cyclopropyl groups or oxo (=O);

R5、R6各自独立地为氢原子、氘原子、卤素、氰基、羟基、氨基、C1-6烷基、卤代C1-6烷基、3-6元环烷基、C1-6烷氧基、卤代C1-6烷氧基、3-12元环烷基氧基、C1-6烷基氨基、二(C1-6烷基)氨基；R 5 and R 6 are each independently a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a 3-6 membered cycloalkyl group, a C 1-6 alkoxy group, a halogenated C 1-6 alkoxy group, a 3-12 membered cycloalkyloxy group, a C 1-6 alkylamino group, or a di(C 1-6 alkyl)amino group;

或者，R5与R6和所连接的C原子一起形成环丙基、环丁基、环戊基或环己基，所述环丙基、环丁基、环戊基或环己基任选地被一个或者多个甲基、乙基、卤素、氘原子或环丙基取代；Alternatively, R 5 and R 6 together with the attached C atom form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group is optionally substituted with one or more methyl, ethyl, halogen, deuterium atom or cyclopropyl group;

R7为亚甲基、亚乙基或亚丙基； R7 is methylene, ethylene or propylene;

优选地，L1为化学键、O、NR4、CR5R6、-OR7-或C(＝O)；Preferably, L 1 is a chemical bond, O, NR 4 , CR 5 R 6 , -OR 7 - or C(=O);

R4为氢原子、甲基、乙基、异丙基、1,2-二羟基丙-3-基、乙酰基、甲氧基乙基、乙氰基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、环丁基、丙烯基或丙炔基； R4 is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a 1,2-dihydroxypropan-3-yl group, an acetyl group, a methoxyethyl group, an acetylcyano group, a deuterated methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a propenyl group or a propynyl group;

R5、R6各自独立地为氢原子、氘原子、卤素、氰基、羟基、氨基、甲基、乙基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、甲氨基、二甲氨基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基、三氟乙氧基、丙烯基或丙炔基；R 5 and R 6 are each independently a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, a deuterated methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a cyclopropyl group, a methylamino group, a dimethylamino group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a propenyl group, or a propynyl group;

或者，R5与R6和所连接的C原子一起形成环丙基或环丁基，所述环丙基或环丁基任选地被一个或者多个甲基、乙基、卤素、氘原子或环丙基取代；Alternatively, R 5 and R 6 together with the attached C atom form a cyclopropyl or cyclobutyl group, wherein the cyclopropyl or cyclobutyl group is optionally substituted with one or more methyl groups, ethyl groups, halogen groups, deuterium atoms or cyclopropyl groups;

R7为亚甲基。 R7 is a methylene group.

在某些实施方式中，L2为化学键或NR4；In certain embodiments, L 2 is a chemical bond or NR 4 ;

R4为氢原子、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C2-4烯基、C2-4炔基或3-12元环烷基，所述C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C2-4烯基、C2-4炔基或3-12元环烷基任选地被一个或者多个甲基、乙基、卤素、氘原子、氰基、羟基、甲氧基、环丙基或氧代(＝O)取代； R4 is a hydrogen atom, a C1-6 alkyl group, a halogenated C1-6 alkyl group, a deuterated C1-6 alkyl group, a C2-4 alkenyl group, a C2-4 alkynyl group or a 3-12 membered cycloalkyl group, wherein the C1-6 alkyl group, the halogenated C1-6 alkyl group, the deuterated C1-6 alkyl group, the C2-4 alkenyl group, the C2-4 alkynyl group or the 3-12 membered cycloalkyl group is optionally substituted with one or more methyl groups, ethyl groups, halogen groups, deuterium atoms, cyano groups, hydroxyl groups, methoxy groups, cyclopropyl groups or oxo (=O);

优选地，L2为化学键或NR4；Preferably, L 2 is a chemical bond or NR 4 ;

R4为氢原子、甲基、乙基、异丙基、1,2-二羟基丙-3-基、乙酰基、甲氧基乙基、乙氰基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、环丁基、丙烯基或丙炔基。R 4 is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a 1,2-dihydroxyprop-3-yl group, an acetyl group, a methoxyethyl group, an acetylcyano group, a deuterated methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a propenyl group or a propynyl group.

在某些实施方式中，L3为NR4；In certain embodiments, L 3 is NR 4 ;

R4为氢原子、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C2-4烯基、C2-4炔基或3-12元环烷基，所述C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C2-4烯基、C2-4炔基或3-12元环烷基任选地被一个或者多个甲基、乙基、卤素、氘原子、氰基、羟基、甲氧基、环丙基或氧代(＝O)取代； R4 is a hydrogen atom, a C1-6 alkyl group, a halogenated C1-6 alkyl group, a deuterated C1-6 alkyl group, a C2-4 alkenyl group, a C2-4 alkynyl group or a 3-12 membered cycloalkyl group, wherein the C1-6 alkyl group, the halogenated C1-6 alkyl group, the deuterated C1-6 alkyl group, the C2-4 alkenyl group, the C2-4 alkynyl group or the 3-12 membered cycloalkyl group is optionally substituted with one or more methyl groups, ethyl groups, halogen groups, deuterium atoms, cyano groups, hydroxyl groups, methoxy groups, cyclopropyl groups or oxo (=O);

优选地，L3为NR4；Preferably, L 3 is NR 4 ;

R4为氢原子、甲基、乙基、异丙基、1,2-二羟基丙-3-基、乙酰基、甲氧基乙基、乙氰基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、环丁基、丙烯基或丙炔基。R 4 is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a 1,2-dihydroxyprop-3-yl group, an acetyl group, a methoxyethyl group, an acetylcyano group, a deuterated methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a propenyl group or a propynyl group.

在某些实施方式中，L4为O或CR5R6；In certain embodiments, L 4 is O or CR 5 R 6 ;

R5、R6各自独立地为氢原子、氘原子、卤素、氰基、羟基、氨基、C1-6烷基、卤代C1-6烷基、3-6元环烷基、C1-6烷氧基、卤代C1-6烷氧基、3-12元环烷基氧基、C1-6烷基氨基、二(C1-6烷基)氨基；R 5 and R 6 are each independently a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a 3-6 membered cycloalkyl group, a C 1-6 alkoxy group, a halogenated C 1-6 alkoxy group, a 3-12 membered cycloalkyloxy group, a C 1-6 alkylamino group, or a di(C 1-6 alkyl)amino group;

或者，R5与R6和所连接的C原子一起形成环丙基、环丁基、环戊基或环己基，所述环丙基、环丁基、环戊基或环己基任选地被一个或者多个甲基、乙基、卤素、氘原子或环丙基取代；Alternatively, R 5 and R 6 together with the attached C atom form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group is optionally substituted with one or more methyl, ethyl, halogen, deuterium atom or cyclopropyl group;

优选地，L4为O或CR5R6；Preferably, L 4 is O or CR 5 R 6 ;

R5、R6各自独立地为氢原子、氘原子、卤素、氰基、羟基、氨基、甲基、乙基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、甲氨基、二甲氨基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基、三氟乙氧基、丙烯基或丙炔基；R 5 and R 6 are each independently a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, a deuterated methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a cyclopropyl group, a methylamino group, a dimethylamino group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a propenyl group, or a propynyl group;

或者，R5与R6和所连接的C原子一起形成环丙基或环丁基，所述环丙基或环丁基任选地被一个或者多个甲基、乙基、卤素、氘原子或环丙基取代。Alternatively, R 5 and R 6 together with the attached C atom form a cyclopropyl or cyclobutyl group, which is optionally substituted with one or more methyl, ethyl, halogen, deuterium atoms or cyclopropyl groups.

在某些实施方式中，M为C＝O或S(＝O)2；In certain embodiments, M is C=O or S(=O) 2 ;

优选地，M为C＝O；Preferably, M is C=O;

在某些实施方式中，Y1为N或CRa；In certain embodiments, Y 1 is N or CR a ;

Ra为氢原子、氘原子、卤素、氰基、C1-6烷基、C2-4烯基、C2-4炔基、4-10元杂环基、ORa1、SRa1或NRa1，所述C1-6烷基、C2-4烯基、C2-4炔基、4-10元杂环基任选地被一个或者多个R′取代；R a is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a 4-10 membered heterocyclic group, OR a1 , SR a1 or NR a1 , wherein the C 1-6 alkyl group, the C 2-4 alkenyl group, the C 2-4 alkynyl group or the 4-10 membered heterocyclic group is optionally substituted by one or more R′;

Ra1为氢原子、C1-4烷基、3-6元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基、3-6元环烷基-C1-6烷基或含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基-C1-6烷基，所述C1-4烷基、3-6元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基、3-6元环烷基-C1-6烷基或含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基-C1-6烷基任选地被一个或者多个卤素、氘原子、甲基、乙基、或氧代取代；R a1 is a hydrogen atom, a C 1-4 alkyl group, a 3-6 membered cycloalkyl group, a 3-6 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , a 3-6 membered cycloalkyl-C 1-6 alkyl group, or a 3-6 membered heterocyclyl-C 1-6 alkyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , wherein the C 1-4 alkyl group, the 3-6 membered cycloalkyl group, the 3-6 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , the 3-6 membered cycloalkyl-C 1-6 alkyl group, or the 3-6 membered heterocyclyl-C 1-6 alkyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 are optionally substituted with one or more halogen, a deuterium atom, a methyl group, an ethyl group, or an oxo group;

R′为氘原子、F、Cl、氰基、羟基、氨基、甲基、乙基、二氟甲基、三氟甲基、甲氧基、二氟甲氧基、三氟甲氧基、环丙基、甲氧基、吡咯烷基、1-甲基吡咯烷-3-基或氧代(＝O)；R′ is a deuterium atom, F, Cl, cyano, hydroxy, amino, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, methoxy, pyrrolidinyl, 1-methylpyrrolidin-3-yl, or oxo (═O);

优选地，Y1为N或CRa；Preferably, Y 1 is N or CR a ;

Ra为氢原子、氘原子、F、Cl、Br、氰基、羟基、氨基、甲基、乙基、正丙基、异丙基、二氟甲基、三氟甲基、乙炔基、2-(1,3-二甲基吡咯烷-3-基)乙炔基、乙氰基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基、三氟乙氧基、羟基乙氧基、N',N'-二甲氨基乙氧基、N'-甲基氨基乙氧基、吗啉基、2-氧杂-6-氮杂螺[3.3]环庚烷基、吗啉基-乙氧基、羟基丙氧基、N',N'-二甲氨基丙氧基、N'-甲基氨基丙氧基、吗啉基-丙氧基、哌嗪-1-基-乙氧基、4-甲基哌嗪-1-基-乙氧基、4-甲基哌嗪-1-基-丙氧基、哌嗪-1-基-丙氧基、吡咯烷-1-基-乙氧基、吡咯烷-1-基-丙氧基、四氢呋喃-3-氧基、甲硫基、甲氨基、乙胺基、乙酰胺基、丙酰胺基、甲氧基乙基、甲氧基乙胺基或甲氧基乙氧基。 Ra is a hydrogen atom, a deuterium atom, F, Cl, Br, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a difluoromethyl group, a trifluoromethyl group, an ethynyl group, a 2-(1,3-dimethylpyrrolidin-3-yl)ethynyl group, an acetylcyano group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a hydroxyethoxy group, an N',N'-dimethylaminoethoxy group, an N'-methylaminoethoxy group, a morpholinyl group, a 2-oxa-6-azaspiro[3.3]cycloheptyl group, a morpholinyl group -ethoxy, hydroxypropoxy, N',N'-dimethylaminopropoxy, N'-methylaminopropoxy, morpholinyl-propoxy, piperazin-1-yl-ethoxy, 4-methylpiperazin-1-yl-ethoxy, 4-methylpiperazin-1-yl-propoxy, piperazin-1-yl-propoxy, pyrrolidin-1-yl-ethoxy, pyrrolidin-1-yl-propoxy, tetrahydrofuran-3-oxy, methylthio, methylamino, ethylamino, acetamido, propionamido, methoxyethyl, methoxyethylamino or methoxyethoxy.

在某些实施方式中，Y2为N或CRb；In certain embodiments, Y 2 is N or CR b ;

Rb为氢原子、氘原子、卤素、氰基、C1-6烷基、C2-4烯基、C2-4炔基、4-10元杂环基、ORa1、SRa1或NRa1，所述C1-6烷基、C2-4烯基、C2-4炔基、4-10元杂环基任选地被一个或者多个R′取代；R b is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a 4-10 membered heterocyclic group, OR a1 , SR a1 or NR a1 , wherein the C 1-6 alkyl group, the C 2-4 alkenyl group, the C 2-4 alkynyl group or the 4-10 membered heterocyclic group is optionally substituted by one or more R′;

Ra1为氢原子、C1-4烷基、3-6元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基、3-6元环烷基-C1-6烷基或含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基-C1-6烷基，所述C1-4烷基、3-6元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基、3-6元环烷基-C1-6烷基或含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基-C1-6烷基任选地被一个或者多个卤素、氘原子、甲基、乙基、或氧代取代；R a1 is a hydrogen atom, a C 1-4 alkyl group, a 3-6 membered cycloalkyl group, a 3-6 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , a 3-6 membered cycloalkyl-C 1-6 alkyl group, or a 3-6 membered heterocyclyl-C 1-6 alkyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , wherein the C 1-4 alkyl group, the 3-6 membered cycloalkyl group, the 3-6 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , the 3-6 membered cycloalkyl-C 1-6 alkyl group, or the 3-6 membered heterocyclyl-C 1-6 alkyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 are optionally substituted with one or more halogen, a deuterium atom, a methyl group, an ethyl group, or an oxo group;

或者，Rb与Rd和所连接的原子一起形成4-7元环烷基或含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的5-7元杂环基，所述4-7元环烷基或含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的5-7元杂环基任选地被一个或者多个R′取代；Alternatively, R b and R d together with the atoms to which they are attached form a 4-7 membered cycloalkyl group or a 5-7 membered heterocyclyl group containing 1 or 2 heteroatoms selected from N, O, S, S═O, S(O) 2 , wherein the 4-7 membered cycloalkyl group or the 5-7 membered heterocyclyl group containing 1 or 2 heteroatoms selected from N, O, S, S═O, S(O) 2 are optionally substituted with one or more R ′;

R′为氘原子、F、Cl、氰基、羟基、氨基、甲基、乙基、二氟甲基、三氟甲基、甲氧基、二氟甲氧基、三氟甲氧基、环丙基、甲氧基、吡咯烷基、1-甲基吡咯烷-3-基或氧代(＝O)；R′ is a deuterium atom, F, Cl, cyano, hydroxy, amino, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, methoxy, pyrrolidinyl, 1-methylpyrrolidin-3-yl, or oxo (═O);

优选地，Y2为N或CRb；Preferably, Y 2 is N or CR b ;

Rb为氢原子、氘原子、F、Cl、Br、氰基、羟基、氨基、甲基、乙基、正丙基、异丙基、二氟甲基、三氟甲基、乙炔基、2-(1,3-二甲基吡咯烷-3-基)乙炔基、乙氰基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基、三氟乙氧基、羟基乙氧基、N',N'-二甲氨基乙氧基、N'-甲基氨基乙氧基、吗啉基、2-氧杂-6-氮杂螺[3.3]环庚烷基、吗啉基-乙氧基、羟基丙氧基、N',N'-二甲氨基丙氧基、N'-甲基氨基丙氧基、吗啉基-丙氧基、哌嗪-1-基-乙氧基、4-甲基哌嗪-1-基-乙氧基、4-甲基哌嗪-1-基-丙氧基、哌嗪-1-基-丙氧基、吡咯烷-1-基-乙氧基、吡咯烷-1-基-丙氧基、四氢呋喃-3-氧基、甲硫基、甲氨基、乙胺基、乙酰胺基、丙酰胺基、甲氧基乙基、甲氧基乙胺基或甲氧基乙氧基；R b is a hydrogen atom, a deuterium atom, F, Cl, Br, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a difluoromethyl group, a trifluoromethyl group, an ethynyl group, a 2-(1,3-dimethylpyrrolidin-3-yl)ethynyl group, an acetylcyano group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a hydroxyethoxy group, an N',N'-dimethylaminoethoxy group, an N'-methylaminoethoxy group, a morpholinyl group, a 2-oxa-6-azaspiro[3.3]cycloheptyl group, a morpholinyl group -ethoxy, hydroxypropoxy, N',N'-dimethylaminopropoxy, N'-methylaminopropoxy, morpholinyl-propoxy, piperazin-1-yl-ethoxy, 4-methylpiperazin-1-yl-ethoxy, 4-methylpiperazin-1-yl-propoxy, piperazin-1-yl-propoxy, pyrrolidin-1-yl-ethoxy, pyrrolidin-1-yl-propoxy, tetrahydrofuran-3-oxy, methylthio, methylamino, ethylamino, acetamido, propionamido, methoxyethyl, methoxyethylamino or methoxyethoxy;

或者，Rb与Rd和所连接的原子一起形成吗啉基、四氢呋喃基、二氢咪唑基、硫代吗啉基、四氢吡喃基、四氢吡喃酮基、1,4-二氧六环基、六氢-1,4-氧氮杂卓基、六氢-1,4-硫氮杂卓基、4-硫代吗啉基-1-氧化物、4-硫代吗啉基-1,1-二氧化物、六氢-1,4-硫氮杂卓基-1-氧化物或六氢-1,4-硫氮杂卓基-1,1-二氧化物，所述吗啉基、硫代吗啉基、四氢吡喃基、四氢吡喃酮基、1,4-二氧六环基、六氢-1,4-氧氮杂卓基、六氢-1,4-硫氮杂卓基、4-硫代吗啉基-1-氧化物、4-硫代吗啉基-1,1-二氧化物、六氢-1,4-硫氮杂卓基-1-氧化物或六氢-1,4-硫氮杂卓基-1,1-二氧化物任选地被一个或多个氘原子、F、Cl、氰基、羟基、氨基、甲基、乙基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、甲氨基、二甲氨基、二甲氨基烷基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基或三氟乙氧基取代。Alternatively, Rb and Rd , together with the atoms to which they are attached, form a morpholinyl, tetrahydrofuranyl, dihydroimidazolyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide or hexahydro-1,4-thiazepinyl-1,1-dioxide, wherein the morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxazepinyl, The isopropyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide or hexahydro-1,4-thiazepinyl-1,1-dioxide is optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, dimethylaminoalkyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy.

在某些实施方式中，Y3为N或CRc；In certain embodiments, Y 3 is N or CR c ;

Rc为氢原子、卤素、氰基、氨基、甲基、乙基、异丙基、环丙基、甲氧基或环丙氧基，所述氨基、甲基、异丙基、乙基、环丙基、甲氧基和环丙氧基任选地被一个或者多个R′取代；R c is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group, wherein the amino group, the methyl group, the isopropyl group, the ethyl group, the cyclopropyl group, the methoxy group and the cyclopropyloxy group are optionally substituted by one or more R ′;

R′为氘原子、F、Cl、氰基、羟基、氨基、甲基、乙基、二氟甲基、三氟甲基、甲氧基、二氟甲氧基、三氟甲氧基、环丙基、甲氧基、吡咯烷基、1-甲基吡咯烷-3-基或氧代(＝O)；R′ is a deuterium atom, F, Cl, cyano, hydroxy, amino, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, methoxy, pyrrolidinyl, 1-methylpyrrolidin-3-yl, or oxo (═O);

优选地，Y3为N或CRc；Preferably, Y 3 is N or CR c ;

Rc为氢原子、卤素、氰基、氨基、甲基、乙基、异丙基、环丙基、甲氧基或环丙氧基。R c is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group.

在某些实施方式中，Y4为N或CRd；In certain embodiments, Y 4 is N or CR d ;

Rd为氢原子、卤素、氰基、氨基、甲基、乙基、异丙基、环丙基、甲氧基或环丙氧基，所述氨基、甲基、异丙基、乙基、环丙基、甲氧基和环丙氧基任选地被一个或者多个R′取代；R d is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group, wherein the amino group, the methyl group, the isopropyl group, the ethyl group, the cyclopropyl group, the methoxy group and the cyclopropyloxy group are optionally substituted by one or more R's;

或者，Rb与Rd和所连接的原子一起形成4-7元环烷基或含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的5-7元杂环基，所述的4-7元环烷基或含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的5-7元杂环基任选地被一个或者多个R′取代；Alternatively, Rb , Rd and the atoms to which they are attached together form a 4-7 membered cycloalkyl group or a 5-7 membered heterocyclyl group containing 1 or 2 heteroatoms selected from N, O, S, S=O, S(O) 2 , wherein the 4-7 membered cycloalkyl group or the 5-7 membered heterocyclyl group containing 1 or 2 heteroatoms selected from N, O, S, S=O, S(O) 2 are optionally substituted by one or more R';

R′为氘原子、F、Cl、氰基、羟基、氨基、甲基、乙基、二氟甲基、三氟甲基、甲氧基、二氟甲氧基、三氟甲氧基、环丙基、甲氧基、吡咯烷基、1-甲基吡咯烷-3-基或氧代(＝O)；R′ is a deuterium atom, F, Cl, cyano, hydroxy, amino, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, methoxy, pyrrolidinyl, 1-methylpyrrolidin-3-yl, or oxo (═O);

优选地，Y4为N或CRd；Preferably, Y 4 is N or CR d ;

Rb与Rd和所连接的原子一起形成吗啉基、四氢呋喃基、二氢咪唑基、硫代吗啉基、四氢吡喃基、四氢吡喃酮基、1,4-二氧六环基、六氢-1,4-氧氮杂卓基、六氢-1,4-硫氮杂卓基、4-硫代吗啉基-1-氧化物、4-硫代吗啉基-1,1-二氧化物、六氢-1,4-硫氮杂卓基-1-氧化物或六氢-1,4-硫氮杂卓基-1,1-二氧化物，所述吗啉基、硫代吗啉基、四氢吡喃基、四氢吡喃酮基、1,4-二氧六环基、六氢-1,4-氧氮杂卓基、六氢-1,4-硫氮杂卓基、4-硫代吗啉基-1-氧化物、4-硫代吗啉基-1,1-二氧化物、六氢-1,4-硫氮杂卓基-1-氧化物或六氢-1,4-硫氮杂卓基-1,1-二氧化物任选地被一个或多个氘原子、F、Cl、氰基、羟基、氨基、甲基、乙基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、甲氨基、二甲氨基、二甲氨基烷基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基或三氟乙氧基取代。 Rb and Rd together with the atoms to which they are attached form a morpholinyl, tetrahydrofuranyl, dihydroimidazolyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide or hexahydro-1,4-thiazepinyl-1,1-dioxide, wherein the morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxazepinyl, The isopropyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide or hexahydro-1,4-thiazepinyl-1,1-dioxide is optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, dimethylaminoalkyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy.

在某些实施方式中，Y5为N、CRe或C；当L2为化学键，Y5为N；当L2为O或NR4时，Y5为CRe或C；In certain embodiments, Y 5 is N, CR e or C; when L 2 is a chemical bond, Y 5 is N; when L 2 is O or NR 4 , Y 5 is CR e or C;

优选地，Y5为N、CH或C；当L2为化学键，Y5为N；当L2为O或NR4时，Y5为CH或C。Preferably, Y 5 is N, CH or C; when L 2 is a chemical bond, Y 5 is N; when L 2 is O or NR 4 , Y 5 is CH or C.

在某些实施方式中，R1为卤代甲基、乙烯基、丙烯基、乙炔基、丙炔基、丁炔基、环氧丙烷基、环丁烯基、环戊烯基或环己烯基，所述卤代甲基、乙烯基、丙烯基、乙炔基、丙炔基、丁炔基、环氧丙烷基、环丁烯基、环戊烯基或环己烯基任选地被一个或者多个F、Cl、甲基、乙基、环丙基、吖丁啶基、吡咯烷基、哌啶基、环氧丙烷基、环氧丁烷基、氘原子、苯基、吡啶基或NRxRy取代，所述甲基、乙基、环丙基、吖丁啶基、吡咯烷基、哌啶基、环氧丙烷基、环氧丁烷基、苯基或吡啶基任选地被一个或者多个R′取代；In certain embodiments, R 1 is a halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, oxetyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl group, wherein the halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, oxetyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl group is optionally substituted with one or more F, Cl, methyl, ethyl, cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetyl, butylene oxide, a deuterium atom, a phenyl, pyridinyl, or NR x R y , wherein the methyl, ethyl, cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetyl, butylene oxide, a phenyl, or pyridinyl group is optionally substituted with one or more R ′;

Rx、Ry各自独立地为氢原子、甲基、乙基、异丙基、环丙基、环丁基、环戊基、金刚烷基、甲氧基乙基、环丙基甲基、环丁基甲基、环丙基乙基、环丁基乙基、吖丁啶基甲基或吖丁啶基乙基，所述甲基、乙基、异丙基、环丙基、环丁基、环戊基、金刚烷基、甲氧基乙基、环丙基甲基、环丁基甲基、环丙基乙基、环丁基乙基、吖丁啶基甲基或吖丁啶基乙基任选地被一个或者多个R′取代；R x and R y are each independently a hydrogen atom, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, azetidinylmethyl or azetidinylethyl, and the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, azetidinylmethyl or azetidinylethyl is optionally substituted with one or more R′;

或者，NRxRy中Rx与Ry和所连接的N原子一起形成吖丁啶基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、二氧化硫代吗啉基、7-氮杂双环[2.2.1]庚烷基、9-氮杂双环[3.3.1]壬烷基、2-氮杂双环[4.1.0]庚烷基或2-氮杂双环[3.1.0]己烷基，所述吖丁啶基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、二氧化硫代吗啉基、7-氮杂双环[2.2.1]庚烷基、9-氮杂双环[3.3.1]壬烷基、2-氮杂双环[4.1.0]庚烷基或2-氮杂双环[3.1.0]己烷基任选地被一个或者多个R′取代；or wherein R in NRxRy is taken together with Ry and the nitrogen atom to which it is attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1] heptanyl , 9-azabicyclo[3.3.1]nonanyl, 2-azabicyclo[4.1.0]heptanyl, or 2-azabicyclo[3.1.0]hexanyl, said azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptanyl, 9-azabicyclo[3.3.1]nonanyl, 2-azabicyclo[4.1.0]heptanyl, or 2-azabicyclo[3.1.0]hexanyl being optionally substituted with one or more R′;

R′为氘原子、F、Cl、氰基、羟基、氨基、甲基、乙基、乙烯基、乙炔基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、甲氨基、二甲氨基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基、三氟乙氧基或氧代(＝O)R′ is a deuterium atom, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, vinyl, ethynyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, or oxo (═O)

优选地，R1选自以下基团：

Preferably, R 1 is selected from the following groups:

在某些实施方式中，R2为氢原子、氘原子、氰基、卤素、C1-6烷基、C2-4烯基、C2-4炔基、卤代C1- 4烷基、氘代C1-4烷基、3-6元环烷基、C1-4烷氧基-C1-4烷基、卤代C1-4烷氧基或氧代(＝O)，所述C1-6烷基、C2-4烯基、C2-4炔基、卤代C1-4烷基、氘代C1-4烷基、3-6元环烷基、C1-4烷氧基-C1-4烷基、卤代C1-4烷氧基任选地被一个或者多个R′取代；In certain embodiments, R2 is a hydrogen atom, a deuterium atom, a cyano group, a halogen, a C1-6 alkyl group, a C2-4 alkenyl group, a C2-4 alkynyl group, a halo-substituted C1-4 alkyl group, a deuterated C1-4 alkyl group, a 3-6 membered cycloalkyl group, a C1-4 alkoxy- C1-4 alkyl group, a halo-substituted C1-4 alkoxy group, or an oxo group (=O), wherein the C1-6 alkyl group, the C2-4 alkenyl group, the C2-4 alkynyl group, the halo-substituted C1-4 alkyl group, the deuterated C1-4 alkyl group, the 3-6 membered cycloalkyl group, the C1-4 alkoxy- C1-4 alkyl group, the halo-substituted C1-4 alkoxy group is optionally substituted with one or more R';

或者，Rb与R2和所连接的原子一起形成含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的5-7元杂环基或含有1、2、3、4个选自N、O、S杂原子的5-6元杂芳基，所述含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的5-7元杂环基、含有1、2、3、4个选自N、O、S杂原子的5-6元杂芳基任选地被一个或者多个R′取代；Alternatively, Rb , R2 and the atoms to which they are attached form a 5-7 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, S=O, S(O) 2 , or a 5-6 membered heteroaryl group containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, wherein the 5-7 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, S=O, and S(O) 2 , or the 5-6 membered heteroaryl group containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S are optionally substituted by one or more R';

优选地，R2为氢原子、氘原子、F、Cl、甲基、乙基、异丙基、叔丁基、环丙基、环丁基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、乙烯基、丙烯基、乙炔基、丙炔基、氰基、二氟甲氧基、三氟甲氧基、甲氧基、甲氧基甲基或氧代(＝O)；Preferably, R 2 is a hydrogen atom, a deuterium atom, F, Cl, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a cyclopropyl group, a cyclobutyl group, a deuterated methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a vinyl group, a propenyl group, an ethynyl group, a propynyl group, a cyano group, a difluoromethoxy group, a trifluoromethoxy group, a methoxy group, a methoxymethyl group or an oxo group (═O);

或者，Rb与R2和所连接的原子一起形成吗啉基、四氢呋喃基、二氢咪唑基、硫代吗啉基、六氢-1,4-氧氮杂卓基、六氢-1,4-硫氮杂卓基、4-硫代吗啉基-1-氧化物、4-硫代吗啉基-1,1-二氧化物、六氢-1,4-硫氮杂卓基-1-氧化物或六氢-1,4-硫氮杂卓基-1,1-二氧化物，所述吗啉基、硫代吗啉基、六氢-1,4-氧氮杂卓基、六氢-1,4-硫氮杂卓基、4-硫代吗啉基-1-氧化物、4-硫代吗啉基-1,1-二氧化物、六氢-1,4-硫氮杂卓基-1-氧化物或六氢-1,4-硫氮杂卓基-1,1-二氧化物任选地被一个或多个氘原子、F、Cl、氰基、羟基、氨基、甲基、乙基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、甲氨基、二甲氨基、二甲氨基烷基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基或三氟乙氧基取代。Alternatively, Rb together with R2 and the atoms to which they are attached form a morpholinyl, tetrahydrofuranyl, dihydroimidazolyl, thiomorpholinyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide or hexahydro-1,4-thiazepinyl-1,1-dioxide, wherein the morpholinyl, thiomorpholinyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, 4-thiomorpholinyl-1,1-dioxide and 4-thiomorpholinyl-1,1-dioxide are substituted or substituted with morpholinyl, thiomorpholinyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1,1-dioxide. 1-dioxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide or hexahydro-1,4-thiazepinyl-1,1-dioxide is optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, dimethylaminoalkyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy.

在某些实施方式中，R3为氢原子、氘原子、卤素、氰基、硝基、C1-4烷基、C2-4烯基、C2-4炔基、3-6元饱和或不饱和环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元饱和或不饱和杂环基、卤代C1-4烷基、卤代C1-4烷氧基、ORe、SORe、S(O)2Re、C(＝O)Re、C(＝O)NRe、NReRf、NReC(＝O)Rf、S(O)2NRe、P(O)(Re)2，所述C1-4烷基、C2-4烯基、C2-4炔基、3-6元饱和或不饱和环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元饱和或不饱和杂环基、卤代C1-4烷基、卤代C1-4烷氧基任选地被一个或者多个R′取代；In certain embodiments, R 3 is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a nitro group, a C 1-4 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a 3-6 membered saturated or unsaturated cycloalkyl group, a 3-6 membered saturated or unsaturated heterocyclic group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , a halogenated C 1-4 alkyl group, a halogenated C 1-4 alkoxy group, OR e , SOR e , S(O) 2 R e , C(═O)R e , C(═O)NR e , NRe R f , NRe C(═O)R f , S(O) 2 NRe , P(O)(R e ) 2 , wherein the C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4- membered alkynyl, 3-6-membered saturated or unsaturated cycloalkyl, 3-6-membered saturated or unsaturated heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O) 2 , halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, optionally substituted by one or more R';

Re、Rf各自独立地为氢原子、氘原子、C1-4烷基、卤代C1-4烷基、3-12元环烷基；R e and R f are each independently a hydrogen atom, a deuterium atom, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, or a 3-12 membered cycloalkyl group;

或者，NReRf中Re和Rf与连接的N原子一起形成含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基；Alternatively, Re and Rf in NR e R f together with the attached N atom form a 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 ;

优选地，R3为氢原子、氘原子、F、Cl、氰基、硝基、甲基、乙基、异丙基、乙烯、乙炔、环丙基、环丁基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、羟基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧、甲氨基、乙胺基、SOCH3、S(O)2CH3、C(＝O)CH3、C(＝O)NCH3、NHC(＝O)CH3、S(O)2NCH3、P(O)(CH3)2或P(O)(CH2CH3)2，所述甲基、乙基、异丙基、乙烯、乙炔、环丙基、环丁基、二氟乙基、三氟乙基、羟基、甲氧基、乙氧基、甲氨基、乙胺基、SOCH3、S(O)2CH3、C(＝O)CH3、C(＝O)NCH3、NHC(＝O)CH3、S(O)2NCH3、P(O)(CH3)2或P(O)(CH2CH3)2任选地被一个或者多个氘原子、F、Cl、羟基、甲基、乙基、异丙基或环丙基取代。Preferably, R 3 is a hydrogen atom, a deuterium atom, F, Cl, a cyano group, a nitro group, a methyl group, an ethyl group, an isopropyl group, an ethylene group, an acetylene group, a cyclopropyl group, a cyclobutyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a hydroxyl group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a methylamino group, an ethylamino group, SOCH 3 , S(O) 2 CH 3 , C(═O)CH 3 , C(═O)NCH 3 , NHC(═O)CH 3 , S(O) 2 NCH 3 , P(O)(CH 3 ) 2 or P(O)(CH 2 CH 3 ) 2 , wherein the methyl group, ethyl group, isopropyl group, an ethylene group, an acetylene group, a cyclopropyl group, a cyclobutyl group, a difluoroethyl group, a trifluoroethyl group, a hydroxyl group, a methoxy group, an ethoxy group, a methylamino group, an ethylamino group, SOCH 3 , S(O) 2 CH 3 , C(═O)CH 3 , C(=O) NCH3 , NHC(=O) CH3 , S(O) 2NCH3 , P(O)( CH3 ) 2 or P(O)( CH2CH3 ) 2 are optionally substituted with one or more deuterium atoms, F, Cl, hydroxyl, methyl, ethyl, isopropyl or cyclopropyl .

在某些实施方式中，在式I中，Rb与Rd和所连接的原子一起形成G环，所述G环为4-7元环烷基、含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的4-7元杂环基，所述4-7元环烷基、含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的4-7元杂环基任选地被一个或者多个R′取代；In certain embodiments, in Formula I, R b and R d together with the atoms to which they are attached form a G ring, wherein the G ring is a 4-7 membered cycloalkyl group, a 4-7 membered heterocyclyl group containing 1 or 2 heteroatoms selected from N, O, S, S═O, S(O) 2 , and the 4-7 membered cycloalkyl group, the 4-7 membered heterocyclyl group containing 1 or 2 heteroatoms selected from N, O, S, S═O, S(O) 2 are optionally substituted with one or more R ′;

或者，Rb与R2和所连接的原子一起形成G环，所述G环为4-7元环烷基、含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的4-7元杂环基，所述4-7元环烷基、含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的4-7元杂环基任选地被一个或者多个R′取代；Alternatively, R b and R 2 together with the atoms to which they are attached form a G ring, wherein the G ring is a 4-7 membered cycloalkyl group, a 4-7 membered heterocyclyl group containing 1 or 2 heteroatoms selected from N, O, S, S═O, S(O) 2 , and the 4-7 membered cycloalkyl group, the 4-7 membered heterocyclyl group containing 1 or 2 heteroatoms selected from N, O, S, S═O, S(O) 2 are optionally substituted with one or more R ′;

优选地，G环为吗啉基、四氢呋喃基、二氢咪唑基、硫代吗啉基、四氢吡喃基、四氢吡喃酮基、1,4-二氧六环基、六氢-1,4-氧氮杂卓基、六氢-1,4-硫氮杂卓基、4-硫代吗啉基-1-氧化物、4-硫代吗啉基-1,1-二氧化物、六氢-1,4-硫氮杂卓基-1-氧化物或六氢-1,4-硫氮杂卓基-1,1-二氧化物，所述吗啉基、硫代吗啉基、四氢吡喃基、四氢吡喃酮基、1,4-二氧六环基、六氢-1,4-氧氮杂卓基、六氢-1,4-硫氮杂卓基、4-硫代吗啉基-1-氧化物、4-硫代吗啉基-1,1-二氧化物、六氢-1,4-硫氮杂卓基-1-氧化物或六氢-1,4-硫氮杂卓基-1,1-二氧化物任选地被一个或多个氘原子、F、Cl、氰基、羟基、氨基、甲基、乙基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、甲氨基、二甲氨基、二甲氨基烷基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基或三氟乙氧基取代。Preferably, the G ring is morpholinyl, tetrahydrofuranyl, dihydroimidazolyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide or hexahydro-1,4-thiazepinyl-1,1-dioxide, the morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxazepinyl , hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide or hexahydro-1,4-thiazepinyl-1,1-dioxide is optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, dimethylaminoalkyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy.

在某些实施方式中，所述式I化合物进一步具有如式II结构，
In certain embodiments, the compound of formula I further has a structure as shown in formula II,

A环为含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的4-9元杂环基(例如为含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的4-7元杂环基)、3-6环烷基；Ring A is a 4-9 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, S=O, S(O) 2 (for example, a 4-7 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, S=O, S(O) 2), or a 3-6 membered cycloalkyl group;

E环为苯基或含有1、2、3、4个选自N、O、S杂原子的5-6元杂芳基；Ring E is phenyl or a 5-6 membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O and S;

G环为4-7元环烷基、含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的5-7元杂环基；Ring G is a 4-7 membered cycloalkyl group, or a 5-7 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, S=O, and S(O) 2 ;

Q1为所述地任选地被一个或多个氘原子、F、Cl、氰基、羟基、氨基、甲基、乙基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、甲氨基、二甲氨基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基或三氟乙氧基取代； Q1 is Said place optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy;

L1为化学键、O、NR4、CR5R6、-OR7-或C(＝O)；L 1 is a chemical bond, O, NR 4 , CR 5 R 6 , -OR 7 - or C(=O);

L2为化学键或NR4；L 2 is a chemical bond or NR 4 ;

L3为NR4；L 3 is NR 4 ;

L4为O或CR5R6；L 4 is O or CR 5 R 6 ;

M为C＝O或S(＝O)2；M is C=O or S(=O) 2 ;

Y1为N或CRa； Y1 is N or CR a ;

Y3为N或CRc；Y 3 is N or CR c ;

Y5为N、CH或C；当L2为化学键，Y5为N；当L2为O或NR4时，Y5为CH或C；Y 5 is N, CH or C; when L 2 is a chemical bond, Y 5 is N; when L 2 is O or NR 4 , Y 5 is CH or C;

R1为卤代甲基、乙烯基、丙烯基、乙炔基、丙炔基、丁炔基、环氧丙烷基、环丁烯基、环戊烯基或环己烯基，所述卤代甲基、乙烯基、丙烯基、乙炔基、丙炔基、丁炔基、环氧丙烷基、环丁烯基、环戊烯基或环己烯基任选地被一个或者多个F、Cl、甲基、乙基、环丙基、吖丁啶基、吡咯烷基、哌啶基、环氧丙烷基、环氧丁烷基、氘原子、苯基、吡啶基或NRxRy取代，所述甲基、乙基、环丙基、吖丁啶基、吡咯烷基、哌啶基、环氧丙烷基、环氧丁烷基、苯基或吡啶基任选地被一个或者多个R′取代；R 1 is a halomethyl group, vinyl group, propenyl group, ethynyl group, propynyl group, butynyl group, oxetyl group, cyclobutenyl group, cyclopentenyl group or cyclohexenyl group, wherein the halomethyl group, vinyl group, propenyl group, ethynyl group, propynyl group, butynyl group, oxetyl group, cyclobutenyl group, cyclopentenyl group or cyclohexenyl group is optionally substituted with one or more F, Cl, methyl group, ethyl group, cyclopropyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, oxetyl group, butylene oxide group, deuterium atom, phenyl group, pyridinyl group or NR x R y , wherein the methyl group, ethyl group, cyclopropyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, oxetyl group, butylene oxide group, phenyl group or pyridinyl group is optionally substituted with one or more R ′;

R2为氢原子、氘原子、氰基、卤素、C1-6烷基、C2-4烯基、C2-4炔基、卤代C1-4烷基、氘代C1-4烷基、3-6元环烷基、C1-4烷氧基-C1-4烷基、卤代C1-4烷氧基或氧代(＝O)，所述C1-6烷基、C2-4烯基、C2- 4炔基、卤代C1-4烷基、氘代C1-4烷基、3-6元环烷基、C1-4烷氧基-C1-4烷基、卤代C1-4烷氧基任选地被一个或者多个R′取代； R2 is a hydrogen atom, a deuterium atom, a cyano group, a halogen, a C1-6 alkyl group, a C2-4 alkenyl group, a C2-4 alkynyl group, a halo-substituted C1-4 alkyl group, a deuterated C1-4 alkyl group, a 3-6-membered cycloalkyl group, a C1-4 alkoxy- C1-4 alkyl group, a halo-substituted C1-4 alkoxy group or an oxo group (=O), wherein the C1-6 alkyl group, the C2-4 alkenyl group, the C2-4 alkynyl group, the halo-substituted C1-4 alkyl group, the deuterated C1-4 alkyl group, the 3-6-membered cycloalkyl group, the C1-4 alkoxy- C1-4 alkyl group and the halo-substituted C1-4 alkoxy group are optionally substituted with one or more R';

R3为氢原子、氘原子、卤素、氰基、硝基、C1-4烷基、C2-4烯基、C2-4炔基、3-6元饱和或不饱和环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元饱和或不饱和杂环基、卤代C1- 4烷基、卤代C1-4烷氧基、ORe、SORe、S(O)2Re、C(＝O)Re、C(＝O)NRe、NReRf、NReC(＝O)Rf、S(O)2NRe、P(O)(Re)2，所述C1-4烷基、C2-4烯基、C2-4炔基、3-6元饱和或不饱和环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元饱和或不饱和杂环基、卤代C1-4烷基、卤代C1-4烷氧基任选地被一个或者多个R′取代；R 3 is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a nitro group, a C 1-4 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a 3-6 membered saturated or unsaturated cycloalkyl group, a 3-6 membered saturated or unsaturated heterocyclic group containing one or more heteroatoms selected from N, O, S, S＝O, and S(O) 2 , a halogenated C 1-4 alkyl group, a halogenated C 1-4 alkoxy group, OR e , SOR e , S(O) 2 R e , C(＝O)R e , C(＝O)NR e , NRe R f , NRe C(＝O)R f , S(O) 2 NRe , P(O)(R e ) 2 , wherein the C 1-4 alkyl group, the C 2-4 alkenyl group, the C 2-4 alkynyl group, the 3-6 membered saturated or unsaturated cycloalkyl group, the 3-6 membered saturated or unsaturated heterocyclic group containing one or more heteroatoms selected from N, O, S, S＝O, and S(O) 2 2 heteroatoms, 3-6 membered saturated or unsaturated heterocyclic group, halogenated C 1-4 alkyl group, halogenated C 1-4 alkoxy group are optionally substituted by one or more R';

R4为氢原子、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C2-4烯基、C2-4炔基或3-12元环烷基，所述C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C2-4烯基、C2-4炔基或3-12元环烷基任选地被一个或者多个甲基、乙基、卤素、氘原子、氰基、羟基、甲氧基或环丙基取代； R4 is a hydrogen atom, a C1-6 alkyl group, a halogenated C1-6 alkyl group, a deuterated C1-6 alkyl group, a C2-4 alkenyl group, a C2-4 alkynyl group or a 3-12 membered cycloalkyl group, wherein the C1-6 alkyl group, the halogenated C1-6 alkyl group, the deuterated C1-6 alkyl group, the C2-4 alkenyl group, the C2-4 alkynyl group or the 3-12 membered cycloalkyl group is optionally substituted with one or more methyl groups, ethyl groups, halogen groups, deuterium atoms, cyano groups, hydroxyl groups, methoxy groups or cyclopropyl groups;

R5、R6各自独立地为氢原子、氘原子、卤素、氰基、羟基、氨基、C1-6烷基、卤代C1-6烷基、3-6元环烷基、C1-6烷氧基、卤代C1-6烷氧基、3-12元环烷基氧基、C1-6烷基氨基、二(C1-6烷基)氨基；R 5 and R 6 are each independently a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a 3-6 membered cycloalkyl group, a C 1-6 alkoxy group, a halogenated C 1-6 alkoxy group, a 3-12 membered cycloalkyloxy group, a C 1-6 alkylamino group, or a di(C 1-6 alkyl)amino group;

或者，R5与R6和所连接的C原子一起形成环丙基、环丁基、环戊基或环己基，所述环丙基、环丁基、环戊基或环己基任选地被一个或者多个甲基、乙基、卤素、氘原子或环丙基取代；Alternatively, R 5 and R 6 together with the attached C atom form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group is optionally substituted with one or more methyl, ethyl, halogen, deuterium atom or cyclopropyl group;

R7为亚甲基、亚乙基或亚丙基； R7 is methylene, ethylene or propylene;

Ra为氢原子、氘原子、卤素、氰基、C1-6烷基、C2-4烯基、C2-4炔基、4-10元杂环基、ORa1、SRa1或NRa1，所述C1-6烷基、C2-4烯基、C2-4炔基、4-10元杂环基任选地被一个或者多个R′取代；R a is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a 4-10 membered heterocyclic group, OR a1 , SR a1 or NR a1 , wherein the C 1-6 alkyl group, the C 2-4 alkenyl group, the C 2-4 alkynyl group or the 4-10 membered heterocyclic group is optionally substituted by one or more R′;

Ra1为氢原子、C1-4烷基、3-6元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基、3-6元环烷基-C1-6烷基或含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基-C1-6烷基，所述C1-4烷基、3-6元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基、3-6元环烷基-C1-6烷基或含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基-C1-6烷基任选地被一个或者多个卤素、氘原子、甲基、乙基、或氧代取代；R a1 is a hydrogen atom, a C 1-4 alkyl group, a 3-6 membered cycloalkyl group, a 3-6 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , a 3-6 membered cycloalkyl-C 1-6 alkyl group, or a 3-6 membered heterocyclyl-C 1-6 alkyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , wherein the C 1-4 alkyl group, the 3-6 membered cycloalkyl group, the 3-6 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , the 3-6 membered cycloalkyl-C 1-6 alkyl group, or the 3-6 membered heterocyclyl-C 1-6 alkyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 are optionally substituted with one or more halogen, a deuterium atom, a methyl group, an ethyl group, or an oxo group;

Rc为氢原子、卤素、氰基、氨基、甲基、乙基、异丙基、环丙基、甲氧基或环丙氧基，所述氨基、甲基、异丙基、乙基、环丙基、甲氧基和环丙氧基任选地被一个或者多个R′取代；R c is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group, wherein the amino group, the methyl group, the isopropyl group, the ethyl group, the cyclopropyl group, the methoxy group and the cyclopropyloxy group are optionally substituted by one or more R ′;

Rx、Ry各自独立地为氢原子、甲基、乙基、异丙基、环丙基、环丁基、环戊基、金刚烷基、甲氧基乙基、环丙基甲基、环丁基甲基、环丙基乙基、环丁基乙基、吖丁啶基甲基或吖丁啶基乙基，所述甲基、乙基、异丙基、环丙基、环丁基、环戊基、金刚烷基、甲氧基乙基、环丙基甲基、环丁基甲基、环丙基乙基、环丁基乙基、吖丁啶基甲基或吖丁啶基乙基任选地被一个或者多个R′取代；R x and R y are each independently a hydrogen atom, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, azetidinylmethyl or azetidinylethyl, and the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, azetidinylmethyl or azetidinylethyl is optionally substituted with one or more R′;

或者，NRxRy中Rx与Ry和所连接的N原子一起形成吖丁啶基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、二氧化硫代吗啉基、7-氮杂双环[2.2.1]庚烷基、9-氮杂双环[3.3.1]壬烷基、2-氮杂双环[4.1.0]庚烷基或2-氮杂双环[3.1.0]己烷基，所述吖丁啶基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、二氧化硫代吗啉基、7-氮杂双环[2.2.1]庚烷基、9-氮杂双环[3.3.1]壬烷基、2-氮杂双环[4.1.0]庚烷基或2-氮杂双环[3.1.0]己烷基任选地被一个或者多个R′取代；or wherein R in NRxRy is taken together with Ry and the nitrogen atom to which it is attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1] heptanyl , 9-azabicyclo[3.3.1]nonanyl, 2-azabicyclo[4.1.0]heptanyl, or 2-azabicyclo[3.1.0]hexanyl, said azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptanyl, 9-azabicyclo[3.3.1]nonanyl, 2-azabicyclo[4.1.0]heptanyl, or 2-azabicyclo[3.1.0]hexanyl being optionally substituted with one or more R′;

Re、Rf各自独立地为氢原子、氘原子、C1-4烷基、卤代C1-4烷基、3-12元环烷基；R e and R f are each independently a hydrogen atom, a deuterium atom, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, or a 3-12 membered cycloalkyl group;

或者，NReRf中Re和Rf与连接的N原子一起形成含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基；Alternatively, Re and Rf in NR e R f together with the attached N atom form a 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 ;

--/---为无或化学键；--/--- is none or chemical bond;

B环为吡咯、咪唑、吡唑、噻唑、噁唑、噁二唑、三氮唑、四氮唑、吡啶、嘧啶、哒嗪、吡嗪或三嗪；Ring B is pyrrole, imidazole, pyrazole, thiazole, oxazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine or triazine;

Xa、Xb、Xc各自独立地为N或CH；X a , X b , and X c are each independently N or CH;

X1为化学键、N、CH、CH2、S、O、S(O)或S(O)2；X 1 is a chemical bond, N, CH, CH 2 , S, O, S(O) or S(O) 2 ;

X2为N、CH、CH2、O、S、S(O)或S(O)2；X 2 is N, CH, CH 2 , O, S, S(O) or S(O) 2 ;

X3、X4各自独立地为N或C，且X3和X4不同时为N，X1、X2和X3不同时为N；X 3 and X 4 are each independently N or C, and X 3 and X 4 are not N at the same time, and X 1 , X 2 and X 3 are not N at the same time;

X5为化学键、N、CH、CH2、O或S；X 5 is a chemical bond, N, CH, CH 2 , O or S;

X6为N、O、S或CH； X6 is N, O, S or CH;

R′各自独立地为氘原子、卤素、氰基、羟基、氨基、C1-6烷基、C2-6烯基、C2-6炔基、卤代C1-4烷基、氘代C1-6烷基、3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基、C1-4烷基氨基、二(C1-4烷基)氨基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、卤代C1-6烷氧基或氧代(＝O)；R′ is each independently a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a halogenated C 1-4 alkyl group, a deuterated C 1-6 alkyl group, a 3-12 membered cycloalkyl group, a 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , a C 1-4 alkylamino group, a di(C 1-4 alkyl)amino group, a C 1-6 alkoxy group, a C 1-6 alkoxy-C 1-6 alkyl group, a halogenated C 1-6 alkoxy group, or an oxo(═O);

m、n、t各自独立地为0、1、2、3、4或5。m, n, and t are each independently 0, 1, 2, 3, 4, or 5.

某些实施方式中，所述式I化合物进一步具有如式III结构，
In certain embodiments, the compound of formula I further has a structure of formula III,

A环为含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的4-9元杂环基(例如A环为含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的4-7元杂环基)、3-6环烷基；Ring A is a 4-9 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, S=O, S(O) 2 (for example, Ring A is a 4-7 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, S=O, S(O) 2 ), or a 3-6 membered cycloalkyl group;

E环为苯基或含有1、2、3、4个选自N、O、S杂原子的5-6元杂芳基；Ring E is phenyl or a 5-6 membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O and S;

G环为4-7元环烷基、含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的5-7元杂环基；Ring G is a 4-7 membered cycloalkyl group, or a 5-7 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, S=O, and S(O) 2 ;

W为N、C或CRa；W is N, C or CR a ;

Q1为所述地任选地被一个或多个氘原子、F、Cl、氰基、羟基、氨基、甲基、乙基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、甲氨基、二甲氨基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基或三氟乙氧基取代； Q1 is Said place optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy;

L1为化学键、O、NR4、CR5R6、-OR7-或C(＝O)；L 1 is a chemical bond, O, NR 4 , CR 5 R 6 , -OR 7 - or C(=O);

L2为化学键或NR4；L 2 is a chemical bond or NR 4 ;

L3为NR4；L 3 is NR 4 ;

L4为O或CR5R6；L 4 is O or CR 5 R 6 ;

M为C＝O或S(＝O)2；M is C=O or S(=O) 2 ;

Y1为N或CRa； Y1 is N or CR a ;

Y3为N或CRc；Y 3 is N or CR c ;

Y4为N或CRd；Y 4 is N or CR d ;

Y5为N、CH或C；当L2为化学键，Y5为N；当L2为O或NR4时，Y5为CH或C；Y 5 is N, CH or C; when L 2 is a chemical bond, Y 5 is N; when L 2 is O or NR 4 , Y 5 is CH or C;

R1为卤代甲基、乙烯基、丙烯基、乙炔基、丙炔基、丁炔基、环氧丙烷基、环丁烯基、环戊烯基或环己烯基，所述卤代甲基、乙烯基、丙烯基、乙炔基、丙炔基、丁炔基、环氧丙烷基、环丁烯基、环戊烯基或环己烯基任选地被一个或者多个F、Cl、甲基、乙基、环丙基、吖丁啶基、吡咯烷基、哌啶基、环氧丙烷基、环氧丁烷基、氘原子、苯基、吡啶基或NRxRy取代，所述甲基、乙基、环丙基、吖丁啶基、吡咯烷基、哌啶基、环氧丙烷基、环氧丁烷基、苯基或吡啶基任选地被一个或者多个R′取代；R 1 is a halomethyl group, vinyl group, propenyl group, ethynyl group, propynyl group, butynyl group, oxetyl group, cyclobutenyl group, cyclopentenyl group or cyclohexenyl group, wherein the halomethyl group, vinyl group, propenyl group, ethynyl group, propynyl group, butynyl group, oxetyl group, cyclobutenyl group, cyclopentenyl group or cyclohexenyl group is optionally substituted with one or more F, Cl, methyl group, ethyl group, cyclopropyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, oxetyl group, butylene oxide group, deuterium atom, phenyl group, pyridinyl group or NR x R y , wherein the methyl group, ethyl group, cyclopropyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, oxetyl group, butylene oxide group, phenyl group or pyridinyl group is optionally substituted with one or more R ′;

R2为氢原子、氘原子、氰基、卤素、C1-6烷基、C2-4烯基、C2-4炔基、卤代C1-4烷基、氘代C1-4烷基、3-6元环烷基、C1-4烷氧基-C1-4烷基、卤代C1-4烷氧基或氧代(＝O)，所述C1-6烷基、C2-4烯基、C2- 4炔基、卤代C1-4烷基、氘代C1-4烷基、3-6元环烷基、C1-4烷氧基-C1-4烷基、卤代C1-4烷氧基任选地被一个或者多个R′取代； R2 is a hydrogen atom, a deuterium atom, a cyano group, a halogen, a C1-6 alkyl group, a C2-4 alkenyl group, a C2-4 alkynyl group, a halo-substituted C1-4 alkyl group, a deuterated C1-4 alkyl group, a 3-6-membered cycloalkyl group, a C1-4 alkoxy- C1-4 alkyl group, a halo-substituted C1-4 alkoxy group or an oxo group (=O), wherein the C1-6 alkyl group, the C2-4 alkenyl group, the C2-4 alkynyl group, the halo-substituted C1-4 alkyl group, the deuterated C1-4 alkyl group, the 3-6-membered cycloalkyl group, the C1-4 alkoxy- C1-4 alkyl group and the halo-substituted C1-4 alkoxy group are optionally substituted with one or more R';

R3为氢原子、氘原子、卤素、氰基、硝基、C1-4烷基、C2-4烯基、C2-4炔基、3-6元饱和或不饱和环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元饱和或不饱和杂环基、卤代C1- 4烷基、卤代C1-4烷氧基、ORe、SORe、S(O)2Re、C(＝O)Re、C(＝O)NRe、NReRf、NReC(＝O)Rf、S(O)2NRe、P(O)(Re)2，所述C1-4烷基、C2-4烯基、C2-4炔基、3-6元饱和或不饱和环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元饱和或不饱和杂环基、卤代C1-4烷基、卤代C1-4烷氧基任选地被一个或者多个R′取代；R 3 is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a nitro group, a C 1-4 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a 3-6 membered saturated or unsaturated cycloalkyl group, a 3-6 membered saturated or unsaturated heterocyclic group containing one or more heteroatoms selected from N, O, S, S＝O, and S(O) 2 , a halogenated C 1-4 alkyl group, a halogenated C 1-4 alkoxy group, OR e , SOR e , S(O) 2 R e , C(＝O)R e , C(＝O)NR e , NRe R f , NRe C(＝O)R f , S(O) 2 NRe , P(O)(R e ) 2 , wherein the C 1-4 alkyl group, the C 2-4 alkenyl group, the C 2-4 alkynyl group, the 3-6 membered saturated or unsaturated cycloalkyl group, the 3-6 membered saturated or unsaturated heterocyclic group containing one or more heteroatoms selected from N, O, S, S＝O, and S(O) 2 2 heteroatoms, 3-6 membered saturated or unsaturated heterocyclic group, halogenated C 1-4 alkyl group, halogenated C 1-4 alkoxy group are optionally substituted by one or more R';

R4为氢原子、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C2-4烯基、C2-4炔基或3-12元环烷基，所述C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C2-4烯基、C2-4炔基或3-12元环烷基任选地被一个或者多个甲基、乙基、卤素、氘原子、氰基、羟基、甲氧基或环丙基取代； R4 is a hydrogen atom, a C1-6 alkyl group, a halogenated C1-6 alkyl group, a deuterated C1-6 alkyl group, a C2-4 alkenyl group, a C2-4 alkynyl group or a 3-12 membered cycloalkyl group, wherein the C1-6 alkyl group, the halogenated C1-6 alkyl group, the deuterated C1-6 alkyl group, the C2-4 alkenyl group, the C2-4 alkynyl group or the 3-12 membered cycloalkyl group is optionally substituted with one or more methyl groups, ethyl groups, halogen groups, deuterium atoms, cyano groups, hydroxyl groups, methoxy groups or cyclopropyl groups;

R5、R6各自独立地为氢原子、氘原子、卤素、氰基、羟基、氨基、C1-6烷基、卤代C1-6烷基、3-6元环烷基、C1-6烷氧基、卤代C1-6烷氧基、3-12元环烷基氧基、C1-6烷基氨基、二(C1-6烷基)氨基；R 5 and R 6 are each independently a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a 3-6 membered cycloalkyl group, a C 1-6 alkoxy group, a halogenated C 1-6 alkoxy group, a 3-12 membered cycloalkyloxy group, a C 1-6 alkylamino group, or a di(C 1-6 alkyl)amino group;

或者，R5与R6和所连接的C原子一起形成环丙基、环丁基、环戊基或环己基，所述环丙基、环丁基、环戊基或环己基任选地被一个或者多个甲基、乙基、卤素、氘原子或环丙基取代；Alternatively, R 5 and R 6 together with the attached C atom form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group is optionally substituted with one or more methyl, ethyl, halogen, deuterium atom or cyclopropyl group;

R7为亚甲基、亚乙基或亚丙基； R7 is methylene, ethylene or propylene;

Ra为氢原子、氘原子、卤素、氰基、C1-6烷基、C2-4烯基、C2-4炔基、4-10元杂环基、ORa1、SRa1或NRa1，所述C1-6烷基、C2-4烯基、C2-4炔基、4-10元杂环基任选地被一个或者多个R′取代；R a is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a 4-10 membered heterocyclic group, OR a1 , SR a1 or NR a1 , wherein the C 1-6 alkyl group, the C 2-4 alkenyl group, the C 2-4 alkynyl group or the 4-10 membered heterocyclic group is optionally substituted by one or more R′;

Ra1为氢原子、C1-4烷基、3-6元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基、3-6元环烷基-C1-6烷基或含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基-C1-6烷基，所述C1-4烷基、3-6元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基、3-6元环烷基-C1-6烷基或含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基-C1-6烷基任选地被一个或者多个卤素、氘原子、甲基、乙基、或氧代取代；R a1 is a hydrogen atom, a C 1-4 alkyl group, a 3-6 membered cycloalkyl group, a 3-6 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , a 3-6 membered cycloalkyl-C 1-6 alkyl group, or a 3-6 membered heterocyclyl-C 1-6 alkyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , wherein the C 1-4 alkyl group, the 3-6 membered cycloalkyl group, the 3-6 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , the 3-6 membered cycloalkyl-C 1-6 alkyl group, or the 3-6 membered heterocyclyl-C 1-6 alkyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 are optionally substituted with one or more halogen, a deuterium atom, a methyl group, an ethyl group, or an oxo group;

Rc为氢原子、卤素、氰基、氨基、甲基、乙基、异丙基、环丙基、甲氧基或环丙氧基，所述氨基、甲基、异丙基、乙基、环丙基、甲氧基和环丙氧基任选地被一个或者多个R′取代；R c is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group, wherein the amino group, the methyl group, the isopropyl group, the ethyl group, the cyclopropyl group, the methoxy group and the cyclopropyloxy group are optionally substituted by one or more R ′;

Rd为氢原子、卤素、氰基、氨基、甲基、乙基、异丙基、环丙基、甲氧基或环丙氧基，所述氨基、甲基、异丙基、乙基、环丙基、甲氧基和环丙氧基任选地被一个或者多个R′取代；R d is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group, wherein the amino group, the methyl group, the isopropyl group, the ethyl group, the cyclopropyl group, the methoxy group and the cyclopropyloxy group are optionally substituted by one or more R's;

Rx、Ry各自独立地为氢原子、甲基、乙基、异丙基、环丙基、环丁基、环戊基、金刚烷基、甲氧基乙基、环丙基甲基、环丁基甲基、环丙基乙基、环丁基乙基、吖丁啶基甲基或吖丁啶基乙基，所述甲基、乙基、异丙基、环丙基、环丁基、环戊基、金刚烷基、甲氧基乙基、环丙基甲基、环丁基甲基、环丙基乙基、环丁基乙基、吖丁啶基甲基或吖丁啶基乙基任选地被一个或者多个R′取代；R x and R y are each independently a hydrogen atom, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, azetidinylmethyl or azetidinylethyl, and the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, azetidinylmethyl or azetidinylethyl is optionally substituted with one or more R′;

或者，NRxRy中Rx与Ry和所连接的N原子一起形成吖丁啶基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、二氧化硫代吗啉基、7-氮杂双环[2.2.1]庚烷基、9-氮杂双环[3.3.1]壬烷基、2-氮杂双环[4.1.0]庚烷基或2-氮杂双环[3.1.0]己烷基，所述吖丁啶基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、二氧化硫代吗啉基、7-氮杂双环[2.2.1]庚烷基、9-氮杂双环[3.3.1]壬烷基、2-氮杂双环[4.1.0]庚烷基或2-氮杂双环[3.1.0]己烷基任选地被一个或者多个R′取代；or wherein R in NRxRy is taken together with Ry and the nitrogen atom to which it is attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1] heptanyl , 9-azabicyclo[3.3.1]nonanyl, 2-azabicyclo[4.1.0]heptanyl, or 2-azabicyclo[3.1.0]hexanyl, said azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptanyl, 9-azabicyclo[3.3.1]nonanyl, 2-azabicyclo[4.1.0]heptanyl, or 2-azabicyclo[3.1.0]hexanyl being optionally substituted with one or more R′;

Re、Rf各自独立地为氢原子、氘原子、C1-4烷基、卤代C1-4烷基、3-12元环烷基；R e and R f are each independently a hydrogen atom, a deuterium atom, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, or a 3-12 membered cycloalkyl group;

或者，NReRf中Re和Rf与连接的N原子一起形成含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基；Alternatively, Re and Rf in NR e R f together with the attached N atom form a 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 ;

--/---为无或化学键；--/--- is none or chemical bond;

B环为吡咯、咪唑、吡唑、噻唑、噁唑、噁二唑、三氮唑、四氮唑、吡啶、嘧啶、哒嗪、吡嗪或三嗪；Ring B is pyrrole, imidazole, pyrazole, thiazole, oxazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine or triazine;

Xa、Xb、Xc各自独立地为N或CH；X a , X b , and X c are each independently N or CH;

X1为化学键、N、CH、CH2、S、O、S(O)或S(O)2；X 1 is a chemical bond, N, CH, CH 2 , S, O, S(O) or S(O) 2 ;

X2为N、CH、CH2、O、S、S(O)或S(O)2；X 2 is N, CH, CH 2 , O, S, S(O) or S(O) 2 ;

X3、X4各自独立地为N或C，且X3和X4不同时为N，X1、X2和X3不同时为N；X 3 and X 4 are each independently N or C, and X 3 and X 4 are not N at the same time, and X 1 , X 2 and X 3 are not N at the same time;

X5为化学键、N、CH、CH2、O或S；X 5 is a chemical bond, N, CH, CH 2 , O or S;

X6为N、O、S或CH； X6 is N, O, S or CH;

R′各自独立地为氘原子、卤素、氰基、羟基、氨基、C1-6烷基、C2-6烯基、C2-6炔基、卤代C1-4烷基、氘代C1-6烷基、3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基、C1-4烷基氨基、二(C1-4烷基)氨基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、卤代C1-6烷氧基或氧代(＝O)；R′ is each independently a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a halogenated C 1-4 alkyl group, a deuterated C 1-6 alkyl group, a 3-12 membered cycloalkyl group, a 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , a C 1-4 alkylamino group, a di(C 1-4 alkyl)amino group, a C 1-6 alkoxy group, a C 1-6 alkoxy-C 1-6 alkyl group, a halogenated C 1-6 alkoxy group, or an oxo(═O);

m、n、t各自独立地为0、1、2、3、4或5。m, n, and t are each independently 0, 1, 2, 3, 4, or 5.

在某些实施方式中，R′各自独立地为氘原子、卤素、氰基、羟基、氨基、C1-4烷基、C2-4烯基、C2- 4炔基、卤代C1-4烷基、氘代C1-4烷基、3-10元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-10元杂环基、C1-4烷基氨基、二(C1-4烷基)氨基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、卤代C1-6烷氧基或氧代(＝O)；In certain embodiments, R′ is each independently a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-4 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a halo-substituted C 1-4 alkyl group, a deuterated C 1-4 alkyl group, a 3-10 membered cycloalkyl group, a 3-10 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , a C 1-4 alkylamino group, a di(C 1-4 alkyl)amino group, a C 1-6 alkoxy group, a C 1-6 alkoxy-C 1-6 alkyl group, a halo-substituted C 1-6 alkoxy group, or an oxo(═O);

优选地，R′各自独立地为氘原子、卤素、氰基、羟基、氨基、C1-4烷基、C2-4烯基、C2-4炔基、卤代C1-4烷基、氘代C1-4烷基、3-6元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的4-7元杂环基、C1-4烷基氨基、二(C1-4烷基)氨基、C1-4烷氧基、C1-4烷氧基-C1-4烷基、卤代C1-4烷氧基或氧代(＝O)；Preferably, R′ is each independently a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-4 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a halogenated C 1-4 alkyl group, a deuterated C 1-4 alkyl group, a 3-6 membered cycloalkyl group, a 4-7 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , a C 1-4 alkylamino group, a di(C 1-4 alkyl)amino group, a C 1-4 alkoxy group, a C 1-4 alkoxy-C 1-4 alkyl group, a halogenated C 1-4 alkoxy group, or an oxo(═O) group;

优选地，R′为氘原子、F、Cl、氰基、羟基、氨基、甲基、乙基、乙烯基、乙炔基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、甲氨基、二甲氨基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基、三氟乙氧基或氧代(＝O)。Preferably, R′ is a deuterium atom, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, vinyl, ethynyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy or oxo (═O).

在某些具体实施方式中，在式I，II或III中，In certain embodiments, in Formula I, II or III,

A环为含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的4-9元杂环基(例如A环为含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的4-7元杂环基)、3-6环烷基；Ring A is a 4-9 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, S=O, S(O) 2 (for example, Ring A is a 4-7 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, S=O, S(O) 2 ), or a 3-6 membered cycloalkyl group;

E环为苯基或含有1、2、3、4个选自N、O、S杂原子的5-6元杂芳基；Ring E is phenyl or a 5-6 membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O and S;

Q1为所述地任选地被一个或多个氘原子、F、Cl、氰基、羟基、氨基、甲基、乙基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、甲氨基、二甲氨基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基或三氟乙氧基取代； Q1 is Said place optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy;

L1为化学键、O、NR4、CR5R6、-OR7-或C(＝O)；L 1 is a chemical bond, O, NR 4 , CR 5 R 6 , -OR 7 - or C(=O);

L2为化学键或NR4；L 2 is a chemical bond or NR 4 ;

L3为NR4；L 3 is NR 4 ;

L4为O或CR5R6；L 4 is O or CR 5 R 6 ;

M为C＝O或S(＝O)2；M is C=O or S(=O) 2 ;

Y1为N或CRa； Y1 is N or CR a ;

Y2为N或CRb；Y 2 is N or CR b ;

Y3为N或CRc；Y 3 is N or CR c ;

Y4为N或CRd；Y 4 is N or CR d ;

Y5为N、CH或C；当L2为化学键，Y5为N；当L2为O或NR4时，Y5为CH或C；Y 5 is N, CH or C; when L 2 is a chemical bond, Y 5 is N; when L 2 is O or NR 4 , Y 5 is CH or C;

R1为卤代甲基、乙烯基、丙烯基、乙炔基、丙炔基、丁炔基、环氧丙烷基、环丁烯基、环戊烯基或环己烯基，所述卤代甲基、乙烯基、丙烯基、乙炔基、丙炔基、丁炔基、环氧丙烷基、环丁烯基、环戊烯基或环己烯基任选地被一个或者多个F、Cl、甲基、乙基、环丙基、吖丁啶基、吡咯烷基、哌啶基、环氧丙烷基、环氧丁烷基、氘原子、苯基、吡啶基或NRxRy取代，所述甲基、乙基、环丙基、吖丁啶基、吡咯烷基、哌啶基、环氧丙烷基、环氧丁烷基、苯基或吡啶基任选地被一个或者多个R′取代；R 1 is a halomethyl group, vinyl group, propenyl group, ethynyl group, propynyl group, butynyl group, oxetyl group, cyclobutenyl group, cyclopentenyl group or cyclohexenyl group, wherein the halomethyl group, vinyl group, propenyl group, ethynyl group, propynyl group, butynyl group, oxetyl group, cyclobutenyl group, cyclopentenyl group or cyclohexenyl group is optionally substituted with one or more F, Cl, methyl group, ethyl group, cyclopropyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, oxetyl group, butylene oxide group, deuterium atom, phenyl group, pyridinyl group or NR x R y , wherein the methyl group, ethyl group, cyclopropyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, oxetyl group, butylene oxide group, phenyl group or pyridinyl group is optionally substituted with one or more R ′;

R2为氢原子、氘原子、氰基、卤素、C1-6烷基、C2-4烯基、C2-4炔基、卤代C1-4烷基、氘代C1-4烷基、3-6元环烷基、C1-4烷氧基-C1-4烷基、卤代C1-4烷氧基或氧代(＝O)，所述C1-6烷基、C2-4烯基、C2- 4炔基、卤代C1-4烷基、氘代C1-4烷基、3-6元环烷基、C1-4烷氧基-C1-4烷基、卤代C1-4烷氧基任选地被一个或者多个R′取代； R2 is a hydrogen atom, a deuterium atom, a cyano group, a halogen, a C1-6 alkyl group, a C2-4 alkenyl group, a C2-4 alkynyl group, a halo-substituted C1-4 alkyl group, a deuterated C1-4 alkyl group, a 3-6-membered cycloalkyl group, a C1-4 alkoxy- C1-4 alkyl group, a halo-substituted C1-4 alkoxy group or an oxo group (=O), wherein the C1-6 alkyl group, the C2-4 alkenyl group, the C2-4 alkynyl group, the halo-substituted C1-4 alkyl group, the deuterated C1-4 alkyl group, the 3-6-membered cycloalkyl group, the C1-4 alkoxy- C1-4 alkyl group and the halo-substituted C1-4 alkoxy group are optionally substituted with one or more R';

R3为氢原子、氘原子、卤素、氰基、硝基、C1-4烷基、C2-4烯基、C2-4炔基、3-6元饱和或不饱和环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元饱和或不饱和杂环基、卤代C1- 4烷基、卤代C1-4烷氧基、ORe、SORe、S(O)2Re、C(＝O)Re、C(＝O)NRe、NReRf、NReC(＝O)Rf、S(O)2NRe、P(O)(Re)2，所述C1-4烷基、C2-4烯基、C2-4炔基、3-6元饱和或不饱和环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元饱和或不饱和杂环基、卤代C1-4烷基、卤代C1-4烷氧基任选地被一个或者多个R′取代；R 3 is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a nitro group, a C 1-4 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a 3-6 membered saturated or unsaturated cycloalkyl group, a 3-6 membered saturated or unsaturated heterocyclic group containing one or more heteroatoms selected from N, O, S, S＝O, and S(O) 2 , a halogenated C 1-4 alkyl group, a halogenated C 1-4 alkoxy group, OR e , SOR e , S(O) 2 R e , C(＝O)R e , C(＝O)NR e , NRe R f , NRe C(＝O)R f , S(O) 2 NRe , P(O)(R e ) 2 , wherein the C 1-4 alkyl group, the C 2-4 alkenyl group, the C 2-4 alkynyl group, the 3-6 membered saturated or unsaturated cycloalkyl group, the 3-6 membered saturated or unsaturated heterocyclic group containing one or more heteroatoms selected from N, O, S, S＝O, and S(O) 2 2 heteroatoms, 3-6 membered saturated or unsaturated heterocyclic group, halogenated C 1-4 alkyl group, halogenated C 1-4 alkoxy group are optionally substituted by one or more R';

R4为氢原子、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C2-4烯基、C2-4炔基或3-12元环烷基，所述C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C2-4烯基、C2-4炔基或3-12元环烷基任选地被一个或者多个甲基、乙基、卤素、氘原子、氰基、羟基、甲氧基或环丙基取代； R4 is a hydrogen atom, a C1-6 alkyl group, a halogenated C1-6 alkyl group, a deuterated C1-6 alkyl group, a C2-4 alkenyl group, a C2-4 alkynyl group or a 3-12 membered cycloalkyl group, wherein the C1-6 alkyl group, the halogenated C1-6 alkyl group, the deuterated C1-6 alkyl group, the C2-4 alkenyl group, the C2-4 alkynyl group or the 3-12 membered cycloalkyl group is optionally substituted with one or more methyl groups, ethyl groups, halogen groups, deuterium atoms, cyano groups, hydroxyl groups, methoxy groups or cyclopropyl groups;

R5、R6各自独立地为氢原子、氘原子、卤素、氰基、羟基、氨基、C1-6烷基、卤代C1-6烷基、3-6元环烷基、C1-6烷氧基、卤代C1-6烷氧基、3-12元环烷基氧基、C1-6烷基氨基、二(C1-6烷基)氨基；R 5 and R 6 are each independently a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a 3-6 membered cycloalkyl group, a C 1-6 alkoxy group, a halogenated C 1-6 alkoxy group, a 3-12 membered cycloalkyloxy group, a C 1-6 alkylamino group, or a di(C 1-6 alkyl)amino group;

或者，R5与R6和所连接的C原子一起形成环丙基、环丁基、环戊基或环己基，所述环丙基、环丁基、环戊基或环己基任选地被一个或者多个甲基、乙基、卤素、氘原子或环丙基取代；Alternatively, R 5 and R 6 together with the attached C atom form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group is optionally substituted with one or more methyl, ethyl, halogen, deuterium atom or cyclopropyl group;

R7为亚甲基、亚乙基或亚丙基； R7 is methylene, ethylene or propylene;

G环为4-7元环烷基、含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的5-7元杂环基；Ring G is a 4-7 membered cycloalkyl group, or a 5-7 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, S=O, and S(O) 2 ;

W为N、C或CRa；W is N, C or CR a ;

Ra、Rb各自独立地为氢原子、氘原子、卤素、氰基、C1-6烷基、C2-4烯基、C2-4炔基、4-10元杂环基、ORa1、SRa1或NRa1，所述C1-6烷基、C2-4烯基、C2-4炔基、4-10元杂环基任选地被一个或者多个R′取代；R a and R b are each independently a hydrogen atom, a deuterium atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a 4-10 membered heterocyclic group, OR a1 , SR a1 or NR a1 , wherein the C 1-6 alkyl group, the C 2-4 alkenyl group, the C 2-4 alkynyl group or the 4-10 membered heterocyclic group is optionally substituted by one or more R′;

Rc为氢原子、卤素、氰基、氨基、甲基、乙基、异丙基、环丙基、甲氧基或环丙氧基，所述氨基、甲基、异丙基、乙基、环丙基、甲氧基和环丙氧基任选地被一个或者多个R′取代；R c is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group, wherein the amino group, the methyl group, the isopropyl group, the ethyl group, the cyclopropyl group, the methoxy group and the cyclopropyloxy group are optionally substituted by one or more R ′;

Rd不存在或为氢原子、氘原子、卤素、氰基、氨基、C1-6烷基、C1-6烷氧基、C1-6烷基巯基或C1- 6烷基氨基，所述氨基、C1-6烷基、C1-6烷氧基、C1-6烷基巯基或C1-6烷基氨基任选地被一个或者多个R′取代；R d is absent or is a hydrogen atom, a deuterium atom, a halogen, a cyano group, an amino group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkylthio group or a C 1-6 alkylamino group, wherein the amino group, the C 1-6 alkyl group, the C 1-6 alkoxy group, the C 1-6 alkylthio group or the C 1-6 alkylamino group is optionally substituted with one or more R′;

Rb与Rd和所连接的原子一起形成4-7元环烷基或含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的5-7元杂环基，所述4-7元环烷基或含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的5-7元杂环基任选地被一个或者多个R′取代；R b and R d together with the atoms to which they are attached form a 4-7 membered cycloalkyl group or a 5-7 membered heterocyclyl group containing 1 or 2 heteroatoms selected from N, O, S, S=O, S(O) 2 , wherein the 4-7 membered cycloalkyl group or the 5-7 membered heterocyclyl group containing 1 or 2 heteroatoms selected from N, O, S, S=O, S(O) 2 are optionally substituted by one or more R ′;

或者，Rb与R2和所连接的原子一起形成含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的5-7元杂环基或含有1、2、3、4个选自N、O、S杂原子的5-6元杂芳基，所述含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的5-7元杂环基、含有1、2、3、4个选自N、O、S杂原子的5-6元杂芳基任选地被一个或者多个R′取代；Alternatively, Rb , R2 and the atoms to which they are attached form a 5-7 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, S=O, S(O) 2 , or a 5-6 membered heteroaryl group containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, wherein the 5-7 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, S=O, and S(O) 2 , or the 5-6 membered heteroaryl group containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S are optionally substituted by one or more R';

Re、Rf各自独立地为氢原子、氘原子、C1-4烷基、卤代C1-4烷基、3-12元环烷基；R e and R f are each independently a hydrogen atom, a deuterium atom, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, or a 3-12 membered cycloalkyl group;

或者，NReRf中Re和Rf与连接的N原子一起形成含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基；Alternatively, Re and Rf in NR e R f together with the attached N atom form a 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 ;

Rx、Ry各自独立地为氢原子、甲基、乙基、异丙基、环丙基、环丁基、环戊基、金刚烷基、甲氧基乙基、环丙基甲基、环丁基甲基、环丙基乙基、环丁基乙基、吖丁啶基甲基或吖丁啶基乙基，所述甲基、乙基、异丙基、环丙基、环丁基、环戊基、金刚烷基、甲氧基乙基、环丙基甲基、环丁基甲基、环丙基乙基、环丁基乙基、吖丁啶基甲基或吖丁啶基乙基任选地被一个或者多个R′取代；R x and R y are each independently a hydrogen atom, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, azetidinylmethyl or azetidinylethyl, and the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, azetidinylmethyl or azetidinylethyl is optionally substituted with one or more R′;

或者，NRxRy中Rx与Ry和所连接的N原子一起形成吖丁啶基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、二氧化硫代吗啉基、7-氮杂双环[2.2.1]庚烷基、9-氮杂双环[3.3.1]壬烷基、2-氮杂双环[4.1.0]庚烷基或2-氮杂双环[3.1.0]己烷基，所述吖丁啶基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、二氧化硫代吗啉基、7-氮杂双环[2.2.1]庚烷基、9-氮杂双环[3.3.1]壬烷基、2-氮杂双环[4.1.0]庚烷基或2-氮杂双环[3.1.0]己烷基任选地被一个或者多个R′取代；or wherein R in NRxRy is taken together with Ry and the nitrogen atom to which it is attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1] heptanyl , 9-azabicyclo[3.3.1]nonanyl, 2-azabicyclo[4.1.0]heptanyl, or 2-azabicyclo[3.1.0]hexanyl, said azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptanyl, 9-azabicyclo[3.3.1]nonanyl, 2-azabicyclo[4.1.0]heptanyl, or 2-azabicyclo[3.1.0]hexanyl being optionally substituted with one or more R′;

Ra1为氢原子、C1-4烷基、3-6元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基、3-6元环烷基-C1-6烷基或含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基-C1-6烷基，所述C1-4烷基、3-6元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基、3-6元环烷基-C1-6烷基或含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基-C1-6烷基任选地被一个或者多个卤素、氘原子、甲基、乙基、或氧代取代；R a1 is a hydrogen atom, a C 1-4 alkyl group, a 3-6 membered cycloalkyl group, a 3-6 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , a 3-6 membered cycloalkyl-C 1-6 alkyl group, or a 3-6 membered heterocyclyl-C 1-6 alkyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , wherein the C 1-4 alkyl group, the 3-6 membered cycloalkyl group, the 3-6 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , the 3-6 membered cycloalkyl-C 1-6 alkyl group, or the 3-6 membered heterocyclyl-C 1-6 alkyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 are optionally substituted with one or more halogen, a deuterium atom, a methyl group, an ethyl group, or an oxo group;

--/---为无或化学键；--/--- is none or chemical bond;

B环为吡咯、咪唑、吡唑、噻唑、噁唑、噁二唑、三氮唑、四氮唑、吡啶、嘧啶、哒嗪、吡嗪或三嗪；Ring B is pyrrole, imidazole, pyrazole, thiazole, oxazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine or triazine;

Xa、Xb、Xc各自独立地为N或CH；X a , X b , and X c are each independently N or CH;

X1为化学键、N、CH、CH2、S、O、S(O)或S(O)2；X 1 is a chemical bond, N, CH, CH 2 , S, O, S(O) or S(O) 2 ;

X2为N、CH、CH2、O、S、S(O)或S(O)2；X 2 is N, CH, CH 2 , O, S, S(O) or S(O) 2 ;

X3、X4各自独立地为N或C，且X3和X4不同时为N，X1、X2和X3不同时为N；X 3 and X 4 are each independently N or C, and X 3 and X 4 are not N at the same time, and X 1 , X 2 and X 3 are not N at the same time;

X5为化学键、N、CH、CH2、O或S；X 5 is a chemical bond, N, CH, CH 2 , O or S;

X6为N、O、S或CH； X6 is N, O, S or CH;

R′为氘原子、F、Cl、氰基、羟基、氨基、甲基、乙基、异丙基、乙烯基、乙炔基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、环丁基、甲氨基、二甲氨基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基、三氟乙氧基、吡咯烷基、1-甲基吡咯烷-3-基或氧代(＝O)；R′ is a deuterium atom, F, Cl, cyano, hydroxy, amino, methyl, ethyl, isopropyl, vinyl, ethynyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, pyrrolidinyl, 1-methylpyrrolidin-3-yl, or oxo (═O);

m、n、t各自独立地为0、1、2或3。m, n, and t are each independently 0, 1, 2, or 3.

在另一些具体实施方式中，在式I、II或III中：In other specific embodiments, in Formula I, II or III:

A环为哌啶基、吖丁啶基、吡咯烷基、哌嗪基、高哌啶、高哌嗪、1,4-氮杂氧杂环庚烷、环丙基、环丁基、环戊基、环己基、2-氮杂二环[2.2.2]辛烷、2-氮杂二环[2.2.1]庚烷、2,5-二氮杂二环[2.2.2]辛烷、2,5-二氮杂二环[2.2.1]庚烷、8-氮杂双环[3.2.1]辛烷、6-氮杂双环[3.1.1]庚烷或7-氮杂双环[2.2.1]庚烷；Ring A is piperidinyl, azetidinyl, pyrrolidinyl, piperazinyl, homopiperidine, homopiperazine, 1,4-azaoxepane, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-azabicyclo[2.2.2]octane, 2-azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.2]octane, 2,5-diazabicyclo[2.2.1]heptane, 8-azabicyclo[3.2.1]octane, 6-azabicyclo[3.1.1]heptane or 7-azabicyclo[2.2.1]heptane;

E环为苯基、吡啶基、嘧啶、哒嗪、吡嗪、噻吩或吡唑；Ring E is phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene or pyrazole;

Q1选自以下基团：
所述Q1任选地被一个或多个氘原子、F、Cl、氰基、羟基、氨基、甲基、氘代甲基、乙基、异丙基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、甲氨基、二甲氨基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基或三氟乙氧基取代； Q1 is selected from the following groups:
said Q 1 is optionally substituted by one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, deuterated methyl, ethyl, isopropyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy;

L1为化学键、O、NR4、CR5R6、-OR7-或C(＝O)；L 1 is a chemical bond, O, NR 4 , CR 5 R 6 , -OR 7 - or C(=O);

L2为化学键或NR4；L 2 is a chemical bond or NR 4 ;

L3为NR4；L 3 is NR 4 ;

L4为O或CR5R6；L 4 is O or CR 5 R 6 ;

M为C＝O；M is C=O;

R4为氢原子、甲基、乙基、异丙基、1,2-二羟基丙-3-基、乙酰基、甲氧基乙基、乙氰基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、环丁基、丙烯基或丙炔基； R4 is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a 1,2-dihydroxypropan-3-yl group, an acetyl group, a methoxyethyl group, an acetylcyano group, a deuterated methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a propenyl group or a propynyl group;

R5、R6各自独立地为氢原子、氘原子、卤素、氰基、羟基、氨基、甲基、乙基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、甲氨基、二甲氨基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基、三氟乙氧基、丙烯基或丙炔基；R 5 and R 6 are each independently a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, a deuterated methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a cyclopropyl group, a methylamino group, a dimethylamino group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a propenyl group, or a propynyl group;

或者，R5与R6和所连接的C原子一起形成环丙基或环丁基，所述环丙基或环丁基任选地被一个或者多个甲基、乙基、卤素、氘原子或环丙基取代；Alternatively, R 5 and R 6 together with the attached C atom form a cyclopropyl or cyclobutyl group, wherein the cyclopropyl or cyclobutyl group is optionally substituted with one or more methyl groups, ethyl groups, halogen groups, deuterium atoms or cyclopropyl groups;

R7为亚甲基； R7 is methylene;

Y1为N或CRa； Y1 is N or CR a ;

Y2为N或CRb；Y 2 is N or CR b ;

Y3为N或CRc；Y 3 is N or CR c ;

Y4为N或CRd；Y 4 is N or CR d ;

Y5为N、CH或C；当L2为化学键，Y5为N；当L2为O或NR4时，Y5为CH或C；Y 5 is N, CH or C; when L 2 is a chemical bond, Y 5 is N; when L 2 is O or NR 4 , Y 5 is CH or C;

Ra为氢原子、氘原子、F、Cl、Br、氰基、羟基、氨基、甲基、乙基、正丙基、异丙基、二氟甲基、三氟甲基、乙炔基、2-(1,3-二甲基吡咯烷-3-基)乙炔基、乙氰基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基、三氟乙氧基、羟基乙氧基、N',N'-二甲氨基乙氧基、N'-甲基氨基乙氧基、吗啉基、2-氧杂-6-氮杂螺[3.3]环庚烷基、吗啉基-乙氧基、羟基丙氧基、N',N'-二甲氨基丙氧基、N'-甲基氨基丙氧基、吗啉基-丙氧基、哌嗪-1-基-乙氧基、4-甲基哌嗪-1-基-乙氧基、4-甲基哌嗪-1-基-丙氧基、哌嗪-1-基-丙氧基、吡咯烷-1-基-乙氧基、吡咯烷-1-基-丙氧基、四氢呋喃-3-氧基、甲硫基、甲氨基、乙胺基、乙酰胺基、丙酰胺基、甲氧基乙基、甲氧基乙胺基或甲氧基乙氧基； Ra is a hydrogen atom, a deuterium atom, F, Cl, Br, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a difluoromethyl group, a trifluoromethyl group, an ethynyl group, a 2-(1,3-dimethylpyrrolidin-3-yl)ethynyl group, an acetylcyano group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a hydroxyethoxy group, an N',N'-dimethylaminoethoxy group, an N'-methylaminoethoxy group, a morpholinyl group, a 2-oxa-6-azaspiro[3.3]cycloheptyl group, a morpholinyl group -ethoxy, hydroxypropoxy, N',N'-dimethylaminopropoxy, N'-methylaminopropoxy, morpholinyl-propoxy, piperazin-1-yl-ethoxy, 4-methylpiperazin-1-yl-ethoxy, 4-methylpiperazin-1-yl-propoxy, piperazin-1-yl-propoxy, pyrrolidin-1-yl-ethoxy, pyrrolidin-1-yl-propoxy, tetrahydrofuran-3-oxy, methylthio, methylamino, ethylamino, acetamido, propionamido, methoxyethyl, methoxyethylamino or methoxyethoxy;

Rc为氢原子、卤素、氰基、氨基、甲基、乙基、异丙基、环丙基、甲氧基或环丙氧基；R c is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group;

Rb与Rd和所连接的原子一起形成吗啉基、四氢呋喃基、二氢咪唑基、硫代吗啉基、四氢吡喃基、四氢吡喃酮基、1,4-二氧六环基、六氢-1,4-氧氮杂卓基、六氢-1,4-硫氮杂卓基、4-硫代吗啉基-1-氧化物、4-硫代吗啉基-1,1-二氧化物、六氢-1,4-硫氮杂卓基-1-氧化物或六氢-1,4-硫氮杂卓基-1,1-二氧化物，所述吗啉基、硫代吗啉基、四氢吡喃基、四氢吡喃酮基、1,4-二氧六环基、六氢-1,4-氧氮杂卓基、六氢-1,4-硫氮杂卓基、4-硫代吗啉基-1-氧化物、4-硫代吗啉基-1,1-二氧化物、六氢-1,4-硫氮杂卓基-1-氧化物或六氢-1,4-硫氮杂卓基-1,1-二氧化物任选地被一个或多个氘原子、F、Cl、氰基、羟基、氨基、甲基、乙基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、甲氨基、二甲氨基、二甲氨基烷基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基或三氟乙氧基取代； Rb and Rd together with the atoms to which they are attached form a morpholinyl, tetrahydrofuranyl, dihydroimidazolyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide or hexahydro-1,4-thiazepinyl-1,1-dioxide, wherein the morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide, or hexahydro-1,4-thiazepinyl-1,1-dioxide is optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, dimethylaminoalkyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy;

R1选自以下基团：

 R1 is selected from the following groups:

R2为氢原子、氘原子、F、Cl、甲基、乙基、异丙基、叔丁基、环丙基、环丁基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、乙烯基、丙烯基、乙炔基、丙炔基、氰基、二氟甲氧基、三氟甲氧基、甲氧基、甲氧基甲基或氧代(＝O)； R2 is a hydrogen atom, a deuterium atom, F, Cl, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a cyclopropyl group, a cyclobutyl group, a deuterated methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a vinyl group, a propenyl group, an ethynyl group, a propynyl group, a cyano group, a difluoromethoxy group, a trifluoromethoxy group, a methoxy group, a methoxymethyl group, or an oxo group (=O);

或者，Rb与R2和所连接的原子一起形成吗啉基、四氢呋喃基、二氢咪唑基、硫代吗啉基、六氢-1,4-氧氮杂卓基、六氢-1,4-硫氮杂卓基、4-硫代吗啉基-1-氧化物、4-硫代吗啉基-1,1-二氧化物、六氢-1,4-硫氮杂卓基-1-氧化物或六氢-1,4-硫氮杂卓基-1,1-二氧化物，所述吗啉基、硫代吗啉基、六氢-1,4-氧氮杂卓基、六氢-1,4-硫氮杂卓基、4-硫代吗啉基-1-氧化物、4-硫代吗啉基-1,1-二氧化物、六氢-1,4-硫氮杂卓基-1-氧化物或六氢-1,4-硫氮杂卓基-1,1-二氧化物任选地被一个或多个氘原子、F、Cl、氰基、羟基、氨基、甲基、乙基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、甲氨基、二甲氨基、二甲氨基烷基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基或三氟乙氧基取代；Alternatively, Rb together with R2 and the atoms to which they are attached form a morpholinyl, tetrahydrofuranyl, dihydroimidazolyl, thiomorpholinyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide or hexahydro-1,4-thiazepinyl-1,1-dioxide, wherein the morpholinyl, thiomorpholinyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, 4-thiomorpholinyl-1,1-dioxide and 4-thiomorpholinyl-1,1-dioxide are substituted or substituted with morpholinyl, thiomorpholinyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1,1-dioxide. 1-dioxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide, or hexahydro-1,4-thiazepinyl-1,1-dioxide is optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, dimethylaminoalkyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy;

R3为氢原子、氘原子、F、Cl、氰基、硝基、甲基、乙基、异丙基、乙烯、乙炔、环丙基、环丁基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、羟基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧、甲氨基、乙胺基、SOCH3、S(O)2CH3、C(＝O)CH3、C(＝O)NCH3、NHC(＝O)CH3、S(O)2NCH3、P(O)(CH3)2或P(O)(CH2CH3)2，所述甲基、乙基、异丙基、乙烯、乙炔、环丙基、环丁基、二氟乙基、三氟乙基、羟基、甲氧基、乙氧基、甲氨基、乙胺基、SOCH3、S(O)2CH3、C(＝O)CH3、C(＝O)NCH3、NHC(＝O)CH3、S(O)2NCH3、P(O)(CH3)2或P(O)(CH2CH3)2任选地被一个或者多个氘原子、F、Cl、羟基、甲基、乙基、异丙基或环丙基取代；R 3 is a hydrogen atom, a deuterium atom, F, Cl, a cyano group, a nitro group, a methyl group, an ethyl group, an isopropyl group, an ethylene group, an acetylene group, a cyclopropyl group, a cyclobutyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a hydroxyl group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a methylamino group, an ethylamino group, SOCH 3 , S(O) 2 CH 3 , C(═O)CH 3 , C(═O)NCH 3 , NHC(═O)CH 3 , S(O) 2 NCH 3 , P(O)(CH 3 ) 2 or P(O)(CH 2 CH 3 ) 2 , wherein the methyl group, ethyl group, isopropyl group, an ethylene group, an acetylene group, a cyclopropyl group, a cyclobutyl group, a difluoroethyl group, a trifluoroethyl group, a hydroxyl group, a methoxy group, an ethoxy group, a methylamino group, an ethylamino group, SOCH 3 , S(O) 2 CH 3 , C(═O)CH 3 , C(=O)NCH 3 , NHC(=O)CH 3 , S(O) 2 NCH 3 , P(O)(CH 3 ) 2 or P(O)(CH 2 CH 3 ) 2 are optionally substituted with one or more deuterium atoms, F, Cl, hydroxyl, methyl, ethyl, isopropyl or cyclopropyl;

G环为吗啉基、四氢呋喃基、二氢咪唑基、硫代吗啉基、四氢吡喃基、四氢吡喃酮基、1,4-二氧六环基、六氢-1,4-氧氮杂卓基、六氢-1,4-硫氮杂卓基、4-硫代吗啉基-1-氧化物、4-硫代吗啉基-1,1-二氧化物、六氢-1,4-硫氮杂卓基-1-氧化物或六氢-1,4-硫氮杂卓基-1,1-二氧化物，所述吗啉基、硫代吗啉基、四氢吡喃基、四氢吡喃酮基、1,4-二氧六环基、六氢-1,4-氧氮杂卓基、六氢-1,4-硫氮杂卓基、4-硫代吗啉基-1-氧化物、4-硫代吗啉基-1,1-二氧化物、六氢-1,4-硫氮杂卓基-1-氧化物或六氢-1,4-硫氮杂卓基-1,1-二氧化物任选地被一个或多个氘原子、F、Cl、氰基、羟基、氨基、甲基、乙基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、甲氨基、二甲氨基、二甲氨基烷基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基或三氟乙氧基取代；Ring G is morpholinyl, tetrahydrofuranyl, dihydroimidazolyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide or hexahydro-1,4-thiazepinyl-1,1-dioxide, and the morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, hexahydro-1,4-thiazepinyl, hexahydro-1,1-dioxide, hydrogen-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide, or hexahydro-1,4-thiazepinyl-1,1-dioxide optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, dimethylaminoalkyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy;

W为C或CH；W is C or CH;

m、n、t各自独立地为0、1、2或3。m, n, and t are each independently 0, 1, 2, or 3.

在又一些具体实施方式中，在式I，II或III中：In yet other specific embodiments, in Formula I, II or III:

A环为哌啶基、吖丁啶基、吡咯烷基、哌嗪基、高哌嗪、1,4-氮杂氧杂环庚烷、环戊基、环己基、8-氮杂双环[3.2.1]辛烷；Ring A is piperidinyl, azetidinyl, pyrrolidinyl, piperazinyl, homopiperazine, 1,4-azaoxepane, cyclopentyl, cyclohexyl, or 8-azabicyclo[3.2.1]octane;

E环为苯基；Ring E is phenyl;

Q1选自以下基团：
 Q1 is selected from the following groups:

L1为化学键、O、NR4、CR5R6或C(＝O)；L 1 is a chemical bond, O, NR 4 , CR 5 R 6 or C(═O);

L2为化学键或NH；L 2 is a chemical bond or NH;

L3为NH；L 3 is NH;

L4为O或CR5R6；L 4 is O or CR 5 R 6 ;

M为C＝O；M is C=O;

R4为氢原子、甲基、乙基、异丙基、1,2-二羟基丙-3-基、乙酰基、甲氧基乙基、乙氰基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、环丁基、丙烯基或丙炔基； R4 is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a 1,2-dihydroxypropan-3-yl group, an acetyl group, a methoxyethyl group, an acetylcyano group, a deuterated methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a propenyl group or a propynyl group;

R5、R6各自独立地为氢原子、氘原子、卤素、氰基、羟基、氨基、甲基、乙基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、甲氨基、二甲氨基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基、三氟乙氧基、丙烯基或丙炔基；R 5 and R 6 are each independently a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, a deuterated methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a cyclopropyl group, a methylamino group, a dimethylamino group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a propenyl group, or a propynyl group;

或者，R5与R6和所连接的C原子一起形成环丙基或环丁基，所述环丙基或环丁基任选地被一个或者多个甲基、乙基、卤素、氘原子或环丙基取代；Alternatively, R 5 and R 6 together with the attached C atom form a cyclopropyl or cyclobutyl group, wherein the cyclopropyl or cyclobutyl group is optionally substituted with one or more methyl groups, ethyl groups, halogen groups, deuterium atoms or cyclopropyl groups;

Y1为N或CRa； Y1 is N or CR a ;

Y2为N或CRb；Y 2 is N or CR b ;

Y3为N；Y 3 is N;

Y4为N或CRd；Y 4 is N or CR d ;

Y5为N、CH或C；当L2为化学键，Y5为N；当L2为O或NR4时，Y5为CH或C；Y 5 is N, CH or C; when L 2 is a chemical bond, Y 5 is N; when L 2 is O or NR 4 , Y 5 is CH or C;

Ra为氢原子、氘原子、F、Cl、Br、氰基、羟基、氨基、甲基、乙基、正丙基、异丙基、二氟甲基、三氟甲基、乙炔基、2-(1,3-二甲基吡咯烷-3-基)乙炔基、乙氰基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基、三氟乙氧基、羟基乙氧基、N',N'-二甲氨基乙氧基、N'-甲基氨基乙氧基、吗啉基、2-氧杂-6-氮杂螺[3.3]环庚烷基、吗啉基-乙氧基、羟基丙氧基、N',N'-二甲氨基丙氧基、N'-甲基氨基丙氧基、吗啉基-丙氧基、哌嗪-1-基-乙氧基、4-甲基哌嗪-1-基-乙氧基、4-甲基哌嗪-1-基-丙氧基、哌嗪-1-基-丙氧基、吡咯烷-1-基-乙氧基、吡咯烷-1-基-丙氧基、四氢呋喃-3-氧基、甲硫基、甲氨基、乙胺基、乙酰胺基、丙酰胺基、甲氧基乙基、甲氧基乙胺基或甲氧基乙氧基； Ra is a hydrogen atom, a deuterium atom, F, Cl, Br, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a difluoromethyl group, a trifluoromethyl group, an ethynyl group, a 2-(1,3-dimethylpyrrolidin-3-yl)ethynyl group, an acetylcyano group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a hydroxyethoxy group, an N',N'-dimethylaminoethoxy group, an N'-methylaminoethoxy group, a morpholinyl group, a 2-oxa-6-azaspiro[3.3]cycloheptyl group, a morpholinyl group -ethoxy, hydroxypropoxy, N',N'-dimethylaminopropoxy, N'-methylaminopropoxy, morpholinyl-propoxy, piperazin-1-yl-ethoxy, 4-methylpiperazin-1-yl-ethoxy, 4-methylpiperazin-1-yl-propoxy, piperazin-1-yl-propoxy, pyrrolidin-1-yl-ethoxy, pyrrolidin-1-yl-propoxy, tetrahydrofuran-3-oxy, methylthio, methylamino, ethylamino, acetamido, propionamido, methoxyethyl, methoxyethylamino or methoxyethoxy;

Rb与Rd和所连接的原子一起形成吗啉基、四氢呋喃基、二氢咪唑基、硫代吗啉基、四氢吡喃基、四氢吡喃酮基、1,4-二氧六环基、六氢-1,4-氧氮杂卓基、六氢-1,4-硫氮杂卓基、4-硫代吗啉基-1-氧化物、4-硫代吗啉基-1,1-二氧化物、六氢-1,4-硫氮杂卓基-1-氧化物或六氢-1,4-硫氮杂卓基-1,1-二氧化物，所述吗啉基、硫代吗啉基、四氢吡喃基、四氢吡喃酮基、1,4-二氧六环基、六氢-1,4-氧氮杂卓基、六氢-1,4-硫氮杂卓基、4-硫代吗啉基-1-氧化物、4-硫代吗啉基-1,1-二氧化物、六氢-1,4-硫氮杂卓基-1-氧化物或六氢-1,4-硫氮杂卓基-1,1-二氧化物任选地被一个或多个氘原子、F、Cl、氰基、羟基、氨基、甲基、乙基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、甲氨基、二甲氨基、二甲氨基烷基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基或三氟乙氧基取代； Rb and Rd together with the atoms to which they are attached form a morpholinyl, tetrahydrofuranyl, dihydroimidazolyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide or hexahydro-1,4-thiazepinyl-1,1-dioxide, wherein the morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide, or hexahydro-1,4-thiazepinyl-1,1-dioxide is optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, dimethylaminoalkyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy;

R1选自以下基团：

 R1 is selected from the following groups:

R2为氢原子、氘原子、F、Cl、甲基、乙基、异丙基、叔丁基、环丙基、环丁基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、乙烯基、丙烯基、乙炔基、丙炔基、氰基、二氟甲氧基、三氟甲氧基、甲氧基、甲氧基甲基或氧代(＝O)； R2 is a hydrogen atom, a deuterium atom, F, Cl, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a cyclopropyl group, a cyclobutyl group, a deuterated methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a vinyl group, a propenyl group, an ethynyl group, a propynyl group, a cyano group, a difluoromethoxy group, a trifluoromethoxy group, a methoxy group, a methoxymethyl group, or an oxo group (=O);

或者，Rb与R2和所连接的原子一起形成吗啉基、四氢呋喃基、二氢咪唑基、硫代吗啉基、六氢-1,4-氧氮杂卓基、六氢-1,4-硫氮杂卓基、4-硫代吗啉基-1-氧化物、4-硫代吗啉基-1,1-二氧化物、六氢-1,4-硫氮杂卓基-1-氧化物或六氢-1,4-硫氮杂卓基-1,1-二氧化物，所述吗啉基、硫代吗啉基、六氢-1,4-氧氮杂卓基、六氢-1,4-硫氮杂卓基、4-硫代吗啉基-1-氧化物、4-硫代吗啉基-1,1-二氧化物、六氢-1,4-硫氮杂卓基-1-氧化物或六氢-1,4-硫氮杂卓基-1,1-二氧化物任选地被一个或多个氘原子、F、Cl、氰基、羟基、氨基、甲基、乙基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、甲氨基、二甲氨基、二甲氨基烷基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基或三氟乙氧基取代；Alternatively, Rb together with R2 and the atoms to which they are attached form a morpholinyl, tetrahydrofuranyl, dihydroimidazolyl, thiomorpholinyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide or hexahydro-1,4-thiazepinyl-1,1-dioxide, wherein the morpholinyl, thiomorpholinyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, 4-thiomorpholinyl-1,1-dioxide and 4-thiomorpholinyl-1,1-dioxide are substituted or substituted with morpholinyl, thiomorpholinyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1,1-dioxide. 1-dioxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide, or hexahydro-1,4-thiazepinyl-1,1-dioxide is optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, dimethylaminoalkyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy;

R3为氢原子、氘原子、F、Cl、氰基、硝基、甲基、乙基、异丙基、乙烯、乙炔、环丙基、环丁基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、羟基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧、甲氨基、乙胺基，所述甲基、乙基、异丙基、乙烯、乙炔、环丙基、环丁基、二氟乙基、三氟乙基、羟基、甲氧基、乙氧基、甲氨基、乙胺基任选地被一个或者多个氘原子、F、Cl、羟基、甲基、乙基、异丙基或环丙基取代； R3 is a hydrogen atom, a deuterium atom, F, Cl, a cyano group, a nitro group, a methyl group, an ethyl group, an isopropyl group, an ethylene group, an acetylene group, a cyclopropyl group, a cyclobutyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a hydroxyl group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a methylamino group, an ethylamino group, and the methyl group, ethyl group, isopropyl group, an ethylene group, an acetylene group, a cyclopropyl group, a cyclobutyl group, a difluoroethyl group, a trifluoroethyl group, a hydroxyl group, a methoxy group, an ethoxy group, a methylamino group, an ethylamino group is optionally substituted with one or more deuterium atoms, F, Cl, hydroxyl group, methyl group, ethyl group, isopropyl group or cyclopropyl group;

G环为吗啉基、四氢呋喃基、二氢咪唑基、四氢吡喃基、四氢吡喃酮基、1,4-二氧六环基、六氢-1,4-氧氮杂卓基，所述吗啉基、硫代吗啉基、四氢吡喃基、四氢吡喃酮基、1,4-二氧六环基、六氢-1,4-氧氮杂卓基任选地被一个或多个氘原子、F、Cl、氰基、羟基、氨基、甲基、乙基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、甲氨基、二甲氨基、二甲氨基烷基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基或三氟乙氧基取代；Ring G is morpholinyl, tetrahydrofuranyl, dihydroimidazolyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxazepinyl, wherein the morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxazepinyl is optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, dimethylaminoalkyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy;

W为C或CH；W is C or CH;

m、n、t各自独立地为0、1、2或3。m, n, and t are each independently 0, 1, 2, or 3.

在一个更具体的实施方式中，式I所示的化合物选自下列的化合物：







In a more specific embodiment, the compound represented by formula I is selected from the following compounds:







第二方面，在某些实施方案中，本发明提供一种制备式II化合物的方法，该方法包括如下反应步骤：In a second aspect, in certain embodiments, the present invention provides a method for preparing a compound of formula II, comprising the following reaction steps:

(1)化合物II-1与化合物II-2发生取代反应关环形成化合物II-3；(1) Compound II-1 and Compound II-2 undergo a substitution reaction to form Compound II-3;

(2)化合物II-3发生还原反应形成化合物II-5；或化合物II-3发生卤代反应形成化合物II-4，然后化合物II-4发生偶联反应形成化合物II-5；(2) Compound II-3 undergoes a reduction reaction to form Compound II-5; or Compound II-3 undergoes a halogenation reaction to form Compound II-4, and Compound II-4 then undergoes a coupling reaction to form Compound II-5;

(3)化合物II-5与DMF-DMA反应形成化合物II-6；(3) Compound II-5 reacts with DMF-DMA to form compound II-6;

(4)化合物II-6与化合物II-7反应关环形成化合物II-8；(4) Compound II-6 reacts with compound II-7 to form compound II-8;

(5)化合物II-8脱保护形成化合物II-9；(5) deprotection of compound II-8 to form compound II-9;

(6)化合物II-9与化合物II-10或化合物II-11发生取代反应形成式II所示化合物；(6) Compound II-9 undergoes a substitution reaction with Compound II-10 or Compound II-11 to form a compound represented by Formula II;

反应路线见图1。The reaction route is shown in Figure 1.

在某些实施实施方案中，本发明提供一种制备式III化合物的方法，该方法包括如下反应步骤：In certain embodiments, the present invention provides a method for preparing a compound of formula III, comprising the following reaction steps:

(1)化合物III-1与化合物III-2发生取代反应关环形成化合物III-3；(1) Compound III-1 and compound III-2 undergo a substitution reaction to form compound III-3;

(2)化合物III-3发生还原反应形成化合物III-5；或化合物III-3发生卤代反应形成化合物III-4，然后化合物III-4发生偶联反应形成化合物III-5；(2) Compound III-3 undergoes a reduction reaction to form Compound III-5; or Compound III-3 undergoes a halogenation reaction to form Compound III-4, and Compound III-4 then undergoes a coupling reaction to form Compound III-5;

(3)化合物III-5与DMF-DMA反应形成化合物III-6；(3) Compound III-5 reacts with DMF-DMA to form compound III-6;

(4)化合物III-6与化合物III-7反应关环形成化合物III-8；(4) Compound III-6 reacts with compound III-7 to form compound III-8;

(5)化合物III-8脱保护形成化合物III-9；(5) deprotection of compound III-8 to form compound III-9;

(6)化合物III-9与化合物III-10或化合物III-11发生取代反应形成式III所示化合物；(6) Compound III-9 undergoes a substitution reaction with Compound III-10 or Compound III-11 to form a compound represented by Formula III;

反应路线见图2。The reaction route is shown in Figure 2.

其中，在图1和图2的反应路线中，A、E、Q1、M、Y1、Y3、Y4、Y5、L1、L2、L3、L4、R1、R2、R3、R'、G、W、m、n、t的定义如上所述，X'为NO2或H；X”为卤素、Boc为叔丁氧羰基(tert-butyloxycarbonyl)。1 and 2 , A, E, Q 1 , M, Y 1 , Y 3 , Y 4 , Y 5 , L 1 , L 2 , L 3 , L 4 , R 1 , R 2 , R 3 , R ' , G, W, m, n, and t are as defined above; X' is NO 2 or H; X" is a halogen; and Boc is tert-butyloxycarbonyl.

第三方面，本发明提供包含上述化合物或其药学上可接受的盐、立体异构体、消旋体、互变异构体、同位素标记物、氘代物、N-氧化物、前药分子、水合物或溶剂合物以及药学上可接受的载体或赋形剂的药物组合物；In a third aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof and a pharmaceutically acceptable carrier or excipient;

优选地，所述药物组合物为片剂、胶囊剂、丸剂、颗粒剂、散剂、栓剂、注射剂、溶液剂、混悬剂、膏剂、贴剂、洗剂、滴剂、擦剂、喷雾剂。Preferably, the pharmaceutical composition is in the form of tablets, capsules, pills, granules, powders, suppositories, injections, solutions, suspensions, ointments, patches, lotions, drops, liniments, or sprays.

第四方面，本发明提供上述化合物或其药学上可接受的盐、立体异构体、消旋体、互变异构体、同位素标记物、氘代物、N-氧化物、前药分子、水合物或溶剂合物或包含上述化合物或其药学上可接受的盐、立体异构体、消旋体、互变异构体、同位素标记物、氘代物、N-氧化物、前药分子、水合物或溶剂合物以及药学上可接受的载体或赋形剂的药物组合物在制备治疗HER2异常介导的疾病中的应用；In a fourth aspect, the present invention provides the use of the aforementioned compound or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate, or a pharmaceutical composition comprising the aforementioned compound or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate and a pharmaceutically acceptable carrier or excipient in the preparation of a pharmaceutical composition for treating diseases mediated by abnormal HER2;

优选地，所述疾病为肿瘤性疾病；Preferably, the disease is a tumor disease;

更优选地，所述肿瘤性疾病包括：头颈部癌、鼻咽癌、黑色素瘤、膀胱癌、食道癌、肾癌、乳腺癌、结肠直肠癌、卵巢癌、宫颈癌、胰腺癌、胶质瘤、前列腺癌、白血病、淋巴瘤、胃癌、肺癌、肝癌、胃肠道基质瘤、甲状腺癌、鳞状细胞癌、胆管癌、子宫内膜癌、多发性骨髓瘤或者间皮瘤、动脉粥样硬化或者肺纤维化。More preferably, the tumor disease includes: head and neck cancer, nasopharyngeal cancer, melanoma, bladder cancer, esophageal cancer, kidney cancer, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, pancreatic cancer, glioma, prostate cancer, leukemia, lymphoma, gastric cancer, lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, squamous cell carcinoma, bile duct cancer, endometrial cancer, multiple myeloma or mesothelioma, atherosclerosis or pulmonary fibrosis.

第五方面，本发明提供一种治疗HER2异常介导的疾病的方法，该方法包括向有需要的患者给予治疗有效量的上述化合物或其药学上可接受的盐、立体异构体、消旋体、互变异构体、同位素标记物、氘代物、N-氧化物、前药分子、水合物或溶剂化物或药物组合物。In a fifth aspect, the present invention provides a method for treating diseases mediated by abnormal HER2, which comprises administering to a patient in need thereof a therapeutically effective amount of the above-mentioned compound or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate or pharmaceutical composition.

优选地，所述疾病为肿瘤性疾病；Preferably, the disease is a tumor disease;

更优选地，所述肿瘤性疾病包括：头颈部癌、鼻咽癌、黑色素瘤、膀胱癌、食道癌、肾癌、乳腺癌、结肠直肠癌、卵巢癌、宫颈癌、胰腺癌、胶质瘤、前列腺癌、白血病、淋巴瘤、胃癌、肺癌、肝癌、胃肠道基质瘤、甲状腺癌、鳞状细胞癌、胆管癌、子宫内膜癌、多发性骨髓瘤或者间皮瘤、动脉粥样硬化或者肺纤维化。More preferably, the tumor disease includes: head and neck cancer, nasopharyngeal cancer, melanoma, bladder cancer, esophageal cancer, kidney cancer, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, pancreatic cancer, glioma, prostate cancer, leukemia, lymphoma, gastric cancer, lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, squamous cell carcinoma, bile duct cancer, endometrial cancer, multiple myeloma or mesothelioma, atherosclerosis or pulmonary fibrosis.

第六方面，本发明提供一种治疗肿瘤的方法，该方法包括向有需要的患者给予治疗有效量的上述化合物或其药学上可接受的盐、立体异构体、消旋体、互变异构体、同位素标记物、氘代物、N-氧化物、前药分子、水合物或溶剂化物或药物组合物。In a sixth aspect, the present invention provides a method for treating tumors, which comprises administering to a patient in need thereof a therapeutically effective amount of the above-mentioned compound or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate or pharmaceutical composition.

所述的患者优选哺乳动物，所述哺乳动物优选为人。The patient is preferably a mammal, and the mammal is preferably a human.

在某些实施方式中，给药方式包括：口腔、粘膜、舌下、眼部、局部、肠道外、直肠、脑池、阴道、腹膜、膀胱、鼻部给药。In certain embodiments, the administration routes include oral, mucosal, sublingual, ocular, topical, parenteral, rectal, intracisternal, vaginal, peritoneal, bladder, and nasal administration.

在某些实施方式中，所述肿瘤包括：头颈部癌、黑色素瘤、膀胱癌、食道癌、间变性大细胞淋巴瘤、肾细胞癌、乳腺癌、结肠直肠癌、卵巢癌、宫颈癌、胰腺癌、胶质瘤、胶质母细胞瘤、前列腺癌、白血病、淋巴瘤、非霍奇金淋巴瘤、胃癌、肺癌、肝癌、胃肠道基质瘤、甲状腺癌、鳞状细胞癌、胆管癌、子宫内膜癌、多发性骨髓瘤或间皮瘤。In some embodiments, the tumor comprises: head and neck cancer, melanoma, bladder cancer, esophageal cancer, anaplastic large cell lymphoma, renal cell carcinoma, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, pancreatic cancer, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, non-Hodgkin lymphoma, gastric cancer, lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, squamous cell carcinoma, bile duct cancer, endometrial cancer, multiple myeloma, or mesothelioma.

本发明涉及的化合物或其药学上可接受的盐、立体异构体、消旋体、互变异构体、同位素标记物、氘代物、N-氧化物、前药分子、水合物或溶剂化物或药物组合物可通过任何合适的途径进入生物体内，比如通过口服、静脉注射、鼻内、外用、肌注、真皮内注射、经皮给药或皮下途径。The compounds of the present invention or their pharmaceutically acceptable salts, stereoisomers, racemates, tautomers, isotope-labeled substances, deuterated substances, N-oxides, prodrug molecules, hydrates or solvates or pharmaceutical compositions can be introduced into the body through any suitable route, such as oral administration, intravenous injection, intranasal administration, external application, intramuscular injection, intradermal injection, transdermal administration or subcutaneous administration.

在某些实施方式中，本发明中提供的化合物或其药学上可接受的盐、立体异构体、消旋体、互变异构体、同位素标记物、氘代物、N-氧化物、前药分子、水合物或溶剂化物或药物组合物可以被制成适于药物释放的剂型，通过注射途径给药(如皮下、静脉、肌肉、动脉、鞘膜、囊内、框内、心脏内、真皮内、腹膜内、经气管、表皮、关节内、囊下、蛛网膜下、脊柱内、胸骨内、和/或输液)和非注射途径给药(如口服、肠道、口腔、鼻、鼻内、粘膜、表皮、贴膏剂、真皮、眼药、肺部、舌下、直肠、阴道或表皮局部给药)。In certain embodiments, the compounds provided herein, or pharmaceutically acceptable salts, stereoisomers, racemates, tautomers, isotopically labeled substances, deuterated substances, N-oxides, prodrug molecules, hydrates or solvates thereof, or pharmaceutical compositions thereof, can be formulated into dosage forms suitable for drug release and administered by injection (e.g., subcutaneous, intravenous, intramuscular, arterial, intrathecal, intracapsular, intrathecal, intracardial, intradermal, intraperitoneal, transtracheal, epidermal, intraarticular, subcapsular, subarachnoid, intraspinal, intrasternal, and/or infusion) and non-injection routes of administration (e.g., oral, enteral, buccal, nasal, intranasal, mucosal, epidermal, patch, dermal, ophthalmic, pulmonary, sublingual, rectal, vaginal or epidermal topical administration).

合适的剂型包括(但不限于)注射用途的剂型比如乳状液、溶液和混悬液，口服用途的剂型如片剂、胶囊、丸剂、糖衣丸、粉末和颗粒，局部用药或经皮肤吸收的剂型如喷剂、软膏、糊剂、乳霜、洗剂、凝胶、溶液、药物贴片和吸入剂，阴道或直肠给药的剂型如栓剂。这些剂型可根据化合物以及合适的赋形剂在合适条件下制备，制备方法及工艺众所周知，比如由Remington：在The Science and Practice of Pharmacy(Gennaro ed.20th edition,Williams&Wilkins PA,USA)(2000)提供。Suitable dosage forms include, but are not limited to, dosage forms for injection such as emulsions, solutions and suspensions, dosage forms for oral administration such as tablets, capsules, pills, dragees, powders and granules, dosage forms for topical or transdermal administration such as sprays, ointments, pastes, creams, lotions, gels, solutions, drug patches and inhalants, and dosage forms for vaginal or rectal administration such as suppositories. These dosage forms can be prepared according to the compound and suitable excipients under suitable conditions, and the preparation methods and processes are well known, for example, provided by Remington: In The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000).

在某些实施方式中，HER2异常指HER2基因突变、HER2扩增或HER2过表达；In certain embodiments, HER2 abnormality refers to HER2 gene mutation, HER2 amplification, or HER2 overexpression;

优选地，HER2基因突变包括18-21号外显子突变、跨膜结构域突变和胞外区域突变；所述突变包括点突变(例如20号外显子点突变)、缺失突变和插入突变(例如20号外显子插入突变)；Preferably, the HER2 gene mutation includes mutations in exons 18-21, transmembrane domain mutations, and extracellular region mutations; the mutations include point mutations (e.g., exon 20 point mutations), deletion mutations, and insertion mutations (e.g., exon 20 insertion mutations);

更优选地，20号外显子插入突变包括Y772_A775dup、G776delinsVC、G778_P780dup、G776delinsLC、E770delinsEAYVM、E770_A771insAYVM、Y772_V773insMMAY、M774delinsWLV、A775_G776insYVMS、A775_G776insVVMA、A775_G776insSVMA、A775_G776insTVMA、A775_G776insC、G776delinsAVGC、G776delinsVV、G776delinsVG、G776_V777delinsCVC、G776_V777delinsVC、G776delinsIC、V777delinsAPL、V777_G778insC、G778insGSP、G778_S779insCPG；20号外显子点突变包括G776C、G776D、G776S、G776V、V777L、D778H、V782I、T791A、L806P、R811L、N813T、R816C、Q820K、Q828H、M774AYVM。More preferably, the exon 20 insertion mutations include Y772_A775dup, G776delinsVC, G778_P780dup, G776delinsLC, E770delinsEAYVM, E770_A771insAYVM, Y772_V773insMMAY, M774delinsWLV, A775_G776insYVMS, A775_G776insVVMA, A775_G776insSVMA, A775_G776insTVMA, A775_G776insC, G776delinsAVGC, G776 76delinsVV, G776delinsVG, G776_V777delinsCVC, G776_V777delinsVC, G776delinsIC, V777delinsAPL, V777_G778insC, G778insGSP, G778_S779insCPG; point mutations in exon 20 include G776C, G776D, G776S, G776V, V777L, D778H, V782I, T791A, L806P, R811L, N813T, R816C, Q820K, Q828H, M774AYVM.

在某些实施方式中，本发明涉及的化合物或药物组合物可以与一种或多种具有另外药理活性物质同时进行施用，这样能在生物体内达到叠加甚至协同的作用。例如，本发明涉及的化合物可以和具有另外药理活性物质组合成一个药物组合物，或者以单独的组合物同时施用，或者以单独的组合物依次施用。能与本发明化合物同时施用、用于治疗癌症的具有另外药理活性物质包括但不局限于：1)EGFR家族抑制剂、单/双抗体或ADC等，如：奥希替尼、阿美替尼、伏美替尼、贝福替尼、瑞齐替尼、瑞厄替尼、利厄替尼、olmutinib、Lazertinib、PLB1004、阿法替尼、达可替尼、厄洛替尼、吉非替尼、埃克替尼、西妥昔单抗、帕尼单抗、Amivantamab、拉帕替尼、来那替尼、图卡替尼、曲妥珠单抗、帕妥珠单抗、margetuximab、恩美曲妥珠单抗、德曲妥珠单抗等；2)下游通路或其他通路靶点抑制剂单/双抗体或ADC等，所述的靶点包括但不限于MEK、RET、PI3K、mTOR、c-Met、PARP或有丝分裂激酶抑制剂(如CDK4/6)等。如：曲美替尼、比美替尼、司美替尼、帕拉西替尼、艾德拉尼、Copanlisib、Duvelisib、Alpelisib、umbralisib、Parsaclisib，雷帕霉素、替西罗莫司、依维莫司、卡马替尼、特泊替尼、赛沃替尼、谷美替尼、伯瑞替尼、卡博替尼、Emibetuzumab、Telisotuzumab、尼拉帕尼、帕博西尼、瑞博西尼、abemaciclib等；3)抗血管生成药物，如贝伐单抗、阿柏西普、雷莫芦单抗、尼达尼布等；4)细胞凋亡诱导剂(如Bcl-2)，如：obatoclax、维奈克拉等；5)化疗药物，如：氟尿嘧啶、阿霉素、柔红霉素、它莫西芬、亮丙瑞林、戈舍瑞林、氟他米特、尼鲁米特、非那雄胺、地塞米松、氨鲁米特、安吖啶、阿那曲唑、天冬酰胺酶、卡介苗、比卡鲁胺、博来霉素、白消安、喜树碱、卡培他滨、卡铂、顺铂、卡莫司汀、苯丁酸氮芥、克拉屈滨、秋水仙碱、环磷酰胺、环丙孕酮、阿糖胞苷、达卡巴嗪、正定霉素、双烯雌酚、己烯雌酚、多西紫杉醇、阿霉素、亚德里亚霉素、表柔比星、雌二醇、雌氮芥、依托泊苷、依西美坦、非格司亭、氟达拉滨、氟氢可的松、氟甲睾酮、氟他米特、吉西他滨、戈舍瑞林、替尼泊苷、睾酮、二氯化二茂钛、拓普泰康、维甲酸、长春花碱、羟基脲、伊达比星、异环磷酰胺、伊立替康、来曲唑、甲酰四氢叶酸、喷司他丁、光神霉素、甲基苄肼、雷替曲塞、卟菲尔钠、利妥昔、链脲菌素、苏拉明、亮丙瑞林、左旋咪唑、环己亚硝脲、氮芥、甲羟孕酮、甲地孕酮、美法仑、巯嘌呤、巯乙磺酸钠、甲氨蝶呤、丝裂霉素、米托坦、米托蒽醌、尼鲁米特、诺考达唑、奥曲肽、紫杉醇、帕米磷酸、硫鸟嘌呤、三胺硫磷、氯甲烷、拓扑替康二茂钛、维甲酸、长春花碱、长春新碱、长春地辛、长春瑞斌、培美曲塞。In certain embodiments, the compounds or pharmaceutical compositions of the present invention can be administered simultaneously with one or more other pharmacologically active substances, thereby achieving additive or even synergistic effects in vivo. For example, the compounds of the present invention can be combined with other pharmacologically active substances to form a single pharmaceutical composition, or administered simultaneously as separate compositions, or administered sequentially as separate compositions. Additional pharmacologically active substances that can be administered concurrently with the compounds of the present invention for the treatment of cancer include, but are not limited to: 1) EGFR family inhibitors, monoclonal/diabodies, or ADCs, such as osimertinib, ametinib, vumetinib, befortinib, rizitinib, riertinib, liertinib, olmutinib, lazertinib, PLB1004, afatinib, dacomitinib, erlotinib, gefitinib, icotinib, cetuximab, panitumumab, amivantamab, lapatinib, neratinib, tucatinib, trastuzumab, pertuzumab, margetuximab, emtansinetrastuzumab, denatinib, and the like; 2) monoclonal/diabodies or ADCs that are inhibitors of downstream pathways or other pathway targets, such as, but not limited to, MEK, RET, PI3K, mTOR, c-Met, PARP, or mitotic kinase inhibitors (such as CDK4/6). Such as: Trametinib, Bimetinib, Selumetinib, Palacitinib, Idranib, Copanlisib, Duvelisib, Alpelisib, Umbralisib, Parsaclisib, Rapamycin, Temsirolimus, Everolimus, Capmatinib, Tepotinib, Saivotinib, Gumetinib, Berretinib, Cabozantinib, Emibetuzumab, Telisotuzumab, Niraparib, Palbociclib, Ribociclib, Abemaciclib, etc. ; 3) Anti-angiogenic drugs, such as bevacizumab, aflibercept, ramucirumab, nintedanib, etc.; 4) Apoptosis inducers (such as Bcl-2), such as obatoclax, venetoclax, etc.; 5) Chemotherapeutic drugs, such as fluorouracil, doxorubicin, daunorubicin, tamoxifen, leuprorelin, goserelin, flutamide, nilutamide, finasteride, dexamethasone, aminoglutethimide, amsacrine, anastrozole, asparaginase, BCG, bicalutamide, bleomycin, busulfan, camptothecin, capecitabine, carboplatin, cisplatin, carboplatin, Mustine, chlorambucil, cladribine, colchicine, cyclophosphamide, cyproterone acetate, cytarabine, dacarbazine, daunorubicin, dienestilbestrol, diethylstilbestrol, docetaxel, doxorubicin, adriamycin, epirubicin, estradiol, estramustine, etoposide, exemestane, filgrastim, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, goserelin, teniposide, testosterone, titanocene dichloride, topotecan, tretinoin, vinblastine, hydroxyurea, idarubicin, ifosfamide, irinotecan, letrozole Azoles, leucovorin, pentostatin, mithramycin, procarbazine, raltitrexed, porfibril sodium, rituximab, streptozotocin, suramin, leuprorelin, levamisole, lomustine, nitrogen mustard, medroxyprogesterone acetate, megestrol acetate, melphalan, mercaptopurine, sodium mercaptoethanesulfonate, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, nocodazole, octreotide, paclitaxel, pamidronate, thioguanine, triazolam, methyl chloride, topotecan titanocene, tretinoin, vinblastine, vincristine, vindesine, vinorelbine, pemetrexed.

在某些实施方式中，本发明提供的化合物可与免疫治疗剂同时使用。合适的免疫治疗剂包括：PD-1抑制剂、PD-L1抑制剂、CTLA-4抑制剂，如杜瓦鲁单抗；肿瘤细胞多药耐药性逆转剂(比如维拉帕米)、霉酚酸酯、沙利度胺、环孢霉素和单克隆抗体类。In certain embodiments, the compounds provided herein can be used concurrently with immunotherapeutic agents. Suitable immunotherapeutic agents include: PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, such as durvalumab; agents that reverse multidrug resistance in tumor cells (such as verapamil), mycophenolate mofetil, thalidomide, cyclosporine, and monoclonal antibodies.

在某些实施方式中，本发明提供的化合物可与非化学方法同时使用进行癌症治疗。在某些实施方式中，本发明提供的化合物可与放射疗法同时进行。在某些实施方式中，本发明提供的化合物可与外科手术，肿瘤热治疗，超声聚焦疗法，冷冻疗法或以上几种疗法结合使用。In certain embodiments, the compounds provided herein can be used concurrently with non-chemical methods for cancer treatment. In certain embodiments, the compounds provided herein can be used concurrently with radiotherapy. In certain embodiments, the compounds provided herein can be used in combination with surgery, tumor thermal therapy, focused ultrasound therapy, cryotherapy, or a combination of these therapies.

下面将结合本发明实施例对本发明的技术方案进行清楚、完整地描述，显然，所描述的实施例是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。The following will clearly and completely describe the technical solutions of the present invention in conjunction with the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without making any creative efforts shall fall within the scope of protection of the present invention.

特别需要指出的是，针对本发明所做出的类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。It is particularly important to note that similar substitutions and modifications made to the present invention will be obvious to those skilled in the art and are considered to be included in the present invention. It is obvious that relevant persons can modify or appropriately change and combine the methods and applications described herein to implement and apply the technology of the present invention without departing from the content, spirit, and scope of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments.

本发明如未注明具体条件者，均按照常规条件或制造商建议的条件进行，所用原料药或辅料，以及所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。Unless otherwise specified, the present invention was carried out under conventional conditions or those recommended by the manufacturer. The raw materials or excipients, as well as the reagents or instruments used, for which the manufacturer is not specified, are all conventional products that can be purchased commercially.

除非另外指出，阐明下列定义以举例说明和定义用于描述本发明的各种术语的含义和范围。Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the present invention.

---/--表示无或化学键。---/-- means no or chemical bond.

表示连接位点。 Indicates the attachment site.

碳氢基团中碳原子含量的最小值和最大值通过前缀表示，例如，前缀(Ca-b)烷基表示任何含“a”至“b”个碳原子的烷基。因此，例如，C1-6烷基是指包含1至6个碳原子的烷基。所述的烷基是支链的或直链的。The minimum and maximum carbon atom content of a hydrocarbon group is indicated by a prefix. For example, the prefix (C ab )alkyl represents any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C 1-6 alkyl refers to an alkyl group containing from 1 to 6 carbon atoms. The alkyl group can be branched or straight chain.

本发明化合物中所述的原子包括其同位素，例如，氢可以是氘或氚。The atoms described in the compounds of the present invention include their isotopes, for example, hydrogen may be deuterium or tritium.

“桥环”是指任意两个环共用两个直接连接或不直接连接的原子的多环基团，可以含有一个或多个双键，但是没有一个环具有完全共轭的π电子体系，环原子可以是全碳原子也可以其中一个或多个环原子选自N，O，S，SO或S(O)2。优选为7-10环。"Bridged ring" refers to a polycyclic group in which any two rings share two atoms that are directly or indirectly connected. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. The ring atoms may be all carbon atoms or one or more of the ring atoms may be selected from N, O, S, SO or S(O) 2. 7-10 rings are preferred.

“螺环”是指任意两个环共用一个碳原子的多环基团，可以含有一个或多个双键，但是没有一个环具有完全共轭的π电子体系，环原子可以是全碳原子也可以其中一个或多个环原子选自N，O，S，SO或S(O)2。优选为5-10环。"Spirocyclic" refers to a polycyclic group in which any two rings share a common carbon atom, may contain one or more double bonds, but no ring has a completely conjugated π electron system, and the ring atoms may be all carbon atoms or one or more of the ring atoms may be selected from N, O, S, SO or S(O) 2. Preferably, the ring has 5-10 rings.

稠环：指每个环与体系中的其他环共用两个毗邻原子的多环基团。可以含有一个或多个双键或具有完全共轭的π电子体系，环原子可以是全碳原子也可以其中一个或多个环原子选自N，O，S，SO或S(O)2。优选为5-10环。Fused ring: refers to a polycyclic group in which each ring shares two adjacent atoms with other rings in the system. It may contain one or more double bonds or have a completely conjugated π-electron system. The ring atoms may be all carbon atoms or one or more ring atoms may be selected from N, O, S, SO, or S(O) 2 . It preferably has 5-10 rings.

联环：指任意两个环或两个以上环通过化学键连接。Linked ring: refers to any two or more rings connected by chemical bonds.

根据组成环的数目可以分为双环、三环、四环或多环基团，优选为双环、三环或四环，更优选为双环或三环。According to the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group.

一个环状基团可通过多种方式与另一基团键合。如果未明确键合方式，则表示包括所有可能的方式。例如，“吡啶基”包括2-、3-、或4-吡啶基，而“噻吩基”包括2-或3-噻吩基。A cyclic group can be bonded to another group in a variety of ways. If the bonding method is not specified, all possible methods are included. For example, "pyridyl" includes 2-, 3-, or 4-pyridyl, and "thienyl" includes 2- or 3-thienyl.

“烷基”是指直链或带有支链的，单价的，饱和烃基，包括但不限于如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基以及其它类似基团。优选C1-8烷基。更优选C1-6烷基。更优选C1-4烷基。烷基可以被一个或多个取代基取代或未被取代的，当被取代时，取代基可以在任何连接点上取代，所述的取代基优先为以下基团："Alkyl" refers to a linear or branched, monovalent, saturated hydrocarbon group, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and other similar groups. Preferably, it is a C 1-8 alkyl group. More preferably, it is a C 1-6 alkyl group. More preferably, it is a C 1-4 alkyl group. The alkyl group may be substituted or unsubstituted with one or more substituents. When substituted, the substituents may be substituted at any point of attachment. The substituents are preferably the following groups:

氘原子、卤素、氰基、硝基、叠氮基、羟基、C1-10烷基、C2-10烯基、C2-10炔基、C2-6杂烯基、3-12元饱和或不饱和环烷基、3-12元饱和或不饱和杂环基、C1-10烷氧基、卤代C1-10烷基、卤代C1-10烷氧基、氘代C1-10烷基、氘代C1-10烷氧基、6-10元芳基、5-10元杂芳基、氧代(＝O)。a deuterium atom, a halogen, a cyano group, a nitro group, an azide group, a hydroxyl group, a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, a C 2-6 heteroalkenyl group, a 3-12-membered saturated or unsaturated cycloalkyl group, a 3-12-membered saturated or unsaturated heterocyclic group, a C 1-10 alkoxy group, a halogenated C 1-10 alkyl group, a halogenated C 1-10 alkoxy group, a deuterated C 1-10 alkyl group, a deuterated C 1-10 alkoxy group, a 6-10 membered aryl group, a 5-10 membered heteroaryl group, and an oxo group (═O).

“环烷基”是指饱和或部分不饱和的单环或多环环状烃基，能与其它基团组合。单环环状烃基包括但不限于如环丙基、环丁基、环戊基、环己基、环庚基、环辛基。优选3-8元环烷基。优选4-7元环烷基。更优选3-6元环烷基。所述部分不饱和的单环或多环环状烃基指环烯基。多环环状烃基包括联环、螺环、稠环或桥环环状脂肪烃基，包括但不限于以下基团：
"Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, which can be combined with other groups. Monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 3-8 membered cycloalkyl groups are preferred. 4-7 membered cycloalkyl groups are preferred. 3-6 membered cycloalkyl groups are more preferred. The partially unsaturated monocyclic or polycyclic hydrocarbon group refers to a cycloalkenyl group. Polycyclic hydrocarbon groups include linked, spirocyclic, fused, or bridged ring cyclic aliphatic hydrocarbon groups, including but not limited to the following groups:

“环烯基”是指部分不饱和的具有至少一个碳-碳双键的单环或多环环烃基，但是不形成完全共轭的Π电子系统，能与其它基团组合。单环环烯基包括但不限于如环丙烯基、环丁烯基、环戊烯基、环己烯基、环己二烯基、环庚烯基、环庚三烯基、环辛烯基等。优选3-8元环烯基。更优选3-6元环烯基。更优选5-6元环烯基。多环环烯基包括联环、螺环、稠环或桥环环烯基。包括但不限于以下基团：
"Cycloalkenyl" refers to a partially unsaturated monocyclic or polycyclic hydrocarbon ring having at least one carbon-carbon double bond, but does not form a completely conjugated π electron system and can be combined with other groups. Monocyclic cycloalkenyls include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptatrienyl, cyclooctenyl, etc. Preferably, a 3-8 membered cycloalkenyl. More preferably, a 3-6 membered cycloalkenyl. More preferably, a 5-6 membered cycloalkenyl. Polycyclic cycloalkenyls include linked rings, spiro rings, fused rings, or bridged ring cycloalkenyls. Including but not limited to the following groups:

所述的环烷基或环烯基可以稠和芳基、杂芳基或杂环基，包括但不限于四氢萘基、苯并环庚基等。The cycloalkyl or cycloalkenyl group may be fused with an aryl, heteroaryl or heterocyclic group, including but not limited to tetrahydronaphthyl, benzocycloheptyl and the like.

“烯基”指直链、带有支链或环状的含有一个或多个碳-碳双键的烃基，包括但不限于乙烯基、丙烯基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基。优选C2-6烯基。更优选C2-4烯基。"Alkenyl" refers to a linear, branched, or cyclic hydrocarbon group containing one or more carbon-carbon double bonds, including but not limited to ethenyl, propenyl, (E)-2-methylethenyl, (Z)-2-methylethenyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, and (Z)-but-1-enyl. Preferably, it is a C2-6 alkenyl group. More preferably, it is a C2-4 alkenyl group.

“炔基”指直链、带有支链或环状的含有一个或多个碳-碳三键的烃基，包括但不限于乙炔基、丙-1-炔基、丙-2-炔基、丁-1-炔基、丁-2-炔基、丁-3-炔基。优选C2-6炔基。更优选C2-4炔基。"Alkynyl" refers to a linear, branched, or cyclic hydrocarbon group containing one or more carbon-carbon triple bonds, including but not limited to ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, and but-3-ynyl. Preferably, it is a C2-6 alkynyl group. More preferably, it is a C2-4 alkynyl group.

“亚烷基”是指直链或带有支链的、二价的饱和烃基，即烷基的一个氢原子进一步被取代，包括但不限于如“亚甲基”指-CH2-、“亚乙基”指-CH2CH2-、“亚丙基”指-CH2CH2CH2-、“亚丁基”指-CH2CH2CH2CH2-或-CH2CH(CH3)CH2-。"Alkylene" refers to a straight or branched, divalent saturated hydrocarbon group, i.e., one hydrogen atom of the alkyl group is further substituted, including but not limited to "methylene" refers to -CH2- , "ethylene" refers to -CH2CH2- , "propylene" refers to -CH2CH2CH2- , and "butylene" refers to -CH2CH2CH2CH2- or -CH2CH ( CH3 ) CH2- .

“卤素”是指氟、氯、溴或碘，优选氟、氯或溴。"Halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

“卤代烷基”是指本文定义的烷基，其中一个或多个氢已经被相同或不同卤素取代。包括但不限于如-CH2Cl，-CHF2，-CH2CF3，-CH2CCl3，全氟烷基(例如，-CF3)等。"Haloalkyl" refers to an alkyl group as defined herein, wherein one or more hydrogen atoms have been replaced by the same or different halogen atoms, including but not limited to -CH2Cl , -CHF2 , -CH2CF3 , -CH2CCl3 , perfluoroalkyl (e.g., -CF3 ), and the like.

“烷基氨基”是指经烷基取代的NH3。包括但不限于如甲氨基、乙氨基、丙氨基、异丙氨基等。"Alkylamino" refers to NH 3 substituted by an alkyl group, including but not limited to methylamino, ethylamino, propylamino, isopropylamino, and the like.

“二烷基氨基”是指具有结构N(C1-6烷基)2的基团。包括但不限于如二甲氨基、二乙氨基、甲基(乙基)氨基、二丙基氨基、二异丙基氨基等。"Dialkylamino" refers to a group having the structure N( C1-6alkyl ) 2 , including but not limited to dimethylamino, diethylamino, methyl(ethyl)amino, dipropylamino, diisopropylamino, and the like.

“芳基”是指具有一个或多个稠合或非稠合芳香族环的单环或多环碳环体系，包括但不限于如苯基、萘基、茚基。优选6-10元单环或双环芳香基团。更优选苯基或萘基。最优选苯基。"Aryl" refers to a monocyclic or polycyclic carbocyclic ring system having one or more fused or unfused aromatic rings, including but not limited to phenyl, naphthyl, and indenyl. A 6-10 membered monocyclic or bicyclic aromatic group is preferred. Phenyl or naphthyl is more preferred. Phenyl is most preferred.

“杂环基”是指具有环碳原子和1-4个环杂原子的3-12元非芳香族单环或多环环体系的基团，包括只有单键的饱和环和至少有一个双键(C＝C、C＝N或N＝N)的不饱和环，但是不形成完全共轭的Π电子系统。其中杂原子独立地选自N、O、S、氧化氮(NO)、亚砜、S(O)(＝NH)和砜基。多环体系包括稠环、桥环或螺环体系。单环杂环基部分的实例包括但不限于：氮杂环丙基、氮杂环丁烷基、氧杂环丁烷基、吡咯烷基，哌啶基，哌嗪基，高哌嗪基，氧代哌啶基、氧代哌嗪基、氧代高哌嗪基、四氢呋喃基、咪唑啉基，吗啉基，噁唑烷基，异噁唑烷基，噻唑烷基，异噻唑烷基，奎宁环基，噻二唑烷基，二氢呋喃基，四氢呋喃基，二氢吡喃基，四氢吡喃基，硫代吗啉基，硫代吗啉基亚砜，硫代吗啉基砜等。优选4-7元杂环基。更优选4-6元杂环基。多环杂环基部分的实例包括但不限于：2-氮杂双环[2.2.1]庚基、2-氧杂-5-氮杂双环[2.2.1]庚基、2,5-二氮杂双环[2.2.1]庚基、1-氮杂双环[2.2.2]辛基、3-氮杂双环[3.2.1]辛基、3,8-二氮杂双环[3.2.1]辛基、6-氧杂-2-氮杂双环[3.2.1]辛基、6-氧杂-3-氮杂双环[3.2.1]辛基、8-氧杂-3-氮杂双环[3.2.1]辛基、3,8-二氮杂双环[3.2.1]辛基、8-氮杂双环[3.2.1]辛基、8-氮杂双环[5.1.0]辛基、六氢-1H-呋喃[3,4-b]吡咯基、六氢-1H-呋喃[3,4-c]吡咯基、2-氧杂-6-氮杂螺[3.3]庚基、5-氧杂-2-氮杂螺[3.4]辛基、6-氧杂-2-氮杂螺[3.4]辛基、1-氧杂-7-氮杂螺[3.5]壬-7-基、1,4-二氧杂-8-氮杂螺[4.5]癸-8-基和1,4-二氧杂-9-氮杂螺[5.5]十一-9-基等。不饱和杂环基部分的实例包括但不限于：
"Heterocyclyl" refers to a 3-12 membered non-aromatic monocyclic or polycyclic ring system having ring carbon atoms and 1-4 ring heteroatoms, including saturated rings with only single bonds and unsaturated rings with at least one double bond (C=C, C=N or N=N), but not forming a completely conjugated π electron system. The heteroatoms are independently selected from N, O, S, nitrogen oxide (NO), sulfoxide, S(O)(=NH) and sulfone. Polycyclic ring systems include fused, bridged or spiro ring systems. Examples of monocyclic heterocyclic moieties include, but are not limited to, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, oxopiperidinyl, oxopiperazinyl, oxohomopiperazinyl, tetrahydrofuranyl, imidazolinyl, morpholinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, quinuclidinyl, thiadiazolidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, etc. Preferred are 4-7 membered heterocyclic groups. More preferred are 4-6 membered heterocyclic groups. Examples of polycyclic heterocyclyl moieties include, but are not limited to, 2-azabicyclo[2.2.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 1-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2.1]octyl, 6-oxa-2-azabicyclo[3.2.1]octyl, 6-oxa-3-azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2 .1]octyl, 8-azabicyclo[3.2.1]octyl, 8-azabicyclo[5.1.0]octyl, hexahydro-1H-furo[3,4-b]pyrrolyl, hexahydro-1H-furo[3,4-c]pyrrolyl, 2-oxa-6-azaspiro[3.3]heptyl, 5-oxa-2-azaspiro[3.4]octyl, 6-oxa-2-azaspiro[3.4]octyl, 1-oxa-7-azaspiro[3.5]nonan-7-yl, 1,4-dioxa-8-azaspiro[4.5]dec-8-yl and 1,4-dioxa-9-azaspiro[5.5]undec-9-yl, etc. Examples of unsaturated heterocyclic moieties include, but are not limited to:

所述的杂环基可以稠合于芳基、杂芳基或环烷基上，包括并不限于以下基团：
The heterocyclic group may be fused to an aryl group, a heteroaryl group or a cycloalkyl group, including but not limited to the following groups:

杂环基任选取代的或未取代的，取代的取代基优先为一个或多个以下基团：氘原子、卤素、CN、硝基、羟基、叠氮基、C1-10烷基、C2-10烯基、C2-10炔基、C2-6杂烯基、3-12元饱和或不饱和环烷基、3-12元饱和或不饱和杂环基、卤代C1-10烷基、C1-10烷氧基、卤代C1-10烷氧基、氘代C1-10烷基、氘代C1-10烷氧基、6-10元芳基、5-10元杂芳基、氧代(＝O)。The heterocyclic group is optionally substituted or unsubstituted, and the substituted substituents are preferably one or more of the following groups: a deuterium atom, a halogen, CN, a nitro group, a hydroxyl group, an azido group, a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, a C 2-6 heteroalkenyl group, a 3-12 membered saturated or unsaturated cycloalkyl group, a 3-12 membered saturated or unsaturated heterocyclic group, a halogenated C 1-10 alkyl group, a C 1-10 alkoxy group, a halogenated C 1-10 alkoxy group, a deuterated C 1-10 alkyl group, a deuterated C 1-10 alkoxy group, a 6-10 membered aryl group, a 5-10 membered heteroaryl group, and an oxo (═O) group.

“杂芳基”是指取代或未取代的5元或6元单杂芳环系，或取代或未取代的9元或10元稠合或双杂芳环系，其中包含1、2、3或4个独立选自N、O、S(＝O)、S(＝O)2或S杂原子，其余环原子是碳原子。杂芳基部分的实例包括但不限于：噻吩基，呋喃基，咪唑基，异噁唑基，噁唑基，吡唑基，吡咯基，噻二唑基，噁二唑基，三唑基，吡啶基，吡嗪基、哒嗪基，嘧啶基，吲哚基，吲唑基，喹啉基，异喹啉基，苯并咪唑基或苯并噻唑基。"Heteroaryl" refers to a substituted or unsubstituted 5-membered or 6-membered monoheteroaromatic ring system, or a substituted or unsubstituted 9-membered or 10-membered fused or biheteroaromatic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(=O), S(=O) 2 , or S, with the remaining ring atoms being carbon atoms. Examples of heteroaryl moieties include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiadiazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, or benzothiazolyl.

所述的杂芳基可以稠合于芳基、杂环基或环烷基上，包括并不限于以下基团：
The heteroaryl group may be fused to an aryl group, a heterocyclic group or a cycloalkyl group, including but not limited to the following groups:

杂芳基任选取代的或未取代的，取代的取代基优先为一个或多个以下基团：氘原子、卤素、CN、硝基、羟基、叠氮基、C1-10烷基、C1-10烷氧基、C2-10烯基、C2-10炔基、C2-6杂烯基、3-12元饱和或不饱和环烷基、3-12元饱和或不饱和杂环基、卤代C1-10烷基、卤代C1-10烷氧基、氘代C1-10烷基、氘代C1-10烷氧基、6-10元芳基、5-10元杂芳基、氧代(＝O)。The heteroaryl group is optionally substituted or unsubstituted, and the substituted substituent is preferably one or more of the following groups: a deuterium atom, a halogen, CN, a nitro group, a hydroxyl group, an azido group, a C 1-10 alkyl group, a C 1-10 alkoxy group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, a C 2-6 heteroalkenyl group, a 3-12 membered saturated or unsaturated cycloalkyl group, a 3-12 membered saturated or unsaturated heterocyclic group, a halogenated C 1-10 alkyl group, a halogenated C 1-10 alkoxy group, a deuterated C 1-10 alkyl group, a deuterated C 1-10 alkoxy group, a 6-10 membered aryl group, a 5-10 membered heteroaryl group, and an oxo group (=O).

“烷氧基”是指与一氧原子键合的直链或带有支链的，单价的，饱和烷基，包括但不限于如甲氧基、乙氧基、丙氧基、丁氧基、异丁氧基、叔丁氧基以及其它类似基团。优选C1-8烷氧基。更优选C1-6烷氧基。更优选C1-4烷氧基。"Alkoxy" refers to a linear or branched, monovalent, saturated alkyl group bonded to an oxygen atom, including but not limited to methoxy, ethoxy, propoxy, butoxy, isobutoxy, tert-butoxy, and similar groups. Preferably, it is a C1-8 alkoxy group. More preferably, it is a C1-6 alkoxy group. More preferably, it is a C1-4 alkoxy group.

“环烷氧基”是指-O-环烷基，其中环烷基如上所述。优选C3-8环烷氧基。包括但不限于环丙氧基、环丁氧基、环戊氧基、环己氧基以及其他类似基团。"Cycloalkoxy" refers to an -O-cycloalkyl group, wherein the cycloalkyl group is as described above. Preferably, a C 3-8 cycloalkoxy group is included. Examples include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and other similar groups.

“杂环氧基”是指-O-杂环基，其中杂环基如上所述。包括但不限于氮杂环丁基氧基、氧杂环丁基氧基、吡咯烷基氧基、氧杂环己基氧基、哌啶基氧基及其他类似基团。"Heterocyclyloxy" refers to an -O-heterocyclyl group, wherein the heterocyclyl group is as defined above, including but not limited to azetidinyloxy, oxetanyloxy, pyrrolidinyloxy, oxhexyloxy, piperidinyloxy and other similar groups.

“药学上可接受的盐”指常规的酸加成盐或碱加成盐，其保留式I化合物的生物有效性和性质，其由适宜的非毒性有机或无机酸或有机或无机碱形成。酸加成盐的例子包括衍生自无机酸和衍生自有机酸的那些盐，所述无机酸例如盐酸、氢溴酸、氢碘酸、硫酸、氨基磺酸、磷酸和硝酸。所述有机酸例如乙酸、丙酸、乙醇酸、草酸、硬脂酸、抗坏血酸、对甲苯磺酸、水杨酸、甲磺酸、乙磺酸、草酸、琥珀酸、柠檬酸、马来酸、羟基马来酸、乳酸、富马酸、酒石酸、苹果酸、羟乙基磺酸、苯磺酸、三氟乙酸、扁桃酸等。碱加成盐的例子包括衍生自无机酸和衍生自有机酸的那些盐，所述无机碱例如铵盐、钙盐、铁盐、铝盐、钠盐、钾盐、锌盐、镁盐。所述有机碱包括伯胺、仲胺和叔胺的盐，例如三甲胺、三乙胺、三丙胺、二乙醇胺、乙二胺、乙醇胺、等。将药用化合物(即药物)化学改性成盐是药剂师公知的技术，用以获得化合物的改善的物理和化学稳定性、吸湿性、流动性和溶解性。"Pharmaceutically acceptable salt" refers to conventional acid addition salts or base addition salts that retain the biological effectiveness and properties of the compound of Formula I and are formed by suitable non-toxic organic or inorganic acids or organic or inorganic bases. Examples of acid addition salts include those derived from inorganic acids and those derived from organic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid. Examples of organic acids include acetic acid, propionic acid, glycolic acid, oxalic acid, stearic acid, ascorbic acid, p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, oxalic acid, succinic acid, citric acid, maleic acid, hydroxymaleic acid, lactic acid, fumaric acid, tartaric acid, malic acid, isethionic acid, benzenesulfonic acid, trifluoroacetic acid, mandelic acid, etc. Examples of base addition salts include those derived from inorganic acids and those derived from organic acids, such as ammonium salts, calcium salts, iron salts, aluminum salts, sodium salts, potassium salts, zinc salts, and magnesium salts. The organic bases include salts of primary, secondary and tertiary amines, such as trimethylamine, triethylamine, tripropylamine, diethanolamine, ethylenediamine, ethanolamine, etc. Chemical modification of pharmaceutical compounds (i.e., drugs) into salts is a technique well known to pharmacists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of the compounds.

“前药分子”指可以在体内转化为本发明所涉及的化合物及其药学可接受的盐的结构的前药。"Prodrug molecule" refers to a prodrug that can be converted into a compound of the present invention and a pharmaceutically acceptable salt thereof in vivo.

“N-氧化物”是指当化合物中含有胺官能团或含N原子的杂芳基化合物时，可将1个或大于1个的N原子氧化形成含有N+的化合物，优选为叔胺的N-氧化物或含有N的杂芳基的N-氧化物。"N-oxide" means that when a compound contains an amine functional group or a heteroaryl compound containing a N atom, one or more N atoms can be oxidized to form a compound containing N + , preferably an N-oxide of a tertiary amine or an N-oxide of a heteroaryl compound containing N.

“水合物”是指与一定量的水形成的缔合物。"Hydrate" refers to an association formed with a certain amount of water.

“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但不限于甲醇、乙醇、异丙醇、乙酸乙酯、乙酸等。"Solvate" refers to an association formed between one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, methanol, ethanol, isopropanol, ethyl acetate, acetic acid, and the like.

“药物组合物”是指将本发明中的化合物中的一个或多个或其药学上可接受的盐、溶剂化物、水合物或前药与其他的化学成分，例如药学上可接受的载体、赋形剂或稀释剂混合。药物组合物的目的是促进给药给动物的过程。药物组合物可能包括药学上可接受的辅料，以模拟生理条件，比如pH调节和缓冲剂、毒性调节剂等等，如乙酸钠、氯化钠、氯化钾、氯化钙、乳酸钠等。A "pharmaceutical composition" refers to a mixture of one or more of the compounds of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, with other chemical components, such as a pharmaceutically acceptable carrier, excipient, or diluent. The purpose of a pharmaceutical composition is to facilitate administration to an animal. Pharmaceutical compositions may include pharmaceutically acceptable excipients to simulate physiological conditions, such as pH adjusting and buffering agents, toxicity modifiers, and the like, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, and sodium lactate.

“药学上可接受的载体”是指一种药学上可接受的物质，成分或者介质，比如液体或固体填充剂、稀释剂、赋形剂、溶剂或灌封材料，其参与将本发明涉及的化合物从某一位置，体液、组织、器官(内部或外部)、或身体部分装载或传递到另一位置，体液、器官(内部或外部)、或身体部分。药学上可接受的载体可以是介质、稀释剂、赋形剂或者其它没有过度毒性或者副作用并能用于接触动物组织的材料。"Pharmaceutically acceptable carrier" means a pharmaceutically acceptable substance, ingredient, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that participates in carrying or delivering a compound of the invention from one location, body fluid, tissue, organ (internal or external), or body part to another location, body fluid, organ (internal or external), or body part. A pharmaceutically acceptable carrier can be a medium, diluent, excipient, or other material that is not unduly toxic or has adverse effects and is suitable for use in contact with animal tissue.

一些药学上可接受的载体的物质包括：(1)糖类，比如乳糖、葡萄糖和蔗糖；(2)淀粉，比如玉米淀粉和马铃薯淀粉；(3)纤维素和其衍生物，比如羧甲基纤维素钠、乙基纤维素、醋酸纤维素；(4)西黄蓍胶粉；(5)麦芽糖；(6)明胶；(7)滑石粉；(8)赋形剂，比如可可脂和栓剂蜡；(9)油类，比如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油；(10)二醇类，比如丙二醇；(11)多元醇类，比如甘油、山梨醇、甘露醇和聚乙二醇；(12)脂类，比如油酸乙酯、月桂酸乙酯；(13)琼脂胶；(14)缓冲剂，比如氢氧化镁和氢氧化铝；(15)海藻酸；(16)灭菌无热原水；(17)生理盐水；(18)林格氏溶液；(19)醇类，比如乙醇和丙醇；(20)磷酸缓冲液；(21)其它在药物剂型中无毒性可相容的物质，比如丙酮。Some pharmaceutically acceptable carrier substances include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) tragacanth; (5) maltose; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) Glycols, such as propylene glycol; (11) Polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) Lipids, such as ethyl oleate and ethyl laurate; (13) Agarose; (14) Buffers, such as magnesium hydroxide and aluminum hydroxide; (15) Alginic acid; (16) Sterile pyrogen-free water; (17) Physiological saline; (18) Ringer's solution; (19) Alcohols, such as ethanol and propanol; (20) Phytophosphate buffer; (21) Other non-toxic substances compatible in pharmaceutical dosage forms, such as acetone.

每种药学上可接受的载体应该与其它组成成分相容，例如与本发明中提供的化合物形成制剂，对生物活体组织或者器官没有过度毒性、刺激、过敏性反应、免疫原性或其它问题或并发症，且有较合理的效益风险比。Each pharmaceutically acceptable carrier should be compatible with the other components, for example, forming a formulation with the compound provided in the present invention, without excessive toxicity, irritation, allergic reaction, immunogenicity or other problems or complications to living tissues or organs, and with a reasonable benefit-risk ratio.

药物成分可制成任何合适的剂型，如固体剂型(例如片剂、胶囊、粉末、颗粒等)和液体剂型(例如水溶液、乳浊液、酏剂、糖浆等)。药物组合物的制备方法工艺已众所周知，可根据常规工艺进行制备，比如在Remington，The Science and Practice of Pharmacy(Gennaro ed.20th edition,Williams&Wilkins PA,USA)(2003)中提供。The pharmaceutical composition can be prepared into any suitable dosage form, such as solid dosage forms (e.g., tablets, capsules, powders, granules, etc.) and liquid dosage forms (e.g., aqueous solutions, emulsions, elixirs, syrups, etc.). The preparation methods and processes of pharmaceutical compositions are well known and can be prepared according to conventional techniques, such as those provided in Remington, The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2003).

附图说明BRIEF DESCRIPTION OF THE DRAWINGS

图1为制备式II化合物的反应路线；Figure 1 is a reaction scheme for preparing the compound of formula II;

图2为制备式III化合物的反应路线。Figure 2 is a reaction scheme for preparing the compound of formula III.

具体实施方式DETAILED DESCRIPTION

第一组制备例：中间体制备The first group of preparation examples: intermediate preparation

(2-(羟甲基)哌啶-4-基)氨基甲酸叔丁酯的制备
Preparation of tert-butyl (2-(hydroxymethyl)piperidin-4-yl)carbamate

第一步：将4-氨基吡啶甲酸甲酯(10.0g,65.72mmol)溶于二氯甲烷(100mL)中，依次加入二甲氨基吡啶(0.8g,6.57mmol)和三乙胺(10.0g,98.59mmol)，降温至0℃，缓慢滴加二碳酸二叔丁酯(15.8g,72.30mmol)，室温搅拌4h。反应完全后，往反应液中加水(50mL)，用乙酸乙酯(60mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶柱层析以乙酸乙酯/石油醚(0-100％)为洗脱剂梯度洗脱分离纯化得到4-((叔丁氧羰基)氨基)吡啶甲酸甲酯(白色固体,12g,70.9％)。MS(ESI+)m/z＝253.2[M+H]+。Step 1: Dissolve methyl 4-aminopicolinate (10.0 g, 65.72 mmol) in dichloromethane (100 mL). Add dimethylaminopyridine (0.8 g, 6.57 mmol) and triethylamine (10.0 g, 98.59 mmol) sequentially. Cool to 0°C, then slowly add di-tert-butyl dicarbonate (15.8 g, 72.30 mmol) dropwise. Stir at room temperature for 4 h. After the reaction is complete, add water (50 mL) to the reaction solution, extract with ethyl acetate (60 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain the crude product. The crude product is isolated and purified by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-100%) to obtain methyl 4-(tert-butoxycarbonyl)amino)picolinate (white solid, 12 g, 70.9%). MS(ESI + )m/z=253.2[M+H] + .

第二步：氮气保护下，将4-((叔丁氧羰基)氨基)吡啶甲酸甲酯(11.7g,46.38mmol)溶于醋酸(100mL)中，加入二氧化铂(5.3g,23.19mmol)，置换氢气，升温至60℃搅拌过夜。反应完全后冷却至室温，过滤，滤液加碳酸氢钠溶液调pH至碱性，混合液用二氯甲烷/甲醇(10/1,50mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶柱层析以甲醇/二氯甲烷(0-30％)为洗脱剂梯度洗脱分离纯化得到4-((叔丁氧羰基)氨基)哌啶-2-甲酸甲酯(淡黄色油状物,8.3g,69.3％)。MS(ESI+)m/z＝259.2[M+H]+。Step 2: Under nitrogen, methyl 4-((tert-butoxycarbonyl)amino)picolinate (11.7 g, 46.38 mmol) was dissolved in acetic acid (100 mL). Platinum dioxide (5.3 g, 23.19 mmol) was added to displace the hydrogen atmosphere. The mixture was heated to 60°C and stirred overnight. After completion of the reaction, the mixture was cooled to room temperature and filtered. The filtrate was adjusted to a basic pH by adding sodium bicarbonate solution. The mixture was extracted with dichloromethane/methanol (10/1, 50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography using a gradient elution of methanol/dichloromethane (0-30%) to obtain methyl 4-((tert-butoxycarbonyl)amino)piperidine-2-carboxylate (pale yellow oil, 8.3 g, 69.3%). MS (ESI + ) m/z = 259.2 [M+H] + .

第三步：氮气保护下，将4-((叔丁氧羰基)氨基)哌啶-2-甲酸甲酯(8.3g,32.13mmol)溶于四氢呋喃(60mL)中，降温至0℃，缓慢加入硼氢化锂(2.1g,96.39mmol)，室温搅拌过夜。反应完全后冷却至室温，反应液中加甲醇(30mL)，减压浓缩得到粗产品，粗产品经硅胶柱层析以甲醇/二氯甲烷(0-50％)为洗脱剂梯度洗脱分离纯化得到(2-(羟甲基)哌啶-4-基)氨基甲酸叔丁酯(淡黄色油状物,5.1g,68.9％)。MS(ESI+)m/z＝231.0[M+H]+。Step 3: Under nitrogen, dissolve methyl 4-((tert-butoxycarbonyl)amino)piperidine-2-carboxylate (8.3 g, 32.13 mmol) in tetrahydrofuran (60 mL), cool to 0°C, slowly add lithium borohydride (2.1 g, 96.39 mmol), and stir at room temperature overnight. After the reaction is complete, cool to room temperature, add methanol (30 mL), and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography using a gradient elution of methanol/dichloromethane (0-50%) to afford tert-butyl (2-(hydroxymethyl)piperidin-4-yl)carbamate (pale yellow oil, 5.1 g, 68.9%). MS (ESI + ) m/z = 231.0 [M+H] + .

5-氯-2,3-二氟异烟腈的制备
Preparation of 5-chloro-2,3-difluoroisonicotinonitrile

第一步：氮气保护下，将5-氯-2,3-二氟吡啶(15.0g,0.10mol)溶于四氢呋喃(150mL)中，降温至-78℃，加入二异丙基氨基锂(2M,60.2mL,0.12mol)，然后在-78℃下搅拌1h，加入固体干冰(15.0g,0.34mol)，缓慢恢复至室温搅拌2h。反应完全后减压浓缩，剩余物用二氯甲烷(100mL)和氢氧化钠溶液(100mL)稀释。混合液用二氯甲烷(100mL×3)萃取，水相用盐酸溶液调pH至1，用乙酸乙酯萃取(100mL×3)，合并有机相用饱和食盐水(100mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到5-氯-2,3-二氟异烟酸(淡黄色固体,14g,粗品)。Step 1: Under nitrogen, 5-chloro-2,3-difluoropyridine (15.0 g, 0.10 mol) was dissolved in tetrahydrofuran (150 mL), cooled to -78°C, and lithium diisopropylamide (2 M, 60.2 mL, 0.12 mol) was added. The mixture was stirred at -78°C for 1 hour. Solid dry ice (15.0 g, 0.34 mol) was added, and the mixture was slowly warmed to room temperature and stirred for 2 hours. After the reaction was complete, it was concentrated under reduced pressure. The residue was diluted with dichloromethane (100 mL) and sodium hydroxide solution (100 mL). The mixture was extracted with dichloromethane (100 mL × 3). The aqueous phase was adjusted to pH 1 with hydrochloric acid solution and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield 5-chloro-2,3-difluoroisonicotinic acid (pale yellow solid, 14 g, crude product).

第二步：将5-氯-2,3-二氟异烟酸(14.0g,72.34mmol)溶于N,N-二甲基甲酰胺(140mL)中，降温至0℃，依次加入HATU(41.2g,108.5mmol)，氯化铵(3.9g,72.34mmol)和N,N-二异丙基乙胺(28.0g,217.02mmol)，室温搅拌1h。反应完全后，往反应液中加水(100mL)，用乙酸乙酯(200mL×3)萃取，合并有机相用饱和食盐水溶液(100mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶柱层析以乙酸乙酯/石油醚(44％)为洗脱剂分离纯化得到5-氯-2,3-二氟异烟酰胺(白色固体,7.8g,56.1％)。Step 2: Dissolve 5-chloro-2,3-difluoroisonicotinic acid (14.0 g, 72.34 mmol) in N,N-dimethylformamide (140 mL), cool to 0°C, and sequentially add HATU (41.2 g, 108.5 mmol), ammonium chloride (3.9 g, 72.34 mmol), and N,N-diisopropylethylamine (28.0 g, 217.02 mmol). Stir at room temperature for 1 h. After the reaction is complete, add water (100 mL) to the reaction solution, extract with ethyl acetate (200 mL x 3), and combine the organic phases, wash with saturated brine (100 mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product is isolated and purified by silica gel column chromatography using ethyl acetate/petroleum ether (44%) as the eluent to obtain 5-chloro-2,3-difluoroisonicotinamide (white solid, 7.8 g, 56.1%).

第三步：将5-氯-2,3-二氟异烟酰胺(7.8g,40.51mmol)溶于二氯甲烷(120mL)中，降温至0℃，加入三乙胺(12.3g,121.52mmol)，然后滴加三氟乙酸酐(12.8g,60.76mmol)，室温搅拌2h。反应完全后，往反应液中加水(100mL)，用二氯甲烷(100mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶柱层析以乙酸乙酯/石油醚(14％)为洗脱剂分离纯化得到5-氯-2,3-二氟异烟腈(淡黄色油状物,5.3g,75.1％)。Step 3: Dissolve 5-chloro-2,3-difluoroisonicotinamide (7.8 g, 40.51 mmol) in dichloromethane (120 mL), cool to 0°C, add triethylamine (12.3 g, 121.52 mmol), and then add trifluoroacetic anhydride (12.8 g, 60.76 mmol) dropwise. Stir at room temperature for 2 h. After the reaction is complete, add water (100 mL) to the reaction solution, extract with dichloromethane (100 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product is isolated and purified by silica gel column chromatography using ethyl acetate/petroleum ether (14%) as the eluent to obtain 5-chloro-2,3-difluoroisonicotinonitrile (5.3 g, 75.1%) as a pale yellow oil.

2-氯-[1,2,4]三唑并[1,5-a]吡啶-7-醇的制备
Preparation of 2-chloro-[1,2,4]triazolo[1,5-a]pyridin-7-ol

第一步：氮气保护下，将7-溴-[1,2,4]三唑并[1,5-a]吡啶-2-胺(2.0g,9.39mmol)溶于乙腈(50mL)中，加入氯化铜(1.9g,14.08mmol)，降温至0℃，加入亚硝酸叔丁酯(1.5g,14.08mmol)，升温至90℃搅拌1h。反应完全后冷却至室温，往反应液中加水(50mL)，过滤，滤液用乙酸乙酯(30mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶柱层析以甲醇/二氯甲烷(0-10％)为洗脱剂梯度洗脱分离纯化得到7-溴-2-氯-[1,2,4]三唑并[1,5-a]吡啶(黄色油状物,1.4g,64.1％)。MS(ESI+)m/z＝233.9[M+H]+。Step 1: Under nitrogen, 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (2.0 g, 9.39 mmol) was dissolved in acetonitrile (50 mL). Copper chloride (1.9 g, 14.08 mmol) was added, and the temperature was cooled to 0°C. Tert-butyl nitrite (1.5 g, 14.08 mmol) was added, and the temperature was raised to 90°C with stirring for 1 h. After the reaction was complete, the mixture was cooled to room temperature, and water (50 mL) was added. The mixture was filtered, and the filtrate was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography using a gradient elution of methanol/dichloromethane (0-10%) to obtain 7-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (yellow oil, 1.4 g, 64.1%). MS(ESI + )m/z=233.9[M+H] + .

第二步：氮气保护下，将7-溴-2-氯-[1,2,4]三唑并[1,5-a]吡啶(1.4g,6.02mmol)溶于1,4-二氧六环(20mL)，依次加入联硼酸频那醇酯(2.3g,9.03mmol)，乙酸钾(2.1g,21.08mmol)和Pd(dppf)Cl2(0.4g,0.60mmol)，升温至100℃搅拌1h。反应完全后冷却至室温，往反应液中加水(50mL)，混合液用乙酸乙酯(50mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶柱层析以甲醇/二氯甲烷(0-10％)为洗脱剂梯度洗脱分离纯化得到2-氯-7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-[1,2,4]三唑并[1,5-a]吡啶(黄色油状物,800mg,47.5％)。MS(ESI+)m/z＝280.0[M+H]+。Step 2: Under nitrogen protection, 7-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (1.4 g, 6.02 mmol) was dissolved in 1,4-dioxane (20 mL), and pinacol diboron (2.3 g, 9.03 mmol), potassium acetate (2.1 g, 21.08 mmol) and Pd(dppf)Cl 2 (0.4 g, 0.60 mmol) were added in sequence. The temperature was raised to 100°C and stirred for 1 h. After the reaction was complete, the mixture was cooled to room temperature, and water (50 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography using a gradient elution of methanol/dichloromethane (0-10%) as the eluent to obtain 2-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (yellow oil, 800 mg, 47.5%). MS (ESI + ) m/z = 280.0 [M+H] + .

第三步：将2-氯-7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-[1,2,4]三唑并[1,5-a]吡啶(1.5g,5.37mmol)溶于四氢呋喃(20mL)中，降温至0℃，依次加入氢氧化钠(1M,16.1mL,16.10mmol)和过氧化氢(30％,1.6mL,16.10mmol)，恢复至室温并搅拌1h。反应完全后，反应液用乙酸乙酯(20mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶柱层析以甲醇/二氯甲烷(0-10％)为洗脱剂梯度洗脱分离纯化得到2-氯-[1,2,4]三唑并[1,5-a]吡啶-7-醇(黄色油状物,800mg,87.9％)。MS(ESI+)m/z＝170.1[M+H]+。Step 3: Dissolve 2-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (1.5 g, 5.37 mmol) in tetrahydrofuran (20 mL), cool to 0°C, add sodium hydroxide (1 M, 16.1 mL, 16.10 mmol) and hydrogen peroxide (30%, 1.6 mL, 16.10 mmol) in sequence, return to room temperature and stir for 1 h. After the reaction was complete, the reaction solution was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography using a gradient elution of methanol/dichloromethane (0-10%) as the eluent to obtain 2-chloro-[1,2,4]triazolo[1,5-a]pyridin-7-ol (yellow oil, 800 mg, 87.9%). MS (ESI + ) m/z = 170.1 [M+H] + .

喹唑啉-7-醇的制备
Preparation of quinazolin-7-ol

氮气保护下，将7-溴喹唑啉(1.0g,4.78mmol)溶于二甲基亚砜和水的混合液(4/1,10mL)，加入乙酰丙酮酸铜(25.0mg,0.096mmol)，N,N'-双(4-羟基-2,6-二甲基苯基)草酰胺(31.4mg,0.096mmol)和一水合氢氧化锂(421.5mg,10.05mmol)，升温至80℃搅拌2h。反应完全后冷却至室温，往反应液中加水(50mL)，用乙酸乙酯(50mL×3)萃取，合并有机相用饱和食盐水(50mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶柱层析以甲醇/二氯甲烷(0-10％)为洗脱剂梯度洗脱分离纯化得到喹唑啉-7-醇(淡黄色油状物,470mg,67.2％)。MS(ESI+)m/z＝147.1[M+H]+。Under nitrogen protection, 7-bromoquinazoline (1.0 g, 4.78 mmol) was dissolved in a mixture of dimethyl sulfoxide and water (4/1, 10 mL). Copper acetylacetonate (25.0 mg, 0.096 mmol), N,N'-bis(4-hydroxy-2,6-dimethylphenyl)oxamide (31.4 mg, 0.096 mmol) and lithium hydroxide monohydrate (421.5 mg, 10.05 mmol) were added. The temperature was raised to 80 ° C and stirred for 2 h. After the reaction was complete, the mixture was cooled to room temperature, and water (50 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography using a gradient elution of methanol/dichloromethane (0-10%) to obtain quinazolin-7-ol (pale yellow oil, 470 mg, 67.2%). MS (ESI + ) m/z = 147.1 [M+H] + .

1-甲基-1H-苯并[d][1,2,3]三唑-5-醇的制备
Preparation of 1-methyl-1H-benzo[d][1,2,3]triazol-5-ol

氮气保护下，将5-溴-1-甲基-1H-苯并[d][1,2,3]三唑(2.0g,9.48mmol)溶于二甲基亚砜和水的混合液(4/1,20mL)，加入乙酰丙酮酸铜(49.6mg,0.19mmol)，N,N'-双(4-羟基-2,6-二甲基苯基)草酰胺(62.3mg,0.19mmol)和一水合氢氧化锂(836.1mg,19.91mmol)，升温至80℃搅拌2h。反应完全后冷却至室温，往反应液中加水(10mL)，混合液用正丁醇(30mL×3)萃取，合并有机相用水(20mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶柱层析以甲醇/二氯甲烷(0-20％)为洗脱剂梯度洗脱分离纯化得到1-甲基-1H-苯并[d][1,2,3]三唑-5-醇(淡黄色固体,1.1g,78.6％)。MS(ESI+)m/z＝150.3[M+H]+。Under nitrogen protection, 5-bromo-1-methyl-1H-benzo[d][1,2,3]triazole (2.0 g, 9.48 mmol) was dissolved in a mixture of dimethyl sulfoxide and water (4/1, 20 mL). Copper acetylacetonate (49.6 mg, 0.19 mmol), N,N'-bis(4-hydroxy-2,6-dimethylphenyl)oxamide (62.3 mg, 0.19 mmol) and lithium hydroxide monohydrate (836.1 mg, 19.91 mmol) were added, and the mixture was heated to 80 °C and stirred for 2 h. After the reaction was complete, the mixture was cooled to room temperature, and water (10 mL) was added to the reaction mixture. The mixture was extracted with n-butanol (30 mL × 3). The combined organic phases were washed with water (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography using a gradient elution of methanol/dichloromethane (0-20%) as the eluent to obtain 1-methyl-1H-benzo[d][1,2,3]triazol-5-ol (pale yellow solid, 1.1 g, 78.6%). MS (ESI + ) m/z = 150.3 [M+H] + .

苯并[d]噻唑-5-醇的制备
Preparation of benzo[d]thiazol-5-ol

室温下将5-溴苯并[d]噻唑(5.0g,23.36mmol)溶于二氧六环和水的混合液(60mL,5/1v/v)，依次加入Pd2(dba)3(2.1g,2.34mmol)，t-BuXPhos(2.0g,4.67mmol)和氢氧化钾(5.2g,93.42mmol)，升温至100℃搅拌1h，反应完全后冷却至室温，往反应液中加水(30mL)，用乙酸乙酯(30mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶柱层析以甲醇/二氯甲烷(0-10％)为洗脱剂梯度洗脱分离纯化得到苯并[d]噻唑-5-醇(棕色油状物,1.0g,28.3％)。MS(ESI+)m/z＝152.0[M+H]+。5-Bromobenzo[d]thiazole (5.0 g, 23.36 mmol) was dissolved in a mixture of dioxane and water (60 mL, 5/1 v/v) at room temperature. Pd2 (dba) 3 (2.1 g, 2.34 mmol), t-BuXPhos (2.0 g, 4.67 mmol) and potassium hydroxide (5.2 g, 93.42 mmol) were added in sequence. The temperature was raised to 100°C and stirred for 1 h. After the reaction was complete, the mixture was cooled to room temperature. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was separated and purified by silica gel column chromatography using a gradient elution of methanol/dichloromethane (0-10%) to give benzo[d]thiazol-5-ol (brown oil, 1.0 g, 28.3%). MS(ESI + )m/z=152.0[M+H] + .

苯并[c][1,2,5]噁二唑-5-醇的制备
Preparation of benzo[c][1,2,5]oxadiazole-5-ol

氮气保护下，在40mL反应瓶中，将5-溴苯并[c][1,2,5]噁二唑(2g,10.06mmol)溶于二甲基亚砜/水(10mL,4/1,v/v)的混合溶液，依次加入一水合氢氧化锂(885.6mg,21.10mmol)，N,N'-双(4-羟基-2,6-二甲基苯基)草酰胺(66.0mg,0.20mmol)和乙酰丙酮酸铜(52.6mg,0.20mmol)，升温至80℃下搅拌2h。反应完全后冷却至室温，往反应液中加水(10mL)，混合液用正丁醇(30mL×3)萃取，合并有机相用水(30mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶柱层析以甲醇/二氯甲烷(0-20％)为洗脱剂梯度洗脱分离纯化得到苯并[c][1,2,5]噁二唑-5-醇(棕色油状,500mg,36.5％)。Under nitrogen protection, in a 40 mL reaction bottle, 5-bromobenzo[c][1,2,5]oxadiazole (2 g, 10.06 mmol) was dissolved in a mixed solution of dimethyl sulfoxide/water (10 mL, 4/1, v/v). Lithium hydroxide monohydrate (885.6 mg, 21.10 mmol), N,N'-bis(4-hydroxy-2,6-dimethylphenyl)oxamide (66.0 mg, 0.20 mmol) and copper acetylacetonate (52.6 mg, 0.20 mmol) were added in sequence. The temperature was raised to 80 ° C and stirred for 2 h. After the reaction was complete, the mixture was cooled to room temperature, water (10 mL) was added to the reaction solution, and the mixture was extracted with n-butanol (30 mL × 3). The combined organic phases were washed with water (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography with methanol/dichloromethane (0-20%) as eluent gradient elution to obtain benzo[c][1,2,5]oxadiazole-5-ol (brown oil, 500 mg, 36.5%).

5-氟喹喔啉-6-醇的制备
Preparation of 5-fluoroquinoxalin-6-ol

第一步：氮气保护下，将4-溴-3-氟-1,2-苯二胺(2g,9.76mmol)溶于无水乙醇(20mL)，依次加入碳酸钠(2.70g,19.51mmol)和乙二醛(0.68g,11.70mmol)，室温下搅拌2h。反应完全后，减压浓缩得到粗产品，粗产品经硅胶柱层析以乙酸乙酯/石油醚(0-100％)为洗脱剂梯度洗脱分离纯化得到6-溴-5-氟喹喔啉(黄色固体,2.2g,99.3％)。Step 1: Under nitrogen, dissolve 4-bromo-3-fluoro-1,2-phenylenediamine (2g, 9.76mmol) in anhydrous ethanol (20mL). Add sodium carbonate (2.70g, 19.51mmol) and glyoxal (0.68g, 11.70mmol) sequentially, and stir at room temperature for 2h. After completion of the reaction, concentrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-100%) to afford 6-bromo-5-fluoroquinoxaline (yellow solid, 2.2g, 99.3%).

第二步：氮气保护下，将6-溴-5-氟喹喔啉(1.8g,7.93mmol)溶于1,4-二氧六环和水的混合液(15mL,2/1,v/v)，加入Pd2(dba)3(0.36g,0.40mmol)，t-Buxphos(0.17g,0.40mmol)和氢氧化钾(4.5g,79.28mmol)，升温至100℃下搅拌5h。反应完全后冷却至室温，减压浓缩得到粗产品，粗产品经硅胶柱层析以甲醇/二氯甲烷(0-15％)为洗脱剂梯度洗脱分离纯化得到5-氟喹喔啉-6-醇(棕色固体,1.2g,92.2％)。MS(ESI+)m/z＝165.0[M+H]+。Step 2: Under nitrogen, 6-bromo-5-fluoroquinoxaline (1.8 g, 7.93 mmol) was dissolved in a mixture of 1,4-dioxane and water (15 mL, 2/1, v/v). Pd 2 (dba) 3 (0.36 g, 0.40 mmol), t-Buxphos (0.17 g, 0.40 mmol), and potassium hydroxide (4.5 g, 79.28 mmol) were added. The mixture was heated to 100°C and stirred for 5 h. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography using a gradient elution of methanol/dichloromethane (0-15%) to afford 5-fluoroquinoxalin-6-ol (brown solid, 1.2 g, 92.2%). MS (ESI + ) m/z = 165.0 [M+H] + .

8-氟喹喔啉-6-醇的制备
Preparation of 8-fluoroquinoxalin-6-ol

以5-溴-3-氟-1,2-苯二胺和乙二醛为原料，按照合成5-氟喹喔啉-6-醇的方法制备8-氟喹喔啉-6-醇。MS(ESI+)m/z＝165.1[M+H]+。8-Fluoroquinoxalin-6-ol was prepared using 5-bromo-3-fluoro-1,2-phenylenediamine and glyoxal as raw materials according to the method for synthesizing 5-fluoroquinoxalin-6-ol. MS (ESI + ) m/z = 165.1 [M+H] + .

7-氟喹喔啉-6-醇的制备
Preparation of 7-fluoroquinoxalin-6-ol

以5-溴-4-氟-1,2-苯二胺和乙二醛为原料，按照合成5-氟喹喔啉-6-醇的方法制备7-氟喹喔啉-6-醇。MS(ESI+)m/z＝165.1[M+H]+。7-Fluoroquinoxalin-6-ol was prepared using 5-bromo-4-fluoro-1,2-phenylenediamine and glyoxal as raw materials according to the method for synthesizing 5-fluoroquinoxalin-6-ol. MS (ESI + ) m/z = 165.1 [M+H] + .

四唑并[1,5-a]吡啶-7-醇的制备
Preparation of Tetrazo[1,5-a]pyridin-7-ol

第一步：氮气保护下，将4-苄氧基吡啶N-氧化物(3.0g,14.91mmol)溶于吡啶(2.5mL)，加入二苯氧基磷酰基叠氮(8.2g,29.83mmol)，升温至100℃搅拌12h。反应完全后冷却至室温，往反应液中加水(150mL)，混合液用乙酸乙酯(100mL×3)萃取，合并有机相用饱和食盐水(100mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-100％)为洗脱剂梯度洗脱分离得到7-(苄氧基)四唑并[1,5-a]吡啶(黄色油状物,1.1g,32.6％)。MS(ESI+)m/z＝227.2[M+H]+。Step 1: Under nitrogen, 4-benzyloxypyridine N-oxide (3.0 g, 14.91 mmol) was dissolved in pyridine (2.5 mL). Diphenoxyphosphoryl azide (8.2 g, 29.83 mmol) was added, and the mixture was heated to 100°C and stirred for 12 h. After the reaction was complete, the mixture was cooled to room temperature and water (150 mL) was added. The mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-100%) to afford 7-(benzyloxy)tetrazo[1,5-a]pyridine (yellow oil, 1.1 g, 32.6%). MS (ESI + ) m/z = 227.2 [M+H] + .

第二步：将7-(苄氧基)四唑并[1,5-a]吡啶(1.1g,4.86mmol)溶于二氯甲烷(5mL)，降温至0℃，缓慢加入三溴化硼(2.4g,9.72mmol)，室温搅拌1h。反应完全后减压浓缩得到四唑并[1,5-a]吡啶-7-醇(淡黄色油状物,1g,粗品)。MS(ESI+)m/z＝137.2[M+H]+。Step 2: Dissolve 7-(Benzyloxy)tetrazo[1,5-a]pyridine (1.1 g, 4.86 mmol) in dichloromethane (5 mL), cool to 0°C, slowly add boron tribromide (2.4 g, 9.72 mmol), and stir at room temperature for 1 hour. After the reaction is complete, concentrate under reduced pressure to yield tetrazo[1,5-a]pyridin-7-ol (pale yellow oil, 1 g, crude product). MS (ESI + ) m/z = 137.2 [M+H] + .

1-乙基-4-羟基吡啶-2(1H)-酮的制备
Preparation of 1-ethyl-4-hydroxypyridin-2(1H)-one

第一步：氮气保护下，将4-(苄氧基)吡啶-2(1H)-酮(1g,4.97mmol)溶于N,N-二甲基甲酰胺(15mL)，依次加入碳酸钾(1.4g,9.95mmol)和溴乙烷(1.2g,10.94mmol)，升温至80℃搅拌2h，反应完全后冷却至室温，往反应液中加水(30mL)，混合液用乙酸乙酯(50mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(10％-90％)为洗脱剂梯度洗脱分离纯化得到4-(苄氧基)-1-乙基吡啶-2(1H)-酮(白色固体,710mg,62.4％)。MS(ESI+)m/z＝230.0[M+H]+。Step 1: Under nitrogen, 4-(benzyloxy)pyridin-2(1H)-one (1 g, 4.97 mmol) was dissolved in N,N-dimethylformamide (15 mL). Potassium carbonate (1.4 g, 9.95 mmol) and ethyl bromide (1.2 g, 10.94 mmol) were added sequentially. The mixture was heated to 80°C and stirred for 2 h. After the reaction was complete, it was cooled to room temperature. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was isolated and purified by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (10%-90%) to obtain 4-(benzyloxy)-1-ethylpyridin-2(1H)-one (white solid, 710 mg, 62.4%). MS (ESI + ) m/z = 230.0 [M+H] + .

第二步：氮气保护下，将4-(苄氧基)-1-乙基吡啶-2(1H)-酮(710mg,3.10mmol)溶于无水乙醇(20mL)，加入钯/碳(20％,700mg)，置换氢气，室温搅拌2h，反应完全后，过滤，滤液减压浓缩得到1-乙基-4-羟基吡啶-2(1H)-酮(黄色油状物,400mg,粗品)。MS(ESI+)m/z＝140.0[M+H]+。Step 2: Under nitrogen, 4-(benzyloxy)-1-ethylpyridin-2(1H)-one (710 mg, 3.10 mmol) was dissolved in anhydrous ethanol (20 mL). Palladium/carbon (20%, 700 mg) was added to displace the hydrogen. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the mixture was filtered and the filtrate was concentrated under reduced pressure to yield 1-ethyl-4-hydroxypyridin-2(1H)-one (yellow oil, 400 mg, crude product). MS (ESI + ) m/z = 140.0 [M+H] + .

4-羟基-1-异丙基吡啶-2(1H)-酮的制备
Preparation of 4-hydroxy-1-isopropylpyridin-2(1H)-one

第一步：氮气保护下，将4-(苄氧基)吡啶-2(1H)-酮(1g,4.97mmol)溶于N,N-二甲基甲酰胺(15mL)，依次加入碳酸铯(3.2g,9.95mmol)和2-碘丙烷(1.86g,10.94mmol)，升温至80℃搅拌2h，反应完全后冷却至室温，往反应液中加水(30mL)，混合液用乙酸乙酯(50mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(10％-90％)为洗脱剂梯度洗脱分离纯化得到4-(苄氧基)-1-异丙基吡啶-2(1H)-酮(白色固体,660mg,55.0％)。MS(ESI+)m/z＝244.2[M+H]+。Step 1: Under nitrogen, 4-(benzyloxy)pyridin-2(1H)-one (1 g, 4.97 mmol) was dissolved in N,N-dimethylformamide (15 mL). Cesium carbonate (3.2 g, 9.95 mmol) and 2-iodopropane (1.86 g, 10.94 mmol) were added sequentially. The mixture was heated to 80°C and stirred for 2 h. After the reaction was complete, it was cooled to room temperature. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was isolated and purified by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (10%-90%) to obtain 4-(benzyloxy)-1-isopropylpyridin-2(1H)-one (white solid, 660 mg, 55.0%). MS (ESI + ) m/z = 244.2 [M+H] + .

第二步：氮气保护下，将4-(苄氧基)-1-异丙基吡啶-2(1H)-酮(660mg,2.71mmol)溶于无水乙醇(20mL)，加入钯/碳(20％,700mg)，置换氢气，室温搅拌2h，反应完全后，减压浓缩得到4-羟基-1-异丙基吡啶-2(1H)-酮(黄色油状物,360mg,粗品)。MS(ESI+)m/z＝154.0[M+H]+。Step 2: Under nitrogen, 4-(benzyloxy)-1-isopropylpyridin-2(1H)-one (660 mg, 2.71 mmol) was dissolved in anhydrous ethanol (20 mL). Palladium/carbon (20%, 700 mg) was added to displace the hydrogen. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the mixture was concentrated under reduced pressure to yield 4-hydroxy-1-isopropylpyridin-2(1H)-one (yellow oil, 360 mg, crude product). MS (ESI + ) m/z = 154.0 [M+H] + .

1-环丙基-4-羟基吡啶-2(1H)-酮的制备
Preparation of 1-cyclopropyl-4-hydroxypyridin-2(1H)-one

第一步：氮气保护下，将4-(苄氧基)吡啶-2(1H)-酮(2.0g,9.94mmol)溶于1,2-二氯乙烷(70mL)，依次加入碳酸钠(2.4g,22.86mmol)，醋酸铜(1.9g,10.64mmol)，2,2'-联吡啶(1.7g,10.88mmol)和环丙基硼酸(1.9g,22.9mmol)，升温至70℃搅拌过夜。反应完全后冷却至室温，减压浓缩，所得残余物溶于乙酸乙酯(300mL)，依次用水(100mL×3)和饱和食盐水(50mL×2)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(50％)为洗脱剂分离纯化得到4-(苄氧基)-1-环丙基吡啶-2(1H)-酮(橙黄色油状物,1.8g,75.0％)。MS(ESI+)m/z＝242.0[M+H]+。Step 1: Under nitrogen protection, dissolve 4-(benzyloxy)pyridin-2(1H)-one (2.0 g, 9.94 mmol) in 1,2-dichloroethane (70 mL), and add sodium carbonate (2.4 g, 22.86 mmol), copper acetate (1.9 g, 10.64 mmol), 2,2'-bipyridine (1.7 g, 10.88 mmol) and cyclopropylboronic acid (1.9 g, 22.9 mmol) in sequence. Heat to 70°C and stir overnight. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (300 mL) and washed sequentially with water (100 mL × 3) and saturated brine (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography using ethyl acetate/petroleum ether (50%) as eluent to provide 4-(benzyloxy)-1-cyclopropylpyridin-2(1H)-one (orange-yellow oil, 1.8 g, 75.0%). MS (ESI + ) m/z = 242.0 [M+H] + .

第二步：氮气保护下，将4-(苄氧基)-1-环丙基吡啶-2(1H)-酮(800.0mg,3.31mmol)溶于甲醇，加入钯/碳(25％,200.0mg)。置换氢气，室温搅拌过夜。过滤，滤液减压浓缩得到1-环丙基-4-羟基吡啶-2(1H)-酮(类白色固体,426mg,85.1％)。MS(ESI+)m/z＝152.0[M+H]+。Step 2: Under nitrogen, dissolve 4-(benzyloxy)-1-cyclopropylpyridin-2(1H)-one (800.0 mg, 3.31 mmol) in methanol and add palladium/carbon (25%, 200.0 mg). Replace the hydrogen atmosphere and stir at room temperature overnight. Filter, and concentrate the filtrate under reduced pressure to yield 1-cyclopropyl-4-hydroxypyridin-2(1H)-one (off-white solid, 426 mg, 85.1%). MS (ESI + ) m/z = 152.0 [M+H] + .

3-乙炔基-1,3-二甲基吡咯烷的制备
Preparation of 3-ethynyl-1,3-dimethylpyrrolidine

第一步：在100mL茄型瓶中将3-(羟甲基)-3-甲基吡咯烷-1-甲酸叔丁酯(1g,4.65mmol)溶于二氯甲烷(10mL)，降温至0℃，加入戴斯-马丁氧化剂(2.4g,5.57mmol)，室温下搅拌2h。反应完全后，往反应液中加入水(5mL)，混合液用二氯甲烷(30mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-50％)为洗脱剂梯度洗脱分离纯化得到3-甲酰基-3-甲基吡咯烷-1-甲酸叔丁酯(无色透明液体,670mg,67.6％)。Step 1: Dissolve tert-butyl 3-(hydroxymethyl)-3-methylpyrrolidine-1-carboxylate (1 g, 4.65 mmol) in dichloromethane (10 mL) in a 100 mL eggplant-shaped flask. Cool to 0°C, add Dess-Martin periodinane (2.4 g, 5.57 mmol), and stir at room temperature for 2 h. After the reaction is complete, add water (5 mL), extract the mixture with dichloromethane (30 mL x 3), and combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue is purified by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-50%) to afford tert-butyl 3-formyl-3-methylpyrrolidine-1-carboxylate (colorless, transparent liquid, 670 mg, 67.6%).

第二步：在100mL茄型瓶中将3-甲酰基-3-甲基吡咯烷-1-甲酸叔丁酯(670mg,3.14mmol)溶于无水甲醇(15mL)，加入碳酸钾(868.3mg,6.28mmol)，降温至0℃，缓慢滴加P-(重氮甲基)磷酸二甲酯(905.3mg,4.71mmol)，恢复至室温搅拌20min。反应完全后，往反应液中加入水(5mL)，混合液用乙酸乙酯(30mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-50％)为洗脱剂梯度洗脱分离纯化得到3-乙炔基-3-甲基吡咯烷-1-甲酸叔丁酯(淡黄色油状物,530mg,80.6％)。Step 2: In a 100 mL eggplant-shaped flask, tert-butyl 3-formyl-3-methylpyrrolidine-1-carboxylate (670 mg, 3.14 mmol) was dissolved in anhydrous methanol (15 mL). Potassium carbonate (868.3 mg, 6.28 mmol) was added, the temperature was cooled to 0°C, and dimethyl p-(diazomethyl)phosphate (905.3 mg, 4.71 mmol) was slowly added dropwise. The mixture was returned to room temperature and stirred for 20 min. After the reaction was complete, water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-50%) to afford tert-butyl 3-ethynyl-3-methylpyrrolidine-1-carboxylate (pale yellow oil, 530 mg, 80.6%).

第三步：在100mL茄型瓶中将3-乙炔基-3-甲基吡咯烷-1-甲酸叔丁酯(530mg,2.53mmol)溶于二氯甲烷(6mL)，加入三氟乙酸(2mL)，室温下搅拌1h。反应完全后，减压浓缩得到3-乙炔基-3-甲基吡咯烷(无色油状,787mg,粗品)。MS(ESI+)m/z＝110.2[M+H]+。Step 3: Dissolve tert-butyl 3-ethynyl-3-methylpyrrolidine-1-carboxylate (530 mg, 2.53 mmol) in dichloromethane (6 mL) in a 100 mL eggplant-shaped flask. Add trifluoroacetic acid (2 mL) and stir at room temperature for 1 hour. After the reaction is complete, concentrate under reduced pressure to yield 3-ethynyl-3-methylpyrrolidine (787 mg, crude, colorless oil). MS (ESI + ) m/z = 110.2 [M+H] + .

第四步：在100mL的茄型瓶中将3-乙炔基-3-甲基吡咯烷(747mg,6.84mmol)溶于无水甲醇(20mL)，缓慢滴加20％甲醛水溶液(2.1g,13.68mmol)，搅拌均匀，然后滴加乙酸(41.1mg,0.68mmol)，降温至0℃，加入氰基硼氢化钠(860.0mg,13.68mmol)，恢复至室温搅拌1h。反应完全后，往反应液中加入水(20mL)，混合液用乙酸乙酯(40mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到3-乙炔基-1,3-二甲基吡咯烷(绿色油状物,230mg,粗品)。MS(ESI+)m/z＝124.2[M+H]+。Step 4: In a 100 mL eggplant-shaped flask, 3-ethynyl-3-methylpyrrolidine (747 mg, 6.84 mmol) was dissolved in anhydrous methanol (20 mL). 20% aqueous formaldehyde (2.1 g, 13.68 mmol) was slowly added dropwise and stirred until uniform. Acetic acid (41.1 mg, 0.68 mmol) was then added dropwise. The temperature was lowered to 0°C, and sodium cyanoborohydride (860.0 mg, 13.68 mmol) was added. The mixture was returned to room temperature and stirred for 1 hour. After the reaction was complete, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield 3-ethynyl-1,3-dimethylpyrrolidine (230 mg, crude, green oil). MS (ESI + ) m/z = 124.2 [M+H] + .

1-(溴甲基-d2)-4-氯-2-氟苯的制备
Preparation of 1-(bromomethyl-d 2 )-4-chloro-2-fluorobenzene

第一步：氮气保护下，将4-氯-2-氟苯甲酸(10.0g,57.29mmol)溶于四氢呋喃(150mL)，降温至0℃，分批缓慢加入氘代氢化锂铝(3.6g,85.93mmol)，加毕，升温至70℃搅拌12h。反应完全后冷却至室温，往反应液中加水(10mL)，混合液用乙酸乙酯(10mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以酸乙酯/石油醚(0-15％)为洗脱剂梯度洗脱分离得到(4-氯-2-氟苯基)甲烷-d2-醇(淡黄色油状物,4.5g,48.3％)。1H NMR(300MHz,DMSO-d6)δ7.47(t,J＝8.2Hz,1H),7.39-7.05(m,2H),5.30(d,J＝1.8Hz,1H)。Step 1: Under nitrogen, 4-chloro-2-fluorobenzoic acid (10.0 g, 57.29 mmol) was dissolved in tetrahydrofuran (150 mL). The temperature was lowered to 0°C, and lithium aluminum hydride (3.6 g, 85.93 mmol) was slowly added portionwise. After addition, the temperature was raised to 70°C and stirred for 12 h. After the reaction was complete, the mixture was cooled to room temperature and water (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using a gradient elution ratio of ethyl acetate/petroleum ether (0-15%) to afford (4-chloro-2-fluorophenyl)methane- d2 -ol (pale yellow oil, 4.5 g, 48.3%). 1 H NMR (300MHz, DMSO-d 6 ) δ7.47 (t, J = 8.2 Hz, 1H), 7.39-7.05 (m, 2H), 5.30 (d, J = 1.8 Hz, 1H).

第二步：氮气保护下，将(4-氯-2-氟苯基)甲烷-d2-醇(4.5g,27.68mmol)溶于二氯甲烷(60mL)，降温至0℃，加入三溴化磷(11.2g,41.52mmol)，室温搅拌1h。反应完全后，往反应液中加水(30mL)，混合液用二氯甲烷(30mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-10％)为洗脱剂梯度洗脱分离得到1-(溴甲基-d2)-4-氯-2-氟苯(淡黄色油状物,4.5g,72.1％)。1H NMR(300MHz,DMSO-d6)δ7.57(t,J＝8.3Hz,1H),7.51-7.43(m,1H),7.30(d,J＝8.3Hz,1H)。Step 2: Under nitrogen, (4-chloro-2-fluorophenyl)methane-d 2 -ol (4.5 g, 27.68 mmol) was dissolved in dichloromethane (60 mL), cooled to 0°C, and phosphorus tribromide (11.2 g, 41.52 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-10%) to afford 1-(bromomethyl-d 2 )-4-chloro-2-fluorobenzene (pale yellow oil, 4.5 g, 72.1%). 1 H NMR (300MHz, DMSO-d 6 ) δ7.57 (t, J = 8.3 Hz, 1H), 7.51-7.43 (m, 1H), 7.30 (d, J = 8.3 Hz, 1H).

5-溴-2-(溴甲基)-1-氯-3-氟苯的制备
Preparation of 5-bromo-2-(bromomethyl)-1-chloro-3-fluorobenzene

第一步：氮气保护下，将4-溴-2-氯-6-氟-苯甲醛(2.8g,11.79mmol)溶于甲醇(40mL)，降温至0℃，加入硼氢化钠(892.2mg,23.58mmol)，0℃搅拌1h。反应完全后恢复至室温，往反应液中加水(50mL)，混合液用二氯甲烷(50mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以甲醇/二氯甲烷(0-10％)为洗脱剂梯度洗脱分离，得到(4-溴-2-氯-6-氟苯基)甲醇(白色固体,2.6g,92.2％)。1H NMR(300MHz,DMSO-d6)δ7.65-7.54(m,2H),5.30(t,J＝5.5Hz,1H),4.53(dd,J＝5.6,2.2Hz,2H)。Step 1: Under nitrogen, dissolve 4-bromo-2-chloro-6-fluoro-benzaldehyde (2.8 g, 11.79 mmol) in methanol (40 mL), cool to 0°C, add sodium borohydride (892.2 mg, 23.58 mmol), and stir at 0°C for 1 hour. After the reaction is complete, return to room temperature, add water (50 mL), and extract the mixture with dichloromethane (50 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue is separated by silica gel column chromatography using a gradient elution of methanol/dichloromethane (0-10%) to afford (4-bromo-2-chloro-6-fluorophenyl)methanol (white solid, 2.6 g, 92.2%). 1 H NMR (300MHz, DMSO-d 6 ) δ7.65-7.54 (m, 2H), 5.30 (t, J = 5.5 Hz, 1H), 4.53 (dd, J = 5.6, 2.2 Hz, 2H).

第二步：氮气保护下，将(4-溴-2-氯-6-氟苯基)甲醇(2.6g,10.86mmol)溶于二氯甲烷和四氢呋喃混合液(1/1v/v,30mL)，降温至0℃，加入三溴化磷(4.4g,16.29mmol)。室温搅拌1h。反应完全后，反应液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-10％)为洗脱剂梯度洗脱分离，得到5-溴-2-(溴甲基)-1-氯-3-氟苯(白色固体,1.4g,42.7％)。Step 2: Under nitrogen, (4-bromo-2-chloro-6-fluorophenyl)methanol (2.6 g, 10.86 mmol) was dissolved in a mixture of dichloromethane and tetrahydrofuran (1/1 v/v, 30 mL). The temperature was cooled to 0°C, and phosphorus tribromide (4.4 g, 16.29 mmol) was added. Stirring was continued at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-10%) to afford 5-bromo-2-(bromomethyl)-1-chloro-3-fluorobenzene (white solid, 1.4 g, 42.7%).

[1,2,4]三唑并[1,5-a]吡啶-2-d-7-醇-d的制备
Preparation of [1,2,4]triazolo[1,5-a]pyridine-2-d-7-ol-d

第一步：氮气保护下，将7-溴-[1,2,4]三唑并[1,5-a]吡啶-2-胺(2.0g,9.38mmol)溶于乙腈(50.0mL)，搅拌下加入氯化铜(1.9g,14.08mmol)，降温至0℃，加入亚硝酸叔丁酯(1.4g,14.08mmol)，升温至90℃搅拌1h。反应完全后恢复至室温，往反应液中加水(50mL)，过滤，滤液用乙酸乙酯(50mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以甲醇/二氯甲烷(0-10％)为洗脱剂梯度洗脱分离得到7-溴-2-氯-[1,2,4]三唑并[1,5-a]吡啶(黄色油状物,1.4g,59.6％)。MS(ESI+)m/z＝231.9[M+H]+。Step 1: Under nitrogen, 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (2.0 g, 9.38 mmol) was dissolved in acetonitrile (50.0 mL). Copper chloride (1.9 g, 14.08 mmol) was added with stirring. The temperature was lowered to 0°C, and tert-butyl nitrite (1.4 g, 14.08 mmol) was added. The temperature was raised to 90°C and stirred for 1 h. After the reaction was complete, the mixture was returned to room temperature. Water (50 mL) was added to the reaction mixture, and the mixture was filtered. The filtrate was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using a gradient elution of methanol/dichloromethane (0-10%) to afford 7-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (yellow oil, 1.4 g, 59.6%). MS(ESI + )m/z=231.9[M+H] + .

第二步：氮气保护下，将7-溴-2-氯-[1,2,4]三唑并[1,5-a]吡啶(1.4g,6.02mmol)溶于二氧六环(20.00mL)，依次加入联硼酸频那醇酯(2.3g,9.03mmol)，Pd(dppf)Cl2(0.4g,0.60mmol)和乙酸钾(2.1g,21.08mmol)，升温至100℃搅拌1h。反应完全后恢复至室温，往反应液中加水(50mL)，混合液用乙酸乙酯(50mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以甲醇/二氯甲烷(0-10％)为洗脱剂梯度洗脱分离得到2-氯-7-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-[1,2,4]三唑并[1,5-a]吡啶(黄色油状物,800mg,73.6％)。MS(ESI+)m/z＝280.0[M+H]+。Step 2: Under nitrogen protection, 7-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (1.4 g, 6.02 mmol) was dissolved in dioxane (20.00 mL), and pinacol diboron (2.3 g, 9.03 mmol), Pd(dppf)Cl 2 (0.4 g, 0.60 mmol) and potassium acetate (2.1 g, 21.08 mmol) were added in sequence. The temperature was raised to 100°C and stirred for 1 h. After the reaction was complete, the reaction mixture was returned to room temperature and water (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using a gradient elution of methanol/dichloromethane (0-10%) to afford 2-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (yellow oil, 800 mg, 73.6%). MS (ESI + ) m/z = 280.0 [M+H] + .

第三步：将2-氯-7-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-[1,2,4]三唑并[1,5-a]吡啶(1.5g,5.36mmol)溶于四氢呋喃(20mL)，降温至0℃，加入氢氧化钠(16.1mL,1M,16.08mmol)和过氧化氢(30％,1.8mL,16.08mmol)，恢复至室温搅拌1h。用乙酸乙酯(20mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以甲醇/二氯甲烷(0-10％)为洗脱剂梯度洗脱分离得到2-氯-[1,2,4]三唑并[1,5-a]吡啶-7-醇(黄色油状物,800mg,79.1％)。MS(ESI+)m/z＝170.1[M+H]+。Step 3: Dissolve 2-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (1.5 g, 5.36 mmol) in tetrahydrofuran (20 mL), cool to 0°C, add sodium hydroxide (16.1 mL, 1 M, 16.08 mmol) and hydrogen peroxide (30%, 1.8 mL, 16.08 mmol), return to room temperature and stir for 1 hour. Extract with ethyl acetate (20 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue is purified by silica gel column chromatography using a gradient elution of methanol/dichloromethane (0-10%) to afford 2-chloro-[1,2,4]triazolo[1,5-a]pyridin-7-ol (800 mg, 79.1%) as a yellow oil. MS(ESI + )m/z=170.1[M+H] + .

第四步：氮气保护下，将2-氯-[1,2,4]三唑并[1,5-a]吡啶-7-醇(300.0mg,1.77mmol)溶于氘代甲醇(20mL)，加入Pd/C(1.9g,17.69mmol)，然后置换氘气，升温至40℃搅拌24h。反应完全后，过滤，滤渣用甲醇(100mL)洗涤，收集滤液减压浓缩得到[1,2,4]三唑并[1,5-a]吡啶-2-d-7-醇-d(棕色固体,270mg,粗品)。MS(ESI+)m/z＝138.2[M+H]+。Step 4: Under nitrogen, 2-chloro-[1,2,4]triazolo[1,5-a]pyridin-7-ol (300.0 mg, 1.77 mmol) was dissolved in deuterated methanol (20 mL). Pd/C (1.9 g, 17.69 mmol) was added, and the deuterium atmosphere was replaced. The mixture was heated to 40°C and stirred for 24 h. After the reaction was complete, the mixture was filtered, and the residue was washed with methanol (100 mL). The filtrate was collected and concentrated under reduced pressure to yield [1,2,4]triazolo[1,5-a]pyridin-2-d-7-ol-d (brown solid, 270 mg, crude product). MS (ESI + ) m/z = 138.2 [M+H] + .

3-氯-[1,2,4]三唑并[4,3-a]吡啶-7-醇的制备
Preparation of 3-chloro-[1,2,4]triazolo[4,3-a]pyridin-7-ol

氮气保护下，将7-溴-3-氯-[1,2,4]三唑并[4,3-a]吡啶(1.5g,6.45mmol)溶于1,4-二氧六环(15mL)，依次加入Pd(dppf)Cl2(472.1mg,0.65mmol)，乙酸钾(2.2g,22.58mmol)和联硼酸频哪醇酯(2.5g,9.68mmol)，升温至90℃搅拌2h。反应完全后冷却至室温，过滤，滤渣用四氢呋喃洗涤三次，滤液减压浓缩，所得残余物溶于四氢呋喃(15mL)，降温至0℃，依次滴加30％双氧水(2.2mL,19.36mmol)和氢氧化钠溶液(6.5mL,3M,19.36mmol)，加毕，恢复至室温搅拌2h。反应完全后，反应液减压浓缩，所得残余物经硅胶柱层析以甲醇/二氯甲烷(0-15％)为洗脱剂梯度洗脱分离，得到3-氯-[1,2,4]三唑并[4,3-a]吡啶-7-醇(淡黄色固体,1.0g,91.4％)。MS(ESI+)m/z＝170.1[M+H]+。Under nitrogen, 7-bromo-3-chloro-[1,2,4]triazolo[4,3-a]pyridine (1.5 g, 6.45 mmol) was dissolved in 1,4-dioxane (15 mL). Pd(dppf) Cl₂ (472.1 mg, 0.65 mmol), potassium acetate (2.2 g, 22.58 mmol), and pinacol diboronate (2.5 g, 9.68 mmol) were added sequentially. The mixture was heated to 90°C and stirred for 2 h. After the reaction was complete, the mixture was cooled to room temperature and filtered. The residue was washed three times with tetrahydrofuran. The filtrate was concentrated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (15 mL), cooled to 0°C, and 30% hydrogen peroxide (2.2 mL, 19.36 mmol) and sodium hydroxide solution (6.5 mL, 3 M, 19.36 mmol) were added dropwise. After the additions were complete, the mixture was returned to room temperature and stirred for 2 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography using a gradient elution of methanol/dichloromethane (0-15%) to afford 3-chloro-[1,2,4]triazolo[4,3-a]pyridin-7-ol (pale yellow solid, 1.0 g, 91.4%). MS (ESI + ) m/z = 170.1 [M+H] + .

3-甲基-4-((2-甲基喹喔啉-6-基)氧基)苯胺的制备
Preparation of 3-methyl-4-((2-methylquinoxalin-6-yl)oxy)aniline

第一步：氮气保护下，将4-(苄氧基)苯-1,2-二胺(1.7g,7.93mmol)溶于乙腈(5mL)，加入2-氧代丙醛(0.57g,7.93mmol)，室温搅拌1h。反应完全后，减压浓缩，所得残余物经硅胶柱层析以甲醇/二氯甲烷(0-10％)为洗脱剂梯度洗脱分离得到6-(苄氧基)-2-甲基喹喔啉(黄色油状物,1.7g,85.6％)。MS(ESI+)m/z＝251.1[M+H]+。Step 1: Under nitrogen, dissolve 4-(benzyloxy)benzene-1,2-diamine (1.7 g, 7.93 mmol) in acetonitrile (5 mL), add 2-oxopropanal (0.57 g, 7.93 mmol), and stir at room temperature for 1 hour. After completion of the reaction, concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography using a gradient elution of methanol/dichloromethane (0-10%) to afford 6-(benzyloxy)-2-methylquinoxaline (yellow oil, 1.7 g, 85.6%). MS (ESI + ) m/z = 251.1 [M+H] + .

第二步：将6-(苄氧基)-2-甲基喹喔啉(1.7g,6.79mmol)溶于DCM(10mL)，降温至0℃，缓慢加入三溴化硼(3.4g,13.58mmol)，加毕，恢复至室温搅拌1h。反应完全后，减压浓缩，所得残余物经硅胶柱层析以甲醇/二氯甲烷(0-10％)为洗脱剂梯度洗脱分离得到2-甲基喹喔啉-6-醇(淡黄色油状物,1g,91.9％)。MS(ESI+)m/z＝161.1[M+H]+。Step 2: Dissolve 6-(Benzyloxy)-2-methylquinoxaline (1.7 g, 6.79 mmol) in DCM (10 mL), cool to 0°C, and slowly add boron tribromide (3.4 g, 13.58 mmol). Return to room temperature and stir for 1 hour. After the reaction is complete, concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography using a gradient elution of methanol/dichloromethane (0-10%) to afford 2-methylquinoxalin-6-ol (pale yellow oil, 1 g, 91.9%). MS (ESI + ) m/z = 161.1 [M+H] + .

第二组制备例：中间体A1-A38制备The second group of preparation examples: Preparation of intermediates A1-A38

中间体A1. 8-氰基-7-硝基-2H,4H-螺[苯并[b][1,4]噁嗪-3,4'-哌啶]-1'-甲酸叔丁酯的制备
Intermediate A1. Preparation of tert-butyl 8-cyano-7-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidine]-1'-carboxylate

第一步：将2,3-二氟-6-硝基苯腈(1.0g,5.43mmol)溶于N,N-二甲基甲酰胺(20mL)中，依次加入4-氨基-4-羟甲基哌啶-1-甲酸叔丁酯(1.3g,5.43mmol)和N,N-二异丙基乙胺(1.4g,10.86mmol)，升温至70℃搅拌10h。反应完全后冷却至室温，往反应液中加水(20mL)，用乙酸乙酯(20mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶柱层析以乙酸乙酯/石油醚(85％-100％)为洗脱剂梯度洗脱分离纯化得到4-((3-氰基-2-氟-4-硝基苯基)氨基)-4-(羟甲基)哌啶-1-甲酸叔丁酯(黄色固体,1.1g,50.4％)。MS(ESI+)m/z＝395.3[M+H]+。Step 1: Dissolve 2,3-difluoro-6-nitrobenzonitrile (1.0 g, 5.43 mmol) in N,N-dimethylformamide (20 mL), add tert-butyl 4-amino-4-hydroxymethylpiperidine-1-carboxylate (1.3 g, 5.43 mmol) and N,N-diisopropylethylamine (1.4 g, 10.86 mmol) in sequence, and heat to 70 ° C and stir for 10 h. After the reaction was complete, the mixture was cooled to room temperature, and water (20 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (85%-100%) as the eluent to afford tert-butyl 4-((3-cyano-2-fluoro-4-nitrophenyl)amino)-4-(hydroxymethyl)piperidine-1-carboxylate (yellow solid, 1.1 g, 50.4%). MS (ESI + ) m/z = 395.3 [M+H] + .

第二步：将4-((3-氰基-2-氟-4-硝基苯基)氨基)-4-(羟甲基)哌啶-1-甲酸叔丁酯(1.1g,2.74mmol)溶于N,N-二甲基甲酰胺(20mL)中，降温至0℃，加入NaH(0.1g,4.11mmol)，恢复至室温搅拌2h。反应完全后，往反应液中加水(30mL)，用乙酸乙酯(30mL×3)萃取，合并有机相用饱无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶柱层析以乙酸乙酯/石油醚(50％-60％)为洗脱剂梯度洗脱分离纯化得到8-氰基-7-硝基-2H,4H-螺[苯并[b][1,4]噁嗪-3,4'-哌啶]-1'-甲酸叔丁酯(黄色固体,500mg,48.8％)。MS(ESI+)m/z＝375.2[M+H]+。Step 2: Dissolve tert-butyl 4-((3-cyano-2-fluoro-4-nitrophenyl)amino)-4-(hydroxymethyl)piperidine-1-carboxylate (1.1 g, 2.74 mmol) in N,N-dimethylformamide (20 mL), cool to 0°C, add NaH (0.1 g, 4.11 mmol), and stir at room temperature for 2 h. After the reaction is complete, add water (30 mL) and extract with ethyl acetate (30 mL x 3). The combined organic phases are dried over saturated anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain the crude product. The crude product is isolated and purified by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (50%-60%) to obtain tert-butyl 8-cyano-7-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidine]-1'-carboxylate (yellow solid, 500 mg, 48.8%). MS(ESI + )m/z=375.2[M+H] + .

中间体A2. 8-氰基-4-甲基-7-硝基-2H,4H-螺[苯并[b][1,4]噁嗪-3,4'-哌啶]-1'-甲酸叔丁酯的制备
Intermediate A2. Preparation of tert-butyl 8-cyano-4-methyl-7-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidine]-1'-carboxylate

将中间体A1(300.0mg,0.80mmol)溶于叔丁醇(6mL)中，依次加入叔丁醇钾(179.8mg,1.60mmol)和碘甲烷(1.1g,8.01mmol)，升温至60℃搅拌10h。反应完全后冷却至室温，往反应液中加水(10mL)，用乙酸乙酯(20mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶柱层析以乙酸乙酯/石油醚(40％)为洗脱剂分离纯化得到8-氰基-4-甲基-7-硝基-2H,4H-螺[苯并[b][1,4]噁嗪-3,4'-哌啶]-1'-甲酸叔丁酯(黄色油状物,250mg,80.3％)。MS(ESI+)m/z＝389.2[M+H]+。Intermediate A1 (300.0 mg, 0.80 mmol) was dissolved in tert-butanol (6 mL). Potassium tert-butoxide (179.8 mg, 1.60 mmol) and iodomethane (1.1 g, 8.01 mmol) were added sequentially. The mixture was heated to 60°C and stirred for 10 h. After completion of the reaction, the mixture was cooled to room temperature and water (10 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography using ethyl acetate/petroleum ether (40%) as the eluent to obtain tert-butyl 8-cyano-4-methyl-7-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidine]-1'-carboxylate (yellow oil, 250 mg, 80.3%). MS (ESI + ) m/z = 389.2 [M+H] + .

中间体A3. 4-烯丙基-8-氰基-7-硝基-2H,4H-螺[苯并[b][1,4]噁嗪-3,4'-哌啶]-1'-甲酸叔丁酯的制备
Intermediate A3. Preparation of tert-butyl 4-allyl-8-cyano-7-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidine]-1'-carboxylate

将中间体A1(450.0mg,1.20mmol)溶于DMF(4.5mL)中，加入NaH(60％,144.2mg,3.61mmol)，室温搅拌5min，然后加入烯丙基溴(436.2mg,3.61mmol)，升温至65℃搅拌2h。反应完全后冷却至室温，往反应液中加水(30mL)，用乙酸乙酯(50mL×3)萃取，合并有机相用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶柱层析以乙酸乙酯/石油醚(50％)为洗脱剂分离纯化得到4-烯丙基-8-氰基-7-硝基-2H,4H-螺[苯并[b][1,4]噁嗪-3,4'-哌啶]-1'-甲酸叔丁酯(黄色固体,175mg,35.1％)。MS(ESI+)m/z＝415.2[M+H]+。Intermediate A1 (450.0 mg, 1.20 mmol) was dissolved in DMF (4.5 mL), and NaH (60%, 144.2 mg, 3.61 mmol) was added. The mixture was stirred at room temperature for 5 min, followed by the addition of allyl bromide (436.2 mg, 3.61 mmol). The temperature was raised to 65°C and stirred for 2 h. After the reaction was complete, the mixture was cooled to room temperature, and water (30 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography using ethyl acetate/petroleum ether (50%) as the eluent to obtain tert-butyl 4-allyl-8-cyano-7-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidinyl]-1'-carboxylate (yellow solid, 175 mg, 35.1%). MS(ESI + )m/z=415.2[M+H] + .

中间体A4. 8-氰基-7-硝基-4-(丙-2-炔-1-基)-2H,4H-螺[苯并[b][1,4]噁嗪-3,4'-哌啶]-1'-甲酸叔丁酯的制备
Intermediate A4. Preparation of tert-butyl 8-cyano-7-nitro-4-(prop-2-yn-1-yl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidine]-1'-carboxylate

以中间体A1和炔丙基溴为原料，按照中间体A3的方法制备中间体A4(黄色固体,150mg,27.2％)。MS(ESI+)m/z＝413.1[M+H]+。Intermediate A4 (yellow solid, 150 mg, 27.2%) was prepared using Intermediate A1 and propargyl bromide as starting materials according to the method for Intermediate A3. MS (ESI + ) m/z = 413.1 [M+H] + .

中间体A5. 5-溴-8-氰基-7-硝基-2H,4H-螺[苯并[b][1,4]噁嗪-3,4'-哌啶]-1'-甲酸叔丁酯的制备
Intermediate A5. Preparation of tert-butyl 5-bromo-8-cyano-7-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidine]-1'-carboxylate

将中间体A1(500.0mg,1.34mmol)溶于醋酸(10mL)中，缓慢滴加溴素(320.1mg,2.00mmol)的醋酸溶液(2mL)，室温搅拌2h。反应完全后，往反应液中加水(30mL)，用饱和碳酸氢钠调pH至8，混合液用乙酸乙酯(30mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶柱层析以乙酸乙酯/石油醚(10％-20％)为洗脱剂梯度洗脱分离纯化得到5-溴-8-氰基-7-硝基-2H,4H-螺[苯并[b][1,4]噁嗪-3,4'-哌啶]-1'-甲酸叔丁酯(黄色固体,380mg,62.8％)。MS(ESI+)m/z＝453.1[M+H]+。Intermediate A1 (500.0 mg, 1.34 mmol) was dissolved in acetic acid (10 mL). A solution of bromine (320.1 mg, 2.00 mmol) in acetic acid (2 mL) was slowly added dropwise and stirred at room temperature for 2 h. After the reaction was complete, water (30 mL) was added to the reaction solution, and the pH was adjusted to 8 with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (10%-20%) to obtain tert-butyl 5-bromo-8-cyano-7-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidinyl]-1'-carboxylate (yellow solid, 380 mg, 62.8%). MS (ESI + ) m/z = 453.1 [M+H] + .

中间体A6. 8-氰基-5-甲基-7-硝基-2H,4H-螺[苯并[b][1,4]噁嗪-3,4'-哌啶]-1'-甲酸叔丁酯的制备
Intermediate A6. Preparation of tert-butyl 8-cyano-5-methyl-7-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidine]-1'-carboxylate

氮气保护下，将中间体A5(240.0mg,0.53mmol)溶于1,4-二氧六环/水(10/1,5mL)中，依次加入甲基硼酸(34.9mg,0.58mmol)，Pd(dppf)Cl2(38.7mg,0.053mmol)和碳酸钾(182.9mg,1.32mmol)，升温至90℃搅拌2h。反应完全后冷却至室温，往反应液中加水(20mL)，用乙酸乙酯(20mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶柱层析以乙酸乙酯/石油醚(30％-50％)为洗脱剂梯度洗脱分离纯化得到8-氰基-5-甲基-7-硝基-2H,4H-螺[苯并[b][1,4]噁嗪-3,4'-哌啶]-1'-甲酸叔丁酯(黄色固体,140mg,68.3％)。MS(ESI+)m/z＝389.2[M+H]+。Under nitrogen protection, intermediate A5 (240.0 mg, 0.53 mmol) was dissolved in 1,4-dioxane/water (10/1,5 mL), and methylboric acid (34.9 mg, 0.58 mmol), Pd(dppf)Cl 2 (38.7 mg, 0.053 mmol) and potassium carbonate (182.9 mg, 1.32 mmol) were added in sequence. The temperature was raised to 90°C and stirred for 2 h. After the reaction was complete, the mixture was cooled to room temperature, and water (20 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (30%-50%) as the eluent to afford tert-butyl 8-cyano-5-methyl-7-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidine]-1'-carboxylate (yellow solid, 140 mg, 68.3%). MS (ESI + ) m/z = 389.2 [M+H] + .

中间体A7. 5-氯-8-氰基-7-硝基-2H,4H-螺[苯并[b][1,4]噁嗪-3,4'-哌啶]-1'-甲酸叔丁酯的制备
Intermediate A7. Preparation of tert-butyl 5-chloro-8-cyano-7-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidine]-1'-carboxylate

氮气保护下，将中间体A1(1.8g,4.01mmol)溶于六氟异丙醇(20mL)中，降温至0℃，依次加入三氯异氰尿酸(372.5mg,1.60mmol)和三氟甲磺酸(30.1mg,0.20mmol)，升温至60℃搅拌1h。反应完全后冷却至室温，往反应液中加水(20mL)，用乙酸乙酯(50mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶柱层析以甲醇/二氯甲烷(0-10％)为洗脱剂梯度洗脱分离纯化得到5-氯-8-氰基-7-硝基-2H,4H-螺[苯并[b][1,4]噁嗪-3,4'-哌啶]-1'-甲酸叔丁酯(淡黄色固体,1.5g,76.9％)。MS(ESI+)m/z＝409.1[M+H]+。Under nitrogen, Intermediate A1 (1.8 g, 4.01 mmol) was dissolved in hexafluoroisopropanol (20 mL), cooled to 0°C, and trichloroisocyanuric acid (372.5 mg, 1.60 mmol) and trifluoromethanesulfonic acid (30.1 mg, 0.20 mmol) were added sequentially. The mixture was heated to 60°C and stirred for 1 h. After the reaction was complete, it was cooled to room temperature and water (20 mL) was added. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography using a gradient elution of methanol/dichloromethane (0-10%) to obtain tert-butyl 5-chloro-8-cyano-7-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidinyl]-1'-carboxylate (pale yellow solid, 1.5 g, 76.9%). MS(ESI + )m/z=409.1[M+H] + .

中间体A8. 8-氰基-4-甲基-7-硝基-2H,4H-螺[苯并[b][1,4]噁嗪-3,3'-哌啶]-1'-甲酸叔丁酯的制备
Intermediate A8. Preparation of tert-butyl 8-cyano-4-methyl-7-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,3'-piperidine]-1'-carboxylate

第一步、第二步：以2,3-二氟-6-硝基苯腈和3-氨基-3-(羟甲基)哌啶-1-甲酸叔丁酯为原料，按照合成中间体A1方法制备8-氰基-7-硝基-2H,4H-螺[苯并[b][1,4]噁嗪-3,3'-哌啶]-1'-甲酸叔丁酯(黄色固体)。MS(ESI+)m/z＝375.1[M+H]+。Steps 1 and 2: Using 2,3-difluoro-6-nitrobenzonitrile and tert-butyl 3-amino-3-(hydroxymethyl)piperidine-1-carboxylate as starting materials, prepare tert-butyl 8-cyano-7-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,3'-piperidine]-1'-carboxylate (yellow solid) according to the method for synthesizing Intermediate A1. MS (ESI + ) m/z = 375.1 [M+H] + .

第三步：8-氰基-7-硝基-2H,4H-螺[苯并[b][1,4]噁嗪-3,3'-哌啶]-1'-甲酸叔丁酯和碘甲烷为原料，按照合成中间体A2方法制备中间体A8(黄色油状物)。MS(ESI+)m/z＝389.1[M+H]+。Step 3: Using tert-butyl 8-cyano-7-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,3'-piperidine]-1'-carboxylate and iodomethane as starting materials, Intermediate A8 (yellow oil) was prepared according to the method for synthesizing Intermediate A2. MS (ESI + ) m/z = 389.1 [M+H] + .

中间体A9. 8-氰基-7-硝基-2H,4H-螺[苯并[b][1,4]噁嗪-3,3'-吡咯烷]-1'-甲酸叔丁酯的制备
Intermediate A9. Preparation of tert-butyl 8-cyano-7-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,3'-pyrrolidine]-1'-carboxylate

以2,3-二氟-6-硝基苯腈和3-氨基-3-(羟甲基)吡咯烷-1-甲酸叔丁酯为原料，按照合成中间体A1方法制备中间体A9(黄色油状物,300mg,17.6％)。MS(ESI+)m/z＝361.1[M+H]+。Intermediate A9 (yellow oil, 300 mg, 17.6%) was prepared using 2,3-difluoro-6-nitrobenzonitrile and tert-butyl 3-amino-3-(hydroxymethyl)pyrrolidine-1-carboxylate as starting materials according to the method for synthesizing Intermediate A1. MS (ESI + ) m/z = 361.1 [M+H] + .

中间体A10. 8'-氰基-4'-甲基-7'-硝基-2'H,4'H-螺[氮杂环丁烷-3,3'-苯并[b][1,4]噁嗪]-1-甲酸叔丁酯的制备
Intermediate A10. Preparation of tert-butyl 8'-cyano-4'-methyl-7'-nitro-2'H,4'H-spiro[azetidine-3,3'-benzo[b][1,4]oxazine]-1-carboxylate

以2,3-二氟-6-硝基苯腈和3-氨基-3-(羟甲基)氮杂环丁烷-1-甲酸叔丁酯为原料，按照合成中间体A8方法制备中间体A10(黄色油状物,870mg,46.5％)。MS(ESI+)m/z＝360.9[M+H]+。Intermediate A10 (yellow oil, 870 mg, 46.5%) was prepared using 2,3-difluoro-6-nitrobenzonitrile and tert-butyl 3-amino-3-(hydroxymethyl)azetidine-1-carboxylate as starting materials according to the method for synthesizing Intermediate A8. MS (ESI + ) m/z = 360.9 [M+H] + .

中间体A11. 5-氰基-6-硝基-3H-螺[苯并[b][1,4]二氧六环-2,4'-哌啶]-1'-甲酸叔丁酯的制备
Intermediate A11. Preparation of tert-butyl 5-cyano-6-nitro-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-1'-carboxylate

氮气保护下，将2,3-二氟-6-硝基苯腈(400.0mg,2.17mmol)溶于N,N-二甲基甲酰胺(20mL)中，加入4-羟基-4-(羟甲基)哌啶-1-甲酸叔丁酯(502.5mg,2.17mmol)和碳酸铯(2.1g,6.52mmol)，微波至80℃搅拌1h。反应完全后冷却至室温，往反应液中加水(50mL)，混合液用乙酸乙酯(50mL×3)萃取，合并有机相用饱和食盐水(30mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶柱层析以乙酸乙酯/石油醚(42％)为洗脱剂分离纯化得到5-氰基-6-硝基-3H-螺[苯并[b][1,4]二氧六环-2,4'-哌啶]-1'-甲酸叔丁酯(黄色固体,280mg,34.3％)。MS(ESI+)m/z＝376.2[M+H]+。Under nitrogen protection, 2,3-difluoro-6-nitrobenzonitrile (400.0 mg, 2.17 mmol) was dissolved in N,N-dimethylformamide (20 mL), and tert-butyl 4-hydroxy-4-(hydroxymethyl)piperidine-1-carboxylate (502.5 mg, 2.17 mmol) and cesium carbonate (2.1 g, 6.52 mmol) were added. The mixture was stirred at 80 °C under microwave for 1 h. After the reaction was complete, the mixture was cooled to room temperature. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography using ethyl acetate/petroleum ether (42%) as eluent to obtain tert-butyl 5-cyano-6-nitro-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-1'-carboxylate (yellow solid, 280 mg, 34.3%). MS (ESI + ) m/z = 376.2 [M+H] + .

中间体A12. 7'-氯-8'-氰基-2'H-螺[哌啶-4,3'-[1,4]二氧六环并[2,3-b]吡啶]-1-甲酸叔丁酯的制备
Intermediate A12. Preparation of tert-butyl 7'-chloro-8'-cyano-2'H-spiro[piperidin-4,3'-[1,4]dioxane[2,3-b]pyridine]-1-carboxylate

以5-氯-2,3-二氟异烟腈(1.4g,8.02mmol)和4-羟基-4-(羟甲基)哌啶-1-甲酸叔丁酯为原料，按照中间体A11的合成方法制备中间体A12(淡黄色固体,1g,34.1％)。MS(ESI+)m/z＝366.2[M+H]+。Intermediate A12 (pale yellow solid, 1 g, 34.1%) was prepared using 5-chloro-2,3-difluoroisonicotinonitrile (1.4 g, 8.02 mmol) and tert-butyl 4-hydroxy-4-(hydroxymethyl)piperidine-1-carboxylate as starting materials according to the synthetic method of Intermediate A11. MS (ESI + ) m/z = 366.2 [M+H] + .

中间体A13. 7'-溴-8'-氰基-2'H,4'H-螺[哌啶-4,3'-吡啶并[3,2-b][1,4]噁嗪]-1-甲酸叔丁酯的制备
Intermediate A13. Preparation of tert-butyl 7'-bromo-8'-cyano-2'H,4'H-spiro[piperidin-4,3'-pyrido[3,2-b][1,4]oxazine]-1-carboxylate

第一步：氮气保护下，将2,3-二氟异烟腈(1.0g,7.14mmol)溶于N,N-二甲基甲酰胺(50mL)中，加入4-氨基-4-(羟甲基)哌啶-1-甲酸叔丁酯(1.6g,7.14mmol)和碳酸铯(4.7g,14.28mmol)，升温至80℃搅拌1h。反应完全后冷却至室温，往反应液中加水(50mL)，用乙酸乙酯(100mL×3)萃取，合并有机相用饱和食盐水(50mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶柱层析以乙酸乙酯/石油醚(50％)为洗脱剂分离纯化得到8'-氰基-2'H,4'H-螺[哌啶-4,3'-吡啶并[3,2-b][1,4]噁嗪]-1-甲酸叔丁酯(黄色油状物,600mg,25.5％)。MS(ESI+)m/z＝331.3[M+H]+。Step 1: Under nitrogen protection, dissolve 2,3-difluoroisonicotinonitrile (1.0 g, 7.14 mmol) in N,N-dimethylformamide (50 mL), add tert-butyl 4-amino-4-(hydroxymethyl)piperidine-1-carboxylate (1.6 g, 7.14 mmol) and cesium carbonate (4.7 g, 14.28 mmol), and heat to 80°C and stir for 1 h. After the reaction was complete, the mixture was cooled to room temperature, and water (50 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography using ethyl acetate/petroleum ether (50%) as eluent to obtain tert-butyl 8'-cyano-2'H,4'H-spiro[piperidine-4,3'-pyrido[3,2-b][1,4]oxazine]-1-carboxylate (yellow oil, 600 mg, 25.5%). MS (ESI + ) m/z = 331.3 [M+H] + .

第二步：将8'-氰基-2'H,4'H-螺[哌啶-4,3'-吡啶并[3,2-b][1,4]噁嗪]-1-甲酸叔丁酯(600.0mg,1.82mmol)溶于N,N-二甲基甲酰胺(6mL)中，加入N-溴代琥珀酰亚胺(323.2mg,1.82mmol)，室温搅拌1h。反应完全后，往反应液中加水(20mL)，用乙酸乙酯(50mL×3)萃取，合并有机相用饱和食盐水(30mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶柱层析以乙酸乙酯/石油醚(50％)为洗脱剂分离纯化得到7'-溴-8'-氰基-2'H,4'H-螺[哌啶-4,3'-吡啶并[3,2-b][1,4]噁嗪]-1-甲酸叔丁酯(淡黄色固体,400mg,54.0％)。MS(ESI+)m/z＝409.2[M+H]+。Step 2: Dissolve tert-butyl 8'-cyano-2'H,4'H-spiro[piperidine-4,3'-pyrido[3,2-b][1,4]oxazine]-1-carboxylate (600.0 mg, 1.82 mmol) in N,N-dimethylformamide (6 mL), add N-bromosuccinimide (323.2 mg, 1.82 mmol), and stir at room temperature for 1 h. After the reaction was complete, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography using ethyl acetate/petroleum ether (50%) as eluent to obtain tert-butyl 7'-bromo-8'-cyano-2'H,4'H-spiro[piperidine-4,3'-pyrido[3,2-b][1,4]oxazine]-1-carboxylate (pale yellow solid, 400 mg, 54.0%). MS (ESI + ) m/z = 409.2 [M+H] + .

中间体A14.(R)-3-溴-4-氰基-6a,7,9,10-四氢-6H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8-甲酸叔丁酯的制备
Intermediate A14. Preparation of tert-butyl (R)-3-bromo-4-cyano-6a,7,9,10-tetrahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine-8-carboxylate

以2,3-二氟异烟腈和(3R)-3-(羟甲基)哌嗪-1-羧酸叔丁酯为原料，微波80℃条件下，按照合成中间体A13的方法制备中间体A14(黄色固体,900mg,92.3％)。MS(ESI+)m/z＝339.0[M-56+H]+。Intermediate A14 (yellow solid, 900 mg, 92.3%) was prepared using 2,3-difluoroisonicotinonitrile and tert-butyl (3R)-3-(hydroxymethyl)piperazine-1-carboxylate under microwave evaporation at 80°C according to the method for synthesizing Intermediate A13. MS (ESI + ) m/z = 339.0 [M-56+H] + .

中间体A15. 3-溴-4-氰基-6a,7,9,10-四氢-6H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8-甲酸叔丁酯的制备
Intermediate A15. Preparation of tert-butyl 3-bromo-4-cyano-6a,7,9,10-tetrahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine-8-carboxylate

以2,3-二氟异烟腈和3-羟甲基哌嗪-1-甲酸叔丁酯为原料，微波80℃条件下，按照合成中间体A13的方法制备中间体A15(黄色固体,1.1g,91.9％)。MS(ESI+)m/z＝395.1[M+H]+。Intermediate A15 (yellow solid, 1.1 g, 91.9%) was prepared from 2,3-difluoroisonicotinonitrile and tert-butyl 3-hydroxymethylpiperazine-1-carboxylate under microwave conditions at 80°C according to the method for synthesizing intermediate A13. MS (ESI + ) m/z = 395.1 [M+H] + .

中间体A16. 3-溴-4-氰基-6,7,7a,8,10,11-六氢-9H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂卓-9-甲酸叔丁酯的制备
Intermediate A16. Preparation of tert-butyl 3-bromo-4-cyano-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine-9-carboxylate

第一步和第二步：以2,3-二氟异烟腈(1.0g,7.14mmol)和3-(2-羟乙基)哌嗪-1-甲酸叔丁酯为原料，按照中间体A1合成方法制备4-氰基-6,7,7a,8,10,11-六氢-9H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂卓-9-甲酸叔丁酯(白色油状物,770mg,68.1％)。MS(ESI+)m/z＝331.1[M+H]+。Steps 1 and 2: Using 2,3-difluoroisonicotinonitrile (1.0 g, 7.14 mmol) and tert-butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate as starting materials, tert-butyl 4-cyano-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine-9-carboxylate (white oil, 770 mg, 68.1%) was prepared according to the synthetic method of Intermediate A1. MS (ESI + ) m/z = 331.1 [M+H] + .

第三步：以4-氰基-6,7,7a,8,10,11-六氢-9H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂卓-9-甲酸叔丁酯为原料，按照中间体A13第二步方法制备中间体A16(绿色油状物,800mg,83.9％)。MS(ESI+)m/z＝409.2[M+H]+。Step 3: Starting from tert-butyl 4-cyano-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine-9-carboxylate, Intermediate A16 (green oil, 800 mg, 83.9%) was prepared according to the procedure for Intermediate A13, Step 2. MS (ESI + ) m/z = 409.2 [M+H] + .

中间体A17.(3-溴-4-氰基-6,6a,7,8,9,10-六氢二吡啶并[3,2-b:1',2'-d][1,4]噁嗪-8-基)氨基甲酸叔丁酯的制备
Intermediate A17. Preparation of tert-butyl (3-bromo-4-cyano-6,6a,7,8,9,10-hexahydrodipyrido[3,2-b:1',2'-d][1,4]oxazin-8-yl)carbamate

第一步：氮气保护下，将(2-(羟甲基)哌啶-4-基)氨基甲酸叔丁酯(1.0g,4.34mmol)溶于四氢呋喃(10mL)中，降温至0℃，缓慢滴加双(三甲基硅基)氨基钠(1.6g,8.68mmol)，0℃搅拌20min，然后缓慢滴加2,3-二氟异烟腈(0.6g,4.34mmol)，0℃搅拌2h。反应完全后恢复至室温，往反应液中加氯化铵溶液(10mL)，用乙酸乙酯(40mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶柱层析以乙酸乙酯/石油醚(0-100％)为洗脱剂梯度洗脱分离纯化得到(4-氰基-6,6a,7,8,9,10-六氢二吡啶并[3,2-b:1',2'-d][1,4]噁嗪-8-基)氨基甲酸叔丁酯(黄色固体,550mg,38.3％)。MS(ESI+)m/z＝331.2[M+H]+。Step 1: Under nitrogen protection, dissolve tert-butyl (2-(hydroxymethyl)piperidin-4-yl)carbamate (1.0 g, 4.34 mmol) in tetrahydrofuran (10 mL), cool to 0°C, slowly add sodium bis(trimethylsilyl)amide (1.6 g, 8.68 mmol) dropwise, stir at 0°C for 20 min, then slowly add 2,3-difluoroisonicotinonitrile (0.6 g, 4.34 mmol) dropwise, and stir at 0°C for 2 h. After the reaction was complete, the reaction mixture was returned to room temperature and ammonium chloride solution (10 mL) was added. The mixture was extracted with ethyl acetate (40 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-100%) as the eluent to afford tert-butyl (4-cyano-6,6a,7,8,9,10-hexahydrobipyrido[3,2-b:1',2'-d][1,4]oxazin-8-yl)carbamate (yellow solid, 550 mg, 38.3%). MS (ESI + ) m/z = 331.2 [M+H] + .

第二步：以(4-氰基-6,6a,7,8,9,10-六氢二吡啶并[3,2-b:1',2'-d][1,4]噁嗪-8-基)氨基甲酸叔丁酯为原料，按照中间体A13第二步方法制备中间体A17(淡黄色固体,470mg,68.9％)。MS(ESI+)m/z＝408.9[M+H]+。Step 2: Starting from tert-butyl (4-cyano-6,6a,7,8,9,10-hexahydrodipyrido[3,2-b:1',2'-d][1,4]oxazin-8-yl)carbamate, Intermediate A17 (pale yellow solid, 470 mg, 68.9%) was prepared according to the procedure for Intermediate A13, Step 2. MS (ESI + ) m/z = 408.9 [M+H] + .

中间体A18.(R)-10-溴-7-氰基-8-硝基-1,2,4a,5-四氢苯并[b]吡嗪[1,2-d][1,4]噁嗪-3(4H)-甲酸叔丁酯的制备
Intermediate A18. Preparation of (R)-tert-butyl 10-bromo-7-cyano-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate

第一步、第二步：以2,3-二氟-6-硝基苯腈和(3R)-3-(羟甲基)哌嗪-1-羧酸叔丁酯为原料，按照中间体A1合成方法制备(R)-7-氰基-8-硝基-1,2,4a,5-四氢苯并[b]吡嗪[1,2-d][1,4]噁嗪-3(4H)-甲酸叔丁酯。MS(ESI+)m/z＝361.2[M+H]+。Steps 1 and 2: Using 2,3-difluoro-6-nitrobenzonitrile and tert-butyl (3R)-3-(hydroxymethyl)piperazine-1-carboxylate as starting materials, prepare tert-butyl (R)-7-cyano-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate according to the synthetic method of Intermediate A1. MS (ESI + ) m/z = 361.2 [M+H] + .

第三步：以(R)-7-氰基-8-硝基-1,2,4a,5-四氢苯并[b]吡嗪[1,2-d][1,4]噁嗪-3(4H)-甲酸叔丁酯为原料，按照中间体A13第二步方法制备中间体A18。MS(ESI+)m/z＝383.0[M+H-56]+。Step 3: Starting from tert-butyl (R)-7-cyano-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate, Intermediate A18 was prepared according to the procedure described for Intermediate A13, Step 2. MS (ESI + ) m/z = 383.0 [M+H-56] + .

中间体A19. 10-溴-7-氰基-8-硝基-1,2,4a,5-四氢苯并[b]吡嗪[1,2-d][1,4]噁嗪-3(4H)-甲酸叔丁酯的制备
Intermediate A19. Preparation of tert-butyl 10-bromo-7-cyano-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate

以2,3-二氟-6-硝基苯腈和3-(羟甲基)哌嗪-1-羧酸叔丁酯为原料，按照中间体A18合成方法制备中间体A19。MS(ESI+)m/z＝382.9[M+H-56]+。Intermediate A19 was prepared from 2,3-difluoro-6-nitrobenzonitrile and tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate according to the synthetic method of Intermediate A18. MS (ESI + ) m/z = 382.9 [M+H-56] + .

中间体A20. 1-溴-4-氰基-3-硝基-6,6a,7,8,9,10-六氢苯并[b]吡啶[1,2-d][1,4]噁嗪-8-基-氨基甲酸叔丁酯的制备
Intermediate A20. Preparation of tert-butyl 1-bromo-4-cyano-3-nitro-6,6a,7,8,9,10-hexahydrobenzo[b]pyridin[1,2-d][1,4]oxazin-8-ylcarbamate

以2,3-二氟-6-硝基苯腈和(2-(羟甲基)哌啶-4-基)氨基甲酸叔丁酯为原料，按照中间体A18合成方法制备中间体A20。MS(ESI+)m/z＝397.1[M+H-56]+。Intermediate A20 was prepared using 2,3-difluoro-6-nitrobenzonitrile and tert-butyl (2-(hydroxymethyl)piperidin-4-yl)carbamate as starting materials according to the synthetic method of Intermediate A18. MS (ESI + ) m/z = 397.1 [M+H-56] + .

中间体A21. 5'-氰基-6'-硝基-3'H-螺[氮杂环丁烷-3,2'-苯并[b][1,4]二氧六环]-1-羧酸叔丁酯的制备
Intermediate A21. Preparation of tert-butyl 5'-cyano-6'-nitro-3'H-spiro[azetidine-3,2'-benzo[b][1,4]dioxane]-1-carboxylate

以2,3-二氟-6-硝基苯腈和3-羟基-3-(羟甲基)氮杂环丁烷-1-羧酸叔丁酯为原料，按照中间体A11的合成方法于120℃条件下制备中间体A21(黄色固体,0.99g,47.2％)。MS(ESI+)m/z＝370.1[M+Na]+。Intermediate A21 (yellow solid, 0.99 g, 47.2%) was prepared at 120°C using 2,3-difluoro-6-nitrobenzonitrile and tert-butyl 3-hydroxy-3-(hydroxymethyl)azetidine-1-carboxylate as starting materials according to the synthetic method for Intermediate A11. MS (ESI + ) m/z = 370.1 [M+Na] + .

中间体A22. 7'-溴-8'-氰基-4'-甲基-2'H,4'H-螺[哌啶-4,3'-吡啶并[3,2-b][1,4]噁嗪]-1-羧酸叔丁酯的制备
Intermediate A22. Preparation of tert-butyl 7'-bromo-8'-cyano-4'-methyl-2'H,4'H-spiro[piperidine-4,3'-pyrido[3,2-b][1,4]oxazine]-1-carboxylate

将中间体A13(380mg,0.93mmol)溶于四氢呋喃(4mL)溶液中，0℃下加入NaH(33.4mg,1.39mmol)，0℃搅拌0.5h，然后滴加碘甲烷(197.7mg,1.39mmol)，升温至70℃下搅拌1h。反应完全后冷却至室温，往反应液中加入饱和氯化铵溶液(10mL)，混合液用乙酸乙酯(20mL×3)萃取，合并有机相用饱和食盐水(10mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-100％)为洗脱剂梯度洗脱分离纯化得到7'-溴-8'-氰基-4'-甲基-2'H,4'H-螺[哌啶-4,3'-吡啶并[3,2-b][1,4]噁嗪]-1-羧酸叔丁酯(淡黄色固体,350mg,89.0％)。MS(ESI+)m/z＝423.1[M+H]+。Intermediate A13 (380 mg, 0.93 mmol) was dissolved in tetrahydrofuran (4 mL), and NaH (33.4 mg, 1.39 mmol) was added at 0°C. The mixture was stirred at 0°C for 0.5 h, and then iodomethane (197.7 mg, 1.39 mmol) was added dropwise. The mixture was heated to 70°C and stirred for 1 h. After the reaction was complete, the mixture was cooled to room temperature and saturated ammonium chloride solution (10 mL) was added. The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-100%) as the eluent to provide tert-butyl 7'-bromo-8'-cyano-4'-methyl-2'H,4'H-spiro[piperidine-4,3'-pyrido[3,2-b][1,4]oxazine]-1-carboxylate (pale yellow solid, 350 mg, 89.0%). MS (ESI + ) m/z = 423.1 [M+H] + .

中间体A23-A24的制备Preparation of intermediates A23-A24

以中间体A13和碘乙烷或氘代碘甲烷为原料，按照合成中间体A22的方法制备中间体A23-A24。如表1所示。Intermediates A23-A24 were prepared using intermediate A13 and iodoethane or deuterated iodomethane as raw materials according to the method for synthesizing intermediate A22, as shown in Table 1.

表1中间体A23和A24的结构和MS数据
Table 1 Structures and MS data of intermediates A23 and A24

中间体A25. 7'-溴-8'-氰基-4'-环丙基-2'H,4'H-螺[哌啶-4,3'-吡啶并[3,2-b][1,4]噁嗪]-1-羧酸叔丁酯的制备
Intermediate A25. Preparation of tert-butyl 7'-bromo-8'-cyano-4'-cyclopropyl-2'H,4'H-spiro[piperidine-4,3'-pyrido[3,2-b][1,4]oxazine]-1-carboxylate

将中间体A13(250mg,0.61mmol)溶于DMF(3mL)，加入醋酸铜(332.8mg,1.83mmol)，环丙基硼酸(104.9mg,1.22mmol)和碳酸钠129.3mg,1.22mmol)，升温至60℃下搅拌16h。反应完全后冷却至室温，往反应液中加入水(10mL)，混合液用乙酸乙酯(20mL×3)萃取，合并有机相用饱和食盐水(20mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-80％)为洗脱剂梯度洗脱分离纯化得到7'-溴-8'-氰基-4'-环丙基-2'H,4'H-螺[哌啶-4,3'-吡啶并[3,2-b][1,4]噁嗪]-1-羧酸叔丁酯(淡黄色固体,250mg,91.5％)。MS(ESI+)m/z＝449.1[M+H]+。Intermediate A13 (250 mg, 0.61 mmol) was dissolved in DMF (3 mL), and copper acetate (332.8 mg, 1.83 mmol), cyclopropylboronic acid (104.9 mg, 1.22 mmol) and sodium carbonate (129.3 mg, 1.22 mmol) were added. The mixture was heated to 60°C and stirred for 16 h. After the reaction was complete, the mixture was cooled to room temperature. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-80%) as the eluent to provide tert-butyl 7'-bromo-8'-cyano-4'-cyclopropyl-2'H,4'H-spiro[piperidine-4,3'-pyrido[3,2-b][1,4]oxazine]-1-carboxylate (pale yellow solid, 250 mg, 91.5%). MS (ESI + ) m/z = 449.1 [M+H] + .

中间体A26. 7'-氯-8'-氰基-2'H,4'H-螺[哌啶-4,3'-吡喃并[3,2-b]吡啶]-1-羧酸叔丁酯的制备
Intermediate A26. Preparation of tert-butyl 7'-chloro-8'-cyano-2'H,4'H-spiro[piperidin-4,3'-pyrano[3,2-b]pyridine]-1-carboxylate

第一步：将(5-氯-3-氟吡啶-2-基)甲醇(20g,123.79mmol)溶于二氯甲烷(200mL)中，在0℃下加入二氯亚砜(29.5g,247.59mmol)，恢复至室温搅拌4h，反应完全后减压浓缩，所得残余物加入饱和的碳酸氢钠水溶液(25mL)，混合液用二氯甲烷(30mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到5-氯-2-氯甲基-3-氟吡啶(棕色油状物,粗品)。Step 1: Dissolve (5-chloro-3-fluoropyridin-2-yl)methanol (20 g, 123.79 mmol) in dichloromethane (200 mL), add dichlorothionyl (29.5 g, 247.59 mmol) at 0°C, return to room temperature and stir for 4 hours. After the reaction is complete, concentrate under reduced pressure, add saturated aqueous sodium bicarbonate solution (25 mL) to the residue, and extract the mixture with dichloromethane (30 mL×3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give 5-chloro-2-chloromethyl-3-fluoropyridine (brown oil, crude product).

第二步：氮气保护下，将4-甲基哌啶-1,4-二甲酸1-叔丁基酯(27.3g,112.22mmol)溶于四氢呋喃(200mL)，降温至-78℃，缓慢加入LDA的四氢呋喃溶液(77mL,2M)，在-78℃搅拌2h，然后加入5-氯-2-氯甲基-3-氟吡啶(20.2g,112.22mmol)，在-78℃搅拌2h，反应完全后，往反应液中加入饱和的氯化铵溶液(150mL)，混合液用乙酸乙酯(200mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-50％)为洗脱剂梯度洗脱分离纯化得到4-甲氧基羰基-4-((5-氯-3-氟吡啶-2-基)甲基)哌啶-1-羧酸叔丁酯(白色固体,34.2g,78.8％)。MS(ESI+)m/z＝287.1[M+H-Boc]+。Step 2: Under nitrogen protection, 1-tert-butyl 4-methylpiperidine-1,4-dicarboxylate (27.3 g, 112.22 mmol) was dissolved in tetrahydrofuran (200 mL), cooled to -78 ° C, and a tetrahydrofuran solution of LDA (77 mL, 2 M) was slowly added. The mixture was stirred at -78 ° C for 2 h, and then 5-chloro-2-chloromethyl-3-fluoropyridine (20.2 g, 112.22 mmol) was added. The mixture was stirred at -78 ° C for 2 h. After the reaction was complete, the mixture was added to the reaction mixture. Saturated ammonium chloride solution (150 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (200 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-50%) as the eluent to provide tert-butyl 4-methoxycarbonyl-4-((5-chloro-3-fluoropyridin-2-yl)methyl)piperidine-1-carboxylate (white solid, 34.2 g, 78.8%). MS (ESI + ) m/z = 287.1 [M+H-Boc] + .

第三步：氮气保护下，将4-甲氧基羰基-4-((5-氯-3-氟吡啶-2-基)甲基)哌啶-1-羧酸叔丁酯(34.2g,88.40mmol)溶于四氢呋喃(300mL)，降温至0℃，加入四氢铝锂的四氢呋喃溶液(36mL,2.5M,88.40mmol)，恢复至室温搅拌3h，反应完全后，往反应液中加入酒石酸钠水溶液(10mL)，抽滤，滤液用乙酸乙酯(200mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-100％)为洗脱剂梯度洗脱分离纯化得到4-((5-氯-3-氟吡啶-2-基)甲基)-4-(羟甲基)哌啶-1-羧酸叔丁酯(黄色油状物,23g,72.5％)。MS(ESI+)m/z＝359.2[M+H]+。Step 3: Under nitrogen protection, tert-butyl 4-methoxycarbonyl-4-((5-chloro-3-fluoropyridin-2-yl)methyl)piperidine-1-carboxylate (34.2 g, 88.40 mmol) was dissolved in tetrahydrofuran (300 mL), cooled to 0°C, and a tetrahydrofuran solution of lithium aluminum hydroxide (36 mL, 2.5 M, 88.40 mmol) was added. The mixture was returned to room temperature and stirred for 3 h. After the reaction was complete, an aqueous solution of sodium tartrate was added to the reaction solution. The product was added to a 10 mL flask, filtered, and the filtrate was extracted with ethyl acetate (200 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-100%) as the eluent to give tert-butyl 4-((5-chloro-3-fluoropyridin-2-yl)methyl)-4-(hydroxymethyl)piperidine-1-carboxylate (yellow oil, 23 g, 72.5%). MS (ESI + ) m/z = 359.2 [M+H] + .

第四步：氮气保护下，将4-((5-氯-3-氟吡啶-2-基)甲基)-4-(羟甲基)哌啶-1-羧酸叔丁酯(23g,64.10mmol)溶于N,N-二甲基甲酰胺(200mL)，降温至0℃，分批加入咪唑(13.1g,192.29mmol)，然后滴加叔丁基二甲基氯硅烷的N,N-二甲基甲酰胺溶液(14.5g,96.14mmol,30mL)，室温下搅拌5h，反应完全后冷却至室温，往反应液中加入水(100mL)，混合液用乙酸乙酯(200mL×3)萃取，合并有机相用饱和食盐水(100mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-50％)为洗脱剂梯度洗脱分离纯化得到4-(((叔丁基二甲基硅烷基)氧基)甲基)-4-((5-氯-3-氟吡啶-2-基)甲基)哌啶-1-羧酸叔丁酯(无色油状物,27.1g,89.3％)。MS(ESI+)m/z＝417.2[M+H-56]+。Step 4: Under nitrogen protection, tert-butyl 4-((5-chloro-3-fluoropyridin-2-yl)methyl)-4-(hydroxymethyl)piperidine-1-carboxylate (23 g, 64.10 mmol) was dissolved in N,N-dimethylformamide (200 mL), cooled to 0 ° C, imidazole (13.1 g, 192.29 mmol) was added in batches, and then tert-butyldimethylsilyl chloride N,N-dimethylformamide solution (14.5 g, 96.14 mmol, 30 mL) was added dropwise. Stir at room temperature for 5 h. After the reaction was complete, cool to room temperature and add the reaction mixture. Water (100 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-50%) as eluent to provide tert-butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-((5-chloro-3-fluoropyridin-2-yl)methyl)piperidine-1-carboxylate (colorless oil, 27.1 g, 89.3%). MS (ESI + ) m/z = 417.2 [M+H-56] + .

第五步：氮气保护下，将二异丙胺(12mL)溶于四氢呋喃(230mL)，降温至-78℃，缓慢滴入正丁基锂(29mL,2.5M)，升温至0℃搅拌1h，然后降温至-78℃，缓慢滴加4-(((叔丁基二甲基硅烷基)氧基)甲基)-4-((5-氯-3-氟吡啶-2-基)甲基)哌啶-1-羧酸叔丁酯的四氢呋喃溶液(23g,48.62mmol,50mL)，-78℃下搅拌3h，然后将反应液缓慢倒入碎干冰中，搅拌至干冰挥发，加入冰的碳酸氢铵溶液(150mL)，混合液用乙酸乙酯(250mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到2-((1-(叔丁氧羰基)-4-(((叔丁基二甲基硅烷基)氧基)甲基)哌啶-4-基)甲基)-5-氯-3-氟异烟酸(无色油状物,25g,粗品)。MS(ESI+)m/z＝517.2[M+H]+。Step 5: Under nitrogen protection, diisopropylamine (12 mL) was dissolved in tetrahydrofuran (230 mL), cooled to -78 ° C, and n-butyl lithium (29 mL, 2.5 M) was slowly added dropwise. The temperature was raised to 0 ° C and stirred for 1 h. Then the temperature was lowered to -78 ° C, and a tetrahydrofuran solution of tert-butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-((5-chloro-3-fluoropyridin-2-yl)methyl)piperidine-1-carboxylate (23 g, 48.62 mmol, 50 mL) was slowly added dropwise. The reaction mixture was stirred at -78°C for 3 h, then slowly poured into crushed dry ice and stirred until the dry ice evaporated. Glacial ammonium bicarbonate solution (150 mL) was added, and the mixture was extracted with ethyl acetate (250 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield 2-((1-(tert-butyloxycarbonyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)piperidin-4-yl)methyl)-5-chloro-3-fluoroisonicotinic acid (a colorless oil, 25 g, crude). MS (ESI + ) m/z = 517.2 [M+H] + .

第六步：将2-((1-(叔丁氧羰基)-4-(((叔丁基二甲基硅烷基)氧基)甲基)哌啶-4-基)甲基)-5-氯-3-氟异烟酸(25g,48.35mmol)溶于N,N-二甲基甲酰胺(250mL)，降温至0℃，依次加入HOBT(9.8g,72.52mmol)，EDCI(11.3g,72.52mmol)和氯化铵(7.8g,145.04mmol)，室温下搅拌2h，反应完全后，往反应液中加入水(150mL)，混合液用乙酸乙酯(300mL×3)萃取，合并有机相用饱和食盐水(100mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-100％)为洗脱剂梯度洗脱分离纯化得到4-(((叔丁基二甲基硅烷基)氧基)甲基)-4-((4-氨基甲酰基-5-氯-3-氟吡啶-2-基)甲基)哌啶-1-羧酸叔丁酯(无色油状物,18g,72.1％)。MS(ESI+)m/z＝538.2[M+Na]+。Step 6: Dissolve 2-((1-(tert-butyloxycarbonyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)piperidin-4-yl)methyl)-5-chloro-3-fluoroisonicotinic acid (25 g, 48.35 mmol) in N,N-dimethylformamide (250 mL), cool to 0°C, add HOBT (9.8 g, 72.52 mmol), EDCI (11.3 g, 72.52 mmol) and ammonium chloride (7.8 g, 145.04 mmol) in sequence, stir at room temperature for 2 h, and after the reaction is complete, add The mixture was added to a flask of water (150 mL), extracted with ethyl acetate (300 mL × 3), and the combined organic phases were washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting residue was isolated and purified by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-100%) as the eluent to provide tert-butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-((4-carbamoyl-5-chloro-3-fluoropyridin-2-yl)methyl)piperidine-1-carboxylate (colorless oil, 18 g, 72.1%). MS (ESI + ) m/z = 538.2 [M+Na] + .

第七步：氮气保护下，将4-(((叔丁基二甲基硅烷基)氧基)甲基)-4-((4-氨基甲酰基-5-氯-3-氟吡啶-2-基)甲基)哌啶-1-羧酸叔丁酯(18g,34.88mmol)溶于二氯甲烷(200mL)，降温至0℃，依次滴加三乙胺(10.6g,104.63mmol)和三氟乙酸酐(11.0g,52.31mmol)，室温下搅拌2h。反应完全后，往反应液中加入水(100mL)，混合液用二氯甲烷(200mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-50％)为洗脱剂梯度洗脱分离纯化得到4-(((叔丁基二甲基硅烷基)氧基)甲基)-4-((5-氯-4-氰基-3-氟吡啶-2-基)甲基)哌啶-1-羧酸叔丁酯(黄色油状物,14g,80.6％)。S(ESI+)m/z＝498.3[M+H]+。Step 7: Under nitrogen protection, tert-butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-((4-carbamoyl-5-chloro-3-fluoropyridin-2-yl)methyl)piperidine-1-carboxylate (18 g, 34.88 mmol) was dissolved in dichloromethane (200 mL), cooled to 0°C, and triethylamine (10.6 g, 104.63 mmol) and trifluoroacetic anhydride (11.0 g, 52.31 mmol) were added dropwise in sequence, and stirred at room temperature for 2 h. After the reaction was complete, water (100 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (200 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-50%) as the eluent to provide tert-butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-((5-chloro-4-cyano-3-fluoropyridin-2-yl)methyl)piperidine-1-carboxylate (yellow oil, 14 g, 80.6%). S(ESI + ) m/z = 498.3 [M+H] + .

第八步：氮气保护下，将4-(((叔丁基二甲基硅烷基)氧基)甲基)-4-((5-氯-4-氰基-3-氟吡啶-2-基)甲基)哌啶-1-羧酸叔丁酯(14g,28.11mmol)溶于四氢呋喃(45mL)，加入三乙胺三氢氟酸盐(90mL)，升温至65℃下搅拌5h。反应完全后冷却至室温，往反应液中加入饱和的食盐水(80mL)，混合液用乙酸乙酯(150mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-60％)为洗脱剂梯度洗脱分离纯化得到4-((5-氯-4-氰基-3-氟吡啶-2-基)甲基)-4-(羟甲基)哌啶-1-羧酸叔丁酯(黄色油状物,10.2g,95.5％)。MS(ESI+)m/z＝284.1[M+H-Boc]+。Step 8: Under nitrogen protection, tert-butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-((5-chloro-4-cyano-3-fluoropyridin-2-yl)methyl)piperidine-1-carboxylate (14 g, 28.11 mmol) was dissolved in tetrahydrofuran (45 mL), triethylamine trihydrofluoride (90 mL) was added, and the temperature was raised to 65 ° C and stirred for 5 h. After the reaction was complete, the mixture was cooled to room temperature and saturated brine (80 mL) was added. The mixture was extracted with ethyl acetate (150 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-60%) as eluent to provide tert-butyl 4-((5-chloro-4-cyano-3-fluoropyridin-2-yl)methyl)-4-(hydroxymethyl)piperidine-1-carboxylate (yellow oil, 10.2 g, 95.5%). MS (ESI + ) m/z = 284.1 [M+H-Boc] + .

第九步：氮气保护下，将4-((5-氯-4-氰基-3-氟吡啶-2-基)甲基)-4-(羟甲基)哌啶-1-羧酸叔丁酯(10.2g,26.57mmol)溶于1,4-二氧六环(500mL)，加入碳酸铯(43.3g,132.87mmol)，升温至120℃下搅拌3h。反应完全后冷却至室温，减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-100％)为洗脱剂梯度洗脱分离纯化得到7'-氯-8'-氰基-2'H,4'H-螺[哌啶-4,3'-吡喃并[3,2-b]吡啶]-1-羧酸叔丁酯(白色固体,8g,82.7％)。MS(ESI+)m/z＝308.1[M+H-56]+。Step 9: Under nitrogen, tert-butyl 4-((5-chloro-4-cyano-3-fluoropyridin-2-yl)methyl)-4-(hydroxymethyl)piperidine-1-carboxylate (10.2 g, 26.57 mmol) was dissolved in 1,4-dioxane (500 mL), and cesium carbonate (43.3 g, 132.87 mmol) was added. The mixture was heated to 120°C and stirred for 3 h. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-100%) to obtain tert-butyl 7'-chloro-8'-cyano-2'H,4'H-spiro[piperidine-4,3'-pyrano[3,2-b]pyridine]-1-carboxylate (white solid, 8 g, 82.7%). MS(ESI + )m/z=308.1[M+H-56] + .

中间体A27. 7'-氯-8'-氰基-2'H,4'H-螺[哌啶-4,3'-吡喃并[3,2-b]苯]-1-羧酸叔丁酯的制备
Intermediate A27. Preparation of tert-butyl 7'-chloro-8'-cyano-2'H,4'H-spiro[piperidin-4,3'-pyrano[3,2-b]benzene]-1-carboxylate

第一步:氮气保护下，将叔丁醇钾(4.0g,35.17mmol)溶于四氢呋喃(70mL)，降温至-30℃，加入1-叔丁氧羰基哌啶-4-甲醛(5.0g,23.44mmol)的四氢呋喃溶液(10mL)，-30℃搅拌0.5h，然后滴加1-(溴甲基)-4-氯-2-氟苯(6.3g,28.13mmol)的四氢呋喃溶液(10mL)，-30℃搅拌1h，反应完全后恢复至室温，往反应液中加水(100mL)，混合液用乙酸乙酯(150mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-50％)为洗脱剂梯度洗脱分离，得到4-(4-氯-2-氟苄基)-4-甲酰哌啶-1-甲酸叔丁酯(无色油状物,6g,71.9％)。MS(ESI+)m/z＝300.0[M+H-56]+。Step 1: Under nitrogen protection, potassium tert-butoxide (4.0 g, 35.17 mmol) was dissolved in tetrahydrofuran (70 mL), cooled to -30 ° C, and a tetrahydrofuran solution (10 mL) of 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde (5.0 g, 23.44 mmol) was added, stirred at -30 ° C for 0.5 h, and then a tetrahydrofuran solution (10 mL) of 1-(bromomethyl)-4-chloro-2-fluorobenzene (6.3 g, 28.13 mmol) was added dropwise, and the mixture was stirred at -30 ° C for 0.5 h. The mixture was stirred at 0°C for 1 hour. After the reaction was complete, the temperature was restored to room temperature. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (150 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-50%) as the eluent to give tert-butyl 4-(4-chloro-2-fluorobenzyl)-4-formylpiperidine-1-carboxylate (colorless oil, 6 g, 71.9%). MS (ESI + ) m/z = 300.0 [M+H-56] + .

第二步至第六步：以4-(4-氯-2-氟苄基)-4-甲酰哌啶-1-甲酸叔丁酯为原料，按照中间体A26第三步至第七步方法制备4-(((叔丁基二甲基硅烷基)氧基)甲基)-4-((4-氯-3-氰基-2-氟吡啶-2-基)甲基)哌啶-1-羧酸叔丁酯，MS(ESI+)m/z＝397.3[M+H-Boc]+。Steps 2 to 6: Starting from tert-butyl 4-(4-chloro-2-fluorobenzyl)-4-formylpiperidine-1-carboxylate, tert-butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-((4-chloro-3-cyano-2-fluoropyridin-2-yl)methyl)piperidine-1-carboxylate was prepared according to the procedure of Intermediate A26, Steps 3 to 7. MS (ESI + ) m/z = 397.3 [M+H-Boc] + .

第七步：氮气保护下，将4-(((叔丁基二甲基硅烷基)氧基)甲基)-4-((4-氯-3-氰基-2-氟吡啶-2-基)甲基)哌啶-1-羧酸叔丁酯(4.8g,9.7mmol)溶于四氢呋喃(50mL)，加入TBAF的四氢呋喃溶液(1M,19.3mL,19.3mmol)，室温搅拌1h。反应完全后，往反应液中加水(20mL)，混合液用乙酸乙酯(50mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-100％)为洗脱剂梯度洗脱分离得到7'-氯-8'-氰基-2'H,4'H-螺[哌啶-4,3'-吡喃并[3,2-b]苯]-1-羧酸叔丁酯(白色固体,3.6g,92.5％)。MS(ESI+)m/z＝363.1[M+H]+。Step 7: Under nitrogen protection, tert-butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-((4-chloro-3-cyano-2-fluoropyridin-2-yl)methyl)piperidine-1-carboxylate (4.8 g, 9.7 mmol) was dissolved in tetrahydrofuran (50 mL), and a tetrahydrofuran solution of TBAF (1 M, 19.3 mL, 19.3 mmol) was added and stirred at room temperature for 1 h. After the reaction was complete, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-100%) as the eluent to afford tert-butyl 7'-chloro-8'-cyano-2'H,4'H-spiro[piperidin-4,3'-pyrano[3,2-b]benzene]-1-carboxylate (white solid, 3.6 g, 92.5%). MS (ESI + ) m/z = 363.1 [M+H] + .

中间体A28.(S)-10-溴-7-氰基-8-硝基-1,2,4a,5-四氢苯并[b]吡嗪[1,2-d][1,4]噁嗪-3(4H)-甲酸叔丁酯的制备
Intermediate A28. Preparation of tert-butyl (S)-10-bromo-7-cyano-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate

以2,3-二氟-6-硝基苯腈和(3S)-3-(羟甲基)哌嗪-1-羧酸叔丁酯为原料，按照中间体A18合成方法制备(S)-7-氰基-8-硝基-1,2,4a,5-四氢苯并[b]吡嗪[1,2-d][1,4]噁嗪-3(4H)-甲酸叔丁酯。MS(ESI+)m/z＝383.0[M+H-56]+。(S)-tert-Butyl 7-cyano-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate was prepared using 2,3-difluoro-6-nitrobenzonitrile and tert-butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate as starting materials according to the synthetic method of Intermediate A18. MS (ESI + ) m/z = 383.0 [M+H-56] + .

中间体A29. 8-氯-5-氰基-6-硝基-3H-螺[苯并[b][1,4]二氧六环-2,4'-哌啶]-1'-甲酸叔丁酯的制备
Intermediate A29. Preparation of tert-butyl 8-chloro-5-cyano-6-nitro-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-1'-carboxylate

第一步：将2,3-二氟-6-硝基苯胺(10g,57.44mmol)溶于N,N-二甲基甲酰胺(100mL)，降温至0℃，缓慢加入N-氯代丁二酰亚胺(15.3g,114.87mmol)，升温至80℃搅拌过夜。反应完全后冷却至室温，往反应液中加入水(30mL)，混合液用乙酸乙酯(50mL)萃取，合并有机相用水(30mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0％-20％)为洗脱剂梯度洗脱分离纯化得到4-氯-2,3-二氟-6-硝基苯胺(绿色固体,6.7g,55.9％)。Step 1: Dissolve 2,3-difluoro-6-nitroaniline (10 g, 57.44 mmol) in N,N-dimethylformamide (100 mL), cool to 0°C, slowly add N-chlorosuccinimide (15.3 g, 114.87 mmol), and heat to 80°C with stirring overnight. After the reaction is complete, cool to room temperature, add water (30 mL), and extract the mixture with ethyl acetate (50 mL). The combined organic phases are washed with water (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0%-20%) to afford 4-chloro-2,3-difluoro-6-nitroaniline (green solid, 6.7 g, 55.9%).

第二步：氮气保护下，将4-氯-2,3-二氟-6-硝基苯胺(6.7g,32.13mmol)溶于乙腈(70mL)，加入溴化铜(1.1g,48.19mmol)，降温至0℃，缓慢滴加亚硝酸叔丁酯(6.6g,64.25mmol)，恢复至室温搅拌30min，然后继续升温至60℃搅拌过夜。反应完全后冷却至室温，倒入冰水(50mL)中，加入氨水(30mL)，混合物用乙酸乙酯(50mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-1％)为洗脱剂梯度洗脱分离纯化得到2-溴-5-氯-3,4-二氟-1-硝基苯(黄色液体,5.2g,59.4％)。Step 2: Under nitrogen, 4-chloro-2,3-difluoro-6-nitroaniline (6.7 g, 32.13 mmol) was dissolved in acetonitrile (70 mL). Copper bromide (1.1 g, 48.19 mmol) was added. The temperature was cooled to 0°C, and tert-butyl nitrite (6.6 g, 64.25 mmol) was slowly added dropwise. The mixture was returned to room temperature and stirred for 30 minutes. The temperature was then raised to 60°C and stirred overnight. After the reaction was complete, the mixture was cooled to room temperature and poured into ice water (50 mL). Ammonia (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-1%) to afford 2-bromo-5-chloro-3,4-difluoro-1-nitrobenzene (yellow liquid, 5.2 g, 59.4%).

第三步：氮气保护下，将2-溴-5-氯-3,4-二氟-1-硝基苯(5.2g,19.09mmol)溶于N,N-二甲基甲酰胺(50mL)，加入氰化亚铜(3.4g,38.17mmol)，升温至120℃搅拌6h。反应完全后冷却至室温，往反应液中加入水(20mL)，混合液用乙酸乙酯(50mL)萃取，合并有机相用水(30mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-50％)为洗脱剂梯度洗脱分离纯化得到4-氯-2,3-二氟-6-硝基苯腈(黄色固体,2.5g,59.9％)。Step 3: Under nitrogen, 2-bromo-5-chloro-3,4-difluoro-1-nitrobenzene (5.2 g, 19.09 mmol) was dissolved in N,N-dimethylformamide (50 mL). Cuprous cyanide (3.4 g, 38.17 mmol) was added and the mixture was heated to 120°C and stirred for 6 h. After the reaction was complete, the mixture was cooled to room temperature and water (20 mL) was added. The mixture was extracted with ethyl acetate (50 mL). The combined organic phases were washed with water (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-50%) to afford 4-chloro-2,3-difluoro-6-nitrobenzonitrile (yellow solid, 2.5 g, 59.9%).

第四步：将4-氯-2,3-二氟-6-硝基苯腈(2.5g,11.44mmol)溶于1,4-二氧六环(30mL)，依次加入碳酸铯(18.6g,57.20mmol)和4-羟基-4-(羟甲基)哌啶-1-甲酸叔丁酯(2.7g,11.44mmol)，升温至120℃搅拌1h。反应完全后冷却至室温，往反应液中加入水(20mL)，混合液用乙酸乙酯(30mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-50％)为洗脱剂梯度洗脱分离纯化得到8-氯-5-氰基-6-硝基-3H-螺[苯并[b][1,4]二氧六环-2,4'-哌啶]-1'-甲酸叔丁酯(黄色固体,3.3g,70.4％)。MS(ESI+)m/z＝354.1[M+H-56]+。Step 4: Dissolve 4-chloro-2,3-difluoro-6-nitrobenzonitrile (2.5 g, 11.44 mmol) in 1,4-dioxane (30 mL), add cesium carbonate (18.6 g, 57.20 mmol) and tert-butyl 4-hydroxy-4-(hydroxymethyl)piperidine-1-carboxylate (2.7 g, 11.44 mmol) in sequence, and heat to 120 ° C and stir for 1 h. After the reaction was complete, the mixture was cooled to room temperature and water (20 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-50%) as the eluent to afford tert-butyl 8-chloro-5-cyano-6-nitro-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-1'-carboxylate (yellow solid, 3.3 g, 70.4%). MS (ESI + ) m/z = 354.1 [M+H-56] + .

中间体A30. 8-溴-5-氰基-6-硝基-3H-螺[苯并[b][1,4]二氧六环-2,4'-哌啶]-1'-甲酸叔丁酯的制备
Intermediate A30. Preparation of tert-butyl 8-bromo-5-cyano-6-nitro-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-1'-carboxylate

以中间体A11为原料，按照中间体A13第二步方法制备8-溴-5-氰基-6-硝基-3H-螺[苯并[b][1,4]二氧六环-2,4'-哌啶]-1'-甲酸叔丁酯。Using intermediate A11 as starting material, tert-butyl 8-bromo-5-cyano-6-nitro-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-1'-carboxylate was prepared according to the second step method of intermediate A13.

中间体A31. 7'-氯-8'-氰基-4'-氧代-2'H,4'H-螺[哌啶-4,3'-吡喃并[3,2-b]吡啶]-1-甲酸叔丁酯的制备
Intermediate A31. Preparation of tert-butyl 7'-chloro-8'-cyano-4'-oxo-2'H,4'H-spiro[piperidin-4,3'-pyrano[3,2-b]pyridine]-1-carboxylate

第一步：氮气保护下，将N-Boc-4-哌啶甲酸甲酯(7.0g,28.77mmol)溶于四氢呋喃(100mL)，降温至-78℃，滴加LDA的四氢呋喃溶液(2M,21.6mL,43.16mmol)，-78℃搅拌1h，然后滴加5-氯-3-氟吡啶-2-甲醛(5.0g,31.65mmol)的四氢呋喃溶液(20mL)，继续搅拌1h。反应完全后恢复至室温，往反应液中加饱和氯化铵水溶液(80mL)，混合液用乙酸乙酯(100mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-30％)为洗脱剂梯度洗脱分离，得到N-Boc-4-((5-氯-3-氟吡啶-2-基)(羟基)甲基)哌啶-4-甲酸乙酯(无色透明油状物,9g,77.7％)。MS(ESI+)m/z＝403.2[M+H]+。Step 1: Under nitrogen protection, dissolve methyl N-Boc-4-piperidincarboxylate (7.0 g, 28.77 mmol) in tetrahydrofuran (100 mL), cool to -78 ° C, add LDA solution in tetrahydrofuran (2 M, 21.6 mL, 43.16 mmol) dropwise, stir at -78 ° C for 1 h, then add 5-chloro-3-fluoropyridine-2-carboxaldehyde (5.0 g, 31.65 mmol) in tetrahydrofuran (20 mL) dropwise, and continue stirring for 1 h. After the reaction was complete, the mixture was returned to room temperature and saturated aqueous ammonium chloride (80 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-30%) as the eluent to afford ethyl N-Boc-4-((5-chloro-3-fluoropyridin-2-yl)(hydroxy)methyl)piperidine-4-carboxylate as a colorless, transparent oil (9 g, 77.7%). MS (ESI + ) m/z = 403.2 [M+H] + .

第二步：氮气保护下，将N-Boc-4-((5-氯-3-氟吡啶-2-基)(羟基)甲基)哌啶-4-甲酸乙酯(9.0g,22.34mmol)溶于四氢呋喃(150mL)，降温至0℃，缓慢加入硼氢化锂的四氢呋喃溶液(2M,44.7mL,89.36mmol)，室温搅拌1h。反应完全后，往反应液中加冰水(50mL)，混合液用乙酸乙酯(50mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-50％)为洗脱剂洗脱分离，得到4-((5-氯-3-氟吡啶-2-基)(羟基)甲基)-4-(羟甲基)哌啶-1-甲酸叔丁酯(白色固体,7g,83.6％)。MS(ESI+)m/z＝375.2[M+H]+。Step 2: Under nitrogen, ethyl N-Boc-4-((5-chloro-3-fluoropyridin-2-yl)(hydroxy)methyl)piperidine-4-carboxylate (9.0 g, 22.34 mmol) was dissolved in tetrahydrofuran (150 mL). The temperature was lowered to 0°C, and a 2M solution of lithium borohydride in tetrahydrofuran (44.7 mL, 89.36 mmol) was slowly added. The mixture was stirred at room temperature for 1 h. After the reaction was complete, ice water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography using ethyl acetate/petroleum ether (0-50%) as the eluent to afford tert-butyl 4-((5-chloro-3-fluoropyridin-2-yl)(hydroxy)methyl)-4-(hydroxymethyl)piperidine-1-carboxylate (white solid, 7 g, 83.6%). MS(ESI + )m/z=375.2[M+H] + .

第三步：将4-((5-氯-3-氟吡啶-2-基)(羟基)甲基)-4-(羟甲基)哌啶-1-甲酸叔丁酯(7.0g,18.67mmol)溶于DMF(100mL)，加入咪唑(3.8g,56.02mmol)，降温至0℃，缓慢加入TBSCl(5.6g,37.35mmol),室温搅拌16h。反应完全后，往反应液中加水(50mL)，混合液用乙酸乙酯(50mL×3)萃取，合并有机相用水(50mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-30％)为洗脱剂梯度洗脱分离，得到4-(((叔丁基二甲基硅烷基)氧基)甲基)-4-((5-氯-3-氟吡啶-2-基)(羟基)甲基)哌啶-1-甲酸叔丁酯(无色透明油状物,8g,87.6％)。MS(ESI+)m/z＝489.3[M+H]+。Step 3: Dissolve tert-butyl 4-((5-chloro-3-fluoropyridin-2-yl)(hydroxy)methyl)-4-(hydroxymethyl)piperidine-1-carboxylate (7.0 g, 18.67 mmol) in DMF (100 mL), add imidazole (3.8 g, 56.02 mmol), cool to 0°C, slowly add TBSCl (5.6 g, 37.35 mmol), and stir at room temperature for 16 h. After the reaction was complete, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with water (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-30%) as the eluent to provide tert-butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-((5-chloro-3-fluoropyridin-2-yl)(hydroxy)methyl)piperidine-1-carboxylate (colorless, transparent oil, 8 g, 87.6%). MS (ESI + ) m/z = 489.3 [M+H] + .

第四步：氮气保护下，将4-(((叔丁基二甲基硅烷基)氧基)甲基)-4-((5-氯-3-氟吡啶-2-基)(羟基)甲基)哌啶-1-甲酸叔丁酯(8.0g,16.36mmol)溶于四氢呋喃溶液(150mL)，降温至-78℃，滴加LDA的四氢呋喃溶液(2M,12.3mL,24.54mmol)，-78℃搅拌4h。然后缓慢加入干冰，搅拌1h。反应完全后恢复至室温，往反应液中加饱和氯化铵水溶液(50mL)，混合液用乙酸乙酯(50mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到2-((1-(叔丁氧基羰基)-4-(((叔丁基二甲基硅烷基)氧基)甲基)哌啶-4-基)(羟基)甲基)-5-氯-3-氟异烟酸(白色固体,6.5g,粗品)。MS(ESI+)m/z＝533.3[M+H]+。Step 4: Under nitrogen, dissolve tert-butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-((5-chloro-3-fluoropyridin-2-yl)(hydroxy)methyl)piperidine-1-carboxylate (8.0 g, 16.36 mmol) in tetrahydrofuran (150 mL), cool to -78°C, add LDA solution in tetrahydrofuran (2 M, 12.3 mL, 24.54 mmol) dropwise, and stir at -78°C for 4 h. Then, slowly add dry ice and stir for 1 h. After the reaction was complete, the temperature was restored to room temperature. Saturated aqueous ammonium chloride (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2-((1-(tert-butoxycarbonyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)piperidin-4-yl)(hydroxy)methyl)-5-chloro-3-fluoroisonicotinic acid (white solid, 6.5 g, crude product). MS (ESI + ) m/z = 533.3 [M+H] + .

第五步：氮气保护下，将2-((1-(叔丁氧基羰基)-4-(((叔丁基二甲基硅烷基)氧基)甲基)哌啶-4-基)(羟基)甲基)-5-氯-3-氟异烟酸(6.5g,12.19mmol)溶于DMF(100mL)，依次加入HOBT(2.5g,18.29mmol)和EDCI(3.5g,18.29mmol)，室温搅拌0.5h，然后缓慢加入氯化铵(3.3g,60.97mmol)，室温搅拌1h。反应完全后，往反应液中加水(50mL)，混合液用乙酸乙酯(50mL×3)萃取，合并有机相用水(50mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-100％)为洗脱剂梯度洗脱分离，得到4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-4-((4-氨基甲酰基-5-氯-3-氟吡啶-2-基)(羟基)甲基)哌啶-1-甲酸叔丁酯(白色固体,4.1g,63.2％)。MS(ESI+)m/z＝532.4[M+H]+。Step 5: Under nitrogen protection, 2-((1-(tert-butoxycarbonyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)piperidin-4-yl)(hydroxy)methyl)-5-chloro-3-fluoroisonicotinic acid (6.5 g, 12.19 mmol) was dissolved in DMF (100 mL), and HOBT (2.5 g, 18.29 mmol) and EDCI (3.5 g, 18.29 mmol) were added in sequence. The mixture was stirred at room temperature for 0.5 h, and then ammonium chloride (3.3 g, 60.97 mmol) was slowly added and stirred at room temperature for 1 h. After the reaction was complete, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with water (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-100%) as the eluent to give tert-butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-((4-carbamoyl-5-chloro-3-fluoropyridin-2-yl)(hydroxy)methyl)piperidine-1-carboxylate (white solid, 4.1 g, 63.2%). MS (ESI + ) m/z = 532.4 [M+H] + .

第六步：氮气保护下，将4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-4-((4-氨基甲酰基-5-氯-3-氟吡啶-2-基)(羟基)甲基)哌啶-1-甲酸叔丁酯(4.1g,7.71mmol)溶于二氯甲烷(80mL)，加入三乙胺(7.8g,77.05mmol)，降温至0℃，缓慢加入三氟乙酸酐(8.1g,38.53mmol)，室温搅拌1h。反应完全后，往反应液中加水(30mL)，混合液用二氯甲烷(50mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-100％)为洗脱剂梯度洗脱分离，得到4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-4-((5-氯-4-氰基-3-氟吡啶-2-基)(羟基)甲基)哌啶-1-甲酸叔丁酯(白色固体,2.7g,68.2％)。MS(ESI+)m/z＝414.2[M+H-100]+。Step 6: Under nitrogen protection, tert-butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-((4-carbamoyl-5-chloro-3-fluoropyridin-2-yl)(hydroxy)methyl)piperidine-1-carboxylate (4.1 g, 7.71 mmol) was dissolved in dichloromethane (80 mL), triethylamine (7.8 g, 77.05 mmol) was added, the temperature was lowered to 0°C, trifluoroacetic anhydride (8.1 g, 38.53 mmol) was slowly added, and the mixture was stirred at room temperature for 1 h. After the reaction was complete, water (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-100%) as the eluent to provide tert-butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-((5-chloro-4-cyano-3-fluoropyridin-2-yl)(hydroxy)methyl)piperidine-1-carboxylate (white solid, 2.7 g, 68.2%). MS (ESI + ) m/z = 414.2 [M+H-100] + .

第七步：氮气保护下，将4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-4-((5-氯-4-氰基-3-氟吡啶-2-基)(羟基)甲基)哌啶-1-甲酸叔丁酯(2.7g,5.25mmol)溶于四氢呋喃(40mL)，加入TBAF的四氢呋喃溶液(1M,10.5mL,10.51mmol)，室温搅拌1h。反应完全后，往反应液中加水(10mL)，混合液用乙酸乙酯(50mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-100％)为洗脱剂梯度洗脱分离，得到7'-氯-8'-氰基-4'-羟基-2'H,4'H-螺[哌啶-4,3'-吡喃并[3,2-b]吡啶]-1-甲酸叔丁酯(白色固体,1.4g,70.2％)。MS(ESI+)m/z＝324.1[M+H-56]+。Step 7: Under nitrogen protection, tert-butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-((5-chloro-4-cyano-3-fluoropyridin-2-yl)(hydroxy)methyl)piperidine-1-carboxylate (2.7 g, 5.25 mmol) was dissolved in tetrahydrofuran (40 mL), and a tetrahydrofuran solution of TBAF (1 M, 10.5 mL, 10.51 mmol) was added and stirred at room temperature for 1 h. After the reaction was complete, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-100%) as the eluent to obtain tert-butyl 7'-chloro-8'-cyano-4'-hydroxy-2'H,4'H-spiro[piperidin-4,3'-pyrano[3,2-b]pyridine]-1-carboxylate (white solid, 1.4 g, 70.2%). MS (ESI + ) m/z = 324.1 [M+H-56] + .

第八步：将7'-氯-8'-氰基-4'-羟基-2'H,4'H-螺[哌啶-4,3'-吡喃并[3,2-b]吡啶]-1-甲酸叔丁酯(400.0mg,1.05mmol)溶于氯仿(5mL)，加入二氧化锰(915.5mg,10.53mmol)，升温至60℃搅拌1h。反应完全后冷却至室温，反应液过滤，滤液减压浓缩，得到7'-氯-8'-氰基-4'-氧代-2'H,4'H-螺[哌啶-4,3'-吡喃并[3,2-b]吡啶]-1-甲酸叔丁酯(白色固体,400mg,粗品)。MS(ESI+)m/z＝400.2[M+Na]+。Step 8: Dissolve tert-butyl 7'-chloro-8'-cyano-4'-hydroxy-2'H,4'H-spiro[piperidine-4,3'-pyrano[3,2-b]pyridine]-1-carboxylate (400.0 mg, 1.05 mmol) in chloroform (5 mL). Add manganese dioxide (915.5 mg, 10.53 mmol). Heat to 60°C and stir for 1 hour. After the reaction is complete, cool to room temperature, filter the reaction mixture, and concentrate the filtrate under reduced pressure to obtain tert-butyl 7'-chloro-8'-cyano-4'-oxo-2'H,4'H-spiro[piperidine-4,3'-pyrano[3,2-b]pyridine]-1-carboxylate (white solid, 400 mg, crude). MS (ESI + ) m/z = 400.2 [M+Na] + .

中间体A32. 5-氰基-6-硝基-3H-8'-氮杂螺[苯并[b][1,4]二氧六环-2,3'-双环[3.2.1]辛烷]-8'-甲酸叔丁酯的制备
Intermediate A32. Preparation of tert-butyl 5-cyano-6-nitro-3H-8'-azaspiro[benzo[b][1,4]dioxane-2,3'-bicyclo[3.2.1]octane]-8'-carboxylate

第一步：氮气保护下，将甲基三苯基溴化鏻(23.8g,66.58mmol)溶于四氢呋喃(50mL)，降温至0℃，加入正丁基锂的正己烷溶液(2.5M,26.6mL,66.58mmol)，0℃搅拌1h。加入N-叔丁氧羰基去甲托品酮(5.0g,22.19mmol)，0℃搅拌2h。反应完全后恢复至室温，往反应液中加水(150mL)，混合液用乙酸乙酯(300mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(10％-50％)为洗脱剂梯度洗脱分离，得到3-亚甲基-8-氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(无色油状物,2.5g,50.5％)。Step 1: Under nitrogen, dissolve methyltriphenylphosphonium bromide (23.8 g, 66.58 mmol) in tetrahydrofuran (50 mL), cool to 0°C, add n-butyllithium in n-hexane (2.5 M, 26.6 mL, 66.58 mmol), and stir at 0°C for 1 h. Add N-tert-butyloxycarbonylnortropinone (5.0 g, 22.19 mmol), and stir at 0°C for 2 h. After the reaction was complete, the temperature was restored to room temperature, water (150 mL) was added to the reaction solution, and the mixed solution was extracted with ethyl acetate (300 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography using ethyl acetate/petroleum ether (10%-50%) as an eluent gradient elution to give tert-butyl 3-methylene-8-azabicyclo[3.2.1]octane-8-carboxylate (colorless oil, 2.5 g, 50.5%).

第二步：氮气保护下，将3-亚甲基-8-氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(2.1g,9.41mmol)溶于四氢呋喃和水混合液(4/1v/v,25mL)，降温至0℃，依次加入N-甲基吗啉氧化物(3.3g,28.25mmol),四氧化锇叔丁醇溶液(2％,3mL),恢复至室温并搅拌16h。反应完全后，往反应液中加亚硫酸钠水溶液(20mL)，搅拌0.5h。混合液用乙酸乙酯(50mL×3)萃取，合并有机相用用20％的柠檬酸水溶液(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到3-羟基-3-(羟甲基)-8-氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(黑色油状物,3g,粗品)。MS(ESI+)m/z＝280.2[M+Na]+。Step 2: Under nitrogen, tert-butyl 3-methylene-8-azabicyclo[3.2.1]octane-8-carboxylate (2.1 g, 9.41 mmol) was dissolved in a mixture of tetrahydrofuran and water (4/1 v/v, 25 mL). The mixture was cooled to 0°C, and N-methylmorpholine oxide (3.3 g, 28.25 mmol) and 2% osmium tetroxide in tert-butyl alcohol (3 mL) were added sequentially. The mixture was allowed to return to room temperature and stirred for 16 h. After the reaction was complete, aqueous sodium sulfite solution (20 mL) was added to the reaction mixture and stirred for 0.5 h. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with 20% aqueous citric acid solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield tert-butyl 3-hydroxy-3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (3 g, crude black oil). MS(ESI + )m/z=280.2[M+Na] + .

第三步：以3-羟基-3-(羟甲基)-8-氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和2,3-二氟-6-硝基苯腈为原料，按照中间体A11的合成方法制备中间体A32。MS(ESI+)m/z＝346.1[M+H-56]+。Step 3: Intermediate A32 was prepared using tert-butyl 3-hydroxy-3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate and 2,3-difluoro-6-nitrobenzonitrile as starting materials according to the synthetic method of Intermediate A11. MS (ESI + ) m/z = 346.1 [M+H-56] + .

中间体A33和A34的制备Preparation of intermediates A33 and A34

以市售或制备得到的氟苯化合物和市售4-甲酰哌啶-1-羧酸叔丁酯为原料，按照合成中间体A27的方法制备中间体A33和A34。如表2所示。Intermediates A33 and A34 were prepared using commercially available or prepared fluorobenzene compounds and commercially available tert-butyl 4-formylpiperidine-1-carboxylate as raw materials according to the method for synthesizing intermediate A27, as shown in Table 2.

表2中间体A33和A34的结构、制备原料以及MS数据
Table 2 Structures, raw materials and MS data of intermediates A33 and A34

中间体A35. 7'-氯-8'-氰基-4',4'-二氟-2'H,4'H-螺[哌啶-4,3'-吡喃并[3,2-b]吡啶]-1-甲酸叔丁酯的制备
Intermediate A35. Preparation of tert-butyl 7'-chloro-8'-cyano-4',4'-difluoro-2'H,4'H-spiro[piperidin-4,3'-pyrano[3,2-b]pyridine]-1-carboxylate

氮气保护下，将7'-氯-8'-氰基-4'-氧代-2'H,4'H-螺[哌啶-4,3'-吡喃并[3,2-b]吡啶]-1-甲酸叔丁酯(中间体A31,300.0mg,0.79mmol)溶于BAST(5mL)，室温搅拌3h。反应完全后，0℃下，往反应液中加碳酸氢钠水溶液(10mL)，混合液用乙酸乙酯(10mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以甲醇/二氯甲烷(0-10％)为洗脱剂梯度洗脱分离得到7'-氯-8'-氰基-4',4'-二氟-2'H,4'H-螺[哌啶-4,3'-吡喃并[3,2-b]吡啶]-1-甲酸叔丁酯(白色固体,200mg,63.0％)。MS(ESI+)m/z＝344.1[M+H-56]+。Under nitrogen, tert-butyl 7'-chloro-8'-cyano-4'-oxo-2'H,4'H-spiro[piperidine-4,3'-pyrano[3,2-b]pyridine]-1-carboxylate (Intermediate A31, 300.0 mg, 0.79 mmol) was dissolved in BAST (5 mL) and stirred at room temperature for 3 h. After the reaction was complete, aqueous sodium bicarbonate (10 mL) was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography using a gradient elution of methanol/dichloromethane (0-10%) as the eluent to afford tert-butyl 7'-chloro-8'-cyano-4',4'-difluoro-2'H,4'H-spiro[piperidin-4,3'-pyrano[3,2-b]pyridine]-1-carboxylate (white solid, 200 mg, 63.0%). MS (ESI + ) m/z = 344.1 [M+H-56] + .

中间体A36. 7-氯-8-氰基-4-氧代螺[色烷-3,4'-哌啶]-1'-甲酸叔丁酯的制备
Intermediate A36. Preparation of tert-butyl 7-chloro-8-cyano-4-oxospiro[chromane-3,4'-piperidine]-1'-carboxylate

第一步：以N-Boc-4-哌啶甲酸甲酯(3.0g,12.33mmol)和6-氯-2-氟-3-甲酰苯腈(2.2g,11.71mmol)为原料，按照合成中间体A31第一步的方法制备N-Boc-4-((4-氯-3-氰基-2-氟苯基)(羟基)甲基)哌啶-4-甲酸甲酯(黄色油状物,3g,57.0％)。MS(ESI+)m/z＝449.1[M+Na]+。Step 1: Using methyl N-Boc-4-piperidinylcarboxylate (3.0 g, 12.33 mmol) and 6-chloro-2-fluoro-3-formylbenzonitrile (2.2 g, 11.71 mmol) as starting materials, follow the procedure for Intermediate A31, Step 1, to prepare methyl N-Boc-4-((4-chloro-3-cyano-2-fluorophenyl)(hydroxy)methyl)piperidine-4-carboxylate (yellow oil, 3 g, 57.0%). MS (ESI + ) m/z = 449.1 [M+Na] + .

第二步：氮气保护下，将N-Boc-4-((4-氯-3-氰基-2-氟苯基)(羟基)甲基)哌啶-4-甲酸甲酯(3.0g,7.03mmol)溶于四氢呋喃(50mL)，降温至0℃，加入氢化铝锂(1.1g,28.11mmol)，加毕，恢复至室温搅拌2h。反应完全后，往反应液中加水(50mL)，混合液用乙酸乙酯(30mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-86％)为洗脱剂梯度洗脱分离，得到4-((4-氯-3-氰基-2-氟苯基)(羟基)甲基)-4-(羟甲基)哌啶-1-甲酸叔丁酯(淡黄色固体,2.1g,74.9％)。MS(ESI+)m/z＝299.1[M+H-100]+。Step 2: Under nitrogen, methyl N-Boc-4-((4-chloro-3-cyano-2-fluorophenyl)(hydroxy)methyl)piperidine-4-carboxylate (3.0 g, 7.03 mmol) was dissolved in tetrahydrofuran (50 mL), cooled to 0°C, and lithium aluminum hydride (1.1 g, 28.11 mmol) was added. After addition, the mixture was returned to room temperature and stirred for 2 h. After the reaction was complete, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-86%) to obtain tert-butyl 4-((4-chloro-3-cyano-2-fluorophenyl)(hydroxy)methyl)-4-(hydroxymethyl)piperidine-1-carboxylate (pale yellow solid, 2.1 g, 74.9%). MS(ESI + )m/z=299.1[M+H-100] + .

第三步:将4-((4-氯-3-氰基-2-氟苯基)(羟基)甲基)-4-(羟甲基)哌啶-1-甲酸叔丁酯(2.0g,5.01mmol)溶于1,4-二氧六环(30mL)，加入碳酸铯(3.3g,10.04mmol)，升温至120℃搅拌4h。反应完全后冷却至室温，往反应液中加水(50mL)，混合液用乙酸乙酯(50mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-24％)为洗脱剂梯度洗脱分离，得到7-氯-8-氰基-4-羟基螺[色烷-3,4'-哌啶]-1'-甲酸叔丁酯(淡黄色固体,1.7g,89.4％)。MS(ESI+)m/z＝379.2[M+H]+。Step 3: Dissolve tert-butyl 4-((4-chloro-3-cyano-2-fluorophenyl)(hydroxy)methyl)-4-(hydroxymethyl)piperidine-1-carboxylate (2.0 g, 5.01 mmol) in 1,4-dioxane (30 mL), add cesium carbonate (3.3 g, 10.04 mmol), and heat to 120°C with stirring for 4 h. After the reaction is complete, cool to room temperature, add water (50 mL), and extract the mixture with ethyl acetate (50 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue is separated by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-24%) to obtain tert-butyl 7-chloro-8-cyano-4-hydroxyspiro[chromane-3,4'-piperidine]-1'-carboxylate (pale yellow solid, 1.7 g, 89.4%). MS(ESI + )m/z=379.2[M+H] + .

第四步：以7-氯-8-氰基-4-羟基螺[色烷-3,4'-哌啶]-1'-甲酸叔丁酯(1.7g,4.49mmol)为原料，按照合成中间体A31第八步的方法制备7-氯-8-氰基-4-氧代螺[色烷-3,4'-哌啶]-1'-甲酸叔丁酯(白色固体,1.3g,76.8)。MS(ESI+)m/z＝320.1[M+H-56]+。Step 4: Using tert-butyl 7-chloro-8-cyano-4-hydroxyspiro[chromane-3,4'-piperidine]-1'-carboxylate (1.7 g, 4.49 mmol) as starting material, tert-butyl 7-chloro-8-cyano-4-oxospiro[chromane-3,4'-piperidine]-1'-carboxylate (white solid, 1.3 g, 76.8 g) was prepared according to the procedure for Intermediate A31, Step 8. MS (ESI + ) m/z = 320.1 [M+H-56] + .

中间体A37. 6-氰基-7-硝基-3,4-二氢螺[苯并[b][1,4]二噁英-2,4'-哌啶]-1'-羧酸叔丁酯的制备
Intermediate A37. Preparation of tert-butyl 6-cyano-7-nitro-3,4-dihydrospiro[benzo[b][1,4]dioxin-2,4'-piperidine]-1'-carboxylate

以2,3-氟-6-硝基苯腈和4-羟基-4-(2-羟乙基)哌啶-1-甲酸叔丁酯为原料，按照合成中间体A11的方法，120℃条件下，制备6-氰基-7-硝基-3,4-二氢螺[苯并[b][1,4]二噁英-2,4'-哌啶]-1'-羧酸叔丁酯(黄色固体)。MS(ESI+)m/z＝412.2[M+Na]+。Tert-butyl 6-cyano-7-nitro-3,4-dihydrospiro[benzo[b][1,4]dioxin-2,4'-piperidine]-1'-carboxylate (yellow solid) was prepared using 2,3-fluoro-6-nitrobenzonitrile and tert-butyl 4-hydroxy-4-(2-hydroxyethyl)piperidine-1-carboxylate as starting materials according to the method for synthesizing intermediate A11 at 120°C. MS (ESI + ) m/z = 412.2 [M+Na] + .

中间体A38. 7'-氯-8'-氰基-2'H-8-氮杂螺[双环[3.2.1]辛烷-3,3'-[1,4]二噁英并[2,3-b]吡啶]-8-甲酸叔丁酯的制备
Intermediate A38. Preparation of tert-butyl 7'-chloro-8'-cyano-2'H-8-azaspiro[bicyclo[3.2.1]octane-3,3'-[1,4]dioxino[2,3-b]pyridine]-8-carboxylate

以5-氯-2,3-二氟吡啶-4-甲腈和3-羟基-3-(羟甲基)-8-氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯为原料，按照合成中间体A11的方法，120℃条件下，制备中间体A38。MS(ESI+)m/z＝336.1[M+H-56]+ Intermediate A38 was prepared using 5-chloro-2,3-difluoropyridine-4-carbonitrile and tert-butyl 3-hydroxy-3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate as starting materials, following the method for synthesizing intermediate A11 at 120°C. MS (ESI + ) m/z = 336.1 [M+H-56] +

第三组制备例：中间体B1-B49制备The third group of preparation examples: preparation of intermediates B1-B49

中间体B1. 2-甲氧基-5-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯胺的制备
Intermediate B1. Preparation of 2-methoxy-5-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline

第一步：将1-氟-5-甲氧基-2-甲基-4-硝基苯(1.0g,5.40mmol)溶于N,N-二甲基甲酰胺溶液中(30mL)中，加入1-甲基-1H-苯并[d]咪唑-5-醇(1.2g,8.10mmol)和碳酸铯(5.3g,16.20mmol)，升温至120℃搅拌3h。反应完全后冷却至室温，减压浓缩得到粗产品，粗产品经硅胶柱层析以甲醇/二氯甲烷(10％)为洗脱剂分离纯化得到5-(5-甲氧基-2-甲基-4-硝基苯氧基)-1-甲基-1H-苯并[d]咪唑(类白色固体,1.5g,88.7％)。MS(ESI+)m/z＝314.1[M+H]+。Step 1: Dissolve 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene (1.0 g, 5.40 mmol) in N,N-dimethylformamide (30 mL). Add 1-methyl-1H-benzo[d]imidazol-5-ol (1.2 g, 8.10 mmol) and cesium carbonate (5.3 g, 16.20 mmol). Heat to 120°C and stir for 3 h. After completion, cool to room temperature and concentrate under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using methanol/dichloromethane (10%) as the eluent to afford 5-(5-methoxy-2-methyl-4-nitrophenoxy)-1-methyl-1H-benzo[d]imidazole (off-white solid, 1.5 g, 88.7%). MS (ESI + ) m/z = 314.1 [M+H] + .

第二步：将5-(5-甲氧基-2-甲基-4-硝基苯氧基)-1-甲基-1H-苯并[d]咪唑(1.5g,4.79mmol)溶于N,N-二甲基甲酰胺(30mL)中，降温至0℃，加入四羟基乙硼烷(2.1g,23.94mmol)和4,4'-联吡啶(3.7mg,0.024mmol)，恢复至室温搅拌10min。反应完全后，反应液用甲醇/二氯甲烷(1/10,30mL×3)萃取，合并有机相用水(30mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到2-甲氧基-5-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯胺(淡黄色固体,1g,73.7％)。MS(ESI+)m/z＝284.2[M+H]+。Step 2: Dissolve 5-(5-methoxy-2-methyl-4-nitrophenoxy)-1-methyl-1H-benzo[d]imidazole (1.5 g, 4.79 mmol) in N,N-dimethylformamide (30 mL). Cool to 0°C, add tetrahydroxydiborane (2.1 g, 23.94 mmol) and 4,4'-bipyridine (3.7 mg, 0.024 mmol), and stir at room temperature for 10 min. After the reaction is complete, extract with methanol/dichloromethane (1/10, 30 mL x 3). The combined organic phases are washed with water (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to yield 2-methoxy-5-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline (pale yellow solid, 1 g, 73.7%). MS(ESI + )m/z=284.2[M+H] + .

中间体B2-B8、B11-B29、B34-B49的制备Preparation of intermediates B2-B8, B11-B29, B34-B49

以市售或制备中间体醇或酚化合物和市售氟代硝基苯化合物，或者以市售或制备卤代杂芳基化合物和取代的硝基苯酚化合物为原料，按照合成中间体B1方法制备中间体B2-B8、B11-B29、B34-B49。如表3所示。Intermediates B2-B8, B11-B29, and B34-B49 were prepared using commercially available or prepared intermediate alcohol or phenol compounds and commercially available fluoronitrobenzene compounds, or commercially available or prepared halogenated heteroaryl compounds and substituted nitrophenol compounds as raw materials according to the method for synthesizing intermediate B1, as shown in Table 3.

第一步取代反应也可以通过以下条件制备：Na2CO3/K2CO3,DMF,80℃；K2CO3,DMSO,100℃，第二步还原反应条件也可以通过以下条件制备：氯化铵和铁粉，乙醇/水，80℃～90℃；氯化铵和铁粉，甲醇/水，60℃～80℃；钯碳(50％)和氢气，甲醇，r.t.。The first substitution reaction can also be prepared by the following conditions: Na 2 CO 3 /K 2 CO 3 , DMF, 80°C; K 2 CO 3 , DMSO, 100°C. The second reduction reaction conditions can also be prepared by the following conditions: ammonium chloride and iron powder, ethanol/water, 80°C to 90°C; ammonium chloride and iron powder, methanol/water, 60°C to 80°C; palladium carbon (50%) and hydrogen, methanol, rt.

表3中间体B2-B8、B11-B29、B34-B49的结构和MS数据


Table 3 Structures and MS data of intermediates B2-B8, B11-B29, B34-B49


中间体B9. 2-氟-5-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯胺的制备
Intermediate B9. Preparation of 2-fluoro-5-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline

第一步：以1-氯-5-氟-4-甲基-2-硝基苯和1-甲基-1H-苯并[d]咪唑-5-醇为原料，按照合成中间体B1第一步的方法制备5-(5-氯-2-甲基-4-硝基苯氧基)-1-甲基-1H-苯并[d]咪唑。MS(ESI+)m/z＝318.1[M+H]+。Step 1: Using 1-chloro-5-fluoro-4-methyl-2-nitrobenzene and 1-methyl-1H-benzo[d]imidazol-5-ol as starting materials, 5-(5-chloro-2-methyl-4-nitrophenoxy)-1-methyl-1H-benzo[d]imidazole was prepared according to the procedure for Intermediate B1, Step 1. MS (ESI + ) m/z = 318.1 [M+H] + .

第二步：将5-(5-氯-2-甲基-4-硝基苯氧基)-1-甲基-1H-苯并[d]咪唑(5.0g,15.74mmol)溶于DMSO(200mL)，加入氟化铯(24.0g,157.7mmol)，升温至110℃搅拌6h。反应完全后冷却至室温，往反应液中加入水(200mL)，过滤，收集滤饼并用水洗涤，干燥得到5-(5-氟-2-甲基-4-硝基苯氧基)-1-甲基-1H-苯并[d]咪唑(黄色固体,4.2g,粗品)。无需纯化，直接用于下一步反应。MS(ESI+)m/z＝301.9[M+H]+。Step 2: Dissolve 5-(5-chloro-2-methyl-4-nitrophenoxy)-1-methyl-1H-benzo[d]imidazole (5.0 g, 15.74 mmol) in DMSO (200 mL), add cesium fluoride (24.0 g, 157.7 mmol), and heat to 110°C with stirring for 6 h. After the reaction is complete, cool to room temperature, add water (200 mL), filter, collect the filter cake, wash with water, and dry to yield 5-(5-fluoro-2-methyl-4-nitrophenoxy)-1-methyl-1H-benzo[d]imidazole (yellow solid, 4.2 g, crude). Use directly in the next step without purification. MS (ESI + ) m/z = 301.9 [M+H] + .

第三步：以5-(5-氟-2-甲基-4-硝基苯氧基)-1-甲基-1H-苯并[d]咪唑(4.9g,16.26mmol)为原料，按照合成中间体B1第二步的方法制备2-氟-5-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯胺(黄色固体,3.5g,79.0％)。MS(ESI+)m/z＝272.2[M+H]+。Step 3: Using 5-(5-fluoro-2-methyl-4-nitrophenoxy)-1-methyl-1H-benzo[d]imidazole (4.9 g, 16.26 mmol) as starting material, 2-fluoro-5-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline (yellow solid, 3.5 g, 79.0%) was prepared according to the procedure for Intermediate B1, Step 2. MS (ESI + ) m/z = 272.2 [M+H] + .

中间体B10. 2-氟-3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯胺的制备
Intermediate B10. Preparation of 2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline

以2-氯-4-氟-3-甲基硝基苯和1-甲基-1H-苯并[d]咪唑-5-醇为原料，按照合成中间体B9的方法制备2-氟-3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯胺。MS(ESI+)m/z＝272.2[M+H]+。2-Fluoro-3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline was prepared using 2-chloro-4-fluoro-3-methylnitrobenzene and 1-methyl-1H-benzo[d]imidazol-5-ol according to the method for synthesizing Intermediate B9. MS (ESI + ) m/z = 272.2 [M+H] + .

中间体B30. 4-([1,2,4]三唑并[1,5-a]吡啶-7-基甲基)-3-甲基苯胺的制备
Intermediate B30. Preparation of 4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylaniline

第一步：氮气保护下，将7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-[1,2,4]三唑并[1,5-a]吡啶(1g,4.08mmol)溶于1,4-二氧六环和水的混合液(21mL,6/1,v/v)，依次加入1-溴甲基-2-甲基-4-硝基苯(1.1g,4.90mmol)，碳酸钾(1.7g,12.24mmol)和Pd(DTBPF)Cl2(265.6mg,0.41mmol)，升温至60℃搅拌1h，反应完全后冷却至室温，往反应液中加入水(30mL)，混合液用乙酸乙酯(50mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(10-70％)为洗脱剂梯度洗脱分离纯化得到7-(2-甲基-4-硝基苄基)-[1,2,4]三唑并[1,5-a]吡啶(黄色固体,300mg,27.4％)。MS(ESI+)m/z＝269.1[M+H]+。Step 1: Under nitrogen protection, 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (1 g, 4.08 mmol) was dissolved in a mixture of 1,4-dioxane and water (21 mL, 6/1, v/v). 1-Bromomethyl-2-methyl-4-nitrobenzene (1.1 g, 4.90 mmol), potassium carbonate (1.7 g, 12.24 mmol) and Pd(DTBPF)Cl 2 were added in sequence. The reaction mixture was heated to 60°C and stirred for 1 hour. After the reaction was complete, the mixture was cooled to room temperature and water (30 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (10-70%) to obtain 7-(2-methyl-4-nitrobenzyl)-[1,2,4]triazolo[1,5-a]pyridine (yellow solid, 300 mg, 27.4%). MS (ESI + ) m/z = 269.1 [M+H] + .

第二步：将7-(2-甲基-4-硝基苄基)-[1,2,4]三唑并[1,5-a]吡啶(300mg,1.12mmol)溶于N,N-二甲基甲酰胺(5mL)，加入4,4-联吡啶(8.7mg,0.06mmol)，降温至0℃，然后加入四羟基二硼(300.7mg,3.35mmol)，0℃搅拌30min，反应完全后恢复至室温，往反应液中加入水(20mL)，混合液用乙酸乙酯(20mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以甲醇/二氯甲烷(0-10％)为洗脱剂梯度洗脱分离纯化得到4-([1,2,4]三唑并[1,5-a]吡啶-7-基甲基)-3-甲基苯胺(黄色油状产物,180mg,67.7％)。MS(ESI+)m/z＝239.2[M+H]+。Step 2: Dissolve 7-(2-methyl-4-nitrobenzyl)-[1,2,4]triazolo[1,5-a]pyridine (300 mg, 1.12 mmol) in N,N-dimethylformamide (5 mL), add 4,4-bipyridine (8.7 mg, 0.06 mmol), cool to 0°C, then add tetrahydroxydiboron (300.7 mg, 3.35 mmol), stir at 0°C for 30 min, and return to room temperature after the reaction is complete. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography using a gradient elution of methanol/dichloromethane (0-10%) as the eluent to provide 4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylaniline (yellow oil, 180 mg, 67.7%). MS (ESI + ) m/z = 239.2 [M+H] + .

中间体B31. 4-((3-氯咪唑并[1,2-a]吡啶-7-基)氧基)-3-甲基苯胺的制备
Intermediate B31. Preparation of 4-((3-chloroimidazo[1,2-a]pyridin-7-yl)oxy)-3-methylaniline

第一步：氮气保护下，将7-溴咪唑[1,2-a]吡啶(2g,10.2mmol)溶于二甲基亚砜/水的混合溶液(30mL,4/1v/v)，依次加入一水合氢氧化锂(899.6mg,21.4mmol)，N,N'-双(4-羟基-2,6-二甲基苯基)草酰胺(66.9mg,0.2mmol)和乙酰丙酮酸铜(53.2mg,0.2mmol)，升温至80℃下搅拌2h。反应完全后冷却至室温，往反应液中加入水(10mL)，混合液用二氯甲烷/甲醇(3/1v/v,30mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶柱层析以甲醇/二氯甲烷(15％)为洗脱剂分离纯化得到咪唑[1,2-a]吡啶-7-醇(黄色油状物,1.0g,73.2％)。MS(ESI+)m/z＝157.1[M+Na]+。Step 1: Under nitrogen protection, 7-bromoimidazole [1,2-a] pyridine (2 g, 10.2 mmol) was dissolved in a mixed solution of dimethyl sulfoxide/water (30 mL, 4/1 v/v), and lithium hydroxide monohydrate (899.6 mg, 21.4 mmol), N, N'-bis (4-hydroxy-2,6-dimethylphenyl) oxamide (66.9 mg, 0.2 mmol) and copper acetylacetonate (53.2 mg, 0.2 mmol) were added in sequence. The mixture was heated to 80 ° C and stirred for 2 h. After the reaction was complete, the mixture was cooled to room temperature and water (10 mL) was added. The mixture was extracted with dichloromethane/methanol (3/1 v/v, 30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography using methanol/dichloromethane (15%) as eluent to afford imidazo[1,2-a]pyridin-7-ol (yellow oil, 1.0 g, 73.2%). MS (ESI + ) m/z = 157.1 [M+Na] + .

第二步：将咪唑[1,2-a]吡啶-7-醇(1.0g,7.45mmol)溶于N,N-二甲基甲酰胺(20mL)，依次加入碳酸铯(4.9g,14.91mmol)和1-氟-2-甲基-4-硝基苯(1.2g,7.45mmol)，升温至80℃搅拌3h。反应完全后冷却至室温，往反应液中加入水(30mL)，混合液用乙酸乙酯(30mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以甲醇/二氯甲烷(15％)为洗脱剂洗脱分离得到7-(2-甲基-4-硝基苯氧基)咪唑[1,2-a]吡啶(淡黄色固体,1.1g,55.0％)。MS(ESI+)m/z＝270.0[M+H]+。Step 2: Dissolve imidazo[1,2-a]pyridin-7-ol (1.0 g, 7.45 mmol) in N,N-dimethylformamide (20 mL). Add cesium carbonate (4.9 g, 14.91 mmol) and 1-fluoro-2-methyl-4-nitrobenzene (1.2 g, 7.45 mmol) sequentially. Heat to 80°C and stir for 3 h. After the reaction is complete, cool to room temperature and add water (30 mL). The mixture is extracted with ethyl acetate (30 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography using methanol/dichloromethane (15%) as the eluent to afford 7-(2-methyl-4-nitrophenoxy)imidazo[1,2-a]pyridine (pale yellow solid, 1.1 g, 55.0%). MS(ESI + )m/z=270.0[M+H] + .

第三步：将7-(2-甲基-4-硝基苯氧基)咪唑[1,2-a]吡啶(1.0g,3.71mmol)溶于乙腈(15mL)，加入N-氯代丁二酰亚胺(595.1mg,4.46mmol)，室温搅拌16h。反应完全后，往反应液中加水(30mL)，混合液用乙酸乙酯(40mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(35％)为洗脱剂洗脱分离得到3-氯-7-(2-甲基-4-硝基苯氧基)咪唑[1,2-a]吡啶(黄色固体,360mg,31.9％)。MS(ESI+)m/z＝304.1[M+H]+。Step 3: Dissolve 7-(2-methyl-4-nitrophenoxy)imidazo[1,2-a]pyridine (1.0 g, 3.71 mmol) in acetonitrile (15 mL), add N-chlorosuccinimide (595.1 mg, 4.46 mmol), and stir at room temperature for 16 hours. After the reaction is complete, add water (30 mL) to the reaction mixture, extract with ethyl acetate (40 mL x 3), dry the combined organic phases over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue is purified by silica gel column chromatography using ethyl acetate/petroleum ether (35%) as the eluent to afford 3-chloro-7-(2-methyl-4-nitrophenoxy)imidazo[1,2-a]pyridine (yellow solid, 360 mg, 31.9%). MS (ESI + ) m/z = 304.1 [M+H] + .

第四步：以3-氯-7-(2-甲基-4-硝基苯氧基)咪唑[1,2-a]吡啶为原料，按照中间体B1第二步的方法制备4-((3-氯咪唑[1,2-a]吡啶-7-基)氧基)-3-甲基苯基胺。MS(ESI+)m/z＝274.0[M+H]+。Step 4: Using 3-chloro-7-(2-methyl-4-nitrophenoxy)imidazo[1,2-a]pyridine as starting material, prepare 4-((3-chloroimidazo[1,2-a]pyridin-7-yl)oxy)-3-methylphenylamine according to the procedure for Intermediate B1, Step 2. MS (ESI + ) m/z = 274.0 [M+H] + .

中间体B32. 4-([1,2,4]三唑并[1,5-a]吡啶-7-基甲基)-3-甲基苯胺的制备
Intermediate B32. Preparation of 4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylaniline

第一步：氮气保护下，将7-(4,4,5,5-四甲基-1,3,2-二氧杂硼-2-基)-[1,2,4]三唑并[1,5-a]吡啶(1g,4.08mmol)溶于1,4-二氧六环/水的混合液(6/1v/v,21mL)，依次加入1-(溴甲基)-2-甲基-4-硝基苯(1.1g,4.90mmol)，碳酸钾(1.7g,12.24mmol)和Pd(dtbpf)Cl2(265.6mg,0.41mmol)，升温至60℃搅拌1h，反应完全后冷却至室温，往反应液中加水(30mL)，混合液用乙酸乙酯(50mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-70％)为洗脱剂梯度洗脱分离纯化得到7-(2-甲基-4-硝基苄基)-[1,2,4]三唑并[1,5-a]吡啶(黄色固体,300mg,27.4％)。MS(ESI+)m/z＝269.1[M+H]+。Step 1: Under nitrogen protection, 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (1 g, 4.08 mmol) was dissolved in a mixture of 1,4-dioxane/water (6/1 v/v, 21 mL). 1-(bromomethyl)-2-methyl-4-nitrobenzene (1.1 g, 4.90 mmol), potassium carbonate (1.7 g, 12.24 mmol) and Pd(dtbpf)Cl 2 were added in sequence. The mixture was heated to 60°C and stirred for 1 hour. After the reaction was complete, it was cooled to room temperature. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-70%) to obtain 7-(2-methyl-4-nitrobenzyl)-[1,2,4]triazolo[1,5-a]pyridine (yellow solid, 300 mg, 27.4%). MS (ESI + ) m/z = 269.1 [M+H] + .

第二步：将7-(2-甲基-4-硝基苄基)-[1,2,4]三唑并[1,5-a]吡啶(300mg,1.12mmol)溶于N,N-二甲基甲酰胺(5mL)，加入4,4'-联吡啶(8.7mg,0.06mmol)，降温至0℃，加入四羟基二硼(300.7mg,3.35mmol)，0℃搅拌30min，反应完全后，往反应液中加水(20mL)，混合液用乙酸乙酯(20mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以甲醇/二氯甲烷(0-10％)为洗脱剂梯度洗脱分离纯化得到4-([1,2,4]三唑并[1,5-a]吡啶-7-基甲基)-3-甲基苯胺(黄色油状物,180mg,67.7％)。MS(ESI+)m/z＝239.2[M+H]+。Step 2: Dissolve 7-(2-methyl-4-nitrobenzyl)-[1,2,4]triazolo[1,5-a]pyridine (300 mg, 1.12 mmol) in N,N-dimethylformamide (5 mL), add 4,4'-bipyridine (8.7 mg, 0.06 mmol), cool to 0°C, add tetrahydroxydiboron (300.7 mg, 3.35 mmol), stir at 0°C for 30 min, and after the reaction is complete, reverse the reaction. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using a gradient elution of methanol/dichloromethane (0-10%) as the eluent to afford 4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylaniline (yellow oil, 180 mg, 67.7%). MS (ESI + ) m/z = 239.2 [M+H] + .

中间体B33. 3-氯-2-氟-4-(喹喔啉-6-基氧基)苯胺的制备
Intermediate B33. Preparation of 3-chloro-2-fluoro-4-(quinoxalin-6-yloxy)aniline

以2,3-二氯-1-氟-4-硝基苯和6-羟基喹喔啉为原料，按照合成中间体B9的方法制备3-氯-2-氟-4-(喹喔啉-6-基氧基)苯胺(黄色固体)。MS(ESI+)m/z＝290.0[M+H]+。3-Chloro-2-fluoro-4-(quinoxalin-6-yloxy)aniline (yellow solid) was prepared using 2,3-dichloro-1-fluoro-4-nitrobenzene and 6-hydroxyquinoxaline as starting materials according to the method for synthesizing Intermediate B9. MS (ESI + ) m/z = 290.0 [M+H] + .

第四组制备例：中间体C1-C45制备The fourth group of preparation examples: Preparation of intermediates C1-C45

中间体C1. 8-氰基-7-(((二甲基氨基)亚甲基)氨基)-2H,4H-螺[苯并[b][1,4]噁嗪-3,4'-哌啶]-1'-甲酸叔丁酯的制备
Intermediate C1. Preparation of tert-butyl 8-cyano-7-(((dimethylamino)methylene)amino)-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidine]-1'-carboxylate

第一步：将中间体A1(100.0mg,0.27mmol)溶于乙醇/水(3/1,4mL)中，依次加入铁粉(149.2mg,2.67mmol)和氯化铵(142.9mg,2.67mmol)，升温至70℃搅拌1h。反应完全后冷却至室温，反应液过滤，往滤液中加水(10mL)，用乙酸乙酯(10mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶柱层析以甲醇/二氯甲烷(10％)为洗脱剂分离纯化得到7-氨基-8-氰基-2H,4H-螺[苯并[b][1,4]噁嗪-3,4'-哌啶]-1'-甲酸叔丁酯(淡黄色固体,70mg,76.1％)。MS(ESI+)m/z＝345.2[M+H]+。Step 1: Intermediate A1 (100.0 mg, 0.27 mmol) was dissolved in ethanol/water (3/1, 4 mL). Iron powder (149.2 mg, 2.67 mmol) and ammonium chloride (142.9 mg, 2.67 mmol) were added sequentially. The mixture was heated to 70°C and stirred for 1 h. After the reaction was complete, the mixture was cooled to room temperature and filtered. Water (10 mL) was added to the filtrate, which was then extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford the crude product. The crude product was isolated and purified by silica gel column chromatography using methanol/dichloromethane (10%) as the eluent to afford tert-butyl 7-amino-8-cyano-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidinyl]-1'-carboxylate (pale yellow solid, 70 mg, 76.1%). MS(ESI + )m/z=345.2[M+H] + .

第二步：将7-氨基-8-氰基-2H,4H-螺[苯并[b][1,4]噁嗪-3,4'-哌啶]-1'-甲酸叔丁酯(100.0mg,0.29mmol)溶于N,N-二甲基甲酰胺二甲缩醛(5mL)中，升温至100℃搅拌1h。反应完全后冷却至室温，减压浓缩得到8-氰基-7-(((二甲基氨基)亚甲基)氨基)-2H,4H-螺[苯并[b][1,4]噁嗪-3,4'-哌啶]-1'-甲酸叔丁酯(黄色油状物,170mg,粗品)。MS(ESI+)m/z＝400.3[M+H]+。Step 2: Dissolve tert-butyl 7-amino-8-cyano-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidine]-1'-carboxylate (100.0 mg, 0.29 mmol) in N,N-dimethylformamide dimethyl acetal (5 mL), heat to 100°C, and stir for 1 hour. After the reaction is complete, cool to room temperature and concentrate under reduced pressure to yield tert-butyl 8-cyano-7-(((dimethylamino)methylene)amino)-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidine]-1'-carboxylate as a yellow oil, 170 mg, crude. MS (ESI + ) m/z = 400.3 [M+H] + .

中间体C2-C11、C18-C24、C35、C43的制备Preparation of intermediates C2-C11, C18-C24, C35, and C43

以中间体A2-A11、A18-A21、A28-A30、A32、A37为原料，按照合成中间体C1的方法制备中间体C2-C11、C18-C24、C35、C43。如表4所示。Intermediates A2-A11, A18-A21, A28-A30, A32, and A37 were used as raw materials and intermediates C2-C11, C18-C24, C35, and C43 were prepared according to the method for synthesizing intermediate C1.

表4中间体C2-C11、C18-C24、C35、C43的结构、制备原料、反应条件以及MS数据


Table 4 Structures, raw materials, reaction conditions and MS data of intermediates C2-C11, C18-C24, C35 and C43


中间体C12. 8'-氰基-7'-(((二甲基氨基)亚甲基)氨基)-2'H,4'H-螺[哌啶-4,3'-吡啶并[3,2-b][1,4]噁嗪]-1-甲酸叔丁酯的制备
Intermediate C12. Preparation of tert-butyl 8'-cyano-7'-(((dimethylamino)methylene)amino)-2'H,4'H-spiro[piperidine-4,3'-pyrido[3,2-b][1,4]oxazine]-1-carboxylate

第一步：氮气保护下，将中间体A13(450.0mg,1.10mmol)溶于1,4-二氧六环(5mL)中，依次加入氨基甲酸叔丁酯(154.6mg,1.32mmol)，Pd2(dba)3(100.7mg,0.11mmol)，XantPhos(63.6mg,0.11mmol)和碳酸铯(716.5mg,2.20mmol)，升温至90℃搅拌1h。反应完全后冷却至室温，往反应液中加水(50mL)，用乙酸乙酯(50mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶柱层析以乙酸乙酯/石油醚(54％)为洗脱剂分离纯化得到7'-((叔丁氧羰基)氨基)-8'-氰基-2'H,4'H-螺[哌啶-4,3'-吡啶并[3,2-b][1,4]噁嗪]-1-甲酸叔丁酯(黄色固体,350mg,71.4％)。MS(ESI+)m/z＝446.4[M+H]+。Step 1: Under nitrogen protection, intermediate A13 (450.0 mg, 1.10 mmol) was dissolved in 1,4-dioxane (5 mL), and tert-butyl carbamate (154.6 mg, 1.32 mmol), Pd 2 (dba) 3 (100.7 mg, 0.11 mmol), XantPhos (63.6 mg, 0.11 mmol) and cesium carbonate (716.5 mg, 2.20 mmol) were added in sequence. The temperature was raised to 90°C and stirred for 1 h. After the reaction was complete, the mixture was cooled to room temperature, and water (50 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography using ethyl acetate/petroleum ether (54%) as the eluent to obtain tert-butyl 7'-((tert-butyloxycarbonyl)amino)-8'-cyano-2'H,4'H-spiro[piperidine-4,3'-pyrido[3,2-b][1,4]oxazine]-1-carboxylate (yellow solid, 350 mg, 71.4%). MS (ESI + ) m/z = 446.4 [M+H] + .

第二步：将7'-((叔丁氧羰基)氨基)-8'-氰基-2'H,4'H-螺[哌啶-4,3'-吡啶并[3,2-b][1,4]噁嗪]-1-甲酸叔丁酯(350.0mg,0.79mmol)溶于二氯甲烷(3mL)中，加入三氟乙酸(1mL)，室温搅拌1h。反应完全后，反应液用氮气吹干，加入适量水和乙腈后将混合液冻干，得到7'-氨基-2'H,4'H-螺[哌啶-4,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-甲腈(黄色固体,350mg,粗品)。MS(ESI+)m/z＝246.2[M+H]+。Step 2: Dissolve tert-butyl 7'-((tert-Butyloxycarbonyl)amino)-8'-cyano-2'H,4'H-spiro[piperidine-4,3'-pyrido[3,2-b][1,4]oxazine]-1-carboxylate (350.0 mg, 0.79 mmol) in dichloromethane (3 mL). Add trifluoroacetic acid (1 mL) and stir at room temperature for 1 hour. After the reaction is complete, the reaction mixture is dried with nitrogen. After adding appropriate amounts of water and acetonitrile, the mixture is lyophilized to yield 7'-amino-2'H,4'H-spiro[piperidine-4,3'-pyrido[3,2-b][1,4]oxazine]-8'-carbonitrile (yellow solid, 350 mg, crude). MS (ESI + ) m/z = 246.2 [M+H] + .

第三步：氮气保护下，将7'-氨基-2'H,4'H-螺[哌啶-4,3'-吡啶并[3,2-b][1,4]噁嗪]-8'-甲腈(350.0mg,1.43mmol)溶于四氢呋喃(2mL)和水(2mL)中，降温至0℃，依次加入碳酸氢钠(359.6mg,4.28mmol)和二碳酸二叔丁酯(311.4mg,1.43mmol)，室温搅拌1h。反应完全后，反应液用乙酸乙酯(30mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶柱层析以乙酸乙酯/石油醚(50％)为洗脱剂梯度洗脱分离纯化得到7'-氨基-8'-氰基-2'H,4'H-螺[哌啶-4,3'-吡啶并[3,2-b][1,4]噁嗪]-1-甲酸叔丁酯(淡黄色油状物,120mg,24.4％)。MS(ESI+)m/z＝346.3[M+H]+。Step 3: Under nitrogen protection, 7'-amino-2'H, 4'H-spiro[piperidine-4,3'-pyrido[3,2-b][1,4]oxazine]-8'-carbonitrile (350.0 mg, 1.43 mmol) was dissolved in tetrahydrofuran (2 mL) and water (2 mL), cooled to 0°C, and sodium bicarbonate (359.6 mg, 4.28 mmol) and di-tert-butyl dicarbonate (311.4 mg, 1.43 mmol) were added in sequence, and stirred at room temperature for 1 h. After the reaction was complete, the reaction solution was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (50%) as the eluent to afford tert-butyl 7'-amino-8'-cyano-2'H,4'H-spiro[piperidine-4,3'-pyrido[3,2-b][1,4]oxazine]-1-carboxylate (pale yellow oil, 120 mg, 24.4%). MS (ESI + ) m/z = 346.3 [M+H] + .

第四步：以7'-氨基-8'-氰基-2'H,4'H-螺[哌啶-4,3'-吡啶并[3,2-b][1,4]噁嗪]-1-甲酸叔丁酯为原料，按照合成中间体C1第二步方法制备中间体C12(棕色油状物,100mg,粗品)。MS(ESI+)m/z＝401.0[M+H]+。Step 4: Starting from tert-butyl 7'-amino-8'-cyano-2'H,4'H-spiro[piperidine-4,3'-pyrido[3,2-b][1,4]oxazine]-1-carboxylate, Intermediate C12 (brown oil, 100 mg, crude) was prepared according to the procedure for Intermediate C1, Step 2. MS (ESI + ) m/z = 401.0 [M+H] + .

中间体C25-C31、C36-C38、C45的制备Preparation of intermediates C25-C31, C36-C38, and C45

以中间体A22-A27、A33-A36、A37或市售化合物为原料，按照合成中间体C12的方法(第二步和第三步两步反应可以通过以下条件一步合成7'-氨基-8'-氰基-2'H,4'H-螺[哌啶-4,3'-吡啶并[3,2-b][1,4]噁嗪]-1-甲酸叔丁酯：TABF,THF,60℃)制备中间体C25-C31、C36-C38、C45。如表5所示。Intermediates C25-C31, C36-C38, and C45 were prepared using intermediates A22-A27, A33-A36, and A37 or commercially available compounds as starting materials, following the method for synthesizing intermediate C12 (the second and third steps can be used to synthesize tert-butyl 7'-amino-8'-cyano-2'H,4'H-spiro[piperidine-4,3'-pyrido[3,2-b][1,4]oxazine]-1-carboxylate in a single step under the following conditions: TABF, THF, 60°C). See Table 5.

表5中间体C25-C31、C36-C38、C45的结构、制备原料以及MS数据

Table 5 Structures, raw materials and MS data of intermediates C25-C31, C36-C38 and C45

中间体C132. 8'-氰基-7'-(((二甲基氨基)亚甲基)氨基)-2'H-螺[哌啶-4,3'-[1,4]二氧六环并[2,3-b]吡啶]-1-甲酸叔丁酯的制备
Intermediate C132. Preparation of tert-butyl 8'-cyano-7'-(((dimethylamino)methylene)amino)-2'H-spiro[piperidine-4,3'-[1,4]dioxane[2,3-b]pyridine]-1-carboxylate

第一步：氮气保护下，将中间体A12(1.0g,2.73mmol)溶于1,4-二氧六环(10mL)中，依次加入氨基甲酸叔丁酯(480.4mg,4.10mmol)，EPhos Pd G4(251.1mg,0.27mmol)，EPhos(146.2mg,0.27mmol)和碳酸铯(1.8g,5.47mmol)，升温至100℃搅拌过夜。反应完全后冷却至室温，往反应液中加水(50mL)，用乙酸乙酯(30mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶柱层析以乙酸乙酯/石油醚(70％)为洗脱剂分离纯化得到7'-氨基-8'-氰基-2'H-螺[哌啶-4,3'-[1,4]二氧六环并[2,3-b]吡啶]-1-甲酸叔丁酯(淡黄色固体,580mg,61.2％)。MS(ESI+)m/z＝347.2[M+H]+。Step 1: Under nitrogen protection, intermediate A12 (1.0 g, 2.73 mmol) was dissolved in 1,4-dioxane (10 mL). Tert-butyl carbamate (480.4 mg, 4.10 mmol), EPhos Pd G4 (251.1 mg, 0.27 mmol), EPhos (146.2 mg, 0.27 mmol) and cesium carbonate (1.8 g, 5.47 mmol) were added in sequence. The temperature was raised to 100°C and stirred overnight. After the reaction was complete, the mixture was cooled to room temperature, and water (50 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography using ethyl acetate/petroleum ether (70%) as eluent to obtain tert-butyl 7'-amino-8'-cyano-2'H-spiro[piperidine-4,3'-[1,4]dioxane[2,3-b]pyridine]-1-carboxylate (pale yellow solid, 580 mg, 61.2%). MS (ESI + ) m/z = 347.2 [M+H] + .

第二步：以7'-氨基-8'-氰基-2'H-螺[哌啶-4,3'-[1,4]二氧六环并[2,3-b]吡啶]-1-甲酸叔丁酯为原料，按照合成中间体C1第二步方法制备中间体C13(黄色油状物,200mg,粗品)。MS(ESI+)m/z＝402.2[M+H]+。Step 2: Using tert-butyl 7'-amino-8'-cyano-2'H-spiro[piperidine-4,3'-[1,4]dioxane[2,3-b]pyridine]-1-carboxylate as starting material, Intermediate C13 (yellow oil, 200 mg, crude) was prepared according to the procedure for Intermediate C1, Step 2. MS (ESI + ) m/z = 402.2 [M+H] + .

中间体C14.(R)-4-氰基-3-(((二甲基氨基)亚甲基)氨基)-6a,7,9,10-四氢-6H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8-甲酸叔丁酯的制备
Intermediate C14. Preparation of tert-butyl (R)-4-cyano-3-(((dimethylamino)methylene)amino)-6a,7,9,10-tetrahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine-8-carboxylate

第一步：氮气保护下，将中间体A14(900.0mg,2.28mmol)溶于二甲基亚砜(12mL)中，依次加入碘化亚铜(86.7mg,0.46mmol)，碳酸钾(944.0mg,6.83mmol)，L-脯氨酸(104.9mg,0.91mmol)和氨水(25％,239.4mg,6.83mmol)，升温至90℃搅拌18h。反应完全后冷却至室温，反应液中加饱和食盐水(25mL)，用乙酸乙酯(35mL×3)萃取，合并有机相用饱和食盐水(10mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶柱层析以甲醇/二氯甲烷(0-15％)为洗脱剂梯度洗脱分离纯化得到(R)-3-氨基-4-氰基-6a,7,9,10-四氢-6H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8-甲酸叔丁酯(黄色油状物,590mg,78.1％)。MS(ESI+)m/z＝332.0[M+H]+。Step 1: Under nitrogen protection, intermediate A14 (900.0 mg, 2.28 mmol) was dissolved in dimethyl sulfoxide (12 mL). Cuprous iodide (86.7 mg, 0.46 mmol), potassium carbonate (944.0 mg, 6.83 mmol), L-proline (104.9 mg, 0.91 mmol) and aqueous ammonia (25%, 239.4 mg, 6.83 mmol) were added in sequence. The mixture was heated to 90°C and stirred for 18 h. After the reaction was complete, the mixture was cooled to room temperature. Saturated brine (25 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (35 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography using a gradient elution of methanol/dichloromethane (0-15%) as the eluent to obtain (R)-tert-butyl 3-amino-4-cyano-6a,7,9,10-tetrahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine-8-carboxylate (yellow oil, 590 mg, 78.1%). MS (ESI + ) m/z = 332.0 [M+H] + .

第二步：以(R)-3-氨基-4-氰基-6a,7,9,10-四氢-6H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8-甲酸叔丁酯为原料，按照合成中间体C1第二步方法制备中间体C14(棕色油状物,600mg,粗品)。MS(ESI+)m/z＝387.2[M+H]+。Step 2: Intermediate C14 (brown oil, 600 mg, crude) was prepared using tert-butyl (R)-3-amino-4-cyano-6a,7,9,10-tetrahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine-8-carboxylate according to the procedure for Intermediate C1, Step 2. MS (ESI + ) m/z = 387.2 [M+H] + .

中间体C15-C17的制备Preparation of intermediates C15-C17

以中间体A15-A17为原料，按照合成中间体C14的方法制备中间体C15-C17。如表6所示。Intermediates A15-A17 were used as raw materials and intermediates C15-C17 were prepared according to the method for synthesizing intermediate C14, as shown in Table 6.

表6中间体C15-C17的结构、制备原料以及MS数据
Table 6 Structures, raw materials and MS data of intermediates C15-C17

中间体C32.(E)-5-氰基-6-((二甲氨基)亚甲基)氨基)-8-甲氧基-3H-螺[苯并[b][1,4]二氧六环-2,4'-哌啶]-1'-甲酸叔丁酯的制备
Intermediate C32. Preparation of tert-butyl (E)-5-cyano-6-((dimethylamino)methylene)amino)-8-methoxy-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-1'-carboxylate

氮气保护下，将(E)-8-氯-5-氰基-6-(((二甲氨基)亚甲基)氨基)-3H-螺[苯并[b][1,4]二氧六环-2,4'-哌啶]-1'-甲酸叔丁酯(中间体C23,150mg,0.35mmol)溶于甲醇(8mL)，依次加入t-BuBrettPhos Pd G3(32.8mg,0.03mmol)，t-BuBrettPhos(16.7mg,0.03mmol)和碳酸铯(450.2mg,1.38mmol)，升温至100℃搅拌1h，反应完全后冷却至室温，减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-80％)为洗脱剂梯度洗脱分离纯化得到(E)-5-氰基-6-((二甲氨基)亚甲基)氨基)-8-甲氧基-3H-螺[苯并[b][1,4]二氧六环-2,4'-哌啶]-1'-甲酸叔丁酯(黄色固体,130mg,87.5％)。MS(ESI+)m/z＝431.2[M+H]+。Under nitrogen protection, tert-butyl (E)-8-chloro-5-cyano-6-(((dimethylamino)methylene)amino)-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-1'-carboxylate (Intermediate C23, 150 mg, 0.35 mmol) was dissolved in methanol (8 mL), and t-BuBrettPhos Pd G3 (32.8 mg, 0.03 mmol), t-BuBrettPhos (16.7 mg, 0.03 mmol), and cesium carbonate (450.2 mg, 1.38 mmol) were heated to 100°C and stirred for 1 hour. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-80%) as the eluent to provide tert-butyl (E)-5-cyano-6-((dimethylamino)methylene)amino)-8-methoxy-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-1'-carboxylate (yellow solid, 130 mg, 87.5%). MS (ESI + ) m/z = 431.2 [M+H] + .

中间体C33.(E)-5-氰基-6-((二甲氨基)亚甲基)氨基)-8-乙氧基-3H-螺[苯并[b][1,4]二氧六环-2,4'-哌啶]-1'-甲酸叔丁酯的制备
Intermediate C33. Preparation of tert-butyl (E)-5-cyano-6-((dimethylamino)methylene)amino)-8-ethoxy-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-1'-carboxylate

以(E)-8-氯-5-氰基-6-(((二甲氨基)亚甲基)氨基)-3H-螺[苯并[b][1,4]二氧六环-2,4'-哌啶]-1'-甲酸叔丁酯(中间体C23)为原料，乙醇为溶剂，按照合成中间体C32的方法制备(E)-5-氰基-6-((二甲氨基)亚甲基)氨基)-8-乙氧基-3H-螺[苯并[b][1,4]二氧六环-2,4'-哌啶]-1'-甲酸叔丁酯。MS(ESI+)m/z＝445.4[M+H]+。Tert-butyl (E)-5-cyano-6-((dimethylamino)methylene)amino)-8-ethoxy-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-1'-carboxylate was prepared using tert-butyl (E)-8-chloro-5-cyano-6-(((dimethylamino)methylene)amino)-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-1'-carboxylate (Intermediate C23) as the starting material and ethanol as the solvent, following the procedure for Intermediate C32. MS (ESI + ) m/z = 445.4 [M+H] + .

中间体C34.(E)-5-氰基-6-((二甲氨基)亚甲基)氨基)-8-氰基-3H-螺[苯并[b][1,4]二氧六环-2,4'-哌啶]-1'-甲酸叔丁酯的制备
Intermediate C34. Preparation of tert-butyl (E)-5-cyano-6-((dimethylamino)methylene)amino)-8-cyano-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-1'-carboxylate

氮气保护下，将(E)-8-氯-5-氰基-6-(((二甲氨基)亚甲基)氨基)-3H-螺[苯并[b][1,4]二氧六环-2,4'-哌啶]-1'-甲酸叔丁酯(中间体C23,400mg,0.92mmol)溶于N,N-二甲基甲酰胺(6mL)，搅拌下加入氰化锌(432mg,3.68mmol)，Pd(dppf)Cl2(168.2mg,0.23mmol)，聚甲基氢硅氧烷(PMHS,818.5mg,3.68mmol)，升温至130℃搅拌12h，反应完全后冷却至室温，往反应液中加入水(50mL)，混合液用乙酸乙酯(30mL×3)萃取，合并有机相用饱和食盐水(50mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以甲醇/二氯甲烷(0-10％)为洗脱剂梯度洗脱分离纯化得到(E)-5-氰基-6-((二甲氨基)亚甲基)氨基)-8-氰基-3H-螺[苯并[b][1,4]二氧六环-2,4'-哌啶]-1'-甲酸叔丁酯(黄色固体,375mg,95.8％)。MS(ESI+)m/z＝426.2[M+H]+。Under nitrogen protection, (E)-8-chloro-5-cyano-6-(((dimethylamino)methylene)amino)-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester (Intermediate C23, 400 mg, 0.92 mmol) was dissolved in N,N-dimethylformamide (6 mL), and zinc cyanide (432 mg, 3.68 mmol) and Pd(dppf)Cl 2 were added with stirring. The mixture was stirred at 130 ° C for 12 h. After the reaction was completed, it was cooled to room temperature. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography with a gradient elution of methanol/dichloromethane (0-10%) as the eluent to give (E)-5-cyano-6-((dimethylamino)methylene)amino)-8-cyano-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester (yellow solid, 375 mg, 95.8%). MS(ESI + )m/z=426.2[M+H] + .

中间体C39. 8'-氰基-7'-(((二甲氨基)亚甲基)氨基)-4'-氧代-2'H,4'H-螺[哌啶-4,3'-吡喃[3,2-b]吡啶]-1-甲酸叔丁酯的制备
Intermediate C39. Preparation of tert-butyl 8'-cyano-7'-(((dimethylamino)methylene)amino)-4'-oxo-2'H,4'H-spiro[piperidin-4,3'-pyrano[3,2-b]pyridine]-1-carboxylate

第一步：氮气保护下，将7'-氯-8'-氰基-4'-氧代-2'H,4'H-螺[哌啶-4,3'-吡喃并[3,2-b]吡啶]-1-甲酸叔丁酯(中间体A31,200.0mg,0.53mmol)溶于DMF(5mL)，缓慢加入叠氮化钠(68.8mg,1.06mmol)，升温至100℃搅拌1h。反应完全后冷却至室温，往反应液中加水(5mL)，混合液用乙酸乙酯(5mL×3)萃取，合并有机相用水(5mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以甲醇/二氯甲烷(0-10％)为洗脱剂梯度洗脱分离，得到7'-氨基-8'-氰基-4'-氧代-2'H,4'H-螺[哌啶-4,3'-吡喃并[3,2-b]吡啶]-1-甲酸叔丁酯(黄色固体,140mg,73.8％)。MS(ESI+)m/z＝259.1[M+H-100]+。Step 1: Under nitrogen protection, tert-butyl 7'-chloro-8'-cyano-4'-oxo-2'H,4'H-spiro[piperidine-4,3'-pyrano[3,2-b]pyridine]-1-carboxylate (Intermediate A31, 200.0 mg, 0.53 mmol) was dissolved in DMF (5 mL). Sodium azide (68.8 mg, 1.06 mmol) was slowly added, and the temperature was raised to 100°C and stirred for 1 h. After the reaction was complete, the mixture was cooled to room temperature. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with water (5 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography using a gradient elution of methanol/dichloromethane (0-10%) as the eluent to give tert-butyl 7'-amino-8'-cyano-4'-oxo-2'H,4'H-spiro[piperidin-4,3'-pyrano[3,2-b]pyridine]-1-carboxylate (yellow solid, 140 mg, 73.8%). MS (ESI + ) m/z = 259.1 [M+H-100] + .

第二步：以7'-氨基-8'-氰基-4'-氧代-2'H,4'H-螺[哌啶-4,3'-吡喃并[3,2-b]吡啶]-1-甲酸叔丁酯(100.0mg,0.28mmol)为原料，按照合成中间体C1第二步的方法制备8'-氰基-7'-(((二甲氨基)亚甲基)氨基)-4'-氧代-2'H,4'H-螺[哌啶-4,3'-吡喃并[3,2-b]吡啶]-1-甲酸叔丁酯(黄色固体,120mg,粗品)。MS(ESI+)m/z＝414.2[M+H]+。Step 2: Using tert-butyl 7'-amino-8'-cyano-4'-oxo-2'H,4'H-spiro[piperidine-4,3'-pyrano[3,2-b]pyridine]-1-carboxylate (100.0 mg, 0.28 mmol) as starting material, tert-butyl 8'-cyano-7'-(((dimethylamino)methylene)amino)-4'-oxo-2'H,4'H-spiro[piperidine-4,3'-pyrano[3,2-b]pyridine]-1-carboxylate (yellow solid, 120 mg, crude) was prepared according to the procedure for the synthesis of Intermediate C1, Step 2. MS (ESI + ) m/z = 414.2 [M+H] + .

中间体C40. 5-氯-8-氰基-7-(((二甲氨基)亚甲基)氨基)-4-甲基-2H,4H-螺[苯并[b][1,4]噁嗪-3,4'-哌啶]-1'-甲酸叔丁酯的制备
Intermediate C40. Preparation of tert-butyl 5-chloro-8-cyano-7-(((dimethylamino)methylene)amino)-4-methyl-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidine]-1'-carboxylate

氮气保护下，将5-氯-8-氰基-7-(((二甲基氨基)亚甲基)氨基)-2H,4H-螺[苯并[b][1,4]噁嗪-3,4'-哌啶]-1'-甲酸叔丁酯(中间体C7,200.0mg,0.46mmol)溶于DMF(4mL)，降温至0℃，加入钠氢(60％,50.5mg,1.36mmol)，0℃搅拌15min，加入碘甲烷(196.3mg,1.38mmol)，加毕，升温至60℃搅拌1h。反应完全后冷却至室温，往反应液中加水(25mL)，混合液用乙酸乙酯(40mL×3)萃取，合并有机相用饱和食盐水(50mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以甲醇/二氯甲烷(0-10％)为洗脱剂梯度洗脱分离，得到5-氯-8-氰基-7-(((二甲氨基)亚甲基)氨基)-4-甲基-2H,4H-螺[苯并[b][1,4]噁嗪-3,4'-哌啶]-1'-甲酸叔丁酯(淡黄色固体,200mg,96.9％)。MS(ESI+)m/z＝448.2[M+H]+。Under nitrogen, tert-butyl 5-chloro-8-cyano-7-(((dimethylamino)methylene)amino)-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidine]-1'-carboxylate (Intermediate C7, 200.0 mg, 0.46 mmol) was dissolved in DMF (4 mL), cooled to 0°C, and sodium hydroxide (60%, 50.5 mg, 1.36 mmol) was added. The mixture was stirred at 0°C for 15 min. Methyl iodide (196.3 mg, 1.38 mmol) was added. After the addition was complete, the mixture was heated to 60°C and stirred for 1 h. After the reaction was complete, the mixture was cooled to room temperature. Water (25 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography using a gradient elution of methanol/dichloromethane (0-10%) as the eluent to provide tert-butyl 5-chloro-8-cyano-7-(((dimethylamino)methylene)amino)-4-methyl-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidine]-1'-carboxylate (pale yellow solid, 200 mg, 96.9%). MS (ESI + ) m/z = 448.2 [M+H] + .

中间体C41和中间体C42的制备Preparation of Intermediate C41 and Intermediate C42

以中间体C7市售氘代碘甲烷或碘乙烷为原料，按照合成中间体C40的方法制备中间体C41和中间体C42。如表7所示。Intermediates C41 and C42 were prepared using commercially available deuterated methyl iodide or ethyl iodide as starting materials, following the method for synthesizing intermediate C40. See Table 7.

表7中间体C41和中间体C42的结构和MS数据
Table 7 Structures and MS data of intermediates C41 and C42

中间体C44.N'-(2-氰基-4-羟基-3-甲氧基苯基)-N,N-二甲基甲脒的制备
Preparation of Intermediate C44. N'-(2-cyano-4-hydroxy-3-methoxyphenyl)-N,N-dimethylformamidine

第一步：氮气保护下，将6-氨基-3-溴-2-氟苯腈(10.0g,46.51mmol)溶于四氢呋喃(100mL)，加入甲醇钠(7.5g,0.14mol)，回流搅拌6h。反应完全后冷却至室温，往反应液中加冰水(100mL)，混合液用乙酸乙酯(50mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(10％)为洗脱剂洗脱分离，得到6-氨基-3-溴-2-甲氧基苯腈(淡黄色固体,8.0g,75.8％)。MS(ESI+)m/z＝226.9[M+H]+。Step 1: Under nitrogen, 6-amino-3-bromo-2-fluorobenzonitrile (10.0 g, 46.51 mmol) was dissolved in tetrahydrofuran (100 mL). Sodium methoxide (7.5 g, 0.14 mol) was added and the mixture was stirred at reflux for 6 h. After the reaction was complete, the mixture was cooled to room temperature and ice water (100 mL) was added. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography using ethyl acetate/petroleum ether (10%) as the eluent to afford 6-amino-3-bromo-2-methoxybenzonitrile (pale yellow solid, 8.0 g, 75.8%). MS (ESI + ) m/z = 226.9 [M+H] + .

第二步：将6-氨基-3-溴-2-甲氧基苯腈(8.0g,35.23mmol)溶于乙醇(10mL)，加入DMF-DMA(8.4g,70.47mmol)，升温至回流搅拌1h。反应完全后冷却至室温，减压浓缩得到N'-(4-溴-2-氰基-3-甲氧基苯基)-N,N-二甲基甲脒(黄色固体,9g,粗品)。MS(ESI+)m/z＝282.0[M+H]+。Step 2: Dissolve 6-amino-3-bromo-2-methoxybenzonitrile (8.0 g, 35.23 mmol) in ethanol (10 mL), add DMF-DMA (8.4 g, 70.47 mmol), and heat to reflux with stirring for 1 hour. After the reaction is complete, cool to room temperature and concentrate under reduced pressure to yield N'-(4-bromo-2-cyano-3-methoxyphenyl)-N,N-dimethylformamidine (yellow solid, 9 g, crude product). MS (ESI + ) m/z = 282.0 [M+H] + .

第三步：氮气保护下，将N'-(4-溴-2-氰基-3-甲氧基苯基)-N,N-二甲基甲脒(6.0g,21.27mmol)溶于1,4-二氧六环和水混合液(66mL,10/1v/v)，依次加入KOH(3.6g,63.80mmol)和Brettphos Pd G3(1.9g,2.13mmol)，升温至100℃搅拌4h。反应完全后冷却至室温，往反应液中加水(50mL)，混合液用乙酸乙酯(50mL)反萃，水相用盐酸(2M)调pH至5，用乙酸乙酯(50mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(20％)为洗脱剂洗脱分离得到N'-(2-氰基-4-羟基-3-甲氧基苯基)-N,N-二甲基甲脒(白色固体,1.2g,两步产率:23.3％)。MS(ESI+)m/z＝220.1[M+H]+。Step 3: Under nitrogen protection, N'-(4-bromo-2-cyano-3-methoxyphenyl)-N,N-dimethylformamidine (6.0 g, 21.27 mmol) was dissolved in a mixture of 1,4-dioxane and water (66 mL, 10/1 v/v). KOH (3.6 g, 63.80 mmol) and Brettphos Pd G3 (1.9 g, 2.13 mmol) were added in sequence. The temperature was raised to 100 ° C and stirred for 4 h. After the reaction was complete, the mixture was cooled to room temperature and water (50 mL) was added. The mixture was back-extracted with ethyl acetate (50 mL). The aqueous phase was adjusted to pH 5 with hydrochloric acid (2 M) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (20%) as the eluent to afford N'-(2-cyano-4-hydroxy-3-methoxyphenyl)-N,N-dimethylformamidine (white solid, 1.2 g, two-step yield: 23.3%). MS (ESI + ) m/z = 220.1 [M+H] + .

第五组制备例：终产物制备The fifth group of preparation examples: preparation of final product

实施例1. 1-(10'-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-2'H,4'H-螺[哌啶-4,3'-[1,4]噁嗪并[2,3-f]喹唑啉]-1-基)丙-2-烯-1-酮(终产物1)的制备
Example 1. Preparation of 1-(10'-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-2'H,4'H-spiro[piperidin-4,3'-[1,4]oxazino[2,3-f]quinazoline]-1-yl)prop-2-en-1-one (Final Product 1)

第一步：将中间体C1(110.0mg,0.28mmol)溶于甲基叔丁基醚/醋酸(4mL,1/1v/v)中，加入中间体B7(83.7mg,0.33mmol)，升温至70℃搅拌10h。反应完全后冷却至室温，往反应液中加水(10mL)，混合液用乙酸乙酯(10mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶柱层析以甲醇/二氯甲烷(1/9)为洗脱剂分离纯化得到10'-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-2'H,4'H-螺[哌啶-4,3'-[1,4]噁嗪并[2,3-f]喹唑啉]-1-甲酸叔丁酯(黄色固体,80mg,47.8％)。MS(ESI+)m/z＝608.5[M+H]+。Step 1: Dissolve intermediate C1 (110.0 mg, 0.28 mmol) in methyl tert-butyl ether/acetic acid (4 mL, 1/1 v/v), add intermediate B7 (83.7 mg, 0.33 mmol), and heat to 70°C and stir for 10 h. After the reaction was complete, the mixture was cooled to room temperature. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography using methanol/dichloromethane (1/9) as the eluent to provide tert-butyl 10'-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-2'H,4'H-spiro[piperidine-4,3'-[1,4]oxazino[2,3-f]quinazoline]-1-carboxylate (yellow solid, 80 mg, 47.8%). MS (ESI + ) m/z = 608.5 [M+H] + .

第二步：将10'-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-2'H,4'H-螺[哌啶-4,3'-[1,4]噁嗪并[2,3-f]喹唑啉]-1-甲酸叔丁酯(70.0mg,0.12mmol)溶于二氯甲烷/三氟乙酸(4mL,3/1v/v)中，室温搅拌0.5h。反应完全后，减压浓缩得到N-(3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)-2'H,4'H-螺[哌啶-4,3'-[1,4]噁嗪并[2,3-f]喹唑啉]-10'-胺(黄色油状物,120mg,粗品)。MS(ESI+)m/z＝508.4[M+H]+。Step 2: Dissolve tert-butyl 10'-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-2'H,4'H-spiro[piperidin-4,3'-[1,4]oxazino[2,3-f]quinazoline]-1-carboxylate (70.0 mg, 0.12 mmol) in dichloromethane/trifluoroacetic acid (4 mL, 3/1 v/v) and stir at room temperature for 0.5 h. After the reaction is complete, concentrate under reduced pressure to afford N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-2'H,4'H-spiro[piperidin-4,3'-[1,4]oxazino[2,3-f]quinazoline]-10'-amine as a yellow oil (120 mg, crude). MS(ESI + )m/z=508.4[M+H] + .

第三步：将N-(3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)-2'H,4'H-螺[哌啶-4,3'-[1,4]噁嗪并[2,3-f]喹唑啉]-10'-胺(110.0mg,0.22mmol)溶于四氢呋喃(5mL)中，滴加三乙胺(65.8mg,0.65mmol)调节pH>7，再滴加丙烯酸酐(13.7mg,0.11mmol)，室温搅拌15min。反应完全后，往反应液中加水(10mL)，混合液用乙酸乙酯(10mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经高压制备液相色谱分离纯化(柱型:XBridge BEH Shield RP18 Column,19*250mm,5μm；流动相:乙腈/水(10mmol/L碳酸氢铵)；梯度:29-59-7min,波长:254/220nm；RT1(min):8.5)得到1-(10'-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-2'H,4'H-螺[哌啶-4,3'-[1,4]噁嗪并[2,3-f]喹唑啉]-1-基)丙-2-烯-1-酮(终产物1)。Step 3: Dissolve N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-2'H,4'H-spiro[piperidine-4,3'-[1,4]oxazino[2,3-f]quinazoline]-10'-amine (110.0 mg, 0.22 mmol) in tetrahydrofuran (5 mL), add triethylamine (65.8 mg, 0.65 mmol) dropwise to adjust the pH to >7, then add acrylic anhydride (13.7 mg, 0.11 mmol) dropwise and stir at room temperature for 15 min. After the reaction was completed, water (10 mL) was added to the reaction solution, and the mixed solution was extracted with ethyl acetate (10 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by high-pressure preparative liquid chromatography (column type: XBridge BEH Shield RP18 Column, 19*250 mm, 5 μm; mobile phase: acetonitrile/water (10 mmol/L ammonium bicarbonate); gradient: 29-59-7 min, wavelength: 254/220 nm; RT1 (min): 8.5) to obtain 1-(10'-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-2'H,4'H-spiro[piperidine-4,3'-[1,4]oxazino[2,3-f]quinazoline]-1-yl)prop-2-en-1-one (final product 1).

淡黄色固体.MS(ESI+)m/z＝562.3[M+H]+.1H NMR(300MHz,DMSO-d6)δ9.85(s,1H),8.29(s,1H),8.16(s,1H),7.78-7.68(m,2H),7.56(d,J＝8.7,1H),7.33-7.20(m,2H),7.07(d,J＝2.2Hz,1H),6.98(dd,J＝8.7,2.1Hz,1H),6.95-6.80(m,2H),6.49(s,1H),6.19-6.06(m,1H),5.77-5.64(m,1H),4.25(d,J＝4.8Hz,2H),3.98-3.73(m,5H),3.71-3.47(m,2H),2.23(s,3H),1.78-1.51(m,4H).Pale yellow solid. MS (ESI + ) m/z = 562.3 [M+H] + . 1 H NMR (300 MHz, DMSO-d 6 )δ9.85(s,1H),8.29(s,1H),8.16(s,1H),7.78-7.68(m,2H),7.56(d,J＝8.7,1H ),7.33-7.20(m,2H),7.07(d,J＝2.2Hz,1H),6.98(dd,J＝8.7,2.1Hz,1H),6.95- 6.80(m,2H),6.49(s,1H),6.19-6.06(m,1H),5.77-5.64(m,1H),4.25(d,J＝4.8 Hz,2H),3.98-3.73(m,5H),3.71-3.47(m,2H),2.23(s,3H),1.78-1.51(m,4H).

实施例2-130.终产物2-4、6-11、15-23、25-37、39-48、50-60、62-63、73-75、77-90、92-99、101-109、113-116、120-125、127-128、130-133、135、137-141、145-147、149-151、154、159，177-187的制备Example 2-130. Preparation of final products 2-4, 6-11, 15-23, 25-37, 39-48, 50-60, 62-63, 73-75, 77-90, 92-99, 101-109, 113-116, 120-125, 127-128, 130-133, 135, 137-141, 145-147, 149-151, 154, 159, 177-187

采用终产物1的制备方法(第三步缩合反应还可以通过以下条件制备：丙烯酸或(E)-4-(二甲氨基)丁-2-烯酸或2-丁炔酸，EDCI，吡啶，室温；丙烯酰氯，碳酸氢钠溶液，THF，室温)，以中间体B1-B49或市售取代苯胺化合物、中间体C1-C44和丙烯酸酐为原料制备终产物2-4、6-11、15-23、25-37、39-48、50-60、62-63、73-75、77-90、92-99、101-109、113-116、120-125、127-128、130-133、135、137-141、145-147、149-151、154、159，177-187。如表8所示。The preparation method of the final product 1 is adopted (the third step condensation reaction can also be prepared under the following conditions: acrylic acid or (E)-4-(dimethylamino)but-2-enoic acid or 2-butynoic acid, EDCI, pyridine, room temperature; acryloyl chloride, sodium bicarbonate solution, THF, room temperature), and the final products 2-4, 6-11, 15-23, 25-37, 39-48, 50-60, 62-63, 73-75, 77-90, 92-99, 101-109, 113-116, 120-125, 127-128, 130-133, 135, 137-141, 145-147, 149-151, 154, 159, and 177-187 are prepared using intermediates B1-B49 or commercially available substituted aniline compounds, intermediates C1-C44, and acrylic anhydride as raw materials. As shown in Table 8.

表8终产物2-4、6-11、15-23、25-37、39-48、50-60、62-63、73-75、77-90、92-99、101-109、113-116、120-125、127-128、130-133、135、137-141、145-147、149-151、154、159，177-187的结构、反应中间体和NMR或MS数据



































Table 8 Structures, reaction intermediates and NMR or MS data of final products 2-4, 6-11, 15-23, 25-37, 39-48, 50-60, 62-63, 73-75, 77-90, 92-99, 101-109, 113-116, 120-125, 127-128, 130-133, 135, 137-141, 145-147, 149-151, 154, 159, 177-187



































实施例131. 1-(5'-甲氧基-10'-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-2'H,4'H-螺[哌啶-4,3'-[1,4]噁嗪并[2,3-f]喹唑啉]-1-基)丙-2-烯-1-酮(终产物12)的制备
Example 131. Preparation of 1-(5'-methoxy-10'-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-2'H,4'H-spiro[piperidin-4,3'-[1,4]oxazino[2,3-f]quinazoline]-1-yl)prop-2-en-1-one (Final Product 12)

第一步：以中间体C5和中间体B7为原料，按照实施例1第一步方法制备5'-溴-10'-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-2'H,4'H-螺[哌啶-4,3'-[1,4]噁嗪并[2,3-f]喹唑啉]-1-甲酸叔丁酯(黄色固体,120mg,28.7％)。MS(ESI+)m/z＝686.4[M+H]+。Step 1: Using Intermediates C5 and B7 as starting materials, tert-butyl 5'-bromo-10'-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-2'H,4'H-spiro[piperidine-4,3'-[1,4]oxazino[2,3-f]quinazoline]-1-carboxylate (yellow solid, 120 mg, 28.7%) was prepared according to the method of Example 1, Step 1. MS (ESI + ) m/z = 686.4 [M+H] + .

第二步：氮气保护下，将5'-溴-10'-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-2'H,4'H-螺[哌啶-4,3'-[1,4]噁嗪并[2,3-f]喹唑啉]-1-甲酸叔丁酯(120.0mg,0.17mmol)，t-BuBrettPhos Pd G3(33.2mg,0.035mmol)，t-BuBrettPhos(16.9mg,0.035mmol)和碳酸铯(227.8mg,0.70mmol)溶于甲醇(5mL)中，升温至100℃搅拌2h。反应完全后冷却至室温，减压浓缩得到粗产品，粗产品经硅胶柱层析以甲醇/二氯甲烷(10％-15％)为洗脱剂梯度洗脱分离纯化得到5'-甲氧基-10'-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-2'H,4'H-螺[哌啶-4,3'-[1,4]噁嗪并[2,3-f]喹唑啉]-1-甲酸叔丁酯(黄色固体,80mg,72.0％)。MS(ESI+)m/z＝638.6[M+H]+。Step 2: Under nitrogen protection, tert-butyl 5'-bromo-10'-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-2'H,4'H-spiro[piperidine-4,3'-[1,4]oxazino[2,3-f]quinazoline]-1-carboxylate (120.0 mg, 0.17 mmol), t-BuBrettPhos Pd G3 (33.2 mg, 0.035 mmol), t-BuBrettPhos (16.9 mg, 0.035 mmol) and cesium carbonate (227.8 mg, 0.70 mmol) were dissolved in methanol (5 mL), heated to 100 ° C and stirred for 2 h. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure to afford the crude product, which was then isolated and purified by silica gel column chromatography using a gradient elution ratio of methanol/dichloromethane (10%-15%) to afford tert-butyl 5'-methoxy-10'-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-2'H,4'H-spiro[piperidine-4,3'-[1,4]oxazino[2,3-f]quinazoline]-1-carboxylate (yellow solid, 80 mg, 72.0%). MS (ESI + ) m/z = 638.6 [M+H] + .

第三步、第四步：以5'-甲氧基-10'-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-2'H,4'H-螺[哌啶-4,3'-[1,4]噁嗪并[2,3-f]喹唑啉]-1-甲酸叔丁酯为原料，按照实施例1第二步和第三步方法制备终产物12。Step 3 and Step 4: Using 5'-methoxy-10'-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-2'H,4'H-spiro[piperidine-4,3'-[1,4]oxazino[2,3-f]quinazoline]-1-carboxylic acid tert-butyl ester as raw material, the final product 12 was prepared according to the methods of Step 2 and Step 3 of Example 1.

黄色固体.MS(ESI+)m/z＝592.4[M+H]+.1H NMR(300MHz,DMSO-d6)δ9.70(s,1H),8.30(s,1H),8.16(s,1H),7.78-7.67(m,2H),7.56(d,J＝8.7Hz,1H),7.06(d,J＝2.3Hz,1H),6.98(dd,J＝8.7,2.3Hz,1H),6.94-6.78(m,3H),6.13(dd,J＝16.7,2.5Hz,1H),5.70(dd,J＝10.4,2.5Hz,1H),5.51(s,1H),4.37-4.29(m,2H),3.96(s,3H),3.84(s,5H),3.62-3.42(m,2H),2.23(s,3H),1.79-1.59(m,4H).Yellow solid. MS (ESI + ) m/z = 592.4 [M+H] + . 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.70 (s, 1H), 8.30 (s, 1H), 8.16 (s, 1H), 7.78-7.67 (m, 2H), 7.56 (d, J = 8.7 Hz, 1H), 7.06 (d, J = 2.3 Hz, 1H), 6.98 (dd, J = 8.7, 2.3 Hz, 1H), 6.94-6.78 (m, 3H), 6.13 (d d,J＝16.7,2.5Hz,1H),5.70(dd,J＝10.4,2.5Hz,1H),5.51(s,1H),4.37-4.29(m,2 H),3.96(s,3H),3.84(s,5H),3.62-3.42(m,2H),2.23(s,3H),1.79-1.59(m,4H).

实施例132. 1-(4'-氟-10'-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-2'H,4'H-螺[哌啶-4,3'-吡喃并[2,3-f]喹唑啉]-1-基)丙-2-烯-1-酮(终产物117)的制备
Example 132. Preparation of 1-(4'-fluoro-10'-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-2'H,4'H-spiro[piperidin-4,3'-pyrano[2,3-f]quinazoline]-1-yl)prop-2-en-1-one (Final Product 117)

第一步：以8-氰基-7-(((二甲氨基)亚甲基)氨基)-4-氧代螺[色烷-3,4'-哌啶]-1'-甲酸叔丁酯(中间体C38,150.0mg,0.36mmol)和3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯胺(中间体B7,110.5mg,0.44mmol)为原料，按照合成终产物1第一步的方法制备10'-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-4'-氧代-2'H,4'H-螺[哌啶-4,3'-吡喃并[2,3-f]喹唑啉]-1-甲酸叔丁酯(淡黄色固体,110mg,48.7％)。MS(ESI+)m/z＝621.2[M+H]+。Step 1: From tert-butyl 8-cyano-7-(((dimethylamino)methylene)amino)-4-oxospiro[chromane-3,4'-piperidine]-1'-carboxylate (Intermediate C38, 150.0 mg, 0.36 mmol) and 3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline (Intermediate B7, 110.5 mg, 0.44 mmol), tert-butyl 10'-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-4'-oxo-2'H,4'H-spiro[piperidine-4,3'-pyrano[2,3-f]quinazoline]-1-carboxylate (pale yellow solid, 110 mg, 48.7%) was prepared according to the procedure for the first step of the synthesis of final product 1. MS(ESI + )m/z=621.2[M+H] + .

第二步：将10'-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-4'-氧代-2'H,4'H-螺[哌啶-4,3'-吡喃并[2,3-f]喹唑啉]-1-甲酸叔丁酯(120.0mg,0.19mmol)溶于甲醇(5mL)，降温至0℃，加入硼氢化钠(14.6mg,0.39mmol)，加毕，恢复至室温搅拌2h。反应完全后，往反应液中加水(20mL)，混合液用乙酸乙酯(50mL×3)萃取，合并有机相用水(50mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-50％)为洗脱剂梯度洗脱分离得到4'-羟基-10'-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-2'H,4'H-螺[哌啶-4,3'-吡喃并[2,3-f]喹唑啉]-1-甲酸叔丁酯(淡黄色固体,100mg,83.1％)。MS(ESI+)m/z＝623.2[M+H]+。Step 2: Dissolve tert-butyl 10'-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-4'-oxo-2'H,4'H-spiro[piperidine-4,3'-pyrano[2,3-f]quinazoline]-1-carboxylate (120.0 mg, 0.19 mmol) in methanol (5 mL), cool to 0°C, add sodium borohydride (14.6 mg, 0.39 mmol), and after addition, return to room temperature and stir for 2 h. After the reaction was complete, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with water (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-50%) as the eluent to afford tert-butyl 4'-hydroxy-10'-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-2'H,4'H-spiro[piperidin-4,3'-pyrano[2,3-f]quinazoline]-1-carboxylate (pale yellow solid, 100 mg, 83.1%). MS (ESI + ) m/z = 623.2 [M+H] + .

第三步：将4'-羟基-10'-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-2'H,4'H-螺[哌啶-4,3'-吡喃并[2,3-f]喹唑啉]-1-甲酸叔丁酯(140.0mg,0.23mmol)溶于BAST(3mL)，室温搅拌12h。反应完全后，往反应液中加水(20mL)，混合液用乙酸乙酯(50mL×3)萃取，合并有机相用水(50mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(0-50％)为洗脱剂梯度洗脱分离得到4'-氟-10'-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-2'H,4'H-螺[哌啶-4,3'-吡喃并[2,3-f]喹唑啉]-1-甲酸叔丁酯(黄色固体,65mg,46.3％)。MS(ESI+)m/z＝625.2[M+H]+。Step 3: Dissolve tert-butyl 4'-hydroxy-10'-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-2'H,4'H-spiro[piperidine-4,3'-pyrano[2,3-f]quinazoline]-1-carboxylate (140.0 mg, 0.23 mmol) in BAST (3 mL) and stir at room temperature for 12 h. After the reaction was complete, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with water (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography using a gradient elution of ethyl acetate/petroleum ether (0-50%) as the eluent to afford tert-butyl 4'-fluoro-10'-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-2'H,4'H-spiro[piperidin-4,3'-pyrano[2,3-f]quinazoline]-1-carboxylate (yellow solid, 65 mg, 46.3%). MS (ESI + ) m/z = 625.2 [M+H] + .

第四步、第五步：以4'-氟-10'-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-2'H,4'H-螺[哌啶-4,3'-吡喃并[2,3-f]喹唑啉]-1-甲酸叔丁酯和丙烯酸酐为原料，按照合成终产物1第二步、第三步的方法制备1-(4'-氟-10'-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-2'H,4'H-螺[哌啶-4,3'-吡喃并[2,3-f]喹唑啉]-1-基)丙-2-烯-1-酮。Step 4 and Step 5: Using tert-butyl 4'-fluoro-10'-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-2'H,4'H-spiro[piperidin-4,3'-pyrano[2,3-f]quinazoline]-1-carboxylate and acrylic anhydride as raw materials, 1-(4'-fluoro-10'-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-2'H,4'H-spiro[piperidin-4,3'-pyrano[2,3-f]quinazoline]-1-yl)prop-2-en-1-one was prepared according to the method of Step 2 and Step 3 for synthesizing the final product 1.

黄色固体.MS(ESI+)m/z＝579.3[M+H]+.1H NMR(300MHz,DMSO-d6)δ9.88(s,1H),8.51(s,1H),8.16(s,1H),7.81-7.55(m,4H),7.36(d,J＝8.7Hz,1H),7.13-6.87(m,3H),6.18-6.09(m,1H),5.73-5.45(m,2H),4.91-4.52(m,10H),3.83(s,3H),2.25(s,3H),1.88-1.72(m,1H).Yellow solid. MS (ESI + ) m/z = 579.3 [M+H] + . 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.51 (s, 1H), 8.16 (s, 1H), 7.81-7.55 (m, 4H), 7.36 (d, J = 8.7 Hz, 1H), 7.13-6.87 (m, 3H), 6.18-6.09 (m, 1H), 5.73-5.45 (m, 2H), 4.91-4.52 (m, 10H), 3.83 (s, 3H), 2.25 (s, 3H), 1.88-1.72 (m, 1H).

实施例133.终产物126的制备Example 133. Preparation of final product 126

以8-氰基-7-(((二甲氨基)亚甲基)氨基)-4-氧代螺[色烷-3,4'-哌啶]-1'-甲酸叔丁酯(中间体C38)和3-甲基-4-(喹喔啉-6-基氧基)苯胺(中间体B3)为原料，按照合成终产物117的方法制备终产物126。如表9所示。Final product 126 was prepared using tert-butyl 8-cyano-7-(((dimethylamino)methylene)amino)-4-oxospiro[chromane-3,4'-piperidine]-1'-carboxylate (Intermediate C38) and 3-methyl-4-(quinoxalin-6-yloxy)aniline (Intermediate B3) as starting materials, following the method for synthesizing final product 117. Table 9 shows the reaction.

表9终产物126的结构和NMR或MS数据
Table 9 Structure and NMR or MS data of final product 126

实施例134. 1-(10'-((3-乙炔基-4-(喹喔啉-6-基氧基)苯基)氨基)-2'H-螺[哌啶-4,3'-[1,4]二氧六环并[2,3-f]喹唑啉]-1-基)丙-2-烯-1-酮(终产物129)的制备
Example 134. Preparation of 1-(10'-((3-ethynyl-4-(quinoxalin-6-yloxy)phenyl)amino)-2'H-spiro[piperidin-4,3'-[1,4]dioxane[2,3-f]quinazolin]-1-yl)prop-2-en-1-one (Final Product 129)

第一步：以5-氰基-6-(((二甲基氨基)亚甲基)氨基)-3H-螺[苯并[b][1,4]二氧六环-2,4'-哌啶]-1'-甲酸叔丁酯(中间体C11,400.0mg,1.00mmol)和3-溴-4-(喹喔啉-6-基氧基)苯胺(中间体B43,378.9mg,1.20mmol)为原料，按照合成终产物1第一步的方法制备10'-((3-溴-4-(喹喔啉-6-基氧基)苯基)氨基)-2'H-螺[哌啶-4,3'-[1,4]二氧六环并[2,3-f]喹唑啉]-1-甲酸叔丁酯(淡黄色固体,400mg,59.7％)。MS(ESI+)m/z＝671.1[M+H]+。Step 1: Starting from tert-butyl 5-cyano-6-(((dimethylamino)methylene)amino)-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-1'-carboxylate (Intermediate C11, 400.0 mg, 1.00 mmol) and 3-bromo-4-(quinoxalin-6-yloxy)aniline (Intermediate B43, 378.9 mg, 1.20 mmol), tert-butyl 10'-((3-bromo-4-(quinoxalin-6-yloxy)phenyl)amino)-2'H-spiro[piperidine-4,3'-[1,4]dioxano[2,3-f]quinazoline]-1-carboxylate (pale yellow solid, 400 mg, 59.7%) was prepared according to the procedure for the first step of the synthesis of the final product 1. MS (ESI + ) m/z = 671.1 [M+H] + .

第二步：氮气保护下，将10'-((3-溴-4-(喹喔啉-6-基氧基)苯基)氨基)-2'H-螺[哌啶-4,3'-[1,4]二氧六环并[2,3-f]喹唑啉]-1-甲酸叔丁酯(400.0mg,0.60mmol)溶于DMF(6mL)，依次加入N-甲基二环己基胺(581.8mg,2.98mmol)，cataCXium A Pd G3(43.5mg,0.060mmol)和三甲基硅乙炔(877.6mg,8.93mmol)，升温至90℃搅拌3h。反应完全后冷却至室温，减压浓缩，所得残余物经硅胶柱层析以甲醇/二氯甲烷(0-10％)为洗脱剂梯度洗脱分离得到10'-((4-(喹喔啉-6-基氧基)-3-((三甲基硅烷基)乙炔基)苯基)氨基)-2'H-螺[哌啶-4,3'-[1,4]二氧六环并[2,3-f]喹唑啉]-1-甲酸叔丁酯(淡黄色固体,280mg,68.2％)。MS(ESI+)m/z＝689.2[M+H]+。Step 2: Under nitrogen protection, tert-butyl 10'-((3-bromo-4-(quinoxalin-6-yloxy)phenyl)amino)-2'H-spiro[piperidine-4,3'-[1,4]dioxane[2,3-f]quinazoline]-1-carboxylate (400.0 mg, 0.60 mmol) was dissolved in DMF (6 mL), and N-methyldicyclohexylamine (581.8 mg, 2.98 mmol), cataCXium A Pd G3 (43.5 mg, 0.060 mmol) and trimethylsilylacetylene (877.6 mg, 8.93 mmol) were added in sequence, and the temperature was raised to 90 ° C and stirred for 3 h. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using a gradient elution ratio of methanol/dichloromethane (0-10%) to afford tert-butyl 10'-((4-(quinoxalin-6-yloxy)-3-((trimethylsilyl)ethynyl)phenyl)amino)-2'H-spiro[piperidine-4,3'-[1,4]dioxano[2,3-f]quinazoline]-1-carboxylate (pale yellow solid, 280 mg, 68.2%). MS (ESI + ) m/z = 689.2 [M+H] + .

第三步：将10'-((4-(喹喔啉-6-基氧基)-3-((三甲基硅烷基)乙炔基)苯基)氨基)-2'H-螺[哌啶-4,3'-[1,4]二氧六环并[2,3-f]喹唑啉]-1-甲酸叔丁酯(270.0mg,0.39mmol)溶于四氢呋喃(4mL)，加入三乙胺氢氟酸盐(631.9mg,3.92mmol)，室温搅拌1h。反应完全后，往反应液中加水(15mL)，用碳酸氢钠调pH>7，混合液用乙酸乙酯(30mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到10'-((3-乙炔基-4-(喹喔啉-6-基氧基)苯基)氨基)-2'H-螺[哌啶-4,3'-[1,4]二氧六环并[2,3-f]喹唑啉]-1-甲酸叔丁酯(淡黄色固体,250mg,粗品)。MS(ESI+)m/z＝617.5[M+H]+。Step 3: Dissolve tert-butyl 10'-((4-(quinoxalin-6-yloxy)-3-((trimethylsilyl)ethynyl)phenyl)amino)-2'H-spiro[piperidine-4,3'-[1,4]dioxane[2,3-f]quinazoline]-1-carboxylate (270.0 mg, 0.39 mmol) in tetrahydrofuran (4 mL), add triethylamine hydrofluoride (631.9 mg, 3.92 mmol), and stir at room temperature for 1 h. After the reaction was complete, water (15 mL) was added to the reaction solution, and the pH was adjusted to >7 with sodium bicarbonate. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to provide tert-butyl 10'-((3-ethynyl-4-(quinoxalin-6-yloxy)phenyl)amino)-2'H-spiro[piperidine-4,3'-[1,4]dioxano[2,3-f]quinazoline]-1-carboxylate (pale yellow solid, 250 mg, crude). MS (ESI + ) m/z = 617.5 [M+H] + .

第四步、第五步：以10'-((3-乙炔基-4-(喹喔啉-6-基氧基)苯基)氨基)-2'H-螺[哌啶-4,3'-[1,4]二氧六环并[2,3-f]喹唑啉]-1-甲酸叔丁酯为原料，按照合成终产物1第二步和第三步的方法制备1-(10'-((3-乙炔基-4-(喹喔啉-6-基氧基)苯基)氨基)-2'H-螺[哌啶-4,3'-[1,4]二氧六环并[2,3-f]喹唑啉]-1-基)丙-2-烯-1-酮。Step 4 and Step 5: Using tert-butyl 10'-((3-ethynyl-4-(quinoxalin-6-yloxy)phenyl)amino)-2'H-spiro[piperidine-4,3'-[1,4]dioxane[2,3-f]quinazoline]-1-carboxylate as raw material, prepare 1-(10'-((3-ethynyl-4-(quinoxalin-6-yloxy)phenyl)amino)-2'H-spiro[piperidine-4,3'-[1,4]dioxane[2,3-f]quinazoline]-1-yl)prop-2-en-1-one according to the method of the second and third steps of the synthesis of the final product 1.

白色固体.MS(ESI+)m/z＝571.3[M+H]+.1H NMR(300MHz,DMSO-d6)δ9.89(s,1H),8.93-8.83(m,2H),8.51(s,1H),8.21(d,J＝2.7Hz,1H),8.16(d,J＝9.2Hz,1H),8.05(dd,J＝8.9,2.7Hz,1H),7.71(dd,J＝9.2,2.8Hz,1H),7.53(d,J＝9.0Hz,1H),7.44-7.32(m,2H),7.21(d,J＝2.8Hz,1H),6.87(dd,J＝16.7,10.5Hz,1H),6.14(dd,J＝16.7,2.5Hz,1H),5.71(dd,J＝10.5,2.5Hz,1H),4.40(s,2H),4.30(s,1H),4.24-4.12(m,1H),4.01-3.89(m,1H),3.61-3.44(m,1H),3.31-3.17(m,1H),1.95-1.69(m,4H).White solid. MS (ESI + ) m/z = 571.3 [M+H] + . 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.93-8.83 (m, 2H), 8.51 (s, 1H), 8.21 (d, J = 2.7 Hz, 1H), 8.16 (d, J = 9.2 Hz, 1H), 8.05 (dd, J = 8.9, 2.7 Hz, 1H), 7.71 (dd, J = 9.2, 2.8 Hz, 1H), 7.53 (d, J = 9.0 Hz, 1H), 7.44-7.32 (m, 2H), 7.21 (d, J = 2.8 Hz, 1H) ,6.87(dd,J＝16.7,10.5Hz,1H),6.14(dd,J＝16.7,2.5Hz,1H),5.71(dd,J＝10.5,2.5Hz,1H),4.40(s,2H),4 .30(s,1H),4.24-4.12(m,1H),4.01-3.89(m,1H),3.61-3.44(m,1H),3.31-3.17(m,1H),1.95-1.69(m,4H).

实施例135. 1-(4-((4-((3-氯-4-(喹喔啉-6-基氧基)苯基)氨基)-5-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)丙-2-烯-1-酮(终产物134)的制备
Example 135. Preparation of 1-(4-((4-((3-chloro-4-(quinoxalin-6-yloxy)phenyl)amino)-5-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one (Final Product 134)

第一步：氮气保护下，将N'-(2-氰基-4-羟基-3-甲氧基苯基)-N,N-二甲基甲脒(中间体C44,1.0g,4.65mmol)溶于甲苯和醋酸混合液(10mL,1/1v/v)，加入3-氯-4-(喹喔喔-6-基氧基)苯胺(中间体B18,1.2g,4.56mmol)，升温至100℃搅拌4h。反应完全后冷却至室温，减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯为洗脱剂洗脱分离得到4-((3-氯-4-(喹喔啉-6-基氧基)苯基)氨基)-5-甲氧基喹唑啉-6-醇(黄色固体,1.2g,59.0％)。MS(ESI+)m/z＝446.1[M+H]+。Step 1: Under nitrogen, N'-(2-cyano-4-hydroxy-3-methoxyphenyl)-N,N-dimethylformamidine (Intermediate C44, 1.0 g, 4.65 mmol) was dissolved in a mixture of toluene and acetic acid (10 mL, 1/1 v/v). 3-Chloro-4-(quinoxalin-6-yloxy)aniline (Intermediate B18, 1.2 g, 4.56 mmol) was added and the mixture was heated to 100°C and stirred for 4 h. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate as the eluent to afford 4-((3-chloro-4-(quinoxalin-6-yloxy)phenyl)amino)-5-methoxyquinazolin-6-ol (yellow solid, 1.2 g, 59.0%). MS (ESI + ) m/z = 446.1 [M+H] + .

第二步：将4-((3-氯-4-(喹喔啉-6-基氧基)苯基)氨基)-5-甲氧基喹唑啉-6-醇(1.2g,2.69mmol)溶于四氢呋喃(15mL)，依次加入N-Boc-4-羟基哌啶(812.6mg,4.04mmol)和三苯基膦(776.5mg,2.96mmol)，降温至0℃，缓慢滴加DEAD(562.5mg,3.23mmol)，加毕，恢复至室温搅拌2h。反应完全后，往反应液中加水(10mL)，混合液用乙酸乙酯(5mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以乙酸乙酯/石油醚(33％)为洗脱剂洗脱分离得到4-((4-((3-氯-4-(喹喔啉-6-基氧基)苯基)氨基)-5-甲氧基喹唑啉-6-基)氧基)哌啶-1-甲酸叔丁酯(黄色固体,400mg,23.6％)。MS(ESI+)m/z＝629.2[M+H]+。Step 2: Dissolve 4-((3-chloro-4-(quinoxalin-6-yloxy)phenyl)amino)-5-methoxyquinazolin-6-ol (1.2 g, 2.69 mmol) in tetrahydrofuran (15 mL), add N-Boc-4-hydroxypiperidine (812.6 mg, 4.04 mmol) and triphenylphosphine (776.5 mg, 2.96 mmol) in sequence, cool to 0°C, and slowly add DEAD (562.5 mg, 3.23 mmol) dropwise. After the addition is complete, return to room temperature and stir for 2 h. After the reaction was complete, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (33%) as eluent to afford tert-butyl 4-((4-((3-chloro-4-(quinoxalin-6-yloxy)phenyl)amino)-5-methoxyquinazolin-6-yl)oxy)piperidine-1-carboxylate (yellow solid, 400 mg, 23.6%). MS (ESI + ) m/z = 629.2 [M+H] + .

第三步：将4-((4-((3-氯-4-(喹喔啉-6-基氧基)苯基)氨基)-5-甲氧基喹唑啉-6-基)氧基)哌啶-1-甲酸叔丁酯(150.0mg,0.24mmol)溶于二氯甲烷和三氟乙酸混合液(1/1v/v,4mL)，室温搅拌1h。反应完全后减压浓缩，得到N-(3-氯-4-(喹喔啉-6-基氧基)苯基)-5-甲氧基-6-(哌啶-4-基氧基)喹唑啉-4-胺(黄色油状物,150mg,粗品)。MS(ESI+)m/z＝529.2[M+H]+。Step 3: Dissolve tert-butyl 4-((4-((3-chloro-4-(quinoxalin-6-yloxy)phenyl)amino)-5-methoxyquinazolin-6-yl)oxy)piperidine-1-carboxylate (150.0 mg, 0.24 mmol) in a mixture of dichloromethane and trifluoroacetic acid (1/1 v/v, 4 mL) and stir at room temperature for 1 hour. After completion of the reaction, concentrate under reduced pressure to afford N-(3-chloro-4-(quinoxalin-6-yloxy)phenyl)-5-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine (yellow oil, 150 mg, crude). MS (ESI + ) m/z = 529.2 [M+H] + .

第四步：将N-(3-氯-4-(喹喔啉-6-基氧基)苯基)-5-甲氧基-6-(哌啶-4-基氧基)喹唑啉-4-胺(150.0mg,0.28mmol)溶于四氢呋喃(2mL)，加入饱和碳酸氢钠溶液(2mL)，降温至0℃，加入丙烯酰氯(12.8mg,0.14mmol)的四氢呋喃溶液(2mL)，0℃搅拌0.5h。反应完全后恢复至室温，往反应液中加水(5mL)，混合液用乙酸乙酯(5mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以甲醇/二氯甲烷(10％)为洗脱剂洗脱分离得到1-(4-((4-((3-氯-4-(喹喔啉-6-基氧基)苯基)氨基)-5-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)丙-2-烯-1-酮。Step 4: Dissolve N-(3-chloro-4-(quinoxalin-6-yloxy)phenyl)-5-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine (150.0 mg, 0.28 mmol) in tetrahydrofuran (2 mL), add saturated sodium bicarbonate solution (2 mL), cool to 0°C, add a solution of acryloyl chloride (12.8 mg, 0.14 mmol) in tetrahydrofuran (2 mL), and stir at 0°C for 0.5 h. After the reaction was completed, the temperature was returned to room temperature, water (5 mL) was added to the reaction solution, and the mixed solution was extracted with ethyl acetate (5 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography using methanol/dichloromethane (10%) as eluent to give 1-(4-((4-((3-chloro-4-(quinoxalin-6-yloxy)phenyl)amino)-5-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one.

黄色固体.MS(ESI+)m/z＝583.2[M+H]+.1H NMR(300MHz,DMSO-d6)δ10.32(s,1H),8.93-8.86(m,2H),8.55(s,1H),8.45(d,J＝2.4Hz,1H),8.16(d,J＝9.3Hz,1H),7.93(dd,J＝8.8,2.4Hz,1H),7.86(d,J＝9.3Hz,1H),7.71(dd,J＝9.3,2.7Hz,1H),7.61(d,J＝9.3Hz,1H),7.47(d,J＝8.8Hz,1H),7.19(d,J＝2.7Hz,1H),6.85(dd,J＝16.8,10.5Hz,1H),6.12(dd,J＝16.8,2.4Hz,1H),5.69(dd,J＝10.5,2.4Hz,1H),4.91-4.74(m,1H),4.14(s,3H),3.98-3.79(m,2H),3.59-3.37(m,2H),2.09-1.93(m,2H),1.82-1.58(m,2H).Yellow solid. MS (ESI + ) m/z = 583.2 [M+H] + . 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.32 (s, 1H), 8.93-8.86 (m, 2H), 8.55 (s, 1H), 8.45 (d, J = 2.4 Hz, 1H), 8.16 (d, J = 9.3 Hz, 1H), 7.93 (dd, J = 8.8, 2.4 Hz, 1H), 7.86 (d, J = 9.3 Hz, 1H), 7.71 (dd, J = 9.3, 2.7 Hz, 1H), 7.61 (d, J = 9.3 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7. .19(d,J＝2.7Hz,1H),6.85(dd,J＝16.8,10.5Hz,1H),6.12(dd,J＝16.8,2.4Hz,1H),5.69(dd,J＝10.5,2.4Hz,1H ),4.91-4.74(m,1H),4.14(s,3H),3.98-3.79(m,2H),3.59-3.37(m,2H),2.09-1.93(m,2H),1.82-1.58(m,2H).

实施例136. 8-丙烯酰基-4-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-6,6a,7,8,9,10-六氢吡嗪并[1',2':4,5][1,4]噁嗪并[2,3-f]喹唑啉-12-甲腈(终产物162)的制备
Example 136. Preparation of 8-acryloyl-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-6,6a,7,8,9,10-hexahydropyrazino[1',2':4,5][1,4]oxazino[2,3-f]quinazoline-12-carbonitrile (Final Product 162)

第一步：将10-溴-7-氰基-8-(((二甲氨基)亚甲基)氨基)-1,2,4a,5-四氢苯并[b]吡嗪并[1,2-d][1,4]噁嗪-3(4H)-甲酸叔丁酯(中间体C19,955.0mg,2.06mmol)溶于醋酸(15mL)，依次加入3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯胺(中间体B7,625.1mg,2.47mmol)，升温至60℃搅拌3h。反应完全后冷却至室温，减压浓缩，所得残余物经硅胶柱层析以甲醇/二氯甲烷(0-10％)为洗脱剂梯度洗脱分离得到12-溴-4-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-6a,7,9,10-四氢吡嗪并[1',2':4,5][1,4]噁嗪并[2,3-f]喹唑啉-8(6H)-甲酸叔丁酯(黄色固体,380mg,27.5％)。MS(ESI+)m/z＝674.0[M+H]+。Step 1: Dissolve tert-butyl 10-bromo-7-cyano-8-(((dimethylamino)methylene)amino)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate (Intermediate C19, 955.0 mg, 2.06 mmol) in acetic acid (15 mL). Add 3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline (Intermediate B7, 625.1 mg, 2.47 mmol) in the mixture and heat to 60°C with stirring for 3 h. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using a gradient elution ratio of methanol/dichloromethane (0-10%) to afford tert-butyl 12-bromo-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-6a,7,9,10-tetrahydropyrazino[1',2':4,5][1,4]oxazino[2,3-f]quinazoline-8(6H)-carboxylate (yellow solid, 380 mg, 27.5%). MS (ESI + ) m/z = 674.0 [M+H] + .

第二步：氮气保护下，将12-溴-4-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-6a,7,9,10-四氢吡嗪并[1',2':4,5][1,4]噁嗪并[2,3-f]喹唑啉-8(6H)-甲酸叔丁酯(100.0mg,0.15mmol)溶于DMF(5mL)，依次加入RuPhos Pd G3(12.5mg,0.015mmol)，RuPhos(6.9mg,0.015mmol)和氰化锌(21.0mg,0.18mmol)，升温至100℃搅拌2h。反应完全后冷却至室温，往反应液中加水(10mL)，混合液用乙酸乙酯(10mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以甲醇/二氯甲烷(0-15％)为洗脱剂梯度洗脱分离得到12-氰基-4-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-6a,7,9,10-四氢吡嗪并[1',2':4,5][1,4]噁嗪并[2,3-f]喹唑啉-8(6H)-甲酸叔丁酯(黄色固体,56mg,60.8％)。MS(ESI+)m/z＝619.2[M+H]+。Step 2: Under nitrogen protection, tert-butyl 12-bromo-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-6a,7,9,10-tetrahydropyrazino[1',2':4,5][1,4]oxazino[2,3-f]quinazoline-8(6H)-carboxylate (100.0 mg, 0.15 mmol) was dissolved in DMF (5 mL), and RuPhos Pd G3 (12.5 mg, 0.015 mmol), RuPhos (6.9 mg, 0.015 mmol) and zinc cyanide (21.0 mg, 0.18 mmol) were added in sequence. The temperature was raised to 100 °C and stirred for 2 h. After the reaction was complete, the mixture was cooled to room temperature. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using a gradient elution of methanol/dichloromethane (0-15%) as the eluent to afford tert-butyl 12-cyano-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-6a,7,9,10-tetrahydropyrazino[1',2':4,5][1,4]oxazino[2,3-f]quinazoline-8(6H)-carboxylate (yellow solid, 56 mg, 60.8%). MS (ESI + ) m/z = 619.2 [M+H] + .

第三步、第四步：以12-氰基-4-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-6a,7,9,10-四氢吡嗪并[1',2':4,5][1,4]噁嗪并[2,3-f]喹唑啉-8(6H)-甲酸叔丁酯为原料，按照合成终产物1第二步和第三步的方法制备8-丙烯酰基-4-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-6,6a,7,8,9,10-六氢吡嗪并[1',2':4,5][1,4]噁嗪并[2,3-f]喹唑啉-12-甲腈。Step 3 and Step 4: Using 12-cyano-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-6a,7,9,10-tetrahydropyrazino[1',2':4,5][1,4]oxazino[2,3-f]quinazoline-8(6H)-carboxylic acid tert-butyl ester as raw material, 8-acryloyl-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-6,6a,7,8,9,10-hexahydropyrazino[1',2':4,5][1,4]oxazino[2,3-f]quinazoline-12-carbonitrile was prepared according to the method of Step 2 and Step 3 of the synthesis of the final product 1.

黄色固体.MS(ESI+)m/z＝573.2[M+H]+.1H NMR(300MHz,DMSO-d6)δ9.16(s,1H),8.21(s,1H),7.87(d,J＝1.2Hz,1H),7.62(d,J＝8.7Hz,1H),7.44(s,1H),7.37(d,J＝2.6Hz,1H),7.24-7.13(m,2H),7.05(dd,J＝8.7,2.3Hz,1H),6.93-6.76(m,2H),6.18(dd,J＝16.7,2.4Hz,1H),5.75(d,J＝10.6Hz,1H),4.55-4.45(m,1H),4.31-4.18(m,1H),3.98-3.70(m,7H),3.62-3.56(m,1H),3.48-3.36(m,2H),2.30(s,3H).Yellow solid. MS (ESI + ) m/z = 573.2 [M+H] + . 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.16 (s, 1H), 8.21 (s, 1H), 7.87 (d, J = 1.2 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.44 (s, 1H), 7.37 (d, J = 2.6 Hz, 1H), 7.24-7.13 (m, 2H), 7.05 (dd, J = 8.7, 2.3 Hz, 1H), 6.93-6.76 ( m,2H),6.18(dd,J＝16.7,2.4Hz,1H),5.75(d,J＝10.6Hz,1H),4.55-4.45(m,1H),4.31 -4.18(m,1H),3.98-3.70(m,7H),3.62-3.56(m,1H),3.48-3.36(m,2H),2.30(s,3H).

实施例137. 1-(12-乙炔基-4-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧)苯基)氨基)-6a,7,9,10-四氢吡嗪并[1',2':4,5][1,4]噁嗪并[2,3-f]喹唑啉-8(6H)-基)丙-2-烯-1-酮(终产物163)的制备
Example 137. Preparation of 1-(12-ethynyl-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-6a,7,9,10-tetrahydropyrazino[1',2':4,5][1,4]oxazino[2,3-f]quinazolin-8(6H)-yl)prop-2-en-1-one (Final Product 163)

第一步：将10-溴-7-氰基-8-(((二甲氨基)亚甲基)氨基)-1,2,4a,5-四氢苯并[b]吡嗪代[1,2-d][1,4]噁嗪-3(4H)-甲酸叔丁酯(中间体C19,955mg,2.06mmol)溶于醋酸(15mL)，加入3-甲基-4-[(1-甲基-1，3-苯二唑-5-基)氧基]苯胺(中间体B7,625.1mg,2.47mmol)，升温至60℃搅拌3h，反应完全后冷却至室温，减压浓缩，所得残余物经硅胶柱层析以甲醇/二氯甲烷(0％-15％)为洗脱剂梯度洗脱分离纯化得到12-溴-4-((3-甲基-4-)(((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-6a,7,9,10-四氢吡嗪并[1',2':4,5][1,4]噁唑并[2,3-f]喹唑啉-8(6H)-甲酸叔丁酯(黄色固体,380mg,27.5％)。MS(ESI+)m/z＝672.0[M+H]+。Step 1: Dissolve tert-butyl 10-bromo-7-cyano-8-(((dimethylamino)methylene)amino)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate (Intermediate C19, 955 mg, 2.06 mmol) in acetic acid (15 mL), add 3-methyl-4-[(1-methyl-1,3-benzodiazol-5-yl)oxy]aniline (Intermediate B7, 625.1 mg, 2.47 mmol), heat to 60°C and stir for 3 h. After completion of the reaction, the product was cooled to room temperature and concentrated under reduced pressure. The resulting residue was isolated and purified by silica gel column chromatography using a gradient elution ratio of methanol/dichloromethane (0%-15%) as the eluent to provide tert-butyl 12-bromo-4-((3-methyl-4-)(((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-6a,7,9,10-tetrahydropyrazino[1',2':4,5][1,4]oxazolo[2,3-f]quinazoline-8(6H)-carboxylate (yellow solid, 380 mg, 27.5%). MS (ESI + ) m/z = 672.0 [M+H] + .

第二步：氮气保护下，将12-溴-4-((3-甲基-4-)(((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-6a,7,9,10-四氢吡嗪并[1',2':4,5][1,4]噁唑并[2,3-f]喹唑啉-8(6H)-甲酸叔丁酯(500mg,0.75mmol)溶于四氢呋喃(8mL)，依次加入三甲基甲硅烷基乙炔(109.5mg,1.10mmol)，DBU(339.5mg,2.25mmol)，碘化亚铜(28.5mg,0.15mmol)和Pd(PPh3)2Cl2(52.0mg,0.10mmol)，升温至90℃搅拌1h，反应完全后冷却至室温，减压浓缩，所得残余物经硅胶柱层析以甲醇/二氯甲烷(0％-15％)为洗脱剂梯度洗脱分离纯化得到12-乙炔基-4-((3-甲基-4-)(((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-6a,7,9,10-四氢吡嗪并[1',2':4,5][1,4]噁唑并[2,3-f]喹唑啉-8(6H)-甲酸叔丁酯(黄色固体,200mg,39.0％)。MS(ESI+)m/z＝690.1[M+H]+。Step 2: Under nitrogen protection, tert-butyl 12-bromo-4-((3-methyl-4-)(((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-6a,7,9,10-tetrahydropyrazino[1',2':4,5][1,4]oxazolo[2,3-f]quinazoline-8(6H)-carboxylate (500 mg, 0.75 mmol) was dissolved in tetrahydrofuran (8 mL), and trimethylsilylacetyl (109.5 mg, 1.10 mmol), DBU (339.5 mg, 2.25 mmol), cuprous iodide (28.5 mg, 0.15 mmol) and Pd(PPh 3 ) 2 Cl 2 were added in sequence. The reaction mixture was heated to 90°C and stirred for 1 h. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of methanol/dichloromethane (0%-15%) to afford tert-butyl 12-ethynyl-4-((3-methyl-4-)(((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-6a,7,9,10-tetrahydropyrazino[1',2':4,5][1,4]oxazolo[2,3-f]quinazoline-8(6H)-carboxylate (yellow solid, 200 mg, 39.0%). MS (ESI + ) m/z = 690.1 [M+H] + .

第三步：将12-乙炔基-4-((3-甲基-4-)(((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-6a,7,9,10-四氢吡嗪并[1',2':4,5][1,4]噁唑并[2,3-f]喹唑啉-8(6H)-甲酸叔丁酯(200mg,0.29mmol)溶解于四氢呋喃(5mL)，加入三乙胺三氢氟酸盐(280.4mg,1.74mmol)，室温搅拌1h，反应完全后，往反应液中加水(10mL)，混合液用乙酸乙酯(10mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到4-((3-甲基-4-)((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-12-((三甲基硅基)乙炔基)-6a,7,9,10-四氢吡嗪并[1',2':4,5][1,4]噁唑并[2,3-f]喹唑啉-8(6H)-甲酸叔丁酯(160mg,粗产品)。MS(ESI+)m/z＝618.1[M+H]+。Step 3: Dissolve tert-butyl 12-ethynyl-4-((3-methyl-4-)(((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-6a,7,9,10-tetrahydropyrazino[1',2':4,5][1,4]oxazolo[2,3-f]quinazoline-8(6H)-carboxylate (200 mg, 0.29 mmol) in tetrahydrofuran (5 mL), add triethylamine trihydrofluoride (280.4 mg, 1.74 mmol), stir at room temperature for 1 h, and after the reaction is complete, add ... Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to provide tert-butyl 4-((3-methyl-4-)((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-12-((trimethylsilyl)ethynyl)-6a,7,9,10-tetrahydropyrazino[1',2':4,5][1,4]oxazolo[2,3-f]quinazoline-8(6H)-carboxylate (160 mg, crude product). MS (ESI + ) m/z = 618.1 [M+H] + .

第四步：将4-((3-甲基-4-)((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-12-((三甲基硅基)乙炔基)-6a,7,9,10-四氢吡嗪并[1',2':4,5][1,4]噁唑并[2,3-f]喹唑啉-8(6H)-甲酸叔丁酯(150mg,0.24mmol)溶于二氯甲烷(3mL)，加入三氟乙酸(1mL)，室温搅拌20min，减压浓缩得到12-乙炔基-N-(3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)-6,6a,7,8,9,10-六氢吡嗪基[1',2':4,5][1,4]噁唑并[2,3-f]喹唑啉-4-胺(黄色油状物,140mg,粗品)。MS(ESI+)m/z＝518.3[M+H]+。Step 4: tert-Butyl 4-((3-methyl-4-)((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-12-((trimethylsilyl)ethynyl)-6a,7,9,10-tetrahydropyrazino[1',2':4,5][1,4]oxazolo[2,3-f]quinazoline-8(6H)-carboxylate (150 mg, 0.24 mmol) was dissolved in dichloromethane (3 ml) To the reaction mixture was added 1 mL of trifluoroacetic acid (1 mL), stirred at room temperature for 20 min, and concentrated under reduced pressure to afford 12-ethynyl-N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-6,6a,7,8,9,10-hexahydropyrazinyl[1',2':4,5][1,4]oxazolo[2,3-f]quinazolin-4-amine as a yellow oil, 140 mg, crude product. MS (ESI + ) m/z = 518.3 [M+H] + .

第五步：将12-乙炔基-N-(3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)-6,6a,7,8,9,10-六氢吡嗪基[1',2':4,5][1,4]噁唑并[2,3-f]喹唑啉-4-胺(260mg,0.50mmol)溶于四氢呋喃(5mL)，加入三乙胺(152.5mg,1.51mmol)，调pH＞7，加入丙烯酸酐(31.7mg,0.25mmol)，室温搅拌20min，反应完全后，往反应液中加水(10mL)，混合液用乙酸乙酯(10mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经高压制备液相色谱纯化(柱型:Xselect CSH C18 OBD Column,30*150mm,5μm；流动相:水(0.1％ FA)/乙腈；流速:60mL/min；梯度:4％乙腈到34％10min；波长:254/220nm)得到1-(12-乙炔基-4-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧)苯基)氨基)-6a,7,9,10-四氢吡嗪并[1’,2':4,5][1,4]噁嗪并[2,3-f]喹唑啉-8(6H)-基)丙-2-烯-1-酮。Step 5: 12-Ethynyl-N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-6,6a,7,8,9,10-hexahydropyrazinyl[1',2':4,5][1,4]oxazolo[2,3-f]quinazolin-4-amine (260 mg, 0.50 mmol) was dissolved in tetrahydrofuran (5 mL), triethylamine (152.5 mg, 1.51 mmol) was added, the pH was adjusted to >7, acrylic anhydride (31.7 mg, 0.25 mmol) was added, and the mixture was stirred at room temperature for 20 min. After the reaction was complete, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL×3). The combined organic phases were dried over anhydrous sodium sulfate. , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high pressure preparative liquid chromatography (column type: Xselect CSH C18 OBD Column, 30*150mm, 5μm; mobile phase: water (0.1% FA)/acetonitrile; flow rate: 60mL/min; gradient: 4% acetonitrile to 34% 10min; wavelength: 254/220nm) to obtain 1-(12-ethynyl-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-6a,7,9,10-tetrahydropyrazino[1’,2’:4,5][1,4]oxazino[2,3-f]quinazolin-8(6H)-yl)prop-2-en-1-one.

黄色固体.MS(ESI+)m/z＝572.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),8.49(s,1H),8.43(s,1H),7.69-7.61(m,3H),7.42(s,1H),7.12(d,J＝2.3Hz,1H),7.07(dd,J＝8.8,2.3Hz,1H),6.95-6.81(m,2H),6.19(dd,J＝16.6,2.4Hz,1H),5.80-5.71(m,1H),4.82(s,1H),4.74-4.63(m,1H),4.28(t,J＝10.4Hz,1H),4.22-3.95(m,2H),3.89(s,4H),3.72-3.53(m,2H),3.35-3.26(m,2H),2.25(s,3H).Yellow solid. MS (ESI + ) m/z = 572.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.04 (s, 1H), 8.49 (s, 1H), 8.43 (s, 1H), 7.69-7.61 (m, 3H), 7.42 (s, 1H), 7.12 (d, J = 2.3 Hz, 1H), 7.07 (dd, J = 8.8, 2.3 Hz, 1H), 6.95-6.81 (m, 2H), 6.19 (dd, J = 16.6, 2.4 Hz,1H),5.80-5.71(m,1H),4.82(s,1H),4.74-4.63(m,1H),4.28(t,J＝10.4Hz,1H), 4.22-3.95(m,2H),3.89(s,4H),3.72-3.53(m,2H),3.35-3.26(m,2H),2.25(s,3H).

实施例138-143.终产物91、164-167、171的制备Examples 138-143. Preparation of final products 91, 164-167, 171

以中间体B7-B8、中间体C18-C20、C22或C24、中间体炔化合物或市售炔化合物为原料，采用合成终产物163的方法制备终产物91、164-167、171。如表10所示。Using intermediates B7-B8, intermediates C18-C20, C22 or C24, intermediate alkyne compounds or commercially available alkyne compounds as raw materials, final products 91, 164-167, and 171 were prepared using the method for synthesizing final product 163, as shown in Table 10.

表10终产物终产物91、164-167、171的结构、反应中间体和NMR或MS数据


Table 10 Structures, reaction intermediates and NMR or MS data of final products 91, 164-167, 171


实施例144. 1-(4-((3-甲基-4-)((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-12-吗啉代-6a,7,9,10-四氢吡嗪并[1',2':4,5][1,4]噁唑基[2,3-f]喹唑啉-8(6H)-基)丙-2-烯-1-酮(终产物169)的制备
Example 144. Preparation of 1-(4-((3-methyl-4-)((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-12-morpholino-6a,7,9,10-tetrahydropyrazino[1',2':4,5][1,4]oxazolyl[2,3-f]quinazolin-8(6H)-yl)prop-2-en-1-one (final product 169)

第一步：氮气保护下，将12-溴-4-((3-甲基-4-)(((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-6a,7,9,10-四氢吡嗪并[1',2':4,5][1,4]噁唑并[2,3-f]喹唑啉-8(6H)-甲酸叔丁酯(通过中间体C19和中间体B7按照实施例1第一步方法制备)(100mg,0.145mmol)溶于1,4-二氧六环(5mL)，加入吗啉(19.4mg,0.22mmol)，叔丁醇钾(50.1mg,0.45mmol)和(SP-4-1)-[1,3-双[2,6-双(1-乙基丙基)苯基]-4,5-二氯-1,3-二氢-2H-咪唑-2-亚基]二氯(2-甲基吡啶)钯(12.5mg,0.02mmol)，升温至100℃搅拌1h，反应完全后冷却至室温，往反应液中加水(10mL)，混合液用乙酸乙酯(10mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析以甲醇/二氯甲烷(0-10％)为洗脱剂梯度洗脱分离纯化得到4-((3-甲基-4-)((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-12-吗啉代-6a,7,9,10-四氢吡嗪并[1',2':4,5][1,4]噁唑并[2,3-f]喹唑啉-8(6H)-甲酸叔丁酯(黄色固体,95mg,94.0％)。MS(ESI+)m/z＝679.5[M+H]+。Step 1: Under nitrogen protection, 12-bromo-4-((3-methyl-4-)(((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-6a,7,9,10-tetrahydropyrazino[1',2':4,5][1,4]oxazolo[2,3-f]quinazoline-8(6H)-carboxylic acid tert-butyl ester (prepared by intermediate C19 and intermediate B7 according to the first step of Example 1) (100 mg, 0.145 mmol) was dissolved in 1,4-dioxane (5 mL), and morpholine (19.4 mg, 0.22 mmol), potassium tert-butoxide (50.1 mg, 0.45 mmol) and (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2 -ylidene]dichloro(2-methylpyridine)palladium (12.5 mg, 0.02 mmol), heated to 100 ° C and stirred for 1 h. After the reaction was complete, cooled to room temperature, water (10 mL) was added to the reaction solution, and the mixed solution was extracted with ethyl acetate (10 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography with a gradient elution of methanol/dichloromethane (0-10%) as eluent to give tert-butyl 4-((3-methyl-4-)((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-12-morpholino-6a,7,9,10-tetrahydropyrazino[1',2':4,5][1,4]oxazolo[2,3-f]quinazoline-8(6H)-carboxylate (yellow solid, 95 mg, 94.0%). MS(ESI + )m/z=679.5[M+H] + .

第二步：将4-((3-甲基-4-)((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-12-吗啉代-6a,7,9,10-四氢吡嗪并[1',2':4,5][1,4]噁唑并[2,3-f]喹唑啉-8(6H)-甲酸叔丁酯(85mg,0.125mmol)溶于二氯甲烷(3mL)，加入三氟乙酸(1mL)，室温搅拌30min，反应完全后，减压浓缩得到N-(3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)-12-吗啉代-6,6a,7,8,9,10-六氢吡嗪并[1',2':4,5][1,4]噁唑并[2,3-f]喹唑啉-4-胺(黑色油状物,180mg,粗品)。MS(ESI+)m/z＝579.5[M+H]+。Step 2: tert-Butyl 4-((3-methyl-4-)((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-12-morpholino-6a,7,9,10-tetrahydropyrazino[1',2':4,5][1,4]oxazolo[2,3-f]quinazoline-8(6H)-carboxylate (85 mg, 0.125 mmol) was dissolved in dichloromethane (3 mL) and trifluoromethane was added. Acetic acid (1 mL) was added and stirred at room temperature for 30 minutes. After the reaction was complete, the mixture was concentrated under reduced pressure to afford N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-12-morpholino-6,6a,7,8,9,10-hexahydropyrazino[1',2':4,5][1,4]oxazolo[2,3-f]quinazolin-4-amine as a black oil, 180 mg, crude product. MS (ESI + ) m/z = 579.5 [M+H] + .

第三步：将N-(3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)-12-吗啉代-6,6a,7,8,9,10-六氢吡嗪并[1',2':4,5][1,4]噁唑并[2,3-f]喹唑啉-4-胺(170mg,0.294mmol)溶于四氢呋喃(5mL)，滴加三乙胺(89.18mg,0.882mmol)调pH＞7，然后滴加丙烯酸酐(18.52mg,0.147mmol)，室温搅拌15min，反应完全后，往反应液中加水(10mL)，混合液用乙酸乙酯(30mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经高压液相色谱制备纯化(柱型:Xselect CSH Prep Fluoro-Phenyl Column,19*250,5μm；流动相:水(10mmol/L碳酸氢铵)/乙腈；流速:25mL/min；梯度:48％到73％乙腈,10分钟；波长:254/220nm)得到1-(4-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-12-吗啉代-6a,7,9,10-四氢吡嗪并[1’,2':4,5][1,4]噁嗪并[2,3-f]喹唑啉-8(6H)基)丙-2-烯-1-酮。Step 3: N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-12-morpholino-6,6a,7,8,9,10-hexahydropyrazino[1',2':4,5][1,4]oxazolo[2,3-f]quinazolin-4-amine (170 mg, 0.294 mmol) was dissolved in tetrahydrofuran (5 mL), and triethylamine (89.18 mg, 0.882 mmol) was added dropwise to adjust the pH to >7, and then acrylic anhydride (18.52 mg, 0.147 mmol) was added dropwise. The mixture was stirred at room temperature for 15 min. After the reaction was complete, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and filtered. The resulting liquid was concentrated under reduced pressure and the residue was purified by preparative HPLC (column type: Xselect CSH Prep Fluoro-Phenyl Column, 19*250, 5μm; mobile phase: water (10mmol/L ammonium bicarbonate)/acetonitrile; flow rate: 25mL/min; gradient: 48% to 73% acetonitrile, 10 minutes; wavelength: 254/220nm) to obtain 1-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-12-morpholino-6a,7,9,10-tetrahydropyrazino[1',2':4,5][1,4]oxazino[2,3-f]quinazolin-8(6H)yl)prop-2-en-1-one.

白色固体.MS(ESI+)m/z＝633.5[M+H]+.1H NMR(300MHz,DMSO-d6)δ9.68(s,1H),8.34(s,1H),8.17(s,1H),7.71-7.63(m,2H),7.56(d,J＝8.7Hz,1H),7.08(d,J＝2.2Hz,1H),6.99(dd,J＝8.7,2.3Hz,1H),6.91-6.82(m,2H),6.76(s,1H),6.18(d,J＝16.7Hz,1H),5.75(d,J＝10.3Hz,1H),4.71-4.58(m,1H),4.24(t,J＝10.4Hz,1H),4.18-3.92(m,2H),3.89-3.73(m,7H),3.68-3.48(m,5H),3.44-3.36(m,1H),3.27-3.16(m,1H),3.01-2.88(m,2H),2.24(s,3H).White solid. MS (ESI + ) m/z = 633.5 [M+H] + . 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.68 (s, 1H), 8.34 (s, 1H), 8.17 (s, 1H), 7.71-7.63 (m, 2H), 7.56 (d, J = 8.7 Hz, 1H), 7.08 (d, J = 2.2 Hz, 1H), 6.99 (dd, J = 8.7, 2.3 Hz, 1H), 6.91-6.82 (m, 2H), 6.76 (s, 1H), 6.18 (d, J = 16.7 Hz, 1H), 5 .75(d,J＝10.3Hz,1H),4.71-4.58(m,1H),4.24(t,J＝10.4Hz,1H),4.18-3.92(m,2H),3.89-3.73( m,7H),3.68-3.48(m,5H),3.44-3.36(m,1H),3.27-3.16(m,1H),3.01-2.88(m,2H),2.24(s,3H).

对比化合物A
Comparative Compound A

以中间体B8和中间体M(以(R)-7-氰基-8-硝基-1,2,4a,5-四氢苯并[b]吡嗪[1,2-d][1,4]噁嗪-3(4H)-甲酸叔丁酯为原料，按照合成中间体C18的方法制备得到)为原料，按照合成终产物1的方法制备对比化合物A。Comparative compound A was prepared using intermediate B8 and intermediate M (prepared using (R)-7-cyano-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester as a raw material according to the method for synthesizing intermediate C18) as raw materials and following the method for synthesizing final product 1.

淡黄色固体.MS(ESI+)m/z＝535.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.92(s,1H),8.94(d,J＝7.5Hz,1H),8.38(d,J＝3.7Hz,2H),7.86(d,J＝8.7Hz,1H),7.82(s,1H),7.66(d,J＝9.2Hz,1H),7.33(d,J＝9.1Hz,1H),7.21(d,J＝8.7Hz,1H),7.03(dd,J＝7.5,2.7Hz,1H),6.98-6.86(m,1H),6.78(d,J＝2.6Hz,1H),6.18(dd,J＝16.7,2.3Hz,1H),5.75(d,J＝10.3Hz,1H),4.81-4.71(m,1H),4.53(d,J＝12.9Hz,1H),4.30-4.19(m,2H),4.06(s,1H),3.30-3.20(m,1H),3.11-2.88(m,1H),2.85-2.60(m,2H),2.19(s,3H).Pale yellow solid. MS (ESI + ) m/z = 535.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.94 (d, J = 7.5 Hz, 1H), 8.38 (d, J = 3.7 Hz, 2H), 7.86 (d, J = 8.7 Hz, 1H), 7.82 (s, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.33 (d, J = 9.1 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 7.03 (dd, J = 7.5, 2.7 Hz, 1H), 6.98-6.86 (m, 1H), 6.78 (d,J＝2.6Hz,1H),6.18(dd,J＝16.7,2.3Hz,1H),5.75(d,J＝10.3Hz,1H),4.81-4.71(m,1H),4.53(d,J＝12.9Hz ,1H),4.30-4.19(m,2H),4.06(s,1H),3.30-3.20(m,1H),3.11-2.88(m,1H),2.85-2.60(m,2H),2.19(s,3H).

实验例1细胞增殖抑制实验Experimental Example 1 Cell proliferation inhibition experiment

CellTiter-GloTM活细胞检测试剂盒采用萤光素酶作检测物，发光过程中萤光素酶需要ATP的参与。向细胞培养基中加入CellTiter-GloTM试剂，测量发光值，光信号和体系中ATP量成正比，而ATP又和活细胞数正相关。因此通过使用CellTiter-Glo试剂盒检测ATP含量，可以检测出细胞的增殖情况。The CellTiter-Glo ™ Live Cell Assay Kit uses luciferase as a detector. Luciferase requires ATP to produce luminescence. CellTiter-Glo ™ reagent is added to the cell culture medium and luminescence is measured. The light signal is proportional to the amount of ATP in the system, which in turn is positively correlated with the number of viable cells. Therefore, by measuring ATP levels using the CellTiter-Glo Kit, cell proliferation can be monitored.

本实验采用Celltiter-Glo(CTG)法测量前述制备的化合物在肿瘤细胞株HER2 775-776insYVMA Ba/F3细胞株中增殖抑制作用，并计算50％抑制浓度IC50。In this experiment, the Celltiter-Glo (CTG) method was used to measure the proliferation inhibitory effect of the aforementioned compounds in the tumor cell line HER2 775-776insYVMA Ba/F3 cell line, and the 50% inhibitory concentration IC 50 was calculated.

1.实验设计1. Experimental Design

在所选细胞上测定化合物，并设定溶媒对照，共检测9个浓度，每个浓度2个复孔。Compounds were tested on selected cells and vehicle controls were set up for a total of 9 concentrations, with 2 replicates for each concentration.

2.试剂和耗材
2. Reagents and Consumables

3.实验过程3. Experimental Procedure

3.1细胞培养3.1 Cell culture

a)所有细胞按照ATCC推荐方法进行培养。培养收获处于对数生长期的细胞。检测细胞活力，确保细胞活力在90％以上。a) All cells were cultured according to ATCC recommended methods. Cells were harvested during the logarithmic growth phase. Cell viability was measured to ensure that the cell viability was above 90%.

b)细胞培养基：RPMI1640，10％FBS，1％ P/S。调整细胞浓度，分别添加95μL或90μL细胞悬液至96孔板中。b) Cell culture medium: RPMI 1640, 10% FBS, 1% P/S. Adjust the cell concentration and add 95 μL or 90 μL of cell suspension to a 96-well plate.

c)细胞培养环境：37℃、5％ CO2、95％湿度条件下培养。c) Cell culture environment: cultured at 37°C, 5% CO 2 , and 95% humidity.

3.2药物稀释3.2 Drug dilution

a)药物储存液：药物用DMSO溶解配制成10mM DMSO储存液。a) Drug storage solution: The drug was dissolved in DMSO to prepare a 10 mM DMSO storage solution.

b)药物存储：药物DMSO储存液均在室温干燥器中进行短期储存(最多3个月)。剩余的药物在-20℃保存较长时间。b) Drug Storage: DMSO stock solutions of drugs were stored in a desiccator at room temperature for short-term storage (up to 3 months). The remaining drugs were stored at -20°C for longer periods.

c)配置20X或10X药物溶液：加入2μL药物储存液到98μL或198μL细胞培养基中。c) Prepare 20X or 10X drug solution: Add 2 μL of drug stock solution to 98 μL or 198 μL of cell culture medium.

3.3加药3.3 Dosing

a)所有药物从1μM浓度开始3倍稀释，9个浓度梯度或4倍稀释，8个浓度梯度。a) All drugs were diluted 3-fold starting from 1 μM, with 9 concentration steps or 4-fold dilutions, with 8 concentration steps.

b)配制阳性对照药，DMSO空白对照。b) Prepare positive control drug and DMSO blank control.

c)在接种有细胞的96孔板中每孔加入5μL 20X药物溶液或10μL 10X药物，每个药物浓度设置2个复孔。c) Add 5 μL of 20X drug solution or 10 μL of 10X drug to each well of a 96-well plate seeded with cells, and set up 2 replicate wells for each drug concentration.

d)将已加药的96孔板中的细胞置于37℃、5％ CO2、95％湿度条件下继续培养72小时，之后进行CTG分析。d) The cells in the drug-added 96-well plate were cultured at 37°C, 5% CO 2 , and 95% humidity for 72 hours before CTG analysis.

3.4终点读板3.4 Endpoint plate reading

a)融化CTG试剂，每孔加入50μL的CTG溶液，摇匀。a) Thaw CTG reagent, add 50 μL of CTG solution to each well, and shake well.

b)将细胞板放置在室温下条件下10min稳定发光信号。b) Place the cell plate at room temperature for 10 minutes to stabilize the luminescence signal.

c)通过酶标仪读取荧光值。c) Read the fluorescence value using a microplate reader.

4.数据处理4. Data Processing

使用GraphPad Prism 8.0软件分析数据，利用非线性S曲线回归来拟合数据得出剂量-效应曲线，并由此计算IC50值。The data were analyzed using GraphPad Prism 8.0 software. Nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve, and the IC50 value was calculated based on this.

抑制率(Inh％)＝100-(RLU化合物-RLU空白)/(RLU对照-RLU空白)*100％.Inhibition rate (Inh%) = 100-(RLU compound -RLU blank )/(RLU control -RLU blank )*100%.

5.实验结果5. Experimental Results

化合物对HER2 775_776insYVMA Ba/F3细胞株增殖抑制活性如表11所示。The inhibitory activity of the compounds on the proliferation of HER2 775_776insYVMA Ba/F3 cell line is shown in Table 11.

表11化合物对HER2 775_776insYVMA Ba/F3细胞株增殖抑制活性(IC50,nM)

Table 11 Inhibitory activity of compounds on HER2 775_776insYVMA Ba/F3 cell line proliferation (IC 50 , nM)

从表中可以看出，本发明化合物对HER2 775-776insYVMA Ba/F3细胞株(表达HER2 20号外显子插入突变)具有良好的抑制增殖活性，抑制IC50值达到纳摩尔浓度。As can be seen from the table, the compounds of the present invention have good proliferation inhibition activity against HER2 775-776insYVMA Ba/F3 cell line (expressing HER2 exon 20 insertion mutation), and the inhibition IC 50 value reaches nanomolar concentration.

实验例2：A431磷酸化实验Experimental Example 2: A431 phosphorylation experiment

细胞培养Cell culture

a)所有细胞按照ATCC推荐方法进行培养。培养收获处于对数生长期的细胞。检测细胞活力，确保细胞活力在90％以上。a) All cells were cultured according to ATCC recommended methods. Cells were harvested during the logarithmic growth phase. Cell viability was measured to ensure that the cell viability was above 90%.

b)细胞培养基：DMEM，10％FBS，1％Glutamax和1％P/S。调整细胞浓度，分别添加40μL细胞悬液至384孔板中，1000rpm离心30s，孵育4小时。b) Cell culture medium: DMEM, 10% FBS, 1% Glutamax, and 1% P/S. Adjust the cell concentration and add 40 μL of the cell suspension to each well of a 384-well plate. Centrifuge at 1000 rpm for 30 seconds and incubate for 4 hours.

c)取出培养基，在384孔板中加入25μL HBSS，放置一夜。c) Remove the culture medium, add 25 μL HBSS to the 384-well plate, and leave overnight.

3.2药物稀释3.2 Drug dilution

a)药物储存液：药物用DMSO溶解配制成10mM DMSO储存液。a) Drug storage solution: The drug was dissolved in DMSO to prepare a 10 mM DMSO storage solution.

b)药物存储：药物DMSO储存液均在室温干燥器中进行短期储存(最多3个月)。剩余的药物在-20℃保存较长时间。b) Drug Storage: DMSO stock solutions of drugs were stored in a desiccator at room temperature for short-term storage (up to 3 months). The remaining drugs were stored at -20°C for longer periods.

3.3加药3.3 Dosing

a)所有药物从10mM浓度开始3倍稀释，10个浓度梯度。a) All drugs were diluted 3-fold starting from 10 mM concentration, with 10 concentration steps.

b)将已加药的384孔板中的细胞置于37℃、5％ CO2、95％湿度条件下继续培养30min。b) The cells in the drug-added 384-well plate were cultured at 37°C, 5% CO 2 , and 95% humidity for 30 minutes.

3.4检测3.4 Detection

a)加入EGF作为激活剂，刺激15min。a) Add EGF as an activator and stimulate for 15 minutes.

b)根据制造商的协议制备细胞裂解物并进行检测。b) Cell lysates were prepared and assayed according to the manufacturer's protocol.

c)由Envision读取AlphaScreen。c) AlphaScreen is read by Envision.

4.数据处理4. Data Processing

使用GraphPad Prism 8.0软件分析数据，利用非线性S曲线回归来拟合数据得出剂量-效应曲线，并由此计算IC50值。The data were analyzed using GraphPad Prism 8.0 software. Nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve, and the IC50 value was calculated based on this.

抑制率(Inh％)＝100-(Signal化合物-SignalAve_PC)/(SignalAve_VC-SignalAve_PC)*100％.Inhibition rate (Inh%) = 100-(Signal compound -Signal Ave_PC )/(Signal Ave_VC -Signal Ave_PC )*100%.

SignalAve_PC：整个平板上阳性对照的信号平均值 SignalAve_PC : Average signal value of the positive control on the entire plate

SignalAve_VC：整个平板阴性对照的信号平均值Signal Ave_VC : Average signal value of negative control in the whole plate

表12化合物抑制A431细胞株EGFR磷酸化pEGFR(IC50 nM)
Table 12 Compounds inhibit EGFR phosphorylation of pEGFR in A431 cell line (IC 50 nM)

从表中可以看出，本发明化合物对野生型EGFR抑制较弱，对野生型EGFR具有良好的选择性。It can be seen from the table that the compounds of the present invention have weak inhibition on wild-type EGFR and have good selectivity for wild-type EGFR.

实验例3：P-gp底物评价实验Experimental Example 3: P-gp substrate evaluation experiment

1.试验设计1. Experimental Design

细胞培养Cell culture

1)使用含L-谷氨酰胺的高糖DMEM培养基，添加10％胎牛血清、0.1mg/mL链霉素和0.6μg/mL青霉素。1) Use high-glucose DMEM medium containing L-glutamine, supplemented with 10% fetal bovine serum, 0.1 mg/mL streptomycin, and 0.6 μg/mL penicillin.

2)MDCKII-MDR1培养于T-75细胞培养瓶。培养箱设置为37℃、5％ CO2、保证相对湿度95％。细胞汇合度达到70-90％时可用于接种Transwell。2) MDCKII-MDR1 cells were cultured in T-75 cell culture flasks in an incubator set at 37°C, 5% CO 2 , and a relative humidity of 95%. Cells were seeded in Transwell plates when they reached 70-90% confluence.

3)细胞接种前，向Transwell上室每孔中加入50μL细胞培养基，下层培养板内加入25mL细胞培养基。将培养板置于37℃，5％ CO2培养箱内孵育1小时后可用于接种细胞。3) Before seeding cells, add 50 μL of cell culture medium to each well of the upper Transwell chamber and 25 mL of cell culture medium to the lower culture plate. Incubate the culture plate in a 37°C, 5% CO2 incubator for 1 hour before seeding cells.

4)使用5mL PBS轻轻清洗细胞。弃掉PBS，加入1.5mL含EDTA的胰酶，于37℃孵育5到10分钟至细胞完全脱落。加入含血清的培养基终止消化。4) Gently rinse the cells with 5 mL of PBS. Discard the PBS and add 1.5 mL of trypsin containing EDTA. Incubate at 37°C for 5 to 10 minutes until the cells are completely detached. Terminate the digestion by adding serum-containing medium.

5)吸取细胞混悬液转移至圆底离心管，于120×g离心10分钟。5) Transfer the cell suspension to a round-bottom centrifuge tube and centrifuge at 120 × g for 10 minutes.

6)使用培养基重悬细胞，终浓度为1.56×106cells/mL。6) Resuspend the cells in culture medium to a final concentration of 1.56×10 6 cells/mL.

MDCKII-MDR1细胞接种MDCKII-MDR1 cell inoculation

1)将细胞悬液以50μL每孔加入到96孔Transwell培养板上室中，最终接种密度为1.45×105cells/cm2。1) Add 50 μL of cell suspension to each well of a 96-well Transwell culture plate, with a final seeding density of 1.45×10 5 cells/cm 2 .

2)接种后24小时开始换液，培养4-8天，隔一天换一次培养基。2) Start changing the medium 24 hours after inoculation and culture for 4-8 days, changing the medium every other day.

细胞单层膜完整性的评价Assessment of cell monolayer integrity

1)MDCKII-MDR1和MDCKII经过4-8天培养后，应完全汇合并完成分化。此时，可应用于穿透试验。1) After 4-8 days of culture, MDCKII-MDR1 and MDCKII should be fully confluent and differentiated. At this point, they can be used for penetration assays.

2)用电阻仪(Millipore，USA)测量单层膜电阻，记录每孔电阻。2) The resistance of the monolayer membrane was measured using a resistance meter (Millipore, USA), and the resistance of each pore was recorded.

3)测定结束后，将Transwell培养板放回培养箱。3) After the assay is completed, place the Transwell culture plate back into the incubator.

4)电阻值的计算：4) Calculation of resistance value:

测定电阻值(ohms)×膜面积(cm2)＝TEER值(ohm·cm2)Measured resistance value (ohms) × membrane area (cm 2 ) = TEER value (ohm·cm 2 )

若TEER值<42ohms·cm2，则该孔不能用于穿透试验。If the TEER value is <42 ohms·cm 2 , the hole cannot be used for penetration testing.

药物穿透试验Drug penetration test

1)从培养箱中取出MDCKII-MDR1 Transwell培养板。使用HBSS(10mM HEPES，pH 7.4)缓冲液润洗细胞单层膜两次，37℃条件下孵育30分钟。1) Remove the MDCKII-MDR1 Transwell plate from the incubator. Rinse the cell monolayer twice with HBSS (10 mM HEPES, pH 7.4) and incubate at 37°C for 30 minutes.

2)测定化合物由顶端到基底端的转运速率。向上层小室(顶端)每孔加入125μL测试药物或对照药的HBSS(10mM HEPES，pH 7.4)缓冲液，下层小室(基底端)每孔加入235μL HBSS(10mM HEPES，pH 7.4)缓冲液。2) Determine the apical-to-basolateral transport rate of the compound. Add 125 μL of test drug or control in HBSS (10 mM HEPES, pH 7.4) buffer to each well of the upper chamber (apical) and 235 μL of HBSS (10 mM HEPES, pH 7.4) buffer to each well of the lower chamber (basolateral).

3)测定化合物由基底端到顶端的转运速率。向上层小室(顶端)每孔加入285μL HBSS(10mM HEPES，pH 7.4)缓冲液，下层小室(基底端)每孔加入75μL测试药物或对照药的HBSS(10mM HEPES，pH 7.4)缓冲液。3) Determine the rate of compound transport from the basolateral to the apical end. Add 285 μL of HBSS (10 mM HEPES, pH 7.4) buffer to each well of the upper chamber (apical end) and 75 μL of HBSS (10 mM HEPES, pH 7.4) buffer containing the test drug or control to each well of the lower chamber (basolateral end).

4)将上下的转运装置合并后，37℃条件下孵育2小时。4) Combine the upper and lower transfer devices and incubate at 37°C for 2 hours.

5)孵育完成后，分别从Transwell培养板上室和下室每孔取样50μL加入到新的样品管中。向样品管内加入4倍体积含内标的乙腈(200nM阿普唑仑，200nM拉贝洛尔，200nM双氯芬酸，100nM甲苯磺丁脲)，涡旋5分钟后，于3,220g离心15分钟。吸取上清液100μL，与等体积水稀释之后进行LC-MS/MS分析。所有样品进行三平行制备。5) After incubation, sample 50 μL from each well of the upper and lower chambers of the Transwell plate and transfer to new sample tubes. Add 4 volumes of acetonitrile containing internal standards (200 nM alprazolam, 200 nM labetalol, 200 nM diclofenac, 100 nM tolbutamide) to each tube. Vortex for 5 minutes and centrifuge at 3,220 g for 15 minutes. Aspirate 100 μL of the supernatant, dilute with an equal volume of water, and perform LC-MS/MS analysis. All samples were prepared in triplicate.

6)用荧光黄的渗漏评价孵育2小时后细胞单层膜的完整性，使用HBSS(10mM HEPES,pH 7.4)稀释荧光黄储备液至最终浓度100μM。在上侧的Transwell插板的每个孔中加入荧光黄溶液100μL，下侧接收板的每个孔中加300μL HBSS(10mM HEPES，pH 7.4)。37℃下孵育30分钟后，分别从每孔上下层吸出80μL溶液至一个新的96孔板中。使用酶标仪，激发波长485nm和发射波长530nm条件下进行荧光测定。6) The integrity of the cell monolayer membrane was evaluated by leakage of fluorescein yellow after 2 hours of incubation. The fluorescein yellow stock solution was diluted with HBSS (10mM HEPES, pH 7.4) to a final concentration of 100μM. 100μL of fluorescein yellow solution was added to each well of the upper Transwell insert, and 300μL of HBSS (10mM HEPES, pH 7.4) was added to each well of the lower receiving plate. After incubation at 37°C for 30 minutes, 80μL of solution was aspirated from the upper and lower layers of each well into a new 96-well plate. Fluorescence was measured using a microplate reader with an excitation wavelength of 485nm and an emission wavelength of 530nm.

2.数据处理2. Data Processing

数据计算均使用Excel进行，化合物的表观渗透系数(Papp，单位：cm/s)用以下公式计算得出：
Data calculations were performed using Excel, and the apparent permeability coefficient (P app , unit: cm/s) of the compound was calculated using the following formula:

公式中膜面积为Transwell-96孔板膜面积(0.143cm2)；孵育时间单位为秒(s)。The membrane area in the formula is the membrane area of the Transwell-96 plate (0.143 cm 2 ); the incubation time is in seconds (s).

外排率使用以下的公式计算得出：
The efflux rate is calculated using the following formula:

表13待测化合物的外排率
Table 13 Efflux rate of the test compounds

实验例4：化合物在小鼠体内的cassette药代动力学测试Experimental Example 4: Cassette pharmacokinetic test of the compound in mice

实验目的：以ICR小鼠为受试物，应用LC/MS/MS法测定灌胃(PO)给予化合物，检测不同时刻血浆中化合物的药物浓度，研究本发明的化合物在小鼠体内的药代动力学行为，评价其药代动力学特征。Objective: To investigate the pharmacokinetic behavior of the compounds of the present invention in mice by LC/MS/MS after oral gavage (PO) of the compounds using ICR mice as test subjects and to evaluate their pharmacokinetic characteristics by detecting the drug concentrations in plasma at different time points.

药物配置：化合物均以10％ DMSO+10％ Solutol HS15+5％ Cremophor EL+20％ PEG400+55％(20％ Captisol水溶液)为溶媒配成澄清溶液，用于PO给药，给药方法为盒式给药法(cassette dosing)，化合物的给药剂量为：剂量为10mg/kg，药代动力学参数结果见表14。Drug preparation: The compounds were prepared into clear solutions with 10% DMSO + 10% Solutol HS15 + 5% Cremophor EL + 20% PEG400 + 55% (20% Captisol aqueous solution) as solvents for PO administration. The administration method was cassette dosing. The dosage of the compound was 10 mg/kg. The pharmacokinetic parameters are shown in Table 14.

表14小鼠体内cassette药代动力学测试结果

Table 14 Pharmacokinetic test results of cassette in mice

从表14可以看出，本发明的化合物具有良好的暴露量。对于四并环化合物，当喹唑啉7-位为N时(如化合物135、146)或7-位CH被取代基取代时(如化合物164、166)，表现出较好的暴露量。As can be seen from Table 14, the compounds of the present invention have good exposure. For the tetracyclic compounds, when the quinazoline 7-position is N (such as compounds 135 and 146) or when the 7-position CH is substituted with a substituent (such as compounds 164 and 166), good exposure is shown.

以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。The above embodiments are only intended to help understand the method and core concept of the present invention. It should be noted that, without departing from the principles of the present invention, a number of improvements and modifications may be made to the present invention by those skilled in the art, and such improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims (11)

一种式I所示的螺环/桥环化合物或其药学上可接受的盐、立体异构体、消旋体、互变异构体、同位素标记物、氘代物、N-氧化物、前药分子、水合物或溶剂化物：
A spirocyclic/bridged ring compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof:
其中，在式I中，Wherein, in Formula I, A环为含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基、3-12环烷基；Ring A is a 3-12 membered heterocyclic group or a 3-12 membered cycloalkyl group containing one or more heteroatoms selected from N, O, S, S=O, and S(O) 2 ; E环为6-10元芳基或含有1个或多个选自N、O、S杂原子的5-10元杂芳基；The E ring is a 6-10 membered aryl group or a 5-10 membered heteroaryl group containing one or more heteroatoms selected from N, O, and S; Q1不存在或为6-12元芳基或含有1个或多个选自N、O、S杂原子的5-12元杂芳基，所述6-12元芳基或含有1个或多个选自N、O、S杂原子的5-12元杂芳基任选地被一个或者多个R′取代；Q 1 is absent or is a 6-12 membered aryl group or a 5-12 membered heteroaryl group containing one or more heteroatoms selected from N, O, and S, and the 6-12 membered aryl group or the 5-12 membered heteroaryl group containing one or more heteroatoms selected from N, O, and S is optionally substituted by one or more R'; L1为化学键、O、NR4、CR5R6、-OR7-、C(＝O)、S、S(O)或S(O)2；L 1 is a chemical bond, O, NR 4 , CR 5 R 6 , -OR 7 -, C(=O), S, S(O) or S(O) 2 ; L2为化学键、O或NR4；L 2 is a chemical bond, O or NR 4 ; L3为NR4、O、CR5R6、S、S(O)或S(O)2；L 3 is NR 4 , O, CR 5 R 6 , S, S(O) or S(O) 2 ; L4不存在或为化学键、O、NR4、CR5R6、C(＝O)、S、S(O)或S(O)2；L 4 is absent or is a chemical bond, O, NR 4 , CR 5 R 6 , C(═O), S, S(O) or S(O) 2 ; M为C＝O或S(＝O)2；M is C=O or S(=O) 2 ; Y1为N或CRa； Y1 is N or CR a ; Y2为N或CRb；Y 2 is N or CR b ; Y3为N或CRc；Y 3 is N or CR c ; Y4为N或CRd；Y 4 is N or CR d ; Y5为N、CRe或C；当L2为化学键，Y5为N；当L2为O或NR4时，Y5为CRe或C；Y 5 is N, CR e or C; when L 2 is a chemical bond, Y 5 is N; when L 2 is O or NR 4 , Y 5 is CR e or C; R1为卤代甲基、C2-4烯基、C2-4炔基、环氧丙烷基或C4-6环烯基，所述C2-4烯基、C2-4炔基、环氧丙烷基或C4-6环烯基任选地被一个或者多个卤素、氰基、C1-4烷基、卤代C1-4烷基、3-12元环烷基、氘原子、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基、含有1个或多个选自N、O、S杂原子的5-12元杂芳基、6-12元芳基、C1-3烷氧基-C1-3烷基-或NRxRy取代，所述C1-4烷基、卤代C1-4烷基、3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基、含有1个或多个选自N、O、S杂原子的5-12元杂芳基、6-12元芳基或C1-3烷氧基-C1-3烷基-任选被一个或者多个R′取代；R 1 is a halomethyl, C 2-4 alkenyl, C 2-4 alkynyl, propylene oxide or C 4-6 cycloalkenyl group, wherein the C 2-4 alkenyl, C 2-4 alkynyl, propylene oxide or C 4-6 cycloalkenyl group is optionally substituted by one or more halogen, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, 3-12 membered cycloalkyl, deuterium atom, 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S=O, S(O) 2 , 5-12 membered heteroaryl containing one or more heteroatoms selected from N, O, S, 6-12 membered aryl, C 1-3 alkoxy-C 1-3 alkyl- or NR x R y , wherein the C 1-4 alkyl, halogenated C 1-4 alkyl, 3-12 membered cycloalkyl, containing one or more heteroatoms selected from N, O, S, S=O, S(O) 2 2 heteroatoms, 3-12 membered heterocyclyl, 5-12 membered heteroaryl containing one or more heteroatoms selected from N, O, S, 6-12 membered aryl or C 1-3 alkoxy-C 1-3 alkyl-optionally substituted by one or more R'; R2为氢原子、氘原子、卤素、氰基、羟基、氨基、C1-6烷基、C2-6烯基、C2-6炔基、卤代C1-4烷基、氘代C1-6烷基、3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基、C1-4烷基氨基、二(C1-4烷基)氨基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、卤代C1-6烷氧基或氧代(＝O)，所述羟基、氨基、C1-6烷基、C2-6烯基、C2-6炔基、卤代C1- 4烷基、氘代C1-6烷基、3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基、C1-4烷基氨基、二(C1-4烷基)氨基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、卤代C1-6烷氧基任选地被一个或者多个R′取代；R 2 is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a halogenated C 1-4 alkyl group, a deuterated C 1-6 alkyl group, a 3-12 membered cycloalkyl group, a 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, and S(O) 2 , a C 1-4 alkylamino group, a di(C 1-4 alkyl)amino group, a C 1-6 alkoxy group, a C 1-6 alkoxy -C 1-6 alkyl group, a halogenated C 1-6 alkoxy group, or an oxo(=O) group, wherein the hydroxyl group, the amino group, the C 1-6 alkyl group, the C 2-6 alkenyl group, the C 2-6 alkynyl group, the halogenated C 1-4 alkyl group, the deuterated C 1-6 alkyl group, the 3-12 membered cycloalkyl group, the 3-12 membered cycloalkyl group, the 2 heteroatoms, 3-12 membered heterocyclyl, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, halogenated C 1-6 alkoxy, optionally substituted by one or more R′; R3为氢原子、氘原子、卤素、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、3-12元饱和或不饱和环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元饱和或不饱和杂环基、卤代C1-6烷基、卤代C1-6烷氧基、ORe、SRe、SORe、S(O)2Re、C(＝O)Re、C(＝O)NRe、C(＝O)ORe、NReRf、NReC(＝O)Rf、OC(＝O)Re、SONRf、S(O)2NRe、NHS(O)2Re、NHS(O)Re、NReC(＝O)ORf、NReC(＝O)NRf、-(O)(ORe)2或P(O)(Re)2，所述C1-6烷基、C2-6烯基、C2-6炔基、C2-6杂炔基、3-12元饱和或不饱和环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元饱和或不饱和杂环基、卤代C1-6烷基或卤代C1-6烷氧基任选地被一个或者多个R′取代； R3 is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a nitro group, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a 3-12-membered saturated or unsaturated cycloalkyl group, a 3-12-membered saturated or unsaturated heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, and S(O) 2 , a halogenated C1-6 alkyl group, a halogenated C1-6 alkoxy group, ORe , SRe , SORe , S(O) 2Re , C(=O) Re , C (=O) NRe , C (=O) ORe , NReRf , NReC(=O) Rf , OC(=O) Re , SONRf , S(O) 2NRe , NHS(O) 2Re , NHS(O) Re , NReC (=O) ORf , NReC (=O) NRf , -(O)(OR e ) 2 or P(O)(R e ) 2 , the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 heteroalkynyl, 3-12 membered saturated or unsaturated cycloalkyl, 3-12 membered saturated or unsaturated heterocyclic group containing one or more heteroatoms selected from N, O, S, S═O, S(O) 2 , halogenated C 1-6 alkyl or halogenated C 1-6 alkoxy is optionally substituted by one or more R′; R4为氢原子、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、氰基-C1-6烷基-、羟基C1-6烷基、C2-4烯基、C2-4炔基、C(＝O)Re或3-12元环烷基，所述C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、氰基-C1-6烷基-、羟基C1-6烷基、C2-4烯基、C2-4炔基或3-12元环烷基任选地被一个或者多个R′取代； R4 is a hydrogen atom, a C1-6 alkyl group, a halogenated C1-6 alkyl group, a deuterated C1-6 alkyl group, a cyano- C1-6 alkyl group, a hydroxy C1-6 alkyl group, a C2-4 alkenyl group, a C2-4 alkynyl group, C(=O) Re , or a 3-12-membered cycloalkyl group, wherein the C1-6 alkyl group, the halogenated C1-6 alkyl group, the deuterated C1-6 alkyl group, the cyano- C1-6 alkyl group, the hydroxy C1-6 alkyl group, the C2-4 alkenyl group, the C2-4 alkynyl group, or the 3-12-membered cycloalkyl group is optionally substituted by one or more R's; R5、R6各自独立地为氢原子、氘原子、卤素、氰基、羟基、氨基、C1-6烷基、卤代C1-6烷基、C2-4烯基、C2-4炔基、3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基、C1-6烷氧基、卤代C1-6烷氧基、3-12元环烷基氧基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基氧基、C1-6烷基巯基、C1-6烷基氨基、二(C1-6烷基)氨基、氰基-C1-6烷基-、C1-6烷氧基-C1-6烷基-、3-12元环烷基-C1-6烷基-或含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基-C1-6烷基-，所述羟基、氨基、C1-6烷基、卤代C1-6烷基、C2-4烯基、C2-4炔基、3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基、C1-6烷氧基、卤代C1-6烷氧基、3-12元环烷基氧基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基氧基、C1-6烷基巯基、C1-6烷基氨基、二(C1-6烷基)氨基、氰基-C1-6烷基-、C1-6烷氧基-C1-6烷基-、3-12元环烷基-C1-6烷基-或含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基-C1-6烷基-任选地被一个或者多个R′取代；R 5 and R 6 are each independently a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S=O, and S(O) 2 , a C 1-6 alkoxy group, a halogenated C 1-6 alkoxy group, a 3-12-membered cycloalkyloxy group, a 3-12-membered heterocyclyloxy group containing one or more heteroatoms selected from N, O, S, S=O, and S(O) 2 , a C 1-6 alkylthiol group, a C 1-6 alkylamino group, a di(C 1-6 alkyl)amino group, a cyano-C 1-6 alkyl-, a C 1-6 alkoxy-C 1-6 alkyl-, a 3-12-membered cycloalkyl-C C 1-6 alkyl- or a 3-12 membered heterocyclyl-C 1-6 alkyl-containing one or more heteroatoms selected from N, O, S, S=O, S(O) 2 , the hydroxyl, amino, C 1-6 alkyl, a halogenated C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, a 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S=O, S(O) 2 , a C 1-6 alkoxy, a halogenated C 1-6 alkoxy, a 3-12 membered cycloalkyloxy, a 3-12 membered heterocyclyloxy containing one or more heteroatoms selected from N, O, S, S=O, S(O) 2 , a C 1-6 alkylthiol, a C 1-6 alkylamino, a di(C 1-6 alkyl)amino, a cyano-C 1-6 alkyl-, a C 1-6 alkoxy-C 1-6 alkyl-, 3-12 membered cycloalkyl-C 1-6 alkyl- or 3-12 membered heterocyclyl-C 1-6 alkyl- containing 1 or more heteroatoms selected from N, O, S, S=O, S(O) 2 , optionally substituted with one or more R′; 或R5与R6和所连接的C原子一起形成3-6元环烷基或含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基，所述3-6元环烷基或含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基任选地被一个或者多个R′取代；or R 5 together with R 6 and the C atom to which they are attached form a 3-6 membered cycloalkyl group or a 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O) 2 , which is optionally substituted by one or more R′ ; R7为C1-6亚烷基、C2-4亚烯基、卤代C1-6亚烷基、氘代C1-6亚烷基或卤代C2-4亚烯基； R7 is C1-6 alkylene, C2-4 alkenylene, halogenated C1-6 alkylene, deuterated C1-6 alkylene or halogenated C2-4 alkenylene; Ra、Rb各自独立为氢原子、氘原子、卤素、氰基、C1-6烷基、C2-4烯基、C2-4炔基、3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基、ORa1、SRa1、NRa1、S(＝O)Ra1或S(＝O)2Ra1，所述C1-6烷基、C2-4烯基、C2-4炔基、3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基任选地被一个或者多个R′取代R a and R b are each independently a hydrogen atom, a deuterium atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , OR a1 , SR a1 , NR a1 , S(═O)R a1 or S(═O) 2 R a1 , wherein the C 1-6 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, a 3-12-membered cycloalkyl group, or a 3-12-membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 is optionally substituted by one or more R′ 或者，Ra与R2和所连接的原子一起形成3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基或含有1、2、3、4个选自N、O、S杂原子的5-6元杂芳基，所述3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基或含有1、2、3、4个选自N、O、S杂原子的5-6元杂芳基任选地被一个或者多个R′取代；Alternatively, Ra , R2 and the atoms to which they are attached form a 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S=O, S(O) 2 , or a 5-6 membered heteroaryl containing one, two, three, or four heteroatoms selected from N, O, and S, and the 3-12 membered cycloalkyl, the 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S=O, S(O) 2 , or the 5-6 membered heteroaryl containing one, two, three, or four heteroatoms selected from N, O, and S are optionally substituted with one or more R'; 或者，Rb与R2和所连接的原子一起形成3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基或含有1、2、3、4个选自N、O、S杂原子的5-6元杂芳基，所述3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基或含有1、2、3、4个选自N、O、S杂原子的5-6元杂芳基任选地被一个或者多个R′取代；Alternatively, R b together with R 2 and the atoms to which they are attached form a 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S═O, S(O) 2 , or a 5-6 membered heteroaryl containing one, two, three, or four heteroatoms selected from N, O, and S, and the 3-12 membered cycloalkyl, the 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S═O, S(O) 2 , or a 5-6 membered heteroaryl containing one, two, three, or four heteroatoms selected from N, O, and S are optionally substituted with one or more R ′; Rc为氢原子、氘原子、卤素、氰基、氨基、C1-6烷基、C1-6烷氧基、C1-6烷基巯基、C1- 6烷基氨基或二(C1-6烷基)氨基，所述氨基、C1-6烷基、C1-6烷氧基、C1-6烷基巯基、C1-6烷基氨基或二(C1-6烷基)氨基任选地被一个或者多个R′取代；R c is a hydrogen atom, a deuterium atom, a halogen, a cyano group, an amino group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkylthio group, a C 1-6 alkylamino group or a di(C 1-6 alkyl)amino group, wherein the amino group, the C 1-6 alkyl group, the C 1-6 alkoxy group, the C 1-6 alkylthio group, the C 1-6 alkylamino group or the di(C 1-6 alkyl)amino group is optionally substituted with one or more R ′; Rd不存在或为氢原子、氘原子、卤素、氰基、氨基、C1-6烷基、C1-6烷氧基、C1-6烷基巯基或C1-6烷基氨基，所述氨基、C1-6烷基、C1-6烷氧基、C1-6烷基巯基或C1-6烷基氨基任选地被一个或者多个R′取代；R d is absent or is a hydrogen atom, a deuterium atom, a halogen, a cyano group, an amino group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkylthio group or a C 1-6 alkylamino group, wherein the amino group, the C 1-6 alkyl group, the C 1-6 alkoxy group, the C 1-6 alkylthio group or the C 1-6 alkylamino group is optionally substituted with one or more R′; 或者，Rb与Rd和所连接的原子一起形成3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基或含有1、2、3、4个选自N、O、S杂原子的5-6元杂芳基，所述3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基或含有1、2、3、4个选自N、O、S杂原子的5-6元杂芳基任选地被一个或者多个R′取代；Alternatively, R b and R d together with the atoms to which they are attached form a 3-12 membered cycloalkyl group, a 3-12 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S═O, S(O) 2 , or a 5-6 membered heteroaryl group containing one, two, three, or four heteroatoms selected from N, O, and S, and the 3-12 membered cycloalkyl group, the 3-12 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S═O, S(O) 2 , or the 5-6 membered heteroaryl group containing one, two, three, or four heteroatoms selected from N, O, and S are optionally substituted with one or more R ′; 或者，Ra与Rd和所连接的原子一起形成3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基或含有1、2、3、4个选自N、O、S杂原子的5-6元杂芳基，所述3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基或含有1、2、3、4个选自N、O、S杂原子的5-6元杂芳基任选地被一个或者多个R′取代；Alternatively, Ra and Rd , together with the atoms to which they are attached, form a 3-12 membered cycloalkyl group, a 3-12 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S=O, or S(O) 2 , or a 5-6 membered heteroaryl group containing one, two, three, or four heteroatoms selected from N, O, or S, and the 3-12 membered cycloalkyl group, the 3-12 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S=O, or S(O) 2 , or the 5-6 membered heteroaryl group containing one, two, three, or four heteroatoms selected from N, O, or S are optionally substituted with one or more R'; Re、Rf各自独立地为氢原子、氘原子、C1-4烷基、卤代C1-4烷基、3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基；R e and R f are each independently a hydrogen atom, a deuterium atom, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, a 3-12 membered cycloalkyl group, or a 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 ; 或者，NReRf中Re和Rf与连接的N原子一起形成含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基；Alternatively, Re and Rf in NR e R f together with the attached N atom form a 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 ; Ra1为氢原子、C1-6烷基、3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基、3-12元环烷基-C1-6烷基或含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基-C1-6烷基，所述C1-6烷基、3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基、3-12元环烷基-C1-6烷基或含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基-C1-6烷基任选地被一个或者多个R′取代；R a1 is a hydrogen atom, a C 1-6 alkyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , a 3-12-membered cycloalkyl-C 1-6 alkyl group, or a 3-12-membered heterocyclyl-C 1-6 alkyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , wherein the C 1-6 alkyl group, the 3-12-membered cycloalkyl group, the 3-12-membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , the 3-12-membered cycloalkyl-C 1-6 alkyl group, or the 3-12-membered heterocyclyl-C 1-6 alkyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 are optionally substituted with one or more R′; Rx、Ry各自独立地为氢原子、C1-4烷基、卤代C1-4烷基、3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基、3-12元环烷基-C1-4烷基-、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基-C1-4烷基-、C1-4烷氧基-C1-4烷基-或氘代C1-4烷基，所述C1-4烷基、卤代C1-4烷基、3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基、3-12元环烷基-C1-4烷基-、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基-C1-4烷基-、C1-4烷氧基-C1-4烷基-或氘代C1-4烷基任选地被一个或者多个R′取代； Rx and Ry are each independently a hydrogen atom, a C1-4 alkyl group, a halogenated C1-4 alkyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S=O, and S(O) 2 , a 3-12-membered cycloalkyl- C1-4 alkyl-, a 3-12-membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S=O, and S(O) 2 , a C1-4 alkoxy- C1-4 alkyl-, or a deuterated C1-4 alkyl group, wherein the C1-4 alkyl group, the halogenated C1-4 alkyl group, the 3-12-membered cycloalkyl group, the 3-12-membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S=O, and S(O) 2 , the 3-12-membered cycloalkyl-C1-4 alkyl- 1-4 alkyl-, 3-12 membered heterocyclyl-C 1-4 alkyl- containing 1 or more heteroatoms selected from N, O, S, S=O, S(O) 2 , C 1-4 alkoxy-C 1-4 alkyl- or deuterated C 1-4 alkyl, optionally substituted by one or more R′; 或NRxRy中Rx与Ry和所连接的N原子一起形成含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基，所述含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基任选地被一个或者多个R′取代；or in NRxRy , Rx and Ry together with the nitrogen atom to which they are attached form a 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, and S(O) 2 , wherein the 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, and S(O) 2 is optionally substituted by one or more R'; R′各自独立地为氘原子、卤素、氰基、羟基、氨基、C1-6烷基、C2-6烯基、C2-6炔基、卤代C1-4烷基、氘代C1-6烷基、3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基、C1-4烷基氨基、二(C1-4烷基)氨基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、卤代C1-6烷氧基或氧代(＝O)；R′ is each independently a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a halogenated C 1-4 alkyl group, a deuterated C 1-6 alkyl group, a 3-12 membered cycloalkyl group, a 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , a C 1-4 alkylamino group, a di(C 1-4 alkyl)amino group, a C 1-6 alkoxy group, a C 1-6 alkoxy-C 1-6 alkyl group, a halogenated C 1-6 alkoxy group, or an oxo(═O); m、n各自独立地为0、1、2、3、4或5；m and n are each independently 0, 1, 2, 3, 4 or 5; 条件是，1)Rd或R2任意一个基团与Ra或Rb任意一个基团和它们所连接的原子一起必须形成一个且只有一个环，所述环为3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基或含有1、2、3、4个选自N、O、S杂原子的5-6元杂芳基，所述3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基或含有1、2、3、4个选自N、O、S杂原子的5-6元杂芳基任选地被一个或者多个R′取代；Provided that 1) any one of R d or R 2 and any one of Ra or R b together with the atoms to which they are attached must form one and only one ring, said ring being a 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S=O, S(O) 2 , or a 5-6 membered heteroaryl containing one, two, three, or four heteroatoms selected from N, O, and S, said 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S=O, S(O) 2, or a 5-6 membered heteroaryl containing one, two, three, or four heteroatoms selected from N, O, and S, and said 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S=O, S(O) 2 , or a 5-6 membered heteroaryl containing one, two, three, or four heteroatoms selected from N, O, and S are optionally substituted with one or more R′; 2)当R2与Rb和它们所连接的原子一起形成吗啉环，且Y1为CH时，Q1不为 2) When R 2 and R b together with the atoms to which they are attached form a morpholine ring, and Y 1 is CH, Q 1 is not 根据权利要求1所述的螺环/桥环化合物或其药学上可接受的盐、立体异构体、消旋体、互变异构体、同位素标记物、氘代物、N-氧化物、前药分子、水合物或溶剂化物，所述化合物具有式II或式III所示的结构，
The spirocyclic/bridged ring compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof, wherein the compound has a structure shown in Formula II or Formula III,
其中，in, G环为3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基或含有1、2、3、4个选自N、O、S杂原子的5-6元杂芳基；Ring G is a 3-12 membered cycloalkyl group, a 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O) 2 , or a 5-6 membered heteroaryl group containing one, two, three, or four heteroatoms selected from N, O, and S; W为N、C或CRa；W is N, C or CR a ; t为0、1、2、3、4或5。t is 0, 1, 2, 3, 4, or 5. 根据权利要求1或2所述的螺环/桥环化合物或其药学上可接受的盐、立体异构体、消旋体、互变异构体、同位素标记物、氘代物、N-氧化物、前药分子、水合物或溶剂化物，其中，在式I、II或III中，A环为含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的4-9元杂环基、3-6环烷基；The spiro/bridged ring compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof, wherein, in Formula I, II or III, Ring A is a 4-9 membered heterocyclic group or a 3-6 membered cycloalkyl group containing one or two heteroatoms selected from N, O, S, S=O, or S(O) 2 ; 优选地，在式I、II或III中，A环为哌啶基、吖丁啶基、吡咯烷基、哌嗪基、高哌啶、高哌嗪、1,4-氮杂氧杂环庚烷、环丙基、环丁基、环戊基、环己基、2-氮杂二环[2.2.2]辛烷、2-氮杂二环[2.2.1]庚烷、2,5-二氮杂二环[2.2.2]辛烷或2,5-二氮杂二环[2.2.1]庚烷；Preferably, in formula I, II or III, Ring A is piperidinyl, azetidinyl, pyrrolidinyl, piperazinyl, homopiperidine, homopiperazine, 1,4-azaoxepane, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-azabicyclo[2.2.2]octane, 2-azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.2]octane or 2,5-diazabicyclo[2.2.1]heptane; 优选地，在式I、II或III中，A环为含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的4-7元杂环基；Preferably, in formula I, II or III, ring A is a 4-7 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, S=O, S(O) 2 ; 优选地，在式I、II或III中，A环为哌啶基、吖丁啶基、吡咯烷基、哌嗪基、高哌啶、高哌嗪、1,4-氮杂氧杂环庚烷、环丙基、环丁基、环戊基、环己基、2-氮杂二环[2.2.2]辛烷、2-氮杂二环[2.2.1]庚烷、2,5-二氮杂二环[2.2.2]辛烷、2,5-二氮杂二环[2.2.1]庚烷、8-氮杂双环[3.2.1]辛烷、6-氮杂双环[3.1.1]庚烷或7-氮杂双环[2.2.1]庚烷；Preferably, in formula I, II or III, Ring A is piperidinyl, azetidinyl, pyrrolidinyl, piperazinyl, homopiperidine, homopiperazine, 1,4-azaoxepane, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-azabicyclo[2.2.2]octane, 2-azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.2]octane, 2,5-diazabicyclo[2.2.1]heptane, 8-azabicyclo[3.2.1]octane, 6-azabicyclo[3.1.1]heptane or 7-azabicyclo[2.2.1]heptane; 优选地，在式I、II或III中，E环为苯基或含有1、2、3、4个选自N、O、S杂原子的5-6元杂芳基；Preferably, in formula I, II or III, ring E is phenyl or a 5-6 membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O and S; 优选地，在式I、II或III中，E环为苯基、吡啶基、嘧啶、哒嗪、吡嗪、噻吩或吡唑；Preferably, in formula I, II or III, ring E is phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene or pyrazole; 优选地，在式I、II或III中，Q1为所述地 任选地被一个或多个氘原子、F、Cl、氰基、羟基、氨基、甲基、乙基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、甲氨基、二甲氨基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基或三氟乙氧基取代；Preferably, in Formula I, II or III, Q 1 is Said place optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy; --/---为无或化学键；--/--- is none or chemical bond; B环为吡咯、咪唑、吡唑、噻唑、噁唑、噁二唑、三氮唑、四氮唑、吡啶、嘧啶、哒嗪、吡嗪或三嗪；Ring B is pyrrole, imidazole, pyrazole, thiazole, oxazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine or triazine; Xa、Xb、Xc各自独立地为N或CH；X a , X b , and X c are each independently N or CH; X1为化学键、N、CH、CH2、S、O、S(O)或S(O)2；X 1 is a chemical bond, N, CH, CH 2 , S, O, S(O) or S(O) 2 ; X2为N、CH、CH2、O、S、S(O)或S(O)2；X 2 is N, CH, CH 2 , O, S, S(O) or S(O) 2 ; X3、X4各自独立地为N或C，且X3和X4不同时为N，X1、X2和X3不同时为N；X 3 and X 4 are each independently N or C, and X 3 and X 4 are not N at the same time, and X 1 , X 2 and X 3 are not N at the same time; X5为化学键、N、CH、CH2、O或S；X 5 is a chemical bond, N, CH, CH 2 , O or S; X6为N、O、S或CH； X6 is N, O, S or CH; 优选地，在式I、II或III中，Q1选自以下基团：
所述Q1任选地被一个或多个氘原子、F、Cl、氰基、羟基、氨基、甲基、氘代甲基、乙基、异丙基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、甲氨基、二甲氨基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基或三氟乙氧基取代；Preferably, in formula I, II or III, Q 1 is selected from the following groups:
said Q 1 is optionally substituted by one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, deuterated methyl, ethyl, isopropyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy; 更优选地，在式I、II或III中，Q1选自以下基团：

More preferably, in formula I, II or III, Q 1 is selected from the following groups:

根据权利要求1至3任一项所述的螺环/桥环化合物或其药学上可接受的盐、立体异构体、消旋体、互变异构体、同位素标记物、氘代物、N-氧化物、前药分子、水合物或溶剂化物，其中，在式I、II或III中，L1为化学键、O、NR4、CR5R6、-OR7-或C(＝O)；The spirocyclic/bridged ring compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof, wherein, in Formula I, II or III, L 1 is a chemical bond, O, NR 4 , CR 5 R 6 , -OR 7 - or C(=O); L2为化学键或NR4；L 2 is a chemical bond or NR 4 ; L3为NR4；L 3 is NR 4 ; L4为O或CR5R6；L 4 is O or CR 5 R 6 ; M为C＝O或S(＝O)2；M is C=O or S(=O) 2 ; R4为氢原子、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C2-4烯基、C2-4炔基或3-12元环烷基，所述C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C2-4烯基、C2-4炔基或3-12元环烷基任选地被一个或者多个甲基、乙基、卤素、氘原子、氰基、羟基、甲氧基、环丙基或氧代(＝O)取代； R4 is a hydrogen atom, a C1-6 alkyl group, a halogenated C1-6 alkyl group, a deuterated C1-6 alkyl group, a C2-4 alkenyl group, a C2-4 alkynyl group or a 3-12 membered cycloalkyl group, wherein the C1-6 alkyl group, the halogenated C1-6 alkyl group, the deuterated C1-6 alkyl group, the C2-4 alkenyl group, the C2-4 alkynyl group or the 3-12 membered cycloalkyl group is optionally substituted with one or more methyl groups, ethyl groups, halogen groups, deuterium atoms, cyano groups, hydroxyl groups, methoxy groups, cyclopropyl groups or oxo (=O); R5、R6各自独立地为氢原子、氘原子、卤素、氰基、羟基、氨基、C1-6烷基、卤代C1-6烷基、3-6元环烷基、C1-6烷氧基、卤代C1-6烷氧基、3-12元环烷基氧基、C1-6烷基氨基、二(C1-6烷基)氨基；R 5 and R 6 are each independently a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a 3-6 membered cycloalkyl group, a C 1-6 alkoxy group, a halogenated C 1-6 alkoxy group, a 3-12 membered cycloalkyloxy group, a C 1-6 alkylamino group, or a di(C 1-6 alkyl)amino group; 或者，R5与R6和所连接的C原子一起形成环丙基、环丁基、环戊基或环己基，所述环丙基、环丁基、环戊基或环己基任选地被一个或者多个甲基、乙基、卤素、氘原子或环丙基取代；Alternatively, R 5 and R 6 together with the attached C atom form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group is optionally substituted with one or more methyl, ethyl, halogen, deuterium atom or cyclopropyl group; R7为亚甲基、亚乙基或亚丙基； R7 is methylene, ethylene or propylene; 优选地，L1为化学键、O、NR4、CR5R6、-OR7-或C(＝O)；Preferably, L 1 is a chemical bond, O, NR 4 , CR 5 R 6 , -OR 7 - or C(=O); L2为化学键或NR4；L 2 is a chemical bond or NR 4 ; L3为NR4；L 3 is NR 4 ; L4为O或CR5R6；L 4 is O or CR 5 R 6 ; M为C＝O；M is C=O; R4为氢原子、甲基、乙基、异丙基、1,2-二羟基丙-3-基、乙酰基、甲氧基乙基、乙氰基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、环丁基、丙烯基或丙炔基； R4 is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a 1,2-dihydroxypropan-3-yl group, an acetyl group, a methoxyethyl group, an acetylcyano group, a deuterated methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a propenyl group or a propynyl group; R5、R6各自独立地为氢原子、氘原子、卤素、氰基、羟基、氨基、甲基、乙基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、甲氨基、二甲氨基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基、三氟乙氧基、丙烯基或丙炔基；R 5 and R 6 are each independently a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, a deuterated methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a cyclopropyl group, a methylamino group, a dimethylamino group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a propenyl group, or a propynyl group; 或者，R5与R6和所连接的C原子一起形成环丙基或环丁基，所述环丙基或环丁基任选地被一个或者多个甲基、乙基、卤素、氘原子或环丙基取代；Alternatively, R 5 and R 6 together with the attached C atom form a cyclopropyl or cyclobutyl group, wherein the cyclopropyl or cyclobutyl group is optionally substituted with one or more methyl groups, ethyl groups, halogen groups, deuterium atoms or cyclopropyl groups; R7为亚甲基； R7 is methylene; 优选地，在式I、II或III中，Y1为N或CRa；Preferably, in formula I, II or III, Y 1 is N or CR a ; Y2为N或CRb；Y 2 is N or CR b ; Y3为N或CRc；Y 3 is N or CR c ; Y4为N或CRd；Y 4 is N or CR d ; Y5为N、CRe或C；当L2为化学键，Y5为N；当L2为O或NR4时，Y5为CRe或C；Y 5 is N, CR e or C; when L 2 is a chemical bond, Y 5 is N; when L 2 is O or NR 4 , Y 5 is CR e or C; Ra为氢原子、氘原子、卤素、氰基、C1-6烷基、C2-4烯基、C2-4炔基、4-10元杂环基、ORa1、SRa1或NRa1，所述C1-6烷基、C2-4烯基、C2-4炔基、4-10元杂环基任选地被一个或者多个R′取代；R a is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a 4-10 membered heterocyclic group, OR a1 , SR a1 or NR a1 , wherein the C 1-6 alkyl group, the C 2-4 alkenyl group, the C 2-4 alkynyl group or the 4-10 membered heterocyclic group is optionally substituted by one or more R′; Ra1为氢原子、C1-4烷基、3-6元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基、3-6元环烷基-C1-6烷基或含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基-C1-6烷基，所述C1-4烷基、3-6元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基、3-6元环烷基-C1-6烷基或含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基-C1-6烷基任选地被一个或者多个卤素、氘原子、甲基、乙基、或氧代取代；R a1 is a hydrogen atom, a C 1-4 alkyl group, a 3-6 membered cycloalkyl group, a 3-6 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , a 3-6 membered cycloalkyl-C 1-6 alkyl group, or a 3-6 membered heterocyclyl-C 1-6 alkyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , wherein the C 1-4 alkyl group, the 3-6 membered cycloalkyl group, the 3-6 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 , the 3-6 membered cycloalkyl-C 1-6 alkyl group, or the 3-6 membered heterocyclyl-C 1-6 alkyl group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 are optionally substituted with one or more halogen, a deuterium atom, a methyl group, an ethyl group, or an oxo group; Rc为氢原子、卤素、氰基、氨基、甲基、乙基、异丙基、环丙基、甲氧基或环丙氧基，所述氨基、甲基、异丙基、乙基、环丙基、甲氧基和环丙氧基任选地被一个或者多个R′取代；R c is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group, wherein the amino group, the methyl group, the isopropyl group, the ethyl group, the cyclopropyl group, the methoxy group and the cyclopropyloxy group are optionally substituted by one or more R ′; Rb与Rd和所连接的原子一起形成4-7元环烷基或含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的5-7元杂环基，所述4-7元环烷基或含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的5-7元杂环基任选地被一个或者多个R′取代；R b and R d together with the atoms to which they are attached form a 4-7 membered cycloalkyl group or a 5-7 membered heterocyclyl group containing 1 or 2 heteroatoms selected from N, O, S, S=O, S(O) 2 , wherein the 4-7 membered cycloalkyl group or the 5-7 membered heterocyclyl group containing 1 or 2 heteroatoms selected from N, O, S, S=O, S(O) 2 are optionally substituted by one or more R ′; Re为氢原子、氘原子、C1-4烷基、卤代C1-4烷基、3-12元环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-12元杂环基；R e is a hydrogen atom, a deuterium atom, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, a 3-12 membered cycloalkyl group, or a 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 ; R′为氘原子、F、Cl、氰基、羟基、氨基、甲基、乙基、二氟甲基、三氟甲基、甲氧基、二氟甲氧基、三氟甲氧基、环丙基、甲氧基、吡咯烷基、1-甲基吡咯烷-3-基或氧代(＝O)；R′ is a deuterium atom, F, Cl, cyano, hydroxy, amino, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, methoxy, pyrrolidinyl, 1-methylpyrrolidin-3-yl, or oxo (═O); 优选地，在式I、II或III中，Y1为N或CRa；Preferably, in formula I, II or III, Y 1 is N or CR a ; Y2为N或CRb；Y 2 is N or CR b ; Y3为N或CRc；Y 3 is N or CR c ; Y4为N或CRd；Y 4 is N or CR d ; Y5为N、CH或C；当L2为化学键，Y5为N；当L2为O或NR4时，Y5为CH或C；Ra为氢原子、氘原子、F、Cl、Br、氰基、羟基、氨基、甲基、乙基、正丙基、异丙基、二氟甲基、三氟甲基、乙炔基、2-(1,3-二甲基吡咯烷-3-基)乙炔基、乙氰基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基、三氟乙氧基、羟基乙氧基、N',N'-二甲氨基乙氧基、N'-甲基氨基乙氧基、吗啉基、2-氧杂-6-氮杂螺[3.3]环庚烷基、吗啉基-乙氧基、羟基丙氧基、N',N'-二甲氨基丙氧基、N'-甲基氨基丙氧基、吗啉基-丙氧基、哌嗪-1-基-乙氧基、4-甲基哌嗪-1-基-乙氧基、4-甲基哌嗪-1-基-丙氧基、哌嗪-1-基-丙氧基、吡咯烷-1-基-乙氧基、吡咯烷-1-基-丙氧基、四氢呋喃-3-氧基、甲硫基、甲氨基、乙胺基、乙酰胺基、丙酰胺基、甲氧基乙基、甲氧基乙胺基或甲氧基乙氧基；Y 5 is N, CH or C; when L 2 is a chemical bond, Y 5 is N; when L 2 is O or NR 4 , Y 5 is CH or C; Ra is a hydrogen atom, a deuterium atom, F, Cl, Br, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a difluoromethyl group, a trifluoromethyl group, an ethynyl group, a 2-(1,3-dimethylpyrrolidin-3-yl)ethynyl group, an acetylcyano group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a hydroxyethoxy group, an N',N'-dimethylaminoethoxy group, an N'-methylaminoethoxy group, a morpholinyl group, a 2-oxa-6-azaspiro[3.3]cycloheptyl group, a morpholinyl group -ethoxy, hydroxypropoxy, N',N'-dimethylaminopropoxy, N'-methylaminopropoxy, morpholinyl-propoxy, piperazin-1-yl-ethoxy, 4-methylpiperazin-1-yl-ethoxy, 4-methylpiperazin-1-yl-propoxy, piperazin-1-yl-propoxy, pyrrolidin-1-yl-ethoxy, pyrrolidin-1-yl-propoxy, tetrahydrofuran-3-oxy, methylthio, methylamino, ethylamino, acetamido, propionamido, methoxyethyl, methoxyethylamino or methoxyethoxy; Rc为氢原子、卤素、氰基、氨基、甲基、乙基、异丙基、环丙基、甲氧基或环丙氧基；R c is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group; Rb与Rd和所连接的原子一起形成吗啉基、四氢呋喃基、二氢咪唑基、硫代吗啉基、四氢吡喃基、四氢吡喃酮基、1,4-二氧六环基、六氢-1,4-氧氮杂卓基、六氢-1,4-硫氮杂卓基、4-硫代吗啉基-1-氧化物、4-硫代吗啉基-1,1-二氧化物、六氢-1,4-硫氮杂卓基-1-氧化物或六氢-1,4-硫氮杂卓基-1,1-二氧化物，所述吗啉基、硫代吗啉基、四氢吡喃基、四氢吡喃酮基、1,4-二氧六环基、六氢-1,4-氧氮杂卓基、六氢-1,4-硫氮杂卓基、4-硫代吗啉基-1-氧化物、4-硫代吗啉基-1,1-二氧化物、六氢-1,4-硫氮杂卓基-1-氧化物或六氢-1,4-硫氮杂卓基-1,1-二氧化物任选地被一个或多个氘原子、F、Cl、氰基、羟基、氨基、甲基、乙基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、甲氨基、二甲氨基、二甲氨基烷基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基或三氟乙氧基取代。 Rb and Rd together with the atoms to which they are attached form a morpholinyl, tetrahydrofuranyl, dihydroimidazolyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide or hexahydro-1,4-thiazepinyl-1,1-dioxide, wherein the morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxazepinyl, The isopropyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide or hexahydro-1,4-thiazepinyl-1,1-dioxide is optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, dimethylaminoalkyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy. 根据权利要求1至4任一项所述的螺环/桥环化合物或其药学上可接受的盐、立体异构体、消旋体、互变异构体、同位素标记物、氘代物、N-氧化物、前药分子、水合物或溶剂化物，其中，在式I、II或III中，R1为卤代甲基、乙烯基、丙烯基、乙炔基、丙炔基、丁炔基、环氧丙烷基、环丁烯基、环戊烯基或环己烯基，所述卤代甲基、乙烯基、丙烯基、乙炔基、丙炔基、丁炔基、环氧丙烷基、环丁烯基、环戊烯基或环己烯基任选地被一个或者多个F、Cl、甲基、乙基、环丙基、吖丁啶基、吡咯烷基、哌啶基、环氧丙烷基、环氧丁烷基、氘原子、苯基、吡啶基或NRxRy取代，所述甲基、乙基、环丙基、吖丁啶基、吡咯烷基、哌啶基、环氧丙烷基、环氧丁烷基、苯基或吡啶基任选地被一个或者多个R′取代；The spiro/bridged ring compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof, wherein in Formula I, II or III, R 1 is a halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, epoxypropanyl, cyclobutenyl, cyclopentenyl or cyclohexenyl, and the halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, epoxypropanyl, cyclobutenyl, cyclopentenyl or cyclohexenyl is optionally replaced by one or more F, Cl, methyl, ethyl, cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl, epoxypropanyl, epoxybutanyl, deuterium atom, phenyl, pyridyl or NR x R y , wherein the methyl, ethyl, cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl, propylene oxide, butylene oxide, phenyl or pyridinyl is optionally substituted with one or more R'; Rx、Ry各自独立地为氢原子、甲基、乙基、异丙基、环丙基、环丁基、环戊基、金刚烷基、甲氧基乙基、环丙基甲基、环丁基甲基、环丙基乙基、环丁基乙基、吖丁啶基甲基或吖丁啶基乙基，所述甲基、乙基、异丙基、环丙基、环丁基、环戊基、金刚烷基、甲氧基乙基、环丙基甲基、环丁基甲基、环丙基乙基、环丁基乙基、吖丁啶基甲基或吖丁啶基乙基任选地被一个或者多个R′取代；R x and R y are each independently a hydrogen atom, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, azetidinylmethyl or azetidinylethyl, and the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, azetidinylmethyl or azetidinylethyl is optionally substituted with one or more R′; 或者，NRxRy中Rx与Ry和所连接的N原子一起形成吖丁啶基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、二氧化硫代吗啉基、7-氮杂双环[2.2.1]庚烷基、9-氮杂双环[3.3.1]壬烷基、2-氮杂双环[4.1.0]庚烷基或2-氮杂双环[3.1.0]己烷基，所述吖丁啶基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、二氧化硫代吗啉基、7-氮杂双环[2.2.1]庚烷基、9-氮杂双环[3.3.1]壬烷基、2-氮杂双环[4.1.0]庚烷基或2-氮杂双环[3.1.0]己烷基任选地被一个或者多个R′取代；or wherein R in NRxRy is taken together with Ry and the nitrogen atom to which it is attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1] heptanyl , 9-azabicyclo[3.3.1]nonanyl, 2-azabicyclo[4.1.0]heptanyl, or 2-azabicyclo[3.1.0]hexanyl, said azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptanyl, 9-azabicyclo[3.3.1]nonanyl, 2-azabicyclo[4.1.0]heptanyl, or 2-azabicyclo[3.1.0]hexanyl being optionally substituted with one or more R′; R′为氘原子、F、Cl、氰基、羟基、氨基、甲基、乙基、乙烯基、乙炔基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、甲氨基、二甲氨基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基、三氟乙氧基或氧代(＝O)；R′ is a deuterium atom, F, Cl, cyano, hydroxy, amino, methyl, ethyl, vinyl, ethynyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, or oxo (═O); 优选地，在式I、II或III中，R1选自以下基团：

Preferably, in formula I, II or III, R 1 is selected from the following groups:

优选地，在式I、II或III中，R2为氢原子、氘原子、氰基、卤素、C1-6烷基、C2-4烯基、C2-4炔基、卤代C1-4烷基、氘代C1-4烷基、3-6元环烷基、C1-4烷氧基-C1-4烷基、卤代C1-4烷氧基或氧代(＝O)，所述C1-6烷基、C2-4烯基、C2-4炔基、卤代C1-4烷基、氘代C1-4烷基、3-6元环烷基、C1-4烷氧基-C1-4烷基、卤代C1-4烷氧基任选地被一个或者多个R′取代；Preferably, in formula I, II or III, R2 is a hydrogen atom, a deuterium atom, a cyano group, a halogen, a C1-6 alkyl group, a C2-4 alkenyl group, a C2-4 alkynyl group, a halogenated C1-4 alkyl group, a deuterated C1-4 alkyl group, a 3-6 membered cycloalkyl group, a C1-4 alkoxy- C1-4 alkyl group, a halogenated C1-4 alkoxy group or an oxo group (=O), and the C1-6 alkyl group, the C2-4 alkenyl group, the C2-4 alkynyl group, the halogenated C1-4 alkyl group, the deuterated C1-4 alkyl group, the 3-6 membered cycloalkyl group, the C1-4 alkoxy- C1-4 alkyl group, the halogenated C1-4 alkoxy group is optionally substituted by one or more R'; 或者，Rb与R2和所连接的原子一起形成含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的5-7元杂环基或含有1、2、3或4个选自N、O、S杂原子的5-6元杂芳基，所述含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的5-7元杂环基、含有1、2、3或4个选自N、O、S杂原子的5-6元杂芳基任选地被一个或者多个R′取代；Alternatively, Rb , R2 and the atoms to which they are attached form a 5-7 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, S=O, S(O) 2 , or a 5-6 membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, wherein the 5-7 membered heterocyclic group containing 1 or more heteroatoms selected from N, O, S, S=O, S(O) 2 , or the 5-6 membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O, S are optionally substituted by one or more R'; 优选地，R2为氢原子、氘原子、F、Cl、甲基、乙基、异丙基、叔丁基、环丙基、环丁基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、乙烯基、丙烯基、乙炔基、丙炔基、氰基、二氟甲氧基、三氟甲氧基、甲氧基、甲氧基甲基或氧代(＝O)；Preferably, R 2 is a hydrogen atom, a deuterium atom, F, Cl, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a cyclopropyl group, a cyclobutyl group, a deuterated methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a vinyl group, a propenyl group, an ethynyl group, a propynyl group, a cyano group, a difluoromethoxy group, a trifluoromethoxy group, a methoxy group, a methoxymethyl group or an oxo group (═O); 或者，Rb与R2和所连接的原子一起形成吗啉基、四氢呋喃基、二氢咪唑基、硫代吗啉基、六氢-1,4-氧氮杂卓基、六氢-1,4-硫氮杂卓基、4-硫代吗啉基-1-氧化物、4-硫代吗啉基-1,1-二氧化物、六氢-1,4-硫氮杂卓基-1-氧化物或六氢-1,4-硫氮杂卓基-1,1-二氧化物，所述吗啉基、硫代吗啉基、六氢-1,4-氧氮杂卓基、六氢-1,4-硫氮杂卓基、4-硫代吗啉基-1-氧化物、4-硫代吗啉基-1,1-二氧化物、六氢-1,4-硫氮杂卓基-1-氧化物或六氢-1,4-硫氮杂卓基-1,1-二氧化物任选地被一个或多个氘原子、F、Cl、氰基、羟基、氨基、甲基、乙基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、甲氨基、二甲氨基、二甲氨基烷基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基或三氟乙氧基取代。Alternatively, Rb together with R2 and the atoms to which they are attached form a morpholinyl, tetrahydrofuranyl, dihydroimidazolyl, thiomorpholinyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide or hexahydro-1,4-thiazepinyl-1,1-dioxide, wherein the morpholinyl, thiomorpholinyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, 4-thiomorpholinyl-1,1-dioxide and 4-thiomorpholinyl-1,1-dioxide are substituted or substituted with morpholinyl, thiomorpholinyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1,1-dioxide. 1-dioxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide or hexahydro-1,4-thiazepinyl-1,1-dioxide is optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, dimethylaminoalkyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy. 根据权利要求1至5任一项所述的螺环/桥环化合物或其药学上可接受的盐、立体异构体、消旋体、互变异构体、同位素标记物、氘代物、N-氧化物、前药分子、水合物或溶剂化物，其中，在式I、II或III中，R3为氢原子、氘原子、卤素、氰基、硝基、C1-4烷基、C2- 4烯基、C2-4炔基、3-6元饱和或不饱和环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元饱和或不饱和杂环基、卤代C1-4烷基、卤代C1-4烷氧基、ORe、SORe、S(O)2Re、C(＝O)Re、C(＝O)NRe、NReRf、NReC(＝O)Rf、S(O)2NRe、P(O)(Re)2，所述C1-4烷基、C2-4烯基、C2-4炔基、3-6元饱和或不饱和环烷基、含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元饱和或不饱和杂环基、卤代C1-4烷基、卤代C1-4烷氧基任选地被一个或者多个R′取代；The spiro/bridged ring compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof, wherein, in Formula I, II or III, R 3 is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a nitro group, a C 1-4 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a 3-6 membered saturated or unsaturated cycloalkyl group, a 3-6 membered saturated or unsaturated heterocyclic group containing one or more heteroatoms selected from N, O, S, S＝O, S(O) 2 , a halogenated C 1-4 alkyl group, a halogenated C 1-4 alkoxy group, OR e , SOR e , S(O) 2 R e , C(＝O)R e , C(＝O)NR e , N Re R f , N Re C(＝O)R f , S(O) 2 NR e , P(O)(R e ) 2 , the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-6 membered saturated or unsaturated cycloalkyl, 3-6 membered saturated or unsaturated heterocyclic group containing one or more heteroatoms selected from N, O, S, S═O, S(O) 2 , halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy are optionally substituted by one or more R′; Re、Rf各自独立地为氢原子、氘原子、C1-4烷基、卤代C1-4烷基、3-12元环烷基；R e and R f are each independently a hydrogen atom, a deuterium atom, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, or a 3-12 membered cycloalkyl group; 或者，NReRf中Re和Rf与连接的N原子一起形成含有1个或多个选自N、O、S、S＝O、S(O)2杂原子的3-6元杂环基；Alternatively, Re and Rf in NR e R f together with the attached N atom form a 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S═O, and S(O) 2 ; 优选地，R3为氢原子、氘原子、F、Cl、氰基、硝基、甲基、乙基、异丙基、乙烯、乙炔、环丙基、环丁基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、羟基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧、甲氨基、乙胺基、SOCH3、S(O)2CH3、C(＝O)CH3、C(＝O)NCH3、NHC(＝O)CH3、S(O)2NCH3、P(O)(CH3)2或P(O)(CH2CH3)2，所述甲基、乙基、异丙基、乙烯、乙炔、环丙基、环丁基、二氟乙基、三氟乙基、羟基、甲氧基、乙氧基、甲氨基、乙胺基、SOCH3、S(O)2CH3、C(＝O)CH3、C(＝O)NCH3、NHC(＝O)CH3、S(O)2NCH3、P(O)(CH3)2或P(O)(CH2CH3)2任选地被一个或者多个氘原子、F、Cl、羟基、甲基、乙基、异丙基或环丙基取代；Preferably, R 3 is a hydrogen atom, a deuterium atom, F, Cl, a cyano group, a nitro group, a methyl group, an ethyl group, an isopropyl group, an ethylene group, an acetylene group, a cyclopropyl group, a cyclobutyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a hydroxyl group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a methylamino group, an ethylamino group, SOCH 3 , S(O) 2 CH 3 , C(═O)CH 3 , C(═O)NCH 3 , NHC(═O)CH 3 , S(O) 2 NCH 3 , P(O)(CH 3 ) 2 or P(O)(CH 2 CH 3 ) 2 , wherein the methyl group, ethyl group, isopropyl group, an ethylene group, an acetylene group, a cyclopropyl group, a cyclobutyl group, a difluoroethyl group, a trifluoroethyl group, a hydroxyl group, a methoxy group, an ethoxy group, a methylamino group, an ethylamino group, SOCH 3 , S(O) 2 CH 3 , C(═O)CH 3 , C(=O)NCH 3 , NHC(=O)CH 3 , S(O) 2 NCH 3 , P(O)(CH 3 ) 2 or P(O)(CH 2 CH 3 ) 2 are optionally substituted with one or more deuterium atoms, F, Cl, hydroxyl, methyl, ethyl, isopropyl or cyclopropyl; 优选地，在式II或III中，G环为4-7元环烷基、含有1个或2个选自N、O、S、S＝O、S(O)2杂原子的5-7元杂环基；Preferably, in formula II or III, ring G is a 4-7 membered cycloalkyl group, a 5-7 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, S=O, S(O) 2 ; 优选地，在式II或III中，G环为吗啉基、四氢呋喃基、二氢咪唑基、硫代吗啉基、四氢吡喃基、四氢吡喃酮基、1,4-二氧六环基、六氢-1,4-氧氮杂卓基、六氢-1,4-硫氮杂卓基、4-硫代吗啉基-1-氧化物、4-硫代吗啉基-1,1-二氧化物、六氢-1,4-硫氮杂卓基-1-氧化物或六氢-1,4-硫氮杂卓基-1,1-二氧化物，所述吗啉基、硫代吗啉基、四氢吡喃基、四氢吡喃酮基、1,4-二氧六环基、六氢-1,4-氧氮杂卓基、六氢-1,4-硫氮杂卓基、4-硫代吗啉基-1-氧化物、4-硫代吗啉基-1,1-二氧化物、六氢-1,4-硫氮杂卓基-1-氧化物或六氢-1,4-硫氮杂卓基-1,1-二氧化物任选地被一个或多个氘原子、F、Cl、氰基、羟基、氨基、甲基、乙基、氘代甲基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、环丙基、甲氨基、二甲氨基、二甲氨基烷基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、二氟乙氧基或三氟乙氧基取代。Preferably, in formula II or III, ring G is morpholinyl, tetrahydrofuranyl, dihydroimidazolyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4-oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide or hexahydro-1,4-thiazepinyl-1,1-dioxide, and the morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrone, 1,4-dioxanyl, hexahydro-1,4- The oxazepinyl, hexahydro-1,4-thiazepinyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thiazepinyl-1-oxide or hexahydro-1,4-thiazepinyl-1,1-dioxide is optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, dimethylaminoalkyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy. 根据权利要求1至6任一项所述的螺环/桥环化合物或其药学上可接受的盐、立体异构体、消旋体、互变异构体、同位素标记物、氘代物、N-氧化物、前药分子或溶剂合物，其中，式I、II或III所示的化合物选自下列的化合物：








The spirocyclic/bridged ring compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule or solvate thereof, wherein the compound represented by Formula I, II or III is selected from the following compounds:








一种制备权利要求1至6中任一项所述的螺环/桥环化合物或其药学上可接受的盐、立体异构体、消旋体、互变异构体、同位素标记物、氘代物、N-氧化物、前药分子、水合物或溶剂合物的方法，该方法包括：式II化合物或式III化合物的制备，其中式II化合物的制备包括：A method for preparing the spirocyclic/bridged ring compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof, comprising: preparing a compound of formula II or a compound of formula III, wherein the preparation of the compound of formula II comprises: 1)化合物II-1与化合物II-2发生取代反应关环形成化合物II-3；1) Compound II-1 and compound II-2 undergo a substitution reaction to form compound II-3; 2)化合物II-3发生还原反应形成化合物II-5；或化合物II-3发生卤代反应形成化合物II-4，然后化合物II-4发生偶联反应形成化合物II-5；2) Compound II-3 undergoes a reduction reaction to form Compound II-5; or Compound II-3 undergoes a halogenation reaction to form Compound II-4, and then Compound II-4 undergoes a coupling reaction to form Compound II-5; 3)化合物II-5与DMF-DMA反应形成化合物II-6；3) Compound II-5 reacts with DMF-DMA to form compound II-6; 4)化合物II-6与化合物II-7反应关环形成化合物II-8；4) Compound II-6 reacts with compound II-7 to form compound II-8; 5)化合物II-8脱保护形成化合物II-9；5) deprotecting compound II-8 to form compound II-9; 6)化合物II-9与化合物II-10或化合物II-11发生取代反应形成式II所示化合物；反应路线如图1所示；6) Compound II-9 undergoes a substitution reaction with compound II-10 or compound II-11 to form a compound represented by formula II; the reaction scheme is shown in FIG1 ; 其中式III化合物的制备包括：The preparation of the compound of formula III comprises: 1)化合物III-1与化合物III-2发生取代反应关环形成化合物III-3；1) Compound III-1 and compound III-2 undergo a substitution reaction to form compound III-3; 2)化合物III-3发生还原反应形成化合物III-5；或化合物III-3发生卤代反应形成化合物III-4，然后化合物III-4发生偶联反应形成化合物III-5；2) Compound III-3 undergoes a reduction reaction to form Compound III-5; or Compound III-3 undergoes a halogenation reaction to form Compound III-4, and then Compound III-4 undergoes a coupling reaction to form Compound III-5; 3)化合物III-5与DMF-DMA反应形成化合物III-6；3) Compound III-5 reacts with DMF-DMA to form compound III-6; 4)化合物III-6与化合物III-7反应关环形成化合物III-8；4) Compound III-6 reacts with compound III-7 to form compound III-8; 5)化合物III-8脱保护形成化合物III-9；5) deprotecting compound III-8 to form compound III-9; 6)化合物III-9与化合物III-10或化合物III-11发生取代反应形成式III所示化合物；反应路线如图2所示；6) Compound III-9 undergoes a substitution reaction with Compound III-10 or Compound III-11 to form a compound represented by Formula III; the reaction scheme is shown in FIG2 ; 其中，A、E、Q1、M、Y1、Y3、Y4、Y5、L1、L2、L3、L4、R1、R2、R3、R'、G、W、m、n、t的定义如权利要求1至6中任一项所定义上所述；X'为NO2或H；X”为卤素。wherein A, E, Q 1 , M, Y 1 , Y 3 , Y 4 , Y 5 , L 1 , L 2 , L 3 , L 4 , R 1 , R 2 , R 3 , R', G, W, m, n, and t are as defined in any one of claims 1 to 6; X' is NO 2 or H; and X" is a halogen. 包含如权利要求1-7中任一项所述的螺环/桥环化合物或其药学上可接受的盐、立体异构体、消旋体、互变异构体、同位素标记物、氘代物、N-氧化物、前药分子、水合物或溶剂合物以及药学上可接受的载体或赋形剂的药物组合物；A pharmaceutical composition comprising the spirocyclic/bridged ring compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof, and a pharmaceutically acceptable carrier or excipient; 优选地，所述药物组合物为片剂、胶囊剂、丸剂、颗粒剂、散剂、栓剂、注射剂、溶液剂、混悬剂、膏剂、贴剂、洗剂、滴剂、擦剂、喷雾剂。Preferably, the pharmaceutical composition is in the form of tablets, capsules, pills, granules, powders, suppositories, injections, solutions, suspensions, ointments, patches, lotions, drops, liniments, or sprays. 根据权利要求1-7中任一项所述的螺环/桥环化合物或其药学上可接受的盐、立体异构体、消旋体、互变异构体、同位素标记物、氘代物、N-氧化物、前药分子、水合物或溶剂合物和/或权利要求9所述的药物组合物在制备治疗HER2异常介导的疾病中的应用；Use of the spirocyclic/bridged ring compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof, and/or the pharmaceutical composition according to claim 9, in the preparation of a drug for treating diseases mediated by abnormal HER2; 优选地，所述疾病为肿瘤性疾病；Preferably, the disease is a tumor disease; 更优选地，所述肿瘤性疾病包括：头颈部癌、鼻咽癌、黑色素瘤、膀胱癌、食道癌、肾癌、乳腺癌、结肠直肠癌、卵巢癌、宫颈癌、胰腺癌、胶质瘤、前列腺癌、白血病、淋巴瘤、胃癌、肺癌、肝癌、胃肠道基质瘤、甲状腺癌、鳞状细胞癌、胆管癌、子宫内膜癌、多发性骨髓瘤或者间皮瘤、动脉粥样硬化或者肺纤维化。More preferably, the tumor disease includes: head and neck cancer, nasopharyngeal cancer, melanoma, bladder cancer, esophageal cancer, kidney cancer, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, pancreatic cancer, glioma, prostate cancer, leukemia, lymphoma, gastric cancer, lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, squamous cell carcinoma, bile duct cancer, endometrial cancer, multiple myeloma or mesothelioma, atherosclerosis or pulmonary fibrosis. 一种治疗HER2异常介导的疾病的方法，该方法包括向有需要的患者给予治疗有效量的权利要求1-7中任一项所述的螺环/桥环化合物或其药学上可接受的盐、立体异构体、消旋体、互变异构体、同位素标记物、氘代物、N-氧化物、前药分子、水合物或溶剂化物和/或权利要求9所述的药物组合物；A method for treating a disease mediated by abnormal HER2, comprising administering to a patient in need thereof a therapeutically effective amount of the spirocyclic/bridged ring compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof, and/or the pharmaceutical composition according to claim 9; 优选地，所述疾病为肿瘤性疾病；Preferably, the disease is a tumor disease; 更优选地，所述肿瘤性疾病包括：头颈部癌、鼻咽癌、黑色素瘤、膀胱癌、食道癌、肾癌、乳腺癌、结肠直肠癌、卵巢癌、宫颈癌、胰腺癌、胶质瘤、前列腺癌、白血病、淋巴瘤、胃癌、肺癌、肝癌、胃肠道基质瘤、甲状腺癌、鳞状细胞癌、胆管癌、子宫内膜癌、多发性骨髓瘤或者间皮瘤、动脉粥样硬化或者肺纤维化。More preferably, the tumor disease includes: head and neck cancer, nasopharyngeal cancer, melanoma, bladder cancer, esophageal cancer, kidney cancer, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, pancreatic cancer, glioma, prostate cancer, leukemia, lymphoma, gastric cancer, lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, squamous cell carcinoma, bile duct cancer, endometrial cancer, multiple myeloma or mesothelioma, atherosclerosis or pulmonary fibrosis.
PCT/CN2025/082933 2024-03-19 2025-03-17 Spiro/bridged polycyclic compounds as well as preparation method therefor and use thereof Pending WO2025195327A1 (en)

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