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

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: . 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

Spirocyclic / bridged ring compounds and their preparation methods and applications Technical Field

[0001] 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. Background Art

[0002] 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.

[0003] 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.

[0004] 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 cancers are more likely to develop central nervous system metastases during the course of the disease. Approximately 47% of patients with HER2-mutated non-small cell lung cancer develop brain metastases, which are associated with poor prognosis.

[0005] 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).

[0006] 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. Summary of the Invention

[0007] In order to address the deficiencies of the prior art, the present invention aims to provide a spirocyclic / bridged ring compound, a preparation method, and an application thereof. The spirocyclic / bridged ring compound of the present invention has good activity in inhibiting HER2 exon 20 insertion mutations, has high selectivity for wild-type EGFR, can penetrate the blood-brain barrier, and can be used in particular as a treatment for diseases related to HER2 abnormality induction, especially for the treatment of cancer diseases.

[0008] The present invention is achieved through the following technical solutions.

[0009] 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:

[0010] Wherein, in Formula I,

[0011] 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;

[0012] 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;

[0013] Q1 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′;

[0014] L1 is a chemical bond, O, NR 4 , CR 5 R 6 、-OR 7 -, C(=O), S, S(O) or S(O)2;

[0015] L2 is a chemical bond, O or NR 4 ;

[0016] L3 for NR 4 ,O,CR 5 R 6 , S, S(O) or S(O)2;

[0017] L4 does not exist or is a chemical bond, O, NR 4 , CR 5 R 6 , C(═O), S, S(O) or S(O) 2 ;

[0018] M is C=O or S(=O)2;

[0019] Y 1 N or CR a ;

[0020] Y 2 N or CR b ;

[0021] Y 3 N or CR c ;

[0022] Y 4 N or CR d ;

[0023] Y 5 N, CR e or C; when L2 is a chemical bond, Y 5 N; when L2 is O or NR 4 When Y 5 CR e or C;

[0024] R 1 For halomethyl, C 2-4 Alkenyl, C2-4 Alkynyl, propylene oxide or C 4-6 Cycloalkenyl, the C 2-4 Alkenyl, C 2-4 Alkynyl, propylene oxide or C 4-6 Cycloalkenyl is optionally substituted with one or more halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-12 membered cycloalkyl, deuterium atom, 3-12 membered heterocyclic group 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 Substitute, the C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group 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 or C 1-3 Alkoxy-C 1-3 Alkyl - optionally substituted with one or more R';

[0025] R 2 For hydrogen atoms, deuterium atoms, halogens, cyano groups, hydroxyl groups, amino groups, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-4 Alkyl, deuterated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, 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 or oxo (=O), the hydroxyl, amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-4 Alkyl, deuterated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C 1-6 Alkoxy, C 1-6Alkoxy-C 1-6 Alkyl, halogenated C 1-6 Alkoxy is optionally substituted with one or more R';

[0026] R 3 For hydrogen atoms, deuterium atoms, halogens, cyano groups, nitro groups, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, halogenated C 1-6 Alkoxy, OR e SR e 、SOR e 、S(O)2R e 、C(=O)R e 、C(=O)NR e 、C(=O)OR e NR e R f NR e C(=O)R f 、OC(=O)R e ,SONR f 、S(O)2NR e 、NHS(O)2R e 、NHS(O)R e NR e C(=O)OR f NR e C(=O)NR f 、-(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 with one or more R';

[0027] R 4 For hydrogen atoms, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, cyano-C 1-6 Alkyl-, hydroxyl C 1-6 Alkyl, C2-4 Alkenyl, C 2-4 Alkynyl, C(=O)R e or a 3-12 membered cycloalkyl group, wherein the C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, cyano-C 1-6 Alkyl-, hydroxyl C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or 3-12 membered cycloalkyl is optionally substituted with one or more R';

[0028] R 5 、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, halogenated C 1-6 Alkyl, C 2- 4-alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, C 1-6 Alkylmercapto, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, cyano-C 1-6 Alkyl-, C 1- 6-alkoxy-C 1-6 Alkyl-, 3-12 membered cycloalkyl-C 1-6 Alkyl- or 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2 1-6 Alkyl-, the hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, C 1-6 Alkoxy, halogenated C 1- 6-membered alkoxy, 3-12-membered cycloalkyloxy, 3-12-membered heterocyclyloxy containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, C 1-6 Alkylmercapto, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, cyano-C 1-6 Alkyl-, C1-6 Alkoxy-C 1-6 Alkyl-, 3-12 membered cycloalkyl-C 1-6 Alkyl- or 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2 1-6 Alkyl - optionally substituted with one or more R';

[0029] or R 5 With R 6 Together with the C atom to which it is attached, it forms 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, wherein the 3-6 membered cycloalkyl group or the 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2 are optionally substituted by one or more R';

[0030] R 7 C 1-6 Alkylene, C 2-4 Alkenylene, halogenated C 1-6 Alkylene, deuterated C 1-6 Alkylene or halogenated C 2-4 alkenylene;

[0031] R a 、R b Each is independently a hydrogen atom, a deuterium atom, a halogen, a cyano group, a C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, OR a1 SR a1 NR a1 、S(=O)R a1 or S(=O)2R a1 , the C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, optionally substituted by one or more R';

[0032] Or, R a With R 2Together with the atoms to which they are attached, they 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, wherein 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′;

[0033] Or, R b With R 2 Together with the atoms to which they are attached, they 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, wherein 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′;

[0034] R c For hydrogen atoms, deuterium atoms, halogens, cyano groups, amino groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylmercapto, C 1-6 Alkylamino or di(C 1-6 Alkyl)amino, said amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylmercapto, C 1-6 Alkylamino or di(C 1-6 Alkyl)amino is optionally substituted with one or more R';

[0035] R d Does not exist or is a hydrogen atom, deuterium atom, halogen, cyano group, amino group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylmercapto or C 1- 6 alkylamino group, wherein the amino group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylmercapto or C 1-6 Alkylamino is optionally substituted with one or more R';

[0036] Or, R b With R dTogether with the atoms to which they are attached, they 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, wherein 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′;

[0037] Or, R a With R d Together with the atoms to which they are attached, they 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, wherein 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′;

[0038] R e 、R f are independently a hydrogen atom, a deuterium atom, a C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2;

[0039] Alternatively, NR e R f Middle R e and R f Together with the attached nitrogen atom, it forms a 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, and S(O)2;

[0040] R a1 For hydrogen atoms, C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, 3-12 membered cycloalkyl-C 1-6 Alkyl or 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2 1-6 Alkyl, the C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, 3-12 membered cycloalkyl-C 1-6Alkyl or 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2 1-6 Alkyl is optionally substituted with one or more R';

[0041] R x 、R y are independently a hydrogen atom, C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, 3-12 membered cycloalkyl-C 1-4 Alkyl-, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2 1-4 Alkyl-, C 1-4 Alkoxy-C 1-4 Alkyl- or deuterated C 1-4 Alkyl, the C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, 3-12 membered cycloalkyl-C 1-4 Alkyl-, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2 1-4 Alkyl-, C 1-4 Alkoxy-C 1-4 Alkyl- or deuterated C 1-4 Alkyl is optionally substituted with one or more R';

[0042] or NR x R y Middle R x With R y Together with the N atom to which it is attached, it forms 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';

[0043] R' is independently a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-4 Alkyl, deuterated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, C 1-4 Alkylamino, di(C 1-4Alkyl)amino, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, halogenated C 1-6 Alkoxy or oxo (=O);

[0044] m and n are each independently 0, 1, 2, 3, 4 or 5;

[0045] The conditions are: 1) R d or R 2 Any group and R a or R b Any group together with the atoms to which they are attached must form one and only one ring, wherein the ring is 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, wherein 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, S, is optionally substituted with one or more R′;

[0046] 2) When R 2 With R b Together with the atoms to which they are attached, they form a morpholine ring, and Y 1 When it is CH, Q1 is not

[0047] In certain embodiments, the compound of formula I further has a structure as shown in formula II or formula III,

[0048] in,

[0049] 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, S;

[0050] W is N, C or CR a ;

[0051] t is 0, 1, 2, 3, 4, or 5.

[0052] In certain embodiments, ring A is a 4-7 membered heterocyclyl or a 3-6 membered cycloalkyl containing 1 or 2 heteroatoms selected from N, O, S, S=O, and S(O)2;

[0053] 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.

[0054] 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;

[0055] 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.

[0056] 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;

[0057] Preferably, the E ring is phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene or pyrazole.

[0058] In certain embodiments, 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;

[0059] -- / --- is none or chemical bond;

[0060] Ring B is pyrrole, imidazole, pyrazole, thiazole, oxazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine or triazine;

[0061] X a 、X b 、X c are each independently N or CH;

[0062] X 1 is a chemical bond, N, CH, CH2, S, O, S(O) or S(O)2;

[0063] X 2 is N, CH, CH2, O, S, S(O) or S(O)2;

[0064] X 3 、X 4 are each independently N or C, and X 3 and X 4 Not N, X at the same time 1 、X 2 and X 3 Not all N at the same time;

[0065] X 5 is a chemical bond, N, CH, CH2, O or S;

[0066] X 6 is N, O, S or CH;

[0067] Preferably, Q1 is selected from the following groups: said Q1 is optionally substituted with 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;

[0068] More preferably, Q1 is selected from the following groups:

[0069] In certain embodiments, L1 is a chemical bond, O, NR 4 , CR 5 R 6 、-OR 7 - or C(=O);

[0070] R 4 For hydrogen atoms, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or 3-12 membered cycloalkyl, the C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 The alkynyl or 3-12 membered cycloalkyl group is optionally substituted with one or more methyl, ethyl, halogen, deuterium atom, cyano, hydroxyl, methoxy, cyclopropyl or oxo (=O);

[0071] R5 、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, halogenated C 1-6 Alkyl, 3-6 membered cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, C 1-6 Alkylamino, di(C 1-6 alkyl)amino;

[0072] Or, R 5 With R 6 Together with the C atom to which it is attached, it forms 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 atoms or cyclopropyl groups;

[0073] R 7 is methylene, ethylene or propylene;

[0074] Preferably, L1 is a chemical bond, O, NR 4 , CR 5 R 6 、-OR 7 - or C(=O);

[0075] 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;

[0076] R 5 、R 6 each independently represents 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;

[0077] Or, R 5 With R 6 Together with the C atom to which it is attached, it forms a cyclopropyl or cyclobutyl group, wherein the cyclopropyl or cyclobutyl group is optionally substituted by one or more methyl groups, ethyl groups, halogen groups, deuterium atoms or cyclopropyl groups;

[0078] R 7 For methylene.

[0079] In certain embodiments, L2 is a chemical bond or NR 4 ;

[0080] R 4 For hydrogen atoms, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or 3-12 membered cycloalkyl, the C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 The alkynyl or 3-12 membered cycloalkyl group is optionally substituted with one or more methyl, ethyl, halogen, deuterium atom, cyano, hydroxyl, methoxy, cyclopropyl or oxo (=O);

[0081] Preferably, L2 is a chemical bond or NR 4 ;

[0082] 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.

[0083] In certain embodiments, L3 is NR 4 ;

[0084] R 4 For hydrogen atoms, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or 3-12 membered cycloalkyl, the C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 The alkynyl or 3-12 membered cycloalkyl group is optionally substituted with one or more methyl, ethyl, halogen, deuterium atom, cyano, hydroxyl, methoxy, cyclopropyl or oxo (=O);

[0085] Preferably, L3 is NR 4 ;

[0086] 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.

[0087] In certain embodiments, L4 is O or CR 5 R 6 ;

[0088] R 5 、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, halogenated C 1-6 Alkyl, 3-6 membered cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, C 1-6 Alkylamino, di(C 1-6 alkyl)amino;

[0089] Or, R 5 With R 6 Together with the C atom to which it is attached, it forms 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 atoms or cyclopropyl groups;

[0090] Preferably, L4 is O or CR 5 R 6 ;

[0091] R 5 、R 6 each independently represents 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;

[0092] Or, R 5 With R 6 Together with the attached C atom, it forms a cyclopropyl or cyclobutyl group, which is optionally substituted by one or more methyl, ethyl, halogen, deuterium atoms or cyclopropyl groups.

[0093] In certain embodiments, M is C=O or S(=O)2;

[0094] Preferably, M is C=O;

[0095] In certain embodiments, Y 1 N or CR a ;

[0096] R a For hydrogen atoms, deuterium atoms, halogens, cyano groups, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4Alkynyl, 4-10 membered heterocyclic group, OR a1 SR a1 or NR a1 , the C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 4-10 membered heterocyclyl are optionally substituted by one or more R';

[0097] R a1 For hydrogen atoms, C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, 3-6 membered cycloalkyl-C 1-6 Alkyl or 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2 1-6 Alkyl, the C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, 3-6 membered cycloalkyl-C 1-6 Alkyl or 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2 1-6 The alkyl group is optionally substituted with one or more halogens, deuterium atoms, methyl groups, ethyl groups, or oxo groups;

[0098] 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);

[0099] Preferably, Y 1 N or CR a ;

[0100] R ais 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- 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.

[0101] In certain embodiments, Y 2 N or CR b ;

[0102] R b For hydrogen atoms, deuterium atoms, halogens, cyano groups, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 4-10 membered heterocyclic group, OR a1 SR a1 or NR a1 , the C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 4-10 membered heterocyclyl are optionally substituted by one or more R';

[0103] R a1 For hydrogen atoms, C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, 3-6 membered cycloalkyl-C 1-6 Alkyl or 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2 1-6 Alkyl, the C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, 3-6 membered cycloalkyl-C 1-6 Alkyl or 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2 1-6The alkyl group is optionally substituted with one or more halogens, deuterium atoms, methyl groups, ethyl groups, or oxo groups;

[0104] Or, R b With R d Together with the atoms to which they are attached, they 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, which is optionally substituted with one or more R's;

[0105] 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);

[0106] Preferably, Y 2 N or CR b ;

[0107] 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- 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;

[0108] Or, R b With R dand 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 benzophenone, 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.

[0109] In certain embodiments, Y 3 N or CR c ;

[0110] 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's;

[0111] 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);

[0112] Preferably, Y 3 N or CR c ;

[0113] 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.

[0114] In certain embodiments, Y 4 N or CR d ;

[0115] R dis 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;

[0116] Or, R b With R d Together with the atoms to which they are attached, they 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's;

[0117] 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);

[0118] Preferably, Y 4 N or CR d ;

[0119] R b With R d and 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 benzophenone, 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.

[0120] In certain embodiments, Y 5 N, CR e or C; when L2 is a chemical bond, Y 5 N; when L2 is O or NR 4 When Y5 CR e or C;

[0121] Preferably, Y 5 is N, CH or C; when L2 is a chemical bond, Y 5 N; when L2 is O or NR 4 When Y 5 is CH or C.

[0122] In certain embodiments, R 1 is a halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, epoxypropanyl, cyclobutenyl, cyclopentenyl or cyclohexenyl group, wherein the halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, epoxypropanyl, cyclobutenyl, cyclopentenyl or cyclohexenyl group 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 Substituted, the methyl, ethyl, cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl, propylene oxide, butylene oxide, phenyl or pyridinyl is optionally substituted with one or more R';

[0123] R x 、R y each independently represents a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, an adamantyl group, a methoxyethyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopropylethyl group, a cyclobutylethyl group, an azetidinylmethyl group or an azetidinylethyl group, wherein the methyl group, the ethyl group, the isopropyl group, the cyclopropyl group, the cyclobutyl group, the cyclopentyl group, an adamantyl group, a methoxyethyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopropylethyl group, a cyclobutylethyl group, an azetidinylmethyl group or an azetidinylethyl group is optionally substituted by one or more R′;

[0124] Alternatively, NR x R y Middle R x With R y and the N atom to which it is attached form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl, or 2-azabicyclo[3.1.0]hexanyl, said azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl, or 2-azabicyclo[3.1.0]hexanyl, said azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl, or 2-azabicyclo[3.1.0]hexanyl being optionally substituted with one or more R′;

[0125] 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)

[0126] Preferably, R 1 Selected from the following groups:

[0127] In certain embodiments, R 2 For hydrogen atoms, deuterium atoms, cyano groups, halogens, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1- 4-alkyl, deuterated C 1-4 Alkyl, 3-6 membered cycloalkyl, C 1-4 Alkoxy-C 1-4 Alkyl, halogenated C 1-4 Alkoxy or oxo (=O), the C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-4 Alkyl, deuterated C 1-4 Alkyl, 3-6 membered cycloalkyl, C 1-4 Alkoxy-C 1-4 Alkyl, halogenated C 1-4 Alkoxy is optionally substituted with one or more R';

[0128] Or, R b With R 2 Together with the atoms to which they are attached, they 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, 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 with one or more R′;

[0129] 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);

[0130] Or, R b With R 2 Together with the atoms to which it is attached, it forms 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, the morpholinyl, 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 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.

[0131] In certain embodiments, R 3 For hydrogen atoms, deuterium atoms, halogens, cyano groups, nitro groups, 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, OR e 、SOR e 、S(O)2R e 、C(=O)R e 、C(=O)NR e NR e R f NR e C(=O)R f 、S(O)2NR 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 is optionally substituted with one or more R';

[0132] R e、R f are independently a hydrogen atom, a deuterium atom, a C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-12 membered cycloalkyl;

[0133] Alternatively, NR e R f Middle R e and R f Together with the nitrogen atom to which it is attached, it forms a 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, and S(O)2;

[0134] 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, SOCH3, S(O)2CH3, C(=O)CH3, C(=O)NCH3, NHC(=O)CH3, S(O)2NCH3, P(O)(CH3)2, or P(O)(CH2CH3)2 , the methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoroethyl, trifluoroethyl, hydroxy, methoxy, ethoxy, methylamino, ethylamino, SOCH3, S(O)2CH3, C(=O)CH3, C(=O)NCH3, NHC(=O)CH3, S(O)2NCH3, P(O)(CH3)2 or P(O)(CH2CH3)2 are optionally substituted by one or more deuterium atoms, F, Cl, hydroxy, methyl, ethyl, isopropyl or cyclopropyl.

[0135] In certain embodiments, in Formula I, R b With R d Together with the atoms to which they are attached, they 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';

[0136] Or, R b With R 2 Together with the atoms to which they are attached, they 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';

[0137] 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.

[0138] In certain embodiments, the compound of formula I further has a structure of formula II,

[0139] 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;

[0140] Ring E is phenyl or a 5-6 membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O and S;

[0141] 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;

[0142] 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;

[0143] L1 is a chemical bond, O, NR 4 , CR 5 R 6 、-OR 7 - or C(=O);

[0144] L2 is a chemical bond or NR 4 ;

[0145] L3 for NR 4 ;

[0146] L4 is O or CR 5 R 6 ;

[0147] M is C=O or S(=O)2;

[0148] Y 1 N or CR a ;

[0149] Y 3 N or CR c ;

[0150] Y 5 is N, CH or C; when L2 is a chemical bond, Y 5 N; when L2 is O or NR 4 When Y 5 is CH or C;

[0151] R 1 is a halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, epoxypropanyl, cyclobutenyl, cyclopentenyl or cyclohexenyl group, wherein the halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, epoxypropanyl, cyclobutenyl, cyclopentenyl or cyclohexenyl group 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 Substituted, the methyl, ethyl, cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl, propylene oxide, butylene oxide, phenyl or pyridinyl is optionally substituted with one or more R';

[0152] R 2 For hydrogen atoms, deuterium atoms, cyano groups, halogens, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-4 Alkyl, deuterated C 1-4 Alkyl, 3-6 membered cycloalkyl, C 1-4 Alkoxy-C 1-4 Alkyl, halogenated C 1-4 Alkoxy or oxo (=O), the C 1-6 Alkyl, C 2-4 Alkenyl, C 2- 4-Alkynyl, halo C 1-4 Alkyl, deuterated C 1-4Alkyl, 3-6 membered cycloalkyl, C 1-4 Alkoxy-C 1-4 Alkyl, halogenated C 1-4 Alkoxy is optionally substituted with one or more R';

[0153] R 3 For hydrogen atoms, deuterium atoms, halogens, cyano groups, nitro groups, 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, OR e 、SOR e 、S(O)2R e 、C(=O)R e 、C(=O)NR e NR e R f NR e C(=O)R f 、S(O)2NR 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 is optionally substituted with one or more R';

[0154] R 4 For hydrogen atoms, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or 3-12 membered cycloalkyl, the C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 The 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;

[0155] R 5 、R 6are each independently a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 Alkyl, halogenated C 1-6 Alkyl, 3-6 membered cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, C 1-6 Alkylamino, di(C 1-6 alkyl)amino;

[0156] Or, R 5 With R 6 Together with the C atom to which it is attached, it forms 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 atoms or cyclopropyl groups;

[0157] R 7 is methylene, ethylene or propylene;

[0158] R a For hydrogen atoms, deuterium atoms, halogens, cyano groups, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 4-10 membered heterocyclic group, OR a1 SR a1 or NR a1 , the C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 4-10 membered heterocyclyl are optionally substituted by one or more R';

[0159] R a1 For hydrogen atoms, C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, 3-6 membered cycloalkyl-C 1-6 Alkyl or 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2 1-6 Alkyl, the C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, 3-6 membered cycloalkyl-C 1-6 Alkyl or 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2 1-6 The alkyl group is optionally substituted with one or more halogens, deuterium atoms, methyl groups, ethyl groups, or oxo groups;

[0160] R cis 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;

[0161] R x 、R y each independently represents a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, an adamantyl group, a methoxyethyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopropylethyl group, a cyclobutylethyl group, an azetidinylmethyl group or an azetidinylethyl group, wherein the methyl group, the ethyl group, the isopropyl group, the cyclopropyl group, the cyclobutyl group, the cyclopentyl group, an adamantyl group, a methoxyethyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopropylethyl group, a cyclobutylethyl group, an azetidinylmethyl group or an azetidinylethyl group is optionally substituted by one or more R′;

[0162] Alternatively, NR x R y Middle R x With R y and the N atom to which it is attached form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl, or 2-azabicyclo[3.1.0]hexanyl, said azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl, or 2-azabicyclo[3.1.0]hexanyl, said azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl, or 2-azabicyclo[3.1.0]hexanyl being optionally substituted with one or more R′;

[0163] R e 、R f are independently a hydrogen atom, a deuterium atom, a C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-12 membered cycloalkyl;

[0164] Alternatively, NR e R f Middle R e and R f Together with the nitrogen atom to which it is attached, it forms a 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, and S(O)2;

[0165] -- / --- is none or chemical bond;

[0166] Ring B is pyrrole, imidazole, pyrazole, thiazole, oxazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine or triazine;

[0167] X a 、X b 、X c are each independently N or CH;

[0168] X 1 is a chemical bond, N, CH, CH2, S, O, S(O) or S(O)2;

[0169] X 2 is N, CH, CH2, O, S, S(O) or S(O)2;

[0170] X 3 、X 4 are each independently N or C, and X 3 and X 4 Not N, X at the same time 1 、X 2 and X 3 Not all N at the same time;

[0171] X 5 is a chemical bond, N, CH, CH2, O or S;

[0172] X 6 is N, O, S or CH;

[0173] R' is independently a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-4 Alkyl, deuterated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, 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 or oxo (=O);

[0174] m, n, and t are each independently 0, 1, 2, 3, 4, or 5.

[0175] In certain embodiments, the compound of formula I further has a structure of formula III,

[0176] 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 cycloalkyl group;

[0177] Ring E is phenyl or a 5-6 membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O and S;

[0178] 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;

[0179] W is N, C or CR a ;

[0180] 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;

[0181] L1 is a chemical bond, O, NR 4 , CR 5 R 6 、-OR 7 - or C(=O);

[0182] L2 is a chemical bond or NR 4 ;

[0183] L3 for NR 4 ;

[0184] L4 is O or CR 5 R 6 ;

[0185] M is C=O or S(=O)2;

[0186] Y 1 N or CR a ;

[0187] Y 3 N or CR c ;

[0188] Y 4 N or CR d ;

[0189] Y 5 is N, CH or C; when L2 is a chemical bond, Y 5 N; when L2 is O or NR 4 When Y 5 is CH or C;

[0190] R 1is a halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, epoxypropanyl, cyclobutenyl, cyclopentenyl or cyclohexenyl group, wherein the halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, epoxypropanyl, cyclobutenyl, cyclopentenyl or cyclohexenyl group 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 Substituted, the methyl, ethyl, cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl, propylene oxide, butylene oxide, phenyl or pyridinyl is optionally substituted with one or more R';

[0191] R 2 For hydrogen atoms, deuterium atoms, cyano groups, halogens, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-4 Alkyl, deuterated C 1-4 Alkyl, 3-6 membered cycloalkyl, C 1-4 Alkoxy-C 1-4 Alkyl, halogenated C 1-4 Alkoxy or oxo (=O), the C 1-6 Alkyl, C 2-4 Alkenyl, C 2- 4-Alkynyl, halo C 1-4 Alkyl, deuterated C 1-4 Alkyl, 3-6 membered cycloalkyl, C 1-4 Alkoxy-C 1-4 Alkyl, halogenated C 1-4 Alkoxy is optionally substituted with one or more R';

[0192] R 3 For hydrogen atoms, deuterium atoms, halogens, cyano groups, nitro groups, 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, OR e 、SOR e 、S(O)2R e 、C(=O)R e 、C(=O)NR e NR e R f NR e C(=O)R f 、S(O)2NRe 、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 is optionally substituted with one or more R';

[0193] R 4 For hydrogen atoms, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or 3-12 membered cycloalkyl, the C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 The 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;

[0194] R 5 、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, halogenated C 1-6 Alkyl, 3-6 membered cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, C 1-6 Alkylamino, di(C 1-6 alkyl)amino;

[0195] Or, R 5 With R 6 Together with the C atom to which it is attached, it forms 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 atoms or cyclopropyl groups;

[0196] R 7 is methylene, ethylene or propylene;

[0197] R a For hydrogen atoms, deuterium atoms, halogens, cyano groups, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 4-10 membered heterocyclic group, ORa1 SR a1 or NR a1 , the C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 4-10 membered heterocyclyl are optionally substituted by one or more R';

[0198] R a1 For hydrogen atoms, C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, 3-6 membered cycloalkyl-C 1-6 Alkyl or 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2 1-6 Alkyl, the C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, 3-6 membered cycloalkyl-C 1-6 Alkyl or 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2 1-6 The alkyl group is optionally substituted with one or more halogens, deuterium atoms, methyl groups, ethyl groups, or oxo groups;

[0199] 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's;

[0200] 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;

[0201] R x 、R y each independently represents a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, an adamantyl group, a methoxyethyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopropylethyl group, a cyclobutylethyl group, an azetidinylmethyl group or an azetidinylethyl group, wherein the methyl group, the ethyl group, the isopropyl group, the cyclopropyl group, the cyclobutyl group, the cyclopentyl group, an adamantyl group, a methoxyethyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopropylethyl group, a cyclobutylethyl group, an azetidinylmethyl group or an azetidinylethyl group is optionally substituted by one or more R′;

[0202] Alternatively, NR x R y Middle Rx With R y and the N atom to which it is attached form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl, or 2-azabicyclo[3.1.0]hexanyl, said azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl, or 2-azabicyclo[3.1.0]hexanyl, said azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl, or 2-azabicyclo[3.1.0]hexanyl being optionally substituted with one or more R′;

[0203] R e 、R f are independently a hydrogen atom, a deuterium atom, a C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-12 membered cycloalkyl;

[0204] Alternatively, NR e R f Middle R e and R f Together with the nitrogen atom to which it is attached, it forms a 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, and S(O)2;

[0205] -- / --- is none or chemical bond;

[0206] Ring B is pyrrole, imidazole, pyrazole, thiazole, oxazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine or triazine;

[0207] X a 、X b 、X c are each independently N or CH;

[0208] X 1 is a chemical bond, N, CH, CH2, S, O, S(O) or S(O)2;

[0209] X 2 is N, CH, CH2, O, S, S(O) or S(O)2;

[0210] X 3 、X 4 are each independently N or C, and X 3 and X 4 Not N, X at the same time 1 、X 2 and X 3 Not all N at the same time;

[0211] X 5 is a chemical bond, N, CH, CH2, O or S;

[0212] X 6 is N, O, S or CH;

[0213] R' is independently a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-4 Alkyl, deuterated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, 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 or oxo (=O);

[0214] m, n, and t are each independently 0, 1, 2, 3, 4, or 5.

[0215] In certain embodiments, R' is independently a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-4 Alkyl, C 2-4 Alkenyl, C 2- 4-Alkynyl, halo C 1-4 Alkyl, deuterated C 1-4 Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, 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 or oxo (=O);

[0216] Preferably, R' is independently a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-4 Alkyl, deuterated C 1-4 Alkyl, 3-6 membered cycloalkyl, 4-7 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, halogenated C 1-4 Alkoxy or oxo (=O);

[0217] 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).

[0218] In certain embodiments, in Formula I, II or III,

[0219] 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 cycloalkyl group;

[0220] Ring E is phenyl or a 5-6 membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O and S;

[0221] 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;

[0222] L1 is a chemical bond, O, NR 4 , CR 5 R 6 、-OR 7 - or C(=O);

[0223] L2 is a chemical bond or NR 4 ;

[0224] L3 for NR 4 ;

[0225] L4 is O or CR 5 R 6 ;

[0226] M is C=O or S(=O)2;

[0227] Y 1 N or CR a ;

[0228] Y2 N or CR b ;

[0229] Y 3 N or CR c ;

[0230] Y 4 N or CR d ;

[0231] Y 5 is N, CH or C; when L2 is a chemical bond, Y 5 N; when L2 is O or NR 4 When Y 5 is CH or C;

[0232] R 1 is a halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, epoxypropanyl, cyclobutenyl, cyclopentenyl or cyclohexenyl group, wherein the halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, epoxypropanyl, cyclobutenyl, cyclopentenyl or cyclohexenyl group 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 Substituted, the methyl, ethyl, cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl, propylene oxide, butylene oxide, phenyl or pyridinyl is optionally substituted with one or more R';

[0233] R 2 For hydrogen atoms, deuterium atoms, cyano groups, halogens, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-4 Alkyl, deuterated C 1-4 Alkyl, 3-6 membered cycloalkyl, C 1-4 Alkoxy-C 1-4 Alkyl, halogenated C 1-4 Alkoxy or oxo (=O), the C 1-6 Alkyl, C 2-4 Alkenyl, C 2- 4-Alkynyl, halo C 1-4 Alkyl, deuterated C 1-4 Alkyl, 3-6 membered cycloalkyl, C 1-4 Alkoxy-C 1-4 Alkyl, halogenated C 1-4 Alkoxy is optionally substituted with one or more R';

[0234] R 3 For hydrogen atoms, deuterium atoms, halogens, cyano groups, nitro groups, C1-4 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, OR e 、SOR e 、S(O)2R e 、C(=O)R e 、C(=O)NR e NR e R f NR e C(=O)R f 、S(O)2NR 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 is optionally substituted with one or more R';

[0235] R 4 For hydrogen atoms, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or 3-12 membered cycloalkyl, the C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 The 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;

[0236] R 5 、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, halogenated C 1-6 Alkyl, 3-6 membered cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, C 1-6 Alkylamino, di(C 1-6alkyl)amino;

[0237] Or, R 5 With R 6 Together with the C atom to which it is attached, it forms 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 atoms or cyclopropyl groups;

[0238] R 7 is methylene, ethylene or propylene;

[0239] 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;

[0240] W is N, C or CR a ;

[0241] R a 、R b are independently a hydrogen atom, a deuterium atom, a halogen, a cyano group, a C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 4-10 membered heterocyclic group, OR a1 SR a1 or NR a1 , the C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 4-10 membered heterocyclyl are optionally substituted by one or more R';

[0242] 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's;

[0243] R d Does not exist or is a hydrogen atom, deuterium atom, halogen, cyano group, amino group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylmercapto or C 1- 6 alkylamino group, wherein the amino group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylmercapto or C 1-6 Alkylamino is optionally substituted with one or more R';

[0244] R b With R dTogether with the atoms to which they are attached, they 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, which is optionally substituted with one or more R's;

[0245] Or, R b With R 2 Together with the atoms to which they are attached, they 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, 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 with one or more R′;

[0246] R e 、R f are independently a hydrogen atom, a deuterium atom, a C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-12 membered cycloalkyl;

[0247] Alternatively, NR e R f Middle R e and R f Together with the nitrogen atom to which it is attached, it forms a 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, and S(O)2;

[0248] R x 、R y each independently represents a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, an adamantyl group, a methoxyethyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopropylethyl group, a cyclobutylethyl group, an azetidinylmethyl group or an azetidinylethyl group, wherein the methyl group, the ethyl group, the isopropyl group, the cyclopropyl group, the cyclobutyl group, the cyclopentyl group, an adamantyl group, a methoxyethyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopropylethyl group, a cyclobutylethyl group, an azetidinylmethyl group or an azetidinylethyl group is optionally substituted by one or more R′;

[0249] Alternatively, NR x R y Middle R x With R yand the N atom to which it is attached form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl, or 2-azabicyclo[3.1.0]hexanyl, said azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl, or 2-azabicyclo[3.1.0]hexanyl, said azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl, or 2-azabicyclo[3.1.0]hexanyl being optionally substituted with one or more R′;

[0250] R a1 For hydrogen atoms, C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, 3-6 membered cycloalkyl-C 1-6 Alkyl or 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2 1-6 Alkyl, the C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, 3-6 membered cycloalkyl-C 1-6 Alkyl or 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2 1-6 The alkyl group is optionally substituted with one or more halogens, deuterium atoms, methyl groups, ethyl groups, or oxo groups;

[0251] -- / --- is none or chemical bond;

[0252] Ring B is pyrrole, imidazole, pyrazole, thiazole, oxazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine or triazine;

[0253] X a 、X b 、X c are each independently N or CH;

[0254] X 1 is a chemical bond, N, CH, CH2, S, O, S(O) or S(O)2;

[0255] X 2 is N, CH, CH2, O, S, S(O) or S(O)2;

[0256] X 3 、X 4 are each independently N or C, and X 3 and X4 Not N, X at the same time 1 、X 2 and X 3 Not all N at the same time;

[0257] X 5 is a chemical bond, N, CH, CH2, O or S;

[0258] X 6 is N, O, S or CH;

[0259] 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);

[0260] m, n, and t are each independently 0, 1, 2, or 3.

[0261] In other specific embodiments, in Formula I, II or III:

[0262] 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;

[0263] Ring E is phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene or pyrazole;

[0264] Q1 is selected from the following groups: said Q1 is optionally substituted with 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;

[0265] L1 is a chemical bond, O, NR 4 , CR 5 R 6 、-OR 7 - or C(=O);

[0266] L2 is a chemical bond or NR 4 ;

[0267] L3 for NR 4 ;

[0268] L4 is O or CR 5 R 6 ;

[0269] M is C=O;

[0270] 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;

[0271] R 5 、R 6 each independently represents 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;

[0272] Or, R 5 With R 6 Together with the C atom to which it is attached, it forms a cyclopropyl or cyclobutyl group, wherein the cyclopropyl or cyclobutyl group is optionally substituted by one or more methyl groups, ethyl groups, halogen groups, deuterium atoms or cyclopropyl groups;

[0273] R 7 is a methylene group;

[0274] Y 1 N or CR a ;

[0275] Y 2 N or CR b ;

[0276] Y 3 N or CR c ;

[0277] Y 4 N or CR d ;

[0278] Y 5 is N, CH or C; when L2 is a chemical bond, Y 5 N; when L2 is O or NR 4 When Y 5 is CH or C;

[0279] R ais 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- 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;

[0280] 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;

[0281] R b With R d and 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, 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;

[0282] R 1 Selected from the following groups:

[0283] R 2is 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);

[0284] Or, R b With R 2 Together with the atoms to which it is attached, it forms 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, the morpholinyl, 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 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;

[0285] 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, SOCH3, S(O)2CH3, C(=O)CH3, C(=O)NCH3, NHC(=O)CH3, S(O)2NCH3, P(O)(CH3)2, or P(O)(CH2CH3)2 , the methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoroethyl, trifluoroethyl, hydroxy, methoxy, ethoxy, methylamino, ethylamino, SOCH3, S(O)2CH3, C(=O)CH3, C(=O)NCH3, NHC(=O)CH3, S(O)2NCH3, P(O)(CH3)2 or P(O)(CH2CH3)2 is optionally substituted with one or more deuterium atoms, F, Cl, hydroxy, methyl, ethyl, isopropyl or cyclopropyl;

[0286] 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;

[0287] W is C or CH;

[0288] m, n, and t are each independently 0, 1, 2, or 3.

[0289] In yet other specific embodiments, in Formula I, II or III:

[0290] Ring A is piperidinyl, azetidinyl, pyrrolidinyl, piperazinyl, homopiperazine, 1,4-azaoxepane, cyclopentyl, cyclohexyl, or 8-azabicyclo[3.2.1]octane;

[0291] Ring E is phenyl;

[0292] Q1 is selected from the following groups:

[0293] L1 is a chemical bond, O, NR 4 , CR 5 R 6 or C(=O);

[0294] L2 is a chemical bond or NH;

[0295] L3 is NH;

[0296] L4 is O or CR 5 R 6 ;

[0297] M is C=O;

[0298] R 4is 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;

[0299] R 5 、R 6 each independently represents 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;

[0300] Or, R 5 With R 6 Together with the C atom to which it is attached, it forms a cyclopropyl or cyclobutyl group, wherein the cyclopropyl or cyclobutyl group is optionally substituted by one or more methyl groups, ethyl groups, halogen groups, deuterium atoms or cyclopropyl groups;

[0301] Y 1 N or CR a ;

[0302] Y 2 N or CR b ;

[0303] Y 3 is N;

[0304] Y 4 N or CR d ;

[0305] Y 5 is N, CH or C; when L2 is a chemical bond, Y 5 N; when L2 is O or NR 4 When Y 5 is CH or C;

[0306] R ais 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- 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;

[0307] R b With R d and 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, 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;

[0308] R 1 Selected from the following groups:

[0309] R 2is 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);

[0310] Or, R b With R 2 Together with the atoms to which it is attached, it forms 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, the morpholinyl, 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 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;

[0311] 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, 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 groups, methyl groups, ethyl groups, isopropyl groups or cyclopropyl groups;

[0312] 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;

[0313] W is C or CH;

[0314] m, n, and t are each independently 0, 1, 2, or 3.

[0315] In a more specific embodiment, the compound represented by formula I is selected from the following compounds:

[0316] 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:

[0317] (1) Compound II-1 and Compound II-2 undergo a substitution reaction to form Compound II-3;

[0318] (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;

[0319] (3) Compound II-5 reacts with DMF-DMA to form compound II-6;

[0320] (4) Compound II-6 reacts with compound II-7 to form compound II-8;

[0321] (5) deprotection of compound II-8 to form compound II-9;

[0322] (6) Compound II-9 undergoes a substitution reaction with Compound II-10 or Compound II-11 to form a compound represented by Formula II;

[0323] The reaction scheme is shown in Figure 1.

[0324] In certain embodiments, the present invention provides a method for preparing a compound of formula III, comprising the following reaction steps:

[0325] (1) Compound III-1 and compound III-2 undergo a substitution reaction to form compound III-3;

[0326] (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;

[0327] (3) Compound III-5 reacts with DMF-DMA to form compound III-6;

[0328] (4) Compound III-6 reacts with compound III-7 to form compound III-8;

[0329] (5) deprotection of compound III-8 to form compound III-9;

[0330] (6) Compound III-9 undergoes a substitution reaction with Compound III-10 or Compound III-11 to form a compound represented by Formula III;

[0331] The reaction route is shown in Figure 2.

[0332] Among them, in the reaction routes of Figures 1 and 2, A, E, Q1, M, Y 1 、Y 3 、Y 4 、Y 5 、L1、L2、L3、L4、R 1 、R 2 、R 3 , R', G, W, m, n, t are as defined above, X' is NO2 or H; X" is halogen, and Boc is tert-butyloxycarbonyl.

[0333] 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;

[0334] 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.

[0335] 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;

[0336] Preferably, the disease is a tumor disease;

[0337] 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.

[0338] 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.

[0339] Preferably, the disease is a tumor disease;

[0340] 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.

[0341] 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.

[0342] The patient is preferably a mammal, and the mammal is preferably a human.

[0343] In certain embodiments, the administration routes include oral, mucosal, sublingual, ocular, topical, parenteral, rectal, intracisternal, vaginal, peritoneal, bladder, and nasal administration.

[0344] 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.

[0345] 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.

[0346] 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).

[0347] 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, as provided by Remington: In The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000).

[0348] In certain embodiments, HER2 abnormality refers to HER2 gene mutation, HER2 amplification, or HER2 overexpression;

[0349] 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);

[0350] 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.

[0351] 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.

[0352] 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.

[0353] 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.

[0354] 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.

[0355] 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.

[0356] 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.

[0357] 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.

[0358] --- / -- means no or chemical bond.

[0359] Indicates the attachment site.

[0360] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix (C a-b )alkyl represents any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C 1-6 The alkyl group refers to an alkyl group containing 1 to 6 carbon atoms and is branched or linear.

[0361] The atoms described in the compounds of the present invention include their isotopes, for example, hydrogen may be deuterium or tritium.

[0362] "Bridged ring" refers to a polycyclic group in which any two rings share two atoms, directly or indirectly connected, and 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. Preferably, the ring has 7-10 rings.

[0363] "Spirocyclic" refers to a polycyclic group in which any two rings share a common carbon atom. 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. Preferably, the ring has 5-10 rings.

[0364] 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. Five to ten rings are preferred.

[0365] Linked ring: refers to any two or more rings connected by chemical bonds.

[0366] 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.

[0367] 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.

[0368] "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. 1-8 Alkyl. More preferably C 1-6 Alkyl. More preferably C 1-4 Alkyl. The alkyl group may be substituted with one or more substituents or may be unsubstituted. When substituted, the substituents may be substituted at any point of attachment. The substituents are preferably the following groups:

[0369] Deuterium atoms, halogens, cyano groups, nitro groups, azide groups, hydroxyl groups, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 2-6 Heteroalkenyl, 3-12 membered saturated or unsaturated cycloalkyl, 3-12 membered saturated or unsaturated heterocyclic group, C 1-10 Alkoxy, halogenated C1-10 Alkyl, halogenated C 1-10 Alkoxy, deuterated C 1-10 Alkyl, deuterated C 1-10 Alkoxy, 6-10 membered aryl, 5-10 membered heteroaryl, oxo (=O).

[0370] "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:

[0371] "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:

[0372] The cycloalkyl or cycloalkenyl group may be fused with an aryl group, a heteroaryl group or a heterocyclic group, including but not limited to tetrahydronaphthyl, benzocycloheptyl and the like.

[0373] "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-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl. Preferably C 2-6 More preferably C 2-4 Alkenyl.

[0374] "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, but-3-ynyl. 2-6 More preferably C 2-4 Alkynyl.

[0375] "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-.

[0376] "Halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

[0377] "Haloalkyl" refers to an alkyl group as defined herein in which 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), etc.

[0378] "Alkylamino" refers to NH3 substituted by an alkyl group, including but not limited to methylamino, ethylamino, propylamino, isopropylamino, etc.

[0379] "Dialkylamino" refers to a group having the structure N(C 1-6 The group of alkyl)2 includes but is not limited to dimethylamino, diethylamino, methyl(ethyl)amino, dipropylamino, diisopropylamino and the like.

[0380] "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.

[0381] "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:

[0382] 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:

[0383] The heterocyclic group is optionally substituted or unsubstituted, and the substituted substituents are preferably one or more of the following groups: deuterium atoms, halogen, CN, nitro, hydroxyl, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 2-6Heteroalkenyl, 3-12 membered saturated or unsaturated cycloalkyl, 3-12 membered saturated or unsaturated heterocyclic group, halogenated C 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkoxy, deuterated C 1-10 Alkyl, deuterated C 1-10 Alkoxy, 6-10 membered aryl, 5-10 membered heteroaryl, oxo (=O).

[0384] "Heteroaryl" refers to a substituted or unsubstituted 5- or 6-membered monoheteroaromatic ring system, or a substituted or unsubstituted 9- 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.

[0385] 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:

[0386] Heteroaryl is optionally substituted or unsubstituted, and the substituted substituents are preferably one or more of the following groups: deuterium atoms, halogen, CN, nitro, hydroxyl, azido, C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 2-6 Heteroalkenyl, 3-12 membered saturated or unsaturated cycloalkyl, 3-12 membered saturated or unsaturated heterocyclic group, halogenated C 1-10 Alkyl, halogenated C 1-10 Alkoxy, deuterated C 1-10 Alkyl, deuterated C 1-10 Alkoxy, 6-10 membered aryl, 5-10 membered heteroaryl, oxo (=O).

[0387] "Alkoxy" refers to a straight or branched, monovalent, saturated alkyl group bonded to an oxygen atom, including but not limited to methoxy, ethoxy, propoxy, butoxy, isobutoxy, tert-butoxy and other similar groups. 1-8 Alkoxy. More preferably C 1-6 Alkoxy. More preferably C 1-4 Alkoxy.

[0388] "Cycloalkoxy" refers to an -O-cycloalkyl group wherein the cycloalkyl group is as defined above. Preferably, C 3-8Cycloalkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and other similar groups.

[0389] "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.

[0390] "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.

[0391] "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.

[0392] "N-oxide" refers to a compound containing an amine functional group or a heteroaryl compound containing a nitrogen atom, which can be formed by oxidizing one or more nitrogen atoms. + The compound is preferably an N-oxide of a tertiary amine or an N-oxide of a heteroaryl group containing N.

[0393] "Hydrate" refers to an association formed with a certain amount of water.

[0394] "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.

[0395] 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.

[0396] "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.

[0397] 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.

[0398] 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.

[0399] 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). BRIEF DESCRIPTION OF THE DRAWINGS

[0400] Figure 1 is a reaction scheme for preparing the compound of formula II;

[0401] Figure 2 is a reaction scheme for preparing the compound of formula III. DETAILED DESCRIPTION

[0402] The first group of preparation examples: intermediate preparation

[0403] Preparation of tert-butyl (2-(hydroxymethyl)piperidin-4-yl)carbamate

[0404] 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 separated 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] + .

[0405] 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 the reaction was complete, it was cooled to room temperature and filtered. The filtrate was adjusted to an alkaline 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] + .

[0406] 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 a crude product. The crude product is separated and purified by silica gel column chromatography using a methanol / dichloromethane (0-50%) gradient elution to obtain tert-butyl (2-(hydroxymethyl)piperidin-4-yl)carbamate (pale yellow oil, 5.1 g, 68.9%). MS (ESI) + )m / z=231.0[M+H] + .

[0407] Preparation of 5-chloro-2,3-difluoroisonicotinonitrile

[0408] 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).

[0409] 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%).

[0410] 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.

[0411] Preparation of 2-chloro-[1,2,4]triazolo[1,5-a]pyridin-7-ol

[0412] 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]+ .

[0413] 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)Cl2 (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 solution. 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 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] + .

[0414] 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 × 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 (0-10%) as an eluent gradient elution 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] + .

[0415] Preparation of quinazolin-7-ol

[0416] 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, 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 (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 a gradient elution of methanol / dichloromethane (0-10%) as the eluent to obtain quinazolin-7-ol (pale yellow oil, 470 mg, 67.2%). MS (ESI + )m / z=147.1[M+H] + .

[0417] Preparation of 1-methyl-1H-benzo[d][1,2,3]triazol-5-ol

[0418] 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 solution. 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 a 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 (light yellow solid, 1.1 g, 78.6%). MS (ESI + )m / z=150.3[M+H] + .

[0419] Preparation of benzo[d]thiazol-5-ol

[0420] 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 mixture was heated to 100°C and stirred for 1 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 (30 mL). The organic phase was 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 benzo[d]thiazol-5-ol (brown oil, 1.0 g, 28.3%). MS (ESI + )m / z=152.0[M+H] + .

[0421] Preparation of benzo[c][1,2,5]oxadiazole-5-ol

[0422] 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%).

[0423] Preparation of 5-fluoroquinoxalin-6-ol

[0424] 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%).

[0425] 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). Pd2(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 the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was then separated and purified by silica gel column chromatography using a gradient elution of methanol / dichloromethane (0-15%) to obtain 5-fluoroquinoxalin-6-ol (brown solid, 1.2 g, 92.2%). MS (ESI + )m / z=165.0[M+H] + .

[0426] Preparation of 8-fluoroquinoxalin-6-ol

[0427] 8-Fluoroquinoxaline-6-ol was prepared using 5-bromo-3-fluoro-1,2-phenylenediamine and glyoxal as raw materials according to the method for synthesizing 5-fluoroquinoxaline-6-ol. MS(ESI + )m / z=165.1[M+H] + .

[0428] Preparation of 7-fluoroquinoxalin-6-ol

[0429] 7-Fluoroquinoxaline-6-ol was prepared using 5-bromo-4-fluoro-1,2-phenylenediamine and glyoxal as raw materials according to the method for synthesizing 5-fluoroquinoxaline-6-ol. MS(ESI + )m / z=165.1[M+H] + .

[0430] Preparation of Tetrazo[1,5-a]pyridin-7-ol

[0431] 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 x 3). The combined organic phases were washed with saturated brine (100 mL x 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] + .

[0432] 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 obtain tetrazo[1,5-a]pyridin-7-ol (pale yellow oil, 1 g, crude product). MS (ESI + )m / z=137.2[M+H] + .

[0433] Preparation of 1-ethyl-4-hydroxypyridin-2(1H)-one

[0434] 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 bromoethane (1.2 g, 10.94 mmol) were added sequentially. 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 (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 (10%-90%) as the eluent to obtain 4-(benzyloxy)-1-ethylpyridin-2(1H)-one (white solid, 710 mg, 62.4%). MS (ESI + )m / z=230.0[M+H] + .

[0435] Step 2: Under nitrogen protection, 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 replace the hydrogen, and 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 obtain 1-ethyl-4-hydroxypyridin-2(1H)-one (yellow oil, 400 mg, crude product). MS (ESI + )m / z=140.0[M+H] + .

[0436] Preparation of 4-hydroxy-1-isopropylpyridin-2(1H)-one

[0437] 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 temperature was raised to 80°C and stirred for 2 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 (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 (10%-90%) as the eluent to obtain 4-(benzyloxy)-1-isopropylpyridin-2(1H)-one (white solid, 660 mg, 55.0%). MS (ESI) + )m / z=244.2[M+H] + .

[0438] Step 2: Under nitrogen protection, 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, and the hydrogen was replaced. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain 4-hydroxy-1-isopropylpyridin-2(1H)-one (yellow oil, 360 mg, crude product). MS (ESI + )m / z=154.0[M+H] + .

[0439] Preparation of 1-cyclopropyl-4-hydroxypyridin-2(1H)-one

[0440] 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 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 residue was separated and purified by silica gel column chromatography using ethyl acetate / petroleum ether (50%) as eluent to obtain 4-(benzyloxy)-1-cyclopropylpyridin-2(1H)-one (orange-yellow oil, 1.8 g, 75.0%). MS (ESI + )m / z=242.0[M+H] + .

[0441] Step 2: Under nitrogen protection, 4-(benzyloxy)-1-cyclopropylpyridin-2(1H)-one (800.0 mg, 3.31 mmol) was dissolved in methanol and palladium / carbon (25%, 200.0 mg) was added. The hydrogen atmosphere was replaced and the mixture was stirred at room temperature overnight. Filtered and the filtrate was concentrated under reduced pressure to obtain 1-cyclopropyl-4-hydroxypyridin-2(1H)-one (off-white solid, 426 mg, 85.1%). MS (ESI + )m / z=152.0[M+H] + .

[0442] Preparation of 3-ethynyl-1,3-dimethylpyrrolidine

[0443] 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%).

[0444] 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%).

[0445] 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 h. After the reaction is complete, concentrate under reduced pressure to obtain 3-ethynyl-3-methylpyrrolidine (787 mg, crude, colorless oil). MS (ESI + )m / z=110.2[M+H] + .

[0446] 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 solution (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 h. 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] + .

[0447] Preparation of 1-(bromomethyl-d2)-4-chloro-2-fluorobenzene

[0448] 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, water (10 mL) was added, 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 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-d6) δ7.47 (t, J = 8.2 Hz, 1H), 7.39-7.05 (m, 2H), 5.30 (d, J = 1.8 Hz, 1H).

[0449] Step 2: Under nitrogen, (4-chloro-2-fluorophenyl)methane-d2-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-d2)-4-chloro-2-fluorobenzene (pale yellow oil, 4.5 g, 72.1%). 1 H NMR (300MHz, DMSO-d6) δ7.57 (t, J = 8.3 Hz, 1H), 7.51-7.43 (m, 1H), 7.30 (d, J = 8.3 Hz, 1H).

[0450] Preparation of 5-bromo-2-(bromomethyl)-1-chloro-3-fluorobenzene

[0451] 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-d6) δ7.65-7.54 (m, 2H), 5.30 (t, J = 5.5Hz, 1H), 4.53 (dd, J = 5.6, 2.2Hz, 2H).

[0452] 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%).

[0453] Preparation of [1,2,4]triazolo[1,5-a]pyridine-2-d-7-ol-d

[0454] 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] + .

[0455] 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 diboronic acid pinacol ester (2.3 g, 9.03 mmol), Pd(dppf)Cl2 (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 temperature was restored to room temperature, and water (50 mL) was added to the reaction solution. 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 by silica gel column chromatography using a gradient elution of methanol / dichloromethane (0-10%) as the eluent to give 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] + .

[0456] 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), 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 a gradient elution of methanol / dichloromethane (0-10%) to afford 2-chloro-[1,2,4]triazolo[1,5-a]pyridin-7-ol (yellow oil, 800 mg, 79.1%). MS (ESI) + )m / z=170.1[M+H] + .

[0457] Step 4: Under nitrogen protection, 2-chloro-[1,2,4]triazolo[1,5-a]pyridine-7-ol (300.0 mg, 1.77 mmol) was dissolved in deuterated methanol (20 mL), and Pd / C (1.9 g, 17.69 mmol) was added. Then, the deuterium gas was replaced and the temperature was raised to 40°C and stirred for 24 hours. 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 obtain [1,2,4]triazolo[1,5-a]pyridine-2-d-7-ol-d (brown solid, 270 mg, crude product). MS (ESI +)m / z=138.2[M+H] + .

[0458] Preparation of 3-chloro-[1,2,4]triazolo[4,3-a]pyridin-7-ol

[0459] 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 solution 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%) as the eluent to obtain 3-chloro-[1,2,4]triazolo[4,3-a]pyridin-7-ol (light yellow solid, 1.0 g, 91.4%). MS (ESI + )m / z=170.1[M+H] + .

[0460] Preparation of 3-methyl-4-((2-methylquinoxalin-6-yl)oxy)aniline

[0461] Step 1: Under nitrogen, 4-(benzyloxy)benzene-1,2-diamine (1.7 g, 7.93 mmol) was dissolved in acetonitrile (5 mL), 2-oxopropanal (0.57 g, 7.93 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture 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 6-(benzyloxy)-2-methylquinoxaline (yellow oil, 1.7 g, 85.6%). MS (ESI + )m / z=251.1[M+H] + .

[0462] 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] + .

[0463] The second group of preparation examples: Preparation of intermediates A1-A38

[0464] Intermediate A1. Preparation of tert-butyl 8-cyano-7-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidine]-1'-carboxylate

[0465] 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, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 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 silica gel column chromatography using ethyl acetate / petroleum ether (85%-100%) as an eluent for gradient elution to obtain 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] + .

[0466] 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] + .

[0467] 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

[0468] 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 the reaction was complete, 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 separated 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] + .

[0469] 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

[0470] 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] + .

[0471] 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

[0472] Intermediate A4 (yellow solid, 150 mg, 27.2%) was prepared using intermediate A1 and propargyl bromide as raw materials according to the method of intermediate A3. MS (ESI + )m / z=413.1[M+H] + .

[0473] 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

[0474] Intermediate A1 (500.0 mg, 1.34 mmol) was dissolved in acetic acid (10 mL), and a solution of bromine (320.1 mg, 2.00 mmol) in acetic acid (2 mL) was slowly added dropwise. The mixture was 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 separated 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] + .

[0475] 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

[0476] Under nitrogen protection, intermediate A5 (240.0 mg, 0.53 mmol) was dissolved in 1,4-dioxane / water (10 / 1,5 mL). Methylboric acid (34.9 mg, 0.58 mmol), Pd(dppf)Cl2 (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, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 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 silica gel column chromatography using ethyl acetate / petroleum ether (30%-50%) as an eluent by gradient elution to obtain 8-cyano-5-methyl-7-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester (yellow solid, 140 mg, 68.3%). MS (ESI + )m / z=389.2[M+H] + .

[0477] 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

[0478] 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]+ .

[0479] 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

[0480] Step 1 and Step 2: Using 2,3-difluoro-6-nitrobenzonitrile and tert-butyl 3-amino-3-(hydroxymethyl)piperidine-1-carboxylate as raw materials, tert-butyl 8-cyano-7-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,3'-piperidine]-1'-carboxylate (yellow solid) was prepared according to the method for synthesizing intermediate A1. MS (ESI + )m / z=375.1[M+H] + .

[0481] Step 3: Using 8-cyano-7-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,3'-piperidine]-1'-carboxylic acid tert-butyl ester and iodomethane as raw materials, intermediate A8 (yellow oil) was prepared according to the method for synthesizing intermediate A2. MS (ESI + )m / z=389.1[M+H] + .

[0482] Intermediate A9. Preparation of tert-butyl 8-cyano-7-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,3'-pyrrolidine]-1'-carboxylate

[0483] 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] + .

[0484] 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

[0485] 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 raw materials according to the method for synthesizing intermediate A8. MS (ESI + )m / z=360.9[M+H] + .

[0486] Intermediate A11. Preparation of tert-butyl 5-cyano-6-nitro-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-1'-carboxylate

[0487] 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 and water (50 mL) was added to the reaction solution. 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 (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] + .

[0488] 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

[0489] Intermediate A12 (light 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] + .

[0490] 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

[0491] 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, water (50 mL) was added to the reaction solution, and 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] + .

[0492] 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 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 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] + .

[0493] 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

[0494] Intermediate A14 (yellow solid, 900 mg, 92.3%) was prepared using 2,3-difluoroisonicotinonitrile and tert-butyl (3R)-3-(hydroxymethyl)piperazine-1-carboxylate as raw materials under microwave conditions at 80°C according to the method for synthesizing intermediate A13. MS (ESI +)m / z=339.0[M-56+H] + .

[0495] 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

[0496] Intermediate A15 (yellow solid, 1.1 g, 91.9%) was prepared using 2,3-difluoroisonicotinonitrile and tert-butyl 3-hydroxymethylpiperazine-1-carboxylate as raw materials under microwave conditions at 80°C according to the method for synthesizing intermediate A13. MS (ESI + )m / z=395.1[M+H] + .

[0497] 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

[0498] 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] + .

[0499] Step 3: Using 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 as starting material, intermediate A16 (green oil, 800 mg, 83.9%) was prepared according to the second step of intermediate A13. MS (ESI + )m / z=409.2[M+H] + .

[0500] 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

[0501] 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 temperature was restored to room temperature, and ammonium chloride solution (10 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (40 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 silica gel column chromatography using ethyl acetate / petroleum ether (0-100%) as an eluent gradient elution to obtain 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] + .

[0502] Step 2: Using tert-butyl (4-cyano-6,6a,7,8,9,10-hexahydrobipyrido[3,2-b:1',2'-d][1,4]oxazin-8-yl)carbamate as starting material, intermediate A17 (light yellow solid, 470 mg, 68.9%) was prepared according to the second step method of intermediate A13. MS (ESI + )m / z=408.9[M+H] + .

[0503] 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

[0504] Step 1 and Step 2: Using 2,3-difluoro-6-nitrobenzonitrile and (3R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester as raw materials, (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 was prepared according to the synthesis method of intermediate A1. MS(ESI + )m / z=361.2[M+H] + .

[0505] Step 3: 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 starting material, intermediate A18 was prepared according to the second step method of intermediate A13. MS (ESI+ )m / z=383.0[M+H-56] + .

[0506] 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

[0507] Intermediate A19 was prepared using 2,3-difluoro-6-nitrobenzonitrile and tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate as raw materials according to the synthetic method of intermediate A18. MS (ESI + )m / z=382.9[M+H-56] + .

[0508] 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

[0509] Intermediate A20 was prepared using 2,3-difluoro-6-nitrobenzonitrile and tert-butyl (2-(hydroxymethyl)piperidin-4-yl)carbamate as raw materials according to the synthetic method of intermediate A18. MS (ESI + )m / z=397.1[M+H-56] + .

[0510] Intermediate A21. Preparation of tert-butyl 5'-cyano-6'-nitro-3'H-spiro[azetidine-3,2'-benzo[b][1,4]dioxane]-1-carboxylate

[0511] 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 raw materials according to the synthetic method of intermediate A11. MS (ESI + )m / z=370.1[M+Na] + .

[0512] 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

[0513] 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 to the reaction solution. 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 ethyl acetate / petroleum ether (0-100%) as an eluent to obtain 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] + .

[0514] Preparation of intermediates A23-A24

[0515] 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.

[0516] Table 1 Structures and MS data of intermediates A23 and A24

[0517] 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

[0518] 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 and water (10 mL) was added to the reaction solution. 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 ethyl acetate / petroleum ether (0-80%) as an eluent in a gradient elution to obtain 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] + .

[0519] 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

[0520] 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).

[0521] 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 ethyl acetate / petroleum ether (0-50%) as an eluent gradient elution to obtain 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] + .

[0522] 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. (10 mL), filtered, 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 ethyl acetate / petroleum ether (0-100%) as an eluent gradient elution to obtain 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] + .

[0523] 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 solution, 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 ethyl acetate / petroleum ether (0-50%) as an eluent gradient elution to obtain 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] + .

[0524] 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. , stirred at -78 ° C for 3 hours, then the reaction solution was slowly poured into crushed dry ice and stirred until the dry ice evaporated. Ice-cold ammonium bicarbonate solution (150 mL) was added, and the mixture was extracted with ethyl acetate (250 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2-((1-(tert-butyloxycarbonyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)piperidin-4-yl)methyl)-5-chloro-3-fluoroisonicotinic acid (colorless oil, 25 g, crude product). MS (ESI + )m / z=517.2[M+H] + .

[0525] 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 with 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 was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography using ethyl acetate / petroleum ether (0-100%) as an eluent for gradient elution to obtain 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] + .

[0526] 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 × 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 ethyl acetate / petroleum ether (0-50%) as an eluent gradient elution to obtain 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] + .

[0527] 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 to the reaction solution. The mixture was extracted with ethyl acetate (150 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 (0-60%) as the eluent to obtain 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] + .

[0528] 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), cesium carbonate (43.3 g, 132.87 mmol) was added, and 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 separated and purified 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-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] + .

[0529] 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

[0530] 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 × 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 an eluent gradient elution to obtain 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] + .

[0531] Steps 2 to 6: Using tert-butyl 4-(4-chloro-2-fluorobenzyl)-4-formylpiperidine-1-carboxylate as starting material, 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 method of steps 3 to 7 of intermediate A26. MS (ESI + )m / z=397.3[M+H-Boc] + .

[0532] 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 × 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 (0-100%) as an eluent gradient elution to obtain tert-butyl 7'-chloro-8'-cyano-2'H,4'H-spiro[piperidine-4,3'-pyrano[3,2-b]benzene]-1-carboxylate (white solid, 3.6 g, 92.5%). MS (ESI + )m / z=363.1[M+H] + .

[0533] 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

[0534] (S)-7-cyano-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester was prepared using 2,3-difluoro-6-nitrobenzonitrile and (3S)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester as raw materials according to the synthetic method of intermediate A18. MS(ESI + )m / z=383.0[M+H-56] + .

[0535] Intermediate A29. Preparation of tert-butyl 8-chloro-5-cyano-6-nitro-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-1'-carboxylate

[0536] 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%).

[0537] 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%).

[0538] 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%).

[0539] 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 to the reaction solution. The mixture was extracted with ethyl acetate (30 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 ethyl acetate / petroleum ether (0-50%) as an eluent in a gradient elution to obtain 8-chloro-5-cyano-6-nitro-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester (yellow solid, 3.3 g, 70.4%). MS (ESI + )m / z=354.1[M+H-56] + .

[0540] Intermediate A30. Preparation of tert-butyl 8-bromo-5-cyano-6-nitro-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-1'-carboxylate

[0541] 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.

[0542] 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

[0543] 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 temperature was restored to room temperature. Saturated aqueous ammonium chloride (80 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 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 a gradient elution of ethyl acetate / petroleum ether (0-30%) as the eluent to obtain N-Boc-4-((5-chloro-3-fluoropyridin-2-yl)(hydroxy)methyl)piperidine-4-carboxylic acid ethyl ester (colorless transparent oil, 9 g, 77.7%). MS (ESI + )m / z=403.2[M+H] + .

[0544] 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), cooled 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 hour. 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 obtain 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] + .

[0545] 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 obtain 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] + .

[0546] 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, and a saturated aqueous ammonium chloride solution (50 mL) was added to the reaction solution. 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 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] + .

[0547] 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] + .

[0548] 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 × 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 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] + .

[0549] 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 × 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 (0-100%) as an eluent gradient elution 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] + .

[0550] 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), and heat to 60°C and stir for 1 hour. After the reaction is complete, cool to room temperature, filter the reaction solution, 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 product). MS (ESI + )m / z=400.2[M+Na] + .

[0551] 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

[0552] 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%).

[0553] 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] + .

[0554] Step 3: Using tert-butyl 3-hydroxy-3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate and 2,3-difluoro-6-nitrobenzonitrile as raw materials, intermediate A32 was prepared according to the synthetic method of intermediate A11. MS (ESI + )m / z=346.1[M+H-56] + .

[0555] Preparation of intermediates A33 and A34

[0556] 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.

[0557] Table 2 Structures, raw materials and MS data of intermediates A33 and A34

[0558] 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

[0559] 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, sodium bicarbonate aqueous solution (10 mL) was added to the reaction solution at 0°C, 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 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'-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] + .

[0560] Intermediate A36. Preparation of tert-butyl 7-chloro-8-cyano-4-oxospiro[chromane-3,4'-piperidine]-1'-carboxylate

[0561] 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, N-Boc-4-((4-chloro-3-cyano-2-fluorophenyl)(hydroxy)methyl)piperidine-4-carboxylate (yellow oil, 3 g, 57.0%) was prepared according to the method for synthesizing intermediate A31, step 1. MS (ESI + )m / z=449.1[M+Na] + .

[0562] Step 2: Under nitrogen, dissolve methyl N-Boc-4-((4-chloro-3-cyano-2-fluorophenyl)(hydroxy)methyl)piperidine-4-carboxylate (3.0 g, 7.03 mmol) in tetrahydrofuran (50 mL). The temperature was lowered 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] + .

[0563] 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] + .

[0564] 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) was prepared according to the procedure of Step 8 of Synthesis of Intermediate A31. MS (ESI + )m / z=320.1[M+H-56] + .

[0565] Intermediate A37. Preparation of tert-butyl 6-cyano-7-nitro-3,4-dihydrospiro[benzo[b][1,4]dioxin-2,4'-piperidine]-1'-carboxylate

[0566] 6-Cyano-7-nitro-3,4-dihydrospiro[benzo[b][1,4]dioxin-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester (yellow solid) was prepared using 2,3-fluoro-6-nitrobenzonitrile and tert-butyl 4-hydroxy-4-(2-hydroxyethyl)piperidine-1-carboxylate as raw materials according to the method for synthesizing intermediate A11 at 120°C. + )m / z=412.2[M+Na] + .

[0567] 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

[0568] 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 raw materials according to the method for synthesizing intermediate A11 at 120°C. MS (ESI + )m / z=336.1[M+H-56] +

[0569] The third group of preparation examples: preparation of intermediates B1-B49

[0570] Intermediate B1. Preparation of 2-methoxy-5-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline

[0571] 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 the reaction is complete, cool to room temperature and concentrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography using methanol / dichloromethane (10%) as the eluent to obtain 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] + .

[0572] 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] + .

[0573] Preparation of intermediates B2-B8, B11-B29, B34-B49

[0574] 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.

[0575] The first step substitution reaction can also be prepared by the following conditions: Na2CO3 / K2CO3, DMF, 80°C; K2CO3, DMSO, 100°C. The second step reduction reaction conditions can also be prepared by the following conditions: ammonium chloride and iron powder, ethanol / water, 80°C~90°C; ammonium chloride and iron powder, methanol / water, 60°C~80°C; palladium carbon (50%) and hydrogen, methanol, rt.

[0576] Table 3 Structures and MS data of intermediates B2-B8, B11-B29, B34-B49

[0577] Intermediate B9. Preparation of 2-fluoro-5-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline

[0578] Step 1: Using 1-chloro-5-fluoro-4-methyl-2-nitrobenzene and 1-methyl-1H-benzo[d]imidazol-5-ol as raw materials, 5-(5-chloro-2-methyl-4-nitrophenoxy)-1-methyl-1H-benzo[d]imidazole was prepared according to the method of the first step of the synthesis of intermediate B1. MS (ESI +)m / z=318.1[M+H] + .

[0579] 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 obtain 5-(5-fluoro-2-methyl-4-nitrophenoxy)-1-methyl-1H-benzo[d]imidazole (yellow solid, 4.2 g, crude product). Used directly in the next step without purification. MS (ESI) + )m / z=301.9[M+H] + .

[0580] 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 of Step 2 of Synthesis of Intermediate B1. MS (ESI + )m / z=272.2[M+H] + .

[0581] Intermediate B10. Preparation of 2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline

[0582] 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 as starting materials according to the method for synthesizing intermediate B9. MS (ESI + )m / z=272.2[M+H] + .

[0583] Intermediate B30. Preparation of 4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylaniline

[0584] 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), and 1-bromomethyl-2-methyl-4-nitrobenzene (1.1 g, 4.90 mmol), potassium carbonate (1.7 g, 12.24 mmol) and Pd(DTBPF)Cl2 (265.6 mg, 0.41mmol), heated to 60℃ and stirred for 1h. After the reaction was complete, cooled to room temperature, water (30mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50mL×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 ethyl acetate / petroleum ether (10-70%) as an eluent gradient elution to obtain 7-(2-methyl-4-nitrobenzyl)-[1,2,4]triazolo[1,5-a]pyridine (yellow solid, 300mg, 27.4%). MS (ESI + )m / z=269.1[M+H] + .

[0585] 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 × 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 obtain 4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylaniline (yellow oily product, 180 mg, 67.7%). MS (ESI + )m / z=239.2[M+H] + .

[0586] Intermediate B31. Preparation of 4-((3-chloroimidazo[1,2-a]pyridin-7-yl)oxy)-3-methylaniline

[0587] 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 to the reaction solution. The mixture was extracted with dichloromethane / methanol (3 / 1 v / v, 30 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 silica gel column chromatography using methanol / dichloromethane (15%) as eluent to obtain imidazo[1,2-a]pyridin-7-ol (yellow oil, 1.0 g, 73.2%). MS (ESI + )m / z=157.1[M+Na] + .

[0588] 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] + .

[0589] Step 3: Dissolve 7-(2-methyl-4-nitrophenoxy)imidazole[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 h. After the reaction is complete, add water (30 mL) to the reaction solution, extract the mixture 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)imidazole[1,2-a]pyridine (yellow solid, 360 mg, 31.9%). MS (ESI) +)m / z=304.1[M+H] + .

[0590] Step 4: Using 3-chloro-7-(2-methyl-4-nitrophenoxy)imidazo[1,2-a]pyridine as the starting material, prepare 4-((3-chloroimidazo[1,2-a]pyridin-7-yl)oxy)-3-methylphenylamine according to the method of Step 2 of Intermediate B1. MS (ESI + )m / z=274.0[M+H] + .

[0591] Intermediate B32. Preparation of 4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylaniline

[0592] 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), and 1-(bromomethyl)-2-methyl-4-nitrobenzene (1.1 g, 4.90 mmol), potassium carbonate (1.7 g, 12.24 mmol) and Pd(dtbpf)Cl2 (265.6 mg, 0.41mmol), heated to 60℃ and stirred for 1h. After the reaction was complete, cooled to room temperature, water (30mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50mL×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 ethyl acetate / petroleum ether (0-70%) as an eluent to obtain 7-(2-methyl-4-nitrobenzyl)-[1,2,4]triazolo[1,5-a]pyridine (yellow solid, 300mg, 27.4%). MS (ESI + )m / z=269.1[M+H] + .

[0593] 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 × 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 obtain 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] + .

[0594] Intermediate B33. Preparation of 3-chloro-2-fluoro-4-(quinoxalin-6-yloxy)aniline

[0595] 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 raw materials according to the method for synthesizing intermediate B9. MS (ESI + )m / z=290.0[M+H] + .

[0596] The fourth group of preparation examples: Preparation of intermediates C1-C45

[0597] 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

[0598] 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 obtain the crude product. The crude product was isolated and purified by silica gel column chromatography using methanol / dichloromethane (10%) as the eluent to obtain 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] + .

[0599] 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 h. After the reaction is complete, cool to room temperature and concentrate under reduced pressure to obtain tert-butyl 8-cyano-7-(((dimethylamino)methylene)amino)-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidine]-1'-carboxylate (yellow oil, 170 mg, crude). MS (ESI) + )m / z=400.3[M+H] + .

[0600] Preparation of intermediates C2-C11, C18-C24, C35, and C43

[0601] 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.

[0602] Table 4 Structures, raw materials, reaction conditions and MS data of intermediates C2-C11, C18-C24, C35 and C43

[0603] 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

[0604] 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), Pd2(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, 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 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 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] + .

[0605] 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 h. After the reaction is complete, the reaction solution is blown dry with nitrogen, and appropriate amounts of water and acetonitrile are added, and the mixture is lyophilized to obtain 7'-amino-2'H,4'H-spiro[piperidine-4,3'-pyrido[3,2-b][1,4]oxazine]-8'-carbonitrile (yellow solid, 350 mg, crude product). MS (ESI + )m / z=246.2[M+H] + .

[0606] 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 × 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 (50%) as an eluent for gradient elution to obtain tert-butyl 7'-amino-8'-cyano-2'H,4'H-spiro[piperidine-4,3'-pyrido[3,2-b][1,4]oxazine]-1-carboxylate (light yellow oil, 120 mg, 24.4%). MS (ESI + )m / z=346.3[M+H] + .

[0607] Step 4: Using tert-butyl 7'-amino-8'-cyano-2'H,4'H-spiro[piperidine-4,3'-pyrido[3,2-b][1,4]oxazine]-1-carboxylate as starting material, intermediate C12 (brown oil, 100 mg, crude) was prepared according to the second step method for the synthesis of intermediate C1. MS (ESI + )m / z=401.0[M+H] + .

[0608] Preparation of intermediates C25-C31, C36-C38, and C45

[0609] 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.

[0610] Table 5 Structures, raw materials and MS data of intermediates C25-C31, C36-C38 and C45

[0611] 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

[0612] 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, 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 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 (light yellow solid, 580 mg, 61.2%). MS (ESI + )m / z=347.2[M+H] + .

[0613] Step 2: Using 7'-amino-8'-cyano-2'H-spiro[piperidine-4,3'-[1,4]dioxane[2,3-b]pyridine]-1-carboxylic acid tert-butyl ester as starting material, intermediate C13 (yellow oil, 200 mg, crude product) was prepared according to the second step method of intermediate C1. MS (ESI + )m / z=402.2[M+H] + .

[0614] 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

[0615] 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 solution, 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)-3-amino-4-cyano-6a,7,9,10-tetrahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine-8-carboxylic acid tert-butyl ester (yellow oil, 590 mg, 78.1%). MS (ESI + )m / z=332.0[M+H] + .

[0616] Step 2: Using (R)-3-amino-4-cyano-6a,7,9,10-tetrahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine-8-carboxylic acid tert-butyl ester as starting material, intermediate C14 (brown oil, 600 mg, crude) was prepared according to the second step method of intermediate C1. MS (ESI + )m / z=387.2[M+H] + .

[0617] Preparation of intermediates C15-C17

[0618] 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.

[0619] Table 6 Structures, raw materials and MS data of intermediates C15-C17

[0620] 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

[0621] 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 h. 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 ethyl acetate / petroleum ether (0-80%) as the eluent gradient elution to obtain (E)-5-cyano-6-((dimethylamino)methylene)amino)-8-methoxy-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester (yellow solid, 130 mg, 87.5%). MS (ESI + )m / z=431.2[M+H] + .

[0622] 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

[0623] (E)-5-Cyano-6-((dimethylamino)methylene)amino)-8-ethoxy-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester (Intermediate C23) was used as the starting material and ethanol as the solvent. The method for synthesizing Intermediate C32 was used to prepare (E)-5-Cyano-6-((dimethylamino)methylene)amino)-8-ethoxy-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-1'-carboxylate. MS (ESI + )m / z=445.4[M+H] + .

[0624] 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

[0625] 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, 400 mg, 0.92 mmol) was dissolved in N,N-dimethylformamide (6 mL). Zinc cyanide (432 mg, 3.68 mmol), Pd(dppf)Cl2 (168.2 mg, 0.23 mmol), and polymethylhydrogensiloxane (PMHS, 818.5 mg, 3.68 mmol) were added with stirring. The temperature was raised to 130°C and stirred for 12 min. h. After the reaction was complete, the mixture was cooled to room temperature and water (50 mL) was added to the reaction solution. 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 using a gradient elution of methanol / dichloromethane (0-10%) as the eluent to obtain (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] + .

[0626] 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

[0627] 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 and water (5 mL) was added to the reaction solution. 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 obtain tert-butyl 7'-amino-8'-cyano-4'-oxo-2'H,4'H-spiro[piperidine-4,3'-pyrano[3,2-b]pyridine]-1-carboxylate (yellow solid, 140 mg, 73.8%). MS (ESI + )m / z=259.1[M+H-100]+ .

[0628] 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 method for the second step of the synthesis of intermediate C1. MS (ESI + )m / z=414.2[M+H] + .

[0629] 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

[0630] 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 and water (25 mL) was added to the reaction solution. 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 give 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] + .

[0631] Preparation of Intermediate C41 and Intermediate C42

[0632] Intermediates C41 and C42 were prepared using commercially available deuterated iodomethane or iodoethane as starting materials, following the method for synthesizing intermediate C40, as shown in Table 7.

[0633] Table 7 Structures and MS data of intermediates C41 and C42

[0634] Preparation of Intermediate C44. N'-(2-cyano-4-hydroxy-3-methoxyphenyl)-N,N-dimethylformamidine

[0635] 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 refluxed with stirring 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 obtain 6-amino-3-bromo-2-methoxybenzonitrile (pale yellow solid, 8.0 g, 75.8%). MS (ESI + )m / z=226.9[M+H] + .

[0636] 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 obtain N'-(4-bromo-2-cyano-3-methoxyphenyl)-N,N-dimethylformamidine (yellow solid, 9 g, crude product). MS (ESI + )m / z=282.0[M+H] + .

[0637] 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 to the reaction solution. 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 × 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 (20%) as the eluent to obtain 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] + .

[0638] The fifth group of preparation examples: preparation of final product

[0639] 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)

[0640] 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 and water (10 mL) was added to the reaction solution. 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 to obtain a crude product. The crude product was separated and purified by silica gel column chromatography using methanol / dichloromethane (1 / 9) as eluent to obtain 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 (yellow solid, 80 mg, 47.8%). MS (ESI + )m / z=608.5[M+H] + .

[0641] Step 2: 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]oxazin[2,3-f]quinazoline]-1-carboxylate (70.0 mg, 0.12 mmol) was dissolved in dichloromethane / trifluoroacetic acid (4 mL, 3 / 1 v / v) and stirred at room temperature for 0.5 h. 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)-2'H,4'H-spiro[piperidin-4,3'-[1,4]oxazin[2,3-f]quinazoline]-10'-amine (yellow oil, 120 mg, crude). MS (ESI) + )m / z=508.4[M+H] + .

[0642] 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 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 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[piperidin-4,3'-[1,4]oxazino[2,3-f]quinazolin]-1-yl)prop-2-en-1-one (final product 1).

[0643] Pale yellow solid.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).

[0644] 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

[0645] 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.

[0646] 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

[0647] 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)

[0648] Step 1: Using Intermediate C5 and Intermediate B7 as raw 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 Step 1 in Example 1. MS (ESI + )m / z=686.4[M+H] + .

[0649] 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 the reaction was complete, the mixture was cooled to room temperature and 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 (10%-15%) as the eluent to obtain 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] + .

[0650] 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.

[0651] Yellow solid.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),7.5 6(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,3 H),6.13(dd,J=16.7,2.5Hz,1H),5.70(dd,J=10.4,2.5Hz,1H),5.51(s,1H),4.37-4.2 9(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).

[0652] 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)

[0653] Step 1: Starting 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 the final product 1. MS (ESI + )m / z=621.2[M+H] + .

[0654] 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 give 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] + .

[0655] 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 give 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] + .

[0656] 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.

[0657] Yellow solid.MS(ESI + )m / z=579.3[M+H] + . 1 H 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).

[0658] Example 133. Preparation of final product 126

[0659] 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.

[0660] Table 9 Structure and NMR or MS data of final product 126

[0661] 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)

[0662] 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]dioxane[2,3-f]quinazoline]-1-carboxylate (pale yellow solid, 400 mg, 59.7%) was prepared according to the method for synthesizing the final product 1, Step 1. MS (ESI + )m / z=671.1[M+H] + .

[0663] 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 the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was separated by silica gel column chromatography using a gradient elution of methanol / dichloromethane (0-10%) as the eluent to give 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 (pale yellow solid, 280 mg, 68.2%). MS (ESI + )m / z=689.2[M+H] + .

[0664] 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 × 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 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 (pale yellow solid, 250 mg, crude product). MS (ESI + )m / z=617.5[M+H] + .

[0665] 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.

[0666] White solid.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,2 H),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).

[0667] 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)

[0668] 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] + .

[0669] 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 × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was chromatographed on a silica gel column using ethyl acetate / petroleum ether (33%) as an eluent to obtain 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] + .

[0670] 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 h. After the reaction is complete, concentrate under reduced pressure to give N-(3-chloro-4-(quinoxalin-6-yloxy)phenyl)-5-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine (yellow oil, 150 mg, crude product). MS (ESI) + )m / z=529.2[M+H] + .

[0671] 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.

[0672] Yellow solid.MS(ESI + )m / z=583.2[M+H] + . 1 H 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=10.5,2.4H z,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).

[0673] 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)

[0674] 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 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 (0-10%) 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] + .

[0675] 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 and water (10 mL) was added to the reaction solution. 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 resulting residue was separated by silica gel column chromatography using a gradient elution of methanol / dichloromethane (0-15%) as the eluent to give 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] + .

[0676] 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.

[0677] Yellow solid.MS(ESI + )m / z=573.2[M+H] + . 1 H 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).

[0678] 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)

[0679] 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 the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography using a gradient elution of methanol / dichloromethane (0%-15%) as the eluent to give 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] + .

[0680] 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 were added in sequence. (PPh3)2Cl2 (52.0 mg, 0.10 mmol), heated to 90°C and stirred for 1 h. After the reaction was complete, cooled to room temperature and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography using methanol / dichloromethane (0%-15%) as an eluent gradient elution to obtain 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] + .

[0681] 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 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 to give 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] + .

[0682] 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) L), trifluoroacetic acid (1 mL) was added, stirred at room temperature for 20 min, and concentrated under reduced pressure to give 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 (yellow oil, 140 mg, crude product). MS (ESI + )m / z=518.3[M+H] + .

[0683] 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), and triethylamine (152.5 mg, 1.51 mmol) was added to adjust the pH to >7. Acrylic anhydride (31.7 mg, 0.25 mmol) was added and 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 resulting 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.

[0684] Yellow solid.MS(ESI + )m / z=572.3[M+H] + . 1 H 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).

[0685] Examples 138-143. Preparation of final products 91, 164-167, 171

[0686] 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.

[0687] Table 10 Structures, reaction intermediates and NMR or MS data of final products 91, 164-167, 171

[0688] 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)

[0689] 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 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 resulting residue was separated and purified by silica gel column chromatography using a gradient elution of methanol / dichloromethane (0-10%) as the 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] + .

[0690] 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 min. After the reaction was complete, the mixture was concentrated under reduced pressure to give 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 (black oil, 180 mg, crude product). MS (ESI) + )m / z=579.5[M+H] + .

[0691] 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). Triethylamine (89.18 mg, 0.882 mmol) was added dropwise to adjust the pH to >7. Acrylic anhydride (18.52 mg, 0.147 mmol) was then 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. The mixture was extracted with ethyl acetate (30 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 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.

[0692] White solid.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,1 H),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).

[0693] Comparative Compound A

[0694] 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.

[0695] Pale yellow solid.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=1 2.9Hz,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).

[0696] Experimental Example 1 Cell proliferation inhibition experiment

[0697] CellTiter-Glo TM The live cell detection kit uses luciferase as a detector, and luciferase requires the participation of ATP in the luminescence process. Add CellTiter-Glo to the cell culture medium. TM 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 using the CellTiter-Glo kit to measure ATP content, cell proliferation can be monitored.

[0698] In this experiment, the Celltiter-Glo (CTG) method was used to measure the proliferation inhibitory effect of the above-prepared compounds in the tumor cell line HER2 775-776insYVMA Ba / F3 cell line, and the 50% inhibitory concentration IC was calculated. 50 .

[0699] 1. Experimental Design

[0700] Compounds were tested on selected cells and vehicle controls were set up for a total of 9 concentrations, with 2 replicates for each concentration.

[0701] 2. Reagents and Consumables

[0702] 3. Experimental Procedure

[0703] 3.1 Cell culture

[0704] 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%.

[0705] b) Cell culture medium: RPMI1640, 10% FBS, 1% P / S. Adjust the cell concentration and add 95 μL or 90 μL of cell suspension to a 96-well plate.

[0706] c) Cell culture environment: culture at 37°C, 5% CO2, and 95% humidity.

[0707] 3.2 Drug dilution

[0708] a) Drug stock solution: The drug was dissolved in DMSO to prepare a 10 mM DMSO stock solution.

[0709] 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.

[0710] c) Prepare 20X or 10X drug solution: Add 2 μL of drug stock solution to 98 μL or 198 μL of cell culture medium.

[0711] 3.3 Dosing

[0712] a) All drugs were diluted 3-fold starting from 1 μM, with 9 concentration steps or 4-fold dilutions, with 8 concentration steps.

[0713] b) Prepare positive control drug and DMSO blank control.

[0714] 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 two replicate wells for each drug concentration.

[0715] 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.

[0716] 3.4 Endpoint plate reading

[0717] a) Thaw CTG reagent, add 50 μL of CTG solution to each well, and shake well.

[0718] b) Place the cell plate at room temperature for 10 minutes to stabilize the luminescence signal.

[0719] c) Read the fluorescence value using a microplate reader.

[0720] 4. Data Processing

[0721] Data were analyzed using GraphPad Prism 8.0 software, and nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve, from which the IC 50 value.

[0722] Inhibition rate (Inh%) = 100-(RLU 化合物 -RLU 空白 ) / (RLU 对照 -RLU 空白 )*100%.

[0723] 5. Experimental Results

[0724] The inhibitory activity of the compounds on the proliferation of HER2 775_776insYVMA Ba / F3 cell line is shown in Table 11.

[0725] Table 11: Inhibitory activity of compounds on HER2 775_776insYVMA Ba / F3 cell line proliferation (IC 50 ,nM)

[0726] As can be seen from the table, the compounds of the present invention have good anti-proliferation activity against HER2 775-776insYVMA Ba / F3 cell line (expressing HER2 exon 20 insertion mutation), and the inhibition IC 50 The concentration reached nanomolar.

[0727] Experimental Example 2: A431 phosphorylation experiment

[0728] Cell culture

[0729] 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%.

[0730] 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.

[0731] c) Remove the culture medium and add 25 μL of HBSS to the 384-well plate and leave overnight.

[0732] 3.2 Drug dilution

[0733] a) Drug stock solution: The drug was dissolved in DMSO to prepare a 10 mM DMSO stock solution.

[0734] 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.

[0735] 3.3 Dosing

[0736] a) All drugs were diluted 3-fold starting from 10 mM concentration, with 10 concentration steps.

[0737] b) The cells in the drug-added 384-well plate were cultured for 30 minutes at 37° C., 5% CO 2 , and 95% humidity.

[0738] 3.4 Detection

[0739] a) Add EGF as an activator and stimulate for 15 minutes.

[0740] b) Cell lysates were prepared and assayed according to the manufacturer's protocol.

[0741] c) AlphaScreen is read by Envision.

[0742] 4. Data Processing

[0743] Data were analyzed using GraphPad Prism 8.0 software, and nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve, from which the IC 50 value.

[0744] Inhibition rate (Inh%) = 100-(Signal 化合物 -Signal Ave_PC ) / (Signal Ave_VC -Signal Ave_PC )*100%.

[0745] Signal Ave_PC : Average signal of positive control on the whole plate

[0746] Signal Ave_VC : Average signal of negative control across the entire plate

[0747] Table 12 Compounds inhibit the phosphorylation of EGFR in A431 cell lines (IC 50 nM)

[0748] 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.

[0749] Experimental Example 3: P-gp substrate evaluation experiment

[0750] 1. Experimental Design

[0751] Cell culture

[0752] 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.

[0753] 2) MDCKII-MDR1 cells were cultured in T-75 cell culture flasks in an incubator set at 37°C, 5% CO2, and 95% relative humidity. Cells were seeded in Transwell plates when they reached 70-90% confluence.

[0754] 3) Before cell seeding, 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 the cells.

[0755] 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. Add serum-containing medium to terminate the digestion.

[0756] 5) Transfer the cell suspension to a round-bottom centrifuge tube and centrifuge at 120 × g for 10 minutes.

[0757] 6) Resuspend the cells in culture medium to a final concentration of 1.56 × 10 6 cells / mL.

[0758] MDCKII-MDR1 cell inoculation

[0759] 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 .

[0760] 2) Start changing the medium 24 hours after inoculation and culture for 4-8 days, changing the medium every other day.

[0761] Assessment of cell monolayer integrity

[0762] 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.

[0763] 2) The resistance of the monolayer membrane was measured using a resistance meter (Millipore, USA), and the resistance of each pore was recorded.

[0764] 3) After the assay is completed, place the Transwell culture plate back into the incubator.

[0765] 4) Calculation of resistance value:

[0766] Measure the resistance value (ohms) × membrane area (cm 2 )=TEER value (ohm·cm 2 )

[0767] If the TEER value is less than 42 ohms·cm 2 , then the hole cannot be used for penetration test.

[0768] Drug penetration test

[0769] 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.

[0770] 2) Determine the transport rate of the compound from the apical to the basolateral side. Add 125 μL of test drug or control drug 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).

[0771] 3) Determine the transport rate of the compound from the basolateral to the apical side. Add 285 μL of HBSS (10 mM HEPES, pH 7.4) buffer to each well of the upper chamber (apical side), and add 75 μL of HBSS (10 mM HEPES, pH 7.4) buffer containing the test drug or control drug to each well of the lower chamber (basolateral side).

[0772] 4) Combine the upper and lower transfer devices and incubate at 37°C for 2 hours.

[0773] 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.

[0774] 6) After 2 hours of incubation, the integrity of the cell monolayer membrane was assessed by fluorescein leakage. The fluorescein stock solution was diluted to a final concentration of 100 μM in HBSS (10 mM HEPES, pH 7.4). 100 μL of fluorescein solution was added to each well of the upper Transwell plate, and 300 μL of HBSS (10 mM HEPES, pH 7.4) was added to each well of the lower receiving plate. After incubation at 37°C for 30 minutes, 80 μL of solution was aspirated from each well and transferred to a new 96-well plate. Fluorescence was measured using a microplate reader with an excitation wavelength of 485 nm and an emission wavelength of 530 nm.

[0775] 2. Data Processing

[0776] The data were calculated using Excel. The apparent permeability coefficient (P app , unit: cm / s) is calculated using the following formula:

[0777] The membrane area in the formula is the Transwell-96 well plate membrane area (0.143 cm 2 ); the incubation time unit is seconds (s).

[0778] The efflux rate is calculated using the following formula:

[0779] Table 13 Efflux rate of the test compounds

[0780] Experimental Example 4: Cassette pharmacokinetic test of the compound in mice

[0781] 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.

[0782] Drug Preparation: The compounds were prepared into clear solutions using 10% DMSO + 10% Solutol HS15 + 5% Cremophor EL + 20% PEG400 + 55% (20% Captisol aqueous solution) as the solvent for PO administration. The administration method was cassette dosing. The compound dosage was 10 mg / kg. The pharmacokinetic parameters are shown in Table 14.

[0783] Table 14 Pharmacokinetic test results of cassette in mice

[0784] 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.

[0785] 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

1. 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: in, In Formula 1, 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; 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 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 is a chemical bond, O, NR 4 , CR 5 R 6 、-OR 7 -, C(=O), S, S(O) or S(O)2; L2 is a chemical bond, O or NR 4 ; L3 for NR 4 ,O,CR 5 R 6 , S, S(O) or S(O)2; L4 does not exist or is a chemical bond, O, NR 4 , CR 5 R 6 , C(═O), S, S(O) or S(O) 2 ; M is C=O or S(=O)2; Y 1 N or CR a ; Y 2 N or CR b ; Y 3 N or CR c ; Y 4 N or CR d ; Y 5 N, CR e or C; when L2 is a chemical bond, Y 5 N; when L2 is O or NR 4 When Y 5 CR e or C; R 1 For halomethyl, C 2-4 Alkenyl, C 2-4 Alkynyl, propylene oxide or C 4-6 Cycloalkenyl, the C 2-4 Alkenyl, C 2-4 Alkynyl, propylene oxide or C 4-6 Cycloalkenyl is optionally substituted with one or more halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-12 membered cycloalkyl, deuterium atom, 3-12 membered heterocyclic group 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 Substitute, the C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group 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 or C 1-3 Alkoxy-C 1-3 Alkyl - optionally substituted with one or more R'; R 2 For hydrogen atoms, deuterium atoms, halogens, cyano groups, hydroxyl groups, amino groups, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-4 Alkyl, deuterated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, 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 or oxo (=O), the hydroxyl, amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1- 4-alkyl, deuterated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, 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 is optionally substituted with one or more R'; R 3 For hydrogen atoms, deuterium atoms, halogens, cyano groups, nitro groups, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, halogenated C 1-6 Alkoxy, OR e SR e 、SOR e 、S(O)2R e 、C(=O)R e 、C(=O)NR e 、C(=O)OR e NR e R f NR e C(=O)R f 、OC(=O)R e ,SONR f 、S(O)2NR e 、NHS(O)2R e 、NHS(O)R e NR e C(=O)OR f NR e C(=O)NR f 、-(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 with one or more R'; R 4 For hydrogen atoms, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, cyano-C 1-6 Alkyl-, hydroxyl C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C(=O)R e or a 3-12 membered cycloalkyl group, wherein the C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, cyano-C 1-6 Alkyl-, hydroxyl C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or 3-12 membered cycloalkyl is optionally substituted with one or more R'; R 5 、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, halogenated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, C 1-6 Alkylmercapto, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, cyano-C 1-6 Alkyl-, C 1-6 Alkoxy-C 1-6 Alkyl-, 3-12 membered cycloalkyl-C 1-6 Alkyl- or 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2 1-6 Alkyl-, the hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, C 1-6 Alkylmercapto, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, cyano-C 1-6 Alkyl-, C 1-6 Alkoxy-C 1-6 Alkyl-, 3-12 membered cycloalkyl-C 1-6 Alkyl- or 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2 1-6 Alkyl - optionally substituted with one or more R'; or R 5 With R 6 Together with the C atom to which it is attached, it forms 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, wherein the 3-6 membered cycloalkyl group or the 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2 are optionally substituted by one or more R'; R 7 C 1-6 Alkylene, C 2-4 Alkenylene, halogenated C 1-6 Alkylene, deuterated C 1-6 Alkylene or halogenated C 2-4 alkenylene; R a 、R b Each is independently a hydrogen atom, a deuterium atom, a halogen, a cyano group, a C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, OR a1 SR a1 NR a1 、S(=O)R a1 or S(=O)2R a1 , the C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, optionally substituted by one or more R' Or, R a With R 2 Together with the atoms to which they are attached, they 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, wherein 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′; Or, R b With R 2 Together with the atoms to which they are attached, they 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, wherein 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′; R c For hydrogen atoms, deuterium atoms, halogens, cyano groups, amino groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylmercapto, C 1- 6-alkylamino or di(C 1-6 Alkyl)amino, said amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylmercapto, C 1-6 Alkylamino or di(C 1-6 Alkyl)amino is optionally substituted with one or more R'; R d Does not exist or is a hydrogen atom, deuterium atom, halogen, cyano group, amino group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylmercapto or C 1-6 Alkylamino, the amino group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylmercapto or C 1-6 Alkylamino is optionally substituted with one or more R'; Or, R b With R d Together with the atoms to which they are attached, they 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, wherein 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′; Or, R a With R d Together with the atoms to which they are attached, they 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, wherein 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′; R e 、R f are independently a hydrogen atom, a deuterium atom, a C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2; Alternatively, NR e R f Middle R e and R f Together with the attached nitrogen atom, it forms a 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, and S(O)2; R a1 For hydrogen atoms, C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, 3-12 membered cycloalkyl-C 1-6 Alkyl or 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2 1-6 Alkyl, the C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, 3-12 membered cycloalkyl-C 1-6 Alkyl or 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2 1-6 Alkyl is optionally substituted with one or more R'; R x 、R y are independently a hydrogen atom, C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, 3-12 membered cycloalkyl-C 1-4 Alkyl-, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2 1-4 Alkyl-, C 1-4 Alkoxy-C 1-4 Alkyl- or deuterated C 1-4 Alkyl, the C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, 3-12 membered cycloalkyl-C 1-4 Alkyl-, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2 1-4 Alkyl-, C 1-4 Alkoxy-C 1-4 Alkyl- or deuterated C 1-4 Alkyl is optionally substituted with one or more R'; or NR x R y Middle R x With R y Together with the N atom to which it is attached, it forms 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' is independently a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-4 Alkyl, deuterated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, 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 or oxo (=O); m and n are each independently 0, 1, 2, 3, 4 or 5; The conditions are: 1) R d or R 2 Any group and R a or R b Any group and the atoms to which they are attached must form one and only one ring, wherein the ring is 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′; 2) When R 2 With R b Together with the atoms to which they are attached, they form a morpholine ring, and Y 1 When it is CH, Q1 is not 2. 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, in, 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 is N, C or CR a ; t is 0, 1, 2, 3, 4, or 5.

3. The spirocyclic / 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 1 or 2 heteroatoms selected from N, O, S, S=O, S(O)2; 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; 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; 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; 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; Preferably, in formula I, II or III, ring E is phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene or pyrazole; Preferably, in Formula I, II or III, 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; -- / --- is none or chemical bond; Ring B is pyrrole, imidazole, pyrazole, thiazole, oxazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine or triazine; X a 、X b 、X c are each independently N or CH; X 1 is a chemical bond, N, CH, CH2, S, O, S(O) or S(O)2; X 2 is N, CH, CH2, O, S, S(O) or S(O)2; X 3 、X 4 are each independently N or C, and X 3 and X 4 Not N, X at the same time 1 、X 2 and X 3 Not all N at the same time; X 5 is a chemical bond, N, CH, CH2, O or S; X 6 is N, O, S or CH; Preferably, in formula I, II or III, Q1 is selected from the following groups: said Q1 is optionally substituted with 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; More preferably, in formula I, II or III, Q1 is selected from the following groups:

4. 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, L1 is a chemical bond, O, NR 4 , CR 5 R 6 、-OR 7 - or C(=O); L2 is a chemical bond or NR 4 ; L3 for NR 4 ; L4 is O or CR 5 R 6 ; M is C=O or S(=O)2; R 4 For hydrogen atoms, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or 3-12 membered cycloalkyl, the C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 The alkynyl or 3-12 membered cycloalkyl group is optionally substituted with one or more methyl, ethyl, halogen, deuterium atom, cyano, hydroxyl, methoxy, cyclopropyl or oxo (=O); R 5 、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, halogenated C 1-6 Alkyl, 3-6 membered cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, C 1-6 Alkylamino, di(C 1-6 alkyl)amino; Or, R 5 With R 6 Together with the C atom to which it is attached, it forms 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 atoms or cyclopropyl groups; R 7 is methylene, ethylene or propylene; Preferably, L1 is a chemical bond, O, NR 4 , CR 5 R 6 、-OR 7 - or C(=O); L2 is a chemical bond or NR 4 ; L3 for NR 4 ; L4 is O or CR 5 R 6 ; M is C=O; 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; R 5 、R 6 each independently represents 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; Or, R 5 With R 6 Together with the C atom to which it is attached, it forms a cyclopropyl or cyclobutyl group, wherein the cyclopropyl or cyclobutyl group is optionally substituted by one or more methyl groups, ethyl groups, halogen groups, deuterium atoms or cyclopropyl groups; R 7 is a methylene group; Preferably, in Formula I, II or III, Y 1 N or CR a ; Y 2 N or CR b ; Y 3 N or CR c ; Y 4 N or CR d ; Y 5 N, CR e or C; when L2 is a chemical bond, Y 5 N; when L2 is O or NR 4 When Y 5 CR e or C; R a For hydrogen atoms, deuterium atoms, halogens, cyano groups, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 4-10 membered heterocyclic group, OR a1 SR a1 or NR a1 , the C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 4-10 membered heterocyclyl are optionally substituted by one or more R'; R a1 For hydrogen atoms, C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, 3-6 membered cycloalkyl-C 1-6 Alkyl or 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2 1-6 Alkyl, the C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, 3-6 membered cycloalkyl-C 1-6 Alkyl or 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2 1-6 The alkyl group is optionally substituted with one or more halogens, deuterium atoms, methyl groups, ethyl groups, or oxo groups; 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's; R b With R d Together with the atoms to which they are attached, they 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, which is optionally substituted with one or more R's; R e For hydrogen atoms, deuterium atoms, C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2; 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); Preferably, in Formula I, II or III, Y 1 N or CR a ; Y 2 N or CR b ; Y 3 N or CR c ; Y 4 N or CR d ; Y 5 is N, CH or C; when L2 is a chemical bond, Y 5 N; when L2 is O or NR 4 When Y 5 is CH or C; R a 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- 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; 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; R b With R d and 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 benzophenone, 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.

5. The spirocyclic / bridged ring compound according to any one of claims 1 to 4, 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 1 is a halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, epoxypropanyl, cyclobutenyl, cyclopentenyl or cyclohexenyl group, wherein the halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, epoxypropanyl, cyclobutenyl, cyclopentenyl or cyclohexenyl group 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 Substituted, the methyl, ethyl, cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl, propylene oxide, butylene oxide, phenyl or pyridinyl is optionally substituted with one or more R'; R x 、R y each independently represents a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, an adamantyl group, a methoxyethyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopropylethyl group, a cyclobutylethyl group, an azetidinylmethyl group or an azetidinylethyl group, wherein the methyl group, the ethyl group, the isopropyl group, the cyclopropyl group, the cyclobutyl group, the cyclopentyl group, an adamantyl group, a methoxyethyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopropylethyl group, a cyclobutylethyl group, an azetidinylmethyl group or an azetidinylethyl group is optionally substituted by one or more R′; Alternatively, NR x R y Medium R x With R y and the N atom to which it is attached form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl, or 2-azabicyclo[3.1.0]hexanyl, said azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl, or 2-azabicyclo[3.1.0]hexanyl, said azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl, or 2-azabicyclo[3.1.0]hexanyl being optionally substituted with one or more R′; 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); Preferably, in Formula I, II or III, R 1 Selected from the following groups: Preferably, in Formula I, II or III, R 2 For hydrogen atoms, deuterium atoms, cyano groups, halogens, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-4 Alkyl, deuterated C 1-4 Alkyl, 3-6 membered cycloalkyl, C 1-4 Alkoxy-C 1-4 Alkyl, halogenated C 1-4 Alkoxy or oxo (=O), the C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-4 Alkyl, deuterated C 1-4 Alkyl, 3-6 membered cycloalkyl, C 1-4 Alkoxy-C 1-4 Alkyl, halogenated C 1-4 Alkoxy is optionally substituted with one or more R'; Or, R b With R 2 Together with the atoms to which they are attached, they 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 with one or more R′; 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); Or, R b With R 2 Together with the atoms to which it is attached, it forms 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, the morpholinyl, 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 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.

6. The spirocyclic / 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 For hydrogen atoms, deuterium atoms, halogens, cyano groups, nitro groups, 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, OR e 、SOR e 、S(O)2R e 、C(=O)R e 、C(=O)NR e NR e R f NR e C(=O)R f 、S(O)2NR 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 is optionally substituted with one or more R'; R e 、R f are independently a hydrogen atom, a deuterium atom, a C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-12 membered cycloalkyl; Alternatively, NR e R f Medium R e and R f Together with the attached N atom, it forms a 3-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, and S(O)2; 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, SOCH3, S(O)2CH3, C(=O)CH3, C(=O)NCH3, NHC(=O)CH3, S(O)2NCH3, P(O)(CH3)2, or P(O)(CH2CH3)2 , the methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoroethyl, trifluoroethyl, hydroxy, methoxy, ethoxy, methylamino, ethylamino, SOCH3, S(O)2CH3, C(=O)CH3, C(=O)NCH3, NHC(=O)CH3, S(O)2NCH3, P(O)(CH3)2 or P(O)(CH2CH3)2 is optionally substituted with one or more deuterium atoms, F, Cl, hydroxy, methyl, ethyl, isopropyl or cyclopropyl; 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; 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.

7. 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:

8. 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, the method comprising: The preparation of the compound of formula II or formula III, wherein the preparation of the compound of formula II comprises: 1) Compound II-1 and compound II-2 undergo a substitution reaction to form compound II-3; 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) Compound II-5 reacts with DMF-DMA to form compound II-6; 4) Compound II-6 reacts with compound II-7 to form compound II-8; 5) deprotecting compound II-8 to form compound II-9; 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 ; The preparation of the compound of formula III comprises: 1) Compound III-1 and compound III-2 undergo a substitution reaction to form compound III-3; 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) Compound III-5 reacts with DMF-DMA to form compound III-6; 4) Compound III-6 reacts with compound III-7 to form compound III-8; 5) deprotecting compound III-8 to form compound III-9; 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 ; Among them, A, E, Q1, M, Y 1 、Y 3 、Y 4 、Y 5 、L1、L2、L3、L4、R 1 、R 2 、R 3 , R', G, W, m, n, t are as defined in any one of claims 1 to 6; X' is NO2 or H; X" is a halogen.

9. 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; 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.

10. 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 treatment for a disease mediated by abnormal HER2; Preferably, the disease is a tumor disease; 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.

11. 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; Preferably, the disease is a tumor disease; 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.

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