CN114057771B

CN114057771B - Macrocyclic compounds, their preparation and use

Info

Publication number: CN114057771B
Application number: CN202111459591.5A
Authority: CN
Inventors: 张培龙; 李功; 兰文丽; 薛宝玉
Original assignee: Beijing Anshi Biotechnology Co ltd
Current assignee: Beijing Anshi Biotechnology Co ltd
Priority date: 2020-12-03
Filing date: 2021-12-02
Publication date: 2023-10-03
Anticipated expiration: 2041-12-02
Also published as: CN114057771A; WO2022117051A1

Abstract

The application relates to a macrocyclic compound, a preparation method and application thereof, wherein the macrocyclic compound has a structure shown in the following formula I:therein, A, B, D, R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ Z, X, m, n, p are as defined in the specification. The macrocyclic compound of the application can overcome EGFR C797S mutation and EGFR T790M mutation, and has higher selectivity.

Description

Macrocyclic compounds, their preparation and use

Technical Field

The present application relates to macrocyclic compounds and methods of making and using the same, and in particular to compounds that inhibit, modulate and/or regulate signaling of EGFR kinase, methods of making the same, pharmaceutical compositions containing the same, and uses thereof.

Background

Protein kinases are enzymatic components of the signaling pathway that catalyze the migration of terminal phosphates from ATP to the hydroxyl groups of tyrosine, serine and/or threonine residues of proteins. Thus, compounds that inhibit protein kinase function are valuable tools for assessing the physiological consequences of protein kinase activity. Overexpression or inappropriate expression of mammalian normal or mutant protein kinases has been the subject of extensive research and has been shown to play an important role in the development of many diseases including diabetes, angiogenesis, psoriasis, restenosis, ocular diseases, schizophrenia, rheumatoid arthritis, atherosclerosis, cardiovascular diseases and cancer. Protein kinase inhibitors find particular use in the treatment of human and animal diseases.

EGFR is a member of the ErbB receptor family of receptor tyrosine kinases. When EGFR binds to its ligand EGF extracellularly, the receptor undergoes homo-or heterodimerization and autophosphorylation, activating downstream cascade signaling pathways, ultimately promoting cell growth, proliferation, division, etc. Overexpression (upregulation) or hyperactivity of EGFR has been shown to be associated with a number of cancers including head and neck cancer, ovarian cancer, cervical cancer, bladder cancer, esophageal cancer, gastric cancer, breast cancer, endometrial cancer, colorectal cancer, non-small cell lung cancer, and glioblastoma.

EGFR as an oncogene produces targeted therapies against small molecule inhibitors of EGFR. In non-small cell lung cancer (NSCLC), 50% -80% of patients are caused by EGFR mutations. First generation EGFR inhibitors such as iressa, taroki, etc. have been used in the clinic with great success for the treatment of NSCLC. But has obvious side effects such as rash, diarrhea and the like in clinic, and after one year of use, patients have drug resistance to the drugs. Clinical data indicate that approximately 50% of patient acquired resistance results from the T790M (threonine at position 790 of exon 20 replaced by methionine) mutant. Second generation inhibitors such as afatinib, dacatinib, etc., which bind more strongly to EGFR, but have poor selectivity for the T790M mutant, and cannot reach effective concentrations in vivo at tolerable doses.

The third generation of inhibitor of octreotide can be used for treating T790M mutant patients after first and second generation treatment as well as EGFR sensitive mutant patients without EGFR-TKIs treatment as first line treatment, but after 9.9-18.9 months of treatment of the third generation of EGFR inhibitor of octreotide, the drug resistant mutation of C797S (mutation of 20 th exon 797 site cysteine into serine) is unavoidable.

The earliest report of the treatment of T790M mutation with octenib by Thress KS was that 40% of patients had a C797S resistance mutation, in addition to Lee JY et al reported that 24% of patients had a C797S resistance mutation after administration of octenib to T790M mutant patients, and that analysis of 73 patients who had developed an octenib disease in AURA3 clinical trials revealed that 15% had a C797S resistance mutation. The treatment with octenib as first line treatment in the FLAURA study also showed superior efficacy compared to the first-generation EGFR inhibitor (gefitinib or erlotinib) standard treatment, and 91 patients who took octenib drug resistance progression in the study were studied to find that 7% of patients developed C797S drug resistance mutation.

The result of drug-resistant mutation results in a greatly improved affinity of EGFR for ATP, which impairs competitive binding of small drug molecules to ATP. Zhu SJ et al [ Oncostarget, 2018,9 (17), 13652-13665] found 3 methods of improving small molecule affinity: covalent/irreversible inhibition, ultra-high activity non-covalent/reversible inhibition or non-ATP-competitive inhibition is also known as allosteric inhibition.

In 2019, bolin and Yinghn, inc. [ J.Med. Chem.2019,62,10272-10293] reported a non-covalent macrocyclic compound BI-4020 that could overcome the three mutations in C797S that were resistant to octenib while being highly selective for wild-type wtEGFR, but that did not enter the clinical stage. Presumably, the reason is that the activity of non-covalent compounds is not able to overcome the resistance caused by the T790M double mutation. For the C797S mutation, no effective medicine is treated on the market at present, and few medicines aiming at the C797S mutation are clinically used, and are mainly reversible inhibitors aiming at the C797S triple mutation, and have weak activity on T790M double mutation. Therefore, by introducing warheads on the basis of the structure of BI-4020, irreversible inhibition is formed, and the method has important significance for developing a fourth-generation EGFR inhibitor which can not only overcome C797S mutation but also overcome T790M mutation selectively.

Disclosure of Invention

In order to solve the defects in the prior art, the invention provides a macrocyclic compound which can overcome EGFR C797S mutation and EGFR T790M mutation and has higher selectivity.

The invention is realized by the following technical scheme.

In one aspect, the present invention provides a compound having the structure shown in formula I:

Wherein, the liquid crystal display device comprises a liquid crystal display device,

ring a and ring B are each independently 6-10 membered monocyclic or bicyclic aromatic ring, 5-10 membered monocyclic or bicyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from N, O and S, or 5-10 membered monocyclic or bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from N, O and S, said 6-10 membered monocyclic or bicyclic aromatic ring, 5-10 membered monocyclic or bicyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from N, O and S, or 5-10 membered monocyclic or bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from N, O and S may be optionally substituted with one or more substituents independently selected from: c (C) _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, halo C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkoxy, C _3-6 Cycloalkyl, halo C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, halo C _3-6 Cycloalkoxy radicals C _1-6 alkoxy-C _1-6 Alkyl, hydroxy-C _1-6 Alkyl, amino-C _1-6 Alkyl, C _1-6 alkyl-amino-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl groupOxo, halogen, hydroxy, cyano-C _1-6 Alkyl, amino, C _1-6 Alkyl-amino, di (C) _1-6 Alkyl) -amino, C _3-6 Cycloalkyl-amino, C _1-6 Alkyl-carbonyl, C _3-6 Cycloalkyl-carbonyl, C _1-6 Alkyl-amino-acyl, di (C) _1-6 Alkyl) -amino-acyl, C _3-6 Cycloalkyl-amino-acyl, C _1-6 Alkyl-acyl-amino, substituted with one or more R ^m Substituted or unsubstituted 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O and S, substituted with one or more R ^m Substituted or unsubstituted 6-10 membered aryl, substituted with one or more R ^m Substituted or unsubstituted 4-7 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O and S, substituted with one or more R ^m Substituted or unsubstituted 4-7 membered heterocyclyl-C containing 1-2 heteroatoms independently selected from N, O and S _1-6 Alkyl, -S (=o) ₂ R ^a 、-S(＝O) ₂ NR ^a R ^b 、-P(＝O)R ^a R ^b 、-P(＝O)R ^a NR ^b R ^c 、-P(＝S)R ^a R ^b 、-P(＝S)R ^a NR ^b R ^c 、R ^b S(＝O) ₂ N(R ^a ) -, wherein the C _1-6 Alkyl, C _2-6 Alkenyl, halo C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkoxy, C _3-6 Cycloalkyl, halo C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, halo C _3-6 Cycloalkoxy radicals C _1-6 alkoxy-C _1-6 Alkyl, hydroxy-C _1-6 Alkyl, amino-C _1-6 Alkyl, C _1-6 alkyl-amino-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl, cyano-C _1-6 Alkyl, C _1-6 Alkyl-amino, di (C) _1-6 Alkyl) -amino, C _3-6 Cycloalkyl-amino, C _1-6 Alkyl-carbonyl, C _3-6 Cycloalkyl-carbonyl, C _1-6 Alkyl-amino-acyl, di (C) _1-6 Alkyl) -amino-acyl, C _3-6 Cycloalkyl-amino-acyl, C _1-6 Alkyl-acyl-amino, substituted by one or moreR ^m Substituted or unsubstituted 4-7 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O and S, substituted with one or more R ^m Substituted or unsubstituted 4-7 membered heterocyclyl-C containing 1-2 heteroatoms independently selected from N, O and S _1-6 Alkyl, -S (=o) ₂ R ^a 、-S(＝O) ₂ NR ^a R ^b 、-P(＝O)R ^a R ^b 、-P(＝O)R ^a NR ^b R ^c 、-P(＝S)R ^a R ^b 、-P(＝S)R ^a NR ^b R ^c 、R ^b S(＝O) ₂ N(R ^a ) Optionally together with the carbon atoms to which they are attached, form a ring, said C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, halo C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkoxy, C _3-6 Cycloalkyl, halo C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, halo C _3-6 Cycloalkoxy radicals C _1-6 alkoxy-C _1-6 Alkyl, hydroxy-C _1-6 Alkyl, amino-C _1-6 Alkyl, C _1-6 alkyl-amino-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl, cyano-C _1-6 Alkyl, C _1-6 Alkyl-amino, di (C) _1-6 Alkyl) -amino, C _3-6 Cycloalkyl-amino, C _1-6 Alkyl-carbonyl, C _3-6 Cycloalkyl-carbonyl, C _1-6 Alkyl-amino-acyl, di (C) _1-6 Alkyl) -amino-acyl, C _3-6 Cycloalkyl-amino-acyl, C _1-6 Alkyl-acyl-amino, substituted with one or more R ^m Substituted or unsubstituted 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O and S, substituted with one or more R ^m Substituted or unsubstituted 6-10 membered aryl, substituted with one or more R ^m Substituted or unsubstituted 4-7 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O and S, substituted with one or more R ^m Substituted or unsubstituted 4-7 membered heterocyclyl-C containing 1-2 heteroatoms independently selected from N, O and S _1-6 Alkyl-may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, aminoHydroxy, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 alkoxy-C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkyl-amino, di (C) _1-6 Alkyl) -amino, 4-7 membered heterocyclyl and 4-7 membered heterocyclyl-C _1-6 An alkyl group;

ring D is a 6-10 membered monocyclic or bicyclic aromatic ring, a 5-10 membered monocyclic or bicyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from N, O and S, a 5-10 membered monocyclic or bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from N, O and S, or C _5-7 A cycloalkane;

R ¹ 、R ² 、R ⁴ and R is ⁵ Wherein 1 is a warhead group, when R ¹ R in the case of warhead group ² 、R ⁴ And R is ⁵ Each independently is R ⁶ The method comprises the steps of carrying out a first treatment on the surface of the When R is ² R in the case of warhead group ¹ 、R ⁴ And R is ⁵ Each independently is R ⁶ The method comprises the steps of carrying out a first treatment on the surface of the When R is ⁴ R in the case of warhead group ¹ 、R ² And R is ⁵ Each independently is R ⁶ The method comprises the steps of carrying out a first treatment on the surface of the Or when R is ⁵ R in the case of warhead group ¹ 、R ² And R is ⁴ Each independently is R ⁶ ；

R ³ And R is ⁶ Each independently is a 3-11 membered monocyclic or bridged or spiro heterocyclyl-C containing 1-3 heteroatoms independently selected from N, O or S _0-3 Alkyl, amino, C _1-6 Alkyl-amino, C _3-6 Cycloalkyl-amino, di (C) _1-6 Alkyl) -amino, C _1-6 alkoxy-C _1-6 Alkyl-amino, 4-6 membered heterocyclyl-C _1-6 Alkyl-amino, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl-amino, di (C) _1-6 Alkyl) -amino-C _1-6 alkoxy-C _1-6 Alkyl-amino, hydrogen atom, halogen, hydroxy, cyano, C _1-6 Alkyl, halogenated C _1-6 Alkyl, hydroxy-C _1-6 Alkyl, hydroxy-C _1-6 Alkoxy, C _1-6 alkoxy-C _1-6 Alkyl, cyano-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl, C _3-6 cycloalkyl-amino-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 alkoxy-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 alkyl-amino-C _1-6 Alkyl, C _1-6 Alkoxy, di (C) _1-6 Alkyl) -amino-C _1-6 Alkoxy, C _1-6 Alkyl-carbonyl, C _3-6 Cycloalkyl-carbonyl, C _1-6 Alkoxy-carbonyl, 3-7 membered heterocyclyl-carbonyl containing 1-3 heteroatoms independently selected from N, O or S, C _1-6 alkyl-carbonyl-C _1-6 Alkyl, C _1-6 alkyl-aminoacyl-C _1-6 Alkyl, 3-7 membered heterocyclyl-carbonyl-C containing 1-3 heteroatoms independently selected from N, O or S _1-6 Alkyl, C _1-6 alkyl-OC (O) -C _1-6 Alkyl, or 3-11 membered monocyclic or bridged or spiro heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O or S, said 3-11 membered monocyclic or bridged or spiro heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O or S-C _0-3 Alkyl, C _1-6 Alkyl-amino, C _3-6 Cycloalkyl-amino, di (C) _1-6 Alkyl) -amino, C _1-6 alkoxy-C _1-6 Alkyl-amino, 4-6 membered heterocyclyl-C _1-6 Alkyl-amino, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl-amino, di (C) _1-6 Alkyl) -amino-C _1-6 alkoxy-C _1-6 Alkyl-amino, C _1-6 Alkyl, halogenated C _1-6 Alkyl, hydroxy-C _1-6 Alkyl, hydroxy-C _1-6 Alkoxy, C _1-6 alkoxy-C _1-6 Alkyl, cyano-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl, C _3-6 cycloalkyl-amino-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 alkoxy-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 alkyl-amino-C _1-6 Alkyl, C _1-6 Alkoxy, di (C) _1-6 Alkyl) -amino-C _1-6 Alkoxy, C _1-6 Alkyl-carbonyl, C _3-6 Cycloalkyl-carbonyl, C _1-6 Alkoxy-carbonyl, 3-7 membered heterocyclyl-carbonyl containing 1-3 heteroatoms independently selected from N, O or S, C _1-6 Alkyl-carbonyl group-C _1-6 Alkyl, C _1-6 alkyl-aminoacyl-C _1-6 Alkyl, 3-7 membered heterocyclyl-carbonyl-C containing 1-3 heteroatoms independently selected from N, O or S _1-6 Alkyl, C _1-6 alkyl-OC (O) -C _1-6 An alkyl group, or a 3-11 membered monocyclic or bridged or spiro heterocyclic group containing 1-3 heteroatoms independently selected from N, O or S, may be optionally substituted with one or more substituents independently selected from the group consisting of: c (C) _1-6 Alkyl, halogenated C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkoxy, C _3-6 Cycloalkyl, halo C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, halo C _3-6 Cycloalkoxy radicals C _1-6 alkoxy-C _1-6 Alkyl, C _3-6 cycloalkyl-C _1-6 Alkyl, C _1-6 alkyl-O (O) C-, C _1-6 Alkyl-carbonyl, oxo, halogen, hydroxy, C _1-6 Alkylamino, di (C) _1-6 Alkyl) amino, substituted with 1 or more C _1-6 Alkyl, C _1-6 Alkoxy, oxo, halogen substituted 5-7 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O or S;

alternatively, R ³ And ring D is divided by R ³ Together with any atoms other than the atoms to which they are attached, or R ³ And R is ⁶ Optionally together with the atoms to which they are attached form a heterocyclic ring consisting of 3 to 10 atoms, which contains 1 to 3 heteroatoms selected from N, O or S and which is optionally further substituted on the heterocyclic ring by one or more substituents selected from C _1-6 Alkyl, halogen, 6-10 membered aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O or S, 5-10 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O or S, halogenated C _1-6 Alkyl, hydroxy, cyano, halogen, C _1-6 Alkoxy, 4-6 membered heterocyclylalkyl, C _1-6 Alkylamino and di (C) _1-6 Alkyl) amino;

warhead group is R ⁷ 、-Y ¹ (CR ^a R ^b ) _q NR ⁷ R ⁸ 、

R ⁷ Is thatOr C _1-6 Alkyl C (O);

Y ¹ 、Y ² and Y ³ Each independently is a chemical bond, O, NR ⁸ 、S、S(O) ₂ 、CR ⁸ R ¹⁶ Carbonyl, -amino-acyl, -acyl-amino, -O (CO) -or- (CO) O-;

m is a bond, is bound by one or more R ^m Substituted or unsubstituted-C _1-6 Alkyl-, substituted by one or more R ^m Substituted or unsubstituted-C _3-6 Cycloalkyl-, substituted by one or more R ^m Substituted or unsubstituted-C _3-6 cycloalkyl-C _1-6 Alkyl-, substituted by one or more R ^m Substituted or unsubstituted-C _1-6 alkyl-amino-C _1-6 Alkyl-, substituted by one or more R ^m Substituted or unsubstituted-4-7 membered heterocyclyl-, containing 1-2 heteroatoms independently selected from N, O and S, substituted with one or more R ^m Substituted or unsubstituted-4-7 membered heterocyclyl-C containing 1-2 heteroatoms independently selected from N, O and S _1-6 Alkyl-;

R ⁸ is hydrogen atom, C _1-6 Alkyl, C _3-6 Cycloalkyl, or a 5-7 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O and S and optionally substituted with oxo;

R ⁹ and R is ¹⁰ Independently a hydrogen atom, halogen, cyano, C _1-6 Alkyl, halogenated C _1-6 Alkyl, C _3-6 Cycloalkyl, or heterocyclylalkyl;

R ¹¹ is hydrogen atom, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy radicals C _1-6 alkoxy-C _1-6 Alkyl, C _3-6 cycloalkyl-C _1-6 Alkyl, amino, C _1-6 Alkylamino, di(C _1-6 Alkyl) amino, 4-10 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O or S, said C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy radicals C _1-6 alkoxy-C _1-6 Alkyl, C _3-6 cycloalkyl-C _1-6 Alkyl, C _1-6 Alkylamino, di (C) _1-6 Alkyl) amino, 4-10 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O or S, may be optionally substituted with one or more groups independently selected from: halogen, hydroxy, cyano;

R ¹² and R is ¹³ Each independently is a hydrogen atom, C _1-6 Alkyl, C _3-7 Cycloalkyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O or S, or R ¹² And R is ¹³ With NR ¹² R ¹³ Wherein N together form a 4-10 membered heterocyclic group containing 1-3 heteroatoms independently selected from N, O or S, said C _1-6 Alkyl, C _3-7 Cycloalkyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O or S, or R ¹² And R is ¹³ With NR ¹² R ¹³ Together form a 4-10 membered heterocyclic group containing 1-3 heteroatoms independently selected from N, O or S, optionally substituted with one or more substituents independently selected from the group consisting of: c (C) _1-6 Alkyl, halogenated C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkoxy, C _3-6 Cycloalkyl, halo C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, halo C _3-6 Cycloalkoxy, halogen, hydroxy, cyano, oxo, C _1-6 Alkyl-amino, halo C _1-6 Alkyl-amino, di (C) _1-6 Alkyl) -amino, C _3-6 Cycloalkyl-amino, substituted by one or more R ^m Substituted or unsubstituted 3-7 membered heterocyclic groups containing N, O or S heteroatoms and C _1-6 Alkyl-carbonyl;

R ¹⁴ and R is ¹⁵ Independently is a hydrogen atom, C _1-6 Alkyl, or R ¹⁴ And R is ¹⁵ Together with the carbon atoms to which they are attached form C _3-6 Cycloalkyl;

R ¹⁶ is hydrogen atom, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, or C _3-6 A cycloalkoxy group;

R ^a 、R ^b 、R ^c and R is ^d Each independently is a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, a cyano group, an oxo group, or C _1-6 Alkyl, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 alkoxy-C _1-6 Alkyl, C _1-6 Alkyl-amino, C _1-6 alkyl-amino-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl, C _3-6 Cycloalkyl-amino, 3-7 membered heterocyclyl-C _1-6 Alkyl, said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 alkoxy-C _1-6 Alkyl, C _1-6 Alkyl-amino, C _1-6 alkyl-amino-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl, C _3-6 Cycloalkyl-amino, 3-7 membered heterocyclyl-C _1-6 The alkyl group may be optionally substituted with one or more of the following groups: halogen, hydroxy, cyano, C _1-6 Alkyl, C _3-6 Cycloalkyl and C _1-6 An alkoxy group.

Or R is ^a And R is ^b Together with the carbon atoms to which they are attached form a ring, R ^c And R is ^d Together with the carbon atoms to which they are attached form a ring, said ring being C _3-6 Cycloalkanes or 4-7 membered saturated or partially unsaturated heterocycles containing 1-3 heteroatoms independently selected from N, O or S, said C _3-6 Cycloalkanes, 4-7 membered saturated or partially unsaturated heterocycles containing 1-3 heteroatoms independently selected from N, O or S are optionally substituted with one or more of the following groups: halogen, hydroxy, cyano, C _1-6 Alkyl, C _3-6 Cycloalkyl and C _1-6 An alkoxy group.

Ring E is a ring containing 1 to 3 groups independently selected from N, O orA 4-7 membered saturated or partially unsaturated heterocycle of the S heteroatom, or a 5-10 membered bridged or spiro saturated or partially unsaturated heterocycle containing 1-5 heteroatoms independently selected from N, O or S, said 4-7 membered saturated or partially unsaturated heterocycle and 5-10 membered bridged or spiro saturated or partially unsaturated heterocycle optionally being independently substituted with one or more R ^m Substituted;

ring G is a 4-7 membered saturated or partially unsaturated heterocycle containing 1-3 heteroatoms independently selected from N, O or S, C _3-6 Cycloalkanes, 6-to 10-membered monocyclic or bicyclic aromatic rings, or 5-to 10-membered bridged or spiro saturated or partially unsaturated heterocycles containing 1-5 heteroatoms independently selected from N, O or S, said 4-to 7-membered saturated or partially unsaturated heterocycles, C _3-6 Cycloalkanes, 6-to 10-membered monocyclic or bicyclic aromatic rings, 5-to 10-membered bridged or spiro saturated or partially unsaturated heterocycles, which may optionally be independently substituted by one or more R ^m Substituted;

R ^m is C _1-6 Alkyl, halogenated C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkoxy, C _3-6 Cycloalkyl, halo C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, halo C _3-6 Cycloalkoxy radicals C _1-6 alkoxy-C _1-6 Alkyl, hydroxy-C _1-6 Alkyl, amino-C _1-6 Alkyl, C _1-6 alkyl-amino-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl, C _3-6 cycloalkyl-amino-C _1-6 Alkyl, halogen, hydroxy, cyano-C _1-6 Alkyl, amino, oxo, C _1-6 Alkyl-amino, di (C) _1-6 Alkyl) -amino, C _3-6 Cycloalkyl-amino, C _1-6 Alkyl-carbonyl, C _1-6 Alkyl-amino-acyl, di (C) _1-6 Alkyl) -amino-acyl, C _3-6 Cycloalkyl-amino-acyl, C _1-6 Acyl-amino, C _1-6 alkyl-O (CO) -or C _3-6 cycloalkyl-O (CO) -;

q and t are each independently 0, 1, 2 or 3;

w is 1, 2 or 3;

x is O, S, CR ¹⁷ R ¹⁸ 、NR ¹⁷ CO or S (O) ₂ ；

R ¹⁷ Is hydrogen atom, C _1-6 Alkyl, halogenated C _1-6 Alkyl, C _3-6 Cycloalkyl, halo C _3-6 Cycloalkyl, C _1-6 alkoxy-C _1-6 Alkyl, halogenated C _1-6 alkoxy-C _1-6 Alkyl, hydroxy-C _1-6 Alkyl, amino-C _1-6 Alkyl, C _1-6 alkyl-amino-C _1-6 Alkyl, cyano-C _1-6 Alkyl, C _1-6 Alkyl-carbonyl or C _1-6 Alkyl-sulfone groups;

R ¹⁸ is hydrogen atom, C _1-6 Alkyl, halogenated C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkoxy, C _3-6 Cycloalkyl, halo C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, halo C _3-6 Cycloalkoxy radicals C _1-6 alkoxy-C _1-6 Alkyl, hydroxy-C _1-6 Alkyl, amino-C _1-6 Alkyl, C _1-6 alkyl-amino-C _1-6 Alkyl, oxo, halogen, hydroxy, cyano-C _1-6 Alkyl, amino, C _1-6 Alkyl-amino, di (C) _1-6 Alkyl) -amino, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl, C _3-6 Cycloalkyl-amino, C _1-6 Alkyl-carbonyl, C _1-6 Alkyl-amino-acyl, di (C) _1-6 Alkyl) -amino-acyl, C _3-6 Cycloalkyl-amino-acyl, C _1-6 Alkyl-acyl-amino, C _1-6 alkyl-O (O) C-, C _1-6 alkyl-C (O) O-or C _1-6 Alkyl-sulfone groups;

z is N, O, S, CO, S (O) ₂ -amino-acyl, -acyl-amino, -O (CO) -, - (CO) O-, CR ¹⁹ 、C _3-7 Cycloalkyl or 3-7 membered heterocyclyl, said C _3-7 Cycloalkyl and 3-7 membered heterocyclyl may optionally be independently substituted with one or more R ¹⁸ Substituted;

R ¹⁹ independently is a hydrogen atom, C _1-6 Alkyl or C _3-6 Cycloalkyl;

m and n are independently 0, 1, 2, 3 or 4;

p is 0, 1, 2 or 3.

In certain embodiments, ring a and ring B are each independently a benzene ring, or a 5-6 membered heteroaromatic ring containing 1-2 heteroatoms independently selected from N, O and S, which benzene ring or 5-6 membered heteroaromatic ring may be optionally substituted with one or more substituents independently selected from: c (C) _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, halo C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkoxy, C _3-6 Cycloalkyl, halo C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy radicals C _1-6 alkoxy-C _1-6 Alkyl, hydroxy-C _1-6 Alkyl, amino-C _1-6 Alkyl, oxo, halogen, hydroxy, cyano-C _1-6 Alkyl, amino, C _1-6 Alkyl-amino, di (C) _1-6 Alkyl) -amino, C _1-6 alkyl-amino-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl, C _3-6 Cycloalkyl-amino, said C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, halo C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkoxy, C _3-6 Cycloalkyl, halo C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy radicals C _1-6 alkoxy-C _1-6 Alkyl, hydroxy-C _1-6 Alkyl, amino-C _1-6 Alkyl, cyano-C _1-6 Alkyl, C _1-6 Alkyl-amino, di (C) _1-6 Alkyl) -amino, C _1-6 alkyl-amino-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl, C _3-6 Cycloalkyl-amino groups may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, amino, hydroxy, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl, C _1-6 Alkyl-amino and 4-7 membered heterocyclyl;

preferably, in formula I, ring a and ring B are each independently a benzene ring, pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, pyrrole, thiophene, imidazole, oxazole, isoxazole, furan, thiazole, isothiazole, said benzene The ring, pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, pyrrole, thiophene, imidazole, oxazole, isoxazole, furan, thiazole, and isothiazole may be optionally substituted with one or more substituents independently selected from the group consisting of: c (C) _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, halo C _1-4 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkoxy, C _3-6 Cycloalkyl, halo C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, halo C _3-6 Cycloalkoxy radicals C _1-6 alkoxy-C _1-6 Alkyl, hydroxy-C _1-6 Alkyl, amino-C _1-6 Alkyl, C _1-6 alkyl-amino-C _1-6 Alkyl, oxo, halogen, hydroxy, cyano-C _1-6 Alkyl, amino, C _1-6 Alkyl-amino, di (C) _1-6 Alkyl) -amino, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl and C _3-6 Cycloalkyl-amino.

In certain embodiments, ring D is a benzene ring, a 5-6 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O and S, a 5-7 membered heterocyclic ring containing 1-2 heteroatoms independently selected from N, O and S, or a cyclohexane ring;

preferably, in formula I, ring D is a benzene ring, pyridine, pyrimidine, pyrazine, pyridazine, piperidine, piperazine, pyrazole, imidazole or cyclohexane.

In certain embodiments, R ¹ 、R ² 、R ⁴ And R is ⁵ Wherein 1 is a warhead group, when R ¹ R in the case of warhead group ² 、R ⁴ And R is ⁵ Each independently is R ⁶ When R is ² R in the case of warhead group ¹ 、R ⁴ And R is ⁵ Each independently is R ⁶ The method comprises the steps of carrying out a first treatment on the surface of the When R is ⁴ R in the case of warhead group ¹ 、R ² And R is ⁵ Each independently is R ⁶ The method comprises the steps of carrying out a first treatment on the surface of the Or when R is ⁵ R in the case of warhead group ¹ 、R ² And R is ⁴ Each independently is R ⁶ ；

R ³ And R is ⁶ Each independently is a 3-11 membered monocyclic or bridged or spiro ring containing 1-3 heteroatoms independently selected from N, O or Sheterocyclyl-C _0-3 Alkyl, hydrogen atom, halogen, hydroxy, cyano, C _1-6 Alkyl, halogenated C _1-6 Alkyl, hydroxy-C _1-6 Alkyl, hydroxy-C _1-6 Alkoxy, C _1-6 alkoxy-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl, C _3-6 cycloalkyl-amino-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 alkoxy-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 alkyl-amino-C _1-6 Alkyl, C _1-6 Alkoxy, di (C) _1-6 Alkyl) -amino-C _1-6 Alkoxy, C _1-6 Alkyl-carbonyl, C _1-6 Alkoxy-carbonyl, or 3-7 membered heterocyclyl-carbonyl containing 1-3 heteroatoms independently selected from N, O or S, said 3-11 membered monocyclic or bridged or spiro heterocyclyl-C containing 1-3 heteroatoms independently selected from N, O or S _0-3 Alkyl, C _1-6 Alkyl, halogenated C _1-6 Alkyl, hydroxy-C _1-6 Alkyl, hydroxy-C _1-6 Alkoxy, C _1-6 alkoxy-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl, C _3-6 cycloalkyl-amino-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 alkoxy-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 alkyl-amino-C _1-6 Alkyl, C _1-6 Alkoxy, di (C) _1-6 Alkyl) -amino-C _1-6 Alkoxy, C _1-6 Alkyl-carbonyl, C _1-6 Alkoxy-carbonyl, or 3-7 membered heterocyclyl-carbonyl containing 1-3 heteroatoms independently selected from N, O, or S, may be optionally substituted with one or more substituents independently selected from the group consisting of: c (C) _1-6 Alkyl, halogenated C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy radicals C _1-6 alkoxy-C _1-6 Alkyl, C _3-6 cycloalkyl-C _1-6 Alkyl, C _1-6 alkyl-O (O) C-, C _1-6 Alkyl-carbonyl, oxo, halogen, hydroxy, C _1-6 Alkylamino, di (C) _1-6 Alkyl group) Amino, optionally substituted with 1 or more C _1-6 Alkyl, C _1-6 Alkoxy, oxo, halogen substituted 5-7 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O or S;

warhead group is R ⁷ 、-Y ¹ (CR ^a R ^b ) _q NR ⁷ R ⁸ 、

R ⁷ Is that

Y ¹ 、Y ² And Y ³ Each independently is a bond, O or NR ⁸ ；

R ⁸ Is hydrogen atom, C _1-6 Alkyl or C _3-6 Cycloalkyl;

R ⁹ and R is ¹⁰ Independently a hydrogen atom, halogen or cyano;

R ¹² and R is ¹³ Each independently is a hydrogen atom, C _1-6 Alkyl, C _3-6 Cycloalkyl, or R ¹² And R is ¹³ With NR ¹² R ¹³ Together form a 4-7 membered heterocyclic ring containing 1-3 heteroatoms independently selected from N, O or S, said C _1-6 Alkyl, C _3-6 Cycloalkyl and the 4-7 membered heterocyclic ring formed containing 1-3 heteroatoms independently selected from N, O or S may be optionally substituted with one or more substituents independently selected from the group consisting of: c (C) _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, halogen, hydroxy, cyano, C _1-6 Alkyl-amino, di (C) _1-6 Alkyl) -amino, C _3-6 Cycloalkyl-amino, substituted by one or more R ^m Substituted or unsubstituted 3-7 membered heterocyclic groups containing N, O or S heteroatoms and C _1-6 Alkyl-carbonyl;

R ¹⁴ and R is ¹⁵ Independently is a hydrogen atom, C _1-6 Alkyl or R ¹⁴ And R is ¹⁵ Together with the carbon atoms to which they are attached form C _3-6 Cycloalkyl;

R ^a 、R ^b 、R ^c and R is ^d Each independently is a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, a cyano group, an oxo group, or C _1-6 Alkyl, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 alkoxy-C _1-6 Alkyl, C _1-6 Alkyl-amino, C _1-6 alkyl-amino-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl, C _3-6 Cycloalkyl-amino, 3-7 membered heterocyclyl-C _1-6 Alkyl, said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 alkoxy-C _1-6 Alkyl, C _1-6 Alkyl-amino, C _1-6 alkyl-amino-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl, C _3-6 Cycloalkyl-amino, 3-7 membered heterocyclyl-C _1-6 The alkyl group may be optionally substituted with one or more of the following groups: halogen, hydroxy, cyano, C _1-6 Alkyl, C _3-6 Cycloalkyl and C _1-6 An alkoxy group;

or R is ^a And R is ^b Together with the carbon atoms to which they are attached form a ring, R ^c And R is ^d Together with the carbon atoms to which they are attached form a ring, said ring being C _3-6 Cycloalkanes or 4-7 membered saturated or partially unsaturated heterocycles containing 1-3 heteroatoms independently selected from N, O or S, said C _3-6 Cycloalkanes, 4-7 membered saturated or partially unsaturated heterocycles containing 1-3 heteroatoms independently selected from N, O or S are optionally substituted with one or more of the following groups: halogen, hydroxy, cyano, C _1-6 Alkyl, C _3-6 Cycloalkyl and C _1-6 An alkoxy group;

ring E is a ring containing 1-3 independent groupsA 4-7 membered saturated heterocyclic ring selected from N, O or S heteroatoms, or a 7-10 membered bridged or spiro saturated heterocyclic ring containing 1-5 heteroatoms independently selected from N, O or S, said 4-7 membered saturated heterocyclic ring, 7-10 membered bridged or spiro saturated heterocyclic ring may optionally be independently substituted with one or more R ^m Substituted;

ring G is a 4-7 membered saturated heterocyclic ring containing 1-3 heteroatoms independently selected from N, O or S, C _3-6 Cycloalkane, or 7-to 10-membered bridged or spiro saturated heterocycle containing 1 to 5 heteroatoms independently selected from N, O or S, said 4-to 7-membered saturated heterocycle, C _3-6 Cycloalkanes, 7-to 10-membered bridged rings or spiro saturated heterocycles may optionally be independently substituted with one or more R ^m Substituted;

R ^m is C _1-6 Alkyl, halogenated C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy radicals C _1-6 alkoxy-C _1-6 Alkyl, hydroxy-C _1-6 Alkyl, amino-C _1-6 Alkyl, C _1-6 alkyl-amino-C _1-6 Alkyl, halogen, hydroxy, cyano, amino, oxo, C _1-6 Alkyl-amino, di (C) _1-6 Alkyl) -amino, C _3-6 Cycloalkyl-amino, C _1-6 Alkyl-carbonyl, C _1-6 alkyl-OC (O) -or C _3-6 cycloalkyl-OC (O) -;

q and t are each independently 0, 1, 2 or 3;

w is 1, 2 or 3;

preferably, in formula I, R ¹ 、R ² 、R ⁴ And R is ⁵ Wherein 1 is a warhead group, when R ¹ R in the case of warhead group ² 、R ⁴ And R is ⁵ Each independently is R ⁶ The method comprises the steps of carrying out a first treatment on the surface of the When R is ² R in the case of warhead group ¹ 、R ⁴ And R is ⁵ Each independently is R ⁶ The method comprises the steps of carrying out a first treatment on the surface of the When R is ⁴ R in the case of warhead group ¹ 、R ² And R is ⁵ Each independently is R ⁶ The method comprises the steps of carrying out a first treatment on the surface of the Or when R is ⁵ R in the case of warhead group ¹ 、R ² And R is ⁴ Each independently is R ⁶ ；

R ³ And R is ⁶ Each of which is a single pieceIndependently is a hydrogen atom, halogen, methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, cyano, hydroxy, hydroxymethyl, methoxymethyl, ethoxymethyl, methylcarbonyl, methoxycarbonyl, 4-methylpiperazin-1-ylcarbonyl, dimethylaminomethyl, dimethylaminoethoxy, hydroxyethoxy, dimethylaminoethoxymethyl, N, N, N' -trimethylethylenediamine methyl, N, N-dimethylethylenediamine methyl, pyrrolidinylmethyl, morpholinomethyl, azetidinylmethyl, piperidinylmethyl, 4- (dimethylamino) piperidin-1-ylmethyl, 4- (3-methoxyacridin-1-yl) piperidin-1-ylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5 ] ]Nonan-7-ylmethyl, N, N, N' -trimethylethylenediamine, N, N-dimethylethylenediamine, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hexahydropyranyl, tetrahydrofuranyl, said 4-methylpiperazin-1-ylcarbonyl, pyrrolidinylmethyl, morpholinomethyl, azetidinylmethyl, piperidinylmethyl, 4- (dimethylamino) piperidin-1-ylmethyl, 4- (3-methoxyacridin-1-yl) piperidin-1-ylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5]Nonan-7-ylmethyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hexahydropyranyl, tetrahydrofuranyl may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, methoxymethyl, methoxyethyl, methylcarbonyl, methoxycarbonyl, oxo and dimethylamino;

the warhead group is:

in certain embodiments, X is O or S;

z is N, OS, -amino-acyl, -acyl-amino, or CR ¹⁹ ；

R ¹⁹ Independently is a hydrogen atom, C _1-6 Alkyl or C _3-6 Cycloalkyl;

preferably, in formula I, Z is N, O or CR ¹⁹ ；

R ¹⁹ Independently a hydrogen atom, methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl.

In certain embodiments, in formula I:

ring a and ring B are each independently a benzene ring, or a 5-6 membered heteroaromatic ring containing 1-2 heteroatoms independently selected from N, O and S, which benzene ring or 5-6 membered heteroaromatic ring may be optionally substituted with one or more substituents independently selected from: c (C) _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, halo C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkoxy, C _3-6 Cycloalkyl, halo C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy radicals C _1-6 alkoxy-C _1-6 Alkyl, hydroxy-C _1-6 Alkyl, amino-C _1-6 Alkyl, oxo, halogen, hydroxy, cyano-C _1-6 Alkyl, amino, C _1-6 Alkyl-amino, di (C) _1-6 Alkyl) -amino, C _1-6 alkyl-amino-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl, C _3-6 Cycloalkyl-amino, said C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, halo C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkoxy, C _3-6 Cycloalkyl, halo C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy radicals C _1-6 alkoxy-C _1-6 Alkyl, hydroxy-C _1-6 Alkyl, amino-C _1-6 Alkyl, cyano-C _1-6 Alkyl, amino, C _1-6 Alkyl-amino, di (C) _1-6 Alkyl) -amino, C _1-6 alkyl-amino-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl, C _3-6 Cycloalkyl-amino groups may optionally be substituted with one or more independent groupsIs substituted by a substituent selected from the group consisting of: halogen, cyano, amino, hydroxy, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl, C _1-6 Alkyl-amino and 4-7 membered heterocyclyl;

ring D is a benzene ring, a 5-6 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O and S, a 5-7 membered heterocyclic ring or a cyclohexyl ring containing 1-2 heteroatoms independently selected from N, O and S;

R ³ And R is ⁶ Each independently is a 3-11 membered monocyclic or bridged or spiro heterocyclyl-C containing 1-3 heteroatoms independently selected from N, O or S _0-3 Alkyl, hydrogen atom, halogen, hydroxy, cyano, C _1-6 Alkyl, halogenated C _1-6 Alkyl, hydroxy-C _1-6 Alkyl, hydroxy-C _1-6 Alkoxy, C _1-6 alkoxy-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl, C _3-6 cycloalkyl-amino-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 alkoxy-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 alkyl-amino-C _1-6 Alkyl, C _1-6 Alkoxy, di (C) _1-6 Alkyl) -amino-C _1-6 Alkoxy, C _1-6 Alkyl-carbonyl, C _1-6 Alkoxy-carbonyl, or 3-7 membered heterocyclyl-carbonyl containing 1-3 heteroatoms independently selected from N, O or S, said 3-11 membered monocyclic or bridged or spiro heterocyclyl-C containing 1-3 heteroatoms independently selected from N, O or S _0-3 Alkyl, C _1-6 Alkyl, halogenSubstitute C _1-6 Alkyl, hydroxy-C _1-6 Alkyl, hydroxy-C _1-6 Alkoxy, C _1-6 alkoxy-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl, C _3-6 cycloalkyl-amino-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 alkoxy-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 alkyl-amino-C _1-6 Alkyl, C _1-6 Alkoxy, di (C) _1-6 Alkyl) -amino-C _1-6 Alkoxy, C _1-6 Alkyl-carbonyl, C _1-6 Alkoxy-carbonyl, or 3-7 membered heterocyclyl-carbonyl containing 1-3 heteroatoms independently selected from N, O, or S, may be optionally substituted with one or more substituents independently selected from the group consisting of: c (C) _1-6 Alkyl, halogenated C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy radicals C _1-6 alkoxy-C _1-6 Alkyl, C _3-6 cycloalkyl-C _1-6 Alkyl, C _1-6 alkyl-O (O) C-, C _1-6 Alkyl-carbonyl, oxo, halogen, hydroxy, C _1-6 Alkylamino, di (C) _1-6 Alkyl) -amino groups, optionally substituted with 1 or more C _1-6 Alkyl, C _1-6 Alkoxy, oxo, halogen substituted 5-7 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O or S;

warhead group is R ⁷ 、-Y ¹ (CR ^a R ^b ) _q NR ⁷ R ⁸ 、

R ⁷ Is that

Y ¹ 、Y ² And Y ³ Each independently is a bond, O or NR ⁸ ；

R ⁸ Is hydrogen atom, C _1-6 Alkyl or C _3-6 Cycloalkyl;

R ⁹ and R is ¹⁰ Independently a hydrogen atom, halogen or cyano;

ring E is a 4-7 membered saturated heterocyclic ring containing 1-3 heteroatoms independently selected from N, O or S, or a 7-10 membered bridged or spiro saturated heterocyclic ring containing 1-5 heteroatoms independently selected from N, O or S, which 4-7 membered saturated heterocyclic ring, 7-10 membered bridged or spiro saturated heterocyclic ring may optionally be independently substituted with one or more R ^m Substituted;

R ^m is C _1-6 Alkyl, halogenated C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy radicals C _1-6 alkoxy-C _1-6 Alkyl, hydroxy-C _1-6 Alkyl groupamino-C _1-6 Alkyl, C _1-6 alkyl-amino-C _1-6 Alkyl, halogen, hydroxy, cyano, amino, oxo, C _1-6 Alkyl-amino, di (C) _1-6 Alkyl) -amino, C _3-6 Cycloalkyl-amino, C _1-6 Alkyl-carbonyl, C _1-6 alkyl-OC (O) -and C _3-6 cycloalkyl-OC (O) -;

q and t are each independently 0, 1, 2 or 3;

w is 1, 2 or 3;

x is O or S;

z is N, O, S, -amino-acyl, -acyl-amino, or CR ¹⁹ ；

R ¹⁹ Independently is a hydrogen atom, C _1-6 Alkyl or C _3-6 Cycloalkyl;

m and n are independently 0, 1, 2, 3 or 4;

p is 0, 1, 2 or 3.

In other embodiments, in formula I:

ring a and ring B are each independently a benzene ring, pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, pyrrole, thiophene, imidazole, oxazole, isoxazole, furan, thiazole, isothiazole, which may be optionally substituted with one or more substituents independently selected from the group consisting of: c (C) _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, halo C _1-4 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkoxy, C _3-6 Cycloalkyl, halo C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, halo C _3-6 Cycloalkoxy radicals C _1-6 alkoxy-C _1-6 Alkyl, hydroxy-C _1-6 Alkyl, amino-C _1-6 Alkyl, C _1-6 alkyl-amino-C _1-6 Alkyl, oxo, halogen, hydroxy, cyano-C _1-6 Alkyl, amino, C _1-6 Alkyl-amino, di (C) _1-6 Alkyl) -amino, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl and C _3-6 Cycloalkyl-amino;

ring D is a benzene ring, pyridine, pyrimidine, pyrazine, pyridazine, piperidine, piperazine, pyrazole, imidazole, or hexane;

R ³ And R is ⁶ Each independently is a hydrogen atom, halogen, methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, cyano, hydroxy, hydroxymethyl, methoxymethyl, ethoxymethyl, methylcarbonyl, methoxycarbonyl, 4-methylpiperazin-1-ylcarbonyl, dimethylaminomethyl, dimethylaminoethoxy, hydroxyethoxy, dimethylaminoethoxymethyl, N, N, N' -trimethylethylenediamine methyl, N, N-dimethylethylenediamine methyl, pyrrolidinylmethyl, morpholinomethyl, azetidinylmethyl, piperidinylmethyl, 4- (dimethylamino) piperidin-1-ylmethyl, 4- (3-methoxyacridin-1-yl) piperidin-1-ylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5 ]]Nonan-7-ylmethyl, N, N, N' -trimethylethylenediamine, N, N-dimethylethylenediamine, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hexahydropyranyl, tetrahydrofuranyl, said 4-methylpiperazin-1-ylcarbonyl, pyrrolidinylmethyl, morpholinomethyl, azetidinylmethyl, piperidinylmethyl, 4- (dimethylamino) piperidin-1-ylmethyl, 4- (3-methoxyacridin-1-yl) piperidin-1-ylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5 ]Nonan-7-ylmethyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hexahydropyranyl, tetrahydrofuranThe groups may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, methoxymethyl, methoxyethyl, methylcarbonyl, methoxycarbonyl, oxo and dimethylamino.

The warhead group is:

/>

x is O or S;

z is N, O or CR ¹⁹ ；

R ¹⁹ Independently a hydrogen atom, methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl;

m and n are independently 0, 1, 2, 3 or 4;

p is 0, 1, 2 or 3.

In yet other embodiments, in formula I:

ring a and ring B are each independently a benzene ring, pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, which may be optionally substituted with one or more substituents independently selected from the group consisting of: methyl, ethyl, isopropyl, vinyl, ethynyl, fluoroethyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, methoxy, ethoxy, cyclopropoxy, methoxymethyl, methoxyethyl, hydroxyethyl, hydroxypropyl, aminoethyl, oxo, fluoro, chloro, bromo, hydroxy, cyano, cyanoethyl, cyanopropyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, dimethylaminomethyl, dimethylaminoethyl, methylaminoethyl, cyclopropylamino;

Ring D is a benzene ring, pyridine, pyrimidine, pyrazine, pyridazine, piperidine or piperazine;

R ³ And R is ⁶ Independently is a hydrogen atom, fluoro, chloro, bromo, methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, cyano, hydroxy, hydroxymethyl, methoxymethyl, ethoxymethyl, methylcarbonyl, methoxycarbonyl, 4-methylpiperazin-1-ylcarbonyl, dimethylaminomethyl, dimethylaminoethoxy, hydroxyethoxy, dimethylaminoethoxymethyl, N, N, N' -trimethylethylenediamine methyl, N, N-dimethylethylenediamine methyl, pyrrolidinylmethyl, morpholinomethyl, azetidinylmethyl, piperidinylmethyl, 4- (dimethylamino) piperidin-1-ylmethyl, 4- (3-methoxyacridin-1-yl) piperidin-1-ylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5]Nonan-7-ylmethyl, N, N, N' -trimethylethylenediamine, N, N-dimethylethylenediamine, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hexahydropyranyl, tetrahydrofuranyl, said 4-methylpiperazin-1-ylcarbonyl, pyrrolidinylmethyl, morpholinomethyl, azetidinylmethyl, piperidinylmethyl, 4- (dimethylamino) piperidin-1-ylmethyl, 4- (3-methoxyacridin-1-yl) piperidin-1-ylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5 ]Nonan-7-ylmethyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hexahydropyranyl, tetrahydrofuranyl may be optionally substituted with one or more substituents independently selected from the group consisting of: fluorine, chlorine, bromine, methyl, ethyl, isopropylA group, cyclopropyl, methoxy, methoxymethyl, methoxyethyl, methylcarbonyl, methoxycarbonyl, oxo, and dimethylamino;

the warhead group is:

x is O or S;

z is N, O or CR ¹⁹ ；

R ¹⁹ Independently a hydrogen atom, methyl, ethyl or cyclopropyl;

m and n are independently 0, 1, 2, 3 or 4;

p is 0, 1, 2 or 3.

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

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in another aspect, the application provides a pharmaceutical composition comprising a compound as described above 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.

In yet another aspect, the present application provides the use of a compound and/or pharmaceutical composition comprising the above in the preparation of an antitumor drug. In certain embodiments, the antineoplastic agent is applied to the following conditions: 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, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid cancer, cholangiocarcinoma, endometrial cancer, multiple myeloma, or mesothelioma.

In certain embodiments, the tumor is a malignancy harboring an EGFR gene mutation; preferably, the EGFR gene mutation is selected from: one or more of the Del19 EGFR gene mutation, the L858R EGFR gene mutation, the T790M EGFR gene mutation, and the C797S EGFR gene mutation.

In yet another aspect, the present application provides a method of treating a tumor in a patient in need thereof, comprising administering to the patient, preferably a mammal, preferably a human, a therapeutically effective amount of a compound or pharmaceutical composition as described above.

In certain embodiments, modes of administration include oral, mucosal, sublingual, ocular, topical, parenteral, rectal, cerebral pool, vaginal, peritoneal, bladder, nasal administration.

In certain embodiments, the tumor comprises: head and neck cancer, melanoma, bladder cancer, esophageal cancer, anaplastic large cell lymphoma, renal cell carcinoma, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, pancreatic cancer, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, non-hodgkin's lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid cancer, cholangiocarcinoma, endometrial cancer, multiple myeloma, or mesothelioma.

In certain embodiments, the present application provides a process for preparing a compound of formula I, comprising the reaction steps of:

(1) Reacting compound 1 with compound 2 under basic conditions to form compound 3;

(2) Subjecting compound 3 to a Mitsunobu reaction or nucleophilic substitution reaction or coupling reaction with compound 4 to form compound 5;

(3) Reducing compound 5 to compound 6;

(4) Reacting compound 6 with BrCN to form compound 7;

(5) Hydrolyzing compound 7 to compound 8;

(6) Intramolecular condensation reaction of compound 8 to form compound 9;

(7) Deprotecting compound 9 or coupling or replacing compound 9 prior to deprotecting compound 10;

(8) Reacting compound 10 with compound 11 to form a compound of formula I;

preferably, the base used in step (1) under alkaline conditions is selected from potassium carbonate;

the base used in the hydrolysis in step (5) is selected from lithium hydroxide.

In certain embodiments, the method of preparing a compound of formula I comprises the following reaction steps:

(2) Reducing compound 3 to compound 11;

(3) Reacting compound 11 with BrCN to form compound 12;

(4) Reacting compound 12 with compound 13 to form compound 14;

(5) Closing compound 14 to form compound 9;

(6) Deprotecting compound 9 or coupling or replacing compound 9 prior to deprotecting compound 10;

(7) Reacting compound 10 with compound 11 to form a compound of formula I;

wherein the method comprises the steps ofWhen R is ¹ R in the case of warhead group ²² Is hydrogen atom, -Y ¹ (CR ^a R ^b ) _q NHR ⁸ 、 R ²⁰ R is R with protecting group ²² Halogen, oxygen group with protecting group, amino group with protecting group, etc., R ¹⁸ 、R ¹⁹ 、R ²¹ 、R ²³ 、R ²⁴ And R is ²⁵ Is R ⁶ The method comprises the steps of carrying out a first treatment on the surface of the When R is ² R in the case of warhead group ²³ is-Y ¹ (CR ^a R ^b ) _q NHR ⁸ 、/> R ²¹ R is R with protecting group ²³ Halogen, oxygen group with protecting group, amino group with protecting group, etc., R ¹⁸ 、R ¹⁹ 、R ²⁰ 、R ²² 、R ²⁴ And R is ²⁵ Is R ⁶ The method comprises the steps of carrying out a first treatment on the surface of the When R is ⁴ R in the case of warhead group ²⁴ is-Y ¹ (CR ^a R ^b ) _q NHR ⁸ 、/> R ¹⁸ R is R with protecting group ²⁴ Halogen, oxygen group with protecting group, amino group with protecting group, etc., R ¹⁹ 、R ²⁰ 、R ²¹ 、R ²² 、R ²³ And R is ²⁵ Is R ⁶ The method comprises the steps of carrying out a first treatment on the surface of the Or when R is ⁵ R in the case of warhead group ²⁵ is-Y ¹ (CR ^a R ^b ) _q NHR ⁸ 、 R ¹⁹ R is R with protecting group ²⁵ Halogen, oxygen group with protecting group, amino group with protecting group, etc., R ¹⁸ 、R ²⁰ 、R ²¹ 、R ²² 、R ²³ And R is ²⁴ Is R ⁶ ；

Among the above groups having a protecting group, the protecting group includes, but is not limited to, t-butoxycarbonyl, benzyloxycarbonyl, benzyl or dimethoxybenzyl;

L is hydroxy, halogen or a leaving group;

furthermore, A, B, D, E, G, R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁸ 、R ^a 、R ^b 、R ^c 、R ^d 、Y ¹ 、Y ² 、Y ³ Z, X, p, q, m, n, t, warhead groups are as defined above;

other features and advantages of the present invention will be apparent from the detailed description that follows. The following examples and embodiments are intended to clearly illustrate the technical aspects of the present invention and the technical effects and advantages thereof, and do not limit the scope of the present invention.

Structure of macrocyclic compounds as EGFR kinase inhibitors

The present invention relates to compounds of formula I or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopic label, nitroxide, prodrug molecule, hydrate or solvate thereof:

ring A and ring B are each independently 6-10 membered monocyclic or bicyclic aromatic ring, 5-10 membered containing 1-4 heteroatoms independently selected from N, O and SA monocyclic heteroaryl ring or bicyclic heteroaryl ring, or a 5-10 membered monocyclic heterocycle or bicyclic heterocycle containing 1-4 heteroatoms independently selected from N, O and S, said 6-10 membered monocyclic heteroaryl ring or bicyclic heteroaryl ring, a 5-10 membered monocyclic heteroaryl ring or bicyclic heteroaryl ring containing 1-4 heteroatoms independently selected from N, O and S, or a 5-10 membered monocyclic heterocycle or bicyclic heterocycle containing 1-4 heteroatoms independently selected from N, O and S may be optionally substituted with one or more substituents independently selected from: c (C) _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, halo C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkoxy, C _3-6 Cycloalkyl, halo C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, halo C _3-6 Cycloalkoxy radicals C _1-6 alkoxy-C _1-6 Alkyl, hydroxy-C _1-6 Alkyl, amino-C _1-6 Alkyl, C _1-6 alkyl-amino-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl, oxo, halogen, hydroxy, cyano-C _1-6 Alkyl, amino, C _1-6 Alkyl-amino, di (C) _1-6 Alkyl) -amino, C _3-6 Cycloalkyl-amino, C _1-6 Alkyl-carbonyl, C _3-6 Cycloalkyl-carbonyl, C _1-6 Alkyl-amino-acyl, di (C) _1-6 Alkyl) -amino-acyl, C _3-6 Cycloalkyl-amino-acyl, C _1-6 Alkyl-acyl-amino, substituted with one or more R ^m Substituted or unsubstituted 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O and S, substituted with one or more R ^m Substituted or unsubstituted 6-10 membered aryl, substituted with one or more R ^m Substituted or unsubstituted 4-7 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O and S, substituted with one or more R ^m Substituted or unsubstituted 4-7 membered heterocyclyl-C containing 1-2 heteroatoms independently selected from N, O and S _1-6 Alkyl, -S (=o) ₂ R ^a 、-S(＝O) ₂ NR ^a R ^b 、-P(＝O)R ^a R ^b 、-P(＝O)R ^a NR ^b R ^c 、-P(＝S)R ^a R ^b 、-P(＝S)R ^a NR ^b R ^c 、R ^b S(＝O) ₂ N(R ^a ) -, wherein the C _1-6 Alkyl, C _2-6 Alkenyl, halo C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkoxy, C _3-6 Cycloalkyl, halo C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, halo C _3-6 Cycloalkoxy radicals C _1-6 alkoxy-C _1-6 Alkyl, hydroxy-C _1-6 Alkyl, amino-C _1-6 Alkyl, C _1-6 alkyl-amino-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl, cyano-C _1-6 Alkyl, C _1-6 Alkyl-amino, di (C) _1-6 Alkyl) -amino, C _3-6 Cycloalkyl-amino, C _1-6 Alkyl-carbonyl, C _3-6 Cycloalkyl-carbonyl, C _1-6 Alkyl-amino-acyl, di (C) _1-6 Alkyl) -amino-acyl, C _3-6 Cycloalkyl-amino-acyl, C _1-6 Alkyl-acyl-amino, substituted with one or more R ^m Substituted or unsubstituted 4-7 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O and S, substituted with one or more R ^m Substituted or unsubstituted 4-7 membered heterocyclyl-C containing 1-2 heteroatoms independently selected from N, O and S _1-6 Alkyl, -S (=o) ₂ R ^a 、-S(＝O) ₂ NR ^a R ^b 、-P(＝O)R ^a R ^b 、-P(＝O)R ^a NR ^b R ^c 、-P(＝S)R ^a R ^b 、-P(＝S)R ^a NR ^b R ^c 、R ^b S(＝O) ₂ N(R ^a ) Optionally together with the carbon atoms to which they are attached, form a ring, said C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, halo C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkoxy, C _3-6 Cycloalkyl, halo C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, halo C _3-6 Cycloalkoxy radicals C _1-6 alkoxy-C _1-6 Alkyl, hydroxy-C _1-6 Alkyl, amino-C _1-6 Alkyl, C _1-6 alkyl-amino-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl, cyano-C _1-6 Alkyl, C _1-6 Alkyl-amino, di (C) _1-6 Alkyl) -amino, C _3-6 Cycloalkyl-amino, C _1-6 Alkyl-carbonyl, C _3-6 Cycloalkyl-carbonyl, C _1-6 Alkyl-amino-acyl, di (C) _1-6 Alkyl) -amino-acyl, C _3-6 Cycloalkyl-amino-acyl, C _1-6 Alkyl-acyl-amino, substituted with one or more R ^m Substituted or unsubstituted 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O and S, substituted with one or more R ^m Substituted or unsubstituted 6-10 membered aryl, substituted with one or more R ^m Substituted or unsubstituted 4-7 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O and S, substituted with one or more R ^m Substituted or unsubstituted 4-7 membered heterocyclyl-C containing 1-2 heteroatoms independently selected from N, O and S _1-6 Alkyl-may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, amino, hydroxy, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 alkoxy-C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkyl-amino, di (C) _1-6 Alkyl) -amino, 4-7 membered heterocyclyl and 4-7 membered heterocyclyl-C _1-6 An alkyl group;

R ¹ 、R ² 、R ⁴ and R is ⁵ Wherein 1 is a warhead group, when R ¹ R in the case of warhead group ² 、R ⁴ And R is ⁵ Each independently is R ⁶ The method comprises the steps of carrying out a first treatment on the surface of the When R is ² R in the case of warhead group ¹ 、R ⁴ And R is ⁵ Each independently is R ⁶ The method comprises the steps of carrying out a first treatment on the surface of the When R is ⁴ R in the case of warhead group ¹ 、R ² And R is ⁵ Each independently is R ⁶ The method comprises the steps of carrying out a first treatment on the surface of the Or when R is ⁵ R in the case of warhead group ¹ 、R ² And R is ⁴ Each independently ofThe standing position is R ⁶ ；

R ³ And R is ⁶ Each independently is a 3-11 membered monocyclic or bridged or spiro heterocyclyl-C containing 1-3 heteroatoms independently selected from N, O or S _0-3 Alkyl, amino, C _1-6 Alkyl-amino, C _3-6 Cycloalkyl-amino, di (C) _1-6 Alkyl) -amino, C _1-6 alkoxy-C _1-6 Alkyl-amino, 4-6 membered heterocyclyl-C _1-6 Alkyl-amino, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl-amino, di (C) _1-6 Alkyl) -amino-C _1-6 alkoxy-C _1-6 Alkyl-amino, hydrogen atom, halogen, hydroxy, cyano, C _1-6 Alkyl, halogenated C _1-6 Alkyl, hydroxy-C _1-6 Alkyl, hydroxy-C _1-6 Alkoxy, C _1-6 alkoxy-C _1-6 Alkyl, cyano-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl, C _3-6 cycloalkyl-amino-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 alkoxy-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 alkyl-amino-C _1-6 Alkyl, C _1-6 Alkoxy, di (C) _1-6 Alkyl) -amino-C _1-6 Alkoxy, C _1-6 Alkyl-carbonyl, C _3-6 Cycloalkyl-carbonyl, C _1-6 Alkoxy-carbonyl, 3-7 membered heterocyclyl-carbonyl containing 1-3 heteroatoms independently selected from N, O or S, C _1-6 alkyl-carbonyl-C _1-6 Alkyl, C _1-6 alkyl-aminoacyl-C _1-6 Alkyl, 3-7 membered heterocyclyl-carbonyl-C containing 1-3 heteroatoms independently selected from N, O or S _1-6 Alkyl, C _1-6 alkyl-OC (O) -C _1-6 Alkyl, or 3-11 membered monocyclic or bridged or spiro heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O or S, said 3-11 membered monocyclic or bridged or spiro heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O or S-C _0-3 Alkyl, C _1-6 Alkyl-amino, C _3-6 Cycloalkyl-amino, di (C) _1-6 Alkyl) -amino, C _1-6 alkoxy-C _1-6 Alkyl-amino, 4-6 membered heterocyclyl-C _1-6 Alkyl-amino groupDi (C) _1-6 Alkyl) -amino-C _1-6 Alkyl-amino, di (C) _1-6 Alkyl) -amino-C _1-6 alkoxy-C _1-6 Alkyl-amino, C _1-6 Alkyl, halogenated C _1-6 Alkyl, hydroxy-C _1-6 Alkyl, hydroxy-C _1-6 Alkoxy, C _1-6 alkoxy-C _1-6 Alkyl, cyano-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl, C _3-6 cycloalkyl-amino-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 alkoxy-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 alkyl-amino-C _1-6 Alkyl, C _1-6 Alkoxy, di (C) _1-6 Alkyl) -amino-C _1-6 Alkoxy, C _1-6 Alkyl-carbonyl, C _3-6 Cycloalkyl-carbonyl, C _1-6 Alkoxy-carbonyl, 3-7 membered heterocyclyl-carbonyl containing 1-3 heteroatoms independently selected from N, O or S, C _1-6 alkyl-carbonyl-C _1-6 Alkyl, C _1-6 alkyl-aminoacyl-C _1-6 Alkyl, 3-7 membered heterocyclyl-carbonyl-C containing 1-3 heteroatoms independently selected from N, O or S _1-6 Alkyl, C _1-6 alkyl-OC (O) -C _1-6 An alkyl group, or a 3-11 membered monocyclic or bridged or spiro heterocyclic group containing 1-3 heteroatoms independently selected from N, O or S, may be optionally substituted with one or more substituents independently selected from the group consisting of: c (C) _1-6 Alkyl, halogenated C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkoxy, C _3-6 Cycloalkyl, halo C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, halo C _3-6 Cycloalkoxy radicals C _1-6 alkoxy-C _1-6 Alkyl, C _3-6 cycloalkyl-C _1-6 Alkyl, C _1-6 alkyl-O (O) C-, C _1-6 Alkyl-carbonyl, oxo, halogen, hydroxy, C _1-6 Alkylamino, di (C) _1-6 Alkyl) amino, substituted with 1 or more C _1-6 Alkyl, C _1-6 Alkoxy, oxo, halogen substituted 5-7 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O or S;

warhead group is R ⁷ 、-Y ¹ (CR ^a R ^b ) _q NR ⁷ R ⁸ 、

R ⁷ Is thatOr C _1-6 Alkyl C (O);

m is a bond, is bound by one or more R ^m Substituted or unsubstituted-C _1-6 Alkyl-, substituted by one or more R ^m Substituted or unsubstituted-C _3-6 Cycloalkyl-, substituted by one or more R ^m Substituted or unsubstituted-C _3-6 cycloalkyl-C _1-6 Alkyl-, substituted by one or more R ^m Substituted or unsubstituted-C _1-6 alkyl-amino-C _1-6 Alkyl-, substituted by one or more R ^m Substituted or unsubstituted containing 1-2 units-4-7 membered heterocyclyl-, substituted with one or more R, in situ selected from N, O and S heteroatoms ^m Substituted or unsubstituted-4-7 membered heterocyclyl-C containing 1-2 heteroatoms independently selected from N, O and S _1-6 Alkyl-;

R ¹¹ is hydrogen atom, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy radicals C _1-6 alkoxy-C _1-6 Alkyl, C _3-6 cycloalkyl-C _1-6 Alkyl, amino, C _1-6 Alkylamino, di (C) _1-6 Alkyl) amino, 4-10 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O or S, said C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy radicals C _1-6 alkoxy-C _1-6 Alkyl, C _3-6 cycloalkyl-C _1-6 Alkyl, C _1-6 Alkylamino, di (C) _1-6 Alkyl) amino, 4-10 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O or S, may be optionally substituted with one or more groups independently selected from: halogen, hydroxy, cyano;

R ¹² and R is ¹³ Each independently is a hydrogen atom, C _1-6 Alkyl, C _3-7 Cycloalkyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O or S, or R ¹² And R is ¹³ With NR ¹² R ¹³ Wherein N together form a 4-10 membered heterocyclic group containing 1-3 heteroatoms independently selected from N, O or S, said C _1-6 Alkyl, C _3-7 Cycloalkyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O or S, or R ¹² And R is ¹³ With NR ¹² R ¹³ N in (a) together formA 4-10 membered heterocyclic group containing 1-3 heteroatoms independently selected from N, O or S may be optionally substituted with one or more substituents independently selected from the group consisting of: c (C) _1-6 Alkyl, halogenated C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkoxy, C _3-6 Cycloalkyl, halo C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, halo C _3-6 Cycloalkoxy, halogen, hydroxy, cyano, oxo, C _1-6 Alkyl-amino, halo C _1-6 Alkyl-amino, di (C) _1-6 Alkyl) -amino, C _3-6 Cycloalkyl-amino, substituted by one or more R ^m Substituted or unsubstituted 3-7 membered heterocyclic groups containing N, O or S heteroatoms and C _1-6 Alkyl-carbonyl;

Ring E is a 4-7 membered saturated or partially unsaturated heterocycle containing 1-3 heteroatoms independently selected from N, O or S, or a 5-10 membered bridged or spiro saturated or partially unsaturated heterocycle containing 1-5 heteroatoms independently selected from N, O or S, which 4-7 membered saturated or partially unsaturated heterocycle and 5-10 membered bridged or spiro saturated or partially unsaturated heterocyclyl may optionally be independently substituted with one or more R ^m Substituted;

q and t are each independently 0, 1, 2 or 3;

w is 1, 2 or 3;

x is O, S, CR ¹⁷ R ¹⁸ 、NR ¹⁷ CO or S (O) ₂ ；

R ¹⁹ independently is a hydrogen atom, C _1-6 Alkyl or C _3-6 Cycloalkyl;

m and n are independently 0, 1, 2, 3 or 4;

p is 0, 1, 2 or 3.

preferably, in formula I, ring a and ring B are each independently a benzene ring, pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, pyrrole, thiophene, imidazole, oxazole, isoxazole, furan, thiazole, isothiazole, which may be optionally substituted with one or more substituents independently selected from the group consisting of: c (C) _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, halo C _1-4 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkoxy, C _3-6 Cycloalkyl, halo C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, halo C _3-6 Cycloalkoxy radicals C _1-6 alkoxy-C _1-6 Alkyl, hydroxy-C _1-6 Alkyl, amino-C _1-6 Alkyl, C _1-6 alkyl-amino-C _1-6 Alkyl, oxo, halogen, hydroxy, cyano-C _1-6 Alkyl, amino, C _1-6 Alkyl-amino, di (C) _1-6 Alkyl) -amino, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl and C _3-6 Cycloalkyl-amino.

R ³ And R is ⁶ Each independently is a 3-11 membered monocyclic or bridged or spiro heterocyclyl-C containing 1-3 heteroatoms independently selected from N, O or S _0-3 Alkyl, hydrogen atom, halogen, hydroxy, cyano, C _1-6 Alkyl, halogenated C _1-6 Alkyl, hydroxy-C _1-6 Alkyl, hydroxy-C _1-6 Alkoxy, C _1-6 alkoxy-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl, C _3-6 cycloalkyl-amino-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 alkoxy-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 alkyl-amino-C _1-6 Alkyl, C _1-6 Alkoxy, di (C) _1-6 Alkyl) -amino-C _1-6 Alkoxy, C _1-6 Alkyl-carbonyl, C _1-6 Alkoxy-carbonyl, or 3-7 membered heterocyclyl-carbonyl containing 1-3 heteroatoms independently selected from N, O or S, said 3-11 membered monocyclic or bridged or spiro heterocyclyl-C containing 1-3 heteroatoms independently selected from N, O or S _0-3 Alkyl, C _1-6 Alkyl, halogenated C _1-6 Alkyl, hydroxy-C _1-6 Alkyl, hydroxy-C _1-6 Alkoxy, C _1-6 alkoxy-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl, C _3-6 cycloalkyl-amino-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 alkoxy-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino-C _1-6 alkyl-amino-C _1-6 Alkyl, C _1-6 Alkoxy, di (C) _1-6 Alkyl) -amino-C _1-6 Alkoxy, C _1-6 Alkyl-carbonyl, C _1-6 Alkoxy-carbonyl, or 3-7 membered heterocyclyl-carbonyl containing 1-3 heteroatoms independently selected from N, O, or S, may be optionally substituted with one or more substituents independently selected from the group consisting of: c (C) _1-6 Alkyl, halogenated C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy radicals C _1-6 alkoxy-C _1-6 Alkyl, C _3-6 cycloalkyl-C _1-6 Alkyl, C _1-6 alkyl-O (O) C-, C _1-6 Alkyl-carbonyl, oxo, halogen, hydroxy, C _1-6 Alkylamino, di (C) _1-6 Alkyl) -amino groups, optionally substituted with 1 or more C _1-6 Alkyl, C _1-6 Alkoxy, oxo, halogen substituted 5-7 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O or S;

warhead group is R ⁷ 、-Y ¹ (CR ^a R ^b ) _q NR ⁷ R ⁸ 、

R ⁷ Is that

Y ¹ 、Y ² And Y ³ Each independently is a bond, O or NR ⁸ ；

R ⁸ Is hydrogen atom, C _1-6 Alkyl or C _3-6 Cycloalkyl;

R ⁹ and R is ¹⁰ Independently a hydrogen atomHalogen or cyano;

R ^a 、R ^b 、R ^c and R is ^d Each independently is a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, a cyano group, an oxo group, or C _1-6 Alkyl, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 alkoxy-C _1-6 Alkyl, C _1-6 Alkyl-amino, C _1-6 alkyl-amino-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino, di (C) _1-6 Alkyl) -amino-C _1-6 Alkyl, C _3-6 Cycloalkyl-amino, 3-7 membered heterocyclyl-C _1-6 Alkyl, said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 alkoxy-C _1-6 Alkyl, C _1-6 Alkyl-amino, C _1-6 alkyl-amino-C _1-6 Alkyl, di (C) _1-6 Alkyl) -amino, di (C) _1-6 Alkyl group) -amino-C _1-6 Alkyl, C _3-6 Cycloalkyl-amino, 3-7 membered heterocyclyl-C _1-6 The alkyl group may be optionally substituted with one or more of the following groups: halogen, hydroxy, cyano, C _1-6 Alkyl, C _3-6 Cycloalkyl and C _1-6 An alkoxy group;

q and t are each independently 0, 1, 2 or 3;

w is 1, 2 or 3;

R ³ And R is ⁶ Each independently is a hydrogen atom, halogen, methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, cyano, hydroxy, hydroxymethyl, methoxymethyl, ethoxymethyl, methylcarbonyl, methoxycarbonyl, 4-methylpiperazin-1-ylcarbonyl, dimethylaminomethyl, dimethylaminoethoxy, hydroxyethoxy, dimethylaminoethoxymethyl, N, N, N' -trimethylethylenediamine methyl, N, N-dimethylethylenediamine methyl, pyrrolidinylmethyl, morpholinomethyl, azetidinylmethyl, piperidinylmethyl, 4- (dimethylamino) piperidin-1-ylmethyl, 4- (3-methoxyacridin-1-yl) piperidin-1-ylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5 ] ]Nonan-7-ylmethyl, N, N, N' -trimethylethylenediamine, N, N-dimethylethylenediamine, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hexahydropyranyl, tetrahydrofuranyl, said 4-methylpiperazin-1-ylcarbonyl, pyrrolidinylmethyl, morpholinomethyl, azetidinylmethyl, piperidinylmethyl, 4- (dimethylamino) piperidin-1-ylmethyl, 4- (3-methoxyacridin-1-yl) piperidin-1-ylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethylRadical, 2- (dimethylamino) -7-azaspiro [3.5 ]]Nonan-7-ylmethyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hexahydropyranyl, tetrahydrofuranyl may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, methoxymethyl, methoxyethyl, methylcarbonyl, methoxycarbonyl, oxo and dimethylamino;

the warhead group is:

in certain embodiments, X is O or S;

z is N, O, S, -amino-acyl, -acyl-amino, or CR ¹⁹ ；

R ¹⁹ Independently is a hydrogen atom, C _1-6 Alkyl or C _3-6 Cycloalkyl;

preferably, in formula I, Z is N, O or CR ¹⁹ ；

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 application.

Representing the ligation site.

The minimum and maximum values of the carbon atom content in the hydrocarbon group are represented by prefixes, for example, prefixes (C _a-b ) Alkyl means any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, (C) _1-6 ) Alkyl refers to alkyl groups containing 1 to 6 carbon atoms. The alkyl group is branched or straight chain.

The atoms described in the compounds of the application include isotopes thereof, for example, hydrogen may be deuterium or tritium.

"alkyl" refers to a straight or branched, monovalent, saturated hydrocarbon group including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and the like. Preferably C _1-8 An alkyl group. More preferably C _1-6 An alkyl group. More preferably C _1-4 An alkyl group.

"cycloalkyl" refers to a saturated monocyclic, bicyclic, spiro, fused or bridged cycloalkyl group, possibly in combination with other groups. Cycloalkyl groups include, but are not limited to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Preferably C _3-8 Cycloalkyl groups. More preferably C _3-6 Cycloalkyl groups. More preferably C _3-4 Cycloalkyl groups.

"alkenyl" refers to a straight-chain, branched or cyclic hydrocarbon group containing one or more double bonds, including but not limited to ethenyl, propenyl, (E) -2-methyl vinyl, (Z) -2-methyl vinyl, (E) -but-2-enyl, (Z) -but-2-enyl, (E) -but-1-enyl, and (Z) -but-1-enyl. Preferably C _2-6 Alkenyl groups. More preferably C _2-4 Alkenyl groups.

"alkynyl" refers to a straight-chain, branched or cyclic hydrocarbon group containing one or more triple bonds, including but not limited to ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl. Preferably C _2-6 Alkynyl groups. More preferably C _2-4 Alkynyl groups.

"alkoxy" refers to a straight or branched, monovalent, saturated alkyl group bonded to an oxygen atom and includes, but is not limited to, groups such as methoxy, ethoxy, propoxy, butoxy, isobutoxy, t-butoxy, and the like. Preferably C _1-8 An alkoxy group. More preferably C _1-6 An alkoxy group. More preferably C _1-4 An alkoxy group.

"halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine and bromine.

"haloalkyl" refers to an alkyl group as defined herein wherein one or more hydrogens have been presentSubstituted by identical or different halogens. Including but not limited to e.g. -CH ₂ Cl，-CHF ₂ ，-CH ₂ CF ₃ ，-CH ₂ CCl ₃ Perfluoroalkyl (e.g., -CF) ₃ ) Etc.

"aryl" refers to a substituted or unsubstituted monocyclic or polycyclic aromatic group including, but not limited to, phenyl, naphthyl, for example. Preferably 6-10 membered monocyclic or bicyclic aromatic groups. More preferably phenyl or naphthyl. Most preferred is phenyl.

"heterocyclyl" means a substituted or unsubstituted 3-10 membered non-aromatic monocyclic saturated ring system containing 1 to 3 heteroatoms independently selected from N, O, or S, the remaining ring atoms being carbon atoms. Examples of heterocyclyl moieties include, but are not limited to: azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, oxopiperidinyl, oxopiperazinyl, oxohomopiperazinyl, tetrahydrofuranyl, imidazolinyl, morpholinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, quinuclidinyl, thiadiazolidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and the like. Preferably a 4-7 membered heterocyclyl. More preferably a 4-6 membered heterocyclic group.

"heteroaryl" means a substituted or unsubstituted 5-or 6-membered single heteroaromatic ring system, or a substituted or unsubstituted 9-or 10-membered fused or double heteroaromatic ring system containing 1 to 4 heteroatoms independently selected from N, O, or S, with the remaining ring atoms being carbon atoms. Examples of heteroaryl moieties include, but are not limited to: thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, benzimidazolyl or benzothiazolyl.

"bridged ring" means a polycyclic group wherein any two rings share two atoms not directly attached, may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system, and the ring atoms may be all carbon atoms or one or more ring atoms may be selected from the group consisting of N, O, S, SO, or SO ₂ . Preferably is7-10 rings.

"Spiro" refers to a polycyclic group having any two rings sharing carbon atoms, which may contain one or more double bonds, but no one ring has a fully conjugated pi-electron system, which may be a full carbon atom or in which one or more ring atoms are selected from N, O, S, SO or SO ₂ . Preferably 5-10 rings.

The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic group, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.

One cyclic group may be bonded to another group in a variety of ways. If the bonding means is not explicitly defined, the representation includes all possible means. For example, "pyridyl" includes 2-, 3-, or 4-pyridyl, while "thienyl" includes 2-or 3-thienyl.

"pharmaceutically acceptable salts" refers to conventional acid or base addition salts which retain the biological effectiveness and properties of the compounds of formula I, formed from suitable 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 acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids. Such as acetic acid, propionic acid, glycolic acid, oxalic acid, stearic acid, ascorbic acid, p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, oxalic acid, succinic acid, citric acid, maleic acid, hydroxymaleic acid, lactic acid, fumaric acid, tartaric acid, malic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, mandelic acid and the like. Examples of base addition salts include those derived from inorganic acids and from organic acids, such as ammonium, calcium, ferric, aluminum, sodium, potassium, zinc, magnesium salts. The organic base includes salts of primary, secondary and tertiary amines such as trimethylamine, triethylamine, tripropylamine, diethanolamine, ethylenediamine, ethanolamine, and the like. Chemical modification of pharmaceutical compounds (i.e., drugs) to salts is a technique well known to the pharmaceutical chemist to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds.

"prodrug" refers to a prodrug that can be converted in vivo to the structure of a compound of the application and pharmaceutically acceptable salts thereof.

Process for preparing macrocyclic compounds as EGFR kinase inhibitors

The application also relates to a method for preparing the compound of the formula I. The compounds of the present application may be prepared by any conventional means. Suitable methods for synthesizing these compounds are provided in the examples. In a multi-step synthetic route, the order of the reactions may be adjusted in specific situations.

(3) Reducing compound 5 to compound 6;

(4) Reacting compound 6 with BrCN to form compound 7;

(5) Hydrolyzing compound 7 to compound 8;

(6) Intramolecular condensation reaction of compound 8 to form compound 9;

(8) Reacting compound 10 with compound 11 to form a compound of formula I;

the base used in the hydrolysis in step (5) is selected from lithium hydroxide.

(2) Reducing compound 3 to compound 11;

(3) Reacting compound 11 with BrCN to form compound 12;

(4) Reacting compound 12 with compound 13 to form compound 14;

(5) Closing compound 14 to form compound 9;

(7) Reacting compound 10 with compound 11 to form a compound of formula I;

preferably, the base used in the alkaline condition in step (1) is selected from potassium carbonate

Wherein when R is ¹ R in the case of warhead group ²² Is hydrogen atom, -Y ¹ (CR ^a R ^b ) _q NHR ⁸ 、 R ²⁰ R is R with protecting group ²² Halogen, oxygen group with protecting group, amino group with protecting group, etc., R ¹⁸ 、R ¹⁹ 、R ²¹ 、R ²³ 、R ²⁴ And R is ²⁵ Is R ⁶ The method comprises the steps of carrying out a first treatment on the surface of the When R is ² R in the case of warhead group ²³ is-Y ¹ (CR ^a R ^b ) _q NHR ⁸ 、/> R ²¹ Is provided with a protecting groupR of the group ²³ Halogen, oxygen group with protecting group, amino group with protecting group, etc., R ¹⁸ 、R ¹⁹ 、R ²⁰ 、R ²² 、R ²⁴ And R is ²⁵ Is R ⁶ The method comprises the steps of carrying out a first treatment on the surface of the When R is ⁴ R in the case of warhead group ²⁴ is-Y ¹ (CR ^a R ^b ) _q NHR ⁸ 、/> R ¹⁸ R is R with protecting group ²⁴ Halogen, oxygen group with protecting group, amino group with protecting group, etc., R ¹⁹ 、R ²⁰ 、R ²¹ 、R ²² 、R ²³ And R is ²⁵ Is R ⁶ The method comprises the steps of carrying out a first treatment on the surface of the Or when R is ⁵ R in the case of warhead group ²⁵ is-Y ¹ (CR ^a R ^b ) _q NHR ⁸ 、/> R ¹⁹ R is R with protecting group ²⁵ Halogen, oxygen group with protecting group, amino group with protecting group, etc., R ¹⁸ 、R ²⁰ 、R ²¹ 、R ²² 、R ²³ And R is ²⁴ Is R ⁶ ；

l is hydroxy, halogen or a leaving group;

furthermore, A, B, D, E, G, R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁸ 、R ^a 、R ^b 、R ^c 、R ^d 、Y ¹ 、Y ² 、Y ³ Z, X, p, q, m, n, t, warhead groups as defined aboveMeaning;

macrocyclic compound pharmaceutical compositions as EGFR kinase inhibitors

The invention also provides pharmaceutical compositions comprising the compounds as EGFR kinase inhibitors and a pharmaceutically acceptable carrier or excipient.

The term "pharmaceutical composition" as referred to herein means that one or more of the compounds of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is admixed with other chemical ingredients, such as a pharmaceutically acceptable carrier, excipient or diluent. The purpose of the pharmaceutical composition is to facilitate the process of administration to animals.

By "pharmaceutically acceptable carrier" is meant a pharmaceutically acceptable substance, ingredient or medium, such as a liquid or solid filler, diluent, excipient, solvent or potting material, which participates in the loading or transfer of the compounds of the present invention from one location, body fluid, tissue, organ (internal or external), or body part to another location, body fluid, organ (internal or external), or body part. The pharmaceutically acceptable carrier may be a medium, diluent, excipient or other material that is not overly toxic or otherwise adverse to the animal tissue and that can be used to contact the animal tissue. Typical pharmaceutically acceptable carriers include sugars, starches, celluloses, maltose, tragacanth, gelatin, ringer's solution, alginic acid, physiological saline, buffers and the like.

Each pharmaceutically acceptable carrier should be compatible with the other ingredients, e.g., formulation with the compounds provided herein, without undue toxicity, irritation, allergic response, immunogenicity, or other problems or complications commensurate with a reasonable benefit/risk ratio, for a living organism tissue or organ.

Some pharmaceutically acceptable carrier materials include: (1) saccharides 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) tragacanth powder; (5) maltose; (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 glycerol, sorbitol, mannitol and polyethylene glycol; (12) lipids such as ethyl oleate, ethyl laurate; (13) agar gel; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) sterilizing pyrogen-free water; (17) physiological saline; (18) ringer's solution; (19) alcohols such as ethanol and propanol; (20) phosphate buffer; (21) Other non-toxic compatible substances in pharmaceutical dosage forms, such as acetone.

The pharmaceutical composition may include pharmaceutically acceptable excipients to mimic physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, and the like, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, and the like.

The pharmaceutical ingredients may 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 and processes for preparing pharmaceutical compositions are well known and can be prepared according to conventional techniques, such as provided in Remington, the Science and Practice of Pharmacy (Gennaro ed.20th edition, williams & Wilkins PA, USA) (2000).

In certain embodiments, the compounds or pharmaceutical compositions provided herein may be formulated in a dosage form suitable for drug release by both injectable routes (e.g., subcutaneous, intravenous, intramuscular, arterial, intrathecal, intracapsular, intraframe, intracardiac, intradermal, intraperitoneal, transtracheal, epidermal, intraarticular, subcapsular, subarachnoid, intraspinal, intrasternal, and/or infusion) and non-injectable routes (e.g., oral, enteral, buccal, nasal, intranasal, mucosal, epidermal, patch, dermal, ophthalmic, pulmonary, sublingual, rectal, vaginal, or topical).

Suitable dosage forms include, but are not limited to, dosage forms for injectable use 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 administration such as sprays, ointments, pastes, creams, lotions, gels, solutions, pharmaceutical patches and inhalants, dosage forms for vaginal or rectal administration such as suppositories. These dosage forms may be prepared under suitable conditions, depending on the compound and suitable excipients, and methods and processes for preparation are well known, for example from Remington: provided at The Science and Practice of Pharmacy (Gennaro ed.20th edition, williams & Wilkins PA, USA) (2000).

In certain embodiments, the application provides pharmaceutical compositions comprising the compounds described above and a pharmaceutically acceptable carrier or excipient. In certain embodiments, the pharmaceutical composition is a tablet, capsule, pill, granule, powder, suppository, injection, solution, suspension, ointment, patch, lotion, drop, liniment, spray

Use of macrocyclic compound pharmaceutical compositions as EGFR kinase inhibitors

In another aspect, the application provides the use of the above compounds and/or pharmaceutical compositions for the preparation of a medicament and for the treatment of a disease.

In certain embodiments, the present application provides the use of the above-described compounds and/or pharmaceutical compositions in the preparation of an antitumor drug.

In certain embodiments, the present application provides the use of a pharmaceutical composition comprising the above-described compounds in the preparation of an antitumor drug. In certain embodiments, the antineoplastic agent is applied to the following conditions: 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, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid cancer, cholangiocarcinoma, endometrial cancer, multiple myeloma, or mesothelioma.

In certain embodiments, the present application provides a method of treating a tumor in a patient in need thereof, comprising administering to the patient, preferably a mammal, preferably a human, an effective amount of a compound or pharmaceutical composition described above. In certain embodiments, modes of administration include oral, mucosal, sublingual, ocular, topical, parenteral, rectal, cerebral pool, vaginal, peritoneal, bladder, nasal administration.

The compounds or pharmaceutical compositions of the present invention may be administered into the organism by any suitable route, such as oral, intravenous, intranasal, topical, intramuscular, intradermal, transdermal or subcutaneous. In certain embodiments, the mode of administration of the compounds or pharmaceutical compositions contemplated by the present invention includes buccal, mucosal, sublingual, ocular, topical, parenteral, rectal, cerebral pool, vaginal, peritoneal, bladder, nasal administration.

In certain embodiments, the compounds or pharmaceutical compositions of the present invention may be administered simultaneously with the second active agent, which may provide a superimposed or even synergistic effect in vivo. For example, the compounds of the present invention may be combined with the second active agent into one pharmaceutical composition, or administered simultaneously as separate compositions, or sequentially as separate compositions. Second active agents that can be administered concurrently with the compounds of the present invention for the treatment of cancer include, but are not limited to: fluorouracil, doxorubicin, daunorubicin, tamoxifen, leuprolide, goserelin, flutamide, nilutamide, finasteride, dexamethasone, aminoglutethimide, amritride, anastrozole, asparaginase, bacillus calmette-guerin, bicalutamide, bleomycin, busulfan, camptothecin, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, colchicine, cyclophosphamide, and pharmaceutical compositions containing the same cyproterone, cytarabine, dacarbazine, actinomycin d, secomycin, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, adriamycin, epirubicin, estradiol, estramustine, etoposide, exemestane, febuxostat, fludarabine, fludrocortisone, fluorouracil, fluometione, flutamide, gemcitabine, genistein, goserelin tamoxifen, teniposide, testosterone, titanocene dichloride, topotecan, trastuzumab, retinoic acid, vinblastine, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, letrozole, leucovorin, jetstretin, mithramycin, procarbazine, raltitrexed, porphin sodium, rituximab, streptozotocin, suramin, leuprorelin, levamisole, cyclohexanimustine, nitrogen mustard, medroxyprogesterone, megestrol, melphalan, mercaptopurine, sodium mercaptoethane sulfonate, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, nocodazole, octreotide, paclitaxel, pamidronate, thioguanine, triaminothiophosphore, methyl chloride, topotecan Kang Ermao titanium, trastuzumab, retinoic acid, vincristine, neomycin, vindesine, vinorelbine.

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 may be administered concurrently with radiation therapy. In certain embodiments, the compounds provided herein may be used in conjunction with surgery, tumor thermal therapy, ultrasound focus therapy, cryotherapy, or several of the above.

In certain embodiments, the compounds provided herein may be used concurrently with a steroid. Suitable steroids include, but are not limited to: anciclesonide, beclomethasone, betamethasone, budesonide, prednisone, clobetasol, corticosterone, cortisone, prednisolone, desoxymethasone, dexamethasone, diflorasone, diflunisal butyl, glycyrrhetinic acid, fluzacortisone, flumethasone, flunisolide, fluclonide, fluocinolone acetonide, flubutazone, flucortisone acetate, fluprednisolone acetate, fluprednisone, fludronate, fluocinolone acetonide, aldicasone, clobetasol propionate, halciclesonide, halometasone, hydrocortisone, loteprinocarbonate ethyl, meperide, mevalonate, methylprednisone, 6-methylprednisolone, at any furoate, prasone, prednisolone, dexamethasone, and 25-diethylamine acetate.

In certain embodiments, the compounds provided herein may be used concurrently with immunotherapeutic agents. Suitable immunotherapeutic agents include: tumor cell multidrug resistance reversal agents (such as verapamil), rapamycin, mycophenolate mofetil, thalidomide, cyclophosphamide, cyclosporine, and monoclonal antibodies.

Detailed Description

EXAMPLE 1 Synthesis of tert-butyl (2-aminoethyl) (2-hydroxyethyl) carbamate

The first step: 2, 2-trifluoro-N- (2- ((2-hydroxyethyl) amino) ethyl) acetamide

To a 100mL round bottom flask at 0deg.C was added 2- (2-aminoethylamine) ethanol (10.0 g,96.0 mmol), dried diethyl ether (30 mL) and ethyl trifluoroacetate (13.6 g,96.0 mmol) in sequence, and the resulting mixture was stirred at room temperature for 2h with a white precipitate formed. The mixture was filtered, and the filter cake was washed 2 times with diethyl ether (20 mL. Times.2), and dried to give 2, 2-trifluoro-N- (2- ((2-hydroxyethyl) amino) ethyl) acetamide (14.6 g, white solid), yield: 74.9%.

And a second step of: (2-hydroxyethyl) (2- (2, 2-trifluoroacetamido) ethyl) carbamic acid tert-butyl ester

To a dry 500mL round bottom flask was added 2, 2-trifluoro-N- (2- ((2-hydroxyethyl) amino) ethyl) acetamide (13.4 g,0.066 mol), tetrahydrofuran (200 mL) and Boc in sequence at room temperature ₂ O (14.5 g,0.066 mol), the mixture was stirred at room temperature for 6h. After the completion of the reaction, the mixture was concentrated under reduced pressure, water (100 mL) was added, the mixture was extracted with ethyl acetate (150 mL. Times.3), the organic phases were combined, washed with saturated brine (100 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product (2-hydroxyethyl) (2- (2, 2-trifluoroethyl) productAmido) ethyl) tert-butyl carbamate (20.4 g, colorless oil), yield: 100.0%.

MS(ESI ⁺ )m/z＝323.9[M+Na] ⁺ .

And a third step of: (2-aminoethyl) (2-hydroxyethyl) carbamic acid tert-butyl ester

To a 500mL round bottom flask was added tert-butyl (2-hydroxyethyl) (2- (2, 2-trifluoroacetamido) ethyl) carbamate (20.4 g,0.0677 mol), methanol (50 mL), water (10 mL) and potassium carbonate (5.0 g) in this order, and the mixture was stirred at 60℃for 48h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove methanol, water (30 mL) was added to the residue, the ethyl acetate phase was discarded, and the aqueous phase was concentrated under reduced pressure to give crude t-butyl (2-aminoethyl) (2-hydroxyethyl) carbamate (15.8 g, colorless oil). Yield: 91.4%.

MS(ESI ⁺ )m/z＝205.2[M+H] ⁺ .

Example 2.Synthesis of 5-amino-4-methylpentan-1-ol

The first step: (2, 6-dimethylhept-5-en-1-yl) carbamic acid tert-amyl ester

3, 7-Dimethylocta-6-enoic acid (3.5 g,20.56 mmol) was dissolved in toluene (300 mL), warmed to 50deg.C, triethylamine (2.5 g,24.67 mmol) was added followed by slow addition of diphenyl azide phosphate (5.65 g,20.56 mmol), warmed to 70deg.C and stirred for 12h, 2-methylbutan-2-ol (3.6 g,41.16 mmol), warmed to 110deg.C and stirred for 2h, and then 2-methylbutan-2-ol (3.6 g,41.16 mmol) was added. The reaction mixture was stirred at 110℃for 12h. To the obtained residue was added water (100 mL), extracted with ethyl acetate (200 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system petroleum ether/ethyl acetate=6/1 to 5/1 to give tert-amyl (2, 6-dimethylhept-5-en-1-yl) carbamate (2.5 g, colorless oil), yield: 41.5%.

And a second step of: (5-hydroxy-2-methylpentyl) carbamic acid tert-amyl ester

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To a dried 100mL round bottom flask was added tert-amyl (2, 6-dimethylhept-5-en-1-yl) carbamate (2.5 g,10.11 mmol) and methanol (20 mL) in sequence at room temperature, cooled to-78 ℃, slowly ozone was introduced until the reaction system became sky blue, and stirring was continued for 20min until colorless. Cooling to 0 ℃, slowly adding sodium borohydride (0.95 g,25.1 mmol), after the addition, slowly heating to room temperature and stirring for 12h. Concentrating under reduced pressure, and purifying the obtained residue by silica gel column chromatography with eluent system petroleum ether/ethyl acetate=5/1-1/1 to obtain (5-hydroxy-2-methylpentyl) carbamic acid tert-amyl ester (450 mg, colorless oil), yield: 27.9%.

And a third step of: 5-amino-4-methylpentan-1-ol

A dried 100mL round bottom flask was charged with tert-amyl (5-hydroxy-2-methylpentyl) carbamate (450 mg,1.95 mmol) and 4M hydrochloric acid in dioxane (10 mL) sequentially at room temperature, stirred at room temperature for 2h, and concentrated under reduced pressure to give crude 5-amino-4-methylpentan-1-ol (600 mg, colorless oil).

EXAMPLE 3 Synthesis of (R) -1- ((tert-butoxycarbonyl) amino) propan-2-yl 4-toluenesulfonate

The first step: (R) - (2-hydroxypropyl) carbamic acid tert-butyl ester

(R) -1-aminopropane-2-ol (1.5 g,0.02 mol) and DCM (20 mL) were added sequentially to a 100mL round bottom flask at room temperature, cooled to 0deg.C, and Boc was added slowly ₂ O (4.8 g,0.022 mol) and triethylamine (4.0 g,0.04 mol), and stirred at room temperature for 2 hours. Water (20 mL) was added, extraction was performed with dichloromethane (20 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using an eluent system petroleum ether/ethyl acetate=5/1 to give tert-butyl (R) - (2-hydroxypropyl) carbamate (2.4 g, white solid), yield: 68.6%.

And a second step of: (R) -1- ((tert-Butoxycarbonyl) amino) propan-2-yl 4-toluenesulfonate

Tert-butyl (R) - (2-hydroxypropyl) carbamate (900 mg,5.1 mmol) and pyridine (5 mL) were added sequentially to a 100mL round bottom flask at room temperature, cooled to 0deg.C, and p-toluenesulfonyl chloride (1.07 g,5.6 mmol) was slowly added and warmed to room temperature and stirred for 4-5h. Concentrated under reduced pressure, and the resulting residue was purified using thin layer chromatography with eluent system petroleum ether/ethyl acetate=10/1 to give (R) -1- ((tert-butoxycarbonyl) amino) propan-2-yl 4-tosylate (640 mg, white solid), yield: 38.1%.

Examples 4 to 16 Synthesis of p-toluenesulfonate Compound

The following p-toluenesulfonate compounds were prepared according to the method of synthesizing (R) -1- ((t-butoxycarbonyl) amino) propan-2-yl 4-toluenesulfonate (example 3) starting from commercially available Boc-protected or unprotected amino (cyclo) alkyl alcohol or heterocyclyl (alkyl) alcohol.

TABLE 1 p-toluenesulfonate Compounds

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EXAMPLE 17.2 Synthesis of- ((tert-Butoxycarbonyl) amino) ethyl-1, 1-dideuterium 4-tosylate

The first step: tert-butyl (2-hydroxyethyl-2, 2-dideuterium) carbamate

THF (50 mL) was added to a 250mL round bottom flask at room temperature, cooled to 0deg.C, lithium aluminum deuteride (1.66 g,39.6 mmol) was added in portions, then methyl (t-butoxycarbonyl) glycinate (5 g,26.4 mmol) was added in portions and stirred at room temperature overnight. After the reaction was completed, sodium sulfate decahydrate (1.7 g) was added to quench, and filtered, and the filtrate was dried by spin to give crude tert-butyl (2-hydroxyethyl-2, 2-dideuterium) carbamate (3.6 g, yellow oil), yield: 83.7%.

And a second step of: 2- ((Boc) amino) ethyl-1, 1-dideuterium 4-tosylate

In a 100mL round bottom flask was added tert-butyl (2-hydroxyethyl-2, 2-dideuterium) carbamate (2.5 g,15.3 mmol) and dichloromethane (25 mL), followed by p-toluenesulfonyl chloride (4.4 g,23.0 mmol) and triethylamine (3.1 g,30.6 mmol) and stirred at room temperature overnight. After the reaction was completed, the mixture was slowly poured into water, extracted with dichloromethane (50 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude 2- ((t-butoxycarbonyl) amino) ethyl-1, 1-dideuterium 4-tosylate (3.5 g, yellow solid), yield: 72.0%.

MS(ESI ⁺ )m/z＝218.0[M-100+H] ⁺ .

EXAMPLE 18.2 Synthesis of- ((tert-Butoxycarbonyl) (methyl) amino) ethyl 4-tosylate

To a 100mL round bottom flask was added tert-butyl (2-hydroxyethyl) (methyl) carbamate (2.5 g,15.3 mmol) and methylene chloride (25 mL) in sequence at room temperature, followed by p-toluenesulfonyl chloride (4.4 g,23.0 mmol) and triethylamine (3.1 g,30.6 mmol) and stirred at room temperature overnight. After the reaction was completed, quenched by pouring into water, extracted with dichloromethane (50 ml×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude 2- ((t-butoxycarbonyl) (methyl) amino) ethyl 4-tosylate (3.5 g, yellow solid), yield: 72.0%.

EXAMPLE 19N ₆ - ((benzyloxy) carbonyl) -N ₂ Synthesis of- (tert-butoxycarbonyl) lysine

To a 50mL dry round bottom flask was added (tert-butoxycarbonyl) lysine (2 g,8.13 mmol), THF (20 mL) and sodium carbonate (1.7 g,16.26 mmol) in sequence, cbzCl (1.66 g,9.72 mmol) was added dropwise at 0deg.C and stirred overnight at room temperature. After the reaction, water (20 mL) was added for dilution, ethyl acetate was used for washing (20 ml×1), the pH of the aqueous phase was adjusted to 2 with 2M HCl, extraction was performed with ethyl acetate (20 ml×6), the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude N ₆ - ((benzyloxy) carbonyl) -N ₂ - (tert-butoxycarbonyl) lysine (1.8 g, yellow oily), yield: 66.7%.

EXAMPLE 20 Synthesis of tert-butyl 2-formylazetidine-1-carboxylate

1- (tert-butyl) 2-methylazetidine-1, 2-dicarboxylic acid ester (500 mg,2.32 mmol) and methylene chloride (10 mL) were charged into a 100mL three-necked round bottom flask, diisobutylaluminum hydride (4.65 mL,4.65 mmol) was added dropwise thereto under nitrogen protection, and the mixture was stirred at-78℃for 2 hours after the completion of the addition. After the completion of the reaction, water (15 mL) was added, extracted with dichloromethane (5 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl 2-formylazetidine-1-carboxylate (300 mg, yellow liquid), yield: 69.8%.

EXAMPLE 21 Synthesis of 2- (3-bromopropyl) oxirane

5-bromopentene (10.0 g,67.1 mmol) and methylene chloride (200 mL) were sequentially added to a 250mL round bottom flask in an ice-water bath, and then m-chloroperoxybenzoic acid (23.2 g,134.2 mmol) was added in portions and stirred at room temperature for 16h. After the completion of the reaction, sodium hydrogensulfite (20 g) was added in portions to quench the reaction, the resulting mixture was extracted with dichloromethane (50 ml×5), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude 2- (3-bromopropyl) oxirane (7.0 g, colorless transparent liquid), yield: 56.9%.

EXAMPLE 22 Synthesis of 4- (dimethoxymethyl) -2-fluoronitrobenzene

3-fluoro-4-nitrobenzaldehyde (8.5 g,0.05 mol) and trimethyl orthoformate (8.0 g,0.075 mol) were added to methanol (100 mL) at room temperature, followed by addition of p-toluenesulfonic acid (50 mg), warmed to 70℃and stirred for 18h. The reaction mixture was concentrated under reduced pressure to remove methanol, water (50 mL) was added to the obtained residue, extraction was performed with ethyl acetate (100 ml×3), the ethyl acetate phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude 4- (dimethoxymethyl) -2-fluoro-1-nitrobenzene (10.0 g, black oil), yield: 83.1%.

EXAMPLE 23 Synthesis of 4- (benzyloxy) -2-fluoro-1-nitrobenzene

3-fluoro-4-nitrophenol (5.0 g,31.8 mmol), acetonitrile (150 mL), K were added sequentially to a 250mL round bottom flask at room temperature ₂ CO ₃ (13.2 g,95.4 mmol) and bromobenzyl (5.98 g,35.0 mmol) were heated to reflux and stirred for 2h. After the reaction was completed, the residue was concentrated under reduced pressure, and purified by silica gel column chromatography using an eluent system of ethyl acetate/petroleum ether=1/4 to give 4- (benzyloxy) -2-fluoro-1-nitrobenzene (6.5 g, yellow solid), yield: 78.9%.

MS(ESI ⁺ )m/z＝248.0[M+H] ⁺ .

EXAMPLE 24 Synthesis of 3- (benzyloxy) -2-fluoro-1-nitrobenzene

3- (benzyloxy) -2-fluoro-1-nitrobenzene was synthesized by the method of synthesizing 4- (benzyloxy) -2-fluoro-1-nitrobenzene (example 23) using 2-fluoro-3-nitrophenol as the starting material.

EXAMPLE 25 Synthesis of tert-butyl (2-fluoro-3-nitrobenzyl) (methyl) carbamate

The first step: 1- (2-fluoro-3-nitrophenyl) -N-methyl methylamine

To a 250mL round bottom flask was added 2-fluoro-3-nitrobenzaldehyde (1.5 g,8.87 mmol), methanol (50 mL), acetic acid (2 mL) and methylamine (0.330 g,10.64 mmol) in this order at room temperature, stirred at room temperature for 1-2h, then sodium cyanoborohydride (1.12 g,17.74 mmol) was slowly added, and after the addition, stirred at room temperature for 16h. The solvent methanol was removed by concentration under reduced pressure, water (50 mL) was added to the resulting residue, extraction with ethyl acetate (50 mL. Times.3), the ethyl acetate phase was discarded, and the remaining aqueous phase was concentrated under reduced pressure to give crude 1- (2-fluoro-3-nitrophenyl) -N-methylmethylamine (3.0 g, yellow oil).

MS(ESI ⁺ )m/z＝185.1[M+H] ⁺ .

And a second step of: (2-fluoro-3-nitrobenzyl) (methyl) carbamic acid tert-butyl ester

1- (2-fluoro-3-nitrophenyl) -N-methyl methylamine (3.0 g,16.3 mmol), dichloromethane (100 mL), DIPEA (4.2 g,32.58 mmol) and Boc were added sequentially to a dry 500mL round bottom flask at room temperature ₂ O (4.26 g,16.55 mmol) was stirred at room temperature for 3-4h. After the reaction was completed, the residue was concentrated under reduced pressure, water (100 mL) was added, extracted with dichloromethane (100 ml×3), the organic phases were combined, washed with saturated brine (100 ml×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude t-butyl (2-fluoro-3-nitrobenzyl) (methyl) carbamate (4 g, yellow oil), yield: 82.9%.

EXAMPLE 26 Synthesis of tert-butyl (2-fluoro-3-nitrophenylethyl) carbamate

The first step: (Z) -2-fluoro-1-nitro-3- (2-nitrovinyl) benzene

2-fluoro-3-nitrobenzaldehyde (3.0 g,17.7 mmol) was added to acetic acid (20 mL), nitromethane (1.3 g,21.3 mmol) and ammonium acetate (0.82 g,10.6 mmol) were then sequentially added, and after the reaction was completed, stirring was carried out for 4 to 5 hours, water (50 mL) was added to the residue, extraction was carried out with ethyl acetate (100 ml×3), the organic phases were combined, washed with saturated saline (100 ml×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system ethyl acetate/petroleum ether=1/5 to give (Z) -2-fluoro-1-nitro-3- (2-nitrovinyl) benzene (1.8 g, yellow solid), yield: 43.1%.

And a second step of: 2- (2-fluoro-3-nitrophenyl) ethane-1-amine

Boron trifluoride diethyl etherate (15 mL) was added dropwise to a suspension of sodium borohydride (2.2 g,57.7 mmol) in dry tetrahydrofuran (50 mL) at 0 ℃ and stirred at room temperature for 0.25h, then a solution of (Z) -2-fluoro-1-nitro-3- (2-nitrovinyl) benzene (1.8 g,8.5 mmol) in tetrahydrofuran (20 mL) was slowly added dropwise, stirred at reflux for 6.5h, cooled to room temperature, the reaction mixture was slowly added with ice water (30 mL), extracted with dichloromethane (20 mL), the organic phase was discarded, the aqueous phase was adjusted with saturated sodium bicarbonate solution to ph=7-8, then extracted with dichloromethane (20 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give crude 2- (2-fluoro-3-nitrophenyl) ethane-1-amine (3.0 g, yellow solid).

MS(ESI ⁺ )m/z＝185.1[M+H] ⁺ .

And a third step of: (2-fluoro-3-nitrophenylethyl) carbamic acid tert-butyl ester

2- (2-fluoro-3-nitrophenyl) ethane-1-amine (3) was added sequentially to a 500mL round bottom flask at room temperature.0g,16.3 mmol), dichloromethane (100 mL), boc ₂ O (4.3 g,19.5 mmol) and triethylamine (3.3 g,32.6 mmol) were stirred at room temperature for 12h. After the reaction was completed, the residue was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography using an eluent system of ethyl acetate/petroleum ether=1/5 to give tert-butyl (2-fluoro-3-nitrophenyl) carbamate (1.3 g, yellow oil), yield: 26.6%.

MS(ESI ⁺ )m/z＝307.1[M+Na] ⁺ .

EXAMPLE 27 Synthesis of tert-butyl (3- (2-fluoro-3-nitrophenyl) prop-2-yn-1-yl) carbamate

To a 250mL round bottom flask was added, under nitrogen, 1-bromo-2-fluoro-3-nitrobenzene (5.0 g,0.03 mol), 1, 4-dioxane (50 mL), tert-butyl prop-2-yn-1-ylcarbamate (4.23 g,0.03 mol), N, N-diisopropylethylamine (3.4 g,0.03 mol), cuprous iodide (0.04 g,0.2 mmol), bis-triphenylphosphine palladium dichloride (0.64 g,0.9 mol) and tri-tert-butylphosphine (0.15 g,1.3 mol) in that order at room temperature, warmed to 45℃and stirred for 15h. After the completion of the reaction, filtration was performed using celite, ethyl acetate (60 mL) was added to the filtrate, which was washed with water (20 ml×3) and saturated brine (20 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system petroleum ether/ethyl acetate=10/1 to give tert-butyl (3- (2-fluoro-3-nitrophenyl) prop-2-yn-1-yl) carbamate (3.4 g, yellow oil), yield: 45.4%.

EXAMPLE 28 Synthesis of methyl 6- (2-hydroxyphenyl) isonicotinate

The first step: 2-chloro-6- (2-hydroxyphenyl) isonicotinic acid methyl ester

To a 250mL round bottom flask, methyl 2, 6-dichloroisonicotinate (14.0 g,0.068 mol), ethylene glycol dimethyl ether (140 mL), water (30 mL), 2- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) phenol (16.5 g,0.0748 mol), cesium carbonate (33.2 g,0.102 mol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (1.5 g,0.002 mmol) were sequentially added at room temperature, warmed to 90℃and stirred for 16h. Concentrating under reduced pressure, and purifying the obtained residue by silica gel column chromatography with eluent system petroleum ether/ethyl acetate=20/1 to give methyl 2-chloro-6- (2-hydroxyphenyl) isonicotinate (10.0 g, yellow solid), yield: 50.2%.

MS(ESI ⁺ )m/z＝263.7[M+H] ⁺ .

And a second step of: 2- ((Boc) amino) -6- (2-hydroxyphenyl) isonicotinic acid methyl ester

To a 250mL round bottom flask at room temperature under nitrogen was added methyl 2-chloro-6- (2-hydroxyphenyl) isonicotinate (10 g,0.03 mol), dioxane (100 mL), bocNH ₂ (5.32 g,0.04 mol), cesium carbonate (24.0 g,0.07 mmol), xphos (3.6 g,0.0075 mol) and bis (dibenzylideneacetone) palladium (13.3 mg,0.02 mmol), and the mixture was stirred at 85℃for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and purified by silica gel column chromatography using an eluent system petroleum ether/ethyl acetate=20/1 to give methyl 2- ((tert-butoxycarbonyl) amino) -6- (2-hydroxyphenyl) isonicotinate (5.6 g, yellow solid), yield: 42.8%.

MS(ESI ⁺ )m/z＝344.7[M+H] ⁺ .

EXAMPLE 29 Synthesis of 2- (5-hydroxy-1-methyl-1H-pyrazol-4-yl) -6-methyliisonicotinic acid methyl ester

Under nitrogen, methyl 2-chloro-6-methyliisonicotinic acid (20.0 g,0.11 m)ol) anisole (200 mL) was added followed by 1-methyl-5-hydroxypyrazole (21.2 g,0.2156 mol), sodium carbonate (29.4 g,0.237 mol) and PdCl ₂ (dppf) (2.36 g, 0.003mol). Heating to 130 ℃ and stirring for 16H, concentrating under reduced pressure, purifying the obtained residue by silica gel column chromatography with eluent system dichloromethane/methanol=50/1-30/1 to obtain 2- (5-hydroxy-1-methyl-1H-pyrazol-4-yl) -6-methyliisonicotinic acid methyl ester (16.5 g, mauve solid), yield: 55.7%.

MS(ESI ⁺ )m/z＝248.2[M+H] ⁺ .

EXAMPLE 30 Synthesis of 2-methyl-6- (1-methyl-5- ((2- (trimethylsilyl) ethoxy) methoxy) -1H-pyrazol-4-yl) isonicotinic acid

The first step: 2-methyl-6- (1-methyl-5- ((2- (trimethylsilyl) ethoxy) methoxy) -1H-pyrazol-4-yl) isonicotinic acid methyl ester

2- (5-hydroxy-1-methyl-1H-pyrazol-4-yl) -6-methyliisonicotinic acid methyl ester (2.7 g,10.9 mmol) was dissolved in acetonitrile (30 mL) in a 50mL round bottom flask at room temperature, followed by K ₂ CO ₃ (2.41 g,17.44 mmol) and SEMCl (2.91 g,17.44 mmol) were stirred at room temperature for 5h. After the reaction was completed, the reaction mixture was poured into water (20 mL), extracted with ethyl acetate (30 ml×3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with an eluent system of ethyl acetate/petroleum ether=1/10 to 1/5 to give methyl 2-methyl-6- (1-methyl-5- ((2- (trimethylsilyl) ethoxy) methoxy) -1H-pyrazol-4-yl) isonicotinate (2.4 g, yellow oil), yield: 55.1%.

MS(ESI ⁺ )m/z＝377.9[M+H] ⁺ .

And a second step of: 2-methyl-6- (1-methyl-5- ((2- (trimethylsilyl) ethoxy) methoxy) -1H-pyrazol-4-yl) isonicotinic acid

To a dry 100mL round bottom flask was added methyl 2-methyl-6- (1-methyl-5- ((2- (trimethylsilyl) ethoxy) methoxy) -1H-pyrazol-4-yl) isonicotinate (2.4 g,6.4 mmol), THF (10 mL) and 1M aqueous LiOH (20 mL) in sequence at room temperature, and stirred at room temperature for 5H. After the reaction was completed, the organic phase was removed under reduced pressure, and the residue was adjusted to ph=3-4 with 0.5M diluted hydrochloric acid, suction filtered, and the filter cake was dried to give 2-methyl-6- (1-methyl-5- ((2- (trimethylsilyl) ethoxy) methoxy) -1H-pyrazol-4-yl) isonicotinic acid (1.79 g, pale yellow solid), yield: 73.4%.

MS(ESI ⁺ )m/z＝363.9[M+H] ⁺ .

Example 31.1 ¹ ,2 ⁶ -dimethyl-3-oxo-1 ¹ H,5 ¹ H-11-oxa-4, 8-diaza-5 (2, 1) -benzo [ d ]]Synthesis of tert-butyl imidazo-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundecyl-8-carboxylate (intermediate A1)

The first step: (2-hydroxyethyl) (2- ((2-nitrophenyl) amino) ethyl) carbamic acid tert-butyl ester

To a 250mL round bottom flask was added tert-butyl (2-aminoethyl) (2-hydroxyethyl) carbamate (5.79 g,0.028 mol), DMF (50 mL), 2-fluoronitrobenzene (4.0 g,0.028 mol) and DIPEA (7.3 g,0.056 mol) in sequence and stirred at room temperature for 16h. After the reaction was completed, water (150 mL) was added, extraction was performed with ethyl acetate (100 ml×3), the organic phases were combined, washed with saturated brine (50 ml×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system ethyl acetate/petroleum ether=1/5 to give tert-butyl (2-hydroxyethyl) (2- ((2-nitrophenyl) amino) ethyl) carbamate (8.0 g, yellow oil), yield: 99.0%.

MS(ESI ⁺ )m/z＝348.2[M+Na] ⁺ .

And a second step of: 2- (5- (2- ((tert-Butoxycarbonyl) (2- ((2-nitrophenyl) amino) ethyl) amino) ethoxy) -1-methyl-1H-pyrazol-4-yl) -6-methyliisonicotinic acid methyl ester

To a 250mL round bottom flask was added tert-butyl (2-hydroxyethyl) (2- ((2-nitrophenyl) amino) ethyl) carbamate (3.25 g,0.01 mol), anhydrous tetrahydrofuran (150 mL), methyl 2- (5-hydroxy-1-methyl-1H-pyrazol-4-yl) -6-methyliisonicotinate (2.47 g,0.01 mol), triphenylphosphine (3.14 g,0.012 mol) and diisopropyl azodicarboxylate (2.4 g,0.012 mol) in sequence, and the mixture was warmed to room temperature and stirred for 4H. After the reaction was completed, the mixture was concentrated under reduced pressure, and purified by silica gel column chromatography using an eluent system of dichloromethane/methanol=20/1 to give methyl 2- (5- (2- ((tert-butoxycarbonyl) (2- ((2-nitrophenyl) amino) ethyl) amino) ethoxy) -1-methyl-1H-pyrazol-4-yl) -6-methyliisonicotinic acid (6.5 g, yellow oil), yield: 70.0%.

MS(ESI ⁺ )m/z＝555.1[M+H] ⁺ .

And a third step of: 2- (5- (2- ((2-Aminophenyl) amino) ethyl) (t-butoxycarbonyl) amino) ethoxy) -1-methyl-1H-pyrazol-4-yl) -6-methyliisonicotinic acid methyl ester

To a 250mL round bottom flask was added, in order, methyl 2- (5- (2- ((tert-butoxycarbonyl) (2- ((2-nitrophenyl) amino) ethyl) amino) ethoxy) -1-methyl-1H-pyrazol-4-yl) -6-methyliisonicotinic acid (4.0 g,7.2 mmol), methanol (100 mL) and palladium on carbon (0.4 g, 10%) at room temperature, the gas was replaced with hydrogen 3 times, and stirring was carried out at room temperature for 12H. After the reaction was completed, filtration was performed using celite, and the filtrate was concentrated under reduced pressure to give methyl 2- (5- (2- ((2-aminophenyl) amino) ethyl) (t-butoxycarbonyl) amino) ethoxy) -1-methyl-1H-pyrazol-4-yl) -6-methyliisonicotinic acid (5.0 g, red oil), yield: 88.3%.

MS(ESI ⁺ )m/z＝525.2[M+H] ⁺ .

Fourth step: 2- (5- (2- ((2- (2-amino-1H-benzimidazol-1-yl) ethyl) (t-butoxycarbonyl) amino) ethoxy) -1-methyl-1H-pyrazol-4-yl) -6-methyliisonicotinic acid methyl ester

To a 250mL round bottom flask was added, in order, methyl 2- (5- (2- ((2-aminophenyl) amino) ethyl) (t-butoxycarbonyl) amino) ethoxy) -1-methyl-1H-pyrazol-4-yl) -6-methyliisonicotinic acid (5.0 g,9.5 mmol), methanol (50 mL), water (50 mL) and cyanogen bromide (1.5 g,14.0 mmol) at room temperature, and the mixture was stirred for 4-5H at 70 ℃. After the reaction was completed, the residue was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using an eluent system dichloromethane/methanol=15/1 to give methyl 2- (5- (2- ((2- (2-amino-1H-benzimidazol-1-yl) ethyl) (t-butoxycarbonyl) amino) ethoxy) -1-methyl-1H-pyrazol-4-yl) -6-methyliisonicotinic acid (2.7 g, brown solid), yield: 51.5%.

MS(ESI ⁺ )m/z＝549.9[M+H] ⁺ .

Fifth step: 2- (5- (2- ((2- (2-amino-1H-benzimidazol-1-yl) ethyl) (t-butoxycarbonyl) amino) ethoxy) -1-methyl-1H-pyrazol-4-yl) -6-methyliisonicotinic acid

To a 250mL round bottom flask was added, in order, methyl 2- (5- (2- ((2- (2-amino-1H-benzimidazol-1-yl) ethyl) (t-butoxycarbonyl) amino) ethoxy) -1-methyl-1H-pyrazol-4-yl) -6-methyliisonicotinic acid (1.7 g,0.0031 mol), tetrahydrofuran (50 mL), water (20 mL), and lithium hydroxide monohydrate (0.25 g, 0.006mol) at room temperature. Stirring for 4-5h at room temperature. After the reaction was completed, tetrahydrofuran was removed under reduced pressure, and the resulting residue was added with water (10 mL), and ph=6-7 was adjusted with 1M hydrochloric acid, extracted with ethyl acetate (50 ml×5), the organic phases were combined, washed with saturated brine (50 ml×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude 2- (5- (2- ((2- (2-amino-1H-benzimidazol-1-yl) ethyl) (t-butoxycarbonyl) amino) ethoxy) -1-methyl-1H-pyrazol-4-yl) -6-methyliisonicotinic acid (1.0 g, brown solid), yield: 54.4%.

MS(ESI ⁺ )m/z＝535.9[M+H] ⁺ .

Sixth step: 1 ¹ ,2 ⁶ -dimethyl-3-oxo-1 ¹ H,5 ¹ H-11-oxa-4, 8-diaza-5 (2, 1) -benzo [ d ]]Imidazo-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundecyl-8-carboxylic acid tert-butyl ester

To a 100mL round bottom flask was added 2- (5- (2- ((2- (2-amino-1H-benzimidazol-1-yl) ethyl) (t-butoxycarbonyl) amino) ethoxy) -1-methyl-1H-pyrazol-4-yl) -6-methyliisonicotinic acid (500 mg,0.93 mmol), dichloromethane (15 mL), DIPEA (240 mg,1.86 mmol) and benzotriazol-N, N, N ', N' -tetramethyluronium hexafluorophosphate (3838 mg,1.02 mmol) in sequence at room temperature and the mixture was stirred for 1-2H at room temperature. After the reaction, the residue was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system dichloromethane/methanol=15/1 to give 1 ¹ ,2 ⁶ -dimethyl-3-oxo-1 ¹ H,5 ¹ H-11-oxa-4, 8-diaza-5 (2, 1) -benzo [ d ]]Imidazo-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundecyl-8-carboxylic acid tert-butyl ester (370 mg, light yellow oil), yield: 76.3%.

MS(ESI ⁺ )m/z＝517.9[M+H] ⁺ .

Examples 32 to 41 Synthesis of intermediates A2 to A4 and intermediates B1 to B7

Intermediates A2 to A4 and B1 to B7 were prepared by the procedure of synthetic intermediate A1 (example 31) starting from commercially available or synthetic substituted 2-fluoro-1-nitrobenzene and hydroxyamine.

TABLE 2 intermediates A2-A4 and intermediates B1-B7

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EXAMPLE 42 (E) -5 ⁶ - (hydroxymethyl) -1 ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Synthesis of imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundecan-3-one (intermediate B8)

The first, second and third steps: 2-amino-1- (5-hydroxypentyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester

Methyl 2-amino-1- (5-hydroxypentyl) -1H-benzo [ d ] imidazole-6-carboxylate was prepared according to the method of the first, third and fourth steps of synthesis intermediate A1 (example 31) starting from methyl 3-fluoro-4-nitrobenzoate and 5-aminopentanol.

MS(ESI ⁺ )m/z＝278.1[M+H] ⁺ .

Fourth step: 1- (5-hydroxypentyl) -2- (2-methyl-6- (1-methyl-5- ((2- (trimethylsilyl) ethoxy) methoxy) -1H-pyrazol-4-yl) isonicotinamide) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester

Methyl 2-amino-1- (5-hydroxypentyl) -1H-benzo [ d ] imidazole-6-carboxylate (0.65 g,1.8 mmol), DMF (20 mL), 2-methyl-6- (1-methyl-5- ((2- (trimethylsilyl) ethoxy) methoxy) -1H-pyrazol-4-yl) isonicotinic acid (0.5 g,1.8 mmol), HATU (1.03 g,2.7 mmol) and DIPEA (0.7 g,5.4 mmol) were added sequentially to a 100mL round bottom flask and stirred at room temperature for 3H. After the completion of the reaction, water (20 mL) was added to the reaction mixture, extracted with ethyl acetate (50 ml×5), the organic phases were combined, washed with saturated brine (50 ml×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography to give methyl 1- (5-hydroxypentyl) -2- (2-methyl-6- (1-methyl-5- ((2- (trimethylsilyl) ethoxy) methoxy) -1H-pyrazol-4-yl) isonicotinamide) -1H-benzo [ d ] imidazole-6-carboxylate (500 mg, pale yellow oil), yield: 38.9%.

MS(ESI ⁺ )m/z＝623.0[M+H] ⁺ .

Fifth step: 2- (2- (5-hydroxy-1-methyl-1H-pyrazol-4-yl) -6-methylisonicotinamide) -1- (5-hydroxypentyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester

Methyl 1- (5-hydroxypentyl) -2- (2-methyl-6- (1-methyl-5- ((2- (trimethylsilyl) ethoxy) methoxy) -1H-pyrazol-4-yl) isonicotinamide) -1H-benzo [ d ] imidazole-6-carboxylate (500 mg,0.803 mmol) was dissolved in a dioxane solution of 4M hydrogen chloride (15 mL) under ice-water bath, and stirred at room temperature for 1H. The residue was concentrated under reduced pressure, water (10 mL) was added, ph=6-7 was adjusted with saturated aqueous sodium bicarbonate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system methanol/dichloromethane=1/6 to give methyl 2- (2- (5-hydroxy-1-methyl-1H-pyrazol-4-yl) -6-methylisonicotinamide) -1- (5-hydroxypentyl) -1H-benzo [ d ] imidazole-6-carboxylate (300 mg, purple solid), yield: 67.5%.

MS(ESI ⁺ )m/z＝493.0[M+H] ⁺ .

Sixth step: (E) -1 ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazole-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundecyl-5 ⁶ -carboxylic acid methyl ester

2- (2- (5-hydroxy-1-methyl-1H-pyrazol-4-yl) -6-methylisonicotinamide) -1- (5-hydroxypentyl) -1H-benzo [ d ] at room temperature]Imidazole-6-carboxylic acid methyl ester (300 mg, 0.319 mmol) was dissolved in THF (15 mL), then DIAD (184 mg, 0.284 mmol) and PPh3 (239.64 mg, 0.284 mmol) were added and stirred at room temperature for 3h. After completion of the reaction, the residue was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography using an eluent system of methanol/dichloromethane=1/100 to 1/20 to give (E) -1 ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolundecyl-5 ⁶ Methyl carboxylate (210 mg, pale yellow oil), yield: 69.0%.

MS(ESI ⁺ )m/z＝474.8[M+H] ⁺ .

Seventh step: (E) -5 ⁶ - (hydroxymethyl) -1 ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolycycloundecan-3-one

Under ice-water bath, (E) -1 ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazole-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundecyl-5 ⁶ Methyl carboxylate (84 mg,0.177 mmol) was dissolved in THF (3 mL) and LiAlH was added in portions ₄ (26.7 mg, 0.706 mmol) was stirred for 1h. After completion of the reaction, water (2 mL) was added dropwise to the reaction mixture, suction filtration was performed, the filtrate was concentrated under reduced pressure, and the obtained residue was washed with silica gel column chromatographyPurification of the stripping system methanol/dichloromethane=1/100-1/20 gives (E) -5 ⁶ - (hydroxymethyl) -1 ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundecan-3-one (58 mg, white solid), yield: 66.1%.

MS(ESI ⁺ )m/z＝447.0[M+H] ⁺ .

Example 43.1 ¹ ,2 ⁶ -dimethyl-5 ⁶ - ((4-methylpiperazin-1-yl) methyl) -3-oxo-1 ¹ H,5 ¹ H-11-oxa-4, 8-diaza-5 (2, 1) -benzo [ d ] ]Synthesis of imidazole-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundecyl-8-carboxylic acid tert-butyl ester (intermediate A5)

Intermediate B1 (200 mg,0.37 mmol) was dissolved in dichloromethane (20 mL) in a 100mL round bottom flask at room temperature, then 1-methylpiperazine (40 mg,0.4 mmol) and acetic acid (110 mg,1.83 mmol) were added, stirred at room temperature for 1h, sodium triacetoxyborohydride (300 mg,1.46 mmol) was slowly added, and stirred at room temperature for 4-5h. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by thin layer chromatography using an eluent system of dichloromethane/methanol=15/1 to give 1 ¹ ,2 ⁶ -dimethyl-5 ⁶ - ((4-methylpiperazin-1-yl) methyl) -3-oxo-1 ¹ H,5 ¹ H-11-oxa-4, 8-diaza-5 (2, 1) -benzo [ d ]]Imidazole-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazole cycloundecyl-8-carboxylic acid tert-butyl ester (110 mg, yellow solid), yield: 38.13%.

MS(ESI ⁺ )m/z＝630.8[M+H] ⁺ .

Examples 44 to 49 Synthesis of intermediates A6 to A11

Intermediate A6-A11 was prepared using intermediate B and the aza ring compound as starting materials by the method of synthesizing intermediate A5 (example 43).

TABLE 3 intermediates A6-A11

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EXAMPLE 50 (E) - (2- ((1) ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazole-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolycycloundecane-5 ⁷ -yl) amino) ethyl) carbamic acid tert-butyl ester synthesis (intermediate A12)

The first step: (E) -5 ⁷ - ((3, 4-dimethoxybenzyl) amino) -1 ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolycycloundecan-3-one

Intermediate B3 (15.0 g,0.03 mol), 1, 4-dioxane (100 mL), (2, 4-dimethoxyphenyl) methylamine (7.5 g,0.045 mol), pd were added sequentially to a 100mL round bottom flask at room temperature under nitrogen ₂ (bda) ₃ (2.75 g, 0.003mol), BINAP (3.73 g, 0.006mol) and sodium tert-butoxide (5.77 g,0.06 mol) were stirred overnight at 100 ℃. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, the filtrate was diluted with water (100 mL), extracted with ethyl acetate (100 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system dichloromethane/methanol=20/1 to give (E) -5 ⁷ - ((3, 4-dimethoxybenzyl) amino) -1 ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundecan-3-one (11.4 g, yellow solid), yield: 69.0%.

And a second step of: (E) -5 ⁷ -amino-1 ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolycycloundecan-3-one

Sequentially adding (E) -5 into a 100mL round bottom flask at room temperature ⁷ - ((3, 4-dimethoxybenzyl) amino) -1 ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundecan-3-one (4.0 g,7.27 mmol) and TFA (20 mL) were stirred at room temperature for 3h. After the reaction is finished, concentrating under reduced pressure to obtain (E) -5 ⁷ -amino-1 ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundecan-3-one (2.8 g, yellow solid), yield: 89.2%.

And a third step of: (E) - (2- ((1) ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazole-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolycycloundecane-5 ⁷ -yl) amino) ethyl) carbamic acid tert-butyl ester

Under the protection of nitrogen, adding (E) -5 into a 100mL single-neck round-bottom flask at room temperature ⁷ -amino-1 ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-nitrogenHetero-5 (2, 1) -benzo [ d ]]Imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundecan-3-one (200 mg,0.46 mmol), tert-butyl (2-oxoethyl) carbamate (73.78 mg,0.46 mmol), 4-A molecular sieves (200 mg) and methanol/acetic acid mixtures (10/1, 5.5 ml) were stirred at room temperature for 1h. Sodium cyanoborohydride (58.25 mg,0.93 mmol) was then added and stirred overnight at room temperature. After completion of the reaction, water (10 mL) was added, extraction was performed with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by thin layer chromatography with eluting system dichloromethane/methanol=20/1 to give (E) - (2- ((1) ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazole-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolycycloundecane-5 ⁷ -yl) amino) ethyl) carbamic acid tert-butyl ester (90 mg, yellow liquid), yield: 15.2%.

MS(ESI ⁺ )m/z＝575.3[M+H] ⁺ .

EXAMPLE 51 (E) - (2- ((1) ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazole-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolycycloundecane-5 ⁷ -base) (methyl) amino) ethyl) carbamic acid tert-butyl ester synthesis (intermediate A13)

Under nitrogen protection, add (E) - (2- ((1) to a 50mL single neck round bottom flask at room temperature ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazole-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolycycloundecane-5 ⁷ -amino) ethyl) carbamic acid tert-butyl ester (330 mg,0.58 mmol), formaldehyde (78.23 mg,2.61 mmol), 4A molecular sieve (300 mg) and methanol/acetic acid (10/1, 5 mL) mixture, stirred at room temperature for 1h. Sodium cyanoborohydride (72.82 mg,1.16 mmol) was added to the reaction solution, and stirring was continued for 3 hours. After completion of the reaction, water (20 mL) was added, followed by acetic acidEthyl ester (30 mL x 3) and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the crude product purified by silica gel column chromatography using an eluent system dichloromethane/methanol=10/1 to give (E) - (2- ((1) ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazole-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolycycloundecane-5 ⁷ -yl) (methyl) amino) ethyl) carbamic acid tert-butyl ester (150 mg, yellow solid), yield: 44.0%.

MS(ESI ⁺ )m/z＝589.7[M+H] ⁺ .

Examples 52 to 55 Synthesis of intermediates A14 to A17

In intermediate (E) -5 ⁷ -amino-1 ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazole-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundecan-3-one and alkyl aldehyde or ketone are used as starting materials to prepare intermediate A14-A17 by the method of the third step of synthesizing intermediate A12 (example 50).

TABLE 4 intermediates A14-A17

Example 56 (S, E) - (1- ((1) ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazole-2 (2, 4) -pyridine-1 (4, 5) -pyrazole cycloundecane-5 ⁷ -yl) Synthesis of tert-butyl amino) -1-oxopropan-2-yl carbamate (intermediate A18)

N-BOC-L-alanine (877 mg,4.64 mmol) was dissolved in THF (30 mL), NMM (375 mg,3.7 mmol) was added, cooled to-20℃and isobutyl chloroformate (876.6 mg,4.64 mmol) was added dropwise, stirred at-20℃for 1h, and then (E) -5 was added dropwise ⁷ -amino-1 ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]A solution of imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundecan-3-one (200 mg,0.46 mmol) in THF (15 mL) and NMM (234 mg,2.32 mmol) was stirred overnight at room temperature. After the completion of the reaction, water (30 mL), ethyl acetate extraction (30 mL. Times.3) and washing with saturated brine (50 mL. Times.2) were added, and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude (S, E) - (1- ((1) ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazole-2 (2, 4) -pyridine-1 (4, 5) -pyrazole cycloundecane-5 ⁷ -yl) amino) -1-oxopropan-2-yl carbamic acid tert-butyl ester (70 mg, yellow solid), yield: 25.1%.

MS(ESI ⁺ )m/z＝603.1[M+H] ⁺ .

Examples 57 to 61 Synthesis of intermediate A19 to A23

In intermediate (E) -5 ⁷ -amino-1 ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Intermediate A19-A23 was prepared by synthesizing intermediate A18 (example 56) starting from imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundecan-3-one and the amino acid.

TABLE 5 intermediates A19-A23

Example 62 (E) - (1- ((1) ¹ ,2 ⁶ Dimethyl-3-Oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazole-2 (2, 4) -pyridine-1 (4, 5) -pyrazole cycloundecane-5 ⁷ -yl) Synthesis of tert-butyl amino) -6- (dimethylamino) -1-oxohexane-2-yl carbamate (intermediate A24)

The first step: (E) - (6-amino-1- ((1) ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazole-2 (2, 4) -pyridine-1 (4, 5) -pyrazole cycloundecane-5 ⁷ -yl) amino) -1-oxohexane-2-yl-carbamic acid tert-butyl ester

To a hydrogenation flask was added intermediate A23 (450 mg,0.57 mmol), methanol (10 mL) and palladium on carbon (100 mg) in this order, followed by introducing hydrogen and stirring at 40℃for 4h. Filtering, concentrating the filtrate under reduced pressure to obtain crude product (E) - (6-amino-1- ((1) ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazole-2 (2, 4) -pyridine-1 (4, 5) -pyrazole cycloundecane-5 ⁷ -yl) amino) -tert-butyl 1-oxohexan-2-yl carbamate (240 mg, yellow oil), yield: 64.3%.

MS(ESI ⁺ )m/z＝660.2[M+H] ⁺ .

And a second step of: (E) - (1- ((1) ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazole-2 (2, 4) -pyridine-1 (4, 5) -pyrazole cycloundecane-5 ⁷ -yl) amino) -6- (dimethylamino) -1-oxohexane-2-yl) carbamic acid tert-butyl ester

(E) - (6-amino-1- ((1) in a 50mL round bottom flask at room temperature ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazole-2 (2, 4) -pyridine-1 (4, 5) -pyrazole cycloundecane-5 ⁷ -base) amino) -tert-butyl 1-oxohexane-2-yl carbamate (240 mg,0.36 mmol) was dissolved in methanol (10 mL), acetic acid (0.2 mL) was added, sodium cyanoborohydride (46 mg,0.73 mmol) was added in portions, cooled to 0 ℃ and stirred at room temperature for 1h. Formaldehyde (137 mg,1.82 mmol) was added dropwise thereto after cooling to 0℃and stirred at room temperature for 4h. After completion of the reaction, the reaction was quenched by addition of ammonium chloride, extracted with ethyl acetate (20 ml×2), the organic phases were combined, washed with saturated brine (20 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography with an elution system of dichloromethane/methanol=10/1 to give (E) - (1- ((1) ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazole-2 (2, 4) -pyridine-1 (4, 5) -pyrazole cycloundecane-5 ⁷ -yl) amino) -6- (dimethylamino) -1-oxohexane-2-yl) carbamic acid tert-butyl ester (80 mg, yellow solid), yield: 32%.

MS(ESI ⁺ )m/z＝689.3[M+H] ⁺ .

EXAMPLE 63 (E) - (1) ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazole-2 (2, 4) -pyridine-1 (4, 5) -pyrazole cycloundecane-5 ⁷ -yl) Synthesis of pyrrolidin-3-yl) carbamic acid tert-butyl ester (intermediate A25)

Intermediate B3 (200 mg,0.4 mmol), 1, 4-dioxane (10 mL), pyrrolidin-3-ylcarbamic acid tert-butyl ester (112.78 mg,0.6 mmol), tris (dibenzylideneacetone) dipalladium (3) was added sequentially to a 100mL round bottom flask at room temperature under nitrogen6.97mg,0.04 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (50.27 mg,0.08 mmol) and sodium tert-butoxide (77.59 g,0.81 mmol) were stirred overnight at 100 ℃. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, the filtrate was diluted with water (10 mL), extracted with ethyl acetate (30 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography with eluent system dichloromethane/methanol=20/1 to give (E) - (1) ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazole-2 (2, 4) -pyridine-1 (4, 5) -pyrazole cycloundecane-5 ⁷ -group) pyrrolidin-3-yl) carbamic acid tert-butyl ester (100 mg, yellow oil), yield: 12.4%.

MS(ESI ⁺ )m/z＝601.4[M+H] ⁺ .

Example 64 (E) - (2- ((1) ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazole cycloundecane-5 ⁶ -yl) oxy) ethyl) carbamic acid tert-butyl ester (intermediate A26)

The first step: (E) -5 ⁶ -hydroxy-1 ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolocycloundecan-3-one

Intermediate B4 (200 mg,0.38 mmol) was dissolved in MeOH/EtOAc (10 mL, 1/1) at room temperature, then palladium on carbon (10%, 30 mg) was added, the gas was replaced with hydrogen three times, and stirred at room temperature for 16h. Suction filtering, concentrating the filtrate under reduced pressure to obtain crude product (E) -5 ⁶ -hydroxy-1 ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolocycloundec-3-one (150 mg, tan oil), yield: 72.5%. The crude product obtained was used in the next reaction without purification.

MS(ESI ⁺ )m/z＝433.1[M+H] ⁺ .

And a second step of: (E) - (2- ((1) ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazole cycloundecane-5 ⁶ -group) oxy) ethyl) carbamic acid tert-butyl ester

At room temperature, the reaction mixture was prepared by reacting (E) -5 ⁶ -hydroxy-1 ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolocycloundec-3-one (25 mg,0.058 mmol) is dissolved in DMF (2 mL), followed by the addition of potassium carbonate (24 mg,0.173 mmol) and N-Boc-bromoethylamine (39 mg,0.174 mmol), and stirring is carried out at 70℃for 2h. After completion of the reaction, water (10 mL) was added, extraction was performed with ethyl acetate (10 mL. Times.5), the organic phases were combined, washed with saturated brine (15 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude products (E) - (2- ((1) ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazole cycloundecane-5 ⁶ -group) oxy) ethyl) carbamic acid tert-butyl ester (31 mg, tan oil). The crude product obtained was used in the next reaction without purification.

MS(ESI ⁺ )m/z＝576.1[M+H] ⁺ .

Examples 65 to 83 Synthesis of intermediates A27 to A45

Intermediate A27-A45 was prepared using intermediate B and alkyl bromide or synthetic p-toluenesulfonyl compound as starting materials, by the method of synthesizing intermediate A26 (example 64).

TABLE 6 intermediates A27-A45

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EXAMPLE 84 (S, E) - (1) ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Synthesis of tert-butyl imidazo-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundec-9-yl) carbamate (intermediate A46)

The first step: (S) -2- ((tert-Butoxycarbonyl) amino) -5- ((2-nitrophenyl) amino) pentanoic acid

(S) -5-amino-2- ((tert-butoxycarbonyl) amino) pentanoic acid (1.0 g,4.3 mmol), acetonitrile (20 mL), potassium carbonate (770 mg,5.59 mmol) and 2-fluoronitrobenzene (730 mg,5.2 mmol) were added sequentially to a 100mL round bottom flask at room temperature, and the mixture was stirred for 16h at 70 ℃. The reaction solution was cooled to room temperature, suction-filtered, and the filtrate was concentrated under reduced pressure to give crude (S) -2- ((tert-butoxycarbonyl) amino) -5- ((2-nitrophenyl) amino) pentanoic acid (1.53 g, red oil). The crude product obtained was used in the next reaction without purification.

MS(ESI ⁺ )m/z＝375.8[M+Na] ⁺ .

And a second step of: (S) -2- ((tert-Butoxycarbonyl) amino) -5- ((2-nitrophenyl) amino) pentanoic acid methyl ester

(S) -2- ((tert-Butoxycarbonyl) amino) -5- ((2-nitrophenyl) amino) pentanoic acid (3.0 g,8.5 mmol), methanol (50 mL) and TMSCH were added sequentially in a 100mL round bottom flask at room temperature ₂ N ₂ (2.91 g,25.5 mmol), stirred at room temperature for 16h, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using an eluent system petroleum ether/ethyl acetate=0 to 1/1 to give methyl (S) -2- ((tert-butoxycarbonyl) amino) -5- ((2-nitrophenyl) amino) valerate (1.9 g, yellow oil), yield: 57.7%.

MS(ESI ⁺ )m/z＝390.0[M+Na] ⁺ .

And a third step of: (S) - (1-hydroxy-5- ((2-nitrophenyl) amino) pentan-2-yl) carbamic acid tert-butyl ester

Methyl (S) -2- ((tert-butoxycarbonyl) amino) -5- ((2-nitrophenyl) amino) pentanoate (1.0 g,2.7 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), cooled to 0℃and a mixture of lithium borohydride (356 mg,16.2 mmol) in anhydrous tetrahydrofuran (20 mL) was slowly added dropwise in a 100mL round bottom flask at room temperature. After completion of the dropwise addition, the temperature was raised to room temperature, stirred for 12 hours, the reaction solution was poured into water (20 mL), the mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system ethyl acetate/petroleum ether=0 to 1/1 to give tert-butyl (S) - (1-hydroxy-5- ((2-nitrophenyl) amino) pentan-2-yl) carbamate (810 mg, red oil), yield: 87%.

MS(ESI ⁺ )m/z＝362.0[M+Na] ⁺ .

Fourth, fifth, sixth, seventh and eighth steps: (S, E) - (1) ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazole-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolycycloundec-9-yl) carbamic acid tert-butyl ester

Intermediate a46 was prepared following the second, third, fourth, fifth and sixth steps of the synthesis of intermediate A1 (example 31) starting from tert-butyl (S) - (1-hydroxy-5- ((2-nitrophenyl) amino) pentan-2-yl) carbamate.

EXAMPLE 85 (R, E) - (1) ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Synthesis of tert-butyl imidazole-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundec-9-yl) carbamate (intermediate A47)

Intermediate A47 was prepared following the procedure for the synthesis of intermediate A46 (example 84) starting from (R) -5-amino-2- ((tert-butoxycarbonyl) amino) pentanoic acid and 2-fluoronitrobenzene.

EXAMPLE 86 (E) - (3-oxo-5) ² ,5 ³ -dihydro-5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazole-2 (2, 4) -pyridine-1 (1, 2) -benzocycloundecane-2 ⁶ Tert-butyl carbamate (intermediate A48)

The first step: 2- (2- (5-bromopentyloxy) phenyl) -6- (t-butoxycarbonyl) amino) isonicotinic acid methyl ester

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Methyl 2- ((t-butoxycarbonyl) amino) -6- (2-hydroxyphenyl) isonicotinate (5.6 g,0.016 mol), acetonitrile (50 mL), potassium carbonate (2.70 g,0.019 mol) and 1, 5-dibromopentane (4.12 g,0.018 mol) were added sequentially to a 250mL round bottom flask, and the mixture was stirred at 85℃for 16h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography using an eluent system petroleum ether/ethyl acetate=10/1 to give methyl 2- (2- (5-bromopentyloxy) phenyl) -6- (t-butoxycarbonyl) amino) isonicotinate (1.5 g, yellow oil) in 18.8% yield.

MS(ESI ⁺ )m/z＝492.8[M+H] ⁺ .

And a second step of: 2- (2- ((5- (2-amino-1H-benzo [ d ] imidazol-1-yl) pentyl) oxy) phenyl) -6- ((tert-butoxycarbonyl) amino) isonicotinic acid methyl ester

1H-benzo [ d ] imidazol-2-amine (0.58 g,4.3 mol), acetonitrile (15 mL), potassium carbonate (2.9 g,3.9 mol) and methyl 2- (2- (5-bromopentyl) oxy) phenyl) -6- (t-butoxycarbonyl) amino) isonicotinate (1.5 g,3.6 mmol) were added sequentially to a 100mL round bottom flask at room temperature, and stirred under reflux with heating for 24H. After the reaction was completed, the mixture was concentrated under reduced pressure, and purified by silica gel column chromatography using an eluent system petroleum ether/ethyl acetate=10/1 to give methyl 2- (2- ((5- (2-amino-1H-benzo [ d ] imidazol-1-yl) pentyl) oxy) phenyl) -6- ((tert-butoxycarbonyl) amino) isonicotinate (498 mg, yellow solid), yield: 27.8%.

MS(ESI ⁺ )m/z＝545.9[M+H] ⁺ .

And a third step of: 2- (2- ((5- (2-amino-1H-benzo [ d ] imidazol-1-yl) pentyl) oxy) phenyl) -6- ((tert-butoxycarbonyl) amino) isonicotinic acid

Methyl 2- (2- ((5- (2-amino-1H-benzo [ d ] imidazol-1-yl) pentyl) oxy) phenyl) -6- ((tert-butoxycarbonyl) amino) isonicotinate (498 mg,1.07 mmol), a mixture of tetrahydrofuran and water (6 mL, 5/1), lithium hydroxide monohydrate (449 mg,10.7 mmol) were added sequentially to a 100mL round bottom flask at room temperature, and stirred at room temperature for 3H. After the reaction was completed, tetrahydrofuran was removed under reduced pressure, the resulting residue was added to water (10 mL), ph=6-7 was adjusted using 1M hydrochloric acid, extracted with ethyl acetate (20 mL), and the organic phase was concentrated under reduced pressure to give crude 2- (2- ((5- (2-amino-1H-benzo [ d ] imidazol-1-yl) pentyl) oxy) phenyl) -6- ((t-butoxycarbonyl) amino) isonicotinic acid (0.695 mg, yellow oil), yield: 31.5%.

MS(ESI ⁺ )m/z＝531.8[M+H] ⁺ .

And a third step of: (E) - (3-oxo-5) ² ,5 ³ -dihydro-5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazole-2 (2, 4) -pyridine-1 (1, 2) -benzocycloundecane-2 ⁶ -group) carbamic acid tert-butyl ester

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2- (2- ((5- (2-amino-1H-benzo [ d)) was added sequentially to a 100mL round bottom flask at room temperature]Imidazol-1-yl) pentyl) oxy) phenyl) -6- ((t-butoxycarbonyl) amino) isonicotinic acid (190 mg,0.35 mmol), dichloromethane (3 mL), triethylamine (72.2 mg,0.71 mmol) and 2- (1H-benzotrisazo L-1-yl) -1, 3-tetramethylurea tetrafluoroborate (137.7 mg,0.42 mmol) were stirred at room temperature for 0.5H. After completion of the reaction, methylene chloride (20 mL) was added thereto, the mixture was washed with saturated brine (10 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel with the eluent system petroleum ether/ethyl acetate=10/1 to give (E) - (3-oxo-5) ² ,5 ³ -dihydro-5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazole-2 (2, 4) -pyridine-1 (1, 2) -benzocycloundecane-2 ⁶ Tert-butyl carbamate (150 mg, yellow solid), yield: 65.4%.

MS(ESI ⁺ )m/z＝513.9[M+H] ⁺ .

EXAMPLE 87 (E) -8-propenoyl-1 ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4, 8-diaza-5 (2, 1) -benzo [ d ]]Synthesis of imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundecan-3-one (final product 1)

The first step: (E) -1 ¹ ,2 ⁶ -dimethyl-1 ¹ H,5 ¹ H-11-oxa-4, 8-diaza-5 (2, 1) -benzo [ d ]]Imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundec-3-one

Intermediate A1 (370 mg,0.71 mmol) and dioxane hydrochloride solution (5 mL,4 mol/L) were added sequentially to a 100mL round bottom flask at room temperature, and the mixture was stirred at room temperature for 2-3h. After the reaction is finished, the filtrate is decompressed and concentrated to obtain crude product 1 ¹ ,2 ⁶ -dimethyl-1 ¹ H,5 ¹ H-11-oxa-4, 8-diaza-5 (2, 1) -benzo [ d ]]Imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundec-3-one (160 mg, yellow solid), yield: 53.4%.

MS(ESI ⁺ )m/z＝418.1[M+H] ⁺ .

And a second step of: (E) -8-propenoyl-1 ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4, 8-diaza-5 (2, 1) -benzo [ d ]]Imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundecan-3-one (final product 1)

1 mL of the mixture was added sequentially to a 100mL round bottom flask at room temperature ¹ ,2 ⁶ -dimethyl-1 ¹ H,5 ¹ H-11-oxa-4, 8-diaza-5 (2, 1) -benzo [ d ]]Imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundec-3-one (83 mg,0.2 mmol), dichloromethane (5 mL) and DIPEA (51.6 mg,2.0 mmol), cooled to 0 ℃, slowly added with acryloyl chloride (18 mg,0.2 mmol), and stirred at 0℃for 30min. After the reaction, the residue obtained was concentrated under reduced pressure and purified by thin layer chromatography using an eluent system of dichloromethane/methanol=15/1 to give the product (E) -8-acryloyl-1 ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4, 8-diaza-5 (2, 1) -benzo [ d ]]Imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundecan-3-one (37 mg, white solid), yield: 38.9%.

MS(ESI ⁺ )m/z＝472.1[M+H] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ12.81(s,1H),8.32(d,J＝8.0Hz,1H),7.93-7.92(m,1H),7.71-7.45(m,3H),7.29-7.28(m,2H),7.01-7.00(m,1H),6.35-6.22(m,1H),5.82(t,J＝8.0Hz,1H),4.52-4.30(m,4H),4.22-3.91(m,4H),3.79(d,J＝23.1Hz,3H),2.57(s,3H).

Examples 88-134 Synthesis of end products 4-8, 49, 50, 55, 58, 60, 62, 67-69, 73, 74, 76-78, 80-83, 102, 109, 114, 115, 118-122, 124-126, 131-133, 135, 137-141, 147, 152, 154

Starting from intermediate A, the end products 4-8, 49, 50, 55, 58, 60, 62, 67-69, 73, 74, 76-78, 80-83, 102, 109, 114, 115, 118-122, 124-126, 131-133, 135, 137-141, 147, 152, 154 were prepared according to the procedure of synthetic end product 1 (example 87).

TABLE 7 end products 4-8, 49, 50, 55, 58, 60, 62, 67-69, 73, 74, 76-78, 80-83, 102, 109, 114, 115, 118-122, 124-126, 131-133, 135, 137-141, 147, 152, 154

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EXAMPLE 135 (E) -8- (-4- (dimethylamino) but-2-enoyl) -1 ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H，5 ¹ H-11-oxa-4, 8-diaza-5 (2, 1) -benzo [ d ]]Synthesis of imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundecan-3-one (final product 10)

(E) -4- (dimethylamino) but-2-enoic acid hydrochloride (34 mg,0.26 mmol), dichloromethane (5 mL), N, N-diisopropylethylamine (62 mg,0.48 mmol), benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate (97 mg,0.26 mmol) and (E) -1 were added sequentially to a 100mL round bottom flask at room temperature ¹ ,2 ⁶ -dimethyl-1 ¹ H,5 ¹ H-11-oxa-4, 8-diaza-5 (2, 1) -benzo [ d ]]Imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundec-3-one (100 mg,0.24 mmol) was stirred at room temperature for 1-2h. After the reaction, the residue was concentrated under reduced pressure and purified by preparative liquid chromatography [ column: gemini-C18150x 21.2mm,5um; mobile phase: ACN/H ₂ O (0.1% tfa), gradient: 10-40%]Purifying to obtain the product 8- (-4- (dimethylamino) but-2-enoyl) -1 ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H，5 ¹ H-11-oxa-4, 8-diaza-5 (2, 1) -benzo [ d ]]Imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundecan-3-one (10.9 mg, yellow solid).

MS(ESI ⁺ )m/z＝528.9[M+H] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ12.83(s,1H)8.34(d,J＝11.4Hz,1H),8.15(s,1H),7.88(s,1H),7.64-7.43(m,3H),7.30-7.27(m,2H),6.77-6.72(m,2H),4.48-4.29(m,4H),4.11-4.08(m,2H),4.02-3.89(m,1H),3.79(d,J＝24.6Hz,3H),3.20-3.07(m,3H),2.55(d,J＝11.3Hz,3H),2.23(s,6H).

Examples 136 to 138 Synthesis of end products 52, 92, 93

The final product was prepared by the method of synthetic final product 10 (example 135) starting from the amine obtained by hydrolysis of intermediate a and commercial acid.

TABLE 8 end products 52, 92, 93

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EXAMPLE 139 (E) -3- (1) ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H，5 ¹ H-11-oxa-4, 8-diaza-5 (2, 1) -benzo [ d ]]Synthesis of imidazole-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundec-8-yl) -3-oxopropanenitrile (final product 17)

Into a 100mL round bottom flask at room temperature was successively added 2-cyanoacetic acid (33 mg,0.4 mmol), tetrahydrofuran (5 mL), dicyclohexylcarbodiimide (30 mg,0.23 mmol), 4-dimethylaminopyridine (2 mg,0.02 mmol) and 1 ¹ ,2 ⁶ -dimethyl-1 ¹ H,5 ¹ H-11-oxa-4, 8-diaza-5 (2, 1) -benzo [ d ]]Imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundec-3-one (80 mg,0.2 mmol), was heated to 70℃and stirred for 12h. After the reaction is finished, subtractingThe solvent was removed under pressure and the residue obtained was purified by preparative liquid chromatography [ column: gemini-C18 150x 21.2mm,5um; mobile phase: ACN/H ₂ O (0.1% tfa), gradient: 10-40%]Purifying to obtain the product (E) -3- (1) ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H，5 ¹ H-11-oxa-4, 8-diaza-5 (2, 1) -benzo [ d ]]Imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundec-8-yl) -3-oxopropanenitrile (1.5 mg, yellow solid).

MS(ESI ⁺ )m/z＝485.0[M+H] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ12.79(s,1H),8.32-8.29(m,1H),7.88(s,1H),7.78(d,J＝7.9Hz,1H),7.64-7.40(m,2H),7.38-7.18(m,2H),4.45-4.34(m,6H),4.03-3.97(m,4H),3.76-3.73(m,3H),2.55(s,3H).

EXAMPLE 140 (E) -N- (1) ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Synthesis of imidazole-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolocycloundec-7-yl) acrylamide (end product 18)

The first step: 2-methyl-6- (1-methyl-5- (3- (epoxypropan-2-yl) propoxy) -1H-pyrazol-4-yl) isonicotinic acid methyl ester

Methyl 2- (5-hydroxy-1-methyl-1H-pyrazol-4-yl) -6-methyliisonicotinic acid (2.5 g,10.1 mmol), acetonitrile (50 mL), potassium carbonate (2.09, 15.1 mmol) and 2- (3-bromopropyl) oxirane (2.67 g,16.1 mmol) were successively added to a 100mL round bottom flask at room temperature, and heated to 70℃and stirred for 16H. After the reaction was completed, the mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography using an elution system petroleum ether/ethyl acetate=1/1 to give methyl 2-methyl-6- (1-methyl-5- (3- (epoxypropan-2-yl) propoxy) -1H-pyrazol-4-yl) isonicotinate (1.7 g, pale yellow oil), yield: 50.8%.

MS(ESI ⁺ )m/z＝331.9[M+H] ⁺ .

And a second step of: 2- (5- ((5- (2-amino-1H-benzo [ d ] imidazol-1-yl) -4-hydroxypentyl) oxy) -1-methyl-1H-pyrazol-4-yl) -6-methyliisonicotinic acid

Methyl 2-methyl-6- (1-methyl-5- (3- (epoxypropan-2-yl) propoxy) -1H-pyrazol-4-yl) isonicotinate (700 mg,2.1 mmol), 2-aminobenzimidazole (282 mg,2.1 mmol), meOH/H was added to the tube at room temperature ₂ The O mixture (20 mL, 2.5/1) and KOH (237 mg,4.22 mmol) were stirred at 100deg.C under microwave for 1h. After the reaction is finished, the crude 2- (5- ((5- (2-amino-1H-benzo [ d)) is obtained by decompression concentration]Imidazol-1-yl) -4-hydroxypentyloxy) -1-methyl-1H-pyrazol-4-yl) -6-methyliisonicotinic acid (970 mg, pale yellow oil), the crude product obtained was used in the next reaction without purification.

MS(ESI ⁺ )m/z＝451.1[M+H] ⁺ .

And a third step of: (E) -7-hydroxy-1 ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolycycloundecan-3-one

2- (5- ((5- (2-amino-1H) -benzo [ d) was added sequentially to a 100mL eggplant-shaped bottle at room temperature]Imidazol-1-yl) -4-hydroxypentyloxy) -1-methyl-1H-pyrazol-4-yl) -6-methyliisonicotinic acid (600 mg,1.33 mmol), DMF (20 mL), HATU (1.52 g,4 mmol), HOAT (544 mg,4 mmol), DMAP (163 mg,1.33 mmol) and DIPEA (1.37 g,10.7 mmol) were stirred at room temperature for 16H. After completion of the reaction, water (15 mL) was added to the mixture, extracted with ethyl acetate (10 mL. Times.5), and the organic phases were combined, washed with saturated brine (15 mL. Times.3), and the organic phase was concentrated under reduced pressure, and the obtained residue was used to prepare a liquid phase Chromatography [ column: gemini-C18 150x 21.2mm,5um; mobile phase: ACN/H ₂ O (0.1% fa), gradient: 10-40%]Purifying to obtain (E) -7-hydroxy-1 ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundecan-3-one (0.2 g, pale yellow solid), yield: 32.1%.

MS(ESI ⁺ )m/z＝433.1[M+H] ⁺ .

Fourth step: (E) -1 ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolycycloundec-7-ylmethane sulfonate

(E) -7-hydroxy-1 in a 50mL round bottom flask under an ice-water bath ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundecan-3-one (70 mg,0.162 mmol) was dissolved in dichloromethane (15 mL), then triethylamine (49.1 mg,0.49 mmol) and methylsulfonyl chloride (37.1 mg,0.32 mmol) were added and stirred at this temperature for 1h. After the reaction, the residue was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent system of dichloromethane/methanol=30/1 to give (E) -1 ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolocycloundec-7-yl methanesulfonate (67 mg, yellow oil), yield: 56.8%.

MS(ESI ⁺ )m/z＝510.7[M+H] ⁺ .

Fifth step: (E) -7-azido-1 ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazole-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazole ringUndecan-3-one

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Under the protection of nitrogen, at room temperature, adding (E) -1 into a dried 100mL round-bottom flask in sequence ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolocycloundec-7-ylmethane sulfonate (110 mg,21.5 mmol), DMF (10 mL) and sodium azide (16.8 mg,25.84 mmol) were heated to 100deg.C and stirred for 16h. After the reaction, water (50 mL) is added into the reaction system, suction filtration is carried out, filter cakes are collected and dried to obtain (E) -7-azido-1 ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundecan-3-one (57 mg, light yellow solid), yield: 48.6%.

MS(ESI ⁺ )m/z＝458.1[M+H] ⁺ .

Sixth step: (E) -7-amino-1 ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolycycloundecan-3-one

(E) -7-azido-1 was added sequentially to a 100mL round bottom flask at room temperature ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundecan-3-one (72 mg,0.157 mmol), methanol (10 mL) and palladium on carbon (10%, 20 mg), hydrogen was replaced with gas three times, and stirred at room temperature for 5h. After the reaction, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography using an eluent system of dichloromethane/methanol=20/1 to give (E) -7-amino-1 ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundecan-3-one (35 mg, pale yellow oil), yield: 41.2%.

MS(ESI ⁺ )m/z＝431.8[M+H] ⁺ .

Seventh step: (E) -N- (1) ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolocycloundec-7-yl) acrylamides

Under ice-water bath, (E) -7-amino-1 ¹ ,2 ⁶ -dimethyl-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazol-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolylcycloundecan-3-one (35 mg,0.081 mmol) was dissolved in dichloromethane (5 mL), triethylamine (16.4 mg,0.16 mmol) was added, followed by a further addition of a mixture of acryloyl chloride (9.53 mg,0.11 mmol) and dichloromethane (4 mL), and stirring was continued for 1h after the addition. Concentrating under reduced pressure, and purifying the obtained residue by preparative liquid chromatography [ chromatographic column: gemini-C18 150x 21.2mm,5um; mobile phase: ACN/H ₂ O (0.1% fa), gradient: 10-40%]Obtaining (E) -N- (1) ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazole-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolocycloundec-7-yl) acrylamide (6 mg, yellow solid).

MS(ESI ⁺ )m/z＝485.8[M+H] ⁺ . ¹ H NMR(300MHz,CD ₃ OD)δ8.79(s,1H),8.30(s,1H),8.08(s,1H),7.89(s,1H),7.66-7.37(m,4H),6.10-5.90(m,2H),5.62-5.55(m,1H),4.14-4.10(m,1H),3.98(s,3H),2.82(s,3H),2.71-2.46(m,4H),2.10-1.98(m,2H),1.55-1.45(m,2H).

EXAMPLE 141 (E) -2- (2-chloro-2-fluoroacetamide) -N- (1- ((1) ¹ ,2 ⁶ -dimethylRadical-3 oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazole-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolycycloundecane-5 ⁷ Synthesis of (base) propionamide (end product 136)

(E) -2-amino-N- (1) was added sequentially to a 100mL round bottom flask at room temperature ¹ ,2 ⁶ -dimethyl-3-oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazole-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolycycloundecane-5 ⁷ -base) propionamide (40 mg,0.08 mmol), dichloromethane (2 mL), sodium 2-chloro-2-fluoroacetate (12.84 mg,0.1 mmol), 1-propylphosphoric anhydride (75.98 mg,0.12 mmol) and N, N-diisopropylethylamine (20.58 mg,0.16 mmol) were stirred overnight at room temperature. After the reaction was completed, methylene chloride (10 mL) was added, washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative liquid chromatography [ column: symmetry 7um 19-150mm; mobile phase: ACN/H ₂ O (0.1% tfa), gradient: 10-40%]Purification gives (E) -2- (2-chloro-2-fluoroacetamide) -N- (1- ((1) ¹ ,2 ⁶ -dimethyl-3 oxo-5 ² ,5 ³ -dihydro-1 ¹ H,5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazole-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolycycloundecane-5 ⁷ -base) propionamide (5.9 mg, white solid).

MS(ESI ⁺ )m/z＝597.2[M+H] ⁺ . ¹ H NMR(400MHz,CDCl ₃ )δ8.65(s,1H),8.15(s,1H),7.83(s,1H),7.50-7.48(m,1H),7.29-7.26(m,1H),7.10-7.08(m,1H),6.70-6.30(m,1H),4.60-4.80(m,1H),4.30-4.38(m,4H),3.81(s,3H),2.70(s,3H),2.10-2.13(m,4H),1.88-1.93(m,2H),1.62-1.68(m,3H).

EXAMPLE 142 (E) -2-chloro-2-fluoro-N- (3-oxo-5) ² ,5 ³ -dihydro-5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazole-2 (2, 4) -pyridine-1 (1, 2) -benzocycloundecane-2 ⁶ Synthesis of (base) acetamide (end product 153)

Sequentially adding (E) -2 into a 100mL round bottom flask at room temperature ⁶ -amino-5 ² ,5 ³ -dihydro-5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazol-2 (2, 4) -pyridin-1 (1, 2) -benzocycloundecan-3-one (30.0 mg,0.073 mmol), DMF (5 mL), DIPEA (46.9 mg,0.36 mmol), 2-chloro-2-fluoroacetic acid (19.5 mg,0.15 mmol), cooling to 0℃and slowly adding T ₃ P (91.9 mg,0.29 mmol), HOBt (39.24 mg,0.29 mmol) was added and stirred at room temperature for 16h. After the reaction, the crude product obtained was purified by high pressure liquid chromatography [ column: gemini-C18 150x 21.2mm,5um; mobile phase: ACN/H ₂ O (0.1% fa), gradient: 65-80%]Purifying to obtain (E) -2-chloro-2-fluoro-N- (3-oxo-5) ² ,5 ³ -dihydro-5 ¹ H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazole-2 (2, 4) -pyridine-1 (1, 2) -benzocycloundecane-2 ⁶ -yl) acetamide (3.3 mg, yellow solid).

MS(ESI ⁺ )m/z＝508.0[M+H] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ12.74(s,1H),11.26(s,1H),9.08(s,1H),8.49(s,1H),8.24(dd,J＝7.8,1.8Hz,1H),7.54-7.50(m,2H),7.42-7.37(m,1H),7.26-7.21(m,2H),7.15(d,J＝8.1Hz,1H),7.08-7.04(m,1H),6.93(d,J＝49.6Hz,1H),4.19(dd,J＝8.0,5.6Hz,2H),1.98-1.93(m,6H),1.59-1.41(m,2H).

Example 143.

1. In vitro enzymology experiments

The activity was determined by detecting the residual amount of ATP after EGFR protein kinase reaction using the HTRF KinEASE-TK kit. The intensity of the luminescent signal tested correlated positively with the amount of ATP remaining in the reaction, correlated positively with the activity of the compound, and correlated negatively with the activity of the kinase.

1. Design of experiment

Compounds were assayed on selected kinases and vehicle controls were set up for a total of 10 concentrations, 2 duplicate wells per concentration.

2. Reagent and consumable

3. Experimental procedure

3.1 configuration of 1x kinase buffer

Enzyme buffer with 5mM MgCl ₂ ；1mM DTT；1mM MnCl ₂ The aqueous solution was diluted 5-fold.

3.2 Compound screening

a) Compounds were transferred to 384 well plates using an Echo pipette.

b) The lid was closed and centrifuged at 1000g for 1 minute.

c) Dilution of EGFR L858R/T790M/C797S or EGFR Del19/T790M/C797S with kinase buffer

One time.

d) Mu.l of diluted EGFR L858R/T790M/C797S or EGFR Del19/T790M/C797S were added to 384 well plates.

e) Centrifuge at 1000g for 30 seconds and rest at room temperature for 10min.

f) The mixed solution of TK-substrate-biotin and ATP was diluted twice with kinase buffer.

g) The reaction was started by adding 5. Mu.l of a mixture of TK-substrate-biotin and ATP.

h) Centrifuge at 1000g for 30 seconds, cover, and rest at room temperature for 10min.

i) The buffer was 4-fold diluted with HTRF for detection of Sa-XL 665.

j) Mu.l of Sa-XL 665 and 5. Mu.l of TK-anti-Cryptate were added to each well.

e) Centrifuge for 30 seconds at 1000g revolution and rest for 1h at room temperature.

l) the 615nm (Cryptate) and 665nm (XL 665) fluorescent signals were read in an Envision 2104 multi-label microplate detector.

4.IC ₅₀ Calculation of

Data were analyzed using GraphPad Prism 6.0 software, with nonlinear S-curve backFitting the data by regression yields a dose-response curve, and calculating IC therefrom ₅₀ Values.

Percent enzyme inhibition (%) =100- (Signal) _{Compounds of formula (I)} -Signal _{average_PC} )/(Signal _{average_VC} -Signal _{average_PC} )×100

5. Experimental results

Compounds of Table 9 inhibit EGFR L858R/T790M/C797S and EGFR Del19/T790M/C797S enzyme inhibition IC ₅₀ (nM)

Note that: LR/TM/CS: L858R/T790M/C797S; EGFR Del/TM/CS: del19/T790M/C797S; /: not tested

Compounds of the invention inhibit IC against EGFR L858R/T790M/C797S and EGFR Del19/T790M/C797S enzymatic Activity ₅₀ As shown in table 9.

As can be seen from Table 9, the compounds of the present invention have good inhibitory activity against EGFR L858R/T790M/C797S and EGFR Del19/T790M/C797S triple mutant enzymes, IC ₅₀ The values are at nanomolar level.

2. Cell proliferation inhibition assay

CellTiter-Glo ^TM The living cell detection kit adopts luciferase as a detection object, and the luciferase needs ATP to participate in the luminescence process. Addition of CellTiter-Glo to cell culture Medium ^TM The reagent, the measured luminescence value, the optical signal and the ATP amount in the system are directly proportional, and the ATP is positively related to the number of living cells. Thus, by detecting the ATP content using CellTiter-Glo kit, the proliferation of cells can be detected.

The experiment adopts a celltiter-Glo (CTG) method to measure the compounds prepared in the prior art in tumor cell strains NCI-H1975 and Ba/F ₃ (EGFR-L858R/C797S/T790M)、Ba/F ₃ Proliferation inhibition in (EGFR-Del 19/C797S/T790M) and A431, and calculating 50% inhibition concentration IC ₅₀ 。

1. Design of experiment

Compounds were assayed on selected cells and vehicle controls were set up for a total of 10 concentrations, 2 duplicate wells per concentration.

2. Reagent and consumable

3. Experimental procedure

3.1 cell culture and seeding

a) Cells in the logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was checked by trypan blue exclusion, ensuring that cell viability was above 90%.

b) Regulating the cell concentration; mu.L of the cell suspension was added to 384 well plates, respectively.

Cells in 384 well plates were placed at 37℃in 5% CO ₂ Incubated overnight at 95% humidity.

3.2 dilution and dosing of the drug

a) 10-fold drug solutions were prepared at a maximum concentration of 10mM,10 concentrations, 3-fold dilutions, 10. Mu.L of drug solution was added to each well of 384-well plates inoculated with cells, and 2 multiplex wells were set for each drug concentration. Brigatinib, osimertinib or BI4020 is used as positive control, and DMSO is used as blank.

b) Cells in 384 well plates were placed at 37℃with 5% CO ₂ The culture was continued for 72 hours at 95% humidity, after which CTG analysis was performed.

3.3 end point reading board

a) The CTG reagent was thawed and the cell plates equilibrated to room temperature for 30 minutes.

b) An equal volume of CTG solution was added to each well.

c) Cells were lysed by shaking on an orbital shaker for 5 minutes.

d) The cell plates were left at room temperature for 20 minutes to stabilize the luminescence signal.

e) The luminescence value is read.

4. Data processing

Analysis of data using GraphPad Prism 5.0 software, fitting data to derive dose-response curves using nonlinear S-curve regression, and calculating IC therefrom ₅₀ Values.

Cell viability (%) = (Lum) _{Drug to be tested} -Lum _{Culture broth control} )/(Lum _{Cell control} -Lum _{Culture broth control} )×100％.

5. Experimental results

Proliferation-inhibiting activity IC of the compounds of Table 10 on individual cell lines ₅₀ (nM)

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Compounds of the invention inhibit proliferation activity IC against NCI-H1975, ba/F3 (EGFR-L858R/C797S/T790M), ba/F3 (EGFR-Del 19/C797S/T790M) and A431 cell lines ₅₀ As shown in table 10.

As can be seen from Table 10, the compounds of the present invention have good proliferation inhibition activity against NCI-H1975 double mutant cell line, ba/F3 (EGFR-L858R/C797S/T790M) triple mutant cell line and Ba/F3 (EGFR-Del 19/C797S/T790M) triple mutant cell line, and weak inhibition effect against EGFR wild type cell line A431, indicating that the compounds of the present invention have good cell inhibition activity and selectivity.

Claims

1. A macrocyclic compound of formula I or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer thereof:

wherein, in the formula I,

ring a is pyridine or pyrimidine;

ring B is a benzene ring, pyrazole, isoxazole, isothiazole, imidazole, oxazole, pyridine or pyridazine; wherein ring B may be optionally substituted with one or more substituents independently selected from the group consisting of: hydroxyethyl or hydroxypropyl;

ring D is a benzene ring;

R ¹ 、R ² and R is ⁴ Wherein 1 is a warhead group; when R is ¹ And when the warhead group is selected from the group consisting of:

R ² is a hydrogen atom, halogen, methyl, ethyl, trifluoromethyl, dimethylaminomethyl, N, N, N' -trimethylethylenediamine-based methyl, pyrrolidinylmethyl, morpholinomethyl, azetidinylmethyl, piperidinylmethyl, 4- (dimethylamino) piperidin-1-ylmethyl, 4- (3-methoxyacridin-1-yl) piperidin-1-ylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5]Nonan-7-ylmethyl, pyrrolidinylmethyl, morpholinomethyl, azetidinylmethyl, piperidinylmethyl, 4- (dimethylamino) piperidin-1-ylmethyl, 4- (3-methoxyacridin-1-yl) piperidin-1-ylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5 ]The nonan-7-ylmethyl group may be optionally substituted by one or more substituents independently selected from the group consisting of: halogen, methyl, ethyl, isopropyl, cyclopropyl; r is R ⁴ Is a hydrogen atom or a methyl group;

when R is ² And when the warhead group is selected from the group consisting of:

R ¹ is a hydrogen atom or a methyl group; r is R ⁴ Is a hydrogen atom or a methyl group;

when R is ⁴ And when the warhead group is selected from the group consisting of:

R ¹ is a hydrogen atom or a methyl group; r is R ² Is a hydrogen atom, halogen, methyl, ethyl, trifluoromethyl, dimethylaminomethyl, N, N, N' -trimethylethylenediamine-based methyl, pyrrolidinylmethyl, morpholinomethyl, azetidinylmethyl, piperidinylmethyl, 4- (dimethylamino) piperidin-1-ylmethyl, 4- (3-methoxyacridin-1-yl) piperidin-1-ylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5]Nonan-7-ylmethyl, pyrrolidinylmethyl, morpholinomethyl, azetidinylmethyl, piperidinylmethyl, 4- (dimethylamino) piperidin-1-ylmethyl, 4- (3-methoxyacridin-1-yl) piperidin-1-ylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5 ]The nonan-7-ylmethyl group may be optionally substituted by one or more substituents independently selected from the group consisting of: halogen, methyl, ethyl, isopropyl, cyclopropyl;

R ⁵ is hydrogen or methyl;

R ³ is a hydrogen atom, halogen, methyl, ethyl, trifluoromethyl, dimethylaminomethyl, N, N, N' -trimethylethylenediamine-based methyl, pyrrolidinylmethyl, morpholinomethyl, azetidinylmethyl, piperidinylmethyl, 4- (dimethylamino) piperidin-1-ylmethyl, 4- (3-methoxyacridin-1-yl) piperidin-1-ylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5]Nonan-7-ylmethyl, pyrrolidinylmethyl, morpholinomethyl, azetidinylmethyl, piperidinylmethyl, 4- (dimethylamino) piperidin-1-ylmethyl, 4- (3-methoxyacridin-1-yl) piperidin-1-ylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5]The nonan-7-ylmethyl group may be optionally substituted by one or more substituents independently selected from the group consisting of: halogen, methyl, ethyl, isopropyl, cyclopropyl;

x is O or S;

Z is N or CR ¹⁹ ；

R ¹⁹ Is a hydrogen atom;

m and n are independently 1, 2, 3 or 4;

p is 0, 1, 2 or 3.

2. The macrocyclic compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer thereof, wherein,

when R is ¹ And when the warhead group is selected from the group consisting of:

R ² is a hydrogen atom, halogen, methyl, ethyl, trifluoromethyl, dimethylaminomethyl, N, N, N' -trimethylethylenediamine-based methyl, pyrrolidinylmethyl, morpholinomethyl, azetidinylmethyl, piperidinylmethyl, 4- (dimethylamino) piperidin-1-ylmethyl, 4- (3-methoxyacridin-1-yl) piperidin-1-ylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5]Nonan-7-ylmethyl, pyrrolidinylmethyl, morpholinomethyl, azetidinylmethyl, piperidinylmethyl, 4- (dimethylamino) piperidin-1-ylmethyl, 4- (3-methoxyacridin-1-yl) piperidin-1-ylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5]The nonan-7-ylmethyl group may be optionally substituted by one or more substituents independently selected from the group consisting of: halogen, methyl, ethyl, isopropyl, cyclopropyl; r is R ⁴ Is a hydrogen atom or a methyl group.

3. The macrocyclic compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer thereof, wherein,

R ² is hydrogen atom, halogen, methyl, ethyl, pyrrolidinylmethyl, morpholinomethyl, azetidinylmethyl, piperidinylmethyl, 4- (dimethylamino) piperidin-1-ylmethyl, 4- (3-methoxyacridin-1-yl) piperidin-1-ylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5 ]]Nonan-7-ylmethyl, pyrrolidinylmethyl, morpholinomethyl, azetidinylmethyl, piperidinylmethyl, 4- (dimethylamino) piperidin-1-ylmethyl, 4- (3-methoxyacridin-1-yl) piperidin-1-ylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5]The nonan-7-ylmethyl group may be optionally substituted by one or more substituents independently selected from the group consisting of: halogen, methyl, ethyl, isopropyl, cyclopropyl; r is R ⁴ Is a hydrogen atom or a methyl group.

4. The macrocyclic compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer thereof, wherein,

R ² is hydrogen atom, methyl, ethyl, piperidinylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5 ]]Nonan-7-ylmethyl, piperidinylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5]The nonan-7-ylmethyl group may be optionally substituted by one or more substituents independently selected from the group consisting of: methyl, ethyl; r is R ⁴ Is a hydrogen atom or a methyl group.

5. The macrocyclic compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer thereof, wherein,

R ¹ is a hydrogen atom or a methyl group; r is R ⁴ Is a hydrogen atom or a methyl group.

6. The macrocyclic compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer thereof, wherein,

7. The macrocyclic compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer thereof, wherein,

8. The macrocyclic compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer thereof, wherein,

R ¹ is a hydrogen atom or a methyl group; r is R ² Is a hydrogen atom, halogen, methyl, ethyl, trifluoromethyl, dimethylaminomethyl, N, N, N' -trimethylethylenediamine-based methyl, pyrrolidinylmethyl, morpholinomethyl, azetidinylmethyl, piperidinylmethyl, 4- (dimethylamino) piperidin-1-ylmethyl, 4- (3-methoxyacridin-1-yl) piperidin-1-ylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5]Nonan-7-ylmethyl, pyrrolidinylmethyl, morpholinomethyl, azetidinylmethyl, piperidinylmethyl, 4- (dimethylamino) piperidin-1-ylmethyl, 4- (3-methoxyacridin-1-yl) piperidin-1-ylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5]The nonan-7-ylmethyl group may be optionally substituted by one or more substituents independently selected from the group consisting of: halogen, methyl, ethyl, isopropyl, cyclopropyl.

9. The macrocyclic compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer thereof, wherein,

R ¹ is a hydrogen atom or a methyl group; r is R ² Is hydrogen atom, halogen, methyl, ethyl, pyrrolidinylmethyl, morpholinomethyl, azetidinylmethyl, piperidinylmethyl, 4- (dimethylamino) piperidin-1-ylmethyl, 4- (3-methoxyacridin-1-yl) piperidin-1-ylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-yl-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5 ]]Nonan-7-ylmethyl, pyrrolidinylmethyl, morpholinomethyl, azetidinylmethyl, piperidinylmethyl, 4- (dimethylamino) piperidin-1-ylmethyl, 4- (3-methoxyacridin-1-yl) piperidin-1-ylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5]The nonan-7-ylmethyl group may be optionally substituted by one or more substituents independently selected from the group consisting of: halogen, methyl, ethyl, isopropyl, cyclopropyl.

10. The macrocyclic compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer thereof, wherein,

R ¹ is a hydrogen atom or a methyl group; r is R ² Is hydrogen atom, methyl, ethyl, piperidinylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5 ]]Nonan-7-ylmethyl, piperidinylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5]The nonan-7-ylmethyl group may be optionally substituted by one or more substituents independently selected from the group consisting of: methyl, ethyl.

11. The macrocyclic compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer thereof, wherein,

R ³ is hydrogen atom, halogen, methyl, ethyl, dimethylaminomethyl, N, N, N' -trimethylethylenediamine methyl, pyrrolidinylmethyl, morpholinomethyl, azetidinylmethyl, piperidinylmethyl, 4- (dimethylamino) piperidin-1-ylmethyl, 4- (3-methoxyacridin-1-yl) piperidin-1-ylmethyl, piperazin-1-ylmethyl, 4-methylpiperazine-17-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5 ]]Nonan-7-ylmethyl, pyrrolidinylmethyl, morpholinomethyl, azetidinylmethyl, piperidinylmethyl, 4- (dimethylamino) piperidin-1-ylmethyl, 4- (3-methoxyacridin-1-yl) piperidin-1-ylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5 ]The nonan-7-ylmethyl group may be optionally substituted by one or more substituents independently selected from the group consisting of: halogen, methyl, ethyl, isopropyl, cyclopropyl.

12. The macrocyclic compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer thereof, wherein,

R ³ is hydrogen atom, halogen, methyl, ethyl, pyrrolidinylmethyl, morpholinomethyl, azetidinylmethyl, piperidinylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5 ]]Nonan-7-ylmethyl, pyrrolidinylmethyl, morpholinomethyl, azetidinylmethyl, piperidinylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5 ]]The nonan-7-ylmethyl group may be optionally substituted by one or more substituents independently selected from the group consisting of: halogen, methyl, ethyl, isopropyl, cyclopropyl.

13. The macrocyclic compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer thereof, wherein,

R ³ is hydrogen atom, halogen, methyl, ethyl, piperidinylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5 ] ]Nonan-7-ylmethyl, piperidinylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 2- (dimethylamino) -7-azaspiro [3.5]The nonan-7-ylmethyl group may be optionally substituted by one or more substituents independently selected from the group consisting of: methyl, ethyl.

14. The macrocyclic compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer thereof, wherein,

ring A is pyridine;

ring B is benzene ring and pyrazole.

15. A compound selected from the group consisting of:

/>

16. a pharmaceutical composition comprising a compound of any one of claims 1-15, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer thereof, or a pharmaceutically acceptable carrier or excipient.

17. The pharmaceutical composition of claim 16, wherein the pharmaceutical composition is a tablet, capsule, pill, granule, powder, suppository, injection, solution, suspension, paste, patch, drop.

18. Use of a compound according to any one of claims 1-15, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer thereof, in the manufacture of an antitumor drug;

Wherein the tumor is a malignant tumor carrying EGFR gene mutation.

19. The use of claim 18, wherein the antineoplastic agent is applied to lung cancer.

20. The use according to claim 18 or 19, wherein the EGFR gene mutation is selected from the group consisting of: one or more of the Del19 EGFR gene mutation, the L858R EGFR gene mutation, the T790M EGFR gene mutation, and the C797S EGFR gene mutation.

21. Use of a pharmaceutical composition according to claim 16 or 17 for the preparation of an antitumor drug;

wherein the tumor is a malignant tumor carrying EGFR gene mutation.

22. The use according to claim 21, wherein the antineoplastic agent is applied to lung cancer.

23. The use according to claim 21 or 22, wherein the EGFR gene mutation is selected from the group consisting of: one or more of the Del19 EGFR gene mutation, the L858R EGFR gene mutation, the T790M EGFR gene mutation, and the C797S EGFR gene mutation.