Spiro / bridged ring compound as well as preparation method and application thereof

Abstract

The invention relates to a spiro / bridged ring compound as well as a preparation method and application thereof, the spiro / bridged ring compound has a structure as shown in a formula I, and A, E, Q1, M, Y1, Y2, Y3, Y4, Y5, L1, L2, L3, L4, R1, R2, R3, m and n are defined in the specification. The spiro / bridged ring compound has an efficient inhibition effect on an epidermal growth factor receptor 2 (HER2), and is used for treating related diseases induced by abnormal HER2, especially for treating cancer diseases.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a spiro / bridged compound and a preparation method and application thereof. BACKGROUND

[0002] The human epidermal growth factor receptor 2 (HER2, ErbB2) gene is located on the long arm of chromosome 17 (17q21) and is one of the four members of the ErbB family (EGFR / HER1 / ErbB1, HER2 / ErbB2, HER3 / ErbB31, and HER4 / ErbB4), which has tyrosine kinase activity. No ligand has been found to directly interact with HER2. HER2 can activate the downstream MEK / ERK / MAPK pathway and the PI3K / AKT bypass by forming a heterodimer with other members of the ErbB family to conduct signal transduction, ultimately promoting cell growth, proliferation, and division, etc.

[0003] Overexpression (upregulation) or overactivity (amplification or mutation) of HER2 has been confirmed to be associated with many cancers, including breast cancer, colorectal cancer, gastric cancer, non-small cell lung cancer, head and neck cancer, ovarian cancer, cervical cancer, bladder cancer, esophageal cancer, endometrial cancer, and glioblastoma. The detection rates of HER2 overexpression in lung cancer, breast cancer, gastric cancer, cholangiocarcinoma, ovarian cancer, and endometrial cancer are about 2.5%, 15%-25%, 20%, 20%, 27%, and 18%-80%, respectively.

[0004] The detection rate of HER2 mutation in non-small cell lung cancer is about 2%-4%, among which the insertion mutation of exon 20 accounts 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 mutation V659E (4.1%) and G660D (0.9%), and extracellular region mutation D277Y (1.9%), S310F (7.7%), S310Y (1.9%), and A466V (1.4%). In addition, studies have shown that cancer patients carrying HER2 abnormalities are more likely to have central nervous system metastasis during the disease process, and about 47% of non-small cell lung cancer patients with HER2 mutations have brain metastasis, which is associated with poor prognosis.

[0005] Currently approved drugs for the treatment of HER2 abnormalities in the clinic include monoclonal antibodies (mAbs) (trastuzumab, pertuzumab, etc.), small molecule tyrosine kinase inhibitors (TKIs) (lapatinib, tucatinib, neratinib, pyrotinib, etc.), and antibody conjugate drugs (ADCs) (emtansine, deruxtecan).

[0006] Monoclonal antibodies and antibody conjugate drugs are less selective for wild-type EGFR, and are large molecule drugs that are not easily permeable through the blood-brain barrier, and a portion of patients develop resistance or recurrence after using monoclonal antibodies (mAbs) for a period of time. In addition, antibody conjugate drugs such as deruxtecan, at the approved dose of 5.4 mg / kg, the proportion of grade 3 and above interstitial pneumonia reached 12.9%. TKIs are divided into selective TKIs (tucatinib) and non-selective TKIs (lapatinib, neratinib, and pyrotinib), which show moderate anti-tumor activity against wild-type HER2, but have poor effects on the most common HER2 exon 20 insertion mutation, with a clinical objective response rate ORR of 0-30%. In addition, non-selective TKIs are less selective for wild-type EGFR, and are prone to adverse reactions such as skin rash and diarrhea. Therefore, it is of great significance to develop HER2 inhibitors with selectivity, permeability through the blood-brain barrier, and potential inhibitory effects on HER2 exon 20 insertion mutations. SUMMARY

[0007] In order to solve the defects of the prior art, the present application aims to provide a spiro / bridged compound and a preparation method and application thereof, the spiro / bridged compound of the present application has good inhibitory activity on HER2 exon 20 insertion mutation, and is highly selective for wild-type EGFR, can permeate through the blood-brain barrier, and can be used as a treatment for diseases related to HER2 abnormalities, especially cancer diseases.

[0008] The present application is realized by the following technical solutions.

[0009] In a first aspect, the present application provides a compound having the structure shown in formula I or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically labeled, deuterated, N-oxide, prodrug molecule, hydrate or solvate thereof:

[0010]

[0011] In formula I,

[0012] A ring is a 3-12 membered heterocyclic group, 3-12 membered cycloalkyl group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2;

[0013] E ring is 6-10 membered aryl or 5-10 membered heteroaryl containing 1 or more heteroatoms selected from N, O, S;

[0014] Q1 is absent or 6-12 membered aryl or 5-12 membered heteroaryl containing 1 or more heteroatoms selected from N, O, S, said 6-12 membered aryl or 5-12 membered heteroaryl containing 1 or more heteroatoms selected from N, O, S being optionally substituted by one or more R';

[0015] L1 is a bond, O, NR 4 , CR 5 R 6 , -OR 7 , C(=O), S, S(O) or S(O)2;

[0016] L2 is a bond, O or NR 4 ;

[0017] L3 is NR 4 , O, CR 5 R 6 , S, S(O) or S(O)2;

[0018] L4 is absent or a bond, O, NR 4 , CR 5 R 6 , C(=O), S, S(O) or S(O)2;

[0019] M is C=O or S(=O)2;

[0020] Y 1 is N or CR a ;

[0021] Y 2 is N or CR b ;

[0022] Y 3 is N or CR c ;

[0023] Y 4 is N or CR d ;

[0024] Y 5 is N, CR e or C; when L2 is a bond, Y 5 is N; when L2 is O or NR 4 , Y 5 is CR e or C;

[0025] R 1 is halomethyl, C 2-4 alkenyl, C2-4 alkynyl, cyclopropyloxiranyl or C 4-6 cycloalkenyl, said C 2-4 alkenyl, C 2-4 alkynyl, cyclopropyloxiranyl or C 4-6 cycloalkenyl is optionally substituted by one or more halogen, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, 3-12 membered cycloalkyl, deuterium, 3-12 membered heterocyclyl comprising 1 or more heteroatoms selected from N, O, S, S=O, S(O)2, 5-12 membered heteroaryl comprising 1 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 substituted, said C 1-4 alkyl, halogenated C 1-4 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl comprising 1 or more heteroatoms selected from N, O, S, S=O, S(O)2, 5-12 membered heteroaryl comprising 1 or more heteroatoms selected from N, O, S, 6-12 membered aryl or C 1-3 alkoxy-C 1-3 alkyl- optionally substituted by one or more R';

[0026] R 2 is hydrogen atom, deuterium atom, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-4 alkyl, deuterated C 1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl comprising 1 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), said hydroxyl, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-4 alkyl, deuterated C 1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl comprising 1 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, halo-C 1-6 alkoxy is optionally substituted with one or more R';

[0027] R 3 is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a nitro group, a 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 heterocyclyl containing one or more heteroatoms selected from the group consisting of N, O, S, S=0, S(0)2, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, OR e , SR e , SOR e , S(0)2R e , C(=0)R e , C(=0)NR e , C(=0)OR e , NR e R f , NR e C(=0)R f , OC(=0)R e , SONR f , S(0)2NR e , NHS(0)2R e , NHS(0)R e , NR e C(=0)OR f , NR e C(=0)NR f , -(0)(OR e )2 or P(0)(R e )2, said 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 heterocyclyl containing one or more heteroatoms selected from the group consisting of N, O, S, S=0, S(0)2, halo-C 1-6 alkyl or halo-C 1-6 alkoxy is optionally substituted with one or more R';

[0028] R 4 is a hydrogen atom, a C 1-6 alkyl, halo-C 1-6 alkyl, deuterated-C 1-6 alkyl, cyano-C 1-6 alkyl-, hydroxy-C 1-6 alkyl, C2-4 alkenyl, C 2-4 alkynyl, C(=O)R e or 3- to 12-membered cycloalkyl, said C 1-6 alkyl, haloC 1-6 alkyl, deuterated C 1-6 alkyl, cyano-C 1-6 alkyl-, hydroxyC 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl or 3- to 12-membered cycloalkyl, optionally substituted with one or more R';

[0029] R 5 , R 6 each independently hydrogen atom, deuterium atom, halogen, cyano, hydroxy, amino, C 1-6 alkyl, haloC 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl comprising 1 or more heteroatoms selected from N, O, S, S=O, S(O)2, C 1-6 alkoxy, haloC 1-6 alkoxy, 3- to 12-membered cycloalkyloxy, 3- to 12-membered heterocyclyloxy comprising 1 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- to 12-membered cycloalkyl-C 1-6 alkyl- or 3- to 12-membered heterocyclyl-C comprising 1 or more heteroatoms selected from N, O, S, S=O, S(O)2 1-6 alkyl-, said hydroxy, amino, C 1-6 alkyl, haloC 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl comprising 1 or more heteroatoms selected from N, O, S, S=O, S(O)2, C 1-6 alkoxy, haloC 1-6 alkoxy, 3- to 12-membered cycloalkyloxy, 3- to 12-membered heterocyclyloxy comprising 1 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 heterocyclyl-C containing 1 or more heteroatoms selected from N, O, S, S=O, S(O)2 1-6 alkyl- optionally substituted by one or more R';

[0030] or R 5 with R 6 and the attached C atom together form a 3-6 membered cycloalkyl or a 3-6 membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S, S=O, S(O)2, said 3-6 membered cycloalkyl or 3-6 membered heterocyclyl being optionally substituted by one or more R';

[0031] R 7 is C 1-6 alkylene, C 2-4 alkenylene, halo-C 1-6 alkylene, deuterated-C 1-6 alkylene or halo-C 2-4 alkenylene;

[0032] R a , R b each independently is a hydrogen atom, a deuterium atom, a halogen, a cyano, a C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl containing 1 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 , said C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S, S=O, S(O)2 being optionally substituted by one or more R';

[0033] or, R a with R 2Together with the attached atoms, it forms 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, or S. The 3-12 membered cycloalkyl group, the 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, or S(O)2, or the 5-6 membered heteroaryl group containing one, two, three, or four heteroatoms selected from N, O, or S are optionally substituted by one or more R′.

[0034] Or, R b With R 2 Together with the attached atoms, it forms 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, or S. The 3-12 membered cycloalkyl group, the 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, or S(O)2, or the 5-6 membered heteroaryl group containing one, two, three, or four heteroatoms selected from N, O, or S are optionally substituted by one or more R′.

[0035] R c It consists of hydrogen atoms, deuterium atoms, halogens, cyano groups, amino groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl mercapto, C 1-6 Alkylamino or di(C) 1-6 alkyl)amino, wherein the amino group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl mercapto, C 1-6 Alkylamino or di(C) 1-6 The alkyl)amino group is optionally substituted with one or more R′;

[0036] R d It either does not exist or is a hydrogen atom, deuterium atom, halogen, cyano group, amino group, or C atom. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl mercapto or C 1-6 Alkylamino, wherein the amino group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl mercapto or C 1-6 The alkylamino group is optionally substituted with one or more R′;

[0037] Or, R b With R dTogether with the attached atoms, it forms 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, or S. The 3-12 membered cycloalkyl group, the 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, or S(O)2, or the 5-6 membered heteroaryl group containing one, two, three, or four heteroatoms selected from N, O, or S are optionally substituted by one or more R′.

[0038] Or, R a With R d Together with the attached atoms, it forms 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, or S. The 3-12 membered cycloalkyl group, the 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, or S(O)2, or the 5-6 membered heteroaryl group containing one, two, three, or four heteroatoms selected from N, O, or S are optionally substituted by one or more R′.

[0039] R e R f Each is independently a hydrogen atom, a deuterium atom, and a carbon atom. 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;

[0040] Or, NR e R f Chinese R e and R f Together with the connected N 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;

[0041] 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 groups or 3-12 membered heterocyclic groups containing one or more heteroatoms selected from N, O, S, S=O, and 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 heterocyclyl-C 1-6 alkyl is optionally substituted by one or more R';

[0042] R x , R y each independently is a hydrogen atom, C 1-4 alkyl, haloC 1-4 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S, S=0, S(0)2, 3-12 membered cycloalkyl-C 1-4 alkyl-, 3-12 membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S, S=0, S(0)2-C 1-4 alkyl-, C 1-4 alkoxy-C 1-4 alkyl- or deuterated C 1-4 alkyl, said C 1-4 alkyl, haloC 1-4 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S, S=0, S(0)2, 3-12 membered cycloalkyl-C 1-4 alkyl-, 3-12 membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S, S=0, S(0)2-C 1-4 alkyl-, C 1-4 alkoxy-C 1-4 alkyl- or deuterated C 1-4 alkyl is optionally substituted by one or more R';

[0043] or NR x R y in R x with R y and the N atom to which they are attached form a 3-12 membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S, S=0, S(0)2, which is optionally substituted by one or more R';

[0044] each R' independently is a deuterium atom, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-4 alkyl, deuterated C 1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S, S=0, S(0)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 Alkyl or oxo (=O);

[0045] m and n are each independently 0, 1, 2, 3, 4 or 5;

[0046] The condition is that 1) R d or R 2 Any group and R a or R b Each 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 heterocyclic group containing one or more 3-12 membered heterocyclic groups selected from N, O, S, S=O, S(O)2 heteroatoms, or a 5-6 membered heteroaryl group containing one, two, three or four N, O, S heteroatoms, wherein the 3-12 membered cycloalkyl, the 3-12 membered heterocyclic group containing one or more 3-12 membered heterocyclic groups selected from N, O, S, S=O, S(O)2 heteroatoms, or the 5-6 membered heteroaryl group containing one, two, three or four N, O, S heteroatoms may optionally be substituted by one or more R′;

[0047] 2) When R 2 With R b Together with the atoms they are attached to, they form a morpholine ring, and Y 1 When it is CH, Q1 is not.

[0048] In some embodiments, the compound of formula I further has a structure as shown in formula II or formula III.

[0049]

[0050] in,

[0051] The G ring is a 3-12 membered cycloalkyl group, containing one or more 3-12 membered heterocyclic groups selected from N, O, S, S=O, S(O)2 heteroatoms, or containing one, two, three or four 5-6 membered heteroaryl groups selected from N, O, S heteroatoms;

[0052] W represents N, C, or CR. a ;

[0053] t can be 0, 1, 2, 3, 4 or 5.

[0054] In some embodiments, ring A is a 4-7 membered heterocyclic group or a 3-6 membered cycloalkyl group containing one or two heteroatoms selected from N, O, S, S=O, and S(O)2.

[0055] Preferably, the A ring is piperidinyl, azetidinyl, pyrrolidinyl, piperazinyl, homopiperidinyl, homopiperazinyl, 1,4-azoxepan, 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.

[0056] In certain embodiments, the A ring is a 4-9 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, S=O, S(O)2;

[0057] Preferably, the A ring is piperidinyl, azetidinyl, pyrrolidinyl, piperazinyl, homopiperidinyl, homopiperazinyl, 1,4-azoxepan, 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.

[0058] In certain embodiments, the E ring is phenyl or a 5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, S;

[0059] Preferably, the E ring is phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene, or pyrazole.

[0060] In certain embodiments, Q1is The optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy;

[0061] -- / --- is none or a chemical bond;

[0062] the B ring is pyrrole, imidazole, pyrazole, thiazole, oxazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, or triazine;

[0063] X a , X b , X c each independently N or CH;

[0064] X 1 is a chemical bond, N, CH, CH2, S, O, S(O), or S(O)2;

[0065] X 2 is N, CH, CH2, O, S, S(O) or S(O)2;

[0066] X 3 , X 4 are each independently N or C, and X 3 and X 4 are not simultaneously N, X 1 , X 2 and X 3 are not simultaneously N;

[0067] X 5 is a bond, N, CH, CH2, O or S;

[0068] X 6 is N, O, S or CH;

[0069] Preferably, Q1is selected from the following groups:

[0070] said Q1is optionally substituted with one or more deuterium atom, F, Cl, cyano, hydroxyl, amino, methyl, deuterated methyl, ethyl, isopropyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy;

[0071] More preferably, Q1is selected from the following groups:

[0072]

[0073] In certain embodiments, L1is a bond, O, NR 4 , CR 5 R 6 , -OR 7 - or C(=O);

[0074] R 4 is a hydrogen atom, C 1-6 alkyl, haloC 1-6 alkyl, deuterated C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl or 3-12 membered cycloalkyl, said C 1-6 alkyl, haloC 1-6 alkyl, deuterated C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl or 3-12 membered cycloalkyl, said CThe alkynyl or 3-12 membered cycloalkyl group is optionally substituted with one or more methyl, ethyl, halogen, deuterium, cyano, hydroxyl, methoxy, cyclopropyl or oxo (=O);

[0075] R 5 R 6 Each is independently a hydrogen atom, deuterium atom, halogen, cyano group, hydroxyl group, amino group, 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;

[0076] Or, R 5 With R 6 Together with the attached C atom, it forms a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group is optionally substituted by one or more methyl, ethyl, halogen, deuterium, or cyclopropyl atoms.

[0077] R 7 It is methylene, ethylene, or propylene;

[0078] Preferably, L1 is a chemical bond, O, or NR. 4 CR 5 R 6 -OR 7 - or C (=O);

[0079] R 4 It can be a hydrogen atom, methyl, ethyl, isopropyl, 1,2-dihydroxypropyl-3-yl, acetyl, methoxyethyl, cyano, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, propenyl, or propynyl.

[0080] R 5 R 6 Each can be independently a hydrogen atom, deuterium atom, halogen, cyano, hydroxyl, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, propenyl or propynyl.

[0081] Or, R 5 With R 6 Together with the attached C atom, it forms a cyclopropyl or cyclobutyl group, wherein the cyclopropyl or cyclobutyl group is optionally substituted by one or more methyl, ethyl, halogen, deuterium or cyclopropyl atoms;

[0082] R7 is a methylene group.

[0083] In certain embodiments, L2is a bond or NR 4 ;

[0084] R 4 is a hydrogen atom, C 1-6 alkyl, haloC 1-6 alkyl, deuterated C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, or 3-12 membered cycloalkyl, said C 1-6 alkyl, haloC 1-6 alkyl, deuterated C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, or 3-12 membered cycloalkyl optionally substituted with one or more methyl, ethyl, halogen, deuterium atom, cyano, hydroxyl, methoxy, cyclopropyl, or oxo (=0) groups;

[0085] Preferably, L2is a bond or NR 4 ;

[0086] R 4 is a hydrogen atom, methyl, ethyl, isopropyl, 1,2-dihydroxypropan-3-yl, acetyl, methoxyethyl, ethylnitrile, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, propenyl, or propynyl.

[0087] In certain embodiments, L3is NR 4 ;

[0088] R 4 is a hydrogen atom, C 1-6 alkyl, haloC 1-6 alkyl, deuterated C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, or 3-12 membered cycloalkyl, said C 1-6 alkyl, haloC 1-6 alkyl, deuterated C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, or 3-12 membered cycloalkyl optionally substituted with one or more methyl, ethyl, halogen, deuterium atom, cyano, hydroxyl, methoxy, cyclopropyl, or oxo (=0) groups;

[0089] Preferably, L3is NR 4 ;

[0090] R 4a 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 ethoxycarbonyl group, a deuteromethyl 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.

[0091] In certain embodiments, L4is O or CR 5 R 6 ;

[0092] R 5 , R 6 each independently is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 alkyl group, a haloC 1-6 alkyl group, a 3-6 membered cycloalkyl group, a C 1-6 alkoxy group, a haloC 1-6 alkoxy group, a 3-12 membered cycloalkylalkoxy group, a C 1-6 alkylamino group, a di(C 1-6 alkyl)amino group;

[0093] or, R 5 and R 6 together with the C atom to which they are attached form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, which cyclopropyl group, cyclobutyl group, cyclopentyl group, or cyclohexyl group is optionally substituted with one or more methyl groups, ethyl groups, halogens, deuterium atoms, or cyclopropyl groups;

[0094] Preferably, L4is O or CR 5 R 6 ;

[0095] R 5 , R 6 each independently is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, a deuteromethyl 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;

[0096] or, R 5 and R 6 together with the C atom to which they are attached form a cyclopropyl group or a cyclobutyl group, which cyclopropyl group or cyclobutyl group is optionally substituted with one or more methyl groups, ethyl groups, halogens, deuterium atoms, or cyclopropyl groups.

[0097] In certain embodiments, M is C=O or S(=O)2;

[0098] Preferably, M is C=O;

[0099] In certain embodiments, Y 1 is N or CR a ;

[0100] R a is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a 4-10 membered heterocyclyl group, OR a1 , SR a1 or NR a1 , said C 1-6 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, 4-10 membered heterocyclyl group is optionally substituted with one or more R';

[0101] R a1 is a hydrogen atom, a C 1-4 alkyl group, a 3-6 membered cycloalkyl group, a 3-6 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S=0, S(0)2, a 3-6 membered cycloalkyl-C 1-6 alkyl group, or a 3-6 membered heterocyclyl-C 1-6 alkyl group containing one or more heteroatoms selected from N, O, S, S=0, S(0)2; 1-4 alkyl group, a 3-6 membered cycloalkyl group, a 3-6 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S=0, S(0)2, a 3-6 membered cycloalkyl-C 1-6 alkyl group, or a 3-6 membered heterocyclyl-C 1-6 alkyl group containing one or more heteroatoms selected from N, O, S, S=0, S(0)2;

[0102] R' is a deuterium atom, F, CI, cyano, hydroxyl, amino, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, methoxy, pyrrolidinyl, 1-methylpyrrolidin-3-yl or oxo (=0);

[0103] Preferably, Y 1 is N or CR a ;

[0104] R aa hydrogen atom, a deuterium atom, F, Cl, Br, cyano, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, ethynyl, 2-(l,3-dimethylpyrrolidin-3-yl)ethynyl, ethylnitrile, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, hydroxyethoxy, N',N'-dimethylaminoethoxy, N'-methylaminoethoxy, morpholino, 2-oxa-6-azaspiro[3.3]cycloheptanyl, morpholino-ethoxy, hydroxypropoxy, N',N'-dimethylaminopropoxy, N'-methylaminopropoxy, morpholino-propoxy, piperazin-l-yl-ethoxy, 4-methylpiperazin-l-yl-ethoxy, 4-methylpiperazin-l-yl-propoxy, piperazin-l-yl-propoxy, pyrrolidin-l-yl-ethoxy, pyrrolidin-l-yl-propoxy, tetrahydrofuran-3-yloxy, methylthio, methylamino, ethylamino, acetylamino, propionylamino, methoxyethyl, methoxyethylamino, or methoxyethoxy.

[0105] In certain embodiments, Y 2 is N or CR b ;

[0106] R b is a hydrogen atom, a deuterium atom, halogen, cyano, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 4-10 membered heterocyclyl, OR a1 , SR a1 , or NR a1 , said C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 4-10 membered heterocyclyl is optionally substituted with one or more R';

[0107] R a1 is a hydrogen atom, C 1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S=0, S(0)2, 3-6 membered cycloalkyl-C 1-6 alkyl, or 3-6 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S=0, S(0)2-C 1-6 alkyl, said C 1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S=0, S(0)2, 3-6 membered cycloalkyl-C 1-6 alkyl, or 3-6 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S=0, S(0)2-C 1-6alkyl is optionally substituted with one or more halogen, deuterium atom, methyl, ethyl, or oxo;

[0108] or, R b with R d and the atom to which they are attached form a 4-7 membered cycloalkyl or a 5-7 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, S=O, S(O)2, said 4-7 membered cycloalkyl or 5-7 membered heterocyclyl being optionally substituted with one or more R';

[0109] 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);

[0110] preferably, Y 2 is N or CR b ;

[0111] R b is a hydrogen atom, a deuterium atom, F, Cl, Br, cyano, hydroxy, amino, methyl, ethyl, n-propyl, i-propyl, difluoromethyl, trifluoromethyl, ethynyl, 2-(1,3-dimethylpyrrolidin-3-yl)ethynyl, ethynylcyano, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, hydroxyethoxy, N',N'-dimethylaminoethoxy, N'-methylaminoethoxy, morpholino, 2-oxa-6-azaspiro[3.3]cycloheptanyl, morpholino-ethoxy, hydroxypropoxy, N',N'-dimethylaminopropoxy, N'-methylaminopropoxy, morpholino-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-yloxy, methylthio, methylamino, ethylamino, acetylamido, propionylamido, methoxyethyl, methoxyethylamino, or methoxyethoxy;

[0112] or, R b with R dtogether with the atom to which they are attached form morpholinyl, tetrahydrofuranyl, dihydroimidazolyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyranylone, 1,4-dioxanyl, hexahydro-l,4-oxazepinyl, hexahydro-l,4-thiazepinyl, 4-thiomorpholinyl-l-oxide, 4-thiomorpholinyl-l,l-dioxide, hexahydro-l,4-thiazepinyl-l-oxide, or hexahydro-l,4-thiazepinyl-l,l-dioxide, said morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyranylone, 1,4-dioxanyl, hexahydro-l,4-oxazepinyl, hexahydro-l,4-thiazepinyl, 4-thiomorpholinyl-l-oxide, 4-thiomorpholinyl-l,l-dioxide, hexahydro-l,4-thiazepinyl-l-oxide, or hexahydro-l,4-thiazepinyl-l,l-dioxide being optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, deuteromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, dimethylaminoalkyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy.

[0113] In certain embodiments, Y 3 is N or CR c ;

[0114] R c is a hydrogen atom, halogen, cyano, amino, methyl, ethyl, isopropyl, cyclopropyl, methoxy, or cyclopropoxy, said amino, methyl, isopropyl, ethyl, cyclopropyl, methoxy, and cyclopropoxy being optionally substituted with one or more R';

[0115] R' is a deuterium atom, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, methoxy, pyrrolidinyl, 1-methylpyrrolidin-3-yl, or oxo (=0);

[0116] In certain embodiments, Y 3 is N or CR c ;

[0117] R c is a hydrogen atom, halogen, cyano, amino, methyl, ethyl, isopropyl, cyclopropyl, methoxy, or cyclopropoxy.

[0118] In certain embodiments, Y 4 is N or CR d ;

[0119] R dhalogen, cyano, amino, methyl, ethyl, isopropyl, cyclopropyl, methoxy or cyclopropoxy, which amino, methyl, isopropyl, ethyl, cyclopropyl, methoxy and cyclopropoxy are optionally substituted with one or more R'; R' is a hydrogen atom, halogen, cyano, hydroxy, amino, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, methoxy, pyrrolidinyl, 1-methylpyrrolidin-3-yl or oxo (=0); and

[0120] R b and the atom to which they are attached form a 4-7 membered cycloalkyl or a 5-7 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, S=0, S(0)2, which 4-7 membered cycloalkyl or 5-7 membered heterocyclyl is optionally substituted with one or more R'; R' is a hydrogen atom, halogen, cyano, hydroxy, amino, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, methoxy, pyrrolidinyl, 1-methylpyrrolidin-3-yl or oxo (=0); and d and the atom to which they are attached form a 4-7 membered cycloalkyl or a 5-7 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, S=0, S(0)2, which 4-7 membered cycloalkyl or 5-7 membered heterocyclyl is optionally substituted with one or more R'; R' is a hydrogen atom, halogen, cyano, hydroxy, amino, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, methoxy, pyrrolidinyl, 1-methylpyrrolidin-3-yl or oxo (=0); and

[0121] R' is a hydrogen atom, halogen, cyano, hydroxy, amino, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, methoxy, pyrrolidinyl, 1-methylpyrrolidin-3-yl or oxo (=0); and

[0122] Y 4 is N or CR d ;

[0123] R b and the atom to which they are attached form a 4-7 membered cycloalkyl or a 5-7 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, S=0, S(0)2, which 4-7 membered cycloalkyl or 5-7 membered heterocyclyl is optionally substituted with one or more R'; R' is a hydrogen atom, halogen, cyano, hydroxy, amino, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, methoxy, pyrrolidinyl, 1-methylpyrrolidin-3-yl or oxo (=0); and d and the atom to which they are attached form a 4-7 membered cycloalkyl or a 5-7 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, S=0, S(0)2, which 4-7 membered cycloalkyl or 5-7 membered heterocyclyl is optionally substituted with one or more R'; R' is a hydrogen atom, halogen, cyano, hydroxy, amino, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, methoxy, pyrrolidinyl, 1-methylpyrrolidin-3-yl or oxo (=0); and

[0124] Y 5 is N, CR e or C; when L2 is a bond, Y 5 is N; when L2 is O or NR 4 , Y5 For CR e Or C;

[0125] Preferably, Y 5 For N, CH, or C; when L2 is a chemical bond, Y 5 For N; when L2 is O or NR 4 At that time, Y 5 It is CH or C.

[0126] In some implementations, R 1 The halogenated methyl, vinyl, propynyl, ethynyl, propynyl, butynyl, propylene oxide, cyclobutenyl, cyclopentenyl, or cyclohexenyl groups are optionally replaced by one or more F, Cl, methyl, ethyl, cyclopropyl, acrylidine, pyrrolidine, piperidinyl, propylene oxide, propylene oxide, deuterium, phenyl, pyridinyl, or NR atoms. x R y The methyl, ethyl, cyclopropyl, acridine, pyrrolyl, piperidinyl, propylene oxide, butyl oxide, phenyl, or pyridinyl groups are optionally substituted by one or more R′.

[0127] R x R y Each of the following is independently a hydrogen atom, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, acridinemethyl or acridineethyl, wherein the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, acridinemethyl or acridineethyl is optionally substituted by one or more R′;

[0128] Or, NR x R y Chinese R x With R y Together with the attached N atom, it forms acridine, pyrrolidine, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl dioxide, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl or 2-azabicyclo[3.1.0]hexyl, wherein the acridine, pyrrolidine, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl dioxide, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl or 2-azabicyclo[3.1.0]hexyl is optionally substituted by one or more R′;

[0129] R' is a deuterium atom, F, CI, cyano, hydroxy, amino, methyl, ethyl, ethenyl, ethynyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy or oxo (=0)

[0130] Preferably, R 1 is selected from the group consisting of:

[0131]

[0132]

[0133] In certain embodiments, R 2 is a hydrogen atom, a deuterium atom, cyano, halogen, 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, halo-C 1-4 alkoxy or oxo (=0), said 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, halo-C 1-4 alkoxy is optionally substituted with one or more R';

[0134] or, R b together with R 2 and the atom to which they are attached form a 5-7 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, S=0, S(0)2 or a 5-6 membered heteroaryl containing 1, 2, 3, 4 heteroatoms selected from N, O, S, said 5-7 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, S=0, S(0)2 or 5-6 membered heteroaryl containing 1, 2, 3, 4 heteroatoms selected from N, O, S is optionally substituted with one or more R';

[0135] Preferably, R 2It can be hydrogen atom, deuterium atom, F, Cl, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, vinyl, propynyl, ethynyl, propynyl, cyano, difluoromethoxy, trifluoromethoxy, methoxy, methoxymethyl or oxo (=O);

[0136] Or, R b With R 2 Together with the attached atoms, they form morpholino, tetrahydrofurano, dihydroimidazolyl, thiomorpholino, hexahydro-1,4-oxazaporyl, hexahydro-1,4-thiozaporyl, 4-thiomorpholino-1-oxide, 4-thiomorpholino-1,1-dioxide, hexahydro-1,4-thiozaporyl-1-oxide, or hexahydro-1,4-thiozaporyl-1,1-dioxide, wherein the morpholino, thiomorpholino, hexahydro-1,4-oxazaporyl, hexahydro-1,4-thiozaporyl, or 4-thiomorpholino -1-oxide, 4-thiomorpholino-1,1-dioxide, hexahydro-1,4-thioazaporphyryl-1-oxide or hexahydro-1,4-thioazaporphyryl-1,1-dioxide may optionally be 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.

[0137] In some implementations, R 3 It consists of hydrogen atoms, deuterium atoms, halogens, cyano groups, nitro groups, and carbon atoms. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 member saturated or unsaturated cycloalkyl group, 3-6 member 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 2-4alkyl, haloC 1-4 alkyl, haloC 1-4 alkoxy is optionally substituted with one or more R';

[0138] R e , R f each independently is a hydrogen atom, a deuterium atom, a C 1-4 alkyl, haloC 1-4 alkyl, 3-12 membered cycloalkyl;

[0139] or, NR e R f R e and R f together with the attached N atom form a 3-6 membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S, S=O, S(O)2;

[0140] R 3 is a hydrogen atom, a deuterium atom, F, Cl, cyano, nitro, methyl, ethyl, isopropyl, ethene, ethyne, cyclopropyl, cyclobutyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, 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, said methyl, ethyl, isopropyl, ethene, ethyne, cyclopropyl, cyclobutyl, difluoroethyl, trifluoroethyl, hydroxyl, 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)2is optionally substituted with one or more deuterium atom, F, Cl, hydroxyl, methyl, ethyl, isopropyl, or cyclopropyl.

[0141] In certain embodiments, in Formula I, R b and R d together with the attached atoms form a G ring, said G ring is a 4-7 membered cycloalkyl, a 4-7 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, S=O, S(O)2, said 4-7 membered cycloalkyl, 4-7 membered heterocyclyl is optionally substituted with one or more R';

[0142] or, R b and R 2together with the attached atoms form a G ring which is a 4-7 membered cycloalkyl, a 4-7 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, S=0, S(0)2, said 4-7 membered cycloalkyl, 4-7 membered heterocyclyl optionally substituted with one or more R';

[0143] Preferably, the G ring is morpholinyl, tetrahydrofuranyl, dihydroimidazolyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyranylone, 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, said morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyranylone, 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 optionally substituted with one or more deuterium atom, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, dimethylaminoalkyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy.

[0144] In certain embodiments, the compound of Formula I further has the structure of Formula II,

[0145]

[0146] A ring is a 4-9 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, S=0, S(0)2 (e.g., a 4-7 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, S=0, S(0)2), 3-6 cycloalkyl;

[0147] E ring is phenyl or 5-6 membered heteroaryl containing 1, 2, 3, 4 heteroatoms selected from N, O, S;

[0148] G ring is a 4-7 membered cycloalkyl, a 5-7 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, S=0, S(0)2;

[0149] Q1 is said G optionally substituted by one or more deuterium atom, F, Cl, cyano, hydroxy, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy;

[0150] L1is a bond, O, NR 4 , CR 5 R 6 , -OR 7 , or C(=O);

[0151] L2is a bond or NR 4 ;

[0152] L3is NR 4 ;

[0153] L4is O or CR 5 R 6 ;

[0154] M is C=O or S(=O)2;

[0155] Y 1 is N or CR a ;

[0156] Y 3 is N or CR c ;

[0157] Y 5 is N, CH or C; when L2is a bond, Y 5 is N; when L2is O or NR 4 , Y 5 is CH or C;

[0158] R 1 is halomethyl, ethenyl, propenyl, ethynyl, propynyl, butynyl, oxetanyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl, optionally substituted by one or more F, Cl, methyl, ethyl, cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxetanyl, deuterium atom, phenyl, pyridyl, or NR x R y , said methyl, ethyl, cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxetanyl, phenyl, or pyridyl is optionally substituted by one or more R';

[0159] R 2 is a hydrogen atom, deuterium atom, cyano, halogen, C 1-6 alkyl, C2-4 alkenyl, C 2-4 alkynyl, haloC 1-4 alkyl, deuterated C 1-4 alkyl, 3- to 6-membered cycloalkyl, C 1-4 alkoxy-C 1-4 alkyl, haloC 1-4 alkoxy or oxo (=0), said C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, haloC 1-4 alkyl, deuterated C 1-4 alkyl, 3- to 6-membered cycloalkyl, C 1-4 alkoxy-C 1-4 alkyl, haloC 1-4 alkoxy is optionally substituted by one or more R';

[0160] R 3 is a hydrogen atom, deuterium atom, halogen, cyano, nitro, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3- to 6-membered saturated or unsaturated cycloalkyl, 3- to 6-membered saturated or unsaturated heterocyclyl containing one or more heteroatoms selected from the group consisting of N, O, S, S=0, S(0)2, haloC 1-4 alkyl, haloC 1-4 alkoxy, OR e , SOR e , S(0)2R e , C(=0)R e , C(=0)NR e , NR e R f , NR e C(=0)R f , S(0)2NR e , P(0)(R e )2, said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3- to 6-membered saturated or unsaturated cycloalkyl, 3- to 6-membered saturated or unsaturated heterocyclyl containing one or more heteroatoms selected from the group consisting of N, O, S, S=0, S(0)2, haloC 1-4 alkyl, haloC 1-4 alkoxy is optionally substituted by one or more R';

[0161] R 4 is a hydrogen atom, C 1-6 alkyl, haloC 1-6 alkyl, deuterated C 1-6 alkyl, C 2-4 alkenyl, C2-4 Alkyne or 3-12 membered cycloalkyl, wherein 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, cyano, hydroxyl, methoxy or cyclopropyl groups;

[0162] R 5 R 6 Each is independently a hydrogen atom, deuterium atom, halogen, cyano group, hydroxyl group, amino group, 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;

[0163] Or, R 5 With R 6 Together with the attached C atom, it forms a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group is optionally substituted by one or more methyl, ethyl, halogen, deuterium, or cyclopropyl atoms.

[0164] R 7 It is methylene, ethylene, or propylene;

[0165] R a It consists of hydrogen atoms, deuterium atoms, halogens, cyano groups, and carbon atoms. 1-6 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 4-10 membered heterocyclic group, OR a1 SR a1 or NR a1 The C 1-6 Alkyl, C 2-4 alkenyl, C 2-4 The alkynyl group and the 4-10 membered heterocyclic group are optionally substituted by one or more R′;

[0166] 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 groups or 3-6 membered heterocyclic groups containing one or more heteroatoms selected from N, O, S, S=O, and S(O)2. 1-6 Alkyl, the C 1-4Alkyl, 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 groups or 3-6 membered heterocyclic groups containing one or more heteroatoms selected from N, O, S, S=O, and S(O)2. 1-6 The alkyl group may optionally be substituted with one or more halogens, deuterium atoms, methyl, ethyl, or oxo groups;

[0167] R c The atom is a hydrogen atom, halogen, cyano, amino, methyl, ethyl, isopropyl, cyclopropyl, methoxy, or cyclopropoxy, wherein the amino, methyl, isopropyl, ethyl, cyclopropyl, methoxy, and cyclopropoxy are optionally substituted by one or more R′.

[0168] R x R y Each of the following is independently a hydrogen atom, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, acridinemethyl or acridineethyl, wherein the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, acridinemethyl or acridineethyl is optionally substituted by one or more R′;

[0169] Or, NR x R y Chinese R x With R y Together with the attached N atom, it forms acridine, pyrrolidine, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl dioxide, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl or 2-azabicyclo[3.1.0]hexyl, wherein the acridine, pyrrolidine, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl dioxide, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl or 2-azabicyclo[3.1.0]hexyl is optionally substituted by one or more R′;

[0170] R e R f Each is independently a hydrogen atom, a deuterium atom, and a carbon atom. 1-4 Alkyl, Halogenated C 1-4 Alkyl groups, 3-12 membered cycloalkyl groups;

[0171] Or, NR e R f Chinese Re and R f together with the linking N atom form a 3-6 membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S, S=0, S(0)2;

[0172] - / - is no or a chemical bond;

[0173] B ring is pyrrole, imidazole, pyrazole, thiazole, oxazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine or triazine;

[0174] X a , X b , X c each independently is N or CH;

[0175] X 1 is a chemical bond, N, CH, CH2, S, O, S(O) or S(0)2;

[0176] X 2 is N, CH, CH2, O, S, S(O) or S(0)2;

[0177] X 3 , X 4 each independently is N or C, and X 3 and X 4 are not simultaneously N, X 1 , X 2 and X 3 are not simultaneously N;

[0178] X 5 is a chemical bond, N, CH, CH2, O or S;

[0179] X 6 is N, O, S or CH;

[0180] R' each independently is a deuterium atom, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-4 alkyl, deuterated C 1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S, S=0, S(0)2, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, haloC 1-6 alkoxy or oxo (=0);

[0181] m, n, t are each independently 0, 1, 2, 3, 4, or 5.

[0182] In certain embodiments, the compound of Formula I further has the structure of Formula III,

[0183]

[0184] A ring is a 4-9 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, S=O, S(O)2(e.g., A ring is a 4-7 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, S=O, S(O)2), 3-6 cycloalkyl;

[0185] E ring is phenyl or 5-6 membered heteroaryl containing 1, 2, 3, 4 heteroatoms selected from N, O, S;

[0186] G ring is 4-7 membered cycloalkyl, 5-7 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, S=O, S(O)2;

[0187] W is N, C, or CR a ;

[0188] Q1is the optionally substituted with one or more deuterium atom, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy;

[0189] L1is a bond, O, NR 4 , CR 5 R 6 , -OR 7 , or C(=O);

[0190] L2is a bond or NR 4 ;

[0191] L3is NR 4 ;

[0192] L4is O or CR 5 R 6 ;

[0193] M is C=O or S(=O)2;

[0194] Y 1 is N or CR a ;

[0195] Y 3 is N or CR c ;

[0196] Y 4 is N or CR d ;

[0197] Y 5 is N, CH or C; when L2is a bond, Y 5 is N; when L2is O or NR 4 , Y 5 is CH or C;

[0198] R 1 is halomethyl, ethenyl, propenyl, ethynyl, propynyl, butynyl, propylenoxyl, butylenoxyl, cyclopentenyl or cyclohexenyl, optionally substituted with one or more F, Cl, methyl, ethyl, cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl, propylenoxyl, butylenoxyl, deuterium, phenyl, pyridyl or NR x R y substituted with one or more R'; methyl, ethyl, cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl, propylenoxyl, butylenoxyl, phenyl or pyridyl are optionally substituted with one or more R';

[0199] R 2 is a hydrogen atom, deuterium atom, cyano, halogen, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, haloC 1-4 alkyl, deuterated C 1-4 alkyl, 3-6 membered cycloalkyl, C 1-4 alkoxy-C 1-4 alkyl, haloC 1-4 alkoxy or oxo (=0), C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, haloC 1-4 alkyl, deuterated C 1-4 alkyl, 3-6 membered cycloalkyl, C 1-4 alkoxy-C 1-4 alkyl, haloC 1-4 alkoxy optionally substituted with one or more R';

[0200] R 3 is a hydrogen atom, deuterium atom, halogen, cyano, nitro, C 1-4 alkyl, C 2-4 alkenyl, C 2-4alkyl, haloC 1-4 alkyl, haloC 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, said 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 heterocyclyl containing 1 or more heteroatoms selected from N, O, S, S=O, S(O)2, haloC 1-4 alkyl, haloC 1-4 alkoxy optionally substituted with one or more R';

[0201] R 4 is a hydrogen atom, C 1-6 alkyl, haloC 1-6 alkyl, deuterated C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl or 3-12 membered cycloalkyl, said C 1-6 alkyl, haloC 1-6 alkyl, deuterated C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl or 3-12 membered cycloalkyl optionally substituted with one or more methyl, ethyl, halogen, deuterium atom, cyano, hydroxy, methoxy or cyclopropyl groups;

[0202] R 5 , R 6 each independently is a hydrogen atom, deuterium atom, halogen, cyano, hydroxy, amino, C 1-6 alkyl, haloC 1-6 alkyl, 3-6 membered cycloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, 3-12 membered cycloalkyloxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino;

[0203] or, R 5R 6 and the connected C atoms form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, which is optionally substituted by one or more methyl, ethyl, halogen, deuterium atom or cyclopropyl groups;

[0204] R 7 is a methylene, ethylene or propylene group;

[0205] R a is a hydrogen atom, deuterium atom, halogen, cyano, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 4-10 membered heterocyclyl, OR a1 , SR a1 or NR a1 , which C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 4-10 membered heterocyclyl is optionally substituted by one or more R';

[0206] R a1 is a hydrogen atom, C 1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl comprising one or more heteroatoms selected from N, O, S, S=0, S(0)2, 3-6 membered cycloalkyl-C 1-6 alkyl or 3-6 membered heterocyclyl-C 1-6 alkyl comprising one or more heteroatoms selected from N, O, S, S=0, S(0)2, which C 1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl comprising one or more heteroatoms selected from N, O, S, S=0, S(0)2, 3-6 membered cycloalkyl-C 1-6 alkyl or 3-6 membered heterocyclyl-C 1-6 alkyl comprising one or more heteroatoms selected from N, O, S, S=0, S(0)2 is optionally substituted by one or more halogen, deuterium atom, methyl, ethyl, or oxo;

[0207] R c is a hydrogen atom, halogen, cyano, amino, methyl, ethyl, isopropyl, cyclopropyl, methoxy or cyclopropyloxy, which amino, methyl, isopropyl, ethyl, cyclopropyl, methoxy and cyclopropyloxy is optionally substituted by one or more R';

[0208] R d is a hydrogen atom, halogen, cyano, amino, methyl, ethyl, isopropyl, cyclopropyl, methoxy or cyclopropyloxy, which amino, methyl, isopropyl, ethyl, cyclopropyl, methoxy and cyclopropyloxy is optionally substituted by one or more R';

[0209] Rx , R y each independently is 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, the methyl group, the ethyl group, the isopropyl group, the cyclopropyl group, the cyclobutyl group, the cyclopentyl group, the adamantyl group, the methoxyethyl group, the cyclopropylmethyl group, the cyclobutylmethyl group, the cyclopropylethyl group, the cyclobutylethyl group, the azetidinylmethyl group, or the azetidinylethyl group being optionally substituted with one or more R';

[0210] or, NR x R y in R x and R y together with the attached N atom form an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, a dioxidothiomorpholinyl group, a 7-azabicyclo[2.2.1]heptanyl group, a 9-azabicyclo[3.3.1]nonanyl group, a 2-azabicyclo[4.1.0]heptanyl group, or a 2-azabicyclo[3.1.0]hexanyl group, the azetidinyl group, the pyrrolidinyl group, the piperidinyl group, the piperazinyl group, the morpholinyl group, the thiomorpholinyl group, the dioxidothiomorpholinyl group, the 7-azabicyclo[2.2.1]heptanyl group, the 9-azabicyclo[3.3.1]nonanyl group, the 2-azabicyclo[4.1.0]heptanyl group, or the 2-azabicyclo[3.1.0]hexanyl group being optionally substituted with one or more R';

[0211] R e , R f each independently is a hydrogen atom, a deuterium atom, a C 1-4 alkyl group, a haloC 1-4 alkyl group, a 3-12 membered cycloalkyl group;

[0212] or, NR e R f in R e and R f together with the attached N atom form a 3-6 membered heterocyclyl group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2;

[0213] -- / --- is nothing or a chemical bond;

[0214] B ring is a pyrrole, an imidazole, a pyrazole, a thiazole, an oxazole, an oxadiazole, a triazole, a tetrazole, a pyridine, a pyrimidine, a pyridazine, a pyrazine, or a triazine;

[0215] X a , X b , X c each independently is N or CH;

[0216] X 1is a bond, N, CH, CH2, S, O, S(O), or S(O)2;

[0217] X 2 is N, CH, CH2, O, S, S(O), or S(O)2;

[0218] X 3 , X 4 are each independently N or C, and X 3 and X 4 are not simultaneously N, X 1 , X 2 and X 3 are not simultaneously N;

[0219] X 5 is a bond, N, CH, CH2, O, or S;

[0220] X 6 is N, O, S, or CH;

[0221] R' are each independently a deuterium atom, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-4 alkyl, deuterated C 1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl containing 1 or more heteroatoms each selected from N, O, S, S=0, S(0)2, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, haloC 1-6 alkoxy, or oxo (=0);

[0222] m, n, t are each independently 0, 1, 2, 3, 4, or 5.

[0223] In certain embodiments, R' are each independently a deuterium atom, halogen, cyano, hydroxyl, amino, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, haloC 1-4 alkyl, deuterated C 1-4 alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl containing 1 or more heteroatoms each selected from N, O, S, S=0, S(0)2, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, haloC1-6 Alkyl or oxo (=O);

[0224] Preferably, R′ is independently a deuterium atom, halogen, cyano group, hydroxyl group, amino group, or C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, 3-6 membered cycloalkyl, 4-7 membered heterocyclic groups 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 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, Halogenated C 1-4 Alkyl or oxo (=O);

[0225] 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, or oxo (=O).

[0226] In some specific embodiments, in formula I, II, or III,

[0227] Ring A is a 4-9 membered heterocyclic group containing one or two heteroatoms selected from N, O, S, S=O, S(O)2 (e.g., ring A is a 4-7 membered heterocyclic group containing one or two heteroatoms selected from N, O, S, S=O, S(O)2), or a 3-6 cyclic alkyl group;

[0228] The E ring is phenyl or contains 1, 2, 3, or 4 5-6 membered heteroaryl groups selected from N, O, and S heteroatoms;

[0229] Q1 is The land Optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy.

[0230] L1 represents chemical bonds, O, and NR. 4 CR 5 R 6 -OR 7 - or C (=O);

[0231] L2 represents a chemical bond or NR.4 ;

[0232] L3is NR 4 ;

[0233] L4is O or CR 5 R 6 ;

[0234] M is C=O or S(=O)2;

[0235] Y 1 is N or CR a ;

[0236] Y 2 is N or CR b ;

[0237] Y 3 is N or CR c ;

[0238] Y 4 is N or CR d ;

[0239] Y 5 is N, CH or C; when L2is a bond, Y 5 is N; when L2is O or NR 4 , Y 5 is CH or C;

[0240] R 1 is halomethyl, ethenyl, propenyl, ethynyl, propynyl, butynyl, propylenoxyl, butylenoxyl, cyclopentenyl or cyclohexenyl, optionally substituted with one or more F, Cl, methyl, ethyl, cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl, propylenoxyl, butylenoxyl, deuterium, phenyl, pyridinyl or NR x R y , said methyl, ethyl, cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl, propylenoxyl, butylenoxyl, phenyl or pyridinyl is optionally substituted with one or more R';

[0241] R 2 is a hydrogen atom, deuterium atom, cyano, halogen, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, 3-6 membered cycloalkyl, C 1-4 alkoxy-C 1-4 alkyl, halogenated C 1-4alkyl, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, haloC 1-4 alkyl, deuterated C 1-4 alkyl, 3-6 membered cycloalkyl, C 1-4 alkoxy-C 1-4 alkyl, haloC 1-4 alkyl, deuterated C

[0242] R 3 is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a nitro group, a 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 heterocyclyl containing one or more heteroatoms selected from the group consisting of N, O, S, S=O, S(O)2, haloC 1-4 alkyl, haloC 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 heterocyclyl containing one or more heteroatoms selected from the group consisting of N, O, S, S=O, S(O)2, haloC 1-4 alkyl, haloC 1-4 alkyl, deuterated C

[0243] R 4 is a hydrogen atom, a C 1-6 alkyl, haloC 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, haloC 1-6 alkyl, deuterated C 1-6 alkyl, C 2-4 alkenyl, C 2-4The alkynyl or 3-12 membered cycloalkyl group is optionally substituted with one or more methyl, ethyl, halogen, deuterium, cyano, hydroxyl, methoxy or cyclopropyl groups;

[0244] R 5 R 6 Each is independently a hydrogen atom, deuterium atom, halogen, cyano group, hydroxyl group, amino group, 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;

[0245] Or, R 5 With R 6 Together with the attached C atom, it forms a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group is optionally substituted by one or more methyl, ethyl, halogen, deuterium, or cyclopropyl atoms.

[0246] R 7 It is methylene, ethylene, or propylene;

[0247] The G ring is a 4-7 membered cycloalkyl group containing one or two 5-7 membered heterocyclic groups selected from N, O, S, S=O, and S(O)2 heteroatoms;

[0248] W represents N, C, or CR. a ;

[0249] R a R b Each is independently composed of a hydrogen atom, a deuterium atom, a halogen, a cyano group, and a carbon atom. 1-6 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 4-10 membered heterocyclic group, OR a1 SR a1 or NR a1 The C 1-6 Alkyl, C 2-4 alkenyl, C 2-4 The alkynyl group and the 4-10 membered heterocyclic group are optionally substituted by one or more R′;

[0250] R c The atom is a hydrogen atom, halogen, cyano, amino, methyl, ethyl, isopropyl, cyclopropyl, methoxy, or cyclopropoxy, wherein the amino, methyl, isopropyl, ethyl, cyclopropyl, methoxy, and cyclopropoxy are optionally substituted by one or more R′.

[0251] R dIt either does not exist or is a hydrogen atom, deuterium atom, halogen, cyano group, amino group, or C atom. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl mercapto or C 1-6 Alkylamino, wherein the amino group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl mercapto or C 1-6 The alkylamino group is optionally substituted with one or more R′;

[0252] R b With R d Together with the attached atoms, they form a 4-7 membered cycloalkyl group or a 5-7 membered heterocyclic group containing one or two heteroatoms selected from N, O, S, S=O, and S(O)2, wherein the 4-7 membered cycloalkyl group or the 5-7 membered heterocyclic group containing one or two heteroatoms selected from N, O, S, S=O, and S(O)2 is optionally substituted by one or more R′.

[0253] Or, R b With R 2 Together with the attached atoms, they form a 5-7 membered heterocyclic group containing one or two heteroatoms selected from N, O, S, S=O, and S(O)2, or a 5-6 membered heteroaryl group containing one, two, three, or four heteroatoms selected from N, O, and S. The 5-7 membered heterocyclic group containing one or two heteroatoms selected from N, O, S, S=O, and S(O)2, or the 5-6 membered heteroaryl group containing one, two, three, or four heteroatoms selected from N, O, and S, is optionally substituted by one or more R′.

[0254] R e R f Each is independently a hydrogen atom, a deuterium atom, and a carbon atom. 1-4 Alkyl, Halogenated C 1-4 Alkyl groups, 3-12 membered cycloalkyl groups;

[0255] Or, NR e R f Chinese R e and R f Together with the connected 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;

[0256] R x R yeach independently is 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, said methyl group, ethyl group, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, adamantyl group, methoxyethyl group, cyclopropylmethyl group, cyclobutylmethyl group, cyclopropylethyl group, cyclobutylethyl group, azetidinylmethyl group, or azetidinylethyl group is optionally substituted with one or more R';

[0257] or NR x R y R x R y and the attached N atom together form an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, a dioxidothiomorpholinyl group, a 7-azabicyclo[2.2.1]heptanyl group, a 9-azabicyclo[3.3.1]nonanyl group, a 2-azabicyclo[4.1.0]heptanyl group, or a 2-azabicyclo[3.1.0]hexanyl group, said azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, dioxidothiomorpholinyl group, 7-azabicyclo[2.2.1]heptanyl group, 9-azabicyclo[3.3.1]nonanyl group, 2-azabicyclo[4.1.0]heptanyl group, or 2-azabicyclo[3.1.0]hexanyl group is optionally substituted with one or more R';

[0258] R a1 is a hydrogen atom, a C 1-4 alkyl group, a 3-6 membered cycloalkyl group, a 3-6 membered heterocyclyl group having one or more heteroatoms each independently selected from N, O, S, S=O, S(O)2, a 3-6 membered cycloalkyl-C 1-6 alkyl group, or a 3-6 membered heterocyclyl-C 1-6 alkyl group, said C 1-4 alkyl group, 3-6 membered cycloalkyl group, 3-6 membered heterocyclyl group having one or more heteroatoms each independently selected from N, O, S, S=O, S(O)2, a 3-6 membered cycloalkyl-C 1-6 alkyl group, or a 3-6 membered heterocyclyl-C 1-6 alkyl group is optionally substituted with one or more halogen, deuterium atom, methyl group, ethyl group, or oxo;

[0259] is nothing or a chemical bond;

[0260] B ring is pyrrole, imidazole, pyrazole, thiazole, oxazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, or triazine;

[0261] X a , Xb , X c each independently N or CH;

[0262] X 1 is a bond, N, CH, CH2, S, O, S(O) or S(O)2;

[0263] X 2 is N, CH, CH2, O, S, S(O) or S(O)2;

[0264] X 3 , X 4 each independently N or C, and X 3 and X 4 are not simultaneously N, X 1 , X 2 and X 3 are not simultaneously N;

[0265] X 5 is a bond, N, CH, CH2, O or S;

[0266] X 6 is N, O, S or CH;

[0267] R' is a deuterium atom, F, Cl, cyano, hydroxy, amino, methyl, ethyl, isopropyl, ethenyl, ethynyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, pyrrolidinyl, 1-methylpyrrolidin-3-yl or oxo (=0);

[0268] m, n, t are each independently 0, 1, 2 or 3.

[0269] In other embodiments, in formula I, II or III:

[0270] A ring is piperidinyl, azetidinyl, pyrrolidinyl, piperazinyl, homopiperidine, homopiperazine, 1,4-azepino, 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;

[0271] E ring is phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene or pyrazole;

[0272] Q1 is selected from the following groups:

[0273] Q1is optionally substituted with one or more deuterium atom, F, Cl, cyano, hydroxyl, amino, methyl, deuterated methyl, ethyl, isopropyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy;

[0274] L1is a bond, O, NR 4 , CR 5 R 6 , -OR 7 - or C(=O);

[0275] L2is a bond or NR 4 ;

[0276] L3is NR 4 ;

[0277] L4is O or CR 5 R 6 ;

[0278] M is C=O;

[0279] R 4 is a hydrogen atom, methyl, ethyl, isopropyl, 1,2-dihydroxypropan-3-yl, acetyl, methoxyethyl, ethylnitrile, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, propenyl, or propynyl;

[0280] R 5 , R 6 are each independently a hydrogen atom, deuterium atom, halogen, cyano, hydroxyl, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, propenyl, or propynyl;

[0281] Alternatively, R 5 and R 6 together with the C atom to which they are attached form a cyclopropyl or cyclobutyl, which is optionally substituted with one or more methyl, ethyl, halogen, deuterium atom, or cyclopropyl;

[0282] R 7 is methylene;

[0283] Y 1 is N or CR a ;

[0284] Y 2 is N or CR b ;

[0285] Y 3 is N or CR c ;

[0286] Y 4 is N or CR d ;

[0287] Y 5 is N, CH or C; when L2is a bond, Y 5 is N; when L2is O or NR 4 , Y 5 is CH or C;

[0288] R a is a hydrogen atom, a deuterium atom, F, Cl, Br, cyano, hydroxy, amino, methyl, ethyl, n-propyl, i-propyl, difluoromethyl, trifluoromethyl, ethynyl, 2-(1,3-dimethylpyrrolidin-3-yl)ethynyl, ethylnitrile, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, hydroxyethoxy, N',N'-dimethylaminoethoxy, N'-methylaminoethoxy, morpholino, 2-oxa-6-azaspiro[3.3]cycloheptanyl, morpholino-ethoxy, hydroxypropoxy, N',N'-dimethylaminopropoxy, N'-methylaminopropoxy, morpholino-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-yloxy, methylthio, methylamino, ethylamino, acetylamido, propionylamido, methoxyethyl, methoxyethylamino or methoxyethoxy;

[0289] R c is a hydrogen atom, a halogen, cyano, amino, methyl, ethyl, i-propyl, cyclopropyl, methoxy or cyclopropoxy;

[0290] R b is a hydrogen atom, a halogen, cyano, amino, methyl, ethyl, i-propyl, cyclopropyl, methoxy or cyclopropoxy; dtogether with the attached atoms form morpholinyl, tetrahydrofuranyl, dihydroimidazolyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyranylone, 1,4-dioxanyl, hexahydro-l,4-oxazepinyl, hexahydro-l,4-thiazepinyl, 4-thiomorpholinyl-l-oxide, 4-thiomorpholinyl-l,l-dioxide, hexahydro-l,4-thiazepinyl-l-oxide, or hexahydro-l,4-thiazepinyl-l,l-dioxide, 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;

[0291] R 1 is selected from the group consisting of:

[0292]

[0293]

[0294] R 2 is a hydrogen atom, deuterium atom, F, Cl, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, ethenyl, propenyl, ethynyl, propynyl, cyano, difluoromethoxy, trifluoromethoxy, methoxy, methoxymethyl, or oxo (=0);

[0295] or, R b is taken together with R 2with the attached atoms form morpholinyl, tetrahydrofuranyl, dihydroimidazolyl, thiomorpholinyl, hexahydro-l,4-oxazepinyl, hexahydro-l,4-thiazepinyl, 4-thiomorpholinyl-l-oxide, 4-thiomorpholinyl-l,l-dioxide, hexahydro-l,4-thiazepinyl-l-oxide, or hexahydro-l,4-thiazepinyl-l,l-dioxide, which 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;

[0296] R 3 is a hydrogen atom, deuterium atom, F, Cl, cyano, nitro, methyl, ethyl, isopropyl, ethene, ethyne, cyclopropyl, cyclobutyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, 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, which is optionally substituted with one or more deuterium atoms, F, Cl, hydroxyl, methyl, ethyl, isopropyl, or cyclopropyl;

[0297] G ring is morpholinyl, tetrahydrofuranyl, dihydroimidazolyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyranylone, 1,4-dioxanyl, hexahydro-l,4-oxazepinyl, hexahydro-l,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, hydroxyl, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, dimethylaminoalkyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy;

[0298] W is C or CH;

[0299] m, n, t are each independently 0, 1, 2, or 3.

[0300] In yet other embodiments, in Formula I, II, or III:

[0301] A ring is piperidinyl, azetidinyl, pyrrolidinyl, piperazinyl, homopiperazine, 1,4-azoxepane, cyclopentyl, cyclohexyl, 8-azabicyclo[3.2.1]octane;

[0302] E ring is phenyl;

[0303] Q1is selected from the following groups:

[0304]

[0305] L1is a bond, O, NR 4 , CR 5 R 6 , or C(=O);

[0306] L2is a bond or NH;

[0307] L3is NH;

[0308] L4is O or CR 5 R 6 ;

[0309] M is C=O;

[0310] R 4a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a 1,2-dihydroxypropan-3-yl group, an acetyl group, a methoxyethyl group, an ethylnitrile 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;

[0311] R 5 , R 6 each independently a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, a deuterated methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a cyclopropyl group, a methylamino group, a dimethylamino group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a propenyl group, or a propynyl group;

[0312] or, R 5 and R 6 together with the C atom to which they are attached form a cyclopropyl group or a cyclobutyl group, which is optionally substituted with one or more methyl groups, ethyl groups, halogens, deuterium atoms, or cyclopropyl groups;

[0313] Y 1 is N or CR a ;

[0314] Y 2 is N or CR b ;

[0315] Y 3 is N;

[0316] Y 4 is N or CR d ;

[0317] Y 5 is N, CH, or C; when L2is a bond, Y 5 is N; when L2is O or NR 4 , Y 5 is CH or C;

[0318] R ahydrogen atom, deuterium atom, F, CI, Br, cyano, hydroxyl, amino, methyl, ethyl, n-propyl, i-propyl, difluoromethyl, trifluoromethyl, ethynyl, 2-(1,3-dimethylpyrrolidin-3-yl)ethynyl, ethylnitrile, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, hydroxyethoxy, N',N'-dimethylaminoethoxy, N'-methylaminoethoxy, morpholinyl, 2-oxa-6-azaspiro[3.3]cycloheptanyl, 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-yloxy, methylthio, methylamino, ethylamino, acetylamino, propionylamino, methoxyethyl, methoxyethylamino or methoxyethoxy;

[0319] R b R d together with the atom to which they are attached form morpholinyl, tetrahydrofuranyl, dihydroimidazolyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyranylone, 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, said morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyranylone, 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 being optionally substituted by one or more deuterium atom, F, CI, cyano, hydroxyl, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, dimethylaminoalkyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy;

[0320] R 1 is selected from the following groups:

[0321]

[0322]

[0323] R 2It can be hydrogen atom, deuterium atom, F, Cl, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, vinyl, propynyl, ethynyl, propynyl, cyano, difluoromethoxy, trifluoromethoxy, methoxy, methoxymethyl or oxo (=O);

[0324] Or, R b With R 2 Together with the attached atoms, they form morpholino, tetrahydrofurano, dihydroimidazolyl, thiomorpholino, hexahydro-1,4-oxazaporyl, hexahydro-1,4-thiozaporyl, 4-thiomorpholino-1-oxide, 4-thiomorpholino-1,1-dioxide, hexahydro-1,4-thiozaporyl-1-oxide, or hexahydro-1,4-thiozaporyl-1,1-dioxide, wherein the morpholino, thiomorpholino, hexahydro-1,4-oxazaporyl, hexahydro-1,4-thiozaporyl, or 4-thiomorpholino -1-oxide, 4-thiomorpholino-1,1-dioxide, hexahydro-1,4-thioazaporphyryl-1-oxide or hexahydro-1,4-thioazaporphyryl-1,1-dioxide may optionally be 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;

[0325] R 3 The group can be hydrogen atom, deuterium atom, F, Cl, cyano, nitro, methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, or ethylamino, wherein the methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, methylamino, or ethylamino groups are optionally substituted with one or more deuterium atoms, F, Cl, hydroxyl, methyl, ethyl, isopropyl, or cyclopropyl groups;

[0326] The G ring is morpholino, tetrahydrofurano, dihydroimidazolyl, tetrahydropyrano, tetrahydropyranone, 1,4-dioxane, or hexahydro-1,4-oxazaporyl, wherein the morpholino, thiomorpholino, tetrahydropyrano, tetrahydropyranone, 1,4-dioxane, or hexahydro-1,4-oxazaporyl 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.

[0327] W is C or CH;

[0328] m, n, t are each independently 0, 1, 2 or 3.

[0329] In a more particular embodiment, the compound of formula I is selected from the group consisting of:

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339] In a second aspect, in certain embodiments, the present application provides a method for preparing a compound of formula II, the method comprising the following reaction steps:

[0340] (1) a substitution reaction of compound II-1 with compound II-2 to form compound II-3;

[0341] (2) a reduction reaction of compound II-3 to form compound II-5; or a halogenation reaction of compound II-3 to form compound II-4, followed by a coupling reaction of compound II-4 to form compound II-5;

[0342] (3) a reaction of compound II-5 with DMF-DMA to form compound II-6;

[0343] (4) a cyclization reaction of compound II-6 with compound II-7 to form compound II-8;

[0344] (5) a deprotection reaction of compound II-8 to form compound II-9;

[0345] (6) a substitution reaction of compound II-9 with compound II-10 or compound II-11 to form a compound of formula II;

[0346] The reaction scheme is shown in Figure 1 .

[0347] In certain embodiments, the present application provides a method for preparing a compound of Formula III, comprising the following reaction steps:

[0348] (1) substituting compound III-1 with compound III-2 to form compound III-3;

[0349] (2) reducing compound III-3 to form compound III-5; or halogenating compound III-3 to form compound III-4, and then coupling compound III-4 to form compound III-5;

[0350] (3) reacting compound III-5 with DMF-DMA to form compound III-6;

[0351] (4) cyclizing compound III-6 with compound III-7 to form compound III-8;

[0352] (5) deprotecting compound III-8 to form compound III-9;

[0353] (6) substituting compound III-9 with compound III-10 or compound III-11 to form a compound of Formula III;

[0354] The reaction route is shown in Figure 2 .

[0355] wherein, in the reaction route of Figure 1 and Figure 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 defined as above, X' is NO2 or H; X" is halogen, Boc is tert-butyloxycarbonyl.

[0356] In a third aspect, the present application provides a pharmaceutical composition comprising the above-mentioned compound or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically-labeled, deuterated, N-oxide, prodrug molecule, hydrate or solvate, and a pharmaceutically acceptable carrier or excipient;

[0357] Preferably, the pharmaceutical composition is a tablet, capsule, pill, granule, powder, suppository, injection, solution, suspension, ointment, patch, lotion, drop, liniment, spray.

[0358] In a fourth aspect, the present application provides use of a compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically-labeled, deuterated, N-oxide, prodrug molecule, hydrate or solvate thereof, or a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically-labeled, deuterated, N-oxide, prodrug molecule, hydrate or solvate thereof and a pharmaceutically acceptable carrier or excipient in the preparation of a medicament for treating a disease mediated by HER2 abnormality.

[0359] Preferably, the disease is a neoplastic disease.

[0360] More preferably, the neoplastic disease includes head and neck cancer, nasopharyngeal carcinoma, melanoma, bladder cancer, esophageal cancer, renal 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, cholangiocarcinoma, endometrial cancer, multiple myeloma or mesothelioma, atherosclerosis or pulmonary fibrosis.

[0361] In a fifth aspect, the present application provides a method for treating a disease mediated by HER2 abnormality, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically-labeled, deuterated, N-oxide, prodrug molecule, hydrate or solvate thereof or a pharmaceutical composition.

[0362] Preferably, the disease is a neoplastic disease.

[0363] More preferably, the neoplastic disease includes head and neck cancer, nasopharyngeal carcinoma, melanoma, bladder cancer, esophageal cancer, renal 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, cholangiocarcinoma, endometrial cancer, multiple myeloma or mesothelioma, atherosclerosis or pulmonary fibrosis.

[0364] In a sixth aspect, the present application provides a method for treating a neoplastic disease, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically-labeled, deuterated, N-oxide, prodrug molecule, hydrate or solvate thereof or a pharmaceutical composition.

[0365] The patient is preferably a mammal, and the mammal is preferably a human.

[0366] In certain embodiments, the mode of administration includes oral, mucosal, sublingual, ocular, topical, parenteral, rectal, cisternal, vaginal, peritoneal, bladder, nasal administration.

[0367] In certain embodiments, the tumor includes 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's lymphoma, gastric cancer, lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, squamous cell carcinoma, cholangiocarcinoma, endometrial cancer, multiple myeloma, or mesothelioma.

[0368] The compounds or their pharmaceutically acceptable salts, stereoisomers, racemates, tautomers, isotopically-labeled, deuterated, N-oxides, prodrug molecules, hydrates or solvates or pharmaceutical compositions of the present application can be administered by any suitable route in the body, such as orally, intravenously, intranasally, topically, intramuscularly, intradermally, transdermally or subcutaneously.

[0369] In certain embodiments, the compounds or their pharmaceutically acceptable salts, stereoisomers, racemates, tautomers, isotopically-labeled, deuterated, N-oxides, prodrug molecules, hydrates or solvates or pharmaceutical compositions of the present application can be formulated into a dosage form suitable for drug delivery by injection routes (such as subcutaneous, intravenous, intramuscular, arterial, intrathecal, intracapsular, intracardiac, intradermal, intraperitoneal, transtracheal, transdermal, intraarticular, subcapsular, subarachnoid, intraspinal, sternal, and / or infusion) and non-injection routes (such as oral, enterally, buccal, nasal, intranasal, mucosally, transdermally, transcutaneously, transmucosally, topically, patch, dermally, ocularly, pulmonarily, sublingually, rectally, vaginally, or topically).

[0370] Suitable dosage forms include, but are not limited to, dosage forms for injection such as emulsions, solutions and suspensions, dosage forms for oral use such as tablets, capsules, pills, dragees, powders and granules, dosage forms for topical or transdermal absorption such as sprays, ointments, pastes, creams, lotions, gels, solutions, drug patches and inhalants, dosage forms for vaginal or rectal administration such as suppositories. These dosage forms can be prepared according to the compounds and suitable excipients under suitable conditions, and the preparation methods and processes are well known, such as provided by Remington: The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000).

[0371] In certain embodiments, HER2 abnormality refers to HER2 gene mutation, HER2 amplification or HER2 overexpression.

[0372] Preferably, the HER2 gene mutation comprises exon 18-21 mutation, transmembrane domain mutation and extracellular region mutation; the mutation comprises point mutation (e.g. exon 20 point mutation), deletion mutation and insertion mutation (e.g. exon 20 insertion mutation);

[0373] More preferably, the exon 20 insertion mutation comprises Y772_A775dup, G776delinsVC, G778_P780dup, G776delinsLC, E770delinsEAYVM, E770_A771insAYVM, Y772_V773insMMAY, M774delinsWLV, A775_G776insYVMS, A775_G776insVVMA, A775_G776insSVMA, A775_G776insTVMA, A775_G776insC, G776delinsAVGC, G776delinsVV, G776delinsVG, G776_V777delinsCVC, G776_V777delinsVC, G776delinsIC, V777delinsAPL, V777_G778insC, G778insGSP, G778_S779insCPG; the exon 20 point mutation comprises G776C, G776D, G776S, G776V, V777L, D778H, V782I, T791A, L806P, R811L, N813T, R816C, Q820K, Q828H, M774AYVM.

[0374] In certain embodiments, the compounds or pharmaceutical compositions of the present application can be administered simultaneously, sequentially or separately with one or more additional pharmacologically active agents to achieve additive or synergistic effects in the body. For example, the compounds of the present application can be combined with additional pharmacologically active agents in a single pharmaceutical composition, or administered simultaneously as separate compositions, or administered sequentially as separate compositions. Additional pharmacologically active agents that can be administered simultaneously with the compounds of the present application for the treatment of cancer include, but are not limited to: 1) EGFR family inhibitors, monoclonal antibodies or ADCs, etc., such as: Osimertinib, Ametanib, Volitinib, Bemforitinib, Recizumab, Rezafungin, Rizamtenib, olmutinib, Lazertinib, PLB1004, Afatinib, Dacomitinib, Erlotinib, Gefitinib, Ecteinacib, Cetuximab, Panitumumab, Amivantamab, Lapatinib, Neratinib, Tucatinib, Trastuzumab, Pertuzumab, Margetuximab, Enavatuzumab, Deruxtezumab, etc.; 2) inhibitors of downstream pathways or other pathway targets, including but not limited to MEK, RET, PI3K, mTOR, c-Met, PARP, or mitotic kinase inhibitors (such as CDK4 / 6), etc.For example, trametinib, binimetinib, selumetinib, pacritinib, idelalisib, Copanlisib, Duvelisib, Alpelisib, umbralisib, Parsaclisib, rapamycin, temsirolimus, everolimus, carmofur, tepotinib, sevacitabine, golvatinib, biricodar, 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, leuprolide, goserelin, flutamide, nilutamide, finasteride, dexamethasone, aminoglutethimide, amsacrine, anastrozole, asparaginase, bacillus calmette-guerin, bicalutamide, bleomycin, busulfan, camptothecin, capecitabine, carboplatin, cisplatin, carmustine, chlorambucil, cladribine, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, dienestrol, 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, leucovorin, pentostatin, plicamycin, procarbazine, raltitrexed, porfimer sodium, rituximab, streptozocin, suramin, leuprolide, levamisole, lomustine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, nocodazole, octreotide, paclitaxel, pamidronate, thioguanine, triethylene thiophosphoramide, chloromethane, topotecan titanocene, tretinoin, vinblastine, vincristine, vindesine, vinorelbine, pemetrexed.

[0375] In certain embodiments, the compounds provided herein can be used simultaneously with an immunotherapeutic agent. Suitable immunotherapeutic agents include: PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, such as Durvalumab; tumor cell multidrug resistance reversal agents (such as verapamil), mycophenolic acid, thalidomide, cyclosporine, and monoclonal antibodies.

[0376] 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 radiation therapy. In certain embodiments, the compounds provided herein can be used concurrently with surgery, tumor hyperthermia, focused ultrasound therapy, cryotherapy, or a combination thereof.

[0377] The technical solutions of the present application will be described clearly and completely below in conjunction with the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments of the present application. Based on the embodiments of the present application, all the other embodiments obtained by those skilled in the art without creative efforts fall within the scope of the present application.

[0378] It is particularly pointed out that similar substitutions and modifications made to the present application are obvious to those skilled in the art, and they are considered to be included in the present application. The related personnel can obviously make changes or appropriate changes and combinations to the methods and applications described herein without departing from the content, spirit and scope of the present application, to realize and apply the technical solutions of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments of the present application.

[0379] Unless otherwise specified, the present application is carried out according to the conventional conditions or the conditions recommended by the manufacturer. The raw materials or excipients used, and the reagents or instruments used, are not specified by the manufacturer, and are conventional products that can be obtained by purchase.

[0380] 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 application.

[0381] --- / -- represents nothing or a chemical bond.

[0382] represents a connection site.

[0383] The minimum and maximum values of the number of carbon atoms in a hydrocarbon group are indicated by a prefix, for example, the prefix (C a-b )alkyl represents any alkyl group containing "a" to "b" carbon atoms. Thus, for example, C 1-6 alkyl means an alkyl group containing 1 to 6 carbon atoms. The alkyl group is branched or straight chain.

[0384] The atoms described in the compounds of the present application include their isotopes, for example, hydrogen can be deuterium or tritium.

[0385] "Bridged ring" means a polycyclic group in which any two rings share two atoms which are either directly connected or not directly connected, can contain one or more double bonds, but no ring has a fully conjugated pi-electron system, and the ring atoms can be all carbon or one or more of the ring atoms can be selected from N, O, S, SO, or S(O)2. Preferably 7-10 rings.

[0386] "Spiro" means a polycyclic group in which any two rings share one carbon atom, can contain one or more double bonds, but no ring has a fully conjugated pi-electron system, and the ring atoms can be all carbon or one or more of the ring atoms can be selected from N, O, S, SO, or S(O)2. Preferably 5-10 rings.

[0387] Fused ring: means a polycyclic group in which each ring shares two adjacent atoms with other rings in the system, can contain one or more double bonds or have a fully conjugated pi-electron system, and the ring atoms can be all carbon or one or more of the ring atoms can be selected from N, O, S, SO, or S(O)2. Preferably 5-10 rings.

[0388] Bicyclic: means a polycyclic group in which any two rings or more are connected by a chemical bond.

[0389] Depending on the number of rings comprising the group, the group can be a bicyclic, tricyclic, tetracyclic, or polycyclic group, preferably a bicyclic, tricyclic, or tetracyclic group, more preferably a bicyclic or tricyclic group.

[0390] A cyclic group can be bonded to another group in a variety of ways. If the manner of bonding is not specified, then all possible ways are meant to be included. For example, "pyridyl" includes 2-, 3-, or 4-pyridyl, and "thiophenyl" includes 2- or 3-thiophenyl.

[0391] "Alkyl" means a straight-chain or branched-chain, monovalent, saturated hydrocarbon group, including but not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, n-hexyl, and other similar groups. Preferably C 1-8 alkyl. More preferably C 1-6 alkyl. More preferably C 1-4 alkyl. Alkyl groups can be substituted or unsubstituted, and when substituted, the substituents can be at any point of attachment, and are preferably one or more of the following groups:

[0392] deuterium, halogen, cyano, nitro, azido, hydroxy, 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 heterocyclyl, 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 aryl, 5-10 heteroaryl, oxo (=O).

[0393] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group that can combine with other groups. Monocyclic cyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Preferably, 3-8 membered cycloalkyl. Preferably 4-7 membered cycloalkyl. More preferably 3-6 membered cycloalkyl. The partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group refers to a cycloalkenyl group. Polycyclic cyclic hydrocarbon groups include linked, spirocyclic, fused, or bridged cyclic aliphatic hydrocarbon groups, including but not limited to the following groups:

[0394]

[0395] "Cycloalkenyl" refers to a partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group having at least one carbon-carbon double bond, but not forming a fully conjugated π-electron system, and capable of combining with other groups. Monocyclic cyclic alkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cyclohepttrienyl, cyclooctenyl, etc. Preferably, 3-8 membered cyclic alkenyl groups are preferred. More preferably, 3-6 membered cyclic alkenyl groups are preferred. More preferably, 5-6 membered cyclic alkenyl groups are preferred. Polycyclic cyclic alkenyl groups include linked, spirocyclic, fused, or bridged cyclic alkenyl groups. Including but not limited to the following groups:

[0396]

[0397] The cycloalkyl or cycloalkenyl group can be fused with aryl, heteroaryl, or heterocyclic groups, including but not limited to tetrahydronaphthyl, benzocycloheptyl, etc.

[0398] "Alkenyl" refers to a straight-chain, branched, or cyclic hydrocarbon group containing one or more carbon-carbon double bonds, including but not limited to vinyl, propenyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, and (Z)-but-1-enyl. C is preferred. 2-6 Alkenyl. More preferably C 2-4 Alkenyl group.

[0399] "Alynyl" refers to a straight-chain, branched, or cyclic hydrocarbon group containing one or more carbon-carbon triple bonds, including but not limited to ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, and but-3-ynyl. C is preferred. 2-6 Alkyne group. More preferably C 2-4 Alkyne group.

[0400] "Alkylene" refers to a straight-chained or branched, divalent saturated hydrocarbon radical, i.e., one hydrogen atom of an alkyl group is further replaced by a substituent, including but not limited to, such as "methylene" refers to -CH2-, "ethylene" refers to -CH2CH2-, "propylene" refers to -CH2CH2CH2-, "butylene" refers to -CH2CH2CH2CH2- or -CH2CH(CH3)CH2-.

[0401] "Halo" refers to fluorine, chlorine, bromine, or iodine, preferably fluorine, chlorine, or bromine.

[0402] "Haloalkyl" refers to an alkyl group as defined herein in which one or more hydrogens have been replaced by the same or different halogen. Included are, but not limited to, such as -CH2Cl, -CHF2, -CH2CF3, -CH2CCl3, perfluoroalkyl (e.g., -CF3), and the like.

[0403] "Alkylamino" refers to NH3substituted with an alkyl group. Included are, but not limited to, such as methylamino, ethylamino, propylamino, isopropylamino, and the like.

[0404] "Dialkylamino" refers to a radical having the structure N(C 1-6 alkyl)2. Included are, but not limited to, such as dimethylamino, diethylamino, methyl(ethyl)amino, dipropylamino, diisopropylamino, and the like.

[0405] "Aryl" refers to a monocyclic or polycyclic carbocyclic ring system having one or more fused or non-fused aromatic rings, including but not limited to, such as phenyl, naphthyl, indenyl. Preferred are 6-10 membered monocyclic or bicyclic aromatic groups. More preferred are phenyl or naphthyl. Most preferred is phenyl.

[0406] "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 pi-electron system. The heteroatoms are independently selected from N, O, S, nitric oxide (NO), sulfoxide, S(O)(=NH), and sulfone groups. Polycyclic ring systems include fused, bridged, or spirocyclic systems. Examples of monocyclic heterocyclyl moieties include, but are not limited to: aziridinyl, 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, and the like. Preferred are 4-7 membered heterocyclyl groups. More preferred are 4-6 membered heterocyclyl 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]non-7-yl, 1,4-dioxa-8-azaspiro[4.5]dec-8-yl, and 1,4-dioxa-9-azaspiro[5.5]undec-9-yl, and the like. Examples of unsaturated heterocyclyl moieties include, but are not limited to:

[0407] The heterocyclyl groups described can be fused to aryl, heteroaryl, or cycloalkyl groups, including, but not limited to the following groups:

[0408]

[0409] The heterocyclyl groups are optionally substituted or unsubstituted, with substituted substituents preferably being one or more of the following: deuterium, halogen, CN, nitro, hydroxyl, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10alkynyl, C 2-6 heteroalkenyl, 3-12 membered saturated or unsaturated cycloalkyl, 3-12 membered saturated or unsaturated heterocyclyl, haloC 1-10 alkyl, C 1-10 alkoxy, haloC 1-10 alkoxy, deuteratedC 1-10 alkyl, deuteratedC 1-10 alkoxy, 6-10 membered aryl, 5-10 membered heteroaryl, oxo (=0).

[0410] "Heteroaryl" means a substituted or unsubstituted 5- or 6-membered mono-heteroaromatic ring system, or a substituted or unsubstituted 9- or 10-membered fused or bi-heteroaromatic ring system, containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(=0), S(=0)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, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, or benzothiazolyl.

[0411] The heteroaryl group can be fused to an aryl, heterocyclyl, or cycloalkyl group, including, but not limited to, the following groups:

[0412]

[0413] Heteroaryl is optionally substituted or unsubstituted, with substituted substituents preferably being one or more of the following: deuterium atom, 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 heterocyclyl, haloC 1-10 alkyl, haloC 1-10 alkoxy, deuteratedC 1-10 alkyl, deuteratedC 1-10 alkoxy, 6-10 membered aryl, 5-10 membered heteroaryl, oxo (=0).

[0414] "Alkoxy" means a straight-chain or branched-chain, monovalent, saturated alkyl group bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, propyloxy, butyloxy, isobutyloxy, t-butyloxy, and other similar groups. Preferably, C 1-8 alkoxy. More preferably, C 1-6 alkoxy. More preferably, C 1-4 alkoxy.

[0415] "Cycloalkoxy" means -O-cycloalkyl, wherein cycloalkyl is as previously described. Preferred C 3-8 Cycloalkoxy. Included, but not limited to, cyclopropoxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and other similar groups.

[0416] "Heterocyclyloxy" means -O-heterocyclyl, wherein heterocyclyl is as previously described. Included, but not limited to, azetidinyloxy, oxetanyloxy, pyrrolidinyloxy, oxepanyloxy, piperidinyloxy and other similar groups.

[0417] "Pharmaceutically acceptable salt" means either a conventional acid addition salt or a base addition salt which retains the biological effectiveness and properties of the compounds of Formula I and is formed from appropriate non-toxic organic or inorganic acids or organic or inorganic bases. Examples of acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, phosphoric, and nitric acids, and organic acids such as acetic, propionic, glycolic, oxalic, stearic, ascorbic, p-toluene sulfonic, salicylic, methane sulfonic, ethanesulfonic, oxalic, succinic, citric, maleic, hydroxymaleic, lactic, fumaric, tartaric, malic, isethionic, benzenesulfonic, trifluoroacetic, mandelic, and the like. Examples of base addition salts include those derived from inorganic bases such as ammonium, calcium, ferric, aluminum, sodium, potassium, zinc, magnesium. The organic bases include salts of primary, secondary and tertiary amines, such as methylamine, di-methylamine, tri-methylamine, di-ethylamine, ethylamine, ethanolamine, and the like. The chemical modification of a pharmaceutical compound (i.e., drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds.

[0418] "Prodrug molecule" means a prodrug that can be converted in vivo to the structure of the compounds of the present invention and pharmaceutically acceptable salts thereof.

[0419] "N-oxide" means the oxidation of one or more than one N atom in a compound containing an amine function or a heteroaryl group containing N atom to form an N-oxide containing N + atom. Preferred are N-oxides of tertiary amines or N-oxides of heteroaryl groups containing N atoms.

[0420] "Hydrate" means an association including amounts of water.

[0421] "Solvate" means an association including one or more solvent molecules and a compound of the present invention. Solvents include, but are not limited to, methanol, ethanol, isopropanol, ethyl acetate, acetic acid and the like.

[0422] A "pharmaceutical composition" refers to a mixture of one or more of the compounds of the present application or pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof with other chemical components, such as pharmaceutically acceptable carriers, excipients, or diluents. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an animal. A pharmaceutical composition can include, as is standard in the art, a pharmaceutically acceptable adjuvant to mimic physiological conditions, such as pH adjustment and buffering agents, toxicity adjustment agents, and the like, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, and the like.

[0423] A "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or

[0424] Some substances of pharmaceutically acceptable carriers 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 carboxymethyl cellulose, ethyl cellulose, cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (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 glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate, ethyl laureate; (13) agar-agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) sterile, pyrogen-free water; (17) saline; (18) Ringer's solution; (19) alcohols, such as ethyl alcohol and propyl alcohol; (20) phosphate buffer solutions; (21) other nontoxic compatible substances such as acetone.

[0425] Each pharmaceutically acceptable carrier should be compatible for use with the other ingredients of the formulation, such as the compounds provided in the present application, and not pose excessive toxicity, irritation, allergic response, immunogenicity or other problem or complication when administered to an organism, and be reasonably safe for its intended use.

[0426] The pharmaceutical ingredients can be formulated 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.). Methods of preparing pharmaceutical compositions are well known and can be prepared according to conventional procedures, such as those provided in Remington, The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2003). BRIEF DESCRIPTION OF DRAWINGS

[0427] Figure 1 Reaction scheme for preparing the compound of Formula II;

[0428] Figure 2 Reaction scheme for preparing the compound of Formula III. DETAILED DESCRIPTION

[0429] First group of preparation examples: intermediate preparation

[0430] Preparation of tert-butyl (2-(hydroxymethyl)piperidin-4-yl)carbamate

[0431]

[0432] First step: methyl 4-aminopicolinate (10.0 g, 65.72 mmol) was dissolved in dichloromethane (100 mL), dimethylaminopyridine (0.8 g, 6.57 mmol) and triethylamine (10.0 g, 98.59 mmol) were added successively, the temperature was lowered to 0 °C, di-tert-butyl dicarbonate (15.8 g, 72.30 mmol) was added dropwise slowly, and the mixture was stirred at room temperature for 4 h. After the reaction was completed, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (60 mL x 3). The combined organic phase was 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 ethyl acetate / petroleum ether (0-100%) as the eluent to obtain methyl 4-((tert-butoxycarbonyl)amino)picolinate (white solid, 12 g, 70.9%). MS (ESI m / z = 253.2 [M+H] + ). + .

[0433] Second step: under nitrogen protection, 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, hydrogen was replaced, and the temperature was raised to 60 °C and stirred overnight. After the reaction was completed, it was cooled to room temperature, filtered, the filtrate was adjusted to basic pH with sodium bicarbonate solution, the mixture was extracted with dichloromethane / methanol (10 / 1, 50 mL x 3), the combined 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 with methanol / dichloromethane (0-30%) as the eluent gradient 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] + .

[0434] Third step: under nitrogen protection, methyl 4-((tert-butoxycarbonyl)amino)piperidine-2-carboxylate (8.3 g, 32.13 mmol) was dissolved in tetrahydrofuran (60 mL), cooled to 0 °C, and lithium borohydride (2.1 g, 96.39 mmol) was slowly added. It was stirred at room temperature overnight. After the reaction was completed, it was cooled to room temperature, methanol (30 mL) was added to the reaction solution, and it was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography with methanol / dichloromethane (0-50%) as the eluent gradient 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] + .

[0435] Preparation of 5-chloro-2,3-difluoroisonicotinonitrile

[0436]

[0437] First step: 5-chloro-2,3-difluoropyridine (15.0 g, 0.10 mol) was dissolved in tetrahydrofuran (150 mL) under nitrogen protection, and cooled to -78 °C. Lithium diisopropylamide (2 M, 60.2 mL, 0.12 mol) was added, and then stirred at -78 °C for 1 h. Solid dry ice (15.0 g, 0.34 mol) was added, and then slowly recovered to room temperature and stirred for 2 h. After the reaction was completed, the residue was concentrated under reduced pressure, and then diluted with dichloromethane (100 mL) and sodium hydroxide solution (100 mL). The mixture was extracted with dichloromethane (100 mL x 3), and the aqueous phase was adjusted to pH 1 with hydrochloric acid solution, extracted with ethyl acetate (100 mL x 3), and then the combined organic phase was washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 5-chloro-2,3-difluoroisonicotinic acid (pale yellow solid, 14 g, crude).

[0438] Second step: 5-chloro-2,3-difluoroisonicotinic acid (14.0 g, 72.34 mmol) was dissolved in N,N-dimethylformamide (140 mL), and cooled to 0 °C. 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) were added in turn, and then stirred at room temperature for 1 h. After the reaction was completed, water (100 mL) was added to the reaction solution, extracted with ethyl acetate (200 mL x 3), and then the combined organic phase was washed with saturated brine solution (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (44%) as the eluent to give 5-chloro-2,3-difluoroisonicotinamide (white solid, 7.8 g, 56.1%).

[0439] Third step: 5-chloro-2,3-difluoroisonicotinamide (7.8 g, 40.51 mmol) was dissolved in dichloromethane (120 mL), and cooled to 0 °C. Triethylamine (12.3 g, 121.52 mmol) was added, and then trifluoroacetic anhydride (12.8 g, 60.76 mmol) was added dropwise, and then stirred at room temperature for 2 h. After the reaction was completed, water (100 mL) was added to the reaction solution, extracted with dichloromethane (100 mL x 3), and then the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (14%) as the eluent to give 5-chloro-2,3-difluoroisonicotinonitrile (pale yellow oil, 5.3 g, 75.1%).

[0440] Preparation of 2-chloro-[1,2,4]triazolo[1,5-a]pyridin-7-ol

[0441]

[0442] Step 1 : 7-Bromo-[l,2,4]triazolo[l,5-a]pyridin-2-amine (2.0 g, 9.39 mmol) was dissolved in acetonitrile (50 mL) under nitrogen protection, copper chloride (1.9 g, 14.08 mmol) was added, the temperature was lowered to 0 °C, and tert-butyl nitrite (1.5 g, 14.08 mmol) was added. The temperature was raised to 90 °C and stirred for 1 h. After the reaction was completed, the reaction solution was cooled to room temperature, water (50 mL) was added, filtered, and the filtrate was 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 (0-10%) as eluent gradient elution to obtain 7-bromo-2-chloro-[l,2,4]triazolo[l,5-a]pyridine (yellow oil, 1.4 g, 64.1%). MS (ESI + m / z = 233.9 [M+H] + .

[0443] Step 2: 7-Bromo-2-chloro-[l,2,4]triazolo[l,5-a]pyridine (1.4 g, 6.02 mmol) was dissolved in 1,4-dioxane (20 mL) under nitrogen protection, and pinacol diboronic acid (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 completed, the reaction solution was cooled to room temperature, water (50 mL) was added, the mixture was extracted with ethyl acetate (50 mL x 3), the combined organic phase was 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 (0-10%) as eluent gradient elution to obtain 2-chloro-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-[l,2,4]triazolo[l,5-a]pyridine (yellow oil, 800 mg, 47.5%). MS (ESI + m / z = 280.0 [M+H] + .

[0444] Step 3: 2-Chloro-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-[l,2,4]triazolo[l,5- a]pyridine (1.5 g, 5.37 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0 °C, and sodium hydroxide (1 M, 16.1 mL, 16.10 mmol) and hydrogen peroxide (30%, 1.6 mL, 16.10 mmol) were added successively. The reaction was allowed to warm to room temperature and stirred for 1 h. After the reaction was completed, the reaction solution was extracted with ethyl acetate (20 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was separated and purified by silica gel column chromatography with methanol / dichloromethane (0-10%) as eluent to give 2-chloro-[l,2,4]triazolo[l,5-a]pyridin-7-ol (yellow oil, 800 mg, 87.9%). MS (ESI + m / z = 170.1 [M+H] + .

[0445] Preparation of quinazolin-7-ol

[0446]

[0447] Quinazolin-7-ol (1.0 g, 6.62 mmol) was dissolved in a mixture of dimethyl sulfoxide and water (4 / 1, 10 mL) under nitrogen protection, and copper acetylacetonate (25.0 mg, 0.096 mmol), N,N'-bis(4-hydroxy-2,6-dimethylphenyl)oxalamide (31.4 mg, 0.096 mmol) and lithium hydroxide monohydrate (421.5 mg, 10.05 mmol) were added successively. The reaction was stirred at 80 °C for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was separated and purified by silica gel column chromatography with methanol / dichloromethane (0-10%) as eluent to give quinazolin-7-ol (pale yellow oil, 470 mg, 67.2%). MS (ESI + m / z = 147.1 [M+H] + .

[0448] Preparation of 1-methyl-lH-benzo[d][l,2,3]triazol-5-ol

[0449]

[0450] Under nitrogen protection, 5-bromo-l-methyl-lH-benzo[d][l,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)oxalamide (62.3 mg, 0.19 mmol) and lithium hydroxide monohydrate (836.1 mg, 19.91 mmol) were added, and the mixture was stirred at 80 °C for 2 h. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with n-butanol (30 mL x 3). The combined organic phase was washed with water (20 mL x 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 to obtain l-methyl-lH-benzo[d][l,2,3]triazol-5-ol (yellowish solid, 1.1 g, 78.6%). MS (ESI + )m / z = 150.3 [M+H] + .

[0451] Preparation of benzo[d]thiazol-5-ol

[0452]

[0453] 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, and 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 stirred at 100 °C for 1 h. After the reaction was completed, the mixture was cooled to room temperature, water (30 mL) was added, 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 a crude product. The crude product was separated and purified by silica gel column chromatography with methanol / dichloromethane (0-10%) as eluent to obtain benzo[d]thiazol-5-ol (brown oil, 1.0 g, 28.3%). MS (ESI + )m / z = 152.0 [M+H] + .

[0454] Preparation of benzo[c][l,2,5]oxadiazol-5-ol

[0455]

[0456] In a 40 mL reaction vial, 5-bromo-benzo[c][l,2,5]oxadiazole (2 g, 10.06 mmol) was dissolved in a mixture of dimethyl sulfoxide / water (10 mL, 4 / 1, v / v) under nitrogen protection, and then lithium hydroxide monohydrate (885.6 mg, 21.10 mmol), N,N'-bis(4-hydroxy-2,6-dimethylphenyl)oxalamide (66.0 mg, 0.20 mmol) and copper acetylacetonate (52.6 mg, 0.20 mmol) were added successively, and the mixture was stirred at 80 °C for 2 h. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with n-butanol (30 mL x 3). The combined organic phase was washed with water (30 mL x 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 column chromatography on silica gel with methanol / dichloromethane (0-20%) as the eluent to obtain benzo[c][l,2,5]oxadiazol-5-ol (brown oil, 500 mg, 36.5%).

[0457] Preparation of 5-fluoroquinoxalin-6-ol

[0458]

[0459] First step: 4-bromo-3-fluoro-l,2-benzenediamine (2 g, 9.76 mmol) was dissolved in anhydrous ethanol (20 mL) under nitrogen protection, and then sodium carbonate (2.70 g, 19.51 mmol) and glyoxal (0.68 g, 11.70 mmol) were added successively, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography on silica gel with ethyl acetate / petroleum ether (0-100%) as the eluent to obtain 6-bromo-5-fluoroquinoxaline (yellow solid, 2.2 g, 99.3%).

[0460] Second step: 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) under nitrogen protection, and then 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, and the mixture was stirred at 100 °C for 5 h. After the reaction was completed, 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 column chromatography on silica gel with methanol / dichloromethane (0-15%) as the eluent to obtain 5-fluoroquinoxalin-6-ol (brown solid, 1.2 g, 92.2%). MS (ESI + m / z = 165.0 [M+H] + .

[0461] Preparation of 8-fluoroquinoxalin-6-ol

[0462]

[0463] 8-fluoroquinoxalin-6-ol was prepared from 5-bromo-3-fluoro-1,2-phenylenediamine and glyoxal according to the method for synthesizing 5-fluoroquinoxalin-6-ol. MS (ESI + )m / z = 165.1 [M+H] + .

[0464] Preparation of 7-fluoroquinoxalin-6-ol

[0465]

[0466] 7-fluoroquinoxalin-6-ol was prepared from 5-bromo-4-fluoro-1,2-phenylenediamine and glyoxal according to the method for synthesizing 5-fluoroquinoxalin-6-ol. MS (ESI + )m / z = 165.1 [M+H] + .

[0467] Preparation of tetrazolo[1,5-a]pyridin-7-ol

[0468]

[0469] Step 1: 4-benzyloxy pyridine N-oxide (3.0 g, 14.91 mmol) was dissolved in pyridine (2.5 mL) under nitrogen protection, diphenyloxyphosphoryl azide (8.2 g, 29.83 mmol) was added, and the mixture was stirred at 100 °C for 12 h. After the reaction was completed, the mixture was cooled to room temperature, water (150 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography with ethyl acetate / petroleum ether (0-100%) as the eluent to give 7-(benzyloxy)tetrazolo[1,5-a]pyridine (yellow oil, 1.1 g, 32.6%). MS (ESI + )m / z = 227.2 [M+H] + .

[0470] Step 2: 7-(benzyloxy)tetrazolo[1,5-a]pyridine (1.1 g, 4.86 mmol) was dissolved in dichloromethane (5 mL), and boron tribromide (2.4 g, 9.72 mmol) was slowly added at 0 °C. The mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was concentrated under reduced pressure to give tetrazolo[1,5-a]pyridin-7-ol (pale yellow oil, 1 g, crude). MS (ESI + )m / z = 137.2 [M+H] + .

[0471] 1-ethyl-4-hydroxypyridin-2(lH)-one

[0472]

[0473] Step 1: Under nitrogen protection, 4-(benzyloxy)pyridin-2(lH)-one (1 g, 4.97 mmol) was dissolved in N,N-dimethylformamide (15 mL), potassium carbonate (1.4 g, 9.95 mmol) and ethyl bromide (1.2 g, 10.94 mmol) were added successively, the reaction mixture was heated to 80 °C and stirred for 2 h, after the reaction was completed, the reaction mixture was cooled to room temperature, water (30 mL) was added, the mixture was extracted with ethyl acetate (50 mL x 3), the combined 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 with ethyl acetate / petroleum ether (10%-90%) as eluent to give 4-(benzyloxy)-l-ethylpyridin-2(lH)-one (white solid, 710 mg, 62.4%). MS (ESI + )m / z = 230.0 [M+H] + .

[0474] Step 2: Under nitrogen protection, 4-(benzyloxy)-l-ethylpyridin-2(lH)-one (710 mg, 3.10 mmol) was dissolved in anhydrous ethanol (20 mL), palladium on carbon (20%, 700 mg) was added, hydrogen was replaced, and the reaction mixture was stirred at room temperature for 2 h, after the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give l-ethyl-4-hydroxypyridin-2(lH)-one (yellow oil, 400 mg, crude). MS (ESI + )m / z = 140.0 [M+H] + .

[0475] Preparation of 4-hydroxy-l-isopropylpyridin-2(lH)-one

[0476]

[0477] Step 1: Under nitrogen protection, 4-(benzyloxy)pyridin-2(lH)-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 successively, the mixture was stirred at 80 °C for 2 h. After the reaction was completed, the mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined 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 with ethyl acetate / petroleum ether (10%-90%) as eluent to give 4-(benzyloxy)-l-isopropylpyridin-2(lH)-one (white solid, 660 mg, 55.0%). MS (ESI) m / z = 244.2 [M+H] + . + .

[0478] Step 2: Under nitrogen protection, 4-(benzyloxy)-l-isopropylpyridin-2(lH)-one (660 mg, 2.71 mmol) was dissolved in anhydrous ethanol (20 mL), palladium on carbon (20%, 700 mg) was added, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure to give 4-hydroxy-l-isopropylpyridin-2(lH)-one (yellow oil, 360 mg, crude). MS (ESI) m / z = 154.0 [M+H] + . + .

[0479] Preparation of l-cyclopropyl-4-hydroxypyridin-2(lH)-one

[0480]

[0481] Step 1: Under nitrogen protection, 4-(benzyloxy)pyridin-2(lH)-one (2.0 g, 9.94 mmol) was dissolved in 1,2-dichloroethane (70 mL), 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) were added successively, and the mixture was stirred at 70 °C overnight. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL), washed with water (100 mL x 3) and saturated brine (50 mL x 2) successively, 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 with ethyl acetate / petroleum ether (50%) as eluent to give 4-(benzyloxy)-l-cyclopropylpyridin-2(lH)-one (orange yellow oil, 1.8 g, 75.0%). MS (ESI) m / z = 244.2 [M+H] +m / z = 242.0 [M+H] + .

[0482] Second Step: 4-(benzyloxy)-l-cyclopropylpyridin-2(lH)-one (800.0 mg, 3.31 mmol) was dissolved in methanol under nitrogen protection, and palladium on carbon (25%, 200.0 mg) was added. Hydrogen was replaced, and the mixture was stirred at room temperature overnight. Filtration was performed, and the filtrate was concentrated under reduced pressure to give l-cyclopropyl-4-hydroxypyridin-2(lH)-one (white solid, 426 mg, 85.1%). MS (ESI + m / z = 152.0 [M+H] + .

[0483] Preparation of 3-ethynyl-l,3-dimethylpyrrolidine

[0484]

[0485] First Step: tert-butyl 3-(hydroxymethyl)-3-methylpyrrolidine-l-carboxylate (1 g, 4.65 mmol) was dissolved in dichloromethane (10 mL) in a 100 mL jar flask, and the mixture was cooled to 0 °C. Dess-Martin oxidant (2.4 g, 5.57 mmol) was added, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, water (5 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (0-50%) as the eluent to give tert-butyl 3-formyl-3-methylpyrrolidine-l-carboxylate (colorless transparent liquid, 670 mg, 67.6%).

[0486] Second Step: tert-butyl 3-formyl-3-methylpyrrolidine-l-carboxylate (670 mg, 3.14 mmol) was dissolved in anhydrous methanol (15 mL) in a 100 mL jar flask, and potassium carbonate (868.3 mg, 6.28 mmol) was added. The mixture was cooled to 0 °C, and P-(diazomethyl) dimethyl phosphate (905.3 mg, 4.71 mmol) was added dropwise slowly. The mixture was stirred at room temperature for 20 min. After the reaction was completed, water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (0-50%) as the eluent to give tert-butyl 3-ethynyl-3-methylpyrrolidine-l-carboxylate (pale yellow oil, 530 mg, 80.6%).

[0487] Step 3: In a 100 mL jar, dissolve 3-ethynyl-3-methylpyrrolidine-1 -carboxylic acid tert-butyl ester (530 mg, 2.53 mmol) in dichloromethane (6 mL), add trifluoroacetic acid (2 mL), and stir at room temperature for 1 h. After the reaction is complete, concentrate under reduced pressure to give 3-ethynyl-3-methylpyrrolidine (colorless oil, 787 mg, crude). MS (ESI + m / z = 110.2 [M+H] + .

[0488] Step 4: In a 100 mL jar, dissolve 3-ethynyl-3-methylpyrrolidine (747 mg, 6.84 mmol) in anhydrous methanol (20 mL), slowly add 20% aqueous formaldehyde solution (2.1 g, 13.68 mmol), stir well, then add acetic acid (41.1 mg, 0.68 mmol), cool to 0 °C, add sodium cyanoborohydride (860.0 mg, 13.68 mmol), and stir at room temperature for 1 h. After the reaction is complete, add water (20 mL) to the reaction, 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 to give 3-ethynyl-1,3-dimethylpyrrolidine (green oil, 230 mg, crude). MS (ESI + m / z = 124.2 [M+H] + .

[0489] Preparation of 1-(bromomethyl-d2)-4-chloro-2-fluorobenzene

[0490]

[0491] Step 1 : Under nitrogen protection, dissolve 4-chloro-2-fluorobenzoic acid (10.0 g, 57.29 mmol) in tetrahydrofuran (150 mL), cool to 0 °C, slowly add lithium aluminum deuteride (3.6 g, 85.93 mmol) in batches, after addition, warm to 70 °C and stir for 12 h. After the reaction is complete, cool to room temperature, add water (10 mL) to the reaction, extract the mixture with ethyl acetate (10 mL x 3), dry the combined organic phases over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue obtained is separated by silica gel column chromatography using ethyl acetate / petroleum ether (0-15%) as eluent to give (4-chloro-2-fluorophenyl)methane-d2-ol (pale yellow oil, 4.5 g, 48.3%). 1 H NMR (300 MHz, DMSO-d6) d 7.47 (t, J = 8.2 Hz, 1H), 7.39 - 7.05 (m, 2H), 5.30 (d, J = 1.8 Hz, 1H).

[0492] Second step: under nitrogen protection, dissolve (4-chloro-2-fluorophenyl)methan-ol-d2 (4.5 g, 27.68 mmol) in dichloromethane (60 mL), cool to 0 °C, add phosphorus tribromide (11.2 g, 41.52 mmol), stir at room temperature for 1 h. After the reaction is complete, add water (30 mL) to the reaction solution, extract the mixture with dichloromethane (30 mL x 3), dry the combined organic phases over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue is separated by silica gel column chromatography using ethyl acetate / petroleum ether (0-10%) as the eluent to give 1-(bromomethyl-d2)-4-chloro-2-fluorobenzene (pale yellow oil, 4.5 g, 72.1%). 1 H NMR (300 MHz, DMSO-d6) δ 7.57 (t, J = 8.3 Hz, 1H), 7.51-7.43 (m, 1H), 7.30 (d, J = 8.3 Hz, 1H).

[0493] Preparation of 5-bromo-2-(bromomethyl)-l-chloro-3-fluorobenzene

[0494]

[0495] First step: under nitrogen protection, 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), stir at 0 °C for 1 h. After the reaction is complete, restore to room temperature, add water (50 mL) to the reaction solution, extract the mixture with dichloromethane (50 mL x 3), dry the combined organic phases over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue is separated by silica gel column chromatography using methanol / dichloromethane (0-10%) as the eluent to give (4-bromo-2-chloro-6-fluorophenyl)methanol (white solid, 2.6 g, 92.2%). 1 H NMR (300 MHz, DMSO-d6) δ 7.65-7.54 (m, 2H), 5.30 (t, J = 5.5 Hz, 1H), 4.53 (dd, J = 5.6, 2.2 Hz, 2H).

[0496] Second step: under nitrogen protection, dissolve (4-bromo-2-chloro-6-fluorophenyl)methanol (2.6 g, 10.86 mmol) in a mixture of dichloromethane and tetrahydrofuran (1 / 1 v / v, 30 mL), cool to 0 °C, add phosphorus tribromide (4.4 g, 16.29 mmol). Stir at room temperature for 1 h. After the reaction is complete, concentrate the reaction solution under reduced pressure, and separate the resulting residue by silica gel column chromatography using ethyl acetate / petroleum ether (0-10%) as the eluent to give 5-bromo-2-(bromomethyl)-l-chloro-3-fluorobenzene (white solid, 1.4 g, 42.7%).

[0497] Preparation of [1,2,4]triazolo[1,5-a]pyridine-2-d-7-ol-d

[0498]

[0499] First step: under nitrogen protection, 7-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-amine (2.0 g, 9.38 mmol) was dissolved in acetonitrile (50.0 mL), and copper chloride (1.9 g, 14.08 mmol) was added under stirring, and the temperature was lowered to 0°C, and tert-butyl nitrite (1.4 g, 14.08 mmol) was added, and the temperature was raised to 90°C, and stirring was carried out for 1 h. After the reaction was completed, the temperature was restored to room temperature, and water (50 mL) was added to the reaction solution, and filtration was carried out, and the filtrate was extracted with ethyl acetate (50 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, and filtration was carried out, and the filtrate was concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography with methanol / dichloromethane (0-10%) as the eluent gradient to obtain 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] + .

[0500] Second step: under nitrogen protection, 7-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (1.4 g, 6.02 mmol) was dissolved in dioxane (20.00 mL), and pinacol diboronic acid (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, and the temperature was raised to 100°C, and stirring was carried out for 1 h. After the reaction was completed, the temperature was restored to room temperature, and water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, and filtration was carried out, and the filtrate was concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography with methanol / dichloromethane (0-10%) as the eluent gradient 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, 73.6%). MS (ESI + )m / z = 280.0 [M+H] + .

[0501] Step 3: 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) was dissolved in tetrahydrofuran (20 mL), cooled to 0 °C, added sodium hydroxide (16.1 mL, 1 M, 16.08 mmol) and hydrogen peroxide (30%, 1.8 mL, 16.08 mmol), and stirred at room temperature for 1 h. Extracted with ethyl acetate (20 mL x 3), combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography with methanol / dichloromethane (0-10%) as eluent gradient to give 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] + .

[0502] Step 4: 2-chloro-[1,2,4]triazolo[1,5-a]pyridin-7-ol (300.0 mg, 1.77 mmol) was dissolved in deuterated methanol (20 mL) under nitrogen protection, added Pd / C (1.9 g, 17.69 mmol), then replaced with deuterium, and stirred at 40 °C for 24 h. After the reaction was completed, filtered, the filter residue was washed with methanol (100 mL), and the filtrate was collected and concentrated under reduced pressure to give [1,2,4]triazolo[1,5-a]pyridin-2-d-7-ol-d (brown solid, 270 mg, crude). MS (ESI + )m / z = 138.2 [M+H] + .

[0503] Preparation of 3-chloro-[1,2,4]triazolo[4,3-a]pyridin-7-ol

[0504]

[0505] Under nitrogen protection, 7-bromo-3-chloro-[l,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 bis(pinacolato)diboron (2.5 g, 9.68 mmol) were added successively, and the mixture was stirred at 90 °C for 2 h. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the residue was washed with tetrahydrofuran three times. The filtrate was concentrated under reduced pressure, and the 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, 3M, 19.36 mmol) were added dropwise successively. After the addition was completed, the mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography with methanol / dichloromethane (0-15%) as the eluent to give 3-chloro-[l,2,4]triazolo[4,3-a]pyridin-7-ol (yellow solid, 1.0 g, 91.4%). MS (ESI + )m / z = 170.1 [M+H] + .

[0506] Preparation of 3-methyl-4-((2-methylquinoxalin-6-yl)oxy)aniline

[0507]

[0508] First step: 4-(benzyloxy)benzene-l,2-diamine (1.7 g, 7.93 mmol) was dissolved in acetonitrile (5 mL) under nitrogen protection, and 2-oxo propanal (0.57 g, 7.93 mmol) was added, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography with methanol / dichloromethane (0-10%) as the eluent to give 6-(benzyloxy)-2-methylquinoxaline (yellow oil, 1.7 g, 85.6%). MS (ESI + )m / z = 251.1 [M+H] + .

[0509] Second step: 6-(benzyloxy)-2-methylquinoxaline (1.7 g, 6.79 mmol) was dissolved in DCM (10 mL), and boron tribromide (3.4 g, 13.58 mmol) was added slowly at 0 °C, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography with methanol / dichloromethane (0-10%) as the eluent to give 2-methylquinoxalin-6-ol (yellow oil, 1 g, 91.9%). MS (ESI + )m / z = 161.1 [M+H] +.

[0510] Second group of preparation examples: Preparation of intermediates A1-A38

[0511] Preparation of intermediate A1,8-cyano-7-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester

[0512]

[0513] Step 1: Dissolve 2,3-difluoro-6-nitrobenzonitrile (1.0 g, 5.43 mmol) in N,N-dimethylformamide (20 mL), then add 4-amino-4-hydroxymethylpiperidine-1-carboxylic acid tert-butyl ester (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 and 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 the crude product. The crude product was purified by silica gel column chromatography using a gradient elution of ethyl acetate / petroleum ether (85%-100%) 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] + .

[0514] Step 2: Dissolve 1.1 g (2.74 mmol) of 4-((3-cyano-2-fluoro-4-nitrophenyl)amino)-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester in N,N-dimethylformamide (20 mL), cool to 0 °C, add NaH (0.1 g, 4.11 mmol), and stir for 2 h at room temperature. After the reaction is complete, add water (30 mL) to the reaction solution, extract with ethyl acetate (30 mL × 3), combine the organic phases, dry with saturated anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain the crude product, and purify the crude product by silica gel column chromatography with 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'-carboxylic acid (yellow solid, 500 mg, 48.8%). MS(ESI + m / z = 375.2[M+H] + .

[0515] Preparation of intermediate A2. tert-butyl 8-cyano-4-methyl-7-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidine]-1'-carboxylate

[0516]

[0517] Intermediate Al (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 successively, and the mixture was stirred at 60 °C for 10 h. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was separated and purified by column chromatography on silica gel using ethyl acetate / petroleum ether (40%) as the eluent to give tert-butyl 8-cyano-4-methyl-7-nitro-2H,4H-spiro[benzo[b][l,4]oxazine-3,4'-piperidin]-l'- carboxylate (yellow oil, 250 mg, 80.3%). MS (ESI) m / z = 389.2 [M+H] + m / z = 389.2 [M+H] + .

[0518] Preparation of Intermediate A3. tert-Butyl 4-allyl-8-cyano-7-nitro-2H,4H-spiro[benzo[b][l,4]oxazine-3,4'- piperidin]-l'-carboxylate

[0519]

[0520] Intermediate Al (450.0 mg, 1.20 mmol) was dissolved in DMF (4.5 mL), NaH (60%, 144.2 mg, 3.61 mmol) was added, and the mixture was stirred at room temperature for 5 min. Then allyl bromide (436.2 mg, 3.61 mmol) was added, and the mixture was stirred at 65 °C for 2 h. After the reaction was completed, the mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was separated and purified by column chromatography on silica gel using ethyl acetate / petroleum ether (50%) as the eluent to give tert-butyl 4-allyl-8-cyano-7-nitro-2H,4H-spiro[benzo[b][l,4]oxazine-3,4'-piperidin]-l'- carboxylate (yellow solid, 175 mg, 35.1%). MS (ESI) m / z = 415.2 [M+H] + m / z = 415.2 [M+H] + .

[0521] Preparation of Intermediate A4. tert-Butyl 8-cyano-7-nitro-4-(prop-2-yn-l-yl)-2H,4H-spiro[benzo[b][l,4]oxazine-3,4'- piperidin]-l'-carboxylate

[0522]

[0523] Intermediate A4 was prepared from intermediate Al and propargyl bromide following the procedure of intermediate A3 (yellow solid, 150 mg, 27.2%). MS (ESI + m / z = 413.1 [M+H] + .

[0524] Preparation of Intermediate A5, tert-butyl 5-bromo-8-cyano-7-nitro-2H,4H- spiro[benzo[b][l,4]oxazin-3,4'-piperidin]-l'-carboxylate

[0525]

[0526] Intermediate Al (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 added dropwise slowly. The reaction was stirred at room temperature for 2 h. After the reaction was completed, water (30 mL) was added to the reaction mixture, and the pH was adjusted to 8 with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (30 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel eluted with ethyl acetate / petroleum ether (10%-20%) to give tert-butyl 5-bromo-8-cyano-7-nitro-2H,4H-spiro[benzo[b][l,4]oxazin-3,4'-piperidin]-l'-carboxylate (yellow solid, 380 mg, 62.8%). MS (ESI + m / z = 453.1 [M+H] + .

[0527] Preparation of Intermediate A6, tert-butyl 8-cyano-5-methyl-7-nitro-2H,4H- spiro[benzo[b][l,4]oxazin-3,4'-piperidin]-l'-carboxylate

[0528]

[0529] Intermediate A5 (240.0 mg, 0.53 mmol) was dissolved in 1,4-dioxane / water (10 / 1, 5 mL) under nitrogen protection, methylboronic 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 successively, and the mixture was stirred at 90 °C for 2 h. After the reaction was completed, the mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was separated and purified by column chromatography on silica gel eluted with ethyl acetate / petroleum ether (30%-50%) as eluent to give tert-butyl 8-cyano-5-methyl-7-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidin]-1'- carboxylate (yellow solid, 140 mg, 68.3%). MS (ESI + )m / z = 389.2 [M+H] + .

[0530] Preparation of Intermediate A7. tert-Butyl 5-chloro-8-cyano-7-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidin]-1'-carboxylate

[0531]

[0532] Intermediate A1 (1.8 g, 4.01 mmol) was dissolved in hexafluoroisopropanol (20 mL) under nitrogen protection, and the mixture was cooled to 0 °C. Trichloroisocyanuric acid (372.5 mg, 1.60 mmol) and trifluoromethanesulfonic acid (30.1 mg, 0.20 mmol) were added successively, and the mixture was stirred at 60 °C for 1 h. After the reaction was completed, the mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was separated and purified by column chromatography on silica gel eluted with methanol / dichloromethane (0-10%) as eluent to give tert-butyl 5-chloro-8-cyano-7-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidin]-1'-carboxylate (pale yellow solid, 1.5 g, 76.9%). MS (ESI + )m / z = 409.1 [M+H] + .

[0533] Preparation of Intermediate A8. tert-Butyl 8-cyano-4-methyl-7-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,3'-piperidin]-1'-carboxylate

[0534]

[0535] First Step, Second Step: 8-cyano-7-nitro-2H,4H-spiro[benzo[b][l,4]oxazin-3,3'- piperidin]-l'-carboxylic acid tert-butyl ester (yellow solid) was prepared from 2,3-difluoro-6-nitrobenzonitrile and 3-amino-3-(hydroxymethyl)piperidine-l-carboxylic acid tert-butyl ester following the method for the synthesis of Intermediate Al. MS (ESI + m / z = 375.1 [M+H] + .

[0536] Third Step: Intermediate A8 (yellow oil) was prepared from 8-cyano-7-nitro-2H,4H-spiro[benzo[b][l,4]oxazin-3,3'-piperidin]-l'-carboxylic acid tert-butyl ester and iodomethane following the method for the synthesis of Intermediate A2. MS (ESI + m / z = 389.1 [M+H] + .

[0537] Preparation of Intermediate A9. 8-cyano-7-nitro-2H,4H-spiro[benzo[b][l,4]oxazin-3,3'- pyrrolidin]-l'-carboxylic acid tert-butyl ester

[0538]

[0539] Intermediate A9 (yellow oil, 300 mg, 17.6%) was prepared from 2,3-difluoro-6-nitrobenzonitrile and 3-amino-3-(hydroxymethyl)pyrrolidine-l-carboxylic acid tert-butyl ester following the method for the synthesis of Intermediate Al. MS (ESI + m / z = 361.1 [M+H] + .

[0540] Preparation of Intermediate A10. 8'-cyano-4'-methyl-7'-nitro-2'H,4'H-spiro[azetidine-3,3'- benzo[b][l,4]oxazin]-l-carboxylic acid tert-butyl ester

[0541]

[0542] Intermediate A10 (yellow oil, 870 mg, 46.5%) was prepared from 2,3-difluoro-6-nitrobenzonitrile and 3-amino-3-(hydroxymethyl)azetidine-l-carboxylic acid tert-butyl ester following the method for the synthesis of Intermediate A8. MS (ESI + m / z = 360.9 [M+H] + .

[0543] Preparation of Intermediate A11. tert-Butyl 5-cyano-6-nitro-3H-spiro[benzo[b][l,4]dioxan-2,4'-piperidin]-l'- carboxylate

[0544]

[0545] Under nitrogen protection, 2,3-difluoro-6-nitrobenzonitrile (400.0 mg, 2.17 mmol) was dissolved in N,N-dimethylformamide (20 mL), added with tert-butyl 4-hydroxy-4- (hydroxymethyl)piperidine-l-carboxylate (502.5 mg, 2.17 mmol) and cesium carbonate (2.1 g, 6.52 mmol), and stirred at 80 °C for 1 h. After the reaction was completed, the reaction solution was cooled to room temperature, added with water (50 mL), and the mixture was extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (42%) as the eluent to obtain tert-butyl 5-cyano-6-nitro-3H-spiro[benzo[b][l,4]dioxan-2,4'-piperidin]-l'- carboxylate (yellow solid, 280 mg, 34.3%). MS (ESI + m / z = 376.2 [M+H] + .

[0546] Preparation of Intermediate A12. tert-Butyl 7'-chloro-8'-cyano-2'H-spiro[piperidin-4,3'-[l,4]dioxino[2,3-b]pyridine]-l-carboxylate

[0547]

[0548] Intermediate A12 (pale yellow solid, 1 g, 34.1%) was prepared according to the synthetic method of Intermediate Al l with 5-chloro-2,3-difluoroisonicotinonitrile (1.4 g, 8.02 mmol) and tert-butyl 4-hydroxy-4-(hydroxymethyl)piperidine-l-carboxylate as starting materials. MS (ESI + m / z = 366.2 [M+H] + .

[0549] Preparation of Intermediate A13. tert-Butyl 7'-bromo-8'-cyano-2'H,4'H-spiro[piperidin-4,3'- pyrido[3,2-b][l,4]oxazin]-l-carboxylate

[0550]

[0551] Step 1: 2,3-difluoroisonicotinitrile (1.0 g, 7.14 mmol) was dissolved in N,N- dimethylformamide (50 mL) under nitrogen protection, 4-amino-4-(hydroxymethyl)piperidine- 1 -carboxylic acid tert-butyl ester (1.6 g, 7.14 mmol) and cesium carbonate (4.7 g, 14.28 mmol) were added, the reaction mixture was stirred at 80 °C for 1 h. After the reaction was completed, the reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3), the combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography on silica gel using ethyl acetate / petroleum ether (50%) as the eluent to give 8'-cyano-2'H,4'H-spiro[piperidin-4,3'-pyrido[3,2- b][1,4]oxazin]-1 -carboxylic acid tert-butyl ester (yellow oil, 600 mg, 25.5%). MS (ESI + m / z = 331.3 [M+H] + .

[0552] Step 2: 8'-cyano-2'H,4'H-spiro[piperidin-4,3'-pyrido[3,2-b][1,4]oxazin]-1-carboxylic acid tert-butyl ester (600.0 mg, 1.82 mmol) was dissolved in N,N-dimethylformamide (6 mL), N-bromosuccinimide (323.2 mg, 1.82 mmol) was added, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography on silica gel using ethyl acetate / petroleum ether (50%) as the eluent to give 7'-bromo-8'-cyano-2'H,4'H-spiro[piperidin-4,3'-pyrido[3,2-b][1,4]oxazin]-1-carboxylic acid tert-butyl ester (pale yellow solid, 400 mg, 54.0%). MS (ESI + m / z = 409.2 [M+H] + .

[0553] Preparation of Intermediate A14. (R)-3-bromo-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

[0554]

[0555] Intermediate A14. Preparation of tert-butyl 3-bromo-4-cyano-6a,7,9,10- tetrahydro-6H-pyrazino[l,2-d]pyrido[3,2-b][l,4]oxazin-8-carboxylate from 2,3- difluoroisonicotinitrile and tert-butyl (3R)-3-(hydroxymethyl)piperazine-l-carboxylate. MS (ESI) m / z = 339.0 [M-56+H] + m / z = 339.0 [M-56+H] + .

[0556] Intermediate A15. Preparation of tert-butyl 3-bromo-4-cyano-6,7,7a,8,10,11- hexahydro-9H-pyrazino[l,2-d]pyrido[3,2-b][l,4]oxazepine-9-carboxylate

[0557]

[0558] Intermediate A15. Preparation of tert-butyl 3-bromo-4-cyano-6,7,7a,8,10,11- hexahydro-9H-pyrazino[l,2-d]pyrido[3,2-b][l,4]oxazepine-9-carboxylate from 2,3- difluoroisonicotinitrile and tert-butyl 3-hydroxymethylpiperazine-l-carboxylate. MS (ESI) m / z = 395.1 [M+H] + m / z = 339.0 [M-56+H] + .

[0559] Intermediate A16. Preparation of tert-butyl 3-bromo-4-cyano-6,7,7a,8,10,11- hexahydro-9H-pyrazino[l,2-d]pyrido[3,2-b][l,4]oxazepine-9-carboxylate

[0560]

[0561] First and second steps: tert-butyl 4-cyano-6,7,7a,8,10,11-hexahydro-9H- pyrazino[l,2-d]pyrido[3,2-b][l,4]oxazepine-9-carboxylate was prepared from 2,3- difluoroisonicotinitrile (1.0 g, 7.14 mmol) and tert-butyl 3-(2-hydroxyethyl)piperazine-l- carboxylate following the procedure for the synthesis of intermediate Al (white oil, 770 mg, 68.1 %). MS (ESI) m / z = 331.1 [M+H] + m / z = 339.0 [M-56+H] + .

[0562] Third step: Intermediate A16 was prepared from tert-butyl 4-cyano-6,7,7a,8,10,11- hexahydro-9H-pyrazino[l,2-d]pyrido[3,2-b][l,4]oxazepine-9-carboxylate following the procedure for the second step of the synthesis of intermediate A13 (green oil, 800 mg, 83.9 %). MS (ESI) m / z = 409.2 [M+H] + m / z = 339.0 [M-56+H] + .

[0563] Preparation of Intermediate A17. tert-Butyl (3-bromo-4-cyano-6,6a,7,8,9,10- hexahydridodipyrido[3,2-b:1',2'-d][1,4]oxazin-8-yl)carbamate

[0564]

[0565] First step: tert-Butyl (2-(hydroxymethyl)piperidin-4-yl)carbamate (1.0 g, 4.34 mmol) was dissolved in tetrahydrofuran (10 mL) under nitrogen protection, cooled to 0 °C, slowly added sodium bis(trimethylsilyl)amide (1.6 g, 8.68 mmol), stirred at 0 °C for 20 min, then slowly added 2,3-difluoroisonicotinonitrile (0.6 g, 4.34 mmol), stirred at 0 °C for 2 h. After the reaction was completed, it was restored to room temperature, ammonium chloride solution (10 mL) was added to the reaction solution, extracted with ethyl acetate (40 mL x 3), the combined 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 with ethyl acetate / petroleum ether (0-100%) as eluent gradient elution to obtain tert-butyl (4-cyano-6,6a,7,8,9,10-hexahydridodipyrido[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] + .

[0566] Second step: tert-Butyl (4-cyano-6,6a,7,8,9,10-hexahydridodipyrido[3,2-b:1',2'- d][1,4]oxazin-8-yl)carbamate was used as the raw material, and Intermediate A17 was prepared according to the method of the second step of Intermediate A13 (pale yellow solid, 470 mg, 68.9%). MS (ESI + )m / z = 408.9 [M+H] + .

[0567] Preparation of Intermediate A18. tert-Butyl (R)-10-bromo-7-cyano-8-nitro-1,2,4a,5- tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazole-3(4H)-carboxylate

[0568]

[0569] First Step, Second Step: (R)-7-cyano-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2- d][1,4]oxazin-3(4H)-carboxylic acid tert-butyl ester was prepared from 2,3-difluoro-6- nitrobenzonitrile and (3R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester following the synthetic method of Intermediate A1. MS (ESI + m / z = 361.2 [M+H] + .

[0570] Third Step: Intermediate A18 was prepared from (R)-7-cyano-8-nitro-1,2,4a,5- tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-carboxylic acid tert-butyl ester following the second step method of Intermediate A13. MS (ESI + m / z = 383.0 [M+H-56] + .

[0571] Preparation of Intermediate A19. tert-Butyl 10-bromo-7-cyano-8-nitro-1,2,4a,5- tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-carboxylate

[0572]

[0573] Intermediate A19 was prepared from 2,3-difluoro-6-nitrobenzonitrile and tert-butyl 3- (hydroxymethyl)piperazine-1-carboxylate following the synthetic method of Intermediate A18. MS (ESI + m / z = 382.9 [M+H-56] + .

[0574] Preparation of Intermediate A20. tert-Butyl 1-bromo-4-cyano-3-nitro-6,6a,7,8,9,10- hexahydrobenzo[b]pyridino[1,2-d][1,4]oxazin-8-yl-carbamate

[0575]

[0576] Intermediate A20 was prepared from 2,3-difluoro-6-nitrobenzonitrile and tert-butyl (2- (hydroxymethyl)piperidin-4-yl)carbamate following the synthetic method of Intermediate A18. MS (ESI + m / z = 397.1 [M+H-56] + .

[0577] Preparation of Intermediate A21. tert-Butyl 5'-cyano-6'-nitro-3'H-spiro[azetidine-3,2'- benzo[b][1,4]dioxan]-1-carboxylate

[0578]

[0579] Intermediate A21 was prepared according to the procedure for the synthesis of Intermediate A11 using 2,3-difluoro-6-nitrobenzonitrile and tert-butyl 3-hydroxy-3- (hydroxymethyl)azetidine-1-carboxylate as starting materials at 120 °C (yellow solid, 0.99 g, 47.2%). MS (ESI + m / z = 370.1 [M+Na] + .

[0580] Preparation of Intermediate A22, tert-butyl 7'-bromo-8'-cyano-4'-methyl-2'H,4'H- spiro[piperidine-4,3'-pyrido[3,2-b][1,4]oxazin]-1-carboxylate

[0581]

[0582] Intermediate A13 (380 mg, 0.93 mmol) was dissolved in tetrahydrofuran (4 mL), NaH (33.4 mg, 1.39 mmol) was added at 0 °C, stirred at 0 °C for 0.5 h, then iodomethane (197.7 mg, 1.39 mmol) was added dropwise, the reaction was stirred at 70 °C for 1 h. After the reaction was completed, the reaction was cooled to room temperature, saturated ammonium chloride solution (10 mL) was added to the reaction, the mixture was extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (0-100%) as eluent gradient to give tert-butyl 7'-bromo-8'-cyano-4'-methyl-2'H,4'H-spiro[piperidine-4,3'- pyrido[3,2-b][1,4]oxazin]-1-carboxylate (pale yellow solid, 350 mg, 89.0%). MS (ESI + m / z = 423.1 [M+H] + .

[0583] Preparation of Intermediates A23-A24

[0584] Intermediates A23-A24 were prepared according to the procedure for the synthesis of Intermediate A22 using Intermediate A13 and iodoethane or deuterated iodomethane as starting materials. The structures and MS data of Intermediates A23 and A24 are shown in Table 1.

[0585] Table 1 Structures and MS data of Intermediates A23 and A24

[0586]

[0587]

[0588] Preparation of Intermediate A25. 7'-Bromo-8'-cyano-4'-cyclopropyl-2'H,4'H- spiro[piperidine-4,3'-pyrido[3,2-b][l,4]oxazin]-l-carboxylic acid tert-butyl ester

[0589]

[0590] Intermediate A13 (250 mg, 0.61 mmol) was dissolved in DMF (3 mL), 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 stirred at 60 °C for 16 h. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added, the mixture was extracted with ethyl acetate (20 mL x 3), the organic phase was combined and washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography on silica gel with ethyl acetate / petroleum ether (0-80%) as eluent to give 7'-bromo-8'-cyano-4'-cyclopropyl-2'H,4'H-spiro[piperidine-4,3'- pyrido[3,2-b][l,4]oxazin]-l-carboxylic acid tert-butyl ester (yellowish solid, 250 mg, 91.5%). MS (ESI) m / z = 449.1 [M+H] + m / z = 449.1 [M+H] + .

[0591] Preparation of Intermediate A26. 7'-Chloro-8'-cyano-2'H,4'H-spiro[piperidine-4,3'- pyrano[3,2-b]pyridine]-l-carboxylic acid tert-butyl ester

[0592]

[0593] First step: (5-Chloro-3-fluoropyridin-2-yl)methanol (20 g, 123.79 mmol) was dissolved in dichloromethane (200 mL), dichlorosulfoxide (29.5 g, 247.59 mmol) was added at 0 °C, the mixture was stirred at room temperature for 4 h, after the reaction was completed, the residue was added to saturated aqueous sodium bicarbonate solution (25 mL), the mixture was extracted with dichloromethane (30 mL x 3), the organic phase was combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 5-chloro-2-chloromethyl-3-fluoropyridine (brown oil, crude).

[0594] Step 2: Under nitrogen protection, 27.3 g (112.22 mmol) of 1-tert-butyl 4-methylpiperidine-1,4-dicarboxylic acid was dissolved in tetrahydrofuran (200 mL). The mixture was 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. Then, 20.2 g (112.22 mmol) of 5-chloro-2-chloromethyl-3-fluoropyridine was added, and 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 liquid. 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 residue was purified by silica gel column chromatography using a gradient elution of ethyl acetate / petroleum ether (0-50%) to obtain tert-butyl 4-methoxycarbonyl-4-((5-chloro-3-fluoropyridin-2-yl)methyl)piperidin-1-carboxylic acid (white solid, 34.2 g, 78.8%). MS (ESI) + m / z = 287.1[M + H - Boc] + .

[0595] Step 3: Under nitrogen protection, 34.2 g (88.40 mmol) of 4-methoxycarbonyl-4-((5-chloro-3-fluoropyridin-2-yl)methyl)piperidin-1-carboxylic acid tert-butyl ester was dissolved in tetrahydrofuran (300 mL). The mixture was cooled to 0 °C, and a tetrahydrofuran solution of lithium aluminum hydride (36 mL, 2.5 M, 88.40 mmol) was added. The mixture was then brought back 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, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with a gradient elution of ethyl acetate / petroleum ether (0-100%) to obtain 4-((5-chloro-3-fluoropyridin-2-yl)methyl)-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (yellow oil, 23 g, 72.5%). MS (ESI) + m / z = 359.2[M+H] + .

[0596] Fourth step: tert-butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-((5-chloro-3- fluoropyridin-2-yl)methyl)piperidine-l-carboxylate (23 g, 64.10 mmol) was dissolved in N,N-dimethylformamide (200 mL), cooled to 0 °C, and then imidazole (13.1 g, 192.29 mmol) was added in portions, followed by dropwise addition of tert-butyldimethylsilyl chloride in N,N-dimethylformamide (14.5 g, 96.14 mmol, 30 mL). The mixture was stirred at room temperature for 5 h. After the reaction was completed, the mixture was cooled to room temperature, and then water (100 mL) was added. The mixture was extracted with ethyl acetate (200 mL x 3), and the combined organic phases were washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography on silica gel using ethyl acetate / petroleum ether (0-50%) as the eluent to give tert-butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-((5-chloro-3- fluoropyridin-2-yl)methyl)piperidine-l-carboxylate (colorless oil, 27.1 g, 89.3%). MS (ESI + )m / z = 417.2 [M + H - 56] + .

[0597] Fifth step: Diisopropylamine (12 mL) was dissolved in tetrahydrofuran (230 mL), cooled to -78 °C, and then n-butyllithium (29 mL, 2.5 M) was slowly added dropwise. The mixture was stirred at 0 °C for 1 h, and then the temperature was lowered to -78 °C. A tetrahydrofuran solution (50 mL) of tert-butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-((5-chloro-3- fluoropyridin-2-yl)methyl)piperidine-l-carboxylate (23 g, 48.62 mmol) was slowly added dropwise. The mixture was stirred at -78 °C for 3 h, and then the reaction mixture was slowly poured into dry ice. The mixture was stirred until the dry ice evaporated, and then an ice solution of ammonium bicarbonate (150 mL) was added. The mixture was extracted with ethyl acetate (250 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-((l-(tert-butoxycarbonyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)piperidin-4-yl)methyl)-5-chloro-3-fluoroisonicotinic acid (colorless oil, 25 g, crude). MS (ESI + )m / z = 517.2 [M + H] + .

[0598] Step 6: 2-((1-(tert-butoxycarbonyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)piperidin-4- yl)methyl)-5-chloro-3-fluoroisonicotinic acid (25 g, 48.35 mmol) was dissolved in N,N- dimethylformamide (250 mL), cooled to 0 °C, and then HOBT (9.8 g, 72.52 mmol), EDCI (11.3 g, 72.52 mmol) and ammonium chloride (7.8 g, 145.04 mmol) were added successively. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, water (150 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (300 mL x 3). The combined organic phase was washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography on silica gel with ethyl acetate / petroleum ether (0-100%) as eluent to give 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-((4- carbamoyl-5-chloro-3-fluoropyridin-2-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (colorless oil, 18 g, 72.1%). MS (ESI + m / z = 538.2 [M+Na] + .

[0599] Step 7: 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-((4-carbamoyl-5-chloro-3- fluoropyridin-2-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (18 g, 34.88 mmol) was dissolved in dichloromethane (200 mL), cooled to 0 °C, and then triethylamine (10.6 g, 104.63 mmol) and trifluoroacetic anhydride (11.0 g, 52.31 mmol) were added successively dropwise. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, water (100 mL) was added to the reaction mixture. The mixture was extracted with dichloromethane (200 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography on silica gel with ethyl acetate / petroleum ether (0-50%) as eluent to give 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-((5-chloro-4-cyano-3- fluoropyridin-2-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (yellow oil, 14 g, 80.6%). MS (ESI + m / z = 498.3 [M+H] + .

[0600] Eighth step: 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) under nitrogen protection, triethylamine trifluoride (90 mL) was added, and the mixture was stirred at 65 °C for 5 h. After the reaction was completed, the mixture was cooled to room temperature, saturated brine (80 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (150 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography on silica gel with ethyl acetate / petroleum ether (0-60%) as eluent to give 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] + .

[0601] Ninth step: 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) under nitrogen protection, cesium carbonate (43.3 g, 132.87 mmol) was added, and the mixture was stirred at 120 °C for 3 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by column chromatography on silica gel with ethyl acetate / petroleum ether (0-100%) as eluent to give tert-butyl 7'-chloro-8'-cyano-2'H,4'H-spiro[piperidine-4,3'- pyranobenzo[3,2-b]pyridine]-1-carboxylate (white solid, 8 g, 82.7%). MS (ESI + )m / z = 308.1 [M+H-56] + .

[0602] Preparation of intermediate A27. tert-butyl 7'-chloro-8'-cyano-2'H,4'H-spiro[piperidine-4,3'- pyranobenzo[3,2-b]pyridine]-1-carboxylate

[0603]

[0604] Step 1 : Under nitrogen, potassium tert-butoxide (4.0 g, 35.17 mmol) was dissolved in tetrahydrofuran (70 mL) and cooled to -30 °C. A solution of 1-tert-butoxycarbonylpiperidine-4-carbaldehyde (5.0 g, 23.44 mmol) in tetrahydrofuran (10 mL) was added and stirred at -30 °C for 0.5 h. Then a solution of 1-(bromomethyl)-4-chloro-2-fluorobenzene (6.3 g, 28.13 mmol) in tetrahydrofuran (10 mL) was added dropwise and stirred at -30 °C for 1 h. After the reaction was completed, the reaction mixture was allowed to warm to room temperature. Water (100 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (150 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography on silica gel using ethyl acetate / petroleum ether (0-50%) as eluent to give tert-butyl 4-(4-chloro-2-fluorobenzyl)-4-formylpiperidine-1-carboxylate (colorless oil, 6 g, 71.9%). MS (ESI + )m / z = 300.0 [M+H-56] + .

[0605] Steps 2-6: tert-Butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-((4-chloro-3-cyano-2-fluoropyridin-2-yl)methyl)piperidine-1-carboxylate was prepared from tert-butyl 4-(4-chloro-2-fluorobenzyl)-4-formylpiperidine-1-carboxylate according to the procedures described in Steps 3-7 of Intermediate A26. MS (ESI + )m / z = 397.3 [M+H-Boc] + .

[0606] Step 7: Under nitrogen, 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). TBAF solution in tetrahydrofuran (1 M, 19.3 mL, 19.3 mmol) was added and stirred at room temperature for 1 h. After the reaction was completed, water (20 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography on silica gel using ethyl acetate / petroleum ether (0-100%) as eluent to give tert-butyl 7'-chloro-8'-cyano-2'H,4'H-spiro[piperidine-4,3'-pyrano[3,2-b]pyran]-1-carboxylate (white solid, 3.6 g, 92.5%). MS (ESI + )m / z = 363.1 [M+H] + .

[0607] Preparation of Intermediate A28. (S)-tert-Butyl 10-bromo-7-cyano-8-nitro- 1,2,4a,5-tetrahydrobenzo[b]pyrazino[l,2-d][l,4]oxazin-3(4H)-carboxylate

[0608]

[0609] (S)-tert-Butyl 7-cyano-8-nitro-l,2,4a,5-tetrahydrobenzo[b]pyrazino[l,2- d][l,4]oxazin-3(4H)-carboxylate was prepared according to the synthetic method of Intermediate A18 using 2,3-difluoro-6-nitrobenzonitrile and (3S)-3- (hydroxymethyl)piperazine-l-carboxylate as starting materials. MS (ESI + m / z = 383.0 [M+H-56] + .

[0610] Preparation of Intermediate A29. tert-Butyl 8-chloro-5-cyano-6-nitro-3H- spiro[benzo[b][l,4]dioxan-2,4'-piperidin]-l'-carboxylate

[0611]

[0612] Step 1 : 2,3-Difluoro-6-nitrobenzenamine (10 g, 57.44 mmol) was dissolved in N,N-dimethylformamide (100 mL), cooled to 0 °C, N-chlorosuccinimide (15.3 g, 114.87 mmol) was added slowly, and the mixture was stirred at 80 °C overnight. After the reaction was completed, the mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). The combined organic phase was washed with water (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography on silica gel using ethyl acetate / petroleum ether (0% to 20%) as eluent to give 4-chloro-2,3-difluoro-6-nitrobenzenamine (green solid, 6.7 g, 55.9%).

[0613] Second step: under nitrogen protection, 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, cooled to 0°C, slowly added tert-butyl nitrite (6.6 g, 64.25 mmol), recovered to room temperature and stirred for 30 min, then continuously heated to 60°C and stirred overnight. After the reaction was completed, it was cooled to room temperature, poured into ice water (50 mL), ammonia water (30 mL) was added, the mixture was extracted with ethyl acetate (50 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (0-1%) as eluent gradient to give 2-bromo-5-chloro-3,4-difluoro-1-nitrobenzene (yellow liquid, 5.2 g, 59.4%).

[0614] Third step: under nitrogen protection, 2-bromo-5-chloro-3,4-difluoro-1-nitrobenzene (5.2 g, 19.09 mmol) was dissolved in N,N-dimethylformamide (50 mL), copper cyanide (3.4 g, 38.17 mmol) was added, and heated to 120°C and stirred for 6 h. After the reaction was completed, it was cooled to room temperature, water (20 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (50 mL), the combined organic phase was washed with water (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (0-50%) as eluent gradient to give 4-chloro-2,3-difluoro-6-nitrobenzonitrile (yellow solid, 2.5 g, 59.9%).

[0615] Fourth step: 4-chloro-2,3-difluoro-6-nitrobenzonitrile (2.5 g, 11.44 mmol) was dissolved in 1,4-dioxane (30 mL), cesium carbonate (18.6 g, 57.20 mmol) and tert-butyl 4-hydroxy-4-(hydroxymethyl)piperidine-1-carboxylate (2.7 g, 11.44 mmol) were added in turn, heated to 120°C and stirred for 1 h. After the reaction was completed, it was cooled to room temperature, water (20 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (30 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (0-50%) as eluent gradient to give tert-butyl 8-chloro-5-cyano-6-nitro-3H-spiro[benzo[b][1,4]dioxan-2,4'-piperidin]-1'-carboxylate (yellow solid, 3.3 g, 70.4%). MS (ESI + m / z = 354.1 [M+H-56] + .

[0616] Preparation of Intermediate A30. tert-Butyl 8-bromo-5-cyano-6-nitro-3H-spiro[benzo[b][l,4]dioxan-2,4'-piperidin]-l'-carboxylate

[0617]

[0618] tert-Butyl 8-bromo-5-cyano-6-nitro-3H-spiro[benzo[b][l,4]dioxan-2,4'-piperidin]-l'-carboxylate was prepared from Intermediate Al l following the procedure of the second step of Intermediate A13.

[0619] Preparation of Intermediate A31. tert-Butyl 7'-chloro-8'-cyano-4'-oxo-2'H,4'H-spiro[piperidine-4,3'-pyrano[3,2-b]pyridine]-l-carboxylate

[0620]

[0621] Step 1 : N-Boc-4-piperidinecarboxylic acid methyl ester (7.0 g, 28.77 mmol) was dissolved in tetrahydrofuran (100 mL) under nitrogen protection, and cooled to -78 °C. LDA tetrahydrofuran solution (2 M, 21.6 mL, 43.16 mmol) was added dropwise, and stirred at -78 °C for 1 h. Then 5-chloro-3-fluoropyridine-2-carbaldehyde (5.0 g, 31.65 mmol) in tetrahydrofuran (20 mL) was added dropwise, and stirred for another 1 h. After the reaction was completed, the reaction was allowed to warm to room temperature. Saturated aqueous ammonium chloride solution (80 mL) was added to the reaction, and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography on silica gel, eluting with ethyl acetate / petroleum ether (0-30%) as eluent gradient, to give 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] + m / z = 403.2 [M+H] + .

[0622] Second step: N-Boc-4-((5-chloro-3-fluoropyridin-2-yl)(hydroxy)methyl)piperidine-4- carboxylate ethyl ester (9.0 g, 22.34 mmol) was dissolved in tetrahydrofuran (150 mL), and the solution was cooled to 0 °C. Lithium borohydride tetrahydrofuran solution (2 M, 44.7 mL, 89.36 mmol) was slowly added. The mixture was stirred at room temperature for 1 h. After the reaction was completed, ice water (50 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography with ethyl acetate / petroleum ether (0-50%) as the eluent to give 4-((5-chloro-3-fluoropyridin-2-yl)(hydroxy)methyl)-4- (hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (white solid, 7 g, 83.6%). MS (ESI) m / z = 375.2 [M+H] + m / z = 375.2 [M+H] + .

[0623] Third step: 4-((5-chloro-3-fluoropyridin-2-yl)(hydroxy)methyl)-4- (hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (7.0 g, 18.67 mmol) was dissolved in DMF (100 mL). Imidazole (3.8 g, 56.02 mmol) was added, and the solution was cooled to 0 °C. TBSCl (5.6 g, 37.35 mmol) was slowly added. The mixture was stirred at room temperature for 16 h. After the reaction was completed, water (50 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with water (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography with ethyl acetate / petroleum ether (0-30%) as the eluent to give 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-((5-chloro-3-fluoropyridin-2- yl)(hydroxy)methyl)piperidine-1-carboxylic acid tert-butyl ester (colorless transparent oil, 8 g, 87.6%). MS (ESI) m / z = 489.3 [M+H] + m / z = 489.3 [M+H] + .

[0624] Fourth step: 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) was dissolved in tetrahydrofuran (150 mL) under nitrogen protection, and the solution was cooled to -78 °C. LDA tetrahydrofuran solution (2 M, 12.3 mL, 24.54 mmol) was added dropwise, and the mixture was stirred at -78 °C for 4 h. Dry ice was then slowly added, and the mixture was stirred for 1 h. After the reaction was completed, the solution was allowed to return to room temperature, saturated aqueous ammonium chloride solution (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 to give tert-butyl 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). MS (ESI + )m / z = 533.3 [M+H] + .

[0625] Fifth step: tert-butyl 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) under nitrogen protection, and HOBT (2.5 g, 18.29 mmol) and EDCI (3.5 g, 18.29 mmol) were added sequentially. The mixture was stirred at room temperature for 0.5 h, and then ammonium chloride (3.3 g, 60.97 mmol) was slowly added. The mixture was stirred at room temperature for 1 h. After the reaction was completed, 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 washed with water (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography using 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] + .

[0626] Step 6: Under nitrogen, 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 solution was cooled to 0 °C, and trifluoroacetic anhydride (8.1 g, 38.53 mmol) was added slowly. The reaction was stirred at room temperature for 1 h. After the reaction was completed, water (30 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography on silica gel using ethyl acetate / petroleum ether (0-100%) as eluent to give 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] + m / z = 414.2 [M+H-100] + .

[0627] Step 7: Under nitrogen, 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 TBAF solution in tetrahydrofuran (1 M, 10.5 mL, 10.51 mmol) was added. The reaction was stirred at room temperature for 1 h. After the reaction was completed, water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography on silica gel using ethyl acetate / petroleum ether (0-100%) as eluent to give tert-butyl 7'-chloro-8'-cyano-4'-hydroxy-2'H,4'H-spiro[piperidine-4,3'- pyranoben]pyridine-1-carboxylate (white solid, 1.4 g, 70.2%). MS (ESI) m / z = 324.1 [M+H-56] + m / z = 414.2 [M+H-100] + .

[0628] Eighth step: Dissolve 7'-chloro-8'-cyano-4'-hydroxy-2'H,4'H-spiro[piperidine-4,3'- pyrano[3,2-b]pyridine]-1-carboxylic acid tert-butyl ester (400.0 mg, 1.05 mmol) in chloroform (5 mL), add manganese dioxide (915.5 mg, 10.53 mmol), warm up to 60 °C and stir for 1 h. After the reaction is complete, cool to room temperature, filter the reaction, and concentrate the filtrate under reduced pressure to give 7'-chloro-8'-cyano-4'-oxo-2'H,4'H-spiro[piperidine-4,3'- pyrano[3,2-b]pyridine]-1-carboxylic acid tert-butyl ester (white solid, 400 mg, crude). MS (ESI + m / z = 400.2 [M+Na] + .

[0629] Preparation of Intermediate A32. 5-cyano-6-nitro-3H-8'-azaspiro[benzo[b][1,4]dioxan-2,3'- bicyclo[3.2.1]octane]-8'-carboxylic acid tert-butyl ester

[0630]

[0631] First step: Dissolve methyltriphenylphosphonium bromide (23.8 g, 66.58 mmol) in tetrahydrofuran (50 mL), cool to 0 °C, and add n-butyllithium in n-hexane (2.5 M, 26.6 mL, 66.58 mmol). Stir at 0 °C for 1 h. Add N-tert-butoxycarbonyl normetopon (5.0 g, 22.19 mmol), and stir at 0 °C for 2 h. After the reaction is complete, restore to room temperature, add water (150 mL) to the reaction, extract the mixture with ethyl acetate (300 mL x 3), dry the combined organic phases with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Separate the resulting residue by silica gel column chromatography using ethyl acetate / petroleum ether (10%-50%) as the eluent to give 3-methylene-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (colorless oil, 2.5 g, 50.5%).

[0632] Step 2: tert-Butyl 3-hydroxy-3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8- carboxylate (black oil, 3 g, crude) was prepared from tert-butyl 3-methylene-8- azabicyclo[3.2.1]octane-8-carboxylate (2.1 g, 9.41 mmol) following the procedure for the synthesis of Intermediate Al l. MS (ESI) m / z = 280.2 [M+Na] + m / z = 346.1 [M+H-56] + .

[0633] Step 3: Intermediate A32 was prepared from tert-butyl 3-hydroxy-3-(hydroxymethyl)-8- azabicyclo[3.2.1]octane-8-carboxylate and 2,3-difluoro-6-nitrobenzonitrile following the procedure for the synthesis of Intermediate Al l. MS (ESI) m / z = 346.1 [M+H-56] + m / z = 346.1 [M+H-56] + .

[0634] Preparation of Intermediates A33 and A34

[0635] Intermediates A33 and A34 were prepared from commercially available or prepared fluorobenzene compounds and commercially available tert-butyl 4-formylpiperidine-l- carboxylate following the procedure for the synthesis of Intermediate A27. See Table 2.

[0636] Table 2. Structures, starting materials for preparation, and MS data of Intermediates A33 and A34

[0637]

[0638] Preparation of Intermediate A35. tert-Butyl 7'-chloro-8'-cyano-4',4'-difluoro-2'H,4'H- spiro[piperidine-4,3'-pyrano[3,2-b]pyridine]-l-carboxylate

[0639]

[0640] Intermediate A31. tert-Butyl 7'-chloro-8'-cyano-4'-oxo-2'H,4'H-spiro[piperidine-4,3'- pyrano[3,2-b]pyridine]-1-carboxylate (300.0 mg, 0.79 mmol) was dissolved in BAST (5 mL) and stirred at room temperature for 3 h under nitrogen. After the reaction was completed, 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 x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography with methanol / dichloromethane (0-10%) as eluent to give tert-butyl 7'-chloro-8'-cyano-4',4'-difluoro-2'H,4'H-spiro[piperidine-4,3'- pyrano[3,2-b]pyridine]-1-carboxylate (white solid, 200 mg, 63.0%). MS (ESI + )m / z = 344.1 [M+H-56] + .

[0641] Intermediate A36. Preparation of tert-butyl 7-chloro-8-cyano-4-oxospiro[chromane-3,4'- piperidine]-1'-carboxylate

[0642]

[0643] First step: N-Boc-4-((4-chloro-3-cyano-2-fluorophenyl)(hydroxy)methyl)piperidine-4- carboxylic acid methyl ester (yellow oil, 3 g, 57.0%) was prepared from N-Boc-4- piperidinecarboxylic acid methyl ester (3.0 g, 12.33 mmol) and 6-chloro-2-fluoro-3- formylbenzonitrile (2.2 g, 11.71 mmol) according to the method of the first step of the synthesis of Intermediate A31. MS (ESI + )m / z = 449.1 [M+Na] + .

[0644] Second step: N-Boc-4-((4-chloro-3-cyano-2-fluorophenyl)(hydroxy)methyl)piperidine-4- carboxylic acid methyl ester (3.0 g, 7.03 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to 0 °C. Lithium aluminum hydride (1.1 g, 28.11 mmol) was added, and after the addition, the temperature was allowed to return to room temperature, and the mixture was stirred for 2 h. After the reaction was completed, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography with ethyl acetate / petroleum ether (0-86%) as eluent to give 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] + .

[0645] Step 3: tert-Butyl 4-((4-chloro-3-cyano-2-fluorophenyl)(hydroxy)methyl)-4- (hydroxymethyl)piperidine-1-carboxylate (2.0 g, 5.01 mmol) was dissolved in 1,4- dioxane (30 mL), cesium carbonate (3.3 g, 10.04 mmol) was added, and the reaction mixture was stirred at 120 °C for 4 h. After the reaction was completed, the reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography on silica gel eluted with ethyl acetate / petroleum ether (0-24%) as eluent to give 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] + .

[0646] Step 4: tert-Butyl 7-chloro-8-cyano-4-hydroxyspiro[chromane-3,4'-piperidine]-1'- carboxylate (1.7 g, 4.49 mmol) was used as the raw material to prepare tert-butyl 7- chloro-8-cyano-4-oxospiro[chromane-3,4'-piperidine]-1'-carboxylate (white solid, 1.3 g, 76.8) according to the method of Step 8 of Intermediate A31. MS (ESI + m / z = 320.1 [M+H-56] + .

[0647] Preparation of Intermediate A37. tert-Butyl 6-cyano-7-nitro-3,4-dihydrospiro[benzo[b][1,4] dioxin-2,4'-piperidine]-1'-carboxylate

[0648]

[0649] tert-Butyl 6-cyano-7-nitro-3,4-dihydrospiro[benzo[b][1,4]dioxin-2,4'-piperidine]-1'- carboxylate (yellow solid) was prepared according to the method of Intermediate A11 using 2,3-difluoro-6-nitrobenzonitrile and tert-butyl 4-hydroxy-4-(2- hydroxyethyl)piperidine-1-carboxylate as the raw materials at 120 °C. MS (ESI + m / z = 412.2 [M+Na] + .

[0650] 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

[0651]

[0652] Intermediate A38 was prepared from 5-chloro-2,3-difluoropyridine-4-carbonitrile and tert-butyl 3-hydroxy-3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate following the procedure for the synthesis of Intermediate A11 at 120 °C. MS (ESI + )m / z = 336.1 [M+H-56] +

[0653] Third Set of Preparation Examples: Preparation of Intermediates B1-B49

[0654] Intermediate B1. Preparation of 2-methoxy-5-methyl-4-((1-methyl-1H- benzo[d]imidazol-5-yl)oxy)aniline

[0655]

[0656] First Step: 1-Fluoro-5-methoxy-2-methyl-4-nitrobenzene (1.0 g, 5.40 mmol) was dissolved in N,N-dimethylformamide solution (30 mL), added 1-methyl-1H- benzo[d]imidazol-5-ol (1.2 g, 8.10 mmol) and cesium carbonate (5.3 g, 16.20 mmol), warmed to 120 °C and stirred for 3 h. After the reaction was complete, it was cooled to room temperature and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography on silica gel with methanol / dichloromethane (10%) as 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] + .

[0657] Second step: 5-(5-methoxy-2-methyl-4-nitrophenoxy)-l-methyl-lH- benzo[d]imidazole (1.5 g, 4.79 mmol) was dissolved in N,N-dimethylformamide (30 mL), cooled to 0 °C, tetrahydroxyboron (2.1 g, 23.94 mmol) and 4,4'-dipyridine (3.7 mg, 0.024 mmol) were added, and the reaction was stirred at room temperature for 10 min. After the reaction was completed, the reaction solution was extracted with methanol / dichloromethane (1 / 10, 30 mL x 3), and the combined organic phase was washed with water (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2-methoxy-5-methyl-4-((l-methyl-lH-benzo[d]imidazol-5-yl)oxy)aniline (pale yellow solid, 1 g, 73.7%). MS (ESI + m / z = 284.2 [M+H] + .

[0658] Preparation of intermediates B2-B8, B11-B29, B34-B49

[0659] Intermediates B2-B8, B11-B29, B34-B49 were prepared according to the procedure for the synthesis of intermediate Bl, starting from commercially available or prepared intermediate alcohol or phenol compounds and commercially available fluoro-nitrobenzene compounds, or commercially available or prepared halogenated heteroaryl compounds and substituted nitrophenol compounds. The structures and MS data of intermediates B2-B8, B11-B29, B34-B49 are shown in Table 3.

[0660] The first step substitution reaction can also be prepared by the following conditions: Na2CO3 / K2CO3, DMF, 80 °C; K2CO3, DMSO, 100 °C, and 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 on carbon (50%) and hydrogen, methanol, r.t.

[0661] Table 3. Structures and MS data of intermediates B2-B8, B11-B29, B34-B49

[0662]

[0663]

[0664] Preparation of intermediate B9. 2-fluoro-5-methyl-4-((l-methyl-lH- benzo[d]imidazol-5-yl)oxy)aniline

[0665]

[0666] Step 1: 5-(5-chloro-2-methyl-4-nitrophenoxy)-l-methyl-lH-benzo[d]imidazole was prepared from l-chloro-5-fluoro-4-methyl-2-nitrobenzene and l-methyl-lH- benzo[d]imidazol-5-ol according to the method of Step 1 of Intermediate Bl. MS (ESI + m / z = 318.1 [M+H] + .

[0667] Step 2: 5-(5-chloro-2-methyl-4-nitrophenoxy)-l-methyl-lH-benzo[d]imidazole (5.0 g, 15.74 mmol) was dissolved in DMSO (200 mL), cesium fluoride (24.0 g, 157.7 mmol) was added, and the reaction mixture was stirred at 110 °C for 6 h. After the reaction was completed, the reaction mixture was cooled to room temperature, water (200 mL) was added, and the mixture was filtered. The collected solid was washed with water and dried to give 5-(5-fluoro-2-methyl-4-nitrophenoxy)-l-methyl-lH- benzo[d]imidazole (yellow solid, 4.2 g, crude). It was used in the next step without purification. MS (ESI + m / z = 301.9 [M+H] + .

[0668] Step 3: 2-fluoro-5-methyl-4-((l-methyl-lH-benzo[d]imidazol-5-yl)oxy)aniline was prepared from 5-(5-fluoro-2-methyl-4-nitrophenoxy)-l-methyl-lH-benzo[d]imidazole (4.9 g, 16.26 mmol) according to the method of Step 2 of Intermediate Bl. MS (ESI + m / z = 272.2 [M+H] + .

[0669] Intermediate BlO. Preparation of 2-fluoro-3-methyl-4-((l-methyl-lH-benzo[d]imidazol-5- yl)oxy)aniline

[0670]

[0671] 2-fluoro-3-methyl-4-((l-methyl-lH-benzo[d]imidazol-5-yl)oxy)aniline was prepared from 2-chloro-4-fluoro-3-methylnitrobenzene and l-methyl-lH-benzo[d]imidazol-5-ol according to the method of Intermediate B9. MS (ESI + m / z = 272.2 [M+H] + .

[0672] Intermediate B30. Preparation of 4-([l,2,4]triazolo[l,5-a]pyridin-7-ylmethyl)-3- methylbenzenamine

[0673]

[0674] Step 1: 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-[l,2,4]triazolo[l,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) under nitrogen protection, 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, 0.41 mmol) were added successively, the reaction mixture was warmed to 60 °C and stirred for 1 h, after the reaction was completed, the reaction mixture was cooled to room temperature, water (30 mL) was added, the mixture was extracted with ethyl acetate (50 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (10-70%) as eluent to give 7-(2-methyl-4-nitrobenzyl)-[l,2,4]triazolo[l,5-a]pyridine (yellow solid, 300 mg, 27.4%). MS (ESI) m / z = 269.1 [M+H] + + .

[0675] Step 2: 7-(2-methyl-4-nitrobenzyl)-[l,2,4]triazolo[l,5-a]pyridine (300 mg, 1.12 mmol) was dissolved in N,N-dimethylformamide (5 mL), 4,4-bipyridine (8.7 mg, 0.06 mmol) was added, the reaction mixture was cooled to 0 °C, then tetrahydroxyboron (300.7 mg, 3.35 mmol) was added, the reaction mixture was stirred at 0 °C for 30 min, after the reaction was completed, the reaction mixture was allowed to warm to room temperature, water (20 mL) was added, the mixture was extracted with ethyl acetate (20 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography with methanol / dichloromethane (0-10%) as eluent to give 4-([l,2,4]triazolo[l,5-a]pyridin-7-ylmethyl)-3-methylaniline (yellow oily product, 180 mg, 67.7%). MS (ESI) m / z = 239.2 [M+H] + + .

[0676] Preparation of intermediate B31. 4-((3-chloroimidazo[l,2-a]pyridin-7-yl)oxy)-3- methylaniline

[0677]

[0678] ​​Step 1 : 7-Bromoimidazo[l,2-a]pyridine (2 g, 10.2 mmol) was dissolved in dimethyl sulfoxide / water (30 mL, 4 / 1 v / v) under nitrogen protection, and then lithium hydroxide monohydrate (899.6 mg, 21.4 mmol), N,N'-bis(4-hydroxy-2,6-dimethylphenyl)oxalamide (66.9 mg, 0.2 mmol) and copper acetylacetonate (53.2 mg, 0.2 mmol) were added successively. The mixture was stirred at 80 °C for 2 h. After the reaction was completed, the mixture was cooled to room temperature, and then water (10 mL) was added. The mixture was extracted with dichloromethane / methanol (3 / 1 v / v, 30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was separated and purified by silica gel column chromatography with methanol / dichloromethane (15%) as eluent to give imidazo[l,2-a]pyridin-7-ol (yellow oil, 1.0 g, 73.2%). MS (ESI) m / z = 157.1 [M+Na] + m / z = 157.1 [M+Na] + .

[0679] Step 2: Imidazo[l,2-a]pyridin-7-ol (1.0 g, 7.45 mmol) was dissolved in N,N- dimethylformamide (20 mL), and then cesium carbonate (4.9 g, 14.91 mmol) and 1-fluoro-2-methyl-4-nitrobenzene (1.2 g, 7.45 mmol) were added successively. The mixture was stirred at 80 °C for 3 h. After the reaction was completed, the mixture was cooled to room temperature, and then water (30 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3). The combined 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 with methanol / dichloromethane (15%) as eluent to give 7-(2-methyl-4-nitrophenoxy)imidazo[l,2-a]pyridine (pale yellow solid, 1.1 g, 55.0%). MS (ESI) m / z = 270.0 [M+H] + m / z = 270.0 [M+H] + .

[0680] Step 3: 7-(2-Methyl-4-nitrophenoxy)imidazo[l,2-a]pyridine (1.0 g, 3.71 mmol) was dissolved in acetonitrile (15 mL), and then N-chlorosuccinimide (595.1 mg, 4.46 mmol) was added. The mixture was stirred at room temperature for 16 h. After the reaction was completed, the mixture was added with water (30 mL), and then the mixture was extracted with ethyl acetate (40 mL x 3). The combined 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 with ethyl acetate / petroleum ether (35%) as eluent to give 3-chloro-7-(2-methyl-4-nitrophenoxy)imidazo[l,2-a]pyridine (yellow solid, 360 mg, 31.9%). MS (ESI) m / z = 324.0 [M+H] +m / z = 304.1 [M+H] + .

[0681] Fourth Step: 4-((3-chloroimidazo[l,2-a]pyridin-7-yl)oxy)-3-methylphenylamine was prepared from 3-chloro-7-(2-methyl-4-nitrophenoxy)imidazo[l,2-a]pyridine following the procedure of the second step of Intermediate Bl. MS (ESI + m / z = 274.0 [M+H] + .

[0682] Preparation of Intermediate B32. 4-([l,2,4]triazolo[l,5-a]pyridin-7- ylmethyl)-3-methylphenylamine

[0683]

[0684] First Step: 7-(2-methyl-4-nitrobenzyl)-[l,2,4]triazolo[l,5-a]pyridine was prepared from 7-(4,4,5,5-tetramethyl-l,3,2-dioxaboro-2-yl)-[l,2,4]triazolo[l,5- a]pyridine (1 g, 4.08 mmol) following the procedure of the first step of Intermediate B2. MS (ESI + m / z = 269.1 [M+H] + .

[0685] Step 2: 7-(2-methyl-4-nitrobenzyl)-[l,2,4]triazolo[l,5-a]pyridine (300 mg, 1.12 mmol) was dissolved in N,N-dimethylformamide (5 mL), 4,4'-dipyridine (8.7 mg, 0.06 mmol) was added, the temperature was lowered to 0 °C, and tetrahydroxyboron (300.7 mg, 3.35 mmol) was added. The mixture was stirred at 0 °C for 30 min. After the reaction was completed, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined 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 with methanol / dichloromethane (0-10%) as the eluent gradient to give 4-([l,2,4]triazolo[l,5-a]pyridin-7-ylmethyl)-3-methylaniline (yellow oil, 180 mg, 67.7%). MS (ESI + )m / z = 239.2 [M+H] + .

[0686] Preparation of intermediate B33. 3-chloro-2-fluoro-4-(quinoxalin-6-yloxy)aniline

[0687]

[0688] 3-chloro-2-fluoro-4-(quinoxalin-6-yloxy)aniline (yellow solid) was prepared according to the method for synthesizing intermediate B9 using 2,3-dichloro-l-fluoro-4-nitrobenzene and 6-hydroxyquinoxaline as starting materials. MS (ESI + )m / z = 290.0 [M+H] + .

[0689] Fourth group of preparation examples: preparation of intermediates C1-C45

[0690] Preparation of intermediate C1. 8-cyano-7-(((dimethylamino)methylene)amino)-2H,4H- spiro[benzo[b][l,4]oxazin-3,4'-piperidin]-l'-carboxylic acid tert-butyl ester

[0691]

[0692] Step 1: Intermediate Al (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 successively, and the reaction mixture was stirred at 70 °C for 1 h. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and water (10 mL) was added to the filtrate. The mixture was extracted with ethyl acetate (10 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was separated and purified by column chromatography on silica gel using methanol / dichloromethane (10%) as the eluent to give 7-amino-8-cyano-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidin]-1'- carboxylic acid tert-butyl ester (pale yellow solid, 70 mg, 76.1%). MS (ESI) m / z = 345.2 [M+H] + m / z = 345.2 [M+H] + .

[0693] Step 2: 7-amino-8-cyano-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidin]-1'- carboxylic acid tert-butyl ester (100.0 mg, 0.29 mmol) was dissolved in N,N- dimethylformamide dimethyl acetal (5 mL), and the reaction mixture was stirred at 100 °C for 1 h. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to give 8-cyano-7-(((dimethylamino)methylene)amino)-2H,4H-spiro[benzo[b][1,4]oxazine-3,4'-piperidin]-1'-carboxylic acid tert-butyl ester (yellow oil, 170 mg, crude). MS (ESI) m / z = 400.3 [M+H] + m / z = 400.3 [M+H] + .

[0694] Preparation of intermediates C2-C11, C18-C24, C35, C43

[0695] Intermediates C2-C11, C18-C24, C35, C43 were prepared according to the method for synthesizing intermediate C1 using intermediates A2-A11, A18-A21, A28-A30, A32, A37 as raw materials. As shown in Table 4.

[0696] Table 4 Structures, raw materials, reaction conditions, and MS data of intermediates C2-C11, C18-C24, C35, C43

[0697]

[0698]

[0699]

[0700] Preparation of Intermediate C12. 8'-cyano-7'-(((dimethylamino)methylene)amino)- 2'H,4'H-spiro[piperidine-4,3'-pyrido[3,2-b][l,4]oxazin]-l-carboxylic acid tert-butyl ester

[0701]

[0702] First Step: Intermediate A13 (450.0 mg, 1.10 mmol) was dissolved in 1,4- dioxane (5 mL) under nitrogen protection, and then 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 successively, and the mixture was stirred at 90 °C for 1 h. After the reaction was completed, the mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel using ethyl acetate / petroleum ether (54%) as the eluent to give 7'-((tert-butoxycarbonyl)amino)-8'-cyano-2'H,4'H-spiro[piperidine-4,3'- pyrido[3,2-b][l,4]oxazin]-l-carboxylic acid tert-butyl ester (yellow solid, 350 mg, 71.4%). MS (ESI + m / z = 446.4 [M+H] + .

[0703] Second Step: 7'-((tert-butoxycarbonyl)amino)-8'-cyano-2'H,4'H-spiro[piperidine-4,3'- pyrido[3,2-b][l,4]oxazin]-l-carboxylic acid tert-butyl ester (350.0 mg, 0.79 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was blown dry with nitrogen, and then an appropriate amount of water and acetonitrile were added. The mixture was lyophilized to give 7'-amino-2'H,4'H-spiro[piperidine-4,3'-pyrido[3,2-b][l,4]oxazin]-8'-carbonitrile (yellow solid, 350 mg, crude). MS (ESI + m / z = 246.2 [M+H] + .

[0704] Step 3: 7'-Amino-2'H,4'H-spiro[piperidine-4,3'-pyrido[3,2-b][l,4]oxazin]-8'- carbonitrile (350.0 mg, 1.43 mmol) was dissolved in tetrahydrofuran (2 mL) and water (2 mL) under nitrogen protection, and cooled to 0 °C. Sodium bicarbonate (359.6 mg, 4.28 mmol) and di-tert-butyl dicarbonate (311.4 mg, 1.43 mmol) were added successively. The mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was extracted with ethyl acetate (30 mL x 3), and the combined organic phase was 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 ethyl acetate / petroleum ether (50%) as the eluent to obtain 7'-amino-8'-cyano-2'H,4'H-spiro[piperidine-4,3'-pyrido[3,2-b][l,4]oxazin]-l- carboxylic acid tert-butyl ester (pale yellow oil, 120 mg, 24.4%). MS (ESI + m / z = 346.3 [M+H] + .

[0705] Step 4: Intermediate C12 (brown oil, 100 mg, crude) was prepared from 7'-amino-8'- cyano-2'H,4'H-spiro[piperidine-4,3'-pyrido[3,2-b][l,4]oxazin]-l-carboxylic acid tert-butyl ester according to the method of synthesis of intermediate C1 (second step). + m / z = 401.0 [M+H] + .

[0706] Preparation of intermediates C25-C31, C36-C38, C45

[0707] Intermediates C25-C31, C36-C38, C45 were prepared from intermediates A22-A27, A33-A36, A37 or commercially available compounds according to the method of synthesis of intermediate C12 (the second step and the third step can be synthesized in one step by the following conditions: TABF, THF, 60 °C to obtain 7'-amino-8'-cyano-2'H,4'H-spiro[piperidine-4,3'-pyrido[3,2-b][l,4]oxazin]-l-carboxylic acid tert-butyl ester). As shown in Table 5.

[0708] Table 5 Structures, starting materials for preparation, and MS data of intermediates C25-C31, C36-C38, C45

[0709]

[0710]

[0711] Intermediate C132. Preparation of tert-butyl 8'-cyano-7'-(((dimethylamino)methylene)amino)- 2'H-spiro[piperidine-4,3'-[l,4]dioxino[2,3-b]pyridine]-l-carboxylate

[0712]

[0713] First Step: Intermediate Al 2 (1.0 g, 2.73 mmol) was dissolved in 1,4-dioxane (10 mL) under nitrogen protection, and 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 successively. The reaction was stirred at 100 °C overnight. After the reaction was completed, the reaction was cooled to room temperature, water (50 mL) was added to the reaction, and the organic phase was extracted with ethyl acetate (30 mL x 3). The combined organic phase was 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 ethyl acetate / petroleum ether (70%) as the eluent to obtain tert-butyl 7'-amino-8'-cyano-2'H-spiro[piperidine-4,3'-[l,4]dioxino[2,3-b]pyridine]-l-carboxylate (yellow solid, 580 mg, 61.2%). MS (ESI + )m / z = 347.2 [M+H] + .

[0714] Second Step: Intermediate C13 (yellow oil, 200 mg, crude) was prepared according to the method of the second step of the synthesis of Intermediate Cl using tert-butyl 7'-amino-8'-cyano-2'H-spiro[piperidine-4,3'-[l,4]dioxino[2,3-b]pyridine]-l-carboxylate as the starting material. MS (ESI + )m / z = 402.2 [M+H] + .

[0715] Intermediate C14. Preparation of tert-butyl (R)-4-cyano-3-(((dimethylamino)methylene)amino)- 6a,7,9,10-tetrahydro-6H-pyrazino[l,2-d]pyrido[3,2-b][l,4]oxazene-8-carboxylate

[0716]

[0717] Step 1 : Intermediate A14 (900.0 mg, 2.28 mmol) was dissolved in dimethyl sulfoxide (12 mL) under nitrogen atmosphere, and 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 ammonia (25%, 239.4 mg, 6.83 mmol) were added successively. The reaction mixture was stirred at 90 °C for 18 h. After the reaction was completed, the reaction mixture was cooled to room temperature, and saturated brine (25 mL) was added. The mixture was extracted with ethyl acetate (35 mL x 3), and the combined organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel eluted with methanol / dichloromethane (0-15%) as eluent to give (R)-tert-butyl 3-amino-4-cyano-6a,7,9,10-tetrahydro-6H-pyrazino[l,2-d]pyrido[3,2-b][l,4]oxazine-8-carboxylate (yellow oil, 590 mg, 78.1%). MS (ESI) m / z = 332.0 [M+H] + m / z = 332.0 [M+H] + .

[0718] Step 2: Intermediate C14 (brown oil, 600 mg, crude) was prepared from (R)-tert-butyl 3-amino-4-cyano-6a,7,9,10-tetrahydro-6H-pyrazino[l,2-d]pyrido[3,2-b][l,4]oxazine-8-carboxylate according to the method described in Step 2 of the synthesis of Intermediate CI. + m / z = 332.0 [M+H] + .

[0719] Preparation of intermediates C15-C17

[0720] Intermediates C15-C17 were prepared from intermediates A15-A17 according to the method described in the synthesis of Intermediate C14. The structures, starting materials and MS data of intermediates C15-C17 are shown in Table 6.

[0721] Table 6. Structures, starting materials and MS data of intermediates C15-C17

[0722]

[0723] Preparation of Intermediate C32. (E)-5-cyano-6-((dimethylamino)methyleneamino)-8-methoxy-3H-spiro[benzo[b][l,4]dioxan-2,4'-piperidin]-l'-carboxylic acid tert-butyl ester

[0724]

[0725] (E)-8-chloro-5-cyano-6-(((dimethylamino)methylene)amino)-3H- spiro[benzo[b][l,4]dioxepin-2,4'-piperidin]-l'-carboxylic acid tert-butyl ester (Intermediate C23, 150 mg, 0.35 mmol) was dissolved in methanol (8 mL) under nitrogen protection, 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 added successively, the reaction mixture was stirred at 100 °C for 1 h, after the reaction was completed, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (0-80%) as eluent gradient to give (E)-5-cyano-6-((dimethylamino)methylene)amino)-8-methoxy-3H- spiro[benzo[b][l,4]dioxepin-2,4'-piperidin]-l'-carboxylic acid tert-butyl ester (yellow solid, 130 mg, 87.5%). MS (ESI + )m / z = 431.2 [M+H] + .

[0726] Preparation of (E)-5-cyano-6-((dimethylamino)methylene)amino)-8-ethoxy-3H- spiro[benzo[b][l,4]dioxepin-2,4'-piperidin]-l'-carboxylic acid tert-butyl ester

[0727]

[0728] (E)-5-cyano-6-((dimethylamino)methylene)amino)-8-ethoxy-3H- spiro[benzo[b][l,4]dioxepin-2,4'-piperidin]-l'-carboxylic acid tert-butyl ester was prepared from (E)-8-chloro-5-cyano-6-(((dimethylamino)methylene)amino)-3H- spiro[benzo[b][l,4]dioxepin-2,4'-piperidin]-l'-carboxylic acid tert-butyl ester (Intermediate C23), ethanol as solvent, according to the method for synthesizing Intermediate C32. MS (ESI + )m / z = 445.4 [M+H] + .

[0729] Preparation of (E)-5-cyano-6-((dimethylamino)methylene)amino)-8-cyano-3H- spiro[benzo[b][l,4]dioxepin-2,4'-piperidin]-l'-carboxylic acid tert-butyl ester

[0730]

[0731] Intermediate C23, 400 mg, 0.92 mmol) was dissolved in N,N-dimethylformamide (6 mL) under nitrogen protection, zinc cyanide (432 mg, 3.68 mmol), Pd(dppf)Cl2(168.2 mg, 0.23 mmol), polymethylhydrosiloxane (PMHS, 818.5 mg, 3.68 mmol) were added under stirring, the reaction mixture was heated to 130 °C and stirred for 12 h. After the reaction was completed, the reaction mixture was cooled to room temperature, water (50 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography with methanol / dichloromethane (0-10%) as eluent gradient elution to give (E)-5-cyano-6-((dimethylamino)methyleneamino)-8-cyano-3H-spiro[benzo[b][l,4]dioxan-2,4'-piperidin]-l'-carboxylic acid tert-butyl ester (yellow solid, 375 mg, 95.8%). MS (ESI + m / z = 426.2 [M+H] + .

[0732] Preparation of Intermediate C39.8'-cyano-7'-(((dimethylamino)methylene)amino)-4'-oxo-2'H,4'H-spiro[piperidine-4,3'-pyrano[3,2-b]pyridine]-l-carboxylic acid tert-butyl ester

[0733]

[0734] First step: tert-butyl 7'-chloro-8'-cyano-4'-oxo-2'H,4'H-spiro[piperidine-4,3'- pyrano[3,2-b]pyridine]-l-carboxylate (Intermediate A31, 200.0 mg, 0.53 mmol) was dissolved in DMF (5 mL) under nitrogen protection, sodium azide (68.8 mg, 1.06 mmol) was added slowly, and the reaction mixture was heated to 100 °C and stirred for 1 h. After the reaction was completed, the reaction mixture was cooled to room temperature, water (5 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate (5 mL x 3), the combined organic phase was washed with water (5 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography with methanol / dichloromethane (0-10%) as eluent gradient elution to give tert-butyl 7'-amino-8'-cyano-4'-oxo-2'H,4'H-spiro[piperidine-4,3'-pyrano[3,2-b]pyridine]-l-carboxylate (yellow solid, 140 mg, 73.8%). MS (ESI +m / z = 259.1 [M+H-100] + .

[0735] Second Step: 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 from 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) following the procedure of the second step of the synthesis of Intermediate CI. + m / z = 414.2 [M+H] + .

[0736] Preparation of Intermediate C40. tert-butyl 5-chloro-8-cyano-7-(((dimethylamino)methylene)amino)-4-methyl-2H,4H-spiro[benzo[b][1,4]oxazin-3,4'-piperidin]-1'- carboxylate

[0737]

[0738] Under nitrogen protection, tert-butyl 5-chloro-8-cyano-7-(((dimethylamino)methylene)amino)-2H,4H-spiro[benzo[b][1,4]oxazin-3,4'-piperidin]-1'-carboxylate (Intermediate C7, 200.0 mg, 0.46 mmol) was dissolved in DMF (4 mL), cooled to 0 °C, sodium hydride (60%, 50.5 mg, 1.36 mmol) was added, stirred at 0 °C for 15 min, methyl iodide (196.3 mg, 1.38 mmol) was added, after addition, warmed to 60 °C and stirred for 1 h. After the reaction was completed, it was cooled to room temperature, water (25 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (40 mL x 3), the combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography with methanol / dichloromethane (0-10%) as eluent gradient elution to give tert-butyl 5-chloro-8-cyano-7-(((dimethylamino)methylene)amino)-4-methyl-2H,4H-spiro[benzo[b][1,4]oxazin-3,4'-piperidin]-1'-carboxylate (pale yellow solid, 200 mg, 96.9%). MS (ESI + m / z = 448.2 [M+H] + .

[0739] Preparation of Intermediate C41 and Intermediate C42

[0740] Intermediates C41 and C42 were prepared according to the procedure for synthesizing intermediate C40, using commercially available deuterated methyl iodide or ethyl iodide as starting material. The structures and MS data of intermediates C41 and C42 are shown in Table 7.

[0741] Table 7. Structures and MS data of intermediates C41 and C42

[0742]

[0743]

[0744] Preparation of intermediate C44. N'-(2-cyano-4-hydroxy-3-methoxyphenyl)-N,N- dimethylformamidine

[0745]

[0746] First step: 6-amino-3-bromo-2-fluorobenzonitrile (10.0 g, 46.51 mmol) was dissolved in tetrahydrofuran (100 mL) under nitrogen protection, sodium methoxide (7.5 g, 0.14 mol) was added, and the mixture was stirred at reflux for 6 h. After the reaction was completed, the mixture was cooled to room temperature, ice water (100 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography using ethyl acetate / petroleum ether (10%) as the eluent to give 6-amino-3-bromo-2-methoxybenzonitrile (pale yellow solid, 8.0 g, 75.8%). MS (ESI + )m / z = 226.9 [M+H] + .

[0747] Second step: 6-amino-3-bromo-2-methoxybenzonitrile (8.0 g, 35.23 mmol) was dissolved in ethanol (10 mL), DMF-DMA (8.4 g, 70.47 mmol) was added, and the mixture was stirred at reflux for 1 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to give N'-(4-bromo-2-cyano-3-methoxyphenyl)-N,N-dimethylformamidine (yellow solid, 9 g, crude). MS (ESI + )m / z = 282.0 [M+H] + .

[0748] Step 3: N'-((4-bromo-2-cyano-3-methoxyphenyl)carbodiimide (6.0 g, 21.27 mmol) was dissolved in a mixture of 1,4-dioxane and water (66 mL, 10 / 1 v / v) under nitrogen protection, KOH (3.6 g, 63.80 mmol) and Brettphos Pd G3 (1.9 g, 2.13 mmol) were added successively, and the mixture was stirred at 100 °C for 4 h. After the reaction was completed, the mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL) three times. The aqueous phase was adjusted to pH 5 with hydrochloric acid (2 M) and extracted with ethyl acetate (50 mL) three times. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (20%) as the eluent to obtain N'-((2-cyano-4-hydroxy-3-methoxyphenyl)carbodiimide (white solid, 1.2 g, two-step yield: 23.3%). + m / z = 220.1 [M+H] + .

[0749] Fifth group of preparation examples: preparation of final products

[0750] 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]quinolin]-1-yl)prop-2-en-1-one (final product 1)

[0751]

[0752] Step 1: Intermediate C1 (110.0 mg, 0.28 mmol) was dissolved in methyl tert-butyl ether / acetic acid (4 mL, 1 / 1 v / v), and intermediate B7 (83.7 mg, 0.33 mmol) was added. The mixture was stirred at 70 °C for 10 h. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL) three times. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography with methanol / dichloromethane (1 / 9) as the 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]quinoline]-1-carboxylate (yellow solid, 80 mg, 47.8%). MS (ESI + m / z = 608.5 [M+H] + .

[0753] Second step: dissolve 10'-((3-methyl-4-((1-methyl-1 H-benzo[d]imidazol-5- yl)oxy)phenyl)amino)-2'H,4'H-spiro[piperidine-4,3'-[1,4]oxazino[2,3-f]quinoline]-1- carboxylic acid tert-butyl ester (70.0 mg, 0.12 mmol) in dichloromethane / trifluoroacetic acid (4 mL, 3 / 1 v / v), stir at room temperature for 0.5 h. After the reaction is completed, concentrate under reduced pressure to obtain N-(3-methyl-4-((1-methyl-1 H-benzo[d]imidazol-5-yl)oxy)phenyl)-2'H,4'H-spiro[piperidine-4,3'-[1,4]oxazino[2,3-f]quinoline]-10'-amine (yellow oil, 120 mg, crude). MS (ESI + m / z = 508.4 [M+H] + .

[0754] Third step: dissolve N-(3-methyl-4-((1-methyl-1 H-benzo[d]imidazol-5- yl)oxy)phenyl)-2'H,4'H-spiro[piperidine-4,3'-[1,4]oxazino[2,3-f]quinoline]-10'-amine (110.0 mg, 0.22 mmol) in tetrahydrofuran (5 mL), add triethylamine (65.8 mg, 0.65 mmol) to adjust pH > 7, then add acrylic anhydride (13.7 mg, 0.11 mmol) dropwise, stir at room temperature for 15 min. After the reaction is completed, add water (10 mL) to the reaction solution, extract the mixture with ethyl acetate (10 mL x 3), dry the combined organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product, which is 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-1 H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-2'H,4'H-spiro[piperidine-4,3'-[1,4]oxazino[2,3-f]quinoline]-1-yl)prop-2-en-1-one (final product 1).

[0755] pale yellow solid. MS (ESI + m / z = 562.3 [M+H] + . 1H NMR (300 MHz, DMSO-d6) δ 9.85 (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 = 2.2 Hz, 1H), 6.98 (dd, J = 8.7, 2.1 Hz, 1H), 6.95-6.80 (m, 2H), 6.49 (s, 1H), 6.19-6.06 (m, 1H), 5.77-5.64 (m, 1H), 4.25 (d, J = 4.8 Hz, 2H), 3.98-3.73 (m, 5H), 3.71-3.47 (m, 2H), 2.23 (s, 3H), 1.78-1.51 (m, 4H).

[0756] Example 2-130. Preparation of end 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

[0757] End 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 were prepared from intermediates B1-B49 or commercially available substituted aniline compounds, intermediates C1-C44 and acrylic anhydride as starting materials using the preparation method of end product 1 (the third step condensation reaction can also be prepared by 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). As shown in Table 8.

[0758] Table 8. Structures, reaction intermediates and NMR or MS data of end 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

[0759]

[0760]

[0761]

[0762]

[0763]

[0764]

[0765]

[0766]

[0767]

[0768]

[0769]

[0770]

[0771]

[0772]

[0773]

[0774]

[0775]

[0776]

[0777]

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787]

[0788]

[0789]

[0790]

[0791]

[0792]

[0793]

[0794]

[0795] Example 13 Preparation of 1 -(5'-methoxy-10'-((3-methyl-4-((1 -methyl- 1 H- benzo[d]imidazol-5-yl)oxy)phenyl)amino)-2'H,4'H-spiro[piperidine-4,3'- [1,4]oxazino[2,3-f]quinazolin]-1 -yl)prop-2-en-1 -one (Final Product 12)

[0796]

[0797] First Step: 5'-Bromo-10'-((3-methyl-4-((1 -methyl- 1 H-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 (yellow solid, 120 mg, 28.7%) was prepared from Intermediate C5 and Intermediate B7 following the procedure of Example 1, First Step. MS (ESI + m / z = 686.4 [M+H] + .

[0798] Second step: tert-butyl 5'-((3-methoxy-4-((l-methyl-lH-benzo[d]imidazol-5- yl)oxy)phenyl)amino)-2'H,4'H-spiro[piperidine-4,3'-[l,4]oxazino[2,3- f]quinoline]-l-carboxylate (80.0 mg, 0.13 mmol), t-BuBrettPhos Pd G3 (31.0 mg, 0.033 mmol), t-BuBrettPhos (15.0 mg, 0.033 mmol) and cesium carbonate (221.0 mg, 0.68 mmol) were dissolved in methanol (5 mL) and stirred at 100 °C for 2 h under nitrogen. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a crude product. The crude product was separated and purified by silica gel column chromatography with methanol / dichloromethane (10% - 15%) as eluent gradient to give tert-butyl 5'-((3-methoxy-4-((l-methyl-lH-benzo[d]imidazol-5- yl)oxy)phenyl)amino)-2'H,4'H-spiro[piperidine-4,3'-[l,4]oxazino[2,3- f]quinoline]-l-carboxylate (yellow solid, 70 mg, 87.0%). + m / z = 638.6 [M+H] + .

[0799] Third step, fourth step: tert-butyl 5'-((3-methoxy-4-((l-methyl-lH-benzo[d]imidazol-5- yl)oxy)phenyl)amino)-2'H,4'H-spiro[piperidine-4,3'-[l,4]oxazino[2,3- f]quinoline]-l-carboxylate was used as the raw material to prepare the final product 12 according to the method of the second and third steps of Example 1.

[0800] Yellow solid. MS (ESI + m / z = 592.4 [M+H] + . 1H NMR (300 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.30 (s, 1H), 8.16 (s, 1H), 7.78-7.67 (m, 2H), 7.56 (d, J = 8.7 Hz, 1H), 7.06 (d, J = 2.3 Hz, 1H), 6.98 (dd, J = 8.7, 2.3 Hz, 1H), 6.94-6.78 (m, 3H), 6.13 (dd, J = 16.7, 2.5 Hz, 1H), 5.70 (dd, J = 10.4, 2.5 Hz, 1H), 5.51 (s, 1H), 4.37-4.29 (m, 2H), 3.96 (s, 3H), 3.84 (s, 5H), 3.62-3.42 (m, 2H), 2.23 (s, 3H), 1.79-1.59 (m, 4H).

[0801] Example 13 Preparation of 2-(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'- pyranobenzo[d]quinazolin]-1-yl)acetic acid (Final Product 118)

[0802]

[0803] First Step: 10'-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)- 4'-oxo-2'H,4'H-spiro[piperidin-4,3'-pyranobenzo[d]quinazolin]-1-carboxylic acid tert-butyl ester (pale yellow solid, 110 mg, 48.7%) was prepared from 8-cyano-7-(((dimethylamino)methylene)amino)-4-oxospiro[chromane-3,4'-piperidin]-1'-carboxylic acid tert-butyl ester (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) following the method for the first step of the synthesis of Final Product 1. MS (ESI m / z = 621.2 [M+H] + )m / z = 621.2 [M+H] + .

[0804] Step 2: Dissolve 120.0 mg (0.19 mmol) of tert-butyl 10'-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-4'-oxo-2'H,4'H-spiropiperidin-4,3'-pyrano[2,3-f]quinazolin]-1-carboxylic acid in methanol (5 mL), cool to 0 °C, add sodium borohydride (14.6 mg, 0.39 mmol), and after the addition is complete, return to room temperature and stir for 2 h. After the reaction was complete, water (20 mL) was added to the reaction solution. 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 residue was separated by silica gel column chromatography using a gradient elution of ethyl acetate / petroleum ether (0-50%) to obtain 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]quinazolin]-1-carboxylic acid (pale yellow solid, 100 mg, 83.1%). MS (ESI) + m / z = 623.2[M+H] + .

[0805] 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]quinazolin]-1-carboxylic acid (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. 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 residue was separated by silica gel column chromatography using a gradient elution of ethyl acetate / petroleum ether (0-50%) to obtain tert-butyl 4'-fluoro-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]quinazolin]-1-carboxylic acid (yellow solid, 65 mg, 46.3%). MS (ESI) + m / z = 625.2[M+H] + .

[0806] Step 4, 5: 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]quinazolin]-1- yl)prop-2-en-1-one was prepared from 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 following the procedure for the synthesis of the final product 1, Step 2, 3.

[0807] Yellow solid. MS (ESI + m / z = 579.3 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.51 (s, 1H), 8.16 (s, 1H), 7.81 - 7.55 (m, 4H), 7.36 (d, J = 8.7 Hz, 1H), 7.13 - 6.87 (m, 3H), 6.18 - 6.09 (m, 1H), 5.73 - 5.45 (m, 2H), 4.91 - 4.52 (m, 10H), 3.83 (s, 3H), 2.25 (s, 3H), 1.88 - 1.72 (m, 1H).

[0808] Example 133. Preparation of the final product 126

[0809] The final product 126 was prepared from tert-butyl 8-cyano-7-(((dimethylamino) methylene)amino)-4-oxospiro[chromane-3,4'-piperidin]-1'-carboxylate (Intermediate C38) and 3-methyl-4-(quinoxalin-6-yloxy)aniline (Intermediate B3) following the procedure for the synthesis of the final product 117. See Table 9.

[0810] Table 9. Structure and NMR or MS data of the final product 126

[0811]

[0812] Example 134. Preparation of 1-(10'-((3-ethynyl-4-(quinoxalin-6-yloxy)phenyl)amino)- 2'H-spiro[piperidin-4,3'-[1,4]dioxan[2,3-f]quinazolin]-1-yl)prop-2-en-1-one (final product 129)

[0813]

[0814] First step: 10'-((3-bromo-4-(quinolin-6-yloxy)phenyl)amino)-2'H-spiro[piperidine- 4,3'-[1,4]dioxepino[2,3-f]quinazoline]-1-carboxylic acid tert-butyl ester (pale yellow solid, 400 mg, 59.7%) was prepared following the procedure for the first step of the synthesis of the final product 1 starting from 5-cyano-6-(((dimethylamino)methylene)amino)-3H-spiro[benzo[b][1,4]dioxan-2,4'- piperidin]-1'-carboxylic acid tert-butyl ester (Intermediate C11, 400.0 mg, 1.00 mmol) and 3-bromo-4-(quinolin-6-yloxy)aniline (Intermediate B43, 378.9 mg, 1.20 mmol). MS (ESI + )m / z = 671.1 [M+H] + .

[0815] Second step: 10'-((3-bromo-4-(quinolin-6-yloxy)phenyl)amino)-2'H-spiro[piperidine- 4,3'-[1,4]dioxepino[2,3-f]quinazoline]-1-carboxylic acid tert-butyl ester (400.0 mg, 0.60 mmol) was dissolved in DMF (6 mL) under nitrogen protection, N- methyldicyclohexylamine (581.8 mg, 2.98 mmol), cataCXium A Pd G3 (43.5 mg, 0.060 mmol) and trimethylsilylethynyl (877.6 mg, 8.93 mmol) were added successively, and the reaction mixture was stirred at 90 °C for 3 h. After the reaction was completed, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography eluted with methanol / dichloromethane (0-10%) as eluent gradient to give 10'-((4-(quinolin-6-yloxy)-3-((trimethylsilyl)ethynyl)phenyl)amino)-2'H- spiro[piperidine-4,3'-[1,4]dioxepino[2,3-f]quinazoline]-1-carboxylic acid tert-butyl ester (pale yellow solid, 280 mg, 68.2%). MS (ESI + )m / z = 689.2 [M+H] + .

[0816] Third step: 10'-((4-(quinoxalin-6-yloxy)-3-((trimethylsilyl)ethynyl)phenyl)amino)- 2'H-spiro[piperidine-4,3'-[1,4]dioxino[2,3-f]quinazoline]-1-carboxylate (270.0 mg, 0.39 mmol) was dissolved in tetrahydrofuran (4 mL), triethylamine hydrofluoride (631.9 mg, 3.92 mmol) was added, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, water (15 mL) was added to the reaction solution, the pH was adjusted to >7 with sodium bicarbonate, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 10'-((3-ethynyl-4-(quinoxalin-6-yloxy)phenyl)amino)-2'H-spiro[piperidine-4,3'- [1,4]dioxino[2,3-f]quinazoline]-1-carboxylate (pale yellow solid, 250 mg, crude). MS (ESI + )m / z = 617.5 [M+H] + .

[0817] Fourth and fifth steps: 1-(10'-((3-ethynyl-4-(quinoxalin-6-yloxy)phenyl)amino)-2'H- spiro[piperidine-4,3'-[1,4]dioxino[2,3-f]quinazoline]-1-yl)prop-2-en-1-one was prepared according to the method of the second and third steps of the synthesis of the final product 1 using 10'-((3-ethynyl-4-(quinoxalin-6-yloxy)phenyl)amino)-2'H-spiro[piperidine-4,3'- [1,4]dioxino[2,3-f]quinazoline]-1-carboxylate as the raw material.

[0818] White solid. MS (ESI + )m / z = 571.3 [M+H] + . 1H NMR (300 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.93 - 8.83 (m, 2H), 8.51 (s, 1H), 8.21 (d, J = 2.7 Hz, 1H), 8.16 (d, J = 9.2 Hz, 1H), 8.05 (dd, J = 8.9, 2.7 Hz, 1H), 7.71 (dd, J = 9.2, 2.8 Hz, 1H), 7.53 (d, J = 9.0 Hz, 1H), 7.44 - 7.32 (m, 2H), 7.21 (d, J = 2.8 Hz, 1H), 6.87 (dd, J = 16.7, 10.5 Hz, 1H), 6.14 (dd, J = 16.7, 2.5 Hz, 1H), 5.71 (dd, J = 10.5, 2.5 Hz, 1H), 4.40 (s, 2H), 4.30 (s, 1H), 4.24 - 4.12 (m, 1H), 4.01 - 3.89 (m, 1H), 3.61 - 3.44 (m, 1H), 3.31 - 3.17 (m, 1H), 1.95 - 1.69 (m, 4H).

[0819] Example 135. Preparation of 1-(4-((4-((3-chloro-4-(quinoxalin-6-yloxy)phenyl)amino)-5- methoxyquinolin-6-yl)oxy)piperidin-l-yl)prop-2-en-l-one (Final Product 134)

[0820]

[0821] First Step: 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) under nitrogen protection, 3-chloro-4-(quinoxaline-6-yloxy)aniline (Intermediate B18, 1.2 g, 4.56 mmol) was added, and the mixture was stirred at 100 °C for 4 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was separated by column chromatography on silica gel with ethyl acetate as the eluent to give 4-((3-chloro-4-(quinoxalin-6-yloxy)phenyl)amino)-5-methoxyquinolin-6-ol (yellow solid, 1.2 g, 59.0%). MS (ESI m / z = 446.1 [M+H] + )m / z = 446.1 [M+H] + .

[0822] Second step: 4-((3-chloro-4-(quinoxalin-6-yloxy)phenyl)amino)-5- methoxyquinolin-6-ol (1.2 g, 2.69 mmol) was dissolved in tetrahydrofuran (15 mL), N-Boc-4-hydroxypiperidine (812.6 mg, 4.04 mmol) and triphenylphosphine (776.5 mg, 2.96 mmol) were added successively, the temperature was lowered to 0 °C, and DEAD (562.5 mg, 3.23 mmol) was added dropwise slowly. After the addition was completed, the temperature was allowed to return to room temperature, and the mixture was stirred for 2 h. After the reaction was completed, water (10 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (5 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography with ethyl acetate / petroleum ether (33%) as the eluent to obtain 4-((4-((3-chloro-4-(quinoxalin-6-yloxy)phenyl)amino)-5-methoxyquinolin-6-yl)oxy)piperidine-1- carboxylic acid tert-butyl ester (yellow solid, 400 mg, 23.6%). MS (ESI + )m / z = 629.2 [M+H] + .

[0823] Third step: 4-((4-((3-chloro-4-(quinoxalin-6-yloxy)phenyl)amino)-5-methoxyquinolin-6- yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (150.0 mg, 0.24 mmol) was dissolved in a mixture of dichloromethane and trifluoroacetic acid (1 / 1 v / v, 4 mL), and the mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain N-(3-chloro-4-(quinoxalin-6-yloxy)phenyl)-5-methoxy-6-(piperidin-4-yloxy)quinolin-4- amine (yellow oil, 150 mg, crude). MS (ESI + )m / z = 529.2 [M+H] + .

[0824] Step 4: N-(3-chloro-4-(quinoxalin-6-yloxy)phenyl)-5-methoxy-6-(piperidin-4-yloxy)quinazolin-4- amine (150.0 mg, 0.28 mmol) was dissolved in tetrahydrofuran (2 mL), saturated sodium bicarbonate solution (2 mL) was added, the temperature was lowered to 0 °C, acryloyl chloride (12.8 mg, 0.14 mmol) in tetrahydrofuran (2 mL) was added, and the mixture was stirred at 0 °C for 0.5 h. After the reaction was complete, the temperature was allowed to return to room temperature, water (5 mL) was added to the reaction, and the mixture was extracted with ethyl acetate (5 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography on silica gel using methanol / dichloromethane (10%) as the 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.

[0825] Yellow solid. MS (ESI + m / z = 583.2 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.93-8.86 (m, 2H), 8.55 (s, 1H), 8.45 (d, J = 2.4 Hz, 1H), 8.16 (d, J = 9.3 Hz, 1H), 7.93 (dd, J = 8.8, 2.4 Hz, 1H), 7.86 (d, J = 9.3 Hz, 1H), 7.71 (dd, J = 9.3, 2.7 Hz, 1H), 7.61 (d, J = 9.3 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 2.7 Hz, 1H), 6.85 (dd, J = 16.8, 10.5 Hz, 1H), 6.12 (dd, J = 16.8, 2.4 Hz, 1H), 5.69 (dd, J = 10.5, 2.4 Hz, 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).

[0826] 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)

[0827]

[0828] First Step: Dissolve 10-bromo-7-cyano-8-(((dimethylamino)methylene)amino)- 1,2,4a,5-tetrahydrobenzo[b]pyrazino[l,2-d][l,4]oxazin-3(4H)-carboxylic acid tert-butyl ester (Intermediate C19, 955.0 mg, 2.06 mmol) in acetic acid (15 mL), add 3-methyl-4-((l-methyl-lH-benzo[d]imidazol-5-yl)oxy)aniline (Intermediate B7, 625.1 mg, 2.47 mmol) in sequence, warm up to 60 °C and stir for 3 h. After the reaction is completed, cool down to room temperature, concentrate under reduced pressure, the residue is separated by column chromatography on silica gel eluting with methanol / methylene chloride (0-10%) as eluent gradient to get 12-bromo-4-((3-methyl-4-((l-methyl-lH- benzo[d]imidazol-5-yl)oxy)phenyl)amino)-6a,7,9,10-tetrahydropyrazino[l',2':4,5][l,4]oxazino[2,3-f]quinazoline-8(6H)-carboxylic acid tert-butyl ester (yellow solid, 380 mg, 27.5%). MS (ESI + )m / z = 674.0 [M+H] + .

[0829] Second Step: Dissolve 12-bromo-4-((3-methyl-4-((l-methyl-lH- benzo[d]imidazol-5-yl)oxy)phenyl)amino)-6a,7,9,10-tetrahydropyrazino[l',2':4,5][l,4]oxazino[2,3-f]quinazoline-8(6H)-carboxylic acid tert-butyl ester (100.0 mg, 0.15 mmol) in DMF (5 mL), add 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) in sequence, warm up to 100 °C and stir for 2 h. After the reaction is completed, cool down to room temperature, add water (10 mL) to the reaction, extract the mixture with ethyl acetate (10 mL x 3), dry the combined organic phase over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, the residue is separated by column chromatography on silica gel eluting with methanol / methylene chloride (0-15%) as eluent gradient to get 12-cyano-4-((3-methyl-4-((l-methyl-lH- benzo[d]imidazol-5-yl)oxy)phenyl)amino)-6a,7,9,10-tetrahydropyrazino[l',2':4,5][l,4]oxazino[2,3-f]quinazoline-8(6H)-carboxylic acid tert-butyl ester (yellow solid, 56 mg, 60.8%). MS (ESI + )m / z = 619.2 [M+H] + .

[0830] Step 3, 4: 8-acryloyl-4-((3-methyl-4-((l-methyl-lH-benzo[d]imidazol-5- yl)oxy)phenyl)amino)-6,6a,7,8,9,10-hexahydropyrazino[l',2':4,5][l,4]oxazino[2,3- f]quinoline-12-carbonitrile was prepared from tert-butyl 12-cyano-4-((3-methyl-4-((l- methyl-lH-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-6a,7,9,10- tetrahydropyrazino[l',2':4,5][l,4]oxazino[2,3-f]quinoline-8(6H)-carboxylate following the procedures for the synthesis of final product 1, Step 2 and Step 3.

[0831] Yellow solid. MS (ESI + m / z = 573.2 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.21 (s, 1H), 7.87 (d, J = 1.2 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.44 (s, 1H), 7.37 (d, J = 2.6 Hz, 1H), 7.24 - 7.13 (m, 2H), 7.05 (dd, J = 8.7, 2.3 Hz, 1H), 6.93 - 6.76 (m, 2H), 6.18 (dd, J = 16.7, 2.4 Hz, 1H), 5.75 (d, J = 10.6 Hz, 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).

[0832] Example 13 7. Preparation of l-(12-ethynyl-4-((3-methyl-4-((l-methyl-lH- benzo[d]imidazol-5-yl)oxy)phenyl)amino)-6a,7,9,10-tetrahydropyrazino[l',2':4,5][l,4]oxazino[2,3-f]quinolin-8(6H)-yl)prop-2-en-l-one (Final Product 163)

[0833]

[0834] First Step: Dissolve 10-bromo-7-cyano-8-(((dimethylamino)methylene)amino)- 1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-carboxylic acid tert-butyl ester (Intermediate C19, 955 mg, 2.06 mmol) in acetic acid (15 mL), add 3-methyl-4-[(1-methyl-1,3-benzoxazol-5-yl)oxy]aniline (Intermediate B7, 625.1 mg, 2.47 mmol), warm to 60 °C and stir for 3 h. Cool to room temperature and concentrate under reduced pressure. Purify the residue by column chromatography on silica gel eluting with methanol / methylene chloride (0% to 15%) as eluent gradient to give 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 (yellow solid, 380 mg, 27.5%). MS (ESI + )m / z = 672.0 [M+H] + .

[0835] Second Step: Dissolve 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 (500 mg, 0.75 mmol) in tetrahydrofuran (8 mL), add trimethylsilyl acetylene (109.5 mg, 1.10 mmol), DBU (339.5 mg, 2.25 mmol), cuprous iodide (28.5 mg, 0.15 mmol) and Pd(PPh3)2Cl2(52.0 mg, 0.10 mmol) and warm to 90 °C and stir for 1 h. Cool to room temperature and concentrate under reduced pressure. Purify the residue by column chromatography on silica gel eluting with methanol / methylene chloride (0% to 15%) as eluent gradient to give 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)-carboxylic acid tert-butyl ester (yellow solid, 200 mg, 39.0%). MS (ESI + )m / z = 690.1 [M+H] + .

[0836] Step 3: 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]quinoline-8(6H)-carboxylic acid tert-butyl ester (200 mg, 0.29 mmol) was dissolved in tetrahydrofuran (5 mL), triethylamine trifluoride (280.4 mg, 1.74 mmol) was added, stirred at room temperature for 1 h, after the reaction was completed, water (10 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (10 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 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]quinoline-8(6H)-carboxylic acid tert-butyl ester (160 mg, crude product). MS (ESI + )m / z = 618.1 [M+H] + .

[0837] Step 4: 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]quinoline-8(6H)-carboxylic acid tert-butyl ester (150 mg, 0.24 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, stirred at room temperature for 20 min, 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-hexahydropyrazino[1',2':4,5][1,4]oxazolo[2,3-f]quinolin-4-amine (yellow oil, 140 mg, crude product). MS (ESI + )m / z = 518.3 [M+H] + .

[0838] Step 5: 12-ethynyl-N-(3-methyl-4-((l-methyl-lH-benzo[d]imidazol-5-yl)oxy)phenyl)- 6,6a,7,8,9,10-hexahydropyrazino[l',2':4,5][l,4]oxazolo[2,3-f]quinolin-4-amine (260 mg, 0.50 mmol) was dissolved in tetrahydrofuran (5 mL), triethylamine (152.5 mg, 1.51 mmol) was added, pH > 7, acrylic anhydride (31.7 mg, 0.25 mmol) was added, stirred at room temperature for 20 min, after the reaction was complete, water (10 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (10 mL x 3), the combined organic phase was 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: 60 mL / min; gradient: 4% acetonitrile to 34% 10 min; wavelength: 254 / 220 nm) to give l-(12-ethynyl-4-((3-methyl-4-((l-methyl-lH-benzo[d]imidazol-5- yl)oxy)phenyl)amino)-6a,7,9,10-tetrahydropyrazino[l',2':4,5][l,4]oxazolo[2,3-f]quinolin-8(6H)- yl)prop-2-en-l-one.

[0839] Yellow solid. MS (ESI + m / z = 572.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.49 (s, 1H), 8.43 (s, 1H), 7.69-7.61 (m, 3H), 7.42 (s, 1H), 7.12 (d, J = 2.3 Hz, 1H), 7.07 (dd, J = 8.8, 2.3 Hz, 1H), 6.95-6.81 (m, 2H), 6.19 (dd, J = 16.6, 2.4 Hz, 1H), 5.80-5.71 (m, 1H), 4.82 (s, 1H), 4.74-4.63 (m, 1H), 4.28 (t, J = 10.4 Hz, 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).

[0840] Examples 138-143. Preparation of end products 91, 164-167, 171

[0841] Final products 91, 164-167, 171 were prepared from intermediates B7-B8, intermediates C18-C20, C22 or C24, intermediate alkyne compounds or commercially available alkyne compounds using the method for synthesizing final product 163. The structures, reaction intermediates and NMR or MS data of final products 91, 164-167, 171 are shown in Table 10.

[0842] Table 10 Structures, reaction intermediates and NMR or MS data of final products 91, 164-167, 171

[0843]

[0844]

[0845]

[0846] 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]oxazolo[2,3-f]quinazolin-8(6H)-yl)prop-2-en-1-one (Final Product 169)

[0847]

[0848] First Step: 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]quinoline-8(6H)-carboxylate (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), 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-imidazol-2-ylidene]dichloro(2- methylpyridine)palladium (12.5 mg, 0.02 mmol) were added, the mixture was warmed to 100 °C and stirred for 1 h, after the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate (10 mL x 3), the organic phase was combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography with methanol / dichloromethane (0-10%) as eluent to give tert-butyl 4-((3-methyl-4-(((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)- 12-morpholino-6a,7,9,10-tetrahydropyrazino[1',2':4,5][1,4]oxazolo[2,3-f]quinoline-8(6H)- carboxylate (yellow solid, 95 mg, 94.0%). MS (ESI + m / z = 679.5 [M+H] + .

[0849] Second Step: 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]quinoline-8(6H)- carboxylate (85 mg, 0.125 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, the mixture was stirred at room temperature for 30 min, after the reaction was completed, 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]quinolin-4-amine (black oil, 180 mg, crude). MS (ESI + m / z = 579.5 [M+H] + .

[0850] Step 3: N-(3-methyl-4-((l-methyl-lH-benzo[d]imidazol-5-yl)oxy)phenyl)- 12-morpholino-6,6a,7,8,9,10-hexahydropyrazino[l',2':4,5][l,4]oxazocino[2,3- f]quinolin-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 pH > 7, then acrylic anhydride (18.52 mg, 0.147 mmol) was added dropwise, stirred at room temperature for 15 min, after the reaction was completed, water (10 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (30 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by high pressure liquid chromatography (column type: Xselect CSH Prep Fluoro-Phenyl Column, 19*250, 5 μm; mobile phase: water (10 mmol / L ammonium bicarbonate) / acetonitrile; flow rate: 25 mL / min; gradient: 48% to 73% acetonitrile, 10 min; wavelength: 254 / 220 nm) to obtain 1-(4-((3-methyl-4-((l-methyl-lH-benzo[d]imidazol-5-yl)oxy)phenyl)amino)- 12-morpholino-6a,7,9,10-tetrahydropyrazino[l',2':4,5][l,4]oxazocino[2,3-f]quinolin-8(6H)yl)prop-2-en-l-one.

[0851] White solid. MS (ESI + m / z = 633.5 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.34 (s, 1H), 8.17 (s, 1H), 7.71-7.63 (m, 2H), 7.56 (d, J = 8.7 Hz, 1H), 7.08 (d, J = 2.2 Hz, 1H), 6.99 (dd, J = 8.7, 2.3 Hz, 1H), 6.91-6.82 (m, 2H), 6.76 (s, 1H), 6.18 (d, J = 16.7 Hz, 1H), 5.75 (d, J = 10.3 Hz, 1H), 4.71-4.58 (m, 1H), 4.24 (t, J = 10.4 Hz, 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).

[0852] Comparative Compound A

[0853]

[0854] Using intermediate B8 and intermediate M (tert-butyl (R)-7-cyano-8-nitro- 1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazole-3(4H)-carboxylate as a raw material, prepared according to the method for synthesizing intermediate C18) as a raw material, the comparative compound A was prepared according to the method for synthesizing the final product 1.

[0855] pale yellow solid. MS (ESI + )m / z = 535.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.94 (d, J = 7.5 Hz, 1H), 8.38 (d, J = 3.7 Hz, 2H), 7.86 (d, J = 8.7 Hz, 1H), 7.82 (s, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.33 (d, J = 9.1 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 7.03 (dd, J = 7.5, 2.7 Hz, 1H), 6.98 - 6.86 (m, 1H), 6.78 (d, J = 2.6 Hz, 1H), 6.18 (dd, J = 16.7, 2.3 Hz, 1H), 5.75 (d, J = 10.3 Hz, 1H), 4.81 - 4.71 (m, 1H), 4.53 (d, J = 12.9 Hz, 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).

[0856] Experimental Example 1 Cell proliferation inhibition experiment

[0857] CellTiter-Glo TM CellTiter-Glo TM luminescence value is proportional to the amount of ATP in the system, and ATP is positively correlated with the number of living cells. Therefore, by detecting the content of ATP using the CellTiter-Glo kit, the proliferation of cells can be detected.

[0858] In this experiment, the Celltiter-Glo (CTG) method was used to measure the proliferation inhibition effect of the compound prepared in the foregoing on the tumor cell strain HER2775-776insYVMA Ba / F3 cell strain, and the 50% inhibition concentration IC50 .

[0859] 1. Experimental design

[0860] Compounds were tested on selected cells with vehicle control, 9 concentrations were tested, 2 replicates per concentration.

[0861] 2. Reagents and consumables

[0862]

[0863] 3. Experimental procedure

[0864] 3.1 Cell culture

[0865] a) All cells were cultured according to ATCC recommended methods. Cells were harvested at log phase of growth. Cell viability was tested to ensure cell viability was above 90%.

[0866] b) Cell culture medium: RPMI1640, 10% FBS, 1% P / S. Cell concentration was adjusted, 95 μL or 90 μL cell suspension was added to 96-well plates, respectively.

[0867] c) Cell culture environment: 37°C, 5% CO2, 95% humidity.

[0868] 3.2 Drug dilution

[0869] a) Drug stock solution: drugs were dissolved in DMSO to make 10 mM DMSO stock solution.

[0870] b) Drug storage: drug DMSO stock solution was stored in a short-term (up to 3 months) in a room temperature desiccator. The remaining drug was stored at -20°C for a longer period.

[0871] c) Preparation of 20X or 10X drug solution: 2 μL drug stock solution was added to 98 μL or 198 μL cell culture medium.

[0872] 3.3 Drug addition

[0873] a) All drugs were diluted 3-fold starting from 1 μM concentration, 9 concentration gradients or 4-fold dilution, 8 concentration gradients.

[0874] b) Positive control drug was prepared, DMSO blank control.

[0875] c) 5 μL 20X drug solution or 10 μL 10X drug was added to each well of the 96-well plate seeded with cells, 2 replicates were set up for each drug concentration.

[0876] d) The cells in the drug-added 96-well plate were incubated at 37°C, 5% CO2, 95% humidity for 72 hours, and then CTG analysis was performed.

[0877] 3.4 End-point plate reading

[0878] a) Thaw the CTG reagent, and add 50 μL of the CTG solution to each well, and shake well.

[0879] b) Place the cell plate at room temperature for 10 min to stabilize the luminescence signal.

[0880] c) Read the fluorescence value by the enzyme label meter.

[0881] 4. Data processing

[0882] The data were analyzed using GraphPad Prism 8.0 software, and the dose-effect curve was fitted by non-linear S-curve regression, and the IC 50 value was calculated therefrom.

[0883] Inhibition rate (Inh%) = 100- (RLU 化合物 -RLU 空白 ) / (RLU 对照 -RLU 空白 )*100%.

[0884] 5. Experimental results

[0885] The inhibitory activity of the compounds on the proliferation of HER2 775_776insYVMA Ba / F3 cell lines is shown in Table 11.

[0886] Table 11 Inhibitory activity (IC 50 , nM) of compounds on the proliferation of HER2 775_776insYVMA Ba / F3 cell lines

[0887]

[0888]

[0889] As can be seen from the table, the compounds of the present application have good inhibitory activity on the proliferation of HER2 775-776insYVMA Ba / F3 cell lines (expressing HER2 exon 20 insertion mutation), and the inhibitory IC 50 value reaches nanomolar concentration.

[0890] Experimental Example 2: A431 phosphorylation experiment

[0891] Cell culture

[0892] a) All cells were cultured according to ATCC recommended methods. Cells were harvested at log phase of growth. Cell viability was checked to ensure that cell viability was above 90%.

[0893] b) Cell culture medium: DMEM, 10% FBS, 1% Glutamax and 1% P / S. Cells were adjusted to the appropriate concentration and 40 μL of cell suspension was added to each well of a 384-well plate, centrifuged at 1000 rpm for 30 s and incubated for 4 hours.

[0894] c) The medium was removed and 25 μL of HBSS was added to each well of the 384-well plate and left overnight.

[0895] 3.2 Drug dilution

[0896] a) Drug stock solution: Drugs were dissolved in DMSO to make a 10 mM DMSO stock solution.

[0897] b) Drug storage: Drug DMSO stock solutions were stored in a short-term (up to 3 months) in a room temperature desiccator. The remaining drug was stored for a longer period at -20 °C.

[0898] 3.3 Drug addition

[0899] a) All drugs were diluted 3-fold starting from a 10 mM concentration, with 10 concentration gradients.

[0900] b) The cells in the 384-well plate to which the drug had been added were incubated at 37 °C, 5% CO2, 95% humidity for 30 min.

[0901] 3.4 Detection

[0902] a) EGF was added as an activator and stimulation was carried out for 15 min.

[0903] b) Cell lysates were prepared and detected according to the manufacturer's protocol.

[0904] c) AlphaScreen was read by Envision.

[0905] 4. Data processing

[0906] Data were analyzed using GraphPad Prism 8.0 software, and a dose-effect curve was obtained by fitting the data using non-linear S-curve regression, from which the IC 50 value was calculated.

[0907] Inhibition rate (Inh %) = 100 - (Signal 化合物 - Signal Ave_PC ) / (Signal Ave_VC - Signal Ave_PC ) * 100%.

[0908] Signal Ave_PC : average of signal of positive control across the plate

[0909] Signal Ave_VC : average of signal of negative control across the plate

[0910] Table 12 Inhibition of EGFR phosphorylation pEGFR (IC 50 nM)

[0911] End product number [A431 pEGFR(IC 50 nM)]]> End product number [A431 pEGFR(IC 50 nM)]]> 23 665 127 352 30 179 135 2087 50 1034 139 373 52 887 149 3533 80 510 164 811 113 462 / /

[0912] As can be seen from the table, the compounds of the present application have weaker inhibition on wild-type EGFR and have good selectivity for wild-type EGFR.

[0913] Experimental Example 3: P-gp substrate evaluation experiment

[0914] 1. Test design

[0915] Cell culture

[0916] 1) High glucose DMEM medium containing L-glutamine, supplemented with 10% fetal bovine serum, 0.1 mg / mL streptomycin and 0.6 μg / mL penicillin was used.

[0917] 2) MDCKII-MDR1 cells were cultured in T-75 cell culture flasks. The incubator was set at 37°C, 5% CO2, and 95% relative humidity. Cells were used for seeding Transwell when they reached 70-90% confluence.

[0918] 3) Before cell seeding, 50 μL cell culture medium was added to each well of the upper chamber of the Transwell, and 25 mL cell culture medium was added to the lower culture plate. The culture plate was incubated in a 37°C, 5% CO2 incubator for 1 hour and then used for cell seeding.

[0919] 4) The cells were gently washed with 5 mL PBS. The PBS was discarded, and 1.5 mL trypsin containing EDTA was added, and the cells were incubated at 37°C for 5 to 10 minutes until they were completely detached. The digestion was terminated by adding serum-containing medium.

[0920] 5) The cell suspension was transferred to a round-bottom centrifuge tube and centrifuged at 120 x g for 10 minutes.

[0921] 6) The cells were resuspended with medium to a final concentration of 1.56 x 10 6 cells / mL.

[0922] MDCKII-MDR1 cell seeding

[0923] 1) Add 50 μL of cell suspension to each well of a 96-well Transwell plate, resulting in a final seeding density of 1.45 × 10⁶ cells / well. 5 cells / cm 2 .

[0924] 2) Change the medium 24 hours after inoculation and culture for 4-8 days, changing the medium every other day.

[0925] Evaluation of cell monolayer membrane integrity

[0926] 1) After 4-8 days of culture, MDCKII-MDR1 and MDCKII should have completely merged and differentiated. At this point, they can be used for the breakthrough test.

[0927] 2) Measure the resistance of the single-layer film using a resistance meter (Millipore, USA) and record the resistance of each pore.

[0928] 3) After the measurement is completed, put the Transwell culture plate back into the incubator.

[0929] 4) Calculation of resistance value:

[0930] Measure resistance (ohms) × film area (cm²) 2 ) = TEER value (ohm·cm) 2 )

[0931] If the TEER value is <42 ohms·cm 2 If so, the hole cannot be used for a penetration test.

[0932] Drug penetration test

[0933] 1) Remove the MDCKII-MDR1 Transwell culture plate from the incubator. Rinse the cell monolayer twice with HBSS (10mM HEPES, pH 7.4) buffer and incubate at 37°C for 30 minutes.

[0934] 2) Determine the transport rate of the compound from the top to the base. Add 125 μL of HBSS (10 mM HEPES, pH 7.4) buffer of the test drug or control drug to each well in the upper chamber (top), and add 235 μL of HBSS (10 mM HEPES, pH 7.4) buffer to each well in the lower chamber (base).

[0935] 3) Determine the transport rate of the compound from the base to the top. Add 285 μL of HBSS (10 mM HEPES, pH 7.4) buffer to each well in the upper chamber (top) and 75 μL of HBSS (10 mM HEPES, pH 7.4) buffer containing the test drug or control drug to each well in the lower chamber (base).

[0936] 4) After merging the upper and lower transfer devices, incubate at 37°C for 2 hours.

[0937] 5) After incubation, take 50 μL of sample from each well of the upper and lower chambers of the Transwell plate and add it to a new sample tube. Add 4 volumes of acetonitrile containing internal standards (200 nM alprazolam, 200 nM labetalol, 200 nM diclofenac, 100 nM tolbutamide) to the sample tube, vortex for 5 minutes, and then centrifuge at 3,220 g for 15 minutes. Take 100 μL of the supernatant, dilute it with an equal volume of water, and then perform LC-MS / MS analysis. All samples were prepared in triplicate.

[0938] 6) Evaluate the integrity of the cell monolayer after 2 hours of incubation using fluorescein leakage. Dilute the fluorescein stock solution to a final concentration of 100 μM using HBSS (10 mM HEPES, pH 7.4). Add 100 μL of fluorescein solution to each well of the upper Transwell plate and 300 μL of HBSS (10 mM HEPES, pH 7.4) to each well of the lower receiving plate. After incubation at 37°C for 30 minutes, aspirate 80 μL of solution from both the upper and lower layers of each well into a new 96-well plate. Perform fluorescence measurement using a microplate reader at an excitation wavelength of 485 nm and an emission wavelength of 530 nm.

[0939] 2. Data Processing

[0940] All data calculations were performed using Excel, including the apparent permeability coefficient (P) of the compounds. app (Unit: cm / s) is calculated using the following formula:

[0941]

[0942] The membrane area in the formula is the membrane area of ​​the Transwell-96 well plate (0.143 cm²). 2 ); Incubation time is measured in seconds (s).

[0943] The discharge rate is calculated using the following formula:

[0944]

[0945] Table 13 Efflux rates of the test compounds

[0946] End product number ER (Efflux Ratio) 18 2.86 52 0.65 80 1.36 113 1.02 127 0.81

[0947] Experiment Example 4: Cassette pharmacokinetic assay of the compound in mice

[0948] Experimental purpose: ICR mice were used as test objects, and LC / MS / MS method was used to determine the drug concentration of the compound in the plasma at different time points after intragastrical administration (PO) of the compound, to study the pharmacokinetic behavior of the compound in mice, and to evaluate the pharmacokinetic characteristics thereof.

[0949] Drug configuration: The compounds were all configured into clear solutions with 10% DMSO + 10% Solutol HS15 + 5% Cremophor EL + 20% PEG400 + 55% (20% Captisol aqueous solution) as a solvent for PO administration. The administration method was cassette dosing, and the administration dose of the compound was: the dose was 10 mg / kg. The pharmacokinetic parameter results are shown in Table 14.

[0950] Table 14: Results of cassette pharmacokinetic test in mice

[0951]

[0952]

[0953] As can be seen from Table 14, the compound of the present application has good exposure. For the four fused ring compounds, when the quinazoline 7-position is N (such as compounds 135, 146) or the 7-position CH is substituted by a substituent (such as compounds 164, 166), better exposure is shown.

[0954] The above examples are only used to help understand the method of the present application and its core idea. It should be noted that for those skilled in the art, without departing from the principles of the present application, the present application can be improved and modified in several ways, and these improvements and modifications also fall within the scope of protection of the claims of the present application.

Claims

1. A spirocyclic / bridged ring compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, deuterated derivative, N-oxide, prodrug molecule, hydrate, or solvate thereof: in, In equation I, Ring A is a 3-12 membered heterocyclic group or 3-12 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 contains one or more 5-10 membered heteroaryl groups selected from N, O, and S heteroatoms; Q1 is absent or contains a 6-12 aryl group or contains one or more 5-12 heteroaryl groups selected from N, O, and S heteroatoms, wherein the 6-12 aryl group or the 5-12 heteroaryl group containing one or more N, O, and S heteroatoms is optionally substituted by one or more R′. L1 represents chemical bonds, O, and NR. 4 CR 5 R 6 -OR 7 -, C(=O), S, S(O) or S(O)2; L2 represents a chemical bond, O, or NR. 4 ; L3 is NR 4 O, CR 5 R 6 , S, S(O) or S(O)2; L4 is absent or is a chemical bond, O, NR 4 CR 5 R 6 C (=O), S, S(O) or S(O)2; M is either C=O or S(=O)2; Y 1 For N or CR a ; Y 2 For N or CR b ; Y 3 For N or CR c ; Y 4 For N or CR d ; Y 5 For N, CR e Or C; when L2 is a chemical bond, Y 5 For N; when L2 is O or NR 4 At that time, Y 5 For 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 The cycloalkenyl group is optionally replaced by one or more halogens, cyano groups, C groups, etc. 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, 6-12 membered aryl, C 1-3 Alkoxy-C 1-3 Alkyl- or NR x R y Instead, the C 1-4 Alkyl, Halogenated C 1-4 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic groups containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, 5-12 membered heteroaryl, 6-12 membered aryl, or C 1-3 Alkoxy-C 1-3 Alkyl groups are optionally substituted with one or more R′; R 2 It consists of hydrogen atom, deuterium atom, halogen, cyano group, hydroxyl group, amino group, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-4 Alkyl, deuterated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic groups 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, halogenated C 1-4 Alkyl, deuterated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic groups 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 The alkoxy group is optionally substituted by one or more R′; R 3 It consists of hydrogen atoms, deuterium atoms, halogens, cyano groups, nitro groups, and carbon atoms. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-12 membered saturated or unsaturated cycloalkyl group, 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 group, C 2-6 Heterynyl, 3-12 membered saturated or unsaturated cycloalkyl, containing one or more 3-12 membered saturated or unsaturated heterocyclic groups selected from N, O, S, S=O, S(O)2 heteroatoms, halogenated C 1-6 Alkyl or halogenated C 1-6 The alkoxy group is optionally substituted by 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 group, C(=O)R e Or 3-12 membered cycloalkyl, wherein 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 The alkynyl group or 3-12 membered cycloalkyl group may optionally be substituted with one or more R′; R 5 R 6 Each is independently a hydrogen atom, deuterium atom, halogen, cyano group, hydroxyl group, amino group, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-12 membered cycloalkyl group, 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 Alkyloxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclic alkyloxy containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, C 1-6 Alkyl mercapto, 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 group or containing one or more 3-12 membered heterocyclic groups selected from N, O, S, S=O, S(O)2 heteroatoms -C 1-6 alkyl-, the hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-12 membered cycloalkyl group, 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 Alkyloxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclic alkyloxy containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, C 1-6 Alkyl mercapto, 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 group or containing one or more 3-12 membered heterocyclic groups selected from N, O, S, S=O, S(O)2 heteroatoms -C 1-6 Alkyl groups are 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, and 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, and S(O)2 is optionally substituted by one or more R′. R 7 C 1-6 Alkylene, C 2-4 alkenyl, halogenated C 1-6 Alkylene, deuterated C 1-6 Alkylene or halogenated C 2-4 alkenyl; R a R b Each can be independently composed of a hydrogen atom, a deuterium atom, a halogen, a cyano group, and a carbon atom. 1-6 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-12 membered cycloalkyl group, 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 Alkyne, 3-12 membered cycloalkyl, or 3-12 membered heterocyclic groups containing one or more heteroatoms selected from N, O, S, S=O, and S(O)2, optionally substituted with one or more R′. Or, R a With R 2 Together with the attached atoms, it forms 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, or S. The 3-12 membered cycloalkyl group, the 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, or S(O)2, or the 5-6 membered heteroaryl group containing one, two, three, or four heteroatoms selected from N, O, or S are optionally substituted by one or more R′. Or, R b With R 2 Together with the attached atoms, it forms 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, or S. The 3-12 membered cycloalkyl group, the 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, or S(O)2, or the 5-6 membered heteroaryl group containing one, two, three, or four heteroatoms selected from N, O, or S are optionally substituted by one or more R′. R c It consists of hydrogen atoms, deuterium atoms, halogens, cyano groups, amino groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl mercapto, C 1-6 Alkylamino or di(C) 1-6 alkyl)amino, wherein the amino group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl mercapto, C 1-6 Alkylamino or di(C) 1-6 The alkyl)amino group is optionally substituted with one or more R′; R d It either does not exist or is a hydrogen atom, deuterium atom, halogen, cyano group, amino group, or C atom. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl mercapto or C 1-6 Alkylamino, wherein the amino group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl mercapto or C 1-6 The alkylamino group is optionally substituted with one or more R′; Or, R b With R d Together with the attached atoms, it forms 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, or S. The 3-12 membered cycloalkyl group, the 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, or S(O)2, or the 5-6 membered heteroaryl group containing one, two, three, or four heteroatoms selected from N, O, or S are optionally substituted by one or more R′. Or, R a With R d Together with the attached atoms, it forms 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, or S. The 3-12 membered cycloalkyl group, the 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, or S(O)2, or the 5-6 membered heteroaryl group containing one, two, three, or four heteroatoms selected from N, O, or S are optionally substituted by one or more R′. R e R f Each is independently a hydrogen atom, a deuterium atom, and a carbon atom. 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; Or, NR e R f Chinese R e and R f Together with the connected N 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 groups or 3-12 membered heterocyclic groups containing one or more heteroatoms selected from N, O, S, S=O, and 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 groups or 3-12 membered heterocyclic groups containing one or more heteroatoms selected from N, O, S, S=O, and S(O)2. 1-6 The alkyl group is optionally substituted with one or more R′; R x R y Each is 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 group, or a 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, and 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 group, or a 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, and S(O)2. 1-4 Alkyl-, C 1-4 Alkoxy-C 1-4 Alkyl- or deuterated C 1-4 The alkyl group is optionally substituted with one or more R′; or NR x R y Chinese R x With R y Together with the attached N atom, a 3-12 membered heterocyclic group is formed 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′ can be independently a deuterium atom, halogen, cyano group, hydroxyl group, amino group, or C atom. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-4 Alkyl, deuterated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic groups 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 Alkyl or oxo (=O); m and n are each independently 0, 1, 2, 3, 4 or 5; The condition is that 1) R d or R 2 Any group and R a or R b Each 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 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, or S. The 3-12 membered cycloalkyl, the 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, or the 5-6 membered heteroaryl group containing one, two, three, or four heteroatoms selected from N, O, or S are optionally substituted by one or more R′. 2) When R 2 With R b Together with the atoms they are attached to, 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 its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, deuterated derivative, N-oxide, prodrug molecule, hydrate, or solvate, wherein the compound has the structure shown in Formula II or Formula III. in, The G ring is a 3-12 membered cycloalkyl group, containing one or more 3-12 membered heterocyclic groups selected from N, O, S, S=O, S(O)2 heteroatoms, or containing 1, 2, 3, or 4 5-6 membered heteroaryl groups selected from N, O, and S heteroatoms; W represents N, C, or CR. a ; t can be 0, 1, 2, 3, 4 or 5.

3. The spirocyclic / bridged ring compound according to claim 1 or 2, or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, deuterated derivative, N-oxide, prodrug molecule, hydrate, or solvate, wherein, In formula I, II or III, ring A is a 4-9 membered heterocyclic group or a 3-6 cyclic alkyl group containing one or two heteroatoms selected from N, O, S, S=O, S(O)2; Preferably, in formula I, II or III, ring A is piperidinyl, acridineyl, pyrrolyl, piperazine, perpiperidine, perpiperazine, 1,4-azaoxetane, 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 one or two heteroatoms selected from N, O, S, S=O, S(O)2; Preferably, in formula I, II or III, ring A is piperidinyl, acridineyl, pyrrolyl, piperazinyl, perpiperidine, perpiperazine, 1,4-azaoxetane, 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, the E ring is phenyl or contains 1, 2, 3 or 4 5-6 membered heteroaryl groups selected from N, O or S heteroatoms; Preferably, in formula I, II or III, ring E is phenyl, pyridinyl, pyrimidine, pyridazine, pyrazine, thiophene or pyrazole; Preferably, in formula I, II, or III, Q1 is The land Optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy. -- / --- indicates no chemical bond; The B ring is pyrrole, imidazole, pyrazole, thiazole, oxazole, oxadiazole, triazole, tetrazolium, pyridine, pyrimidine, pyridazine, pyrazine, or triazine; X a X b X c Each can be either N or CH independently; X 1 Chemical bonds, N, CH, CH2, S, O, S(O) or S(O)2; X 2 It can be N, CH, CH2, O, S, S(O) or S(O)2; X 3 X 4 Each is independently N or C, and X 3 and X 4 Not simultaneously N, X 1 X 2 and X 3 Not both N; X 5 Chemical bonds, N, CH, CH2, O, or S; X 6 For N, O, S or CH; Preferably, in formula I, II, or III, Q1 is selected from the following groups: The Q1 is optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxyl, 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 its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, deuterated derivative, N-oxide, prodrug molecule, hydrate, or solvate, wherein, In formula I, II, or III, L1 represents a chemical bond, O, or NR. 4 CR 5 R 6 -OR 7 - or C (=O); L2 represents a chemical bond or NR. 4 ; L3 is NR 4 ; L4 is O or CR 5 R 6 ; M is either 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 Alkyne or 3-12 membered cycloalkyl, wherein 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, cyano, hydroxyl, methoxy, cyclopropyl or oxo (=O); R 5 R 6 Each is independently a hydrogen atom, deuterium atom, halogen, cyano group, hydroxyl group, amino group, 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 attached C atom, it forms a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group is optionally substituted by one or more methyl, ethyl, halogen, deuterium, or cyclopropyl atoms. R 7 It is methylene, ethylene, or propylene; Preferably, L1 is a chemical bond, O, or NR. 4 CR 5 R 6 -OR 7 - or C (=O); L2 represents a chemical bond or NR. 4 ; L3 is NR 4 ; L4 is O or CR 5 R 6 ; M is C=O; R 4 It can be a hydrogen atom, methyl, ethyl, isopropyl, 1,2-dihydroxypropyl-3-yl, acetyl, methoxyethyl, cyano, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, propenyl, or propynyl. R 5 R 6 Each can be independently a hydrogen atom, deuterium atom, halogen, cyano, hydroxyl, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, propenyl or propynyl. Or, R 5 With R 6 Together with the attached C atom, it forms a cyclopropyl or cyclobutyl group, wherein the cyclopropyl or cyclobutyl group is optionally substituted by one or more methyl, ethyl, halogen, deuterium or cyclopropyl atoms; R 7 It is methylene; Preferably, in formula I, II, or III, Y 1 For N or CR a ; Y 2 For N or CR b ; Y 3 For N or CR c ; Y 4 For N or CR d ; Y 5 For N, CR e Or C; when L2 is a chemical bond, Y 5 For N; when L2 is O or NR 4 At that time, Y 5 For CR e Or C; R a It consists of hydrogen atoms, deuterium atoms, halogens, cyano groups, and carbon atoms. 1-6 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 4-10 membered heterocyclic group, OR a1 SR a1 or NR a1 The C 1-6 Alkyl, C 2-4 alkenyl, C 2-4 The alkynyl group and the 4-10 membered heterocyclic group 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 groups or 3-6 membered heterocyclic groups containing one or more heteroatoms selected from N, O, S, S=O, and 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 groups or 3-6 membered heterocyclic groups containing one or more heteroatoms selected from N, O, S, S=O, and S(O)2. 1-6 The alkyl group may optionally be substituted with one or more halogens, deuterium atoms, methyl, ethyl, or oxo groups; R c The atom is a hydrogen atom, halogen, cyano, amino, methyl, ethyl, isopropyl, cyclopropyl, methoxy, or cyclopropoxy, wherein the amino, methyl, isopropyl, ethyl, cyclopropyl, methoxy, and cyclopropoxy are optionally substituted by one or more R′. R b With R d Together with the attached atoms, they form a 4-7 membered cycloalkyl group or a 5-7 membered heterocyclic group containing one or two heteroatoms selected from N, O, S, S=O, and S(O)2, wherein the 4-7 membered cycloalkyl group or the 5-7 membered heterocyclic group containing one or two heteroatoms selected from N, O, S, S=O, and S(O)2 is optionally substituted by one or more R′. 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′ can be a deuterium atom, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, methoxy, pyrrolyl, 1-methylpyrrolidine-3-yl, or oxo (=O); Preferably, in formula I, II, or III, Y 1 For N or CR a ; Y 2 For N or CR b ; Y 3 For N or CR c ; Y 4 For N or CR d ; Y 5 For N, CH, or C; when L2 is a chemical bond, Y 5 For N; when L2 is O or NR 4 At that time, Y 5 For CH or C; R a Hydrogen atom, deuterium atom, F, Cl, Br, cyano, hydroxyl, amino, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, ethynyl, 2-(1,3-dimethylpyrrolid-3-yl)ethynyl, acetylated, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, hydroxyethoxy, N',N'-dimethylaminoethoxy, N'-methylaminoethoxy, morpholinyl, 2-oxa-6-azaspiro[3.3]cycloheptyl, morpholinyl- Ethoxy, hydroxypropoxy, N',N'-dimethylaminopropoxy, N'-methylaminopropoxy, morpholino-propoxy, piperazine-1-yl-ethoxy, 4-methylpiperazine-1-yl-ethoxy, 4-methylpiperazine-1-yl-propoxy, piperazine-1-yl-propoxy, pyrrolidine-1-yl-ethoxy, pyrrolidine-1-yl-propoxy, tetrahydrofuran-3-oxy, methylthio, methylamino, ethylamino, acetamido, propamido, methoxyethyl, methoxyethylamino, or methoxyethoxy; R c It can be a hydrogen atom, halogen, cyano group, amino group, methyl group, ethyl group, isopropyl group, cyclopropyl group, methoxy group, or cyclopropoxy group; R b With R d Together with the attached atoms, it forms morpholino, tetrahydrofurano, dihydroimidazolyl, thiomorpholino, tetrahydropyrano, tetrahydropyranone, 1,4-dioxanecycloyl, hexahydro-1,4-oxazaphenoyl, hexahydro-1,4-thioazaphenoyl, 4-thiomorpholino-1-oxide, 4-thiomorpholino-1,1-dioxide, hexahydro-1,4-thioazaphenoyl-1-oxide, or hexahydro-1,4-thioazaphenoyl-1,1-dioxide, wherein the morpholino, thiomorpholino, tetrahydropyrano, tetrahydropyranone, 1,4-dioxanecycloyl, hexahydro-1,4-oxazaphenoyl The phenoyl, hexahydro-1,4-thiazophenoyl, 4-thiomorpholino-1-oxide, 4-thiomorpholino-1,1-dioxide, hexahydro-1,4-thiazophenoyl-1-oxide or hexahydro-1,4-thiazophenoyl-1,1-dioxide 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.

5. The spirocyclic / bridged ring compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, deuterated derivative, N-oxide, prodrug molecule, hydrate, or solvate thereof, wherein, In equation I, II, or III, R 1 The halogenated methyl, vinyl, propynyl, ethynyl, propynyl, butynyl, propylene oxide, cyclobutenyl, cyclopentenyl, or cyclohexenyl groups are optionally replaced by one or more F, Cl, methyl, ethyl, cyclopropyl, acrylidine, pyrrolidine, piperidinyl, propylene oxide, propylene oxide, deuterium, phenyl, pyridinyl, or NR atoms. x R y The methyl, ethyl, cyclopropyl, acridine, pyrrolyl, piperidinyl, propylene oxide, butyl oxide, phenyl, or pyridinyl groups are optionally substituted by one or more R′. R x R y Each of the following is independently a hydrogen atom, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, acridinemethyl or acridineethyl, wherein the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, acridinemethyl or acridineethyl is optionally substituted by one or more R′; Or, NR x R y Chinese R x With R y Together with the attached N atom, it forms acridine, pyrrolidine, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl dioxide, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl or 2-azabicyclo[3.1.0]hexyl, wherein the acridine, pyrrolidine, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl dioxide, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl or 2-azabicyclo[3.1.0]hexyl is optionally substituted by one or more R′; R′ can be 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); Preferably, in formula I, II, or III, R 1 Selected from the following groups: Preferably, in formula I, II, or III, R 2 It consists of hydrogen atoms, deuterium atoms, cyano groups, halogens, and carbon atoms. 1-6 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogenated 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, halogenated 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 The alkoxy group is optionally substituted by one or more R′; Or, R b With R 2 Together with the attached atoms, they form a 5-7 membered heterocyclic group containing one or two 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. The 5-7 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S=O, S(O)2, or the 5-6 membered heteroaryl group containing one, two, three, or four heteroatoms selected from N, O, S, optionally substituted by one or more R′. Preferably, R 2 It can be hydrogen atom, deuterium atom, F, Cl, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, vinyl, propynyl, ethynyl, propynyl, cyano, difluoromethoxy, trifluoromethoxy, methoxy, methoxymethyl or oxo (=O); Or, R b With R 2 Together with the attached atoms, they form morpholino, tetrahydrofurano, dihydroimidazolyl, thiomorpholino, hexahydro-1,4-oxazaporyl, hexahydro-1,4-thiozaporyl, 4-thiomorpholino-1-oxide, 4-thiomorpholino-1,1-dioxide, hexahydro-1,4-thiozaporyl-1-oxide, or hexahydro-1,4-thiozaporyl-1,1-dioxide, wherein the morpholino, thiomorpholino, hexahydro-1,4-oxazaporyl, hexahydro-1,4-thiozaporyl, or 4-thiomorpholino -1-oxide, 4-thiomorpholino-1,1-dioxide, hexahydro-1,4-thioazaporphyryl-1-oxide or hexahydro-1,4-thioazaporphyryl-1,1-dioxide may optionally be 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.

6. The spirocyclic / bridged ring compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, deuterated derivative, N-oxide, prodrug molecule, hydrate, or solvate thereof, wherein, In equation I, II, or III, R 3 It consists of hydrogen atoms, deuterium atoms, halogens, cyano groups, nitro groups, and carbon atoms. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 member saturated or unsaturated cycloalkyl group, 3-6 member 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 Alkyne group, 3-6 member saturated or unsaturated cycloalkyl group, 3-6 member 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 The alkoxy group is optionally substituted by one or more R′; R e R f Each is independently a hydrogen atom, a deuterium atom, and a carbon atom. 1-4 Alkyl, Halogenated C 1-4 Alkyl groups, 3-12 membered cycloalkyl groups; Or, NR e R f Chinese R e and R f Together with the connected 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 The following groups are represented by hydrogen, deuterium, F, Cl, cyano, nitro, methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, 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 The methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoroethyl, trifluoroethyl, hydroxyl, 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 with one or more deuterium atoms, F, Cl, hydroxyl, methyl, ethyl, isopropyl or cyclopropyl; Preferably, in formula II or III, the G ring is a 4-7 membered cycloalkyl group containing one or two 5-7 membered heterocyclic groups selected from N, O, S, S=O, and S(O)2 heteroatoms; Preferably, in formula II or III, ring G is morpholinyl, tetrahydrofuranyl, dihydroimidazolyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyranonel, 1,4-dioxanecycloyl, hexahydro-1,4-oxazaporyl, hexahydro-1,4-thioazaporyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thioazaporyl-1-oxide, or hexahydro-1,4-thioazaporyl-1,1-dioxide. Oxazonyl, hexahydro-1,4-thioazonyl, 4-thiomorpholinyl-1-oxide, 4-thiomorpholinyl-1,1-dioxide, hexahydro-1,4-thioazonyl-1-oxide or hexahydro-1,4-thioazonyl-1,1-dioxide may optionally be 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.

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

8. A method for preparing the spirocyclic / bridged ring compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, deuterated derivative, N-oxide, prodrug molecule, hydrate, or solvate thereof, the method comprising: Preparation of compound II or compound III, wherein the preparation of compound II includes: 1) Compound II-1 undergoes a substitution reaction with compound II-2 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 through cyclization; 5) Compound II-8 was deprotected to form compound II-9; 6) Compound II-9 undergoes a substitution reaction with compound II-10 or compound II-11 to form the compound shown in formula II; the reaction route is shown in Figure 1; The preparation of compound III includes: 1) Compound III-1 undergoes a substitution reaction with compound III-2 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 through cyclization; 5) Compound III-8 is deprotected to form compound III-9; 6) Compound III-9 undergoes a substitution reaction with compound III-10 or compound III-11 to form the compound shown in formula III; the reaction route is shown in Figure 2; Among them, A, E, Q1, M, Y 1 Y 3 Y 4 Y 5 L1, L2, L3, L4, R 1 R 2 R 3 The definitions of R', G, W, m, n, and 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 any one of the spirocyclic / bridged ring compounds as described in any one of claims 1-7, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, deuterated compound, N-oxide, prodrug molecule, hydrate or solvate thereof, and a pharmaceutically acceptable carrier or excipient. Preferably, the pharmaceutical composition is a tablet, capsule, pill, granule, powder, suppository, injection, solution, suspension, ointment, patch, lotion, drop, liniment, or spray.

10. The use of any spirocyclic / bridged ring compound or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, deuterated product, N-oxide, prodrug molecule, hydrate or solvate and / or the pharmaceutical composition of claim 9 in the preparation of a treatment for HER2 abnormality-mediated diseases; Preferably, the disease is a neoplastic disease; More preferably, the neoplastic disease includes: Head and neck cancer, nasopharyngeal carcinoma, melanoma, bladder cancer, esophageal cancer, kidney cancer, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, pancreatic cancer, glioma, prostate cancer, leukemia, lymphoma, stomach 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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