Compounds for treatment and prophylaxis of respiratory syncytial virus infectious diseases

Abstract

The invention provides a compound shown in a formula (I) or a tautomer, a stereoisomer, an isotope derivative or a pharmaceutically acceptable salt thereof. The compound disclosed by the invention has a good inhibition effect on RSV (Respiratory Syndrome Virus). # imgabs0 #

Description

[0001] This application claims the priority of two prior applications filed with the State Intellectual Property Office of China on July 10, 2023, with patent application number 202310837957.0, and filed with the State Intellectual Property Office of China on March 8, 2024, with patent application number 202410267846.5, both of which are entitled "Compounds for the Treatment and Prevention of Respiratory Syncytial Virus Infection Diseases". The full texts of the two applications are incorporated into this application by reference. Technical Field

[0002] The present invention relates to the field of medical technology, and in particular to a RSV inhibitor derivative and a preparation method and use thereof. Background Art

[0003] Respiratory syncytial virus (RSV) is a negative-stranded single-stranded RNA virus of the genus Pneumovirus in the family Paramyxoviridae. Respiratory syncytial virus can cause respiratory tract infections, from the upper respiratory tract to the lower respiratory tract, leading to airway infections and symptoms such as bronchiolitis, pneumonia, and in some cases, respiratory failure. It is estimated that RSV is the most important viral source of acute lower respiratory tract infections (ALRT1) in children under 5 years old. Globally, almost all children are infected with respiratory syncytial virus before the age of 2 years, of which ~40% develop into LRTI, and more severe cases can be seen under 6 months of age (possibly related to the imperfect immune system of infants and young children). In addition to infants, the elderly with underlying cardiopulmonary diseases such as chronic obstructive pulmonary disease are also increasingly considered to be at high risk for severe infections.

[0004] RSV seriously affects human health, but there is still no effective treatment. The FDA has so far only approved the small molecule nucleoside drug ribavirin for the treatment of severe RSV infection in hospitalized children, but its antiviral effect is poor and lacks specificity, resulting in high drug toxicity. It is currently not recommended for clinical use as a therapeutic drug. Other approved drugs such as Palivizumab and Nirsevimab are a class of highly effective monoclonal antibodies that act on fusion proteins related to viral replication and can provide relatively long-term protection for infants. However, the use of such drugs is complicated and expensive, which is not conducive to widespread use.

[0005] So far, a variety of anti-RSV small molecule inhibitors acting on different targets have been reported. Targeting the conserved F protein in the viral replication process, Johnson & Johnson reported a class of inhibitors with benzimidazole as the parent core, with representative molecules such as JNJ-53718678, and Gilead reported a class of pyrrolopyridine inhibitors GS-5806, but they all failed in Phase II clinical trials. Roche reported a class of small molecule inhibitors with quinazoline as the parent core in 2013, which achieved good therapeutic effects in clinical trials in 2022. Multiple small molecule inhibitors have also been reported for other conserved proteins in the viral replication process, such as L protein, N protein, etc. However, no small molecule inhibitors have yet to be approved for marketing.

[0006] Therefore, developing highly effective small molecule inhibitors targeting the specific conformation of the conserved F protein of the RSV virus to exert good antiviral effects can provide new treatment options for RSV infection and related diseases.

[0007] Currently, there is no proven effective antiviral drug for the treatment of RSV. RSV inhibitors in preclinical studies generally have problems with low in vivo exposure and high clearance rate. Therefore, the development of RSV inhibitors has broad prospects and can fill the major gap in the clinical treatment of this disease. Summary of the invention

[0008] The present invention provides a novel structure of anti-RSV virus compounds or their tautomers, stereoisomers, isotope derivatives or pharmaceutically acceptable salts, and also provides the use of the compounds or their tautomers, stereoisomers, isotope derivatives or pharmaceutically acceptable salts in drugs for preventing and / or treating diseases caused by RSV virus infection.

[0009] Specifically, the present invention provides a compound represented by formula (I), or its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt, which has the following structure:

[0010]

[0011] in,

[0012] Cy1 is independently selected from the group consisting of absence, C 4-12 Carbocyclic group, 4-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl; when Cy1 is absent, R 1 Connected to the heteroaromatic ring,

[0013] R 1 are independently selected from: hydrogen, deuterium, halogen, oxo, hydroxy, amino, nitro, cyano, -R a1 、-ORa1 、-SR a1 、-N(R a1 ) 2 、-S(O) 2 R a1 、-S(O) 2 N(R a1 ) 2 、-S(O)R a1 、-S(O)(NR a1 )R a1 、-S(O)N(R a1 ) 2 、-P(O)(OR a1 ) 2 、-P(O)(N(R a1 ) 2 ) 2 、-SC(R a1 ) 3 、-C(R a1 ) 2 OR a1 、-C(R a1 ) 2 N(R a1 ) 2 、-C(O)R a1 、-C(O)OR a1 、-C(O)N(R a1 ) 2 、-C(O)OR a1 -OC(O)R a1 、-C(O)N(R a1 )OR a1 、-OC(O)R a1 、-OC(O)N(R a1 ) 2 、-N(R a1 )C(O)OR a1 、-N(R a1 )C(O)R a1 、-N(R a1 )C(O)N(R a1 ) 2 、-N(R a1 )S(O) 2 R a1 、-C(S)R a1 、-C(S)OR a1 、-C(S)N(R a1 ) 2 、-C(S)N(R a1 )OR a1 、-OC(S)R a1、-OC(S)N(R a1 ) 2 ;

[0014] R a1 Independently selected from: hydrogen, deuterium, C 1-6 Alkyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, optionally substituted with one or more R a2 replace;

[0015] or two R attached to the same atom a1 Together with the atoms to which they are attached, they form deuterated, halogen, oxo, hydroxyl, amino, nitro, cyano, thiol, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl, one or more arbitrarily substituted C 3-12 Carbocyclyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl;

[0016] R a2 are independently selected from: deuterium, halogen, oxo, hydroxyl, amino, nitro, cyano, thiol, C 1-6 Alkyl, C 1-6 Alkoxy;

[0017] X 1 Independently selected from CR 2 or N;

[0018] X is independently selected from CR 2 or N;

[0019] R 2 are independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano, -OR b1 、-SR b1 、-N(R b1 ) 2 、-S(O) 2 R b1 、-S(O) 2 N(R b1 ) 2 、-S(O)R b1 、-S(O)(NR b1 )R b1 、-S(O)N(R b1 ) 2、-P(O)(OR b1 ) 2 、-P(O)(N(R b1 ) 2 ) 2 ,-C(R b1 ) 2 (OR b1 )、-C(R b1 ) 2 N(R b1 ) 2 、-C(O)R b1 、-C(O)OR b1 、-C(O)N(R b1 ) 2 、-C(O)N(R b1 )OR b1 、-OC(O)R b1 、-OC(O)N(R b1 ) 2 、-N(R b1 )C(O)OR b1 、-N(R b1 )C(O)R b1 、-N(R b1 )C(O)N(R b1 ) 2 、-N(R b1 )S(O) 2 R b1 , C 1-6 Alkyl, C 3-7 Carbocyclic group, 3-7 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl is optionally substituted with one or more R b2 replace;

[0020] R b1 Independently selected from: hydrogen, deuterium, C 1-6 Alkyl, C 3-7 carbocyclic group, 4-7 membered heterocyclic group, phenyl group, 5-6 membered heteroaryl group; the C 1-6 Alkyl, C 3-7 The carbocyclic group, 4-7 membered heterocyclic group, phenyl group or 5-6 membered heteroaryl group are optionally substituted with one or more selected from deuterium, halogen, oxo, hydroxyl, amino, nitro, cyano, mercapto, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14substituted by a substituent of an aryl group or a 5-12-membered heteroaryl group;

[0021] or two R attached to the same atom b1 Together with the atoms to which they are attached, they form deuterated, halogen, oxo, hydroxyl, amino, nitro, cyano, thiol, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl, 5-12 membered heteroaryl, one or more arbitrarily substituted C 3-12 Carbocyclyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl;

[0022] R b2 are independently selected from: deuterium, halogen, oxo, hydroxyl, amino, nitro, cyano, thiol, C 1-6 Alkyl, C 1-6 Alkoxy;

[0023] m is independently selected from: 0, 1, 2, 3, 4;

[0024] Q is independently selected from: deuterium, halogen, -R 3 、-OR 3 、-SR 3 、-N(R 3 )-C 0-6 Alkylene-R 3 、-N(R 3 )-C 0-6 Alkylene-N(R 3 ) 2 、-S(O) 2 R 3 、-S(O) 2 N(R 3 ) 2 、-S(O)R 3 、-S(O)(NR 3 )R 3 、-S(O)N(R 3 ) 2 、-P(O)(OR 3 ) 2 、-P(O)(N(R 3 ) 2 ) 2 ,-C(R 3 ) 2 (OR 3 )、-C(R 3 ) 2 N(R 3 ) 2 、-C(O)R 3 、-C(O)OR3 、-C(O)N(R 3 ) 2 、-C(O)N(R 3 )OR 3 、-OC(O)R 3 、-OC(O)N(R 3 ) 2 、-N(R 3 )C(O)OR 3 、-N(R 3 )C(O)R 3 、-N(R 3 )C(O)N(R 3 ) 2 、-N(R 3 )S(O) 2 R 3 The alkylene group is optionally replaced by one or more R c1 replace;

[0025] R 3 Each independently selected from: hydrogen, deuterium, C 1-6 Alkyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, optionally substituted with one or more R c2 replace;

[0026] or two R attached to the same nitrogen atom 3 Together with the nitrogen atom to which they are attached, they form halogen, hydroxyl, amino, -C(O)NH 2 、-(CH 2 ) 1-6 NH 2 , oxo, C 1-6 Alkyl, C 1-6 Alkoxy, oxetanylamino, C 1-6 One or more arbitrarily substituted 3-12 membered heterocyclic groups or 5-12 membered heteroaryl groups in the alkylpiperazinyl group;

[0027] R c1 are independently selected from: deuterium, halogen, hydroxyl, amino, nitro, cyano, thiol, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl;

[0028] R c2Independently selected from: deuterium, oxo, halogen, hydroxyl, amino, cyano, -OR c3 、-SR c3 、-N(R c3 ) 2 、-S(O) 2 R c3 、-S(O) 2 N(R c3 ) 2 、-S(O)R c3 、-S(O)(NR c3 )R c3 、-P(O)(OR c3 ) 2 、-P(O)(N(R c3 ) 2 ) 2 ,-C(R c3 ) 2 (OR c3 )、-C(R c3 ) 2 N(R c3 ) 2 、-C(O)R c3 、-C(O)OR c3 、-C(O)N(R c3 ) 2 、-C(O)N(R c3 )OR c3 、-OC(O)R c3 、-OC(O)N(R c3 ) 2 、-N(R c3 )C(O)OR c3 、-N(R c3 )C(O)R c3 、-N(R c3 )C(O)N(R c3 ) 2 、-N(R c3 )C(O)R c3 N(R c3 )OC(O)R c3 、-N(R c3 )S(O) 2 R c3 , C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl; said C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl or 5-8 membered heteroaryl is optionally substituted with one or more Rc4 replace;

[0029] R c3 , R c4 are independently selected from: hydrogen, deuterium, oxo, halogen, hydroxyl, amino, C 1-18 Alkyl, C 1-6 Alkoxy, C 1-6 haloalkyl, optionally substituted with one or more hydroxyl groups 1-6 alkyl, optionally substituted by one or more amino groups 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-6 membered heteroaryl;

[0030] Het has the following structure:

[0031]

[0032]

[0033] in,

[0034] When A or B and When connected, A and B are independently selected from -C(R d1 )-、-N-、 The "#" is a link one end of

[0035] When A or B does not When connected, A and B are independently selected from a bond, -C(R d1 ) 2 -、-NR d1 -、-C(R d1 ) 2 N(R d1 )-、-NR d1 C(R d1 ) 2 -;

[0036] R d1 are independently selected from: absence, bond, hydrogen, deuterium, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl; or two R attached to the same carbon atom d1 Together they form an oxo group;

[0037] When R d1 When it does not exist, That is

[0038] Y is independently selected from -O-, -N(R d2 )-、-C(R d2 )2 -, -S-, -C(O)-, -C(=N-OC 0-6 Alkyl)-、-S(O)-、-S(O) 2 -、-S(O)(=NR d2 )-;

[0039] R d2 Independently selected from: hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano, -OR d3 、-SR d3 、-N(R d3 ) 2 、-C(O)R d3 、-(C 1-6 Alkylene)-C(O)R d3 、-(C 1-6 Alkylene)-S(O) 2 R d3 、-C(O)OR d3 、-(C 1-6 Alkylene)-C(O)OR d3 、-C(O)N(R d3 ) 2 、-(C 1-6 Alkylene)-C(O)N(R d3 ) 2 、-C(O)-(C 1-6 Alkylene)-N(R d3 ) 2 、-S(O) 2 R d3 、-S(O) 2 N(R d3 ) 2 、-S(O)R d3 、-C(O)N(R d3 )OR d3 、-OC(O)R d3 、-OC(O)N(R d3 ) 2 、-N(R d3 )C(O)OR d3 、-N(R d3 )C(O)R d3 、-N(R d3 )C(O)N(R d3 ) 2 、-N(R d3 )S(O) 2 R d3 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12Carbocyclic group, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 1-6 Alkylene, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, optionally substituted with one or more selected from deuterium, halogen, oxo, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by a substituent of an aryl group or a 5-12-membered heteroaryl group;

[0040] R d3 are independently selected from: hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, optionally substituted with one or more selected from deuterium, halogen, oxo, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0041] R 13 , R 14 , R 15 , R 16 are independently selected from: hydrogen, deuterium, oxo, halogen, hydroxyl, amino, imino, sulfinamide, nitro, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12Aryl, 5-12 membered heteroaryl, optionally substituted with one or more R d4 Replace; when R 13 , R 14 When one of them is selected from oxo and imino, the other is absent; when R 15 , R 16 When one of them is selected from an oxo group and an imino group, the other one does not exist;

[0042] or R 13 and R 14 Together with the carbon atoms to which they are attached, they form groups that are substituted by halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 One or more arbitrarily substituted C 3-12 Carbocyclic group or 3-12 membered heterocyclic group;

[0043] or R 15 and R 16 Together with the carbon atoms to which they are attached, they form groups that are substituted by halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 One or more arbitrarily substituted C 3-12 Carbocyclic group or 3-12 membered heterocyclic group;

[0044] R d4 are independently selected from: deuterium, halogen, oxo, hydroxy, amino, cyano, sulfonyl, urea, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl; said C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl is optionally substituted with one or more halogens;

[0045] Cy2 is independently selected from: phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl;

[0046] Cy3 is independently selected from: phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl;

[0047] R 17 and R 18 are independently selected from: deuterium, halogen, hydroxyl, amino, cyano, nitro, carboxyl, oxo, -OR d5 、-SR d5 、-N(R d5 ) 2 、-S(O) 2 R d5 、-S(O) 2 N(Rd5 ) 2 、-S(O)R d5 、-S(O)(NR d5 )R d5 、-S(O)N(R d5 ) 2 、-P(O)(OR d5 ) 2 、-P(O)(N(R d5 ) 2 ) 2 ,-C(R d5 ) 2 (OR d5 )、-C(R d5 ) 2 N(R d5 ) 2 、-C(O)R d5 、-C(O)OR d5 、-C(O)N(R d5 ) 2 、-C(O)N(R d5 )OR d5 、-OC(O)R d5 、-OC(O)N(R d5 ) 2 、-N(R d5 )C(O)OR d5 、-N(R d5 )C(O)R d5 、-N(R d5 )C(O)N(R d5 ) 2 、-N(R d5 )S(O) 2 R d5 、-N(R d5 )S(O) 2 N(R d5 ) 2 、-N(R d5 )S(O) 2 O(R d5 ), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12Aryl, 5-12 membered heteroaryl, optionally substituted with one or more selected from deuterium, halogen, oxo, hydroxyl, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Substituted by a cycloalkyl substituent;

[0048] R d5 Independently selected from: hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are optionally substituted by one or more substituents selected from deuterium, halogen, hydroxyl, amino, cyano and carboxyl;

[0049] Z is independently selected from C, N;

[0050] E is independently selected from: -C(R d6 ) 2 -、-N(R d6 )-;

[0051] R d6 are independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, amino, cyano, nitro, sulfenamide, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl may be optionally substituted by one or more substituents selected from deuterium, halogen, oxo, hydroxyl, amino, carboxyl, cyano; or two R groups attached to the same carbon atom may be substituted by one or more substituents selected from deuterium, halogen, oxo, hydroxyl, amino, carboxyl, cyano. d6 Together they form an oxo group, a thio group, or an imino group; or two R groups connected to the same carbon atom d6Together with the carbon atoms to which they are attached, they form a C 3-15 Carbocyclic group, 3-15 membered heterocyclic group;

[0052] n and q are independently selected from 0, 1, 2, 3, and 4;

[0053] When multiple R a1 , R a2 , R b1 , R b2 , R c1 , R c2 , R c3 , R c4 , R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R 1 , R 3 , R 17 , R 18 When they appear simultaneously, each R a1 , each R a2 , each R b1 , each R b2 , each R c1 , each R c2 , each R c3 , each R d1 , each R d2 , each R d3 , each R d4 , each R d5 , each R d6 , each R 1 , each R 3 , each R 17 , each R 18 Can be the same or different.

[0054] In some embodiments, a compound represented by the following formula (I), or a tautomer, stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the compound is provided:

[0055]

[0056] in,

[0057] Cy1 is independently selected from the group consisting of absence, C 4-12 Carbocyclic group, 4-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl; when Cy1 is absent, R 1Connected to the heteroaromatic ring,

[0058] R 1 are independently selected from: hydrogen, deuterium, halogen, oxo, hydroxy, amino, nitro, cyano, -R a1 、-OR a1 、-SR a1 、-N(R a1 ) 2 、-S(O) 2 R a1 、-S(O) 2 N(R a1 ) 2 、-S(O)R a1 、-S(O)(NR a1 )R a1 、-S(O)N(R a1 ) 2 、-P(O)(OR a1 ) 2 、-P(O)(N(R a1 ) 2 ) 2 、-SC(R a1 ) 3 ,-C(R a1 ) 2 OR a1 ,-C(R a1 ) 2 N(R a1 ) 2 、-C(O)R a1 、-C(O)OR a1 、-C(O)N(R a1 ) 2 、-C(O)OR a1 -OC(O)R a1 、-C(O)N(R a1 )OR a1 、-OC(O)R a1 、-OC(O)N(R a1 ) 2 、-N(R a1 )C(O)OR a1 、-N(R a1 )C(O)R a1 、-N(R a1 )C(O)N(R a1 ) 2 、-N(R a1 )S(O) 2 R a1 、-C(S)R a1 、-C(S)ORa1 、-C(S)N(R a1 ) 2 、-C(S)N(R a1 )OR a1 、-OC(S)R a1 、-OC(S)N(R a1 ) 2 ;

[0059] R a1 Independently selected from: hydrogen, deuterium, C 1-6 Alkyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, optionally substituted with one or more R a2 replace;

[0060] or two R attached to the same atom a1 Together with the atoms to which they are attached, they form deuterated, halogen, oxo, hydroxyl, amino, nitro, cyano, thiol, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl, one or more arbitrarily substituted C 3-12 Carbocyclyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl;

[0061] R a2 are independently selected from: deuterium, halogen, oxo, hydroxyl, amino, nitro, cyano, thiol, C 1-6 Alkyl, C 1-6 Alkoxy;

[0062] X is independently selected from CR 2 or N;

[0063] R 2 are independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano, -OR b1 、-SR b1 、-N(R b1 ) 2 、-S(O) 2 R b1 、-S(O) 2 N(R b1 ) 2 、-S(O)R b1 、-S(O)(NR b1 )Rb1 、-S(O)N(R b1 ) 2 、-P(O)(OR b1 ) 2 、-P(O)(N(R b1 ) 2 ) 2 ,-C(R b1 ) 2 (OR b1 )、-C(R b1 ) 2 N(R b1 ) 2 、-C(O)R b1 、-C(O)OR b1 、-C(O)N(R b1 ) 2 、-C(O)N(R b1 )OR b1 、-OC(O)R b1 、-OC(O)N(R b1 ) 2 、-N(R b1 )C(O)OR b1 、-N(R b1 )C(O)R b1 、-N(R b1 )C(O)N(R b1 ) 2 、-N(R b1 )S(O) 2 R b1 , C 1-6 Alkyl, C 3-7 Carbocyclic group, 3-7 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl is optionally substituted with one or more R b2 replace;

[0064] R b1 Independently selected from: hydrogen, deuterium, C 1-6 Alkyl, C 3-7 carbocyclic group, 4-7 membered heterocyclic group, phenyl group, 5-6 membered heteroaryl group; the C 1-6 Alkyl, C 3-7 The carbocyclic group, 4-7 membered heterocyclic group, phenyl group or 5-6 membered heteroaryl group are optionally substituted with one or more selected from deuterium, halogen, oxo, hydroxyl, amino, nitro, cyano, mercapto, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 substituted by a substituent of an aryl group or a 5-12-membered heteroaryl group;

[0065] or two R attached to the same atom b1 Together with the atoms to which they are attached, they form deuterated, halogen, oxo, hydroxyl, amino, nitro, cyano, thiol, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl, 5-12 membered heteroaryl, one or more arbitrarily substituted C 3-12 Carbocyclyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl;

[0066] R b2 are independently selected from: deuterium, halogen, oxo, hydroxyl, amino, nitro, cyano, thiol, C 1-6 Alkyl, C 1-6 Alkoxy;

[0067] m is independently selected from: 0, 1, 2, 3, 4;

[0068] Q is independently selected from: deuterium, halogen, -R 3 、-OR 3 、-SR 3 、-N(R 3 )-C 0-6 Alkylene-R 3 、-N(R 3 )-C 0-6 Alkylene-N(R 3 ) 2 、-S(O) 2 R 3 、-S(O) 2 N(R 3 ) 2 、-S(O)R 3 、-S(O)(NR 3 )R 3 、-S(O)N(R 3 ) 2 、-P(O)(OR 3 ) 2 、-P(O)(N(R 3 ) 2 ) 2 ,-C(R 3 ) 2 (OR 3 )、-C(R 3 ) 2 N(R 3 ) 2、-C(O)R 3 、-C(O)OR 3 、-C(O)N(R 3 ) 2 、-C(O)N(R 3 )OR 3 、-OC(O)R 3 、-OC(O)N(R 3 ) 2 、-N(R 3 )C(O)OR 3 、-N(R 3 )C(O)R 3 、-N(R 3 )C(O)N(R 3 ) 2 、-N(R 3 )S(O) 2 R 3 The alkylene group is optionally replaced by one or more R c1 replace;

[0069] R 3 Each independently selected from: hydrogen, deuterium, C 1-6 Alkyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, optionally substituted with one or more R c2 replace;

[0070] or two R attached to the same nitrogen atom 3 Together with the nitrogen atom to which they are attached, they form halogen, hydroxyl, amino, -C(O)NH 2 、-(CH 2 ) 1-6 NH 2 , oxo, C 1-6 Alkyl, C 1-6 Alkoxy, oxetanylamino, C 1-6 One or more arbitrarily substituted 3-12 membered heterocyclic groups or 5-12 membered heteroaryl groups in the alkylpiperazinyl group;

[0071] R c1 are independently selected from: deuterium, halogen, hydroxyl, amino, nitro, cyano, thiol, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl;

[0072] R c2 Independently selected from: deuterium, oxo, halogen, hydroxyl, amino, -OR c3 、-SR c3 、-N(R c3 ) 2 、-S(O) 2 R c3 、-S(O) 2 N(R c3 ) 2 、-S(O)R c3 、-S(O)(NR c3 )R c3 、-P(O)(OR c3 ) 2 、-P(O)(N(R c3 ) 2 ) 2 ,-C(R c3 ) 2 (OR c3 )、-C(R c3 ) 2 N(R c3 ) 2 、-C(O)R c3 、-C(O)OR c3 、-C(O)N(R c3 ) 2 、-C(O)N(R c3 )OR c3 、-OC(O)R c3 、-OC(O)N(R c3 ) 2 、-N(R c3 )C(O)OR c3 、-N(R c3 )C(O)R c3 、-N(R c3 )C(O)N(R c3 ) 2 、-N(R c3 )C(O)R c3 N(R c3 )OC(O)R c3 、-N(R c3 )S(O) 2 R c3 , C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl; said C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8Aryl or 5-8 membered heteroaryl is optionally substituted with one or more R c4 replace;

[0073] R c3 , R c4 are independently selected from: hydrogen, deuterium, oxo, halogen, hydroxyl, amino, C 1-18 Alkyl, C 1-6 Alkoxy, C 1-6 haloalkyl, optionally substituted with one or more hydroxyl groups 1-6 alkyl, optionally substituted by one or more amino groups 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-6 membered heteroaryl;

[0074] Het has the following structure:

[0075]

[0076] in,

[0077] When A or B and When connected, A and B are independently selected from -C(R d1 )-、-N-、 The "#" is a link one end of

[0078] When A or B does not When connected, A and B are independently selected from a bond, -C(R d1 ) 2 -、-NR d1 -、-C(R d1 ) 2 N(R d1 )-、-NR d1 C(R d1 ) 2 -;

[0079] R d1 are independently selected from: absence, bond, hydrogen, deuterium, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl; or two R attached to the same carbon atom d1 Together they form an oxo group;

[0080] Y is independently selected from -O-, -N(R d2 )-、-C(R d2 ) 2 -, -S-, -C(O)-, -C(=N-OC 0-6 Alkyl)-、-S(O)-、-S(O) 2 -、-S(O)(=NRd2 )-;

[0081] R d2 Independently selected from: hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano, -OR d3 、-SR d3 、-N(R d3 ) 2 、-C(O)R d3 、-(C 1-6 Alkylene)-C(O)R d3 、-C(O)OR d3 、-(C 1-6 Alkylene)-C(O)OR d3 、-C(O)N(R d3 ) 2 、-(C 1-6 Alkylene)-C(O)N(R d3 ) 2 、-C(O)-(C 1-6 Alkylene)-N(R d3 ) 2 、-S(O) 2 R d3 、-S(O) 2 N(R d3 ) 2 、-S(O)R d3 、-C(O)N(R d3 )OR d3 、-OC(O)R d3 、-OC(O)N(R d3 ) 2 、-N(R d3 )C(O)OR d3 、-N(R d3 )C(O)R d3 、-N(R d3 )C(O)N(R d3 ) 2 、-N(R d3 )S(O) 2 R d3 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 1-6 Alkylene, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C6-12 Aryl, 5-12 membered heteroaryl, optionally substituted with one or more selected from deuterium, halogen, oxo, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0082] R d3 are independently selected from: hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, optionally substituted with one or more selected from deuterium, halogen, oxo, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0083] R 13 , R 14 , R 15 , R 16 are independently selected from: hydrogen, deuterium, oxo, halogen, hydroxyl, amino, imino, sulfinamide, nitro, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, optionally substituted with one or more R d4 Replace; when R 13 , R 14 When one of them is selected from oxo and imino, the other is absent; when R 15 , R 16 When one of them is selected from an oxo group and an imino group, the other one does not exist;

[0084] or R 13 and R 14Together with the carbon atoms to which they are attached, they form groups that are substituted by halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 One or more arbitrarily substituted C 3-12 Carbocyclic group or 3-12 membered heterocyclic group;

[0085] or R 15 and R 16 Together with the carbon atoms to which they are attached, they form groups that are substituted by halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 One or more arbitrarily substituted C 3-12 Carbocyclic group or 3-12 membered heterocyclic group;

[0086] R d4 are independently selected from: deuterium, halogen, oxo, hydroxy, amino, cyano, sulfonyl, urea, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl; said C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl is optionally substituted with one or more halogens;

[0087] Cy2 is independently selected from: phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl;

[0088] Cy3 is independently selected from: phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl;

[0089] R 17 and R 18 are independently selected from: deuterium, halogen, hydroxyl, amino, cyano, nitro, carboxyl, oxo, -OR d5 、-SR d5 、-N(R d5 ) 2 、-S(O) 2 R d5 、-S(O) 2 N(R d5 ) 2 、-S(O)R d5 、-S(O)(NR d5 )R d5 、-S(O)N(R d5 ) 2 、-P(O)(OR d5 ) 2 、-P(O)(N(R d5 ) 2 ) 2,-C(R d5 ) 2 (OR d5 )、-C(R d5 ) 2 N(R d5 ) 2 、-C(O)R d5 、-C(O)OR d5 、-C(O)N(R d5 ) 2 、-C(O)N(R d5 )OR d5 、-OC(O)R d5 、-OC(O)N(R d5 ) 2 、-N(R d5 )C(O)OR d5 、-N(R d5 )C(O)R d5 、-N(R d5 )C(O)N(R d5 ) 2 、-N(R d5 )S(O) 2 R d5 、-N(R d5 )S(O) 2 N(R d5 ) 2 、-N(R d5 )S(O) 2 O(R d5 ), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, optionally substituted with one or more selected from deuterium, halogen, oxo, hydroxyl, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Substituted by a cycloalkyl substituent;

[0090] R d5Independently selected from: hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are optionally substituted by one or more substituents selected from deuterium, halogen, hydroxyl, amino, cyano and carboxyl;

[0091] Z is independently selected from C, N;

[0092] E is independently selected from: -C(R d6 ) 2 -、-N(R d6 )-;

[0093] R d6 are independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, amino, cyano, nitro, sulfenamide, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl may be optionally substituted by one or more substituents selected from deuterium, halogen, oxo, hydroxyl, amino, carboxyl, cyano; or two R groups attached to the same carbon atom may be substituted by one or more substituents selected from deuterium, halogen, oxo, hydroxyl, amino, carboxyl, cyano. d6 Together they form an oxo group, a thio group, or an imino group; or two R groups connected to the same carbon atom d6 Together with the carbon atoms to which they are attached, they form a C 3-15 Carbocyclic group, 3-15 membered heterocyclic group;

[0094] n and q are independently selected from 0, 1, 2, 3, and 4;

[0095] When multiple R a1 , R a2 , R b1 , R b2 , R c1 , Rc2 , R c3 , R c4 , R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R 1 , R 3 , R 17 , R 18 When they appear simultaneously, each R a1 , each R a2 , each R b1 , each R b2 , each R c1 , each R c2 , each R c3 , each R d1 , each R d2 , each R d3 , each R d4 , each R d5 , each R d6 , each R 1 , each R 3 , each R 17 , each R 18 Can be the same or different.

[0096] In a preferred embodiment of the present invention, wherein Cy1 is independently selected from C 4-6 Carbocyclic group, 4-6 membered heterocyclic group, phenyl group, 5-6 membered heteroaryl group.

[0097] In a further preferred embodiment, wherein Cy1 is independently selected from 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl.

[0098] In a further preferred embodiment, Cy1 is independently selected from a 5-6 membered heterocyclic group, a phenyl group, a 5-6 membered heteroaryl group; the heteroatom in the heterocyclic group or the heteroaryl group is selected from N or S, and the number of the heteroatoms is 1, 2 or 3.

[0099] In a preferred embodiment of the present invention, wherein Cy1 is independently selected from 4-12 membered heterocyclic groups, C 5-12 Aryl.

[0100] In a further preferred embodiment, wherein Cy1 is independently selected from 5-6 membered heterocyclic group and phenyl.

[0101] In a further preferred embodiment, Cy1 is independently selected from a 5-6 membered heterocyclic group and a phenyl group; the heteroatom in the heterocyclic group is selected from N, and the number of the heteroatom is 1.

[0102] In a further preferred embodiment, wherein Cy1 is independently selected from phenyl.

[0103] In a preferred embodiment of the present invention, Cy1 is independently selected from a 5-6 membered heterocyclic group; the heteroatom in the heterocyclic group is selected from N or S.

[0104] In a preferred embodiment of the present invention, wherein Cy1 is independently selected from the following groups:

[0105]

[0106] In a further preferred embodiment, wherein Cy1 is independently selected from the following groups:

[0107] In a preferred embodiment of the present invention, Independently selected from the following groups:

[0108]

[0109] In a further preferred embodiment, wherein, Selected from the following groups:

[0110] More preferred

[0111] In a further preferred embodiment, wherein, Independently selected from the following groups:

[0112] In a preferred embodiment of the present invention, Cy1 is absent.

[0113] In a preferred embodiment of the present invention, Cy1 is absent; R 1 Independently selected from: -C(O)C 1-4 Alkyl, -C 1-4 Alkyl-OH, C 1-4 Alkoxy, -C(O)OC 1-4 Alkyl, -C(O)NHC 1-4 Alkyl, C 1-4 alkyl.

[0114] In a further preferred embodiment, wherein Cy1 is absent; R 1 Independently selected from: -C(O)OCH 3 、-CH 2 OH, -OCH 3 、-C(O)OCH 2 CH 3 、-C(O)NHCH 3 .

[0115] In a preferred embodiment of the present invention, wherein R 1 are independently selected from: hydrogen, halogen, oxo, hydroxy, amino, nitro, cyano, -R a1 、-OR a1 、-SR a1 、-N(R a1 ) 2 、-S(O) 2 R a1 、-S(O) 2 N(R a1 ) 2 、-C(O)R a1 、-C(O)OR a1 、-C(O)N(R a1 ) 2 、-C(O)OR a1 -OC(O)R a1 、-N(R a1 )C(O)R a1 .

[0116] In a further preferred embodiment, wherein R 1 are independently selected from: hydrogen, halogen, oxo, hydroxy, amino, cyano, -R a1 、-S(O) 2 R a1 、-C(O)R a1 、-C(O)OR a1 、-C(O)N(R a1 ) 2 、-C(O)OR a1 -OC(O)R a1 .

[0117] In a further preferred embodiment, wherein R 1 are independently selected from: hydrogen, halogen, oxo, hydroxy, amino, cyano, -R a1 、-C(O)R a1 、-C(O)OR a1 .

[0118] In a preferred embodiment of the present invention, wherein R a1 Independently selected from: hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; said C 1-6 Alkyl, C 3-6 The cycloalkyl group is optionally substituted with one or more R a2 replace.

[0119] In a further preferred embodiment, wherein R a1Independently selected from: hydrogen, C 1-3 Alkyl, C 3-4 Cycloalkyl; said C 1-3 Alkyl, C 3-4 The cycloalkyl group is optionally substituted with one or more R a2 replace.

[0120] In a further preferred embodiment, wherein R a1 Independently selected from: C 1-3 Alkyl; the C 1-3 The alkyl group is optionally substituted with one or more R a2 replace.

[0121] In a further preferred embodiment, wherein R a1 Independently selected from: C 1-6 Alkyl, C 1-6 Halogenated alkyl.

[0122] In a further preferred embodiment, wherein R a1 Independently selected from: methyl, ethyl, n-propyl, isopropyl.

[0123] In a preferred embodiment of the present invention, wherein R a2 are independently selected from: deuterium, halogen, oxo, hydroxyl, amino, nitro, cyano, thiol, C 1-4 Alkyl, C 1-4 Alkoxy.

[0124] In a further preferred embodiment, wherein R a2 Independently selected from halogen (eg, fluorine, chlorine, bromine), hydroxy.

[0125] In a further preferred embodiment, wherein R a2 are independently selected from halogen (eg, fluorine, chlorine, bromine).

[0126] In a further preferred embodiment, wherein R a2 Independently selected from fluorine and hydroxyl.

[0127] In a further preferred embodiment, wherein R a2 are independently selected from fluorine.

[0128] In a preferred embodiment of the present invention, wherein R 1 are independently selected from: hydrogen, fluorine, chlorine, bromine, oxo, hydroxyl, amino, -R a1 、-OR a1 、-S(O) 2 R a1 、-C(O)R a1 、-C(O)OR a1 、-C(O)N(Ra1 ) 2 、-C(O)OR a1 -OC(O)R a1 ;

[0129] R a1 Independently selected from: hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; said C 1-6 Alkyl, C 3-6 The cycloalkyl group is optionally substituted with one or more R a2 replace;

[0130] R a2 Independently selected from: fluorine, chlorine, bromine, oxo, hydroxyl, amino.

[0131] In a preferred embodiment of the present invention, wherein R 1 are independently selected from: hydrogen, halogen, oxo, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, -C(O)OC 1-6 Alkyl, -C(O)NHC 1-6 Alkyl, -C(O)O-(C 1-6 Alkyl)-OC(O)C 1-6 alkyl.

[0132] In a further preferred embodiment, wherein R 1 Independently selected from: hydrogen, halogen, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkyl, -S(O) 2 C 1-4 Alkyl, -C(O)C 1-4 Alkyl, -C(O)C 1-4 Haloalkyl, -C(O)OC 1-4 Alkyl, -C(O)NHC 1-4 Alkyl, -C(O)O-(C 1-4 Alkyl)-OC(O)C 1-4 alkyl.

[0133] In a further preferred embodiment, wherein R 1 Independently selected from: hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, -C(O)OC 1-6 alkyl.

[0134] In a further preferred embodiment, wherein R 1 Independently selected from: hydrogen, fluorine, chlorine, bromine, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, -C(O)C 1-3 Alkyl, -C(O)C 1-3 Haloalkyl, -C(O)OC 1-3 alkyl.

[0135] In a further preferred embodiment, wherein R 1 Independently selected from: hydrogen, C 1-2 Alkyl, C 1-2 Haloalkyl, -C(O)C 1-2 Halogenated alkyl.

[0136] In a further preferred embodiment, wherein R 1 Independently selected from: hydrogen, C 1-2 Alkyl, C 1-2 Halogenated alkyl.

[0137] In a further preferred embodiment, wherein R 1 are independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 F, -CF 2 H, -CF 3 、-CH 2 CF 3 、-C(O)CH 3 、-C(O)CH 2 CH 3 、-S(O) 2 CH 3 、-CH 2 OH, -C(O)CF 3 、-C(O)CF 2 H、-C(O)OCH 3 、-C(O)OCH 2 CH3 、-C(O)NHCH 3 、-C(O)O-CH(CH 3 )-OC(O)CH(CH 3 ) 2 .

[0138] In a further preferred embodiment, wherein R 1 Independently selected from: hydrogen, methyl, -CF 2 H, -C(O)CF 3 More preferably, methyl, -CF 2 H.

[0139] In a preferred embodiment of the present invention, wherein R 1 Independently selected from C 1-4 alkyl.

[0140] In a further preferred embodiment, wherein R 1 are independently selected from methyl.

[0141] In a preferred embodiment of the present invention, wherein X 1 Selected from N.

[0142] In a preferred embodiment of the present invention, wherein X 1 Selected from CR 2 .

[0143] In a preferred embodiment of the present invention, wherein X is selected from N.

[0144] In a preferred embodiment of the present invention, wherein X is selected from CR 2 .

[0145] In a preferred embodiment of the present invention, wherein X 1 is selected from N; and X is selected from N.

[0146] In a preferred embodiment of the present invention, wherein R 2 are independently selected from halogen (e.g. fluorine, chlorine, bromine, preferably fluorine), cyano, C 1-4 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl); 1-4 The alkyl group is optionally substituted with one or more R b2 replace.

[0147] In a further preferred embodiment, wherein R 2 Independently selected from halogen (eg fluorine, chlorine, bromine, preferably fluorine), cyano.

[0148] In a preferred embodiment of the present invention, wherein X is selected from CR 2 or N; R2 independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, cyano, C 1-4 Alkyl (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl).

[0149] In a further preferred embodiment, wherein X is selected from CR 2 ; R 2 Independently selected from fluoro, cyano, methyl.

[0150] In a preferred embodiment of the present invention, m is independently selected from: 0, 1, 2, 3.

[0151] In a further preferred embodiment, wherein m is independently selected from: 0, 1, 2.

[0152] In a further preferred embodiment, wherein m is independently selected from: 1, 2.

[0153] In a further preferred embodiment, wherein m is independently selected from 1.

[0154] In a preferred embodiment of the present invention, wherein Q is independently selected from: halogen, -R 3 、-OR 3 、-N(R 3 )-C 0-6 Alkylene-R 3 、-N(R 3 )-C 0-6 Alkylene-N(R 3 ) 2 ,-C(R 3 ) 2 (OR 3 )、-C(R 3 ) 2 N(R 3 ) 2 、-C(O)R 3 、-C(O)OR 3 、-C(O)N(R 3 ) 2 、-C(O)N(R 3 )OR 3 、-OC(O)R 3 、-OC(O)N(R 3 ) 2 、-N(R 3 )C(O)OR 3 、-N(R 3 )C(O)R 3 、-N(R 3 )C(O)N(R 3 ) 2 、-N(R3 )S(O) 2 R 3 The alkylene group is optionally replaced by one or more R c1 replace.

[0155] In a further preferred embodiment, wherein Q is independently selected from: -R 3 、-N(R 3 )-C 0-6 Alkylene-R 3 、-N(R 3 )-C 0-6 Alkylene-N(R 3 ) 2 、-N(R 3 )C(O)OR 3 、-N(R 3 )C(O)R 3 、-N(R 3 )C(O)N(R 3 ) 2 、-N(R 3 )S(O) 2 R 3 The alkylene group is optionally replaced by one or more R c1 replace.

[0156] In a further preferred embodiment, wherein Q is independently selected from: -R 3 、-N(R 3 )-C 0-6 Alkylene-R 3 、-N(R 3 )-C 0-6 Alkylene-N(R 3 ) 2 The alkylene group is optionally replaced by one or more R c1 replace.

[0157] In a further preferred embodiment, wherein Q is independently selected from: -R 3 、-NH-C 0-4 Alkylene-R 3 、-NH-C 0-4 Alkylene-NHR 3 The alkylene group is optionally replaced by one or more R c1 replace.

[0158] In a further preferred embodiment, wherein Q is independently selected from: -R 3 、-NH-C 1-4 Alkylene-R 3 、-NH-C 1-4 Alkylene-NHR 3The alkylene group is optionally replaced by one or more R c1 replace.

[0159] In a further preferred embodiment, wherein Q is independently selected from: -R 3 、-NH-C 1-2 Alkylene-R 3 、-NH-C 1-4 Alkylene-NHR 3 The alkylene group is optionally replaced by one or more R c1 replace.

[0160] In a preferred embodiment of the present invention, wherein R 3 Independently selected from: hydrogen, C 1-6 Alkyl, C 3-7 carbocyclic group, 3-7 membered heterocyclic group, phenyl group, 5-6 membered heteroaryl group; the C 1-6 Alkyl, C 3-7 Carbocyclic group, 3-7 membered heterocyclic group, phenyl group, 5-6 membered heteroaryl group are optionally substituted with one or more R c2 replace;

[0161] or two R attached to the same nitrogen atom 3 Together with the nitrogen atom to which they are attached, they form halogen, hydroxyl, amino, -C(O)NH 2 、-(CH 2 ) 1-4 NH 2 , oxo, C 1-4 Alkyl, C 1-4 Alkoxy, oxetanylamino, C 1-4 The alkylpiperazinyl group may be one or more arbitrarily substituted 3-7 membered heterocyclic groups or 5-6 membered heteroaryl groups.

[0162] In a preferred embodiment of the present invention, wherein R 3 Independently selected from: hydrogen, C 1-6 Alkyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group; 1-6 Alkyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group is replaced by one or more R c2 replace.

[0163] In a further preferred embodiment, wherein R 3 Independently selected from: hydrogen, C 1-6 Alkyl, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group; said C 1-6 Alkyl, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group is replaced by one or more R c2 replace.

[0164] In a further preferred embodiment, wherein R 3 Independently selected from: hydrogen, C 1-6 Alkyl, C 3-6 Carbocyclic group, 4-10 membered heterocyclic group; said C 1-6 Alkyl, C 3-6 Carbocyclic group, 4-10 membered heterocyclic group is replaced by one or more R c2 replace.

[0165] In a further preferred embodiment, wherein R 3 Independently selected from: hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-6 bridged ring group, 3-6 membered heterocycloalkyl group, 6-10 membered heterospiro ring group, 5-10 membered bridged ring heterocyclic group, 6-10 membered heterocyclic group; the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-6 A bridged ring group, a 3-6 membered heterocycloalkyl group, a 6-10 membered heterospiro ring group, a 5-10 membered bridged ring heterocyclic group, a 6-10 membered heterocyclic group, optionally substituted by one or more R c2 replace.

[0166] In a further preferred embodiment, wherein R 3 Independently selected from: hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-6 a bridged ring group, a 3-6 membered heterocycloalkyl group, a 3-5 membered heterospirocyclic group, a 5-membered / 3-membered heterospirocyclic group, a 4-membered / 4-membered heterospirocyclic group, a 4-membered / 5-membered heterospirocyclic group, a 5-membered / 4-membered heterospirocyclic group, a 5-membered / 5-membered heterospirocyclic group, a 4-membered / 6-membered heterospirocyclic group, a 6-membered / 4-membered heterospirocyclic group, a 7-8 membered bridged ring heterocyclic group, a 3-5 membered heterocyclic group, a 5-membered / 3-membered heterocyclic group, a 4-membered / 4-membered heterocyclic group, a 4-membered / 5-membered heterocyclic group, a 5-membered / 4-membered heterocyclic group, a 5-membered / 4-membered heterocyclic group, a 5-membered / 5-membered heterocyclic group, a 4-membered / 6-membered heterocyclic group, a 6-membered / 4-membered heterocyclic group, a 5-membered / 6-membered heterocyclic group, a 6-membered / 5-membered heterocyclic group; the above groups are optionally replaced by one or more R c2 replace.

[0167] In a further preferred embodiment, wherein R 3 Independently selected from: hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 5-6 bridged ring group, 4-6 membered heterocycloalkyl group, 4-membered / 4-membered heterospiro ring group, 7-8 membered bridged ring heterocyclic group, 3-membered / 5-membered heterocyclic group, 5-membered / 3-membered heterocyclic group, 5-membered / 5-membered heterocyclic group; the above groups are optionally replaced by one or more R c2 replace.

[0168] In a further preferred embodiment, wherein R 3 Independently selected from: hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 6-9 membered heterospirocyclic group; the C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 6-9 membered heterospirocyclic group are optionally substituted with one or more R c2 replace.

[0169] In a further preferred embodiment, wherein R 3 Independently selected from: hydrogen, C 1-4 Alkyl, C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 7 membered heterospirocyclic group; the heteroatom in the 4-6 membered heterocycloalkyl, 7 membered heterospirocyclic group is selected from N or O, and the number of heteroatoms is 1 or 2; the C 1-4 Alkyl, C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 7 membered heterospirocycloalkyl are optionally substituted with one or more R c2 replace.

[0170] In a further preferred embodiment, wherein R 3 Independently selected from: hydrogen, C 1-4 alkyl, 4-6 membered heterocycloalkyl, 7 membered heterospirocycloalkyl; the heteroatom in the 4-6 membered heterocycloalkyl and 7 membered heterospirocycloalkyl is selected from N or O, and the number of heteroatoms is 1; the C 1-4 Alkyl, 4-6 membered heterocycloalkyl, 7 membered heterospirocyclic group are optionally substituted with one or more R c2 replace.

[0171] In a further preferred embodiment, wherein R 3 are independently selected from: hydrogen, methyl, ethyl, n-propyl, isopropyl, The above groups are optionally replaced by one or more R c2 replace.

[0174] In a further preferred embodiment, wherein R 3 are independently selected from: hydrogen, methyl, ethyl, n-propyl, isopropyl, The above groups are optionally replaced by one or more R c2 replace.

[0175] In a further preferred embodiment, wherein R 3 are independently selected from: hydrogen, methyl, ethyl, n-propyl, isopropyl,

[0176]

[0177] In a preferred embodiment of the present invention, wherein R 3 Independently selected from: hydrogen, C 1-6 Alkyl, C 3-6 Carbocyclic group, 4-10 membered heterocyclic group; said C 1-6 Alkyl, C 3-6 Carbocyclic group, 4-10 membered heterocyclic group is replaced by one or more R c2 replace;

[0178] R c2 Independently selected from: halogen, hydroxy, amino, cyano, -OC 1-6 Alkyl, -C(O)OH, -C(O)OC 1-6 Alkyl, C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from halogen, hydroxy, amino.

[0179] In a further preferred embodiment, wherein R 3 Independently selected from: hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-6 bridged ring group, 4-10 membered heterocyclic group; said C 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-6 The bridged ring group, the 4-10 membered heterocyclic group is c2 replace;

[0180] R c2 Independently selected from: halogen, hydroxy, amino, cyano, -OC 1-6 Alkyl, -C(O)OH, -C(O)OC 1-6 Alkyl, C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from halogen, hydroxy, amino.

[0181] In a further preferred embodiment, wherein R 3 Independently selected from: hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 5-6 bridged ring group, 4-6 membered heterocycloalkyl group, 4-membered / 4-membered heterospiro ring group, 7-8 membered bridged ring heterocyclic group, 3-membered / 5-membered heterocyclic group, 5-membered / 3-membered heterocyclic group, 5-membered / 5-membered heterocyclic group; the above groups are optionally replaced by one or more R c2 replace;

[0182] R c2 Independently selected from: halogen, hydroxy, amino, cyano, -OC 1-3Alkyl, -C(O)OH, -C(O)OC 1-3 Alkyl, C 1-3 Alkyl, C 1-3 Haloalkyl, hydroxy substituted C 1-3 Alkyl, amino substituted C 1-3 alkyl.

[0183] In a preferred embodiment of the present invention, wherein R c1 are independently selected from: deuterium, halogen, hydroxyl, amino, nitro, cyano, thiol, C 1-4 Alkyl, C 1-4 Alkoxy.

[0184] In a further preferred embodiment, wherein R c1 Independently selected from: fluorine, chlorine, bromine, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl.

[0185] In a further preferred embodiment, wherein R c1 Independently selected from: fluorine.

[0186] In a preferred embodiment of the present invention, wherein R c2 Independently selected from: deuterium, oxo, halogen, hydroxyl, amino, -OR c3 、-N(R c3 ) 2 ,-C(R c3 ) 2 (OR c3 )、-C(R c3 ) 2 N(R c3 ) 2 、-C(O)R c3 、-C(O)OR c3 、-C(O)N(R c3 ) 2 、-C(O)N(R c3 )OR c3 、-OC(O)R c3 、-OC(O)N(R c3 ) 2 、-N(R c3 )C(O)OR c3 、-N(R c3 )C(O)R c3 、-N(R c3 )C(O)N(R c3 ) 2 、-N(R c3 )S(O) 2 R c3 , C 1-6 Alkyl, C3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, optionally substituted with one or more R c4 replace.

[0187] In a further preferred embodiment, wherein R c2 Independently selected from: halogen, hydroxy, amino, cyano, -OR c3 、-C(O)OR c3 , C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted with one or more R c4 replace.

[0188] In a further preferred embodiment, wherein R c2 Independently selected from: halogen, hydroxy, amino, C 1-4 Alkyl; the C 1-4 The alkyl group is optionally substituted with one or more R c4 replace.

[0189] In a further preferred embodiment, wherein R c2 Independently selected from: halogen (such as fluorine, chlorine, bromine), hydroxyl, amino, methyl, ethyl, n-propyl, isopropyl; the above groups are optionally substituted by one or more substituents selected from halogen (such as fluorine, chlorine, bromine), hydroxyl, amino.

[0190] In a preferred embodiment of the present invention, wherein R c2 Independently selected from: halogen, hydroxy, amino, cyano, -OC 1-6 Alkyl, -C(O)OH, -C(O)OC 1-6 Alkyl, C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from halogen, hydroxy, amino.

[0191] In a further preferred embodiment, wherein R c2 Independently selected from: halogen, hydroxy, amino, cyano, -OC 1-3 Alkyl, -C(O)OH, -C(O)OC 1-3 Alkyl, C 1-3 Alkyl; the C 1-3 The alkyl group is optionally substituted with one or more substituents selected from halogen (eg fluorine, chlorine, bromine), hydroxyl, amino.

[0192] In a further preferred embodiment, wherein R c2are independently selected from: fluorine, chlorine, bromine, hydroxyl, amino, cyano, methoxy, ethoxy, -C(O)OH, -C(O)OCH 3 、-C(O)OCH 2 CH 3 、-CH 2 OH, -CH 2 CH 2 OH, trifluoromethyl, difluoromethyl, monofluoromethyl, -CH 2 NH 2 、-CH 2 CH 2 NH 2 、-C(CH 3 ) 2 NH 2 .

[0193] In a preferred embodiment of the present invention, wherein R c3 , R c4 are independently selected from: hydrogen, halogen, hydroxyl, amino, C 1-6 Alkyl, C 1-6 haloalkyl, optionally substituted with one or more hydroxyl groups 1-6 alkyl.

[0194] In a preferred embodiment of the present invention, wherein R c3 Independently selected from: hydrogen, methyl, ethyl, n-propyl, isopropyl.

[0195] In a preferred embodiment of the present invention, wherein R c4 Independently selected from: halogen, hydroxyl, amino.

[0196] In a further preferred embodiment, wherein R c4 Independently selected from: fluorine, chlorine, bromine, hydroxyl, amino.

[0197] In a further preferred embodiment, wherein R c4 Independently selected from: hydroxyl, amino.

[0198] In a preferred embodiment of the present invention, wherein Q is independently selected from: -R 3 、-N(R 3 )-C 0-6 Alkylene-R 3 、-N(R 3 )-C 0-6 Alkylene-N(R 3 ) 2 The alkylene group is optionally substituted by one or more selected from halogen, hydroxyl, amino, C 1-6 substituted by an alkyl substituent;

[0199] R 3 Each independently selected from: hydrogen, C 1-6 Alkyl, C 3-6 Carbocyclic group, 3-10 membered heterocyclic group; said C 1-6 Alkyl, C 3-6 Carbocyclic group, 3-10 membered heterocyclic group optionally with one or more R c2 replace;

[0200] R c2 Independently selected from: halogen, hydroxy, amino, cyano, -OC 1-6 Alkyl, -C(O)OH, -C(O)OC 1-6 Alkyl, C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from halogen, hydroxy, amino.

[0201] In a further preferred embodiment, wherein Q is independently selected from: 3-10 membered heterocyclyl, -NH-C 0-4 Alkylene-C 3-6 Carbocyclic group, -NH-C 0-4 Alkylene-3-10 membered heterocyclic group, -NH-C 0-4 Alkylene-NH 2 、-NH-C 0-4 Alkylene-NH(C 1-6 Alkyl), -NH-C 0-4 Alkylene-N(C 1-6 alkyl) 2 ; The alkylene group is optionally substituted by one or more substituents selected from halogen (eg, fluorine, chlorine, bromine); the C 1-6 Alkyl, C 3-6 Carbocyclic group, 3-10 membered heterocyclic group optionally with one or more R c2 replace;

[0202] R c2 Independently selected from: halogen, hydroxy, amino, cyano, -OC 1-6 Alkyl, -C(O)OH, -C(O)OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxy substituted C 1-6 Alkyl, amino substituted C 1-6 alkyl.

[0203] In a further preferred embodiment, wherein Q is independently selected from: 3-6 membered heterocycloalkyl, 7-8 membered heterospirocyclyl, 7-8 membered bridged heterocyclyl, 6-10 membered heterocyclyl, -NH-C 0-4 Alkylene-C 3-6 Cycloalkyl, -NH-C0-4 Alkylene-C 5-6 Bridged ring group, -NH-C 0-4 Alkylene-3-6 membered heterocyclic group, -NH-C 0-4 Alkylene-7-8 membered heterospirocyclic group, -NH-C 0-4 Alkylene-NH 2 、-NH-C 0-4 Alkylene-NH(C 1-6 Alkyl), -NH-C 0-4 Alkylene-N(C 1-4 alkyl) 2 ; The alkylene group is optionally substituted by one or more substituents selected from halogen (eg, fluorine, chlorine, bromine); the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 7-8 membered heterospirocyclic group, 7-8 membered bridged heterocyclic group, 6-10 membered heterocyclic group, C 5-6 The bridged ring group is optionally substituted by one or more R c2 replace;

[0204] R c2 Independently selected from: halogen, hydroxy, amino, cyano, -OC 1-3 Alkyl, -C(O)OH, -C(O)OC 1-3 Alkyl, C 1-3 Alkyl, C 1-3 Haloalkyl, hydroxy substituted C 1-3 Alkyl, amino substituted C 1-3 alkyl.

[0205] In a further preferred embodiment, wherein Q is independently selected from: 3-6 membered heterocycloalkyl, 7-8 membered heterospirocyclyl, 7-8 membered bridged heterocyclyl, 6-10 membered heterocyclyl, -NH-C 0-2 Alkylene-C 3-6 Cycloalkyl, -NH-C 0-2 Alkylene-C 5-6 Bridged ring group, -NH-C 0-2 Alkylene-3-6 membered heterocyclic group, -NH-C 0-2 Alkylene-7-8 membered heterospirocyclic group; the cycloalkyl, heterocycloalkyl, heterospirocyclic group, bridged heterocyclic group, heterocyclic group, bridged heterocyclic group are optionally substituted by one or more R c2 The heteroatoms in the 3-6 membered heterocycloalkyl, 7-8 membered heterospirocyclic group, 7-8 membered bridged heterocyclic group, and 6-10 membered heterocyclic group are N, O, and the number of heteroatoms is 1 or 2, and Connected to the N atom in Q;

[0206] R c2 Independently selected from: halogen, hydroxy, amino, cyano, -OC1-3 Alkyl, -C(O)OH, -C(O)OC 1-3 Alkyl, C 1-3 Alkyl, C 1-3 Haloalkyl, hydroxy substituted C 1-3 Alkyl, amino substituted C 1-3 alkyl.

[0207] In a preferred embodiment of the present invention, wherein Q is independently selected from: -R 3 、-N(R 3 )-C 0-6 Alkylene-R 3 、-N(R 3 )-C 0-6 Alkylene-N(R 3 ) 2 The alkylene group is optionally substituted by one or more selected from halogen, hydroxyl, amino, C 1-6 substituted by an alkyl substituent;

[0208] R 3 Each independently selected from: hydrogen, C 1-6 Alkyl, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group; said C 1-6 Alkyl, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group optionally with one or more R c2 replace;

[0209] R c2 Independently selected from: halogen, hydroxy, amino, C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from halogen, hydroxy, amino.

[0210] In a further preferred embodiment, wherein Q is independently selected from: C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -NH-C 0-6 Alkylene-R 3 、-NH-C 0-6 Alkylene-N(R 3 ) 2 ; The alkylene group is optionally substituted by one or more substituents selected from halogen, hydroxyl, amino, methyl, and ethyl;

[0211] R 3 Each independently selected from: hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, 6-9 membered heterospirocyclic group; the C 1-6 Alkyl, C 3-6Cycloalkyl, 3-6 membered heterocyclic group, 6-9 membered heterospirocyclic group are optionally substituted with one or more R c2 replace;

[0212] R c2 Independently selected from: halogen, hydroxy, amino, C 1-6 Alkyl, amino substituted C 1-6 Alkyl, hydroxy substituted C 1-6 alkyl.

[0213] In a further preferred embodiment, wherein Q is independently selected from: C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -NH-C 0-4 Alkylene-C 3-6 Cycloalkyl, -NH-C 0-4 Alkylene-3-6 membered heterocyclic group, -NH-C 0-4 Alkylene-7-membered heterospirocyclic group, -NH-C 0-4 Alkylene-NH 2 、-NH-C 0-4 Alkylene-NH(C 1-4 Alkyl), -NH-C 0-4 Alkylene-N(C 1-4 alkyl) 2 ; The alkylene group is optionally substituted by one or more substituents selected from halogen (eg, fluorine, chlorine, bromine); the C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, 7 membered heterospirocyclic group are optionally substituted by one or more selected from halogen (e.g., fluorine, chlorine, bromine), hydroxyl, amino, C 1-4 Alkyl, amino substituted C 1-4 Alkyl, hydroxy substituted C 1-4 The alkyl group is substituted with an alkyl substituent.

[0214] In a preferred embodiment of the present invention, wherein Q is independently selected from: 3-10 membered nitrogen-containing heterocyclic group (preferably 3-8 membered nitrogen-containing heterocyclic group), -NH-C 0-2 Alkylene-C 3-6 Cycloalkyl-NH 2 、-NH-C 0-2 Alkylene-3-6 membered heterocyclic group; Connected to the nitrogen atom in a 3-10-membered nitrogen-containing heterocyclic group, is a connection site; the heteroatom in the 3-6 membered heterocyclic group is selected from N or O, and the number of heteroatoms is 1 or 2; the 3-10 membered nitrogen-containing heterocyclic group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, optionally substituted by one or more selected from halogen (e.g., fluorine, chlorine, bromine), hydroxyl, amino, -C 1-2 Alkyl-NH 2 , -C1-2 Alkyl-OH, -C(O)OC 1-2 The alkyl group is substituted with an alkyl substituent.

[0215] In a preferred embodiment of the present invention, wherein Q is independently selected from: 3-7 membered nitrogen-containing heterocyclic group (more preferably 4-5 membered nitrogen-containing heterocyclic group), -NH-C 0-2 Alkylene-C 3-6 Cycloalkyl-NH 2 (more preferably -NH-C 0-1 Alkylene-C 4-5 Cycloalkyl-NH 2 ), -NH-C 0-2 Alkylene-3-6 membered heterocyclic group (more preferably -NH-C 0-1 Alkylene-4-5 membered heterocyclic group); Connected to the nitrogen atom in the 3-7 membered nitrogen-containing heterocyclic group, is a connection site; the heteroatom in the 3-6 membered heterocyclic group is selected from N or O, and the number of heteroatoms is 1 or 2; the 3-7 membered nitrogen-containing heterocyclic group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, optionally substituted by one or more selected from halogen (e.g., fluorine, chlorine, bromine), hydroxyl, amino, -C 1-2 Alkyl-NH 2 , -C 1-2 Alkyl-OH, -C(O)OC 1-2 The alkyl group is substituted with an alkyl substituent.

[0216] In a further preferred embodiment, wherein Q is independently selected from: 4-6 membered nitrogen-containing heterocyclic group (more preferably 4-5 membered nitrogen-containing heterocyclic group), -NH-C 4-5 Cycloalkyl-NH 2 (More preferably -NH-cyclobutane-NH 2 ), -NH-C 0-2 Alkylene-4-6 membered heterocyclic group (more preferably -NH-C 0-1 Alkylene-4-5 membered heterocyclic group); Connected to the nitrogen atom in a 4-6-membered nitrogen-containing heterocyclic group, is a connection site; the heteroatom in the 4-6 membered heterocyclic group is selected from N or O, and the number of heteroatoms is 1 or 2; the 4-6 membered nitrogen-containing heterocyclic group and the 4-6 membered heterocyclic group are optionally substituted by one or more selected from halogen (e.g., fluorine, chlorine, bromine), hydroxyl, amino, -C 1-2 Alkyl-NH 2 , -C 1-2 Alkyl-OH, -C(O)OC 1-2 The alkyl group is substituted with an alkyl substituent.

[0217] In a further preferred embodiment, wherein Q is independently selected from: 4-6 membered nitrogen-containing heterocyclic group (more preferably 4-5 membered nitrogen-containing heterocyclic group), -NH-C 4-5 Cycloalkyl-NH 2 (More preferably -NH-cyclobutane-NH 2 ), -NH-C 0-2 Alkylene-4-6 membered heterocyclic group (more preferably -NH-C 0-1 Alkylene-4-5 membered heterocyclic group); Connected to the nitrogen atom in a 4-6-membered nitrogen-containing heterocyclic group, is a connection site; the heteroatom in the 4-6 membered heterocyclic group is selected from N or O, and the number of heteroatoms is 1; the 4-6 membered nitrogen-containing heterocyclic group and the 4-6 membered heterocyclic group are optionally substituted by one or more selected from fluorine, chlorine, hydroxyl, amino, -CH 2 NH 2 、-CH 2 OH, -C(O)OCH 3 substituted by a substituent.

[0218] In a preferred embodiment of the present invention, wherein Q is independently selected from: 4-5 membered nitrogen-containing heterocyclic group, -NH-C 4-5 Cycloalkyl-NH 2 、-NH-C 0-1 Alkylene-4-5 membered heterocyclic group; Connected to the nitrogen atom in a 4-5-membered nitrogen-containing heterocyclic group, is a connection site; the heteroatom in the 4-5 membered heterocyclic group is selected from N or O, and the number of heteroatoms is 1; the 4-5 membered nitrogen-containing heterocyclic group and the 4-6 membered heterocyclic group are optionally substituted by one or more selected from fluorine, hydroxyl, amino, -CH 2 NH 2 、-CH 2 OH, -C(O)OCH 3 substituted by a substituent.

[0219] In a preferred embodiment of the present invention, wherein Q is independently selected from: 4-6 membered nitrogen-containing heterocyclic group, -NH-C 0-1 Alkylene-4-5 membered heterocyclic group; Connected to the nitrogen atom in a 4-6-membered nitrogen-containing heterocyclic group, is a connection site; the heteroatom in the 4-5 membered heterocyclic group is selected from N or O, and the number of heteroatoms is 1; the 4-6 membered nitrogen-containing heterocyclic group and the 4-5 membered heterocyclic group are optionally substituted by one or two selected from fluorine, amino, -CH 2 NH 2 substituted by a substituent.

[0220] In a further preferred embodiment, wherein Q is independently selected from:

[0221]

[0222] In a further preferred embodiment, wherein Q is selected from:

[0223] In a preferred embodiment of the present invention, wherein Het is selected from the following structures:

[0224] In a further preferred embodiment, wherein Het is selected from the following structures:

[0225] In a further preferred embodiment, wherein Het is selected from B is -N-; A is -CH 2 -.

[0226] In a preferred embodiment of the present invention, wherein Het is selected from the following structures: Cy2 is selected from phenyl or pyridyl.

[0227] In a preferred embodiment of the present invention, wherein Het is When Y is selected from -S(O)-, -S(O) 2 -.

[0228] In a preferred embodiment of the present invention, when A or B and When connected, A and B are independently selected from -N-; when A or B is not connected When connected, A and B are independently selected from -C(R d1 ) 2 -.

[0229] In a further preferred embodiment, wherein, when A or B and When connected, A and B are independently selected from -N-; when A or B is not connected When connected, A and B are independently selected from -CH 2 -.

[0230] In a preferred embodiment of the present invention, wherein R d1 Independently selected from: hydrogen, hydroxy, amino, cyano, methyl, ethyl.

[0231] In a further preferred embodiment, wherein R d1 Independently selected from: hydrogen.

[0232] In a preferred embodiment of the present invention, wherein Y is independently selected from -O-, -N(R d2 )-、-S(O)-、-S(O)2 -、-S(O)(=NR d2 )-.

[0233] In a further preferred embodiment, wherein Y is independently selected from -S(O)-, -S(O) 2 -、-S(O)(=NR d2 )-.

[0234] In a further preferred embodiment, wherein Y is independently selected from -S(O) 2 -、-S(O)(=NR d2 )-.

[0235] In a further preferred embodiment, wherein Y is independently selected from -S(O) 2 -.

[0236] In a further preferred embodiment, wherein Y is independently selected from -S(O)(=NR d2 )-.

[0237] In a preferred embodiment of the present invention, wherein R d2 Independently selected from: hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano, -SR d3 、-N(R d3 ) 2 、-C(O)R d3 、-(C 1-6 Alkylene)-C(O)R d3 、-C(O)OR d3 、-(C 1-6 Alkylene)-C(O)OR d3 、-C(O)N(R d3 ) 2 、-(C 1-6 Alkylene)-C(O)N(R d3 ) 2 、-C(O)-(C 1-6 Alkylene)-N(R d3 ) 2 、-S(O) 2 R d3 、-C(O)N(R d3 )OR d3 、-OC(O)R d3 、-OC(O)N(R d3 ) 2 , C 1-6 Alkyl, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-8 Aryl, 5-10 membered heteroaryl; said C 1-6 Alkyl, C1-6 Alkylene, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-8 Aryl, 5-10 membered heteroaryl, optionally substituted with one or more selected from deuterium, halogen, oxo, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 The alkoxy group is substituted with an alkoxy substituent.

[0238] In a further preferred embodiment, wherein R d2 Independently selected from: hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano, -SR d3 、-N(R d3 ) 2 、-C(O)R d3 、-(C 1-4 Alkylene)-C(O)R d3 、-C(O)OR d3 、-(C 1-4 Alkylene)-C(O)OR d3 、-C(O)N(R d3 ) 2 、-(C 1-4 Alkylene)-C(O)N(R d3 ) 2 、-C(O)-(C 1-4 Alkylene)-N(R d3 ) 2 、-S(O) 2 R d3 , C 1-4 Alkyl, C 3-6 carbocyclic group, 3-6 membered heterocyclic group, phenyl group, 5-6 membered heteroaryl group; the C 1-4 Alkyl, C 1-4 Alkylene, C 3-6 Carbocyclic group, 3-6 membered heterocyclic group, phenyl group, 5-6 membered heteroaryl group are optionally substituted with one or more selected from deuterium, halogen, oxo group, hydroxyl, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 The alkoxy group is substituted with an alkoxy substituent.

[0239] In a further preferred embodiment, wherein R d2 Independently selected from: hydrogen, -SR d3 、-C(O)R d3 、-(C 1-4 Alkylene)-C(O)R d3 、-(C 1-4 Alkylene)-S(O) 2 R d3 、-(C 1-4 Alkylene)-C(O)ORd3 、-C(O)N(R d3 ) 2 、-(C 1-4 Alkylene)-C(O)N(R d3 ) 2 、-C(O)-(C 1-4 Alkylene)-N(R d3 ) 2 、-S(O) 2 R d3 , C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered monocyclic heterocyclic group, 7-8 membered spirocyclic heterocyclic group, phenyl, 5-6 membered heteroaryl; the heteroatom in the 3-6 membered monocyclic heterocyclic group, 7-8 membered spirocyclic heterocyclic group, 5-6 membered heteroaryl is selected from N or O, and the number of heteroatoms is 1 or 2; the C 1-6 Alkyl, C 1-4 Alkylene, C 3-6 Cycloalkyl, 3-6 membered monocyclic heterocyclic group, 7-8 membered spirocyclic heterocyclic group, phenyl, 5-6 membered heteroaryl, optionally substituted by one or more selected from deuterium, halogen (such as fluorine, chlorine, bromine, preferably fluorine), oxo, hydroxyl, amino, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 The cycloalkyl group or the 3- to 6-membered heterocyclic group may be substituted.

[0240] In a further preferred embodiment, wherein R d2 Independently selected from: hydrogen, -SR d3 、-C(O)R d3 、-(C 1-4 Alkylene)-C(O)R d3 、-(C 1-4 Alkylene)-C(O)OR d3 、-C(O)N(R d3 ) 2 、-(C 1-4 Alkylene)-C(O)N(R d3 ) 2 、-C(O)-(C 1-4 Alkylene)-N(R d3 ) 2 、-S(O) 2 R d3 , C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl; the heteroatom in the 3-6 membered heterocyclic group and 5-6 membered heteroaryl is selected from N or O, and the number of heteroatoms is 1 or 2; the C 1-4 Alkyl, C 1-4 Alkylene, C3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl are optionally substituted with one or more substituents selected from deuterium, halogen (e.g. fluorine, chlorine, bromine, preferably fluorine), oxo, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, n-propoxy, isopropoxy.

[0241] In a preferred embodiment of the present invention, wherein R d3 are independently selected from: hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, optionally substituted with one or more selected from deuterium, halogen, oxo, hydroxy, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 The alkoxy group is substituted with an alkoxy substituent.

[0242] In a further preferred embodiment, wherein R d3 are independently selected from: hydrogen, halogen, hydroxy, amino, nitro, cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; the C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, optionally substituted by one or more selected from halogen, oxo, hydroxyl, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 The alkoxy group is substituted with an alkoxy substituent.

[0243] In a further preferred embodiment, wherein R d3 Independently selected from: hydrogen, amino, C 1-6 Alkyl, C 3-6 Cycloalkyl; said C 1-6 Alkyl, C 3-6 The cycloalkyl group is optionally substituted by one or more substituents selected from halogen and hydroxy.

[0244] In a further preferred embodiment, wherein R d3 Independently selected from: hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl; the above groups are optionally substituted by one or more substituents selected from fluorine, chlorine, bromine, hydroxyl, amino.

[0245] In a preferred embodiment of the present invention, wherein R d2 Independently selected from: hydrogen, -SRd3 、-C(O)R d3 、-(C 1-6 Alkylene)-C(O)R d3 、-C(O)OR d3 、-(C 1-6 Alkylene)-C(O)OR d3 、-C(O)N(R d3 ) 2 、-(C 1-6 Alkylene)-C(O)N(R d3 ) 2 、-C(O)-(C 1-6 Alkylene)-N(R d3 ) 2 、-S(O) 2 R d3 , C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; the C 1-6 Alkyl, C 1-6 Alkylene, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, optionally substituted with one or more selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0246] R d3 are independently selected from: hydrogen, halogen, hydroxy, amino, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, optionally substituted with one or more selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 The alkoxy group is substituted with an alkoxy substituent.

[0247] In a preferred embodiment of the present invention, wherein R d2 For hydrogen.

[0248] In a preferred embodiment of the present invention, wherein R d2 Independently selected from: -SC 1-6 Alkyl, -C(O)NH 2 、-C(O)NH(C 1-6 alkyl), -C(O)N(C 1-6 alkyl) 2 、-C(O)C 1-6 Alkyl, -C(O)C3-6 Cycloalkyl, -C(O)3-6 membered heterocyclic group, -C(O)-(C 1-4 Alkylene)-NH(C 1-6 alkyl), -C(O)-(C 1-4 Alkylene)-N(C 1-6 alkyl) 2 、-(C 1-4 Alkylene)-C(O)OC 1-6 Alkyl, -(C 1-4 Alkylene)-C(O)C 1-6 Alkyl, -(C 1-4 Alkylene)-S(O) 2 (C 1-6 Alkyl), -(C 1-4 Alkylene)-C(O)NH 2 、-(C 1-4 Alkylene)-C(O)NH(C 1-6 Alkyl), -(C 1-4 Alkylene)-C(O)N(C 1-6 alkyl) 2 、-S(O) 2 C 1-6 Alkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, phenyl, 5-6 membered heteroaryl; the C 1-6 Alkyl, C 1-4 Alkylene, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, optionally substituted with one or more selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl group or the 3- to 6-membered heterocyclic group may be substituted.

[0249] In a preferred embodiment of the present invention, wherein R d2 Independently selected from: -SC 1-3 Alkyl, -C(O)NH 2 、-C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 alkyl) 2 、-C(O)C 1-3 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)3-6 membered heterocyclic group, -C(O)-(C 1-2 Alkylene)-NH(C 1-6 alkyl), -C(O)-(C 1-2 Alkylene)-N(C 1-3 alkyl)2 、-(C 1-2 Alkylene)-C(O)OC 1-3 Alkyl, -(C 1-2 Alkylene)-C(O)C 1-3 Alkyl, -(C 1-2 Alkylene)-S(O) 2 (C 1-3 Alkyl), -(C 1-2 Alkylene)-C(O)NH 2 、-(C 1-2 Alkylene)-C(O)NH(C 1-3 Alkyl), -(C 1-2 Alkylene)-C(O)N(C 1-3 alkyl) 2 、-S(O) 2 C 1-3 Alkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered monocyclic heterocyclic group, 7 membered spirocyclic heterocyclic group, 8 membered spirocyclic heterocyclic group, phenyl, 5-6 membered heteroaryl; the alkyl, alkylene, C 3-6 Cycloalkyl, 3-6 membered monocyclic heterocyclic group, 7 membered spirocyclic heterocyclic group, 8 membered spirocyclic heterocyclic group, phenyl, 5-6 membered heteroaryl, optionally substituted with one or more selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-3 Alkyl, C 1-3 The group may be substituted by an alkoxy group or a 3- to 6-membered heterocyclic group.

[0250] In a further preferred embodiment, wherein R d2 Independently selected from: -SC 1-3 Alkyl, -C(O)NH 2 、-C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 alkyl) 2 、-C(O)C 1-3 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)-(C 1-2 Alkylene)-NH(C 1-3 alkyl), -C(O)-(C 1-2 Alkylene)-N(C 1-3 alkyl) 2 、-(C 1-2 Alkylene)-C(O)OC 1-3 Alkyl, -(C 1-2 Alkylene)-C(O)C 1-3 Alkyl, -(C 1-2 Alkylene)-S(O) 2 (C 1-3Alkyl), -(C 1-2 Alkylene)-C(O)NH 2 、-(C 1-2 Alkylene)-C(O)NH(C 1-3 Alkyl), -(C 1-2 Alkylene)-C(O)N(C 1-3 alkyl) 2 、-S(O) 2 C 1-3 Alkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered monocyclic heterocyclic group, 7 membered spirocyclic heterocyclic group (such as 4 membered / 4 membered spirocyclic heterocyclic group), phenyl, 5-6 membered heteroaryl; the heteroatoms of the monocyclic heterocyclic group, spirocyclic heterocyclic group and heteroaryl are independently selected from O or N, and the number of heteroatoms is 1 or 2; the alkyl, alkylene, cycloalkyl, monocyclic heterocyclic group, spirocyclic heterocyclic group, phenyl and heteroaryl are optionally substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, ethyl, methoxy, ethoxy, cyclopropane, cyclobutane, oxirane and oxetane.

[0251] In a further preferred embodiment, wherein R d2 Independently selected from: hydrogen, -SC 1-4 Alkyl, -C(O)NH 2 、-C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 、-C(O)C 1-4 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)3-6 membered heterocyclic group, -C(O)-(C 1-4 Alkylene)-NH(C 1-4 alkyl), -C(O)-(C 1-4 Alkylene)-N(C 1-4 alkyl) 2 、-(C 1-4 Alkylene)-C(O)OC 1-4 Alkyl, -(C 1-4 Alkylene)-C(O)C 1-4 Alkyl, -(C 1-4 Alkylene)-C(O)NH 2 、-(C 1-4 Alkylene)-C(O)NH(C 1-4 Alkyl), -(C 1-4 Alkylene)-C(O)N(C 1-4 alkyl) 2 、-S(O) 2 C 1-4 Alkyl, C1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; the C 1-4 Alkyl, C 1-4 Alkylene, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl are optionally substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl.

[0252] In a further preferred embodiment, wherein R d2 Independently selected from C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxy, amino, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, and 3-6 membered heterocyclic group.

[0253] In a further preferred embodiment, wherein R d2 Independently selected from C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted by one or more substituents selected from a 3-6 membered heterocyclic group; preferably, the 3-6 membered heterocyclic group contains 1, 2 or more ring atoms selected from N, O or S; preferably, the 3-6 membered heterocyclic group is selected from oxetanyl, thietanyl, tetrahydrofuranyl.

[0254] In a further preferred embodiment, wherein R d2 Independently selected from C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxy, amino, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, and 3-6 membered heterocyclic group.

[0255] In a further preferred embodiment, wherein R d2 Independently selected from C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted by one or more substituents selected from a 3-6 membered heterocyclic group; preferably, the 3-6 membered heterocyclic group contains 1, 2 or more ring atoms selected from N, O or S; preferably, the 3-6 membered heterocyclic group is selected from oxetanyl, thietanyl, tetrahydrofuranyl.

[0256] In a preferred embodiment of the present invention, wherein R d2 Independently selected from: hydrogen, -C(O)NH 2 、-C(O)NH(C 1-3 Alkyl), -C(O)C 1-3Alkyl, -C(O)C 3-6 Cycloalkyl, -(C 1-3 Alkylene)-S(O) 2 (C 1-3 Alkyl), C 1-6 Alkyl (more preferably C 1-5 Alkyl, more preferably C 1-3 Alkyl), C 3-6 Cycloalkyl (more preferably C 3-4 cycloalkyl), 3-7 membered heterocyclyl (more preferably 4-5 membered heterocyclyl), 5-6 membered heteroaryl (more preferably 5 membered heteroaryl containing 2 nitrogen atoms); the alkyl, cycloalkyl, heterocyclyl, heteroaryl are optionally substituted with one or more selected from deuterium, halogen (more preferably fluorine, chlorine, bromine, more preferably fluorine), hydroxyl, amino, cyano, C 1-3 Alkyl (more preferably methyl), C 1-3 The substituent is substituted by an alkoxy group (more preferably a methoxy group) or a 3-6-membered heterocyclic group (more preferably a 4-5-membered oxygen-containing heterocyclic group); the heteroatoms in the heterocyclic group or heteroaryl group are independently selected from O or N, and the number of heteroatoms is 1 or 2.

[0257] In a preferred embodiment of the present invention, wherein R d2 Independently selected from: hydrogen, -C(O)NH 2 、-C(O)NH(C 1-2 Alkyl), -C(O)C 1-2 Alkyl, -C(O)C 3-4 Cycloalkyl, -(C 1-2 Alkylene)-S(O) 2 (C 1-2 Alkyl), C 1-6 Alkyl (more preferably C 1-5 Alkyl, more preferably C 1-3 Alkyl), -C 1-3 Alkylene-C 1-2 Alkoxy, -C 1-2 Alkylene-(3-6 membered heterocyclic group) (more preferably -C 1-2 Alkylene-(4-5 membered heterocyclic group)), C 3-6 Cycloalkyl (more preferably C 3-4 The alkyl group is optionally substituted with one or more substituents selected from deuterium, halogen (more preferably fluorine, chlorine, bromine, more preferably fluorine), hydroxyl, and cyano; the cycloalkyl group is optionally substituted with one or more substituents selected from halogen (more preferably fluorine, chlorine, bromine, more preferably fluorine); the heteroaryl group is optionally substituted with one or more substituents selected from C 1-2The heterocyclic group and the heteroaryl group are substituted by a substituent of an alkyl group (preferably a methyl group); the heteroatoms in the heterocyclic group and the heteroaryl group are independently selected from O or N, and the number of heteroatoms is 1 or 2.

[0258] In a preferred embodiment of the present invention, wherein R d2 Independently selected from: -(C 1-3 Alkylene)-S(O) 2 (C 1-3 Alkyl), C 1-6 Alkyl (more preferably C 1-5 Alkyl, more preferably C 1-3 Alkyl), C 3-6 Cycloalkyl (more preferably C 3-4 cycloalkyl), 3-6 membered heterocyclic group (more preferably 4-5 membered heterocyclic group); the alkyl, cycloalkyl, heterocyclic group are optionally substituted by one or more selected from deuterium, halogen (more preferably fluorine, chlorine, bromine, more preferably fluorine), hydroxyl, cyano, C 1-3 Alkyl (more preferably methyl), C 1-3 The substituent is substituted by an alkoxy group (more preferably a methoxy group) or a 3-6-membered heterocyclic group (more preferably a 4-5-membered heterocyclic group); the heteroatom in the heterocyclic group is O, and the number of heteroatoms is 1.

[0259] In a preferred embodiment of the present invention, wherein R d2 Independently selected from: -(C 1-2 Alkylene)-S(O) 2 (C 1-2 Alkyl), C 1-6 Alkyl (more preferably C 1-5 Alkyl, more preferably C 1-3 Alkyl), -C 1-3 Alkylene-C 1-2 Alkoxy, -C 1-2 Alkylene-(3-6 membered heterocyclic group) (more preferably -C 1-2 Alkylene-(4-5 membered heterocyclic group)), C 3-6 Cycloalkyl (more preferably C 3-4 The alkyl group is optionally substituted by one or more substituents selected from deuterium, halogen (more preferably fluorine, chlorine, bromine, more preferably fluorine), hydroxyl, and cyano; the heteroatom in the heterocyclic group is O, and the number of heteroatoms is 1.

[0260] In a preferred embodiment of the present invention, wherein R d2 Independently selected from: -C 1-2 Alkylene-(3-6 membered heterocyclic group) (more preferably -C 1-2 Alkylene-(4-5 membered heterocyclic group)), C 3-6 Cycloalkyl (more preferably C3-4 cycloalkyl), 3-6 membered heterocyclic group (more preferably 4-5 membered heterocyclic group); the heteroatom in the heterocyclic group is O, and the number of heteroatoms is 1.

[0261] In a preferred embodiment of the present invention, wherein R d2 Independently selected from: -(C 1-2 Alkylene)-S(O) 2 (C 1-2 Alkyl), C 1-3 Alkyl (more preferably C 1-2 Alkyl), -C 1-2 Alkylene-(3-6 membered heterocyclic group) (more preferably -methyl-(4-5 membered heterocyclic group)), C 3-6 Cycloalkyl (more preferably C 3-4 The alkyl group is optionally substituted by one or more substituents selected from deuterium, halogen (more preferably fluorine), and cyano; the heteroatom in the heterocyclic group is O, and the number of heteroatoms is 1.

[0262] In a further preferred embodiment, wherein R d2 Independently selected from: -CH 2 CH 2 SO 2 CH 3 , C 1-2 Alkyl, -CD 3 , -methyl-(4-5 membered heterocyclic group), cyclopropyl, cyclobutyl; the alkyl group is optionally substituted by one or more substituents selected from fluorine and cyano; the heteroatom in the heterocyclic group is O, and the number of heteroatoms is 1.

[0263] In a preferred embodiment of the present invention, wherein R d2 Independently selected from: -C 1-3 Alkylene-C 1-2 Alkoxy, -C 1-2 Alkylene-(3-6 membered heterocyclic group) (more preferably -methyl-(4-5 membered heterocyclic group)), C 3-6 Cycloalkyl (more preferably C 3-4 cycloalkyl), 3-6 membered heterocyclic group (more preferably 4-5 membered heterocyclic group); the heteroatom in the heterocyclic group is O, and the number of heteroatoms is 1.

[0264] In a further preferred embodiment, wherein R d2 Independently selected from: -C(O)NH 2 、-CD 3 , -CF 3 、-SCF 3 、-C(O)CH 3 、-C(O)CH 2OH, -C(O)CH 2 N(CH 3 ) 2 、-CH 2 CN、-CH 2 CH 2 CH 2 CN、-CH 2 CH 2 C(CH 3 ) 2 OH, -CH 2 CH 2 CH 2 OH, -CH(CH 3 )CH 2 OCH 3 、-CH 2 CH 2 CH 2 OCH 3 、-CH 2 -C(O)OCH 3 、-C(O)NHCH 3 、-CH 2 -C(O)NH 2 、-S(O) 2 CH 3 、-C(O)N(CH 3 ) 2 、-CH 2 CF 3 、-CH 2 CH 2 F, -CH 2 CHF 2 、-CH 2 CH 2 SO 2 CH 3 , methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,

[0265] In a further preferred embodiment, wherein R d2 Independently selected from: hydrogen, -C(O)NH 2 、-CD 3 , -CF 3 、-SCF 3 、-C(O)CH 3 、-C(O)CH 2 OH, -C(O)CH 2 N(CH 3 ) 2 、-CH 2 CN、-CH 2-C(O)OCH 3 、-C(O)NHCH 3 、-CH 2 -C(O)NH 2 、-S(O) 2 CH 3 、-C(O)N(CH 3 ) 2 、-CH 2 CF 3 , methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl,

[0267] In a preferred embodiment of the present invention, wherein R 13 , R 14 , R 15 , R 16 are independently selected from: hydrogen, deuterium, oxo, fluorine, chlorine, bromine, methyl; when R 13 , R 14 When one of them is selected from an oxo group, the other is absent; when R 15 , R 16 When one of them is selected from oxo, the other is absent;

[0268] or R 13 and R 14 Together with the carbon atoms to which they are attached, they form cyclopropane, cyclobutane, cyclopentane, cyclohexane;

[0269] or R 15 and R 16 Together with the carbon atoms to which they are attached they form cyclopropane, cyclobutane, cyclopentane, and cyclohexane.

[0270] In a further preferred embodiment, wherein R 13 , R 14 , R 15 , R 16 are independently selected from: hydrogen, oxo, methyl; when R 13 , R 14 When one of them is selected from an oxo group, the other is absent; when R 15 , R 16 When one of them is selected from oxo, the other is absent;

[0271] or R 13 and R 14 Together with the carbon atom to which they are attached they form a cyclopropane group;

[0272] or R 15 and R 16 Together with the carbon atom to which they are attached they form a cyclopropane group.

[0273] In a further preferred embodiment, wherein R 13 , R 14 , R 15 , R 16 are each independently selected from hydrogen.

[0274] In a preferred embodiment of the present invention, wherein R d4 Independently selected from: deuterium, fluorine, chlorine, bromine, oxo, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, isopropyl; the methyl, ethyl, n-propyl, isopropyl are optionally substituted with one or more substituents selected from fluorine, chlorine, and bromine.

[0275] In a preferred embodiment of the present invention, Cy2 is independently selected from: phenyl, 5-6 membered heterocyclic group, 5-6 membered heteroaryl group, the heteroatom in the 5-6 membered heterocyclic group, 5-6 membered heteroaryl group is selected from N, and the number of heteroatoms is 1, 2 or 3.

[0276] In a further preferred embodiment, wherein Cy2 is independently selected from: phenyl, 5-membered heteroaryl, 6-membered heteroaryl.

[0277] In a further preferred embodiment, Cy2 is independently selected from the group consisting of phenyl, pyridyl, pyrazolyl, imidazolyl, pyrrole, and triazole.

[0278] In a preferred embodiment of the present invention, Cy2 is independently selected from: phenyl, 6-membered heteroaryl.

[0279] In a further preferred embodiment, wherein Cy2 is independently selected from: phenyl, pyridyl.

[0280] In a further preferred embodiment, wherein Cy2 is independently selected from: phenyl,

[0281] In a further preferred embodiment, wherein Cy2 is independently selected from phenyl.

[0282] In a preferred embodiment of the present invention, Cy3 is independently selected from: phenyl, 5-6 membered heterocyclic group, 5-6 membered heteroaryl group, the heteroatom in the 5-6 membered heterocyclic group, 5-6 membered heteroaryl group is selected from N, and the number of heteroatoms is 1, 2 or 3.

[0283] In a further preferred embodiment, Cy3 is independently selected from: phenyl, 5-membered heteroaryl, 6-membered heteroaryl.

[0284] In a further preferred embodiment, Cy3 is independently selected from the group consisting of phenyl, pyridyl, pyrazolyl, imidazolyl, pyrrole, and triazole.

[0285] In a further preferred embodiment, wherein Cy3 is independently selected from: phenyl,

[0286] In a preferred embodiment of the present invention, wherein R 17 and R 18 Each is independently selected from: deuterium, halogen.

[0287] In a further preferred embodiment, wherein R 17 and R 18 Each is independently selected from: fluorine and chlorine.

[0288] In a preferred embodiment of the present invention, R d5 Independently selected from: hydrogen, C 1-6 alkyl.

[0289] In a further preferred embodiment, wherein R d5 Independently selected from: hydrogen.

[0290] In a preferred embodiment of the present invention, Z is independently selected from C and N.

[0291] In a preferred embodiment of the present invention, wherein E is independently selected from: -C(R d6 ) 2 -、-N(R d6 )-;

[0292] R d6 Independently selected from: hydrogen, fluorine, chlorine, C 1-4 Alkyl, C 1-4 Haloalkyl; or two R attached to the same carbon atom d6 Together with the carbon atoms to which they are attached, they form a cyclopropane group optionally substituted by one or more of fluorine and chlorine.

[0293] In a preferred embodiment of the present invention, n and q are independently selected from 0, 1, and 2; preferably 0 and 1; more preferably 0.

[0294] The present invention provides a compound represented by formula (II), or its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt:

[0295]

[0296] Among them, Cy1, Cy2, Y, Q, R 1 , R 13 , R 14 , R 15 , R 16 , R 17, m and n are defined as those for the compound represented by formula (I) of the present invention.

[0297] In a further preferred embodiment, wherein Cy1 is independently selected from a 5-6 membered heterocyclic group;

[0298] R 1 are independently selected from: hydrogen, halogen, oxo, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, -C(O)OC 1-6 Alkyl, -C(O)NHC 1-6 Alkyl, -C(O)O-(C 1-6 Alkyl)-OC(O)C 1-6 alkyl;

[0299] Q is independently selected from: C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -NH-C 0-4 Alkylene-C 3-6 Cycloalkyl, -NH-C 0-4 Alkylene-3-6 membered heterocyclic group, -NH-C 0-4 Alkylene-7-9 membered heterospirocyclic group, -NH-C 0-4 Alkylene-NH 2 、-NH-C 0-4 Alkylene-NH(C 1-4 Alkyl), -NH-C 0-4 Alkylene-N(C 1-4 alkyl) 2 ; The alkylene group is optionally substituted by one or more substituents selected from halogen; the C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, 7-9 membered heterospirocyclic group are optionally substituted by one or more selected from halogen, hydroxyl, amino, C 1-4 Alkyl, amino substituted C 1-4 Alkyl, hydroxy substituted C 1-4 substituted by an alkyl substituent;

[0300] Y is independently selected from -N(CH 3 )-、-S(O)-、-S(O) 2 -、-S(O)(=NR d2 )-;

[0301] R d2 Independently selected from: hydrogen, -SC 1-4 Alkyl, -C(O)NH 2 、-C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 、-C(O)C 1-4 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)3-6 membered heterocyclic group, -C(O)-(C 1-4 Alkylene)-NH(C 1-4 alkyl), -C(O)-(C 1-4 Alkylene)-N(C 1-4 alkyl) 2 、-(C 1-4 Alkylene)-C(O)OC 1-4 Alkyl, -(C 1-4 Alkylene)-C(O)C 1-4 Alkyl, -(C 1-4 Alkylene)-C(O)NH 2 、-(C 1-4 Alkylene)-C(O)NH(C 1-4 Alkyl), -(C 1-4 Alkylene)-C(O)N(C 1-4 alkyl) 2 、-S(O) 2 C 1-4 Alkyl, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; the C 1-4 Alkyl, C 1-4 Alkylene, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl are optionally substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl;

[0302] Cy2 is independently selected from: phenyl, 6-membered heteroaryl;

[0303] R 13 , R 14 , R 15 , R 16 are independently selected from: hydrogen, oxo; or R 13 and R 14 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl;

[0304] R 17 are independently selected from halogen.

[0305] In a further preferred embodiment, wherein Y is independently selected from -S(O) 2 -.

[0306] The present invention provides a compound represented by formula (II-1), or its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt:

[0307]

[0308] Among them, Cy2, Y, Q, R 1 , R 13 , R 14 , R 15 , R 16 , R 17 , m and n are defined as those for the compounds represented by formula (I) or (II) of the present invention.

[0309] The present invention provides a compound represented by formula (II-2), or its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt:

[0310]

[0311] Among them, Q, R 1 , R 13 , R 14 , R 15 , R 16 , R 17 , m and n are defined as described in the compounds represented by formula (I) or formula (II) or formula (II-1) of the present invention;

[0312] Cy2 is independently selected from: phenyl, 6-membered heteroaryl; the heteroatom of the heteroaryl is N.

[0313] In a further preferred embodiment, R 1 Selected from: hydrogen, C 1-2 Alkyl (preferably methyl), -C(O)C 1-2 Haloalkyl (preferably -C(O)CF 3 );

[0314] Q is -NH-C 0-2 Alkylene-4-6 membered heterocyclic group; the heteroatom in the 4-6 membered heterocyclic group is selected from N or O, and the number of heteroatoms is 1; the 4-6 membered heterocyclic group is optionally substituted by one or more substituents selected from halogen (such as fluorine, chlorine, bromine) and amino.

[0315] R 13 , R 14 , R 15 , R16 They are hydrogen; Cy2 is phenyl; m is 1; and n is 0.

[0316] In a further preferred embodiment, R 1 Selected from: hydrogen, methyl, -C(O)CF 3 ;

[0317] Q is -NH-C 0-1 Alkylene-4-5 membered heterocyclic group; the heteroatom in the 4-5 membered heterocyclic group is selected from N or O, and the number of heteroatoms is 1; the 4-5 membered heterocyclic group is optionally substituted by one or more substituents selected from fluorine and amino.

[0318] R 13 , R 14 , R 15 , R 16 They are hydrogen; Cy2 is phenyl; m is 1; and n is 0.

[0319] The present invention provides a compound represented by formula (III), or its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt:

[0320]

[0321] Among them, Cy2, Y, Q, R 1 , R 13 , R 14 , R 15 , R 16 , R 17 , m and n are defined as described for the compound represented by formula (I) of the present invention in this application.

[0322] In a further preferred embodiment, wherein Cy2 is independently selected from: phenyl, 6-membered heteroaryl; the heteroatom of the heteroaryl is N;

[0323] R 1 are independently selected from: hydrogen, halogen, oxo, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, -C(O)OC 1-6 Alkyl, -C(O)NHC 1-6 Alkyl, -C(O)O-(C 1-6 Alkyl)-OC(O)C1-6 alkyl;

[0324] Q is selected from:

[0325] Y is independently selected from -S(O)(=NR d2 )-;

[0326] R d2 Independently selected from: hydrogen, -SC 1-4 Alkyl, -C(O)NH 2 、-C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 、-C(O)C 1-4 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)3-6 membered heterocyclic group, -C(O)-(C 1-4 Alkylene)-NH(C 1-4 alkyl), -C(O)-(C 1-4 Alkylene)-N(C 1-4 alkyl) 2 、-(C 1-4 Alkylene)-C(O)OC 1-4 Alkyl, -(C 1-4 Alkylene)-C(O)C 1-4 Alkyl, -(C 1-4 Alkylene)-C(O)NH 2 、-(C 1-4 Alkylene)-C(O)NH(C 1-4 Alkyl), -(C 1-4 Alkylene)-C(O)N(C 1-4 alkyl) 2 、-S(O) 2 C 1-4 Alkyl, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; the C 1-4 Alkyl, C 1-4 Alkylene, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl are optionally substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl;

[0327] R 13 , R 14 , R 15 , R 16 are independently selected from: hydrogen, deuterium, halogen, oxo; or R 13 and R14 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl;

[0328] R 17 are independently selected from halogen.

[0329] The present invention provides a compound represented by formula (III-1), or its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt:

[0330]

[0331] Among them, Cy2, Y, Q, R 1 , R 13 , R 14 , R 15 , R 16 , R 17 , m and n are defined as described in the compound represented by formula (I) or formula (III) of the present invention.

[0332] The present invention provides a compound represented by formula (IV), or its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt:

[0333]

[0334] Among them, X 1 , X, Q, R 1 , R d2 and m are defined as described in the compound of formula (I) of the present invention; "*" indicates that the S atom has a chiral center, and the configuration is R, S or a mixture of the two.

[0335] The present invention provides a compound represented by formula (IV-a), or its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt:

[0336]

[0337] Among them, Q, R 1 , R d2 and m are defined as those for the compounds of formula (I) or (IV) of the present invention; "*" indicates that the S atom has a chiral center, and the configuration is R, S or a mixture of the two.

[0338] In a preferred embodiment of the present invention, Cy1 is selected from

[0339] In a preferred embodiment of the present invention, wherein R 1 Independently selected from: fluorine, chlorine, bromine, C 1-3 Alkyl, C 1-3Alkoxy, C 1-3 Haloalkyl, -C(O)C 1-3 Alkyl, -C(O)C 1-3 Haloalkyl, -C(O)OC 1-3 alkyl.

[0340] In a further preferred embodiment, wherein R 1 Selected from: fluorine, chlorine, bromine, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Fluorinated alkyl, -C(O)C 1-3 Alkyl, -C(O)C 1-3 Fluorinated alkyl, -C(O)OC 1-3 alkyl.

[0341] In a preferred embodiment of the present invention, wherein R 1 are independently selected from: fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, -CH 2 F, -CF 2 H, -CF 3 、-CH 2 CF 3 、-C(O)CH 3 、-C(O)CH 2 CH 3 、-C(O)CF 3 、-C(O)CF 2 H、-C(O)OCH 3 、-C(O)OCH 2 CH 3 .

[0342] In a preferred embodiment of the present invention, Q is independently selected from: 3-10 membered heterocyclyl, -NH-C 0-4 Alkylene-C 3-10 Carbocyclic group, -NH-C 0-4 Alkylene-3-10 membered heterocyclic group; the alkylene group is optionally substituted by one or more substituents selected from halogen; the C 3-10 Carbocyclic group, 3-10 membered heterocyclic group optionally with one or more R c2 replace;

[0343] R c2 Independently selected from: halogen, hydroxy, amino, cyano, -OC 1-6 Alkyl, -C(O)OH, -C(O)OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxy substituted C 1-6Alkyl, amino substituted C 1-6 alkyl.

[0344] In a further preferred embodiment, wherein Q is independently selected from: 3-8 membered heterocyclyl, -NH-C 0-2 Alkylene-C 3-6 Carbocyclic group, -NH-C 0-2 Alkylene-3-8 membered heterocyclic group; the alkylene group is optionally substituted by one or more substituents selected from halogen; the C 3-6 Carbocyclic group, 3-8 membered heterocyclic group are optionally substituted with one or more R c2 replace;

[0345] R c2 Independently selected from: halogen, hydroxy, amino, cyano, -OC 1-6 Alkyl, -C(O)OH, -C(O)OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxy substituted C 1-6 Alkyl, amino substituted C 1-6 alkyl.

[0346] In a further preferred embodiment, wherein Q is independently selected from: 3-6 membered heterocycloalkyl, 7-8 membered heterospirocyclyl, 7-8 membered bridged heterocyclyl, 6-10 membered heterocyclyl, -NH-C 0-2 Alkylene-C 3-6 Cycloalkyl, -NH-C 0-2 Alkylene-C 5-6 Bridged ring group, -NH-C 0-2 Alkylene-3-6 membered heterocyclic group, -NH-C 0-2 Alkylene-7-8 membered heterospirocyclic group; the cycloalkyl, heterocycloalkyl, heterospirocyclic group, bridged heterocyclic group, heterocyclic group, bridged heterocyclic group are optionally substituted by one or more R c2 replace;

[0347] R c2 Independently selected from: halogen, hydroxy, amino, cyano, -OC 1-3 Alkyl, -C(O)OH, -C(O)OC 1-3 Alkyl, C 1-3 Alkyl, C 1-3 Haloalkyl, hydroxy substituted C 1-3 Alkyl, amino substituted C 1-3 alkyl.

[0348] In a further preferred embodiment, wherein Q is independently selected from: 3-6 membered heterocycloalkyl, 7-8 membered heterospirocyclyl, 7-8 membered bridged heterocyclyl, 6-10 membered heterocyclyl, -NH-C 0-2 Alkylene-C3-6 Cycloalkyl, -NH-C 0-2 Alkylene-C 5-6 Bridged ring group, -NH-C 0-2 Alkylene-3-6 membered heterocyclic group, -NH-C 0-2 Alkylene-7-8 membered heterospirocyclic group; the cycloalkyl, heterocycloalkyl, heterospirocyclic group, bridged heterocyclic group, heterocyclic group, bridged heterocyclic group are optionally substituted by one or more R c2 The heteroatoms in the 3-6 membered heterocycloalkyl, 7-8 membered heterospirocyclic group, 7-8 membered bridged heterocyclic group, and 6-10 membered heterocyclic group are N, O, and the number of heteroatoms is 1 or 2, and Connected to the N atom in Q;

[0349] R c2 Independently selected from: halogen, hydroxy, amino, cyano, -OC 1-3 Alkyl, -C(O)OH, -C(O)OC 1-3 Alkyl, C 1-3 Alkyl, C 1-3 Haloalkyl, hydroxy substituted C 1-3 Alkyl, amino substituted C 1-3 alkyl.

[0350] In a further preferred embodiment, wherein Q is independently selected from:

[0351]

[0352]

[0353] In a preferred embodiment of the present invention, wherein R d2 Independently selected from: -SC 1-6 Alkyl, -C(O)NH 2 、-C(O)NH(C 1-6 alkyl), -C(O)N(C 1-6 alkyl) 2 、-C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)3-6 membered heterocyclic group, -C(O)-(C 1-6 Alkylene)-NH(C 1-6 alkyl), -C(O)-(C 1-6 Alkylene)-N(C 1-6 alkyl) 2 、-(C 1-6 Alkylene)-C(O)OC 1-6 Alkyl, -(C 1-6 Alkylene)-C(O)C 1-6 Alkyl, -(C 1-6Alkylene)-S(O) 2 (C 1-6 Alkyl), -(C 1-6 Alkylene)-C(O)NH 2 、-(C 1-6 Alkylene)-C(O)NH(C 1-6 Alkyl), -(C 1-6 Alkylene)-C(O)N(C 1-6 alkyl) 2 、-S(O) 2 C 1-6 Alkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, phenyl, 5-6 membered heteroaryl; the C 1-6 Alkyl, C 1-6 Alkylene, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, optionally substituted with one or more selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl group or the 3- to 6-membered heterocyclic group may be substituted.

[0354] In a further preferred embodiment, wherein R d2 Independently selected from: -SC 1-3 Alkyl, -C(O)NH 2 、-C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 alkyl) 2 、-C(O)C 1-3 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)3-6 membered heterocyclic group, -C(O)-(C 1-2 Alkylene)-NH(C 1-6 alkyl), -C(O)-(C 1-2 Alkylene)-N(C 1-3 alkyl) 2 、-(C 1-2 Alkylene)-C(O)OC 1-3 Alkyl, -(C 1-2 Alkylene)-C(O)C 1-3 Alkyl, -(C 1-2 Alkylene)-S(O) 2 (C 1-3 Alkyl), -(C 1-2 Alkylene)-C(O)NH 2 、-(C 1-2 Alkylene)-C(O)NH(C 1-3 Alkyl), -(C1-2 Alkylene)-C(O)N(C 1-3 alkyl) 2 、-S(O) 2 C 1-3 Alkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered monocyclic heterocyclic group, 7 membered spirocyclic heterocyclic group, 8 membered spirocyclic heterocyclic group, phenyl, 5-6 membered heteroaryl; the alkyl, alkylene, cycloalkyl, monocyclic heterocyclic group, spirocyclic heterocyclic group, phenyl, 5-6 membered heteroaryl are optionally substituted by one or more selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 The cycloalkyl group or the 3- to 6-membered heterocyclic group may be substituted.

[0355] In a further preferred embodiment, wherein R d2 Independently selected from: -SC 1-3 Alkyl, -C(O)NH 2 、-C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 alkyl) 2 、-C(O)C 1-3 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)3-6 membered heterocyclic group, -C(O)-(C 1-2 Alkylene)-NH(C 1-3 alkyl), -C(O)-(C 1-2 Alkylene)-N(C 1-3 alkyl) 2 、-(C 1-2 Alkylene)-C(O)OC 1-3 Alkyl, -(C 1-2 Alkylene)-C(O)C 1-3 Alkyl, -(C 1-2 Alkylene)-S(O) 2 (C 1-3 Alkyl), -(C 1-2 Alkylene)-C(O)NH 2 、-(C 1-2 Alkylene)-C(O)NH(C 1-3 Alkyl), -(C 1-2 Alkylene)-C(O)N(C 1-3 alkyl) 2 、-S(O) 2 C 1-3 Alkyl, C 1-6 Alkyl, C 3-6Cycloalkyl, 3-6 membered monocyclic heterocyclic group, 7 membered spirocyclic heterocyclic group, phenyl, 5-6 membered heteroaryl; the heteroatoms of the monocyclic heterocyclic group, spirocyclic heterocyclic group and heteroaryl are independently selected from O or N, and the number of heteroatoms is 1 or 2; the alkyl, alkylene, cycloalkyl, monocyclic heterocyclic group, spirocyclic heterocyclic group, phenyl and heteroaryl are optionally substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, ethyl, methoxy, ethoxy, cyclopropane, cyclobutane, oxirane and oxetane.

[0356] In a further preferred embodiment, wherein R d2 Independently selected from: -C(O)NH 2 、-CD 3 , -CF 3 、-SCF 3 、-C(O)CH 3 、-C(O)CH 2 OH, -C(O)CH 2 N(CH 3 ) 2 、-CH 2 CN、-CH 2 CH 2 CH 2 CN、-CH 2 CH 2 C(CH 3 ) 2 OH, -CH 2 CH 2 CH 2 OH, -CH(CH 3 )CH 2 OCH 3 、-CH 2 CH 2 CH 2 OCH 3 、-CH 2 -C(O)OCH 3 、-C(O)NHCH 3 、-CH 2 -C(O)NH 2 、-S(O) 2 CH 3 、-C(O)N(CH 3 ) 2 、-CH 2 CF 3 、-CH 2 CH 2 F, -CH 2 CHF 2 、-CH 2 CH 2 SO2 CH 3 , methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,

[0357] In a preferred embodiment of the present invention, wherein R 1 Independently selected from: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, -C(O)OC 1-6 alkyl;

[0358] m is selected from: 1, 2;

[0359] Q is independently selected from: C 3-8 Carbocyclic group, 3-10 membered heterocyclic group, -NH-C 0-4 Alkylene-C 3-8 Carbocyclic group, -NH-C 0-4 Alkylene-3-10 membered heterocyclic group; the alkylene group is optionally substituted by one or more substituents selected from halogen; the C 3-8 Carbocyclic group, 3-10 membered heterocyclic group optionally with one or more R c2 replace;

[0360] R c2 Independently selected from: halogen, hydroxy, amino, cyano, -OC 1-6 Alkyl, -C(O)OH, -C(O)OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxy substituted C 1-6 Alkyl, amino substituted C 1-6 alkyl;

[0361] R d2 Independently selected from: -SC 1-6 Alkyl, -C(O)NH 2 、-C(O)NH(C 1-6 alkyl), -C(O)N(C 1-6 alkyl) 2 、-C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)3-6 membered heterocyclic group, -C(O)-(C 1-4 Alkylene)-NH(C 1-6 alkyl), -C(O)-(C 1-4 Alkylene)-N(C 1-6 alkyl)2 、-(C 1-4 Alkylene)-C(O)OC 1-6 Alkyl, -(C 1-4 Alkylene)-C(O)C 1-6 Alkyl, -(C 1-4 Alkylene)-S(O) 2 (C 1-6 Alkyl), -(C 1-4 Alkylene)-C(O)NH 2 、-(C 1-4 Alkylene)-C(O)NH(C 1-6 Alkyl), -(C 1-4 Alkylene)-C(O)N(C 1-6 alkyl) 2 、-S(O) 2 C 1-6 Alkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, phenyl, 5-6 membered heteroaryl; the C 1-6 Alkyl, C 1-4 Alkylene, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, optionally substituted with one or more selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl group or the 3- to 6-membered heterocyclic group may be substituted.

[0362] In a preferred embodiment of the present invention, wherein R 1 Independently selected from: fluorine, chlorine, bromine, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, -C(O)C 1-3 Alkyl, -C(O)C 1-3 Haloalkyl, -C(O)OC 1-3 alkyl;

[0363] m is selected from: 1, 2;

[0364] Q is independently selected from: C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 7-8 membered heterospirocyclic group, 7-8 membered bridged heterocyclic group, 6-10 membered heterocyclic group, -NH-C 0-2 Alkylene-C 3-6 Cycloalkyl, -NH-C 0-2 Alkylene-C 5-6 Bridged ring group, -NH-C 0-2 Alkylene-3-6 membered heterocyclic group, -NH-C 0-2Alkylene-7-8 membered heterospirocyclic group; the cycloalkyl, heterocycloalkyl, heterospirocyclic group, bridged heterocyclic group, heterocyclic group, bridged heterocyclic group are optionally substituted by one or more R c2 replace;

[0365] R c2 Independently selected from: halogen, hydroxy, amino, cyano, -OC 1-3 Alkyl, -C(O)OH, -C(O)OC 1-3 Alkyl, C 1-3 Alkyl, C 1-3 Haloalkyl, hydroxy substituted C 1-3 Alkyl, amino substituted C 1-3 alkyl;

[0366] R d2 Independently selected from: -SC 1-3 Alkyl, -C(O)NH 2 、-C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 alkyl) 2 、-C(O)C 1-3 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)3-6 membered heterocyclic group, -C(O)-(C 1-2 Alkylene)-NH(C 1-3 alkyl), -C(O)-(C 1-2 Alkylene)-N(C 1-3 alkyl) 2 、-(C 1-2 Alkylene)-C(O)OC 1-3 Alkyl, -(C 1-2 Alkylene)-C(O)C 1-3 Alkyl, -(C 1-2 Alkylene)-S(O) 2 (C 1-3 Alkyl), -(C 1-2 Alkylene)-C(O)NH 2 、-(C 1-2 Alkylene)-C(O)NH(C 1-3 Alkyl), -(C 1-2 Alkylene)-C(O)N(C 1-3 alkyl) 2 、-S(O) 2 C 1-3 Alkyl, C 1-6 Alkyl, C 3-6Cycloalkyl, 3-6 membered monocyclic heterocyclic group, 7 membered spirocyclic heterocyclic group, phenyl, 5-6 membered heteroaryl; the alkyl, alkylene, cycloalkyl, monocyclic heterocyclic group, spirocyclic heterocyclic group, phenyl, 5-6 membered heteroaryl are optionally substituted with one or more selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 The cycloalkyl group or the 3- to 6-membered heterocyclic group may be substituted.

[0367] The present invention provides a compound represented by formula (IV-1) or formula (IV-2), or a tautomer, stereoisomer, isotope derivative or a pharmaceutically acceptable salt thereof:

[0368]

[0369] Among them, Q, R 1 , R d2 and m are defined as those for the compounds of formula (I), (IV) or (IV-a) of the present invention; "*" indicates that the S atom has a chiral center, and the configuration is R, S or a mixture of the two.

[0370] The present invention provides a compound represented by formula (IV-3), or its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt:

[0371]

[0372] Among them, Q, R 1 and R d2 The definition is the same as that of the compounds represented by formula (I), formula (IV), formula (IV-a) or formula (IV-2) of the present invention of the present application; "*" indicates that there is a chiral center at the S atom, and the configuration is R, S or a mixture of the two.

[0373] The present invention provides a compound represented by formula (IV-4) or formula (IV-5), or a tautomer, stereoisomer, isotope derivative or a pharmaceutically acceptable salt thereof:

[0374]

[0375] Among them, R 1 and R d2 The definition is the same as that of the compounds represented by formula (I), formula (IV), formula (IV-a), formula (IV-2) or formula (IV-3) of the present invention of the present application; "*" indicates that there is a chiral center at the S atom, and the configuration is R, S or a mixture of the two.

[0376] The present invention provides a compound represented by formula (IV-6) or formula (IV-7), or a tautomer, stereoisomer, isotope derivative or a pharmaceutically acceptable salt thereof:

[0377]

[0378] Among them, R d2 The definition is the same as that of the compounds represented by formula (I), formula (IV), formula (IV-a), formula (IV-2) or formula (IV-3) of the present invention of the present application; "*" indicates that there is a chiral center at the S atom, and the configuration is R, S or a mixture of the two.

[0379] The above preferred embodiments can be combined arbitrarily.

[0380] Preferably, the compound provided by the present invention or its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395] The present invention also provides an intermediate for preparing the compound of formula (I), which has a structure as shown in formula (Ra):

[0396]

[0397] Among them, R e is selected from a protecting group, hydrogen, R d2 As defined in formula (I), provided that R e and R d2 Not hydrogen at the same time.

[0398] In one embodiment of the present invention, the protecting group is selected from tert-butyloxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (FMOC), benzyloxycarbonyl (Cbz), p-methoxybenzyl (PMB), acetyl (Ac); preferably tert-butyloxycarbonyl (Boc).

[0399] In one embodiment of the present invention, the present invention also provides an intermediate for preparing a compound of formula (I), which has a structure as shown in formula (R-a5) and (R-a6):

[0400]

[0401] Among them, R d2 As defined for compounds of formula (I) and formula (Ra).

[0402] The present invention also provides the following synthetic intermediates for preparing the target compound:

[0403]

[0404]

[0405] The present invention also aims to provide a method for preparing the compound represented by the general formula or its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt.

[0406] The method can be prepared, for example, using the method shown in the following scheme:

[0407]

[0408] i) Compound R-a1 undergoes chemical transformation to obtain compound R-a2;

[0409] For example, compound R-a1 and amino derivatives are used as basic raw materials to obtain compound R-a2 through reaction;

[0410] ii) Compound R-a2 undergoes chemical transformation to obtain compound Ra;

[0411] For example, compound R-a2 and an amine derivative are used as basic raw materials to obtain a compound of formula (I) through reaction;

[0412] In the above general formula, Cy1, X, X 1 , Q, R1 , Het and m are defined as described for the compound represented by formula (I) of the present invention.

[0413] In one embodiment of the present invention, the method can be prepared, for example, using the method shown in the following scheme:

[0414]

[0415] i) Compound R-a1 undergoes chemical transformation to obtain compound R-a2;

[0416] For example, compound R-a1 and amino derivatives are used as basic raw materials to obtain compound R-a2 through reaction;

[0417] ii) Compound R-a2 undergoes chemical transformation to obtain compound Ra;

[0418] For example, compound R-a2 and an amine derivative are used as basic raw materials to obtain a compound of formula (I) through reaction;

[0419] In the above general formula, Cy1, X, Q, R 1 , Het and m are defined as described for the compound represented by formula (I) of the present invention.

[0420] In one embodiment of the present invention, compound R-a2 and an amine derivative are used as basic raw materials to obtain a compound of formula (IV) by reaction as shown below:

[0421]

[0422] i) Compound R-a3 undergoes oxidation reaction to obtain compound R-a4

[0423] For example, compound R-a3 is reacted with iodobenzene acetate, ammonium carbonate and other basic raw materials to obtain R-a4 through chemical reaction;

[0424] ii) Compound R-a4 undergoes substitution reaction to obtain compound R-a5

[0425] For example, compound R-a4 and methanesulfonate substituents and other basic raw materials are used to obtain R-a5 through chemical reaction;

[0426] iii) Reaction of the nitrogen atom in compound R-a5 to obtain compound R-a6

[0427] For example, compound R-a5 and basic raw materials such as trifluoroacetic acid can be used to obtain R-a6 through chemical reaction;

[0428] iv) Compound R-a1 undergoes chemical transformation to obtain compound R-a2;

[0429] For example, compound R-a1 and amino derivatives are used as basic raw materials to obtain compound R-a2 through reaction;

[0430] v) chemical conversion of compounds R-a2 and R-a6 to obtain formula (IV);

[0431] For example, using compounds R-a2 and R-a6 as basic raw materials, a compound of formula (IV) is obtained through a substitution reaction;

[0432] In the above general formula, Cy1, X, X 1 ,Q,R 1 , R d2 and m are defined as described for the compound represented by formula (I) of the present invention.

[0433] In one embodiment of the present invention, compound R-a2 and an amine derivative are used as basic raw materials to obtain a compound of formula (IV-a) by reaction as shown below:

[0434]

[0435] i) Compound R-a3 undergoes oxidation reaction to obtain compound R-a4

[0436] For example, compound R-a3 is reacted with iodobenzene acetate, ammonium carbonate and other basic raw materials to obtain R-a4 through chemical reaction;

[0437] ii) Compound R-a4 undergoes substitution reaction to obtain compound R-a5

[0438] For example, compound R-a4 and methanesulfonate substituents and other basic raw materials are used to obtain R-a5 through chemical reaction;

[0439] iii) Reaction of the nitrogen atom in compound R-a5 to obtain compound R-a6

[0440] For example, compound R-a5 and basic raw materials such as trifluoroacetic acid can be used to obtain R-a6 through chemical reaction;

[0441] iv) Compound R-a1 undergoes chemical transformation to obtain compound R-a2;

[0442] For example, compound R-a1 and amino derivatives are used as basic raw materials to obtain compound R-a2 through reaction;

[0443] v) Compounds R-a2 and R-a6 undergo chemical conversion to obtain formula (IV-a);

[0444] For example, using compounds R-a2 and R-a6 as basic raw materials, a compound of formula (IV-a) is obtained through a substitution reaction;

[0445] In the above general formula, Cy1, X, Q, R1 , R d2 and m are defined as described for the compound represented by formula (I) of the present invention.

[0446] The present invention also provides a pharmaceutical composition comprising the compound of the present invention or its tautomer, stereoisomer, isotope derivative or a pharmaceutically acceptable salt thereof.

[0447] The present invention also provides a pharmaceutical composition, which comprises the compound of the present invention or its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

[0448] The administration of the compounds of the present invention or their tautomers, stereoisomers, isotopic derivatives or pharmaceutically acceptable salts thereof can be carried out in pure form or in the form of suitable pharmaceutical compositions by providing any acceptable mode of administration of drugs of similar use. The pharmaceutical compositions of the present invention can be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable adjuvants. The pharmaceutical compositions of the present invention can be formulated into solid, semi-solid, liquid or gaseous preparations. Generally, the above-mentioned pharmaceutical compositions can be prepared by conventional preparation methods using conventional excipients in the field of preparations.

[0449] The purpose of the present invention also includes providing the use of the compound shown in the present invention or its tautomer, stereoisomer, isotope derivative or its pharmaceutically acceptable salt or pharmaceutical composition in the preparation of drugs for preventing and / or treating diseases infected by RSV virus.

[0450] On the other hand, the present application provides a method for preventing and / or treating diseases caused by RSV virus infection, or for inhibiting RSV virus in patients or biological samples, which comprises administering the compound of the present invention or its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt or the pharmaceutical composition of the present invention to an individual in need, or contacting the biological sample with the compound of the present invention or its pharmaceutical composition.

[0451] In another aspect, the present application provides a compound of the present invention or its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt or pharmaceutical composition of the present invention for preventing and / or treating diseases caused by RSV virus infection, or for inhibiting RSV virus in patients or biological samples.

[0452] Furthermore, the present invention provides a use or method, wherein the compound shown in the present invention or its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt or pharmaceutical composition is used in combination with other drugs.

[0453] The present invention also aims to provide a pharmaceutical composition comprising the compound of the present invention or its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt or the pharmaceutical composition of the present invention, and other compounds. The other compounds are selected from pharmaceutically active ingredients other than the compound of the present invention.

[0454] definition

[0455] “*” indicates that the atom has a chiral center, and the configuration is R, S or a mixture of the two.

[0456] The “plurality” in “optionally substituted with one or more substituents each independently selected from…” refers to 2, 3, 4, 5, 6, 7, 8, 9 or 10; preferably 2, 3 or 4; more preferably 2.

[0457] The terms "optional", "optionally", "optionally" or "arbitrarily" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0458] The term "oxo" refers to two hydrogen atoms at the same substitution position being replaced by the same oxygen atom to form a double bond.

[0459] The term "thio" refers to two hydrogen atoms at the same substitution position being replaced by the same sulfur atom to form a double bond.

[0460] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight or branched chain group containing 1-20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) carbon atoms, preferably a straight or branched chain group containing 1-18 carbon atoms (i.e., C 1-18 Alkyl) or 1-10 carbon atoms (i.e. C 1-10 Alkyl), further preferably containing 1 to 8 carbon atoms (C 1-8 Alkyl), more preferably containing 1 to 6 carbon atoms (i.e. C 1-6 Alkyl), more preferably containing 1-4 carbon atoms (i.e. C 1-4 Alkyl), such as "C 1-6 "Alkyl" means that the group is an alkyl group and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically 1, 2, 3, 4, 5 or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.

[0461] Unless otherwise specified, the term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. The alkenyl group may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2-10 Alkenyl), further preferably containing 2 to 8 carbon atoms (C 2-8 Alkenyl), more preferably containing 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), 2-5 carbon atoms (i.e. C 2-5 alkenyl), 2-4 carbon atoms (i.e. C 2-4 alkenyl), 2-3 carbon atoms (i.e. C 2-3 alkenyl), 2 carbon atoms (i.e. C 2 alkenyl), such as "C 2-6 "Alkenyl" means that the group is an alkenyl group, and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl and 1,3-butadienyl, etc.

[0462] Unless otherwise specified, the term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond. The alkynyl group may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2-10 Alkynyl), further preferably containing 2 to 8 carbon atoms (C 2-8 Alkynyl), more preferably containing 2 to 6 carbon atoms (i.e. C 2-6 Alkynyl), 2-5 carbon atoms (i.e. C 2-5 Alkynyl), 2-4 carbon atoms (i.e. C 2-4 Alkynyl), 2-3 carbon atoms (i.e. C 2-3 Alkynyl), 2 carbon atoms (i.e. C 2 Alkynyl), such as "C 2-6 "Alkynyl" means that the group is an alkynyl group, and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl and 1-butynyl, etc.

[0463] Unless otherwise specified, the term "alkoxy" refers to -O-alkyl, wherein the alkyl is as defined above, i.e., contains 1-20 carbon atoms, preferably, contains 1-10 carbon atoms, more preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5 or 6). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, and the like.

[0464] Unless otherwise specified, the term "halogen" or "halo" refers to F, Cl, Br, I. The term "haloalkyl" refers to an alkyl group as defined above in which one, two or more hydrogen atoms or all hydrogen atoms are replaced by halogen. Representative examples of haloalkyl groups include CCl 3 CF 3 , CHCl 2 , CH 2 Cl, CH 2 Br, CH 2 I. CH 2 CF 3 CF 2 CF 3 wait.

[0465] Unless otherwise specified, the term "carbocyclyl" or "carbocycle" refers to a non-aromatic cyclic hydrocarbon group ("C 3-20 In some embodiments, the carbocyclyl group has 3-12 ring carbon atoms ("C 3-12 carbocyclyl”), or 4-12 ring carbon atoms (“C 4-12 carbocyclyl"), or 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3-8 In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C 3-7 In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C 4-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5-10 carbocyclyl"), or 5 to 7 ring carbon atoms ("C 5-7 "Carbocyclyl"). Exemplary C 3-6Carbocyclyl groups include, but are not limited to, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ) etc. Exemplary C 3-8 Carbocyclyl groups include, but are not limited to, the aforementioned C 3-6 Carbocyclyl groups and cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptyl (C 7 ), bicyclo[2.2.2]octyl (C 8 ) etc. Exemplary C 3-10 Carbocyclyl groups include, but are not limited to, the aforementioned C 3-8 Carbocyclyl groups and cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10 ) and the like. As illustrated in the above examples, in certain embodiments, the carbocyclyl group is a monocyclic ("monocyclic carbocyclyl") or a fused (and carbocyclyl), bridged (bridged ring) or spiro (spirocyclyl) ring system, such as a bicyclic system ("bicyclic carbocyclyl") and may be saturated or may be partially unsaturated. "Carbocyclyl" also includes a ring system in which the carbocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclyl ring, and in such cases, the number of atoms of the carbocyclyl ring system is the number of carbons of the carbocyclyl system after fusion. In certain embodiments, each example of a carbocyclyl group is independently optionally substituted, for example, unsubstituted (an "unsubstituted carbocyclyl") or substituted by one or more substituents (a "substituted carbocyclyl"). In certain embodiments, the carbocyclyl group is an unsubstituted C 3-10 In certain embodiments, the carbocyclyl group is a substituted C 3-10 Carbocyclic group.

[0466] Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a specified number of carbon atoms, preferably containing 3-12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms (i.e., C 3-12 cycloalkyl), more preferably containing 3 to 10 carbon atoms (C 3-10 Cycloalkyl), preferably 3 to 7 carbon atoms (C 3-7 Cycloalkyl), 4-6 carbon atoms (C 4-6 Cycloalkyl), 5-6 carbon atoms (C 5-6 Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.

[0467] Unless otherwise specified, the term "heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic non-aromatic substituent having ring carbon atoms and 1 to 4 ring heteroatoms, containing 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) ring atoms, wherein 1, 2, 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C. Preferably, it contains 3 to 18 ring atoms (3-18-membered heterocyclic group), more preferably 3 to 15 ring atoms (3-15-membered heterocyclic group), or 3 to 12 ring atoms (3-12-membered heterocyclic group), or 4 to 12 ring atoms (4-12-membered heterocyclic group), or 3 to 10 ring atoms (3-10-membered heterocyclic group), or 3 to 8 ring atoms (3-8-membered heterocyclic group), or 3 to 7 ring atoms (3-7-membered heterocyclic group), or 4 to 7 ring atoms (4-7-membered heterocyclic group), or 3 to 6 ring atoms (3-6-membered heterocyclic group), or 4 to 6 ring atoms (4-6-membered heterocyclic group), or 5 to 6 ring atoms (5-6-membered heterocyclic group). The number of heteroatoms is preferably 1 to 4, more preferably 1 to 3 (i.e., 1, 2 or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, etc. Polycyclic heterocyclic groups include heterocyclic, spirocyclic and bridged heterocyclic groups. "Heterocyclic group" can be a monocyclic ("monocyclic heterocyclic group") or a fused (heterocyclic group), bridged ("heterobridged group" or "bridged heterocyclic group") or spiro ("heterospirocyclic group", "spiroheterocyclic group" or "spirocyclic heterocyclic group") ring system, such as a bicyclic system ("bicyclic heterocyclic group"), and can be saturated or partially unsaturated. Heterocyclic bicyclic systems can include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which the heterocyclyl ring as defined above is fused with one or more carbocyclyl groups, wherein the point of attachment is on the carbocyclyl or heterocyclyl ring, or "heterocyclyl" also includes ring systems in which the heterocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, or cycloalkyl rings as defined above are fused with one or more heteroaryl groups, wherein the point of attachment is on the heterocyclyl or cycloalkyl ring, and in such cases, the number of members of the heterocyclyl ring system is the number of atoms in the ring system after fusion. In certain embodiments, each instance of heterocyclyl is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocyclyl") or substituted with one or more substituents (a "substituted heterocyclyl"). Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, aziridine, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl.Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrophenylthio, dihydrophenylthio, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, dithiolanyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithiolanyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazacyclohexane, oxadiazine, thiadiazine, oxathiazine, and dioxaazacyclohexane (dioxazinanyl). Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azepanyl, oxepane, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azacyclooctanyl, oxepane, and thiepanyl. Fused to one C. 6 Exemplary 5-membered heterocyclyl groups on an aryl ring (also referred to herein as a 5,6-bicyclic heterocycle) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocycle) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0468] Unless otherwise specified, the term "spirocyclyl" or "spiro ring" refers to a saturated, monovalent aliphatic hydrocarbon group containing only one spiro carbon atom, which may contain 6-20 ring carbon atoms, preferably 7-10 ring carbon atoms. Spirocyclyl includes 3-membered / 5-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered and 5-membered / 6-membered spirocyclyl, etc., wherein the spiro atom is counted in the number of members of each ring. Exemplary examples of spirocyclyl include (but are not limited to) wait.

[0469] Unless otherwise specified, the term "heterospirocyclyl" or "spiroheterocyclyl" refers to a saturated, monovalent aliphatic group containing only one spiro carbon atom, which may contain 6-20 ring atoms, preferably 7-10 ring atoms, including 1-4 ring heteroatoms, preferably 1-3 (i.e., 1, 2 or 3) ring heteroatoms, and the heteroatoms are independently selected from N, O and S. Heterospirocyclyl includes 3-membered / 5-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered and 5-membered / 6-membered heterospirocyclyl, etc., wherein the spiro atom is counted in the number of members of each ring respectively. Exemplary examples of heterospirocyclyl include (but are not limited to) wait.

[0470] The carbocyclyl group may contain 5-14 ring atoms, preferably 6-12 ring atoms, and more preferably 7-10 ring atoms. The carbocyclyl group includes a bicyclic, tricyclic, tetracyclic or polycyclic carbocyclyl group, preferably a bicyclic, tricyclic or tetracyclic carbocyclyl group, and more preferably a bicyclic or tricyclic carbocyclyl group. Exemplary examples of carbocyclyl groups include (but are not limited to) wait.

[0471] The heterocyclic group may contain 5-14 ring atoms, preferably 6-12 ring atoms, more preferably 7-10 ring atoms, wherein 1-4 ring heteroatoms are contained, preferably 1-3 (i.e., 1, 2 or 3) ring heteroatoms are contained, and the heteroatoms are independently selected from N, O and S. The heterocyclic group includes a bicyclic, tricyclic, tetracyclic or polycyclic heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic heterocyclic group, more preferably a bicyclic or tricyclic heterocyclic group. Exemplary examples of heterocyclic groups include (but are not limited to) wait.

[0472] Unless otherwise specified, the term "bridged ring group" refers to a polycyclic, monovalent aliphatic hydrocarbon group in which any two rings share two ring carbon atoms that are not directly connected, which may contain 5-20 ring carbon atoms, preferably 6-14 ring carbon atoms, more preferably 7-10 ring carbon atoms, and may contain one or more double bonds, but no ring has a completely conjugated π electron system. Bridged ring groups include bicyclic, tricyclic, tetracyclic or polycyclic bridged ring groups, preferably bicyclic, tricyclic or tetracyclic bridged ring groups, more preferably bicyclic or tricyclic bridged ring groups. Exemplary examples of bridged ring groups include (but are not limited to)

[0474] Unless otherwise specified, the term "heterobridged ring group" refers to a polycyclic, monovalent aliphatic group in which any two rings share two ring atoms that are not directly connected, which may contain 5-14 ring atoms, preferably 6-14 ring atoms, more preferably 7-10 ring atoms, wherein 1-4 ring heteroatoms, preferably 1-3 (i.e., 1, 2 or 3) ring heteroatoms, and the heteroatoms are independently selected from N, O and S, and may contain one or more double bonds, but none of the rings has a completely conjugated π electron system. Heterobridged ring groups include bicyclic, tricyclic, tetracyclic or polycyclic heterobridged ring groups, preferably bicyclic, tricyclic or tetracyclic heterobridged ring groups, more preferably bicyclic or tricyclic heterobridged ring groups. Exemplary examples of heterobridged ring groups include (but are not limited to)

[0475] Unless otherwise specified, the term "aryl" or "aromatic ring group" means a monocyclic, bicyclic and tricyclic aromatic carbocyclic ring system containing 6-16 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16) carbon atoms, or 6-14 carbon atoms, or 6-12 carbon atoms, or 6-10 carbon atoms, preferably 6-10 carbon atoms, more preferably 6-8 carbon atoms, more preferably phenyl. The term "aryl" can be used interchangeably with the term "aromatic ring". Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl or pyrenyl, etc.

[0476] Unless otherwise specified, the term "heteroaryl" or "heteroaromatic ring group" means an aromatic monocyclic or polycyclic ring system containing 5-20 members (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 members), or preferably 5-18 members, or preferably 5-12 members, or preferably 5-10 members, or preferably 5-8 members, more preferably 5-6 members, wherein 1, 2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is preferably 1, 2 or 3. Polycyclic heteroaryl is a fused heteroaryl. Examples of heteroaryl groups include, but are not limited to, furanyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolyl, isoquinolyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzopyridinyl, benzopyrimidinyl, benzo pyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, and the like.

[0477] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood to be a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively. The definition of the linking group, such as alkylene, is the same as the definition of the term "alkyl", which is a divalent alkyl group as defined above. Wherein, C 0-6 The definition of alkylene includes C 0 (i.e. the connecting group is only a bond) and C 1-6 Alkylene. 1-6 The definition of alkylene is the same as that of C 1-6 alkyl.

[0478] Unless otherwise specified, the term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to salts that are suitable for contact with mammalian, especially human tissues without excessive toxicity, irritation, allergic reaction, etc. and commensurate with a reasonable benefit / risk ratio within the scope of reasonable medical judgment, such as amines, carboxylic acids and other types of medically acceptable salts of compounds are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or separately by reacting the free base or free acid with a suitable reagent.

[0479] Unless otherwise specified, the term "isotopic derivative" means that the compounds of the present invention may exist in an isotopically traced or enriched form, containing one or more atoms whose atomic mass or mass number is different from the atomic mass or mass number of the largest atom found in nature. Isotopes may be radioactive or non-radioactive isotopes. Isotopes commonly used as isotopic labels are: hydrogen isotopes, 2 H and 3 H; Carbon isotope: 13 C and 14 C; Chlorine isotope: 35 Cl and 37 Cl; Fluorine isotope: 18 F; Iodine isotope: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotope: 15 O. 17 O and 18 O and sulfur isotopes 35 S. These isotope-labeled compounds can be used to study the distribution of drug molecules in tissues. 3 H and 13 C, because they are easy to label and detect, they are more widely used. Some heavy isotopes, such as deuterium ( 2 H) substitution can enhance metabolic stability, prolong half-life, thereby achieving the purpose of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds generally start from labeled starting materials and use known synthesis techniques to complete their synthesis like non-isotope-labeled compounds.

[0480] Unless otherwise specified, the compounds of the present invention also include their "solvates" or "solvates". The terms "solvate" and "solvate" mean the physical association of the compounds of the present invention with one or more solvent molecules (whether organic or inorganic). The physical association includes hydrogen bonds. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to be separated. The solvent molecules in the solvate may exist in a regular arrangement and / or a disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvates" encompass solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art. The term "hydrate" refers to a substance formed by water molecules being bound to cations or anions in a compound by coordination bonds or covalent bonds, or by water ions that are not directly bound to cations or anions but are present in a certain proportion at a determined position in the solid crystal lattice.

[0481] Unless otherwise specified, the term "stereoisomer" refers to a compound having the same chemical constitution but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotational isomers), geometric isomers (cis / trans) isomers, atropisomers, etc. Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography and / or fractional crystallization, based on differences in the physical and chemical properties of the components. Unless otherwise specified, the term "geometric isomer (cis / trans) isomer" may contain carbon-carbon double bonds or carbon-nitrogen double bonds in E or Z configuration, wherein the term "E" represents a higher order substituent on the opposite side of the carbon-carbon or carbon-nitrogen double bond, and the term "Z" represents a higher order substituent on the same side of the carbon-carbon or carbon-nitrogen double bond (determined using the Cahn-Ingold Prelog priority rules). The compounds of the present invention may also exist as a mixture of "E" and "Z" isomers.

[0482] Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can be interconverted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0483] Unless otherwise indicated, the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformational isomers) are all within the scope of the present invention.

[0484] Unless otherwise specified, the compounds of the present invention also include their "prodrugs". The term "prodrug" refers to a drug that is converted into the parent drug in vivo. Prodrugs are generally useful and can improve some determined, undesirable physical or biological properties. Physical properties are generally related to solubility (too high or insufficient lipid or water solubility) or stability, while problematic biological properties include too rapid metabolism or poor bioavailability, which may themselves be related to physicochemical properties. For example, they can be bioavailable by oral administration, while the parent cannot. The solubility of the prodrug in the pharmaceutical composition is also improved compared to the parent drug. An example of a prodrug, but not limited to this, can be any compound of the present invention, which is administered as an ester ("prodrug") to facilitate transmission across the cell membrane, where water solubility is detrimental to mobility, but once inside the cell, water solubility is beneficial, which is then metabolically hydrolyzed to a carboxylic acid, i.e., the active entity. Another example of a prodrug can be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to reveal the active portion.

[0485] Unless otherwise specified, the term "treatment" encompasses any treatment of a disease, disorder or condition in a patient, including: (a) inhibiting the symptoms of the disease, disorder or condition, i.e., arresting its development; or (b) relieving the symptoms of the disease, disorder or condition, i.e., causing regression of the disease or symptoms; or (c) ameliorating or eliminating the disease, disorder or condition or one or more symptoms associated with the disease.

[0486] Abbreviations used in the Preparative Examples, Examples, and elsewhere herein are:

[0487] DCM: dichloromethane; TEA: triethylamine; DIEA: N,N-diisopropylethylamine; DMF: N,N-dimethylformamide; EtOAc:

[0488] Ethyl acetate; H: hour; mL: milliliter; MeOH: methanol; TFA: trifluoroacetic acid; NBSN-bromosuccinimide; NIS: N-iodosuccinimide; THF: tetrahydrofuran; Pd(dppf)Cl 2 :[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride; DMSO-d 6: deuterated dimethyl sulfoxide; Toluene: toluene; mCPBA: m-chloroperbenzoic acid; PE: petroleum ether; EA: ethyl acetate; LAH: lithium aluminum hydride.

[0489] The beneficial effects of the present invention are:

[0490] The present invention designs a class of novel compounds. In vitro cell studies show that the compounds of the present invention have a good inhibitory effect on RSV virus. hERG tests show that the compounds of the present invention have a low risk of cardiotoxicity and good safety. In vivo tests show that the compounds of the present invention have good pharmacokinetic properties and good in vivo antiviral effects. In addition, the present invention studies a specific synthesis method, which has a simple process, is easy to operate, and is conducive to large-scale industrial production and application. DETAILED DESCRIPTION

[0491] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples that do not specify specific conditions are usually performed under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise defined, all professional and scientific terms used in the text have the same meanings as those familiar to professionals in the field. In addition, any method and material similar or equivalent to the described content can be applied to the method of the present invention. The preferred implementation methods and materials shown in the text are for demonstration purposes only.

[0492] The chiral compounds involved in the present invention can be separated and purified using supercritical chromatography equipment, chiral chromatography columns, and conventional solvents as mobile phases to obtain optically pure monomeric compounds.

[0493] The following are preparation examples of exemplary compounds of the present application.

[0494] Intermediate Preparation Example 1-1: Synthesis of 2,4-dichloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

[0495]

[0496] Step 1: Synthesis of 2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

[0497] 2,4-dichloro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylic acid tert-butyl ester (0.5 g, 1.64 mmol), DCM (5 mL), and trifluoroacetic acid (2 mL) were added to a 100 mL reaction bottle in sequence, and the reaction solution was stirred at room temperature for 3 h. LCMS showed that the reaction was complete, and the mixture was post-treated and concentrated to dryness under reduced pressure to obtain a crude 2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, which was used directly in the next step without further purification. ESI-MS (m / z): 204.00 [M+H] + .

[0498] Step 2: Synthesis of 2,4-dichloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

[0499] DCM (4 mL) and methanol (1 mL) were added to the crude 2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine obtained in step 1, and the pH of the reaction solution was adjusted to 9 with triethylamine, and then glacial acetic acid was added dropwise to make the pH of the reaction solution 5. Paraformaldehyde (0.45 g) was added under stirring at room temperature, and then sodium cyanoborohydride (0.31 g, 4.9 mmol) was added after continuing stirring for 1 h, and the reaction was stirred at room temperature overnight. LCMS showed that the reaction was complete, and dichloromethane was added to dilute the reaction solution. The reaction solution was washed with water and concentrated to dryness under reduced pressure. The concentrate was purified by column chromatography (DCM: MeOH = 40: 1 (v / v)) to obtain 2,4-dichloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (0.4 g). ESI-MS (m / z): 218.02 [M+H] + .

[0500] Intermediate Preparation Example 1-2: Synthesis of 2-(bromomethyl)-6-methylquinazolin-4(3H)-one

[0501]

[0502] Step 1: Synthesis of 2-amino-5-methylbenzonitrile

[0503] 5-Methyl-2-nitrobenzonitrile (2g, 12.33mmol), ethanol (20mL), water (40mL), reduced Fe powder (2.8g, 50.00mmol), and ammonium chloride (2.7g, 50.47mmol) were added to a 100mL reaction bottle in sequence, and the system was heated to reflux for 5h. TLC showed that the reaction was complete, and the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 2-amino-5-methylbenzonitrile (1.8g).

[0504] Step 2: Synthesis of N-(2-cyano-4-methylphenyl)-2-methoxyacetamide

[0505] 2-Amino-5-methylbenzonitrile (2g, 15.15mmol) and DMF (12mL) were added to a 100mL reaction bottle in sequence. 2-Methoxyacetyl chloride (2.5g, 23.04mmol) was added to the reaction solution at 0°C, followed by dropwise addition of pyridine (3.6g, 45.51mmol). After the addition was complete, the reaction solution was returned to room temperature for reaction for 1h. TLC showed that the reaction was complete, the reaction solution was poured into water, filtered, and the filter cake was dried to obtain N-(2-cyano-4-methylphenyl)-2-methoxyacetamide (1.0g).

[0506] Step 3: Synthesis of 2-(methoxymethyl)-6-methylquinazolin-4-(3H)-one

[0507] In a 100 mL reaction bottle, N-(2-cyano-4-methylphenyl)-2-methoxyacetamide (1.0 g, 4.90 mmol), acetone (20 mL), water (20 mL), potassium carbonate (2.7 g, 19.54 mmol), urea hydrogen peroxide complex (2.7 g, 28.70 mmol) were added in sequence, and the system was heated to 80 ° C for 6 h. LCMS showed that the reaction was complete, water was added to the reaction solution, and then dichloromethane was added for extraction. The organic phase was concentrated to dryness under reduced pressure to obtain 2-(methoxymethyl)-6-methylquinazolin-4-(3H)-one (1.0 g). ESI-MS (m / z): 205.23 [M+H] + .

[0508] Step 4: Synthesis of 2-(bromomethyl)-6-methylquinazolin-4(3H)-one

[0509] 2-(Methoxymethyl)-6-methylquinazolin-4-(3H)-one (1 g, 4.90 mmol) and 48% HBr (50 mL) were added to a 100 mL reaction bottle, and the reaction temperature was raised to 120°C for 3 days. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM: MeOH = 20: 1 (v / v)) to obtain 2-(bromomethyl)-6-methylquinazolin-4 (3H)-one (0.35 g). ESI-MS (m / z): 253.10 / 255.10 [M+H] + Intermediate Preparation Example 1-3: Synthesis of 2,4-dichloro-6-methylpyrido[2,3-d]pyrimidine

[0510]

[0511] Step 1: Synthesis of 6-methylpyrido[2,3-d]pyrimidine-2,4-diol

[0512] 2-Amino-5-methylnicotinic acid (2 g, 13.14 mmol) and urea (3.95 g, 65.72 mmol) were added to a 100 mL reaction bottle, and the reaction solution was stirred at 195 °C for 2 hours. Then the reaction solution was cooled to room temperature, and NaOH (525.76 mg, 13.14 mmol) and H 2 O (20 mL), the reaction solution was stirred at 95 ° C for 1 hour. After the reaction was completed, the reaction solution was adjusted to pH = 5 with HCl (1 M), and solids were precipitated. The solids were collected and spin-dried, and then slurried with ethyl acetate to obtain 6-methylpyrido [2,3-d] pyrimidine-2,4-diol (1.5 g). ESI-MS (m / z): 178.05 M + H] + .

[0513] Step 2: Synthesis of 2,4-dichloro-6-methylpyrido[2,3-d]pyrimidine

[0514] Dissolve 6-methylpyrido[2,3-d]pyrimidine-2,4-diol (1.36 g, 7.68 mmol) in POCl 3 (13.6 mL), DIEA (1.59 g, 12.28 mmol, 2.14 mL) was added at 0 ° C, and the reaction solution was stirred at 110 ° C for 12 hours. After the reaction was completed by LCMS monitoring, the reaction solution was spin-dried, water (30 mL) was added, and dichloromethane was extracted. The organic phase was washed with saturated NaHCO 3 The crude product was washed with saturated NaCl and distilled under reduced pressure, and purified by column chromatography (PE:EA=10:1) to give 2,4-dichloro-6-methylpyrido[2,3-d]pyrimidine (1.1 g). ESI-MS (m / z): 214.00 [M+H] + . 1 HNMR (400MHz, CDCl 3 )δ=9.16(d,J=2.3Hz,1H),8.36(d,J=1.2Hz,1H),2.65(s,3H).

[0515] Intermediate Preparation Example 1-4: Synthesis of 2,4-dichloro-6-methylpyridone[3,4-d]pyrimidine

[0516]

[0517] Step 1: Synthesis of 6-chloropyrido[3,4-d]pyrimidine-2,4-diol

[0518] 5-Amino-2-chloroisonicotinic acid (10 g, 57.95 mmol) and urea (17.4 g, 289.74 mmol) were added, the reaction solution was stirred at 195 °C for 2 h and then cooled to room temperature, and NaOH (2.32 g, 57.95 mmol) and H 2 O (100 mL), the reaction solution was stirred at 95 ° C for 1 h. LCMS detected that the reaction was complete, and the reaction solution was adjusted to pH 5 with HCl (1 M), and solids were precipitated. The solids were collected and spin-dried, and slurried with EA to obtain 6-chloropyrido [3,4-d] pyrimidine-2,4-diol (10 g), ESI-MS (m / z): 198.00\200.00 [M+H] + .

[0519] Step 2: Synthesis of 6-methylpyrido[3,4-d]pyrimidine-2,4-diol

[0520] 6-Chloropyrido[3,4-d]pyrimidine-2,4-diol (5 g, 25.31 mmol) and trimethylcyclotriboroxane (3.5 M, 36.15 mL) were dissolved in dioxane (60 mL), and K 2 CO 3 (6.99g,50.61mmol) and Pd(dppf)Cl 2 ·CH 2 Cl 2 (2.07 g, 2.53 mmol), the reaction solution was stirred at 110 ° C for 15 h under nitrogen protection. LCMS detected that the reaction was complete, the reaction solution was spin-dried, EA slurried, and purified by prep-HPLC to obtain 6-methylpyrido [3,4-d] pyrimidine-2,4-diol (2 g), ESI-MS (m / z): 178.05 [M+H] + .

[0521] Step 3: Synthesis of 2,4-dichloro-6-methylpyrido[3,4-d]pyrimidine

[0522] Dissolve 6-methylpyrido[3,4-d]pyrimidine-2,4-diol (2 g, 11.29 mmol) in POCl 3 (20mL), DIEA (2.92g, 22.58mmol) was added at 0℃, and the reaction solution was stirred at 110℃ for 6h. LCMS detected that the reaction was complete, the reaction solution was spin-dried, extracted with water and dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure, and purified by column chromatography (PE:EA=5:1) to obtain 2,4-dichloro-6-methylpyrido[3,4-d]pyrimidine (1.05g), ESI-MS (m / z): 214.00[M+H] + .

[0523] Intermediate Preparation Example 2-1: 10,11-Dihydrodibenzo[b,f][1,4]oxazepine Synthesis

[0524]

[0525] Dibenzo[b,f][1,4]oxazepine -11(10H)-ketone (5 g, 23.69 mmol) was dissolved in THF (50 mL) and BH 3 -THF (4.48 g, 52.12 mmol) was added to the reaction solution, and the mixture was stirred at 65°C for 3 h. LCMS detected that the reaction of the raw material was complete. The reaction solution was purified by column chromatography (DCM: MeOH = 15: 1) to obtain 10,11-dihydrodibenzo[b,f][1,4]oxazepine (4.46g), ESI-MS(m / z):198.08[M+H] + .

[0526] Intermediate Preparation Example 2-2: 10,11-Dihydrodibenzo[b,f][1,4]thiazepine Synthesis of 5,5-dioxide

[0527]

[0528] Step 1: 10,11-Dihydrodibenzo[b,f][1,4]thiazepine Synthesis

[0529] Add dibenzo[b,f][1,4]thiazepine into a 250 mL reaction flask. -11(10H)-ketone (2.00 g, 8.8 mmol) and THF (70 mL), borane (62 mL) was slowly added dropwise at 0°C. After the reaction was completed by LCMS, methanol was added to the reaction solution, and the solvent was concentrated to dryness under reduced pressure to obtain 10,11-dihydrodibenzo[b,f][1,4]thiazepine (1.80g). ESI-MS(m / z):214.13[M+H] + .

[0530] Step 2: 1-(Dibenzo[b,f][1,4]thiazepine Synthesis of 1-(10(11H)-yl)ethane-1-one

[0531] Add 10,11-dihydrodibenzo[b,f][1,4]thiazepine to a 100 mL reaction flask. (1.00 g, 4.7 mmol), acetic anhydride (0.67 g, 6.6 mmol), triethylamine (0.85 g, 8.4 mmol) and toluene (20 mL) were reacted at 100 ° C for 1 h. After the reaction was completed by LCMS, ethyl acetate was added to the reaction solution, washed with sodium chloride aqueous solution, and dried over anhydrous sodium sulfate to obtain 1-(dibenzo[b,f][1,4]thiazepine -10(11H)-yl)ethane-1-one (1.10 g, 4.3 mmol, 91%). ESI-MS (m / z): 256.20 [M+H] + .

[0532] Step 3: 1-(5,5-dioxydibenzo[b,f][1,4]thiazepine Synthesis of 1-(10(11H)-yl)ethane-1-one

[0533] Add 1-(dibenzo[b,f][1,4]thiazepine) into a 100 mL reaction flask. -10(11H)-yl)ethane-1-one (1.10 g, 4.3 mmol), mCPBA (2.41 g, 13.9 mmol) and chloroform (20 mL), slowly add mCPBA (2.41 g, 13.9 mmol) dissolved in chloroform at 0°C, and react for 2 h at room temperature. After the reaction is completed by LCMS, it is washed with saturated sodium carbonate solution, sodium thiosulfate and sodium chloride aqueous solution. The organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, washed with ether, and filtered to obtain 1-(5,5-dioxydibenzo[b,f][1,4]thiazepine -10(11H)-yl)ethane-1-one (1.10 g). ESI-MS (m / z): 288.14 [M+H] + .

[0534] Step 4: 10,11-Dihydrodibenzo[b,f][1,4]thiazepine Synthesis of -5,5-dioxide

[0535] Add 1-(5,5-dioxydibenzo[b,f][1,4]thiazepine) into a 100 mL reaction bottle. -10(11H)-yl)ethane-1-one (1.10 g, 3.8 mmol), sodium hydroxide (0.90 g, 22.5 mmol), ethanol (20 mL) and water (10 mL), react at 80 ° C for 6 h. After the reaction is completed by LCMS detection, the organic solvent is dried. The reaction solution is filtered and the filter cake is washed with water to obtain 10,11-dihydrodibenzo[b,f][1,4]thiazepine -5,5-dioxide (0.89 g, 3.6 mmol, 96%). ESI-MS (m / z): 246.14 [M+H] + .

[0536] Intermediate Preparation Example 2-3: 2,3,4,5-Tetrahydrobenzo[f][1,4]thiazepine Synthesis of -1,1-dioxide

[0537]

[0538] Step 1: 3.4-Dihydrobenzo[f][1,4]thiazepine Synthesis of -5(2H)-Ketone

[0539] In a 100 mL reaction bottle, methyl 2-mercaptobenzoate (3.00 g, 17.8 mmol), 2-chloroethylamine hydrochloride (2.07 g, 17.8 mmol), DMF (10 mL) and THF (10 mL) were added. Sodium hydride (2.22 g, 55.5 mmol) was slowly added at 0°C. After the reaction was completed by LCMS, water was added to the reaction solution and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure, slurried with a mixed solution (EA:PE = 1:1), and filtered to obtain 3.4-dihydrobenzo[f][1,4]thiazepine. -5(2H)-ketone (1.30 g). ESI-MS (m / z): 180.05 [M+H] + .

[0540] Step 2: 2,3,4,5-Tetrahydrobenzo[f][1,4]thiazepine Synthesis

[0541] Add 3,4-dihydrobenzo[f][1,4]thiazepine to a 100 mL reaction flask. -5(2H)-ketone (1.30 g, 7.3 mmol) and THF (20 mL). Lithium aluminum tetrahydride was slowly added at 0°C and reacted at 60°C for 7 h. After the reaction was completed by LCMS, water was slowly added at 0°C, and the reaction was quenched by 15% sodium hydroxide solution and water. Filtered, the filtrate was concentrated under reduced pressure to obtain 2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine (1.10g). ESI-MS(m / z):166.06[M+H] + .

[0542] Step 3: 1-(2,3-dihydrobenzo[f][1,4]thiazepine Synthesis of 4-(5H)-1-yl)ethane-1-one

[0543] Add 2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine into a 50 mL reaction flask. (1.10 g, 5.3 mmol), triethylamine (1.11 mL, 6.3 mmol) and dichloromethane (10 mL). Add acetic anhydride (0.75 mL, 6.3 mmol) dropwise at 0 °C. React at room temperature for 1 h. After the reaction is completed by LCMS, the reaction solution is washed with a saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated under reduced pressure to obtain 1-(2,3-dihydrobenzo[f][1,4]thiazepine -4(5H)-yl)ethane-1-one (1.08 g). ESI-MS (m / z): 208.08 [M+H] + .

[0544] Step 4: 1-(1,1-dioxido-2,3-dihydrobenzo[f][1,4]thiazepine Synthesis of 4-(5H)-1-yl)ethane-1-one

[0545] Add 1-(2,3-dihydrobenzo[f][1,4]thiazepine) into a 50 mL reaction bottle. -4(5H)-yl)ethane-1-one (1.08 g, 5.2 mmol) and dichloromethane (10 mL), slowly add mCPBA (2.69 g, 15.6 mmol) dissolved in dichloromethane at 0°C, and react at room temperature for 2 hours. After the reaction is completed by LCMS, wash with saturated aqueous sodium carbonate solution, wash with sodium thiosulfate, and then wash with aqueous sodium chloride solution. The organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then washed with diethyl ether, and filtered to obtain 1-(1,1-dioxido-2,3-dihydrobenzo[f][1,4]thiazepine -4(5H)-yl)ethane-1-one (1.00 g). ESI-MS (m / z): 240.18 [M+H] + .

[0546] Step 5: 2,3,4,5-Tetrahydrobenzo[f][1,4]thiazepine Synthesis of -1,1-dioxide

[0547] Add 1-(1,1-dioxy-2,3-dihydrobenzo[f][1,4]thiazepine) into a 50 mL reaction bottle. -4(5H)-yl)ethane-1-one (1.00 g, 4.2 mmol), sodium hydroxide (0.84 g, 21.0 mmol), ethanol (10 mL) and water (7 mL) were reacted at 80 °C for 16 h. After the reaction was completed by LCMS, the organic solvent was dried by spin drying. Water was added to make a slurry, and the mixture was filtered to obtain 2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -1,1-dioxide (0.66 g). ESI-MS (m / z): 198.11 [M+H] + .

[0548] Intermediate Preparation Example 2-4: 2,3,4,5-Tetrahydrobenzo[b][1,4]thiazepine Synthesis of -1,1-dioxide

[0549]

[0550] Step 1: 2,3,4,5-Tetrahydrobenzo[b][1,4]thiazepine Synthesis

[0551] 2-Aminobenzenethiol (0.50 g, 3.99 mmol), 1,3-dibromopropane (1.45 g, 7.19 mmol), cesium carbonate (6.51 g, 19.97 mmol) and DMF (10 mL) were added to a 100 mL reaction bottle and reacted at 120 ° C for 2 h. After the reaction was completed by LCMS, it was diluted with EA, the organic phase was washed with water, and the organic phase was concentrated to dryness under reduced pressure. The concentrate was purified by silica gel column (PE: EA = 15: 1) to obtain 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine (0.42g). ESI-MS(m / z):166.08[M+H] + .

[0552] Step 2: 1-(3,4-dihydrobenzo[b][1,4]thiazepine Synthesis of 5-(2H)-methyl)ethane-1-one

[0553] Add 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine to a 100 mL reaction flask. (0.42g, 2.51mmol), acetic anhydride (0.51mg, 5.02mmol), triethylamine (0.76mg, 7.53mmol) and toluene (10mL). React at 100℃ for 1h. After the reaction is completed by LCMS, water is added to the reaction solution and extracted with EA. The organic phase is concentrated to dryness under reduced pressure to obtain 1-(3,4-dihydrobenzo[b][1,4]thiazepine -5(2H)-yl)ethane-1-one (0.49 g). ESI-MS (m / z): 208.19 [M+H] + .

[0554] Step 3: 1-(1,1-dioxy-3,4-dihydrobenzo[b][1,4]thiazepine Synthesis of 5-(2H)-methyl)ethane-1-one

[0555] Add 1-(3,4-dihydrobenzo[b][1,4]thiazepine) into a 100 mL reaction bottle. -5(2H)-yl)ethane-1-one (0.49 g, 2.39 mmol) and DCM (10 mL). At 0°C, mCPBA (1.24 g, 7.17 mmol) was slowly added and reacted at room temperature for 5 h. After the reaction was completed, LCMS was used to detect the reaction. 2 CO 3 The organic phase was concentrated under reduced pressure and precipitated with ether to obtain 1-(1,1-dioxido-3,4-dihydrobenzo[b][1,4]thiazepine) -5(2H)-yl)ethane-1-one (0.30 g). ESI-MS (m / z): 240.08 [M+H] + .

[0556] Step 4: 2,3,4,5-Tetrahydrobenzo[b][1,4]thiazepine Synthesis of -1,1-dioxide

[0557] Add 1-(1,1-dioxy-3,4-dihydrobenzo[b][1,4]thiazepine) into a 50 mL reaction bottle. -5(2H)-yl)ethane-1-one (0.30 g, 1.25 mmol), tBuOK (0.70 g, 6.27 mmol) and DMF (5 mL). The reaction was continued at room temperature for 16 h. After the reaction was completed by LCMS, the mixture was diluted with DCM, washed with water, and the organic phase was concentrated to dryness under reduced pressure to obtain 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine -1,1-dioxide (0.11 g). ESI-MS (m / z): 198.12 [M+H] + .

[0558] Intermediate Preparation Example 2-5: 2,3,4,5-Tetrahydropyrido[2,3-f][1,4]thiazepine Synthesis of -1,1-dioxide

[0559]

[0560] Step 1: Synthesis of methyl 3-((2-((tert-butoxycarbonyl)amino)ethyl)thio)picolinate

[0561] 3-Chloropyridine carboxylic acid methyl ester (8 g, 46.63 mmol) was added to DMF (80 mL). 2 CO 3(8g, 46.63mmol, 3eq) and (2-mercaptoethyl)carbamic acid tert-butyl ester (8.26g, 46.63mmol) were added to the reaction solution in sequence, and the reaction solution was stirred at 110°C for 16 hours. LCMS monitored the formation of the product, the reaction solution was extracted with water and ethyl acetate, the organic phase was washed with half-saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, and column chromatography (PE:EA=1:1) was used to obtain 3-((2-((tert-butoxycarbonyl)amino)ethyl)thio)picolinic acid methyl ester (2.8g). ESI-MS (m / z): 313.38 [M+H] + .

[0562] Step 2: Synthesis of methyl 3-((2-aminoethyl)thio)picolinate

[0563] Dissolve methyl 3-((2-((tert-butoxycarbonyl)amino)ethyl)thio)picolinate (2.8 g, 8.96 mmol) in DCM (28 mL) and HCl / 1,4-dioxane (14 mL), and stir the mixture at 20°C for 2 h. TLC detected that the reaction of the raw material was complete. Concentrate under reduced pressure to obtain methyl 3-((2-aminoethyl)thio)picolinate hydrochloride (2.5 g). ESI-MS (m / z): 213.27 [M+H] + .

[0564] Step 3: 3,4-Dihydropyrido[2,3-f][1,4]thiazepine Synthesis of -5(2H)-Ketone

[0565] Methyl 3-((2-aminoethyl)thio)picolinate hydrochloride (2.5 g, 10.05 mmol) was dissolved in THF (125 mL) and MeOH (125 mL). CH 3 ONa (3.26 g, 60.31 mmol) was added to the reaction solution, and the mixture was stirred at 48°C for 16 h. LCMS detected that the raw material was completely reacted. The reaction solution was distilled under reduced pressure to remove the solvent, extracted with water and dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain 3,4-dihydropyrido[2,3-f][1,4]thiazepine -5(2H)-ketone (1.3 g). ESI-MS (m / z): 181.23 [M+H] + .

[0566] Step 4: 2,3,4,5-Tetrahydropyrido[2,3-f][1,4]thiazepine Synthesis

[0567] 3,4-Dihydropyrido[2,3-f][1,4]thiazepine -5(2H)-ketone (1.1 g, 6.10 mmol) was dissolved in THF (22 mL), LAH (463.30 mg, 12.21 mmol) was added to the reaction solution at 0°C, and the mixture was stirred at 60°C for 4 h. LCMS detected that the raw material was completely reacted. The reaction solution was purified by column chromatography (DCM: MeOH = 10: 1) to obtain 2,3,4,5-tetrahydropyrido [2,3-f] [1,4] thiazepine (577.7 mg). ESI-MS(m / z):167.24[M+H] + .

[0568] Step 5: 1-(2,3-dihydropyrido[2,3-f][1,4]thiazepine Synthesis of 4-(5H)-1-yl)ethane-1-one

[0569] 2,3,4,5-tetrahydropyrido[2,3-f][1,4]thiazepine (577.7 mg, 3.48 mmol) was dissolved in DCM (20 mL), triethylamine (0.6 mL, 4.8 mmol) and acetic anhydride (0.3 mL, 4.2 mmol) were added at 0 °C, and the mixture was heated to room temperature and stirred for 2 h. LCMS detected that the raw material reaction was complete. After the reaction solution was distilled under reduced pressure to remove the solvent, it was extracted with water and dichloromethane. The organic phase was dried and purified by silica gel column chromatography (DCM: MeOH = 30: 1) to obtain 1-(2,3-dihydropyrido[2,3-f][1,4]thiazepine -4(5H)-yl)ethan-1-one (347.4 mg). ESI-MS (m / z): 209.28 [M+H] + .

[0570] Step 6: 1-(1,1-dioxo-2,3-dihydropyrido[2,3-f][1,4]thiazepine Synthesis of 4-(5H)-1-yl)ethane-1-one

[0571] 1-(2,3-dihydropyrido[2,3-f][1,4]thiazepine -4(5H)-yl)ethane-1-one (347.4 mg, 1.67 mmol) was dissolved in DCM (20 mL), mCPBA (0.86 g, 4.9 mmol) was added at 0°C, and the mixture was stirred at room temperature for 2 h. LCMS detected that the raw material reaction was complete. After the reaction solution was distilled under reduced pressure to remove the solvent, it was extracted with water and dichloromethane. The organic phase was dried and purified by silica gel column chromatography (DCM: MeOH = 30: 1) to obtain 1-(1,1-dioxo-2,3-dihydropyrido[2,3-f][1,4]thiazepine -4(5H)-yl)ethane-1-one (289.1 mg). ESI-MS (m / z): 241.28 [M+H]+.

[0572] Step 7: 2,3,4,5-Tetrahydropyrido[2,3-f][1,4]thiazepine Synthesis of -1,1-dioxide

[0573] 1-(1,1-dioxo-2,3-dihydropyrido[2,3-f][1,4]thiazepine -4(5H)-yl)ethane-1-one (289.1 mg, 1.20 mmol) was dissolved in EtOH / H 2 O (20mL, v / v=1:1), NaOH (0.48g, 12mmol) was added, and the temperature was raised to 78°C for 20h. LCMS detected that the raw material was completely reacted. The reaction solution was distilled under reduced pressure to remove the solvent and then purified by silica gel column (DCM:MeOH=30:1) to obtain 2,3,4,5-tetrahydropyrido[2,3-f][1,4]thiazepine -1,1-dioxide (110.2 mg). ESI-MS (m / z): 199.24 [M+H] + .

[0574] Intermediate Preparation Example 2-6: 2,3,4,5-Tetrahydropyrido[3,4-f][1,4]thiazepine Synthesis of -1,1-dioxide

[0575]

[0576] The synthesis method is the same as that of the intermediate preparation example 2-5, except that 4-chloronicotinate methyl ester is used as the starting material instead of 3-chloropicolinate methyl ester to obtain 2,3,4,5-tetrahydropyrido[3,4-f][1,4]thiazepine -1,1-dioxide (98.2 mg).

[0577] Intermediate Preparation Example 2-7: 2,3,4,5-Tetrahydropyrido[4,3-f][1,4]thiazepine Synthesis of -1,1-dioxide

[0578]

[0579] The synthesis method is the same as that of the intermediate preparation example 2-5, except that 3-chloroisonicotinic acid methyl ester is used as the starting material instead of 3-chloropicolinic acid methyl ester to obtain 2,3,4,5-tetrahydropyrido[4,3-f][1,4]thiazepine -1,1-dioxide (103.5 mg).

[0580] Intermediate Preparation Example 2-8: 2,3,4,5-Tetrahydropyrido[3,2-f][1,4]thiazepine Synthesis of -1,1-dioxide

[0581]

[0582] Step 1: Synthesis of 2-((2-aminoethyl)thio)nicotinic acid

[0583] 2-Chloronicotinic acid (2g, 12.69mmol) and 2-aminoethane-1-thiol (2.45g, 31.74mmol) were dissolved in EtOH (16mL), and NaOH solution (18M, 1.97mL) was added dropwise to the reaction solution, and the mixture was stirred at 80°C for 2h. LCMS detected that the raw material reaction was complete. After the reaction solution was distilled under reduced pressure to remove the solvent, it was extracted with water and dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain 2-((2-aminoethyl)thio)nicotinic acid (3g). ESI-MS (m / z): 199.24 [M+H] + .

[0584] Step 2: 3,4-Dihydropyrido[3,2-f][1,4]thiazepine Synthesis of -5(2H)-Ketone

[0585] 2-((2-aminoethyl)thio)nicotinic acid (1.1 g, 5.57 mmol) was added to DCM (10 mL), HOBt (1.13 g, 8.36 mmol), EDCI (1.6 g, 8.34 mmol) and TEA (1.68 g, 16.60 mmol) were added to the reaction solution in sequence, and the reaction solution was stirred at 20°C for 12 hours. LCMS detected that the reaction was complete, the reaction solution was extracted with water and ethyl acetate, the organic phase was washed with half-saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, and prep-HPLC obtained 3,4-dihydropyrido[3,2-f][1,4]thiazepine -5(2H)-ketone (0.45 g). ESI-MS (m / z): 181.23 [M+H] + .

[0586] Step 3: 2,3,4,5-Tetrahydropyrido[3,2-f][1,4]thiazepine Synthesis

[0587] 3,4-dihydropyrido[3,2-f][1,4]thiazepine -5(2H)-ketone (0.35 g, 1.94 mmol) was dissolved in THF (10 mL), LAH (0.15 g, 3.88 mmol) was added to the reaction solution at 0°C, and the mixture was stirred at 60°C for 4 h. LCMS detected that the raw material was completely reacted. The reaction solution was purified by prep-HPLC to obtain 2,3,4,5-tetrahydropyrido[3,2-f][1,4]thiazepine (0.2g). ESI-MS(m / z):167.24[M+H] + Step 4: 1-(2,3-dihydropyrido[3,2-f][1,4]thiazepine Synthesis of 4-(5H)-1-yl)ethane-1-one

[0588] 2,3,4,5-tetrahydropyrido[3,2-f][1,4]thiazepine (0.2g, 1.20mmol) was dissolved in DCM (10mL), triethylamine (0.3mL, 4.8mmol) and acetic anhydride (0.2mL, 1.4mmol) were added at 0℃, and the mixture was heated to room temperature and stirred for 2h. LCMS detected that the raw material reaction was complete. After the reaction solution was distilled under reduced pressure to remove the solvent, it was extracted with water and dichloromethane. The organic phase was dried and purified by silica gel column chromatography (DCM:MeOH=30:1) to obtain 1-(2,3-dihydropyrido[3,2-f][1,4]thiazepine -4(5H)-yl)ethane-1-one (120.1 mg). ESI-MS (m / z): 209.28 [M+H] + .

[0589] Step 5: 1-(1,1-dioxo-2,3-dihydropyrido[3,2-f][1,4]thiazepine Synthesis of 4-(5H)-1-yl)ethane-1-one

[0590] 1-(2,3-dihydropyrido[3,2-f][1,4]thiazepine -4(5H)-yl)ethane-1-one (120.1 mg, 0.58 mmol) was dissolved in DCM (20 mL), mCPBA (298 mg, 1.72 mmol) was added at 0°C, and the mixture was stirred at room temperature for 2 h. LCMS detected that the raw material reaction was complete. After the reaction solution was distilled under reduced pressure to remove the solvent, it was extracted with water and dichloromethane. The organic phase was dried and purified by silica gel column chromatography (DCM: MeOH = 30: 1) to obtain 1-(1,1-dioxo-2,3-dihydropyrido[3,2-f][1,4]thiazepine -4(5H)-yl)ethane-1-one (101.0 mg). ESI-MS (m / z): 241.28 [M+H]+ .

[0591] Step 6: 2,3,4,5-Tetrahydropyrido[3,2-f][1,4]thiazepine Synthesis of -1,1-dioxide

[0592] 1-(1,1-dioxo-2,3-dihydropyrido[3,2-f][1,4]thiazepine -4(5H)-yl)ethan-1-one (101.0 mg, 0.42 mmol) was dissolved in EtOH / H 2 O (10mL, v / v=1:1), add NaOH (0.17g, 4.2mmol), and heat to 78℃ for 20h. LCMS detected that the raw material was completely reacted. The reaction solution was distilled under reduced pressure to remove the solvent and purified by silica gel column (DCM:MeOH=30:1) to obtain 2,3,4,5-tetrahydropyrido[3,2-f][1,4]thiazepine -1,1-dioxide (35.0 mg). ESI-MS (m / z): 199.24 [M+H] + .

[0593] Intermediate Preparation Example 2-9: 4,5-Dihydro-3H-spiro[benzo[f][1,4]thiazepine Synthesis of 2,1'-cyclopropane]-1,1-dioxide.

[0594]

[0595] Step 1: 4-(4-methoxybenzyl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Synthesis of -1,1-dioxide

[0596] Add 2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine to a 100 mL reaction flask. -1,1-dioxide (0.50 g, 2.53 mmol), 1-(chloromethyl)-4-methoxybenzene (0.79 g, 5.07 mmol), cesium carbonate (3.30 g, 10.12 mmol) and DMF (20 mL) were reacted at 50 ° C for 7 hours. After the reaction was completed by LCMS, it was diluted with EA, washed with water, and the organic phase was concentrated to dryness under reduced pressure. The concentrate was purified by silica gel column (PE: EA = 8: 2) to obtain 4-(4-methoxybenzyl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -1,1-dioxide (0.43 g). ESI-MS (m / z): 318.21 [M+H] + .

[0597] Step 2: 4-(4-methoxybenzyl)-4,5-dihydro-3H-spiro[benzo[f][1,4]thiazepine Synthesis of [2,1'-cyclopropane]-1,1-dioxide

[0598] Add 4-(4-methoxybenzyl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine to a 100 mL reaction flask. -1,1-dioxide (0.43 g, 1.35 mmol) and THF (20 mL). At -78 ° C, n-butyl lithium (0.43 g, 6.74 mmol) was slowly added dropwise. The temperature was slowly raised to -20 ° C, dibromoethane (2.53 g, 13.48 mmol) was slowly added dropwise, and the reaction was allowed to react overnight at room temperature. After the reaction was completed by LCMS detection, water was added to the reaction solution, extracted with EA, and the organic phase was concentrated to dryness under reduced pressure. The concentrate was purified by silica gel column (MeOH: DCM = 1: 15) to obtain 4-(4-methoxybenzyl)-4,5-dihydro-3H-spiro[benzo[f][1,4]thiazepine -2,1'-cyclopropane]-1,1-dioxide (0.16 g). ESI-MS (m / z): 344.24 [M+H] + .

[0599] Step 3: 4,5-Dihydro-3H-spiro[benzo[f][1,4]thiazepine Synthesis of [2,1'-cyclopropane]-1,1-dioxide

[0600] Add 4-(4-methoxybenzyl)-4,5-dihydro-3H-spiro[benzo[f][1,4]thiazepine -2,1'-cyclopropane]-1,1-dioxide (0.16 g, 0.47 mmol), Pd(OH) 2 / C (16 mg), TFA (16 mL) and EA (5 mL), react under hydrogen at room temperature for 2 h. After the reaction was completed by LCMS, it was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column (MeOH: DCM = 1: 10) to obtain 4,5-dihydro-3H-spiro[benzo[f][1,4]thiazepine -2,1'-cyclopropane]-1,1-dioxide (0.04 g). ESI-MS (m / z): 224.13 [M+H] + Intermediate Preparation Example 2-10: 2,3,4,6-Tetrahydro-1H-aza Synthesis of 5,4,3-cd indole

[0601]

[0602] Step 1: Synthesis of methyl 3-formyl-1H-indole-4-carboxylate

[0603] 1H-indole-4-carboxylic acid methyl ester (2g, 11.42mmol) and DMF (20mL) were added to a 100mL reaction bottle in sequence, the system was cooled to 0°C under nitrogen protection, phosphorus oxychloride (5.2g, 34.25mmol) was added dropwise, and the reaction was carried out at room temperature for 1h. LCMS showed that the reaction was complete, and after post-treatment, sodium bicarbonate aqueous solution was added, and then the system was extracted twice with ethyl acetate, and the obtained organic phase was concentrated under reduced pressure to obtain 3-formyl-1H-indole-4-carboxylic acid methyl ester (2.2g).

[0604] Step 2: Synthesis of (E)-3-(2-nitrovinyl)-1H-indole-4-carboxylic acid methyl ester

[0605] 3-Formyl-1H-indole-4-carboxylic acid methyl ester (2g, 9.85mmol), nitromethane (20mL), and ammonium acetate (0.84g, 10.90mmol) were added to a 100mL reaction bottle in sequence, and the reaction solution was heated to 90°C for 1h. TLC showed that the reaction was complete, and the temperature was cooled to room temperature, and ethyl acetate was added to dilute the reaction solution, and the solution was washed with water and saturated brine respectively, and the organic phase was concentrated to dryness under reduced pressure to obtain (E)-3-(2-nitrovinyl)-1H-indole-4-carboxylic acid methyl ester (2.5g).

[0606] Step 3: Synthesis of methyl 3-(2-nitroethyl)-1H-indole-4-carboxylate

[0607] In a 100 mL reaction bottle, (E)-3-(2-nitrovinyl)-1H-indole-4-carboxylic acid methyl ester (2.5 g, 10.16 mmol) and anhydrous THF (30 mL) were added in sequence, the reaction solution was cooled to 0°C, sodium borohydride (0.8 g, 21.15 mmol) was added, and then methanol (1 mL) was added dropwise. After the addition was complete, the reaction was continued at 0°C for 0.5 h. TLC showed that the reaction was complete, and after post-treatment, a saturated ammonium chloride solution was added to quench the reaction, and then ethyl acetate was added for extraction. The obtained organic phase was concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (PE:EA=4:1 (v / v)) to obtain 3-(2-nitroethyl)-1H-indole-4-carboxylic acid methyl ester (1.2 g).

[0608] Step 4: 2,3,4,6-Tetrahydro-1H-azepine Synthesis of 1-[5,4,3-cd]indol-1-one

[0609] 3-(2-nitroethyl)-1H-indole-4-carboxylic acid methyl ester (1 g, 4.03 mmol), methanol (20 mL), and 5% Pd / C (100 mg) were added to a 100 mL reaction bottle in sequence, and the reaction solution was reacted overnight at room temperature. LCMS showed that the reaction was complete, and the mixture was post-treated, filtered, and the filtrate was concentrated to dryness under reduced pressure. The concentrate was purified by column chromatography (DCM: MeOH = 40: 1 (v / v)) to obtain 2,3,4,6-tetrahydro-1H-azepine [5,4,3-cd]indol-1-one (0.35 g). ESI-MS (m / z): 187.21 [M+H] + .

[0610] Step 5: 2,3,4,6-Tetrahydro-1H-azepine Synthesis of 5,4,3-cd indole

[0611] In a 100 mL reaction bottle, add 2,3,4,6-tetrahydro-1H-aza [5,4,3-cd]indol-1-one (200 mg, 1.08 mmol), anhydrous THF (5 mL), LAH (160 mg, 4.21 mmol) were added at room temperature, and the reaction solution was heated to 70 ° C for 4 hours. LCMS showed that the reaction was complete, and after post-treatment, potassium hydroxide aqueous solution was added to quench the reaction, filtered, and the filtrate was concentrated under reduced pressure to obtain 2,3,4,6-tetrahydro-1H-aza [5,4,3-cd]indole (85 mg). ESI-MS (m / z): 173.23 [M+H] + .

[0612] Intermediate Preparation Example 2-11: 8-Fluoro-2,3,4,6-tetrahydro-1H-azepine Synthesis of 5,4,3-cd indole

[0613]

[0614] The synthesis method is the same as that of step 5 of intermediate preparation example 2-10, except that the raw material of step 5 is 8-fluoro-2,3,4,6-tetrahydro-1H-aza [5,4,3-cd]indol-1-one substituted for 2,3,4,6-tetrahydro-1H-azepine and [5,4,3-cd] indole-1-one to obtain 8-fluoro-2,3,4,6-tetrahydro-1H-azepine [5,4,3-cd]indole (90 mg). ESI-MS (m / z): 191.22 [M+H] + .

[0615] Intermediate Preparation Example 2-12: 5,6-Dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Synthesis

[0616]

[0617] Step 1: Synthesis of (2-nitrobenzyl)glycine methyl ester

[0618] Dissolve 1-(Bromomethyl)-2-nitrobenzene (19 g, 87.95 mmol) and glycine methyl ester (11.74 g, 131.93 mmol) in DMF (190 mL), add DIEA (34.10 g, 263.85 mmol, 45.96 mL), and stir the mixture at 20 ° C for 12 h. TLC detected that the raw material reaction was complete. The reaction solution was extracted with water and ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain (2-nitrobenzyl) glycine methyl ester (25 g). ESI-MS (m / z): 225.22 [M+H] + .

[0619] Step 2: Synthesis of N-(tert-butyloxycarbonyl)-N-(2-nitrobenzyl)glycine methyl ester

[0620] Dissolve (2-nitrobenzyl)glycine methyl ester (24 g, 107.04 mmol) in DCM (500 mL), add Boc anhydride (35.04 g, 160.56 mmol, 36.89 mL), and stir the mixture at 20 ° C for 16 h. LCMS detected that the raw material was completely reacted. After the reaction solution was distilled under reduced pressure to remove the solvent, it was purified by column chromatography (PE: EA = 5: 1) to obtain N-(tert-butyloxycarbonyl)-N-(2-nitrobenzyl)glycine methyl ester (28.9 g). ESI-MS (m / z): 325.33 [M+H] + .

[0621] Step 3: Synthesis of N-(2-aminobenzyl)-N-(tert-butoxycarbonyl)glycine methyl ester

[0622] Dissolve N-(tert-butyloxycarbonyl)-N-(2-nitrobenzyl)glycine methyl ester (17 g, 52.42 mmol) in MeOH (340 mL), add Pd / C (17.00 g, 15.97 mmol, 10% purity), replace the hydrogen three times, and stir the mixture at 20°C for 3 h. LCMS detected that the raw material reacted completely. The reaction solution was filtered and concentrated under reduced pressure to obtain N-(2-aminobenzyl)-N-(tert-butyloxycarbonyl)glycine methyl ester (15 g). ESI-MS (m / z): 295.35 [M+H] + .

[0623] Step 4: 2-Oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine -Synthesis of tert-butyl 4-carboxylate

[0624] N-(2-aminobenzyl)-N-(tert-butoxycarbonyl)glycine methyl ester (15 g, 50.96 mmol) was dissolved in toluene (600 mL), HOBt (4.13 g, 30.57 mmol) was added to the reaction solution, and the mixture was stirred at 100 ° C for 24 h. LCMS detected that the raw material was completely reacted. After the reaction solution was distilled under reduced pressure to remove the solvent, it was purified by column chromatography (PE: EA = 5: 1) to obtain 2-oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine -4-carboxylic acid tert-butyl ester (7g). ESI-MS (m / z): 263.31 [M+H] + .

[0625] Step 5: 2-Thioxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine -Synthesis of tert-butyl 4-carboxylate

[0626] 2-Oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine -4-carboxylic acid tert-butyl ester (3.6 g, 13.72 mmol) was dissolved in THF (120 mL), and Lawson's reagent (2.78 g, 6.86 mmol) was added to the reaction solution, and the mixture was stirred at 65 ° C for 1 h. LCMS detected that the raw material was completely reacted. After the reaction solution was concentrated under reduced pressure, column chromatography (PE: EA = 1: 1) was used to purify 2-thio-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine -4-carboxylic acid tert-butyl ester (3g). ESI-MS (m / z): 279.37 [M+H] + .

[0627] Step 6: 4H-Benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Synthesis of tert-butyl 5(6H)-carboxylate

[0628] 2-Thioxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine -4-carboxylic acid tert-butyl ester (3g, 10.78mmol) was dissolved in toluene (30mL), formic hydrazide (1.94g, 32.33mmol) was dissolved in DMSO (6mL) and added to the reaction solution, and the mixture was stirred at 80°C for 16h. LCMS detected that the raw material reaction was complete. The reaction solution was extracted with water and ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and then purified by column chromatography and prep-TLC (DCM:EA=1:2) to obtain 4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -5(6H)-carboxylic acid tert-butyl ester (2.6 g). ESI-MS (m / z): 287.34 [M+H] + .

[0629] Step 7: 5,6-Dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Synthesis

[0630] 4H-Benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -5(6H)-carboxylic acid tert-butyl ester (2.5 g, 8.73 mmol) was dissolved in DCM (25 mL), HCl / 1,4-dioxane (25 mL, 4 M) was added to the reaction solution, and the mixture was stirred at 20°C for 1 h. LCMS detected that the raw material was completely reacted. The reaction solution was concentrated under reduced pressure to obtain 5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Hydrochloride (2.05 g). ESI-MS (m / z): 187.22 [M+H] + .

[0631] Intermediate Preparation Example 2-13: 4,5-Dihydro-2H-spiro[benzo[f][1,4]thiazepine Synthesis of 3,1'-cyclopropane

[0632]

[0633] Step 1: Synthesis of tert-butyl (1-(hydroxymethyl)cyclopropyl)carbamate

[0634] In a 50 mL reaction bottle, (1-aminocyclopropyl)methanol hydrochloride (2.1 g, 17 mmol), THF (10 ml) and H 2O (10 ml), sodium bicarbonate (3.6 g, 42.5 mmol) and Boc anhydride (4.1 g, 18.8 mmol). React at room temperature for 14 h. Extract with ethyl acetate, wash the combined organic phases with saturated sodium chloride solution and dry over sodium sulfate. The organic phase is concentrated under reduced pressure to obtain tert-butyl (1-(hydroxymethyl)cyclopropyl)carbamate (2.8 g). ESI-MS (m / z): 188.12 [M+H] + .

[0635] Step 2: Synthesis of (1-((tert-butyloxycarbonyl)amino)cyclopropyl)methylmethanesulfonic acid

[0636] Add tert-butyl (1-(hydroxymethyl)cyclopropyl)carbamate (2.6 g, 13.9 mmol), DCM (20 ml), and TEA (3.5 ml, 25 mmol) to a 50 mL reaction bottle. Add methanesulfonyl chloride (1.29 mL, 16.7 mmol) dropwise at 0 °C. React at room temperature for 2 h. After the reaction is completed, extract with dichloromethane and water, collect the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain (1-((tert-butoxycarbonyl)amino)cyclopropyl)methylmethanesulfonic acid (3.7 g). ESI-MS (m / z): 266.10 [M+H] + .

[0637] Step 3: Synthesis of methyl 2-(((1-((tert-butyloxycarbonyl)amino)cyclopropyl)methyl)thio)benzoate

[0638] In a 100 mL single-necked bottle, methyl 2-mercaptobenzoate (1 g, 6 mmol) and (1-((tert-butyloxycarbonyl)amino)cyclopropyl)methylmethanesulfonic acid (1.58 g, 6 mmol) were added to DMF (10 mL), and then Cs 2 CO 3 (3.9 g, 12 mmol). The reaction solution was heated to 80°C and stirred for 12 hours. After the reaction was completed, it was extracted with ethyl acetate and water, the organic phase was collected, the organic phase was washed 3 times with saturated sodium chloride solution, the organic phase was collected and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (PE:EA=10:1) and concentrated under reduced pressure to obtain methyl 2-(((1-((tert-butyloxycarbonyl)amino)cyclopropyl)methyl)thio)benzoate (1.4 g). ESI-MS (m / z): 338.13 [M+H] + .

[0639] Step 4: Synthesis of methyl 2-(((1-aminocyclopropyl)methyl)thio)benzoate

[0640] Methyl 2-(((1-((tert-butyloxycarbonyl)amino)cyclopropyl)methyl)thio)benzoate (1.6 g, 4.7 mmol) was added to a 50 mL reaction bottle, and then HCl / 1,4-dioxane (15 mL, 4 M) was added and reacted at room temperature for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain methyl 2-(((1-aminocyclopropyl)methyl)thio)benzoate (1.6 g). ESI-MS (m / z): 238.08 [M+H] + .

[0641] Step 5: 2H-Spiro[benzo[f][1,4]thiazepine Synthesis of 3,1'-cyclopropane-5(4H)-one

[0642] In a 50 mL reaction bottle, add methyl 2-(((1-aminocyclopropyl)methyl)thio)benzoate (1.6 g, 4.7 mmol) to methanol (15 ml), lower the temperature to 0°C, and then slowly add sodium methoxide (4.25 ml, 5 M) to the bottle. Raise the temperature to 50°C for 2 hours, add sodium methoxide (1.6 ml, 5 M), and continue to react at 50°C for 2 hours. After the reaction is completed, add H 2 O (5 ml), concentrated under reduced pressure to remove methanol, extracted with ethyl acetate and water, washed with saturated sodium chloride solution, collected and dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (PE: EA = 1: 1) to obtain 2H-spiro [benzo [f] [1, 4] thiazepine -3,1'-cyclopropane]-5(4H)-one (915 mg). ESI-MS (m / z): 206.05 [M+H] + .

[0643] Step 6: 4,5-Dihydro-2H-spiro[benzo[f][1,4]thiazepine Synthesis of 3,1'-cyclopropane

[0644] Add 2H-spiro[benzo[f][1,4]thiazepine into a 50 mL reaction bottle. -3,1'-cyclopropane]-5(4H)-one (915mg, 4.46mmol) and THF (10mL). Lithium aluminum tetrahydride (507mg, 13.4mmol) was slowly added at 0℃ and reacted at 60℃ for 2h. After the reaction was completed by LCMS, water (0.5ml), 15% sodium hydroxide solution (0.5ml) and water (1.5ml) were slowly added at 0℃ to quench the reaction. The filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was chromatographed on silica gel (DCM:MeOH=80:1) to obtain 4,5-dihydro-2H-spiro[benzo[f][1,4]thiazepine -3,1'-cyclopropane](570mg)ESI-MS(m / z):192.08[M+H] + .

[0645] Intermediate Preparation Example 2-14: 1-Imino-2,3,4,5-tetrahydro-1H-1λ 4 -Benzo[f][1,4]thiazepine Synthesis of -1-oxide

[0646]

[0647] Step 1: 2,3-Dihydrobenzo[f][1,4]thiazepine -Synthesis of tert-butyl 4(5H)-carboxylate

[0648] Add 2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine into a 50 mL reaction flask. (1 g, 6 mmol), DCM (10 ml), TEA (1.2 g, 12 mmol) and Boc anhydride (1.6 g, 7.2 mmol). After the reaction was completed, H 2 O, DCM extraction, the organic phase was washed with saturated sodium chloride solution, the organic phase was collected and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2,3-dihydrobenzo[f][1,4]thiazepine -4(5H)-carboxylic acid tert-butyl ester (1.6 g, crude product). ESI-MS (m / z): 266.11 [M+H] + .

[0649] Step 2: 1-Imino-1,2,3,5-tetrahydro-4H-1λ 4 -Benzo[f][1,4]thiazepine -Synthesis of tert-butyl 4-carboxylate-1-oxide

[0650] In a 50 mL reaction bottle, 2,3-dihydrobenzo[f][1,4]thiazepine -4(5H)-carboxylic acid tert-butyl ester (1.6 g, 6 mmol) was added to MeOH (20 ml), and then ammonium carbonate (864 mg, 9 mmol) was added. After stirring for 5 minutes, iodophenyl diacetic acid (4.4 g, 13.8 mmol) was added, and the mixture was reacted overnight at room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was chromatographed on silica gel (EA:PE=1:1) to obtain 1-imino-1,2,3,5-tetrahydro-4H-1λ 4 -Benzo[f][1,4]thiazepine -4-carboxylic acid tert-butyl ester 1-oxide (1.3 g). ESI-MS (m / z): 297.12 [M+H] + .

[0651] Step 3: 1-Imino-2,3,4,5-tetrahydro-1H-1λ 4 -Benzo[f][1,4]thiazepine Synthesis of -1-oxide

[0652] Add 1-imino-1,2,3,5-tetrahydro-4H-1λ into a 50 mL reaction bottle. 4 -Benzo[f][1,4]thiazepine -4-carboxylic acid tert-butyl ester-1-oxide (1.3 g, 4.4 mmol), then add HCl / 1,4-dioxane (15 mL, 4 M), and react at room temperature for 14 h. After the reaction is completed, it is concentrated under reduced pressure to obtain a crude product, which is added to water, and a saturated potassium carbonate solution is added to adjust the pH to 9-10, extracted with ethyl acetate, and the organic phase is washed with a saturated sodium chloride solution. The organic phase is collected and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1-imino-2,3,4,5-tetrahydro-1H-1λ 4 -Benzo[f][1,4]thiazepine -1-oxide (560 mg). ESI-MS (m / z): 197.07 [M+H] + .

[0653] Intermediate Preparation Example 2-15: 1-(Methylimino)-2,3,4,5-tetrahydro-1H-1λ 4 -Benzo[f][1,4]thiazepine Synthesis of -1-oxide

[0654] Step 1: 1-(Methylimino)-1,2,3,5-tetrahydro-4H-1λ 4 -Benzo[f][1,4]thiazepine -Synthesis of tert-butyl 4-carboxylate-1-oxide

[0655] Add 1-imino-1,2,3,5-tetrahydro-4H-1λ into a 50 mL reaction bottle. 4 -Benzo[f][1,4]thiazepine -4-carboxylic acid tert-butyl ester-1-oxide (2g, 6.7mmol), THF (20mL). Sodium hydride (400mg, 10mmol) was slowly added at 0℃. The reaction was carried out at room temperature for 0.5h, and then iodomethane (1.05g, 7.4mmol) was added. The reaction was carried out at room temperature for 2h. After the reaction was completed, water was added to the reaction solution and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel chromatography (EA:PE=1:1) to obtain 1-(methylimino)-1,2,3,5-tetrahydro-4H-1λ 4 -Benzo[f][1,4]thiazepine -4-carboxylic acid tert-butyl ester-1-oxide (1.7 g). ESI-MS (m / z): 311.14 [M+H] + .

[0656] Step 2: 1-(Methylimino)-2,3,4,5-tetrahydro-1H-1λ 4 -Benzo[f][1,4]thiazepine Synthesis of -1-oxide

[0657] Add 1-(methylimino)-1,2,3,5-tetrahydro-4H-1λ 4 -Benzo[f][1,4]thiazepine -4-carboxylic acid tert-butyl ester-1-oxide (1.7 g, 5.5 mmol), then add HCl / 1,4-dioxane (20 mL, 4 M), and react at room temperature for 14 h. After the reaction is completed, it is concentrated under reduced pressure to obtain a crude product, which is added to water, and a saturated potassium carbonate solution is added to adjust the pH to 9-10, extracted with ethyl acetate, and the organic phase is washed with a saturated sodium chloride solution. The organic phase is collected and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1-(methylimino)-2,3,4,5-tetrahydro-1H-1λ 4 -Benzo[f][1,4]thiazepine -1-oxide (630 mg). ESI-MS (m / z): 211.08 [M+H] + .

[0658] Intermediate Preparation Example 2-16: N-(1-oxido-2,3,4,5-tetrahydro-1λ 4 -Benzo[f][1,4]thiazepine Synthesis of cyanamide

[0659] Step 1: (E)-1-(Cyanoimido)-1,2,3,5-tetrahydro-4H-1λ 4 -Benzo[f][1,4]thiazepine -Synthesis of tert-butyl 4-carboxylate

[0660] In a 50 mL reaction bottle, 2,3-dihydrobenzo[f][1,4]thiazepine -4(5H)-carboxylic acid tert-butyl ester (1.7 g, 6.4 mmol) was added to MeOH (20 ml), and then ammonium cyanide (422 mg, 9.6 mmol) was added. After stirring for 5 minutes, iodophenyl diacetic acid (2.3 g, 7 mmol) was added, and the mixture was reacted overnight at room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was chromatographed on silica gel (EA:PE=2:1) ​​to obtain (E)-1-(cyanoimino)-1,2,3,5-tetrahydro-4H-1λ4 -Benzo[f][1,4]thiazepine -4-carboxylic acid tert-butyl ester (1.4 g). ESI-MS (m / z): 306.12 [M+H] + .

[0661] Step 2: 1-(Cyanoimido)-1,2,3,5-tetrahydro-4H-1λ 4 -Benzo[f][1,4]thiazepine -Synthesis of tert-butyl 4-carboxylate-1-oxide

[0662] In a 50 mL reaction bottle, (E)-1-(cyanoimido)-1,2,3,5-tetrahydro-4H-1λ 4 -Benzo[f][1,4]thiazepine -4-carboxylic acid tert-butyl ester (1.4 g, 4.6 mmol) was added to ACN (70 ml) and DCM (7 ml), and then ruthenium chloride (9.5 mg, 0.046 mmol) and sodium periodate (1.5 g, 6.9 mmol) were added, and the reaction was carried out overnight at room temperature, and the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was chromatographed on silica gel (EA: PE = 2: 1) to obtain 1-(cyanoimino)-1,2,3,5-tetrahydro-4H-1λ 4 -Benzo[f][1,4]thiazepine -4-carboxylic acid tert-butyl ester-1-oxide (1.1 g). ESI-MS (m / z): 322.11 [M+H] + .

[0663] Step 3: N-(1-oxy-2,3,4,5-tetrahydro-1λ 4 -Benzo[f][1,4]thiazepine Synthesis of cyanamide

[0664] Add 1-(cyanoimido)-1,2,3,5-tetrahydro-4H-1λ into a 50 mL reaction bottle. 4 -Benzo[f][1,4]thiazepine -4-carboxylic acid tert-butyl ester-1-oxide (1.1 g, 3.4 mmol), then add HCl / 1,4-dioxane (15 mL, 4 M), and react at room temperature for 14 h. After the reaction is completed, it is concentrated under reduced pressure to obtain a crude product, which is added to water, and a saturated potassium carbonate solution is added to adjust the pH to 9-10, extracted with ethyl acetate, and the organic phase is washed with a saturated sodium chloride solution. The organic phase is collected and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain N-(1-oxidized-2,3,4,5-tetrahydro-1λ 4 -Benzo[f][1,4]thiazepine -1-ylidene)cyanamide (300 mg). ESI-MS (m / z): 222.06 [M+H] + .

[0665] Intermediate Preparation Example 2-17: 1-(Methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine Synthesis

[0666]

[0667] Step 1: 4-Benzyl-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepine Synthesis of -2-ketone

[0668] In a 100 mL reaction flask, add 1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepine -2-ketone (0.5 g, 3.08 mmol), DCM (10 mL), TEA (0.94 g, 9.29 mmol), the system was cooled to 0 ° C, benzyl bromide (0.7 g, 4.09 mmol) was added dropwise, and the reaction was carried out at room temperature for 6 hours. LCMS showed that the reaction was completed, EA was extracted and the obtained organic phase was concentrated under reduced pressure and purified by column chromatography (DCM: MeOH = 40: 1) to obtain 4-benzyl-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepine -2-ketone (0.48 g). ESI-MS (m / z): 253.32 [M+H] + .

[0669] Step 2: 4-Benzyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine Synthesis

[0670] 4-Benzyl-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one (0.43 g, 1.71 mmol) and anhydrous tetrahydrofuran (5 mL) were added to a 100 mL reaction bottle in sequence, and then LAH (0.26 g, 6.84 mmol) was slowly added. The reaction solution was heated to 70°C for 3 h. LCMS showed that the reaction was complete, and the temperature was cooled to room temperature. Water was added to quench the reaction, and the filtrate was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to obtain 4-benzyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin (0.4g). ESI-MS(m / z):239.33[M+H] + .

[0671] Step 3: 4-Benzyl-1-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine Synthesis

[0672] In a 100 mL reaction flask, add 4-benzyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (0.6 g, 2.52 mmol), DCM (5 mL), TEA (0.8 g, 7.90 mmol), the reaction solution was cooled to 0°C, methylsulfonyl chloride (0.57 g, 4.97 mmol) was added dropwise, and the reaction was restored to room temperature for 3 hours. LCMS showed that the reaction was complete, post-processed, water was added, and the liquid was separated. The obtained organic phase was concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM: MeOH = 80: 1) to obtain 4-benzyl-1-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (0.34g). ESI-MS(m / z):317.42[M+H] + .

[0673] Step 4: 1-(Methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine Synthesis

[0674] In a 100 mL reaction flask, add 4-benzyl-1-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (0.3 g, 0.95 mmol), trifluoroethanol (3 mL), 20% Pd(OH) 2 / C (50 mg), the reaction solution was reacted at room temperature overnight. LCMS showed that the reaction was complete, post-processed, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 1-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (0.25g). ESI-MS(m / z):227.29[M+H] + .

[0675] Intermediate Preparation Example 2-18: 1,2,3,4-Tetrahydronaphtho[1,8-cd]azepine Synthesis

[0676]

[0677] Step 1: Synthesis of methyl 8-bromo-1-naphthoate

[0678] 8-bromo-1-naphthoic acid (2 g, 8.00 mmol), potassium carbonate (1.16 g, 8.37 mmol) and DMF (30 mL) were added to a 100 mL reaction bottle, and MeI (1.19 g, 8.37 mmol) was added dropwise under stirring, and the reaction was carried out at room temperature for 5 h. After the reaction was completed by LCMS, it was diluted with water (50 mL), and then extracted with EA (30 mL × 3), the organic phases were combined, and then washed with water and saturated brine respectively, and purified by column chromatography (PE: EA = 30: 1) to obtain 8-bromo-1-naphthoic acid methyl ester (2.1 g). ESI-MS (m / z): 249.96\251.96 [M+H] + .

[0679] Step 2: Synthesis of methyl 8-(2-((tert-butoxycarbonyl)amino)ethyl)-1-naphthoate

[0680] In a 50 mL reaction bottle, 8-bromo-1-naphthoic acid methyl ester (500 mg, 1.89 mmol), [2-(BOC-amino)ethyl] trifluoroborate potassium (570 mg, 2.27 mmol), Pd(dppf)Cl 2 (138 mg, 0.19 mmol) and cesium carbonate (1.85 g, 5.67 mmol) were dissolved in a mixed solution of toluene and water (3:1), N 2 The mixture was reacted at 80°C for 8 hours under protection. After the reaction was completed by LCMS, it was diluted with water, extracted with EA, washed with saturated brine, and purified by column chromatography (PE:EA=30:1) to obtain 8-(2-((tert-butyloxycarbonyl)amino)ethyl)-1-naphthoic acid methyl ester (621 mg). ESI-MS (m / z): 330.16 [M+H] + .

[0681] Step 3: Synthesis of methyl 8-(2-aminoethyl)-1-naphthoate

[0682] Add 8-(2-((tert-butyloxycarbonyl)amino)ethyl)-1-naphthoic acid methyl ester (621 mg, 1.89 mmol) and DCM (10 mL) to a 50 mL reaction bottle, add TFA (1 mL) dropwise with stirring, and stir at room temperature for 2 h. After the reaction is completed by LCMS detection, the solvent is dried to obtain a crude product of 8-(2-aminoethyl)-1-naphthoic acid methyl ester (432 mg). ESI-MS (m / z): 230.11 [M+H] + .

[0683] Step 4: 3,4-Dihydronaphtho[1,8-cd]azepine Synthesis of -1-(2H)-ketone

[0684] Add 8-(2-aminoethyl)-1-naphthoic acid methyl ester (432 mg) and methanol (15 mL) to a 50 mL reaction bottle, add 5 M sodium methoxide (2.02 mL, 10.1 mmol) under stirring, and stir at room temperature for 2 h. After the reaction is completed by LCMS detection, the solvent is dried and purified by column chromatography (PE: EA = 3:1) to obtain 3,4-dihydronaphtho[1,8-cd]azepine -1-(2H)-ketone (274 mg). ESI-MS (m / z): 198.08 [M+H] + .

[0685] Step 5: 1,2,3,4-Tetrahydronaphtho[1,8-cd]azepine Synthesis

[0686] Add 3,4-dihydronaphtho[1,8-cd]azepine to a 25 mL reaction bottle. -1-(2H)-ketone (274 mg, 1.39 mmol) and THF (10 mL), lithium aluminum hydride (159 mg, 4.17 mmol) was added in batches under stirring, and stirred at 60°C for 2 h. After the reaction was completed by LCMS, water (0.16 mL), 15% NaOH (0.16 mL), and water (0.48 mL) were slowly added, and then anhydrous sodium sulfate was added for drying, filtration, and column chromatography purification (DCM: MeOH = 50: 1) was obtained to obtain 1,2,3,4-tetrahydronaphtho[1,8-cd]azepine (188mg). ESI-MS(m / z):184.10[M+H] + Intermediate Preparation Example 2-19: 1-(Cyclopropylimino)-2,3,4,5-tetrahydro-1H-1λ 4 -Benzo[f][1,4]thiazepine Synthesis of -1-oxide

[0687] Step 1: 1-(Cyclopropylimino)-1,2,3,5-tetrahydro-4H-1λ 4 -Benzo[f][1,4]thiazepine -Synthesis of tert-butyl 4-carboxylate-1-oxide

[0688] Add 1-imino-1,2,3,5-tetrahydro-4H-1λ into a 50 mL reaction bottle. 4 -Benzo[f][1,4]thiazepine -4-carboxylic acid tert-butyl ester-1-oxide (200 mg, 0.7 mmol), Cu(OAc) 2(200 mg, 1.1 mmol), cyclopropylboronic acid (120 mg, 1.4 mmol), pyridine (134 mg, 1.7 mmol), 1,4-dioxane (20 mL). The reaction was carried out at 100 ° C for 8 hours. After the reaction was completed, water was added to the reaction solution and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was chromatographed on silica gel (EA: PE = 1: 1) to obtain 1-(cyclopropylimino)-1,2,3,5-tetrahydro-4H-1λ 4 -Benzo[f][1,4]thiazepine -4-carboxylic acid tert-butyl ester-1-oxide (150 mg). ESI-MS (m / z): 337.15 [M+H] + .

[0689] Step 2: 1-(Cyclopropylimino)-2,3,4,5-tetrahydro-1H-1λ 4 -Benzo[f][1,4]thiazepine Synthesis of -1-oxide

[0690] Add 1-(cyclopropylimino)-1,2,3,5-tetrahydro-4H-1λ 4 -Benzo[f][1,4]thiazepine -4-carboxylic acid tert-butyl ester-1-oxide (150 mg), then HCl / 1,4-dioxane (20 mL, 4 M) was added and reacted at room temperature for 14 h. After the reaction was completed, it was concentrated under reduced pressure to obtain a crude product, which was added to water, and a saturated potassium carbonate solution was added to adjust the pH to 9-10, extracted with ethyl acetate, and the organic phase was washed with a saturated sodium chloride solution. The organic phase was collected and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1-(cyclopropylimino)-2,3,4,5-tetrahydro-1H-1λ 4 -Benzo[f][1,4]thiazepine -1-oxide (100 mg). ESI-MS (m / z): 237.10 [M+H] + .

[0691] Intermediate Preparation Example 3-1: Synthesis of 4-methoxybenzyl (3-(aminomethyl)oxetane-3-yl)carbamate

[0692]

[0693] Step 1: Synthesis of 3-(bromomethyl)oxetane-3-carboxylic acid

[0694] In a 500mL reaction bottle, (3-(bromomethyl)oxetane-3-yl)methanol (8.5g, 46.95mmol), acetonitrile (25mL), water (130mL), KBr (0.57g, 4.79mmol) were added in sequence, and a 7% aqueous sodium hypochlorite solution (120mL) was added dropwise to the reaction solution. The temperature was below 30°C during the addition. After the addition was completed, the reaction was allowed to proceed at room temperature for 4h. LCMS showed that the reaction was complete, and a sodium bicarbonate solution was added to adjust the pH of the system to 10. The system was then extracted with ethyl acetate, and the obtained aqueous phase was adjusted to pH 2 with 5N sulfuric acid, then extracted with dichloromethane, and concentrated to dryness under reduced pressure to obtain 3-(bromomethyl)oxetane-3-carboxylic acid (5.6g).

[0695] Step 2: Synthesis of 4-methoxybenzyl (3-(bromomethyl)oxetan-3-yl)carbamate

[0696] 3-(Bromomethyl)oxetane-3-carboxylic acid (5g, 25.77mmol), toluene (50mL), N-methylmorpholine (3.1g, 30.65mmol), (4-methoxyphenyl)methanol (3.6g, 26.06mmol), DPPA (7.8g, 28.34mmol) were added to a 500mL reaction bottle in sequence, and the reaction solution was heated to 80°C for 4h. LCMS showed that the reaction was complete, and the reaction solution was cooled to room temperature, and ethyl acetate was added to dilute the reaction solution. The obtained system was washed with saturated sodium bicarbonate aqueous solution, water, and saturated brine, respectively, and the organic phase was concentrated under reduced pressure to obtain 4-methoxybenzyl (3-(bromomethyl)oxetane-3-yl) carbamate (7.8g). ESI-MS (m / z): 330.03 [M+H] + .

[0697] Step 3: Synthesis of 4-methoxybenzyl (3-((1,3-dioxoisoindolin-2-yl)methyl)oxetane-3-yl)carbamate

[0698] 4-methoxybenzyl (3-(bromomethyl) oxetane-3-yl) carbamate (7.8 g, 23.71 mmol), DMF (50 mL), potassium phthalimide (4.4 g, 23.78 mmol) were added to a 250 mL reaction bottle in sequence, and the reaction solution was heated to 60 ° C for 3 h. LCMS showed that the reaction was complete, extracted with ethyl acetate, and the organic phase was concentrated to dryness under reduced pressure. The concentrate was slurried with methyl tert-butyl ether to obtain 4-methoxybenzyl (3-((1,3-dioxoisoindolin-2-yl)methyl) oxetane-3-yl) carbamate (3.1 g). ESI-MS (m / z): 397.13 [M+H] + .

[0699] Step 4: Synthesis of 4-methoxybenzyl (3-(aminomethyl)oxetane-3-yl)carbamate

[0700] 4-methoxybenzyl (3-((1,3-dioxoisoindolin-2-yl)methyl)oxetane-3-yl)carbamate (3 g, 7.57 mmol), ethanol (30 mL), 80% hydrazine hydrate (2.3 g, 37.88 mmol) were added to a 250 mL reaction bottle in sequence, and the temperature was raised to 80 ° C for 2 h. LCMS showed that the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 4-methoxybenzyl (3-(aminomethyl)oxetane-3-yl)carbamate (2.0 g). ESI-MS (m / z): 267.13 [M+H] + .

[0701] Intermediate Preparation Example 3-2: Synthesis of 3-(aminomethyl)-N,N-dibenzyloxetane-3-amine

[0702]

[0703] Step 1: Synthesis of 3-(dibenzylamino)oxetane-3-carbonitrile

[0704] Add oxetane-3-one (2g, 27.6mmol), AcOH (80mL), dibenzylamine (9.9g, 55.2mmol), TMSCN (5.5g, 55.2mmol) in sequence to a 250mL reaction bottle, react at room temperature for 3 hours, LCMS shows that the reaction is complete. The acetic acid is spin-dried, diluted with water, and the pH of sodium bicarbonate is adjusted to 8, then ethyl acetate (200mL) is added, extracted, separated, and the obtained organic phase is washed with water and saturated brine respectively, and prepared under medium pressure (PE: EA = 3: 1) to obtain 3-(dibenzylamino)oxetane-3-carbonitrile (5.2g). ESI-MS (m / z): 279.14 [M+H] + Step 2: Synthesis of 3-(aminomethyl)-N,N-dibenzyloxetane-3-amine

[0705] 3-(Dibenzylamino)oxetane-3-carbonitrile (5.2 g, 18.7 mmol) was added to a 250 mL reaction bottle, and then dissolved in 100 mL of tetrahydrofuran. LiAlH 4(0.85g, 22.4mmol) was reacted at room temperature for 4 hours. LCMS showed that the reaction was complete. Under ice bath, water (0.9mL), 15% NaOH (0.9mL), water (2.7mL) were slowly added, and then anhydrous sodium sulfate was added for drying, filtered, concentrated under reduced pressure, and then medium pressure preparative separation (DCM: MeOH = 20: 1) was performed to obtain 3-(aminomethyl)-N,N-dibenzyloxetane-3-amine (3g, 10.6mmol). ESI-MS (m / z): 283.17 [M+H] + .

[0706] Intermediate Preparation 4-1: Synthesis of 2,4-dichloro-6-(difluoromethyl)quinazoline

[0707]

[0708] Step 1: Synthesis of 5-difluoromethyl-2-fluorobenzonitrile

[0709] Add 2-fluoro-5-formyl-benzonitrile (1.49 g) in a 100 mL reaction bottle, add DCM solution to dissolve, and slowly add diethylaminosulfur trifluoride (1.77 g) at 0°C. After the addition is complete, react at room temperature. LCMS detects the end of the reaction. Add ice water, extract with ethyl acetate, combine the organic phases, and dry under reduced pressure to obtain 5-difluoromethyl-2-fluorobenzonitrile (1.5 g). ESI-MS (m / z): 172.03 [M+H] + .

[0710] Step 2: Synthesis of 5-difluoromethyl-2-aminobenzonitrile

[0711] Add 5-difluoromethyl-2-fluorobenzonitrile (1.49 g) to a 20 mL reaction bottle, add THF solution to dissolve, and slowly add ammonia water (1.77 g). After the addition is completed, react at 100 ° C. LCMS detection shows that the reaction is complete. Extract with ethyl acetate, combine the organic phases, and dry under reduced pressure to obtain 5-difluoromethyl-2-aminobenzonitrile (0.3 g). ESI-MS (m / z): 169.03 [M+H] + .

[0712] Step 3: Synthesis of 6-(difluoromethyl)quinazoline-2,4-diol

[0713] In a 20 mL reaction bottle, 5-difluoromethyl-2-aminobenzonitrile (0.3 g) and DBU (2 mL) were added to the DMSO solution to dissolve and the CO was slowly replaced. 2Gas three times, react at 100℃, LCMS detection reaction terminated. Add water, extract with ethyl acetate, combine the organic phases, and spin dry under reduced pressure to obtain 6-(difluoromethyl)quinazoline-2,4-diol (0.1 g). ESI-MS (m / z): 213.04 [M+H] + .

[0714] Step 4: Synthesis of 2,4-dichloro-6-(difluoromethyl)quinazoline

[0715] In a 20 mL reaction bottle, add 6-(difluoromethyl)quinazoline-2,4-diol (0.1 g), phosphorus trichloride (2 mL), and phosphorus pentachloride (2 mL) in sequence, react at 100 ° C, and LCMS detection reaction is terminated. Add water, extract with ethyl acetate, combine the organic phases, and spin dry under reduced pressure to obtain 2,4-dichloro-6-(difluoromethyl)quinazoline (0.05 g). ESI-MS (m / z): 248.97 [M+H] + .

[0716] Example 1-1: 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Synthesis of -1,1-dioxide

[0717]

[0718] Step 1: Synthesis of 2-chloro-N-((3-(dibenzylamino)oxetan-3-yl)methyl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine

[0719] 3-(Aminomethyl)-N, N-dibenzyloxetane-3-amine (517 mg, 1.83 mmol) and methanol (10 mL) were added to a 100 mL reaction bottle, followed by 2,4-dichloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (400 mg, 1.83 mmol) and triethylamine (270 mg, 2.67 mmol). The reaction solution was reacted at room temperature for 3 hours. LCMS showed that the reaction was complete, and after post-treatment, the reaction solution was concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM: MeOH = 30: 1) to obtain 2-chloro-N-((3-(dibenzylamino)oxetane-3-yl)methyl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (130 mg). ESI-MS (m / z): 464.21 [M+H] + .

[0720] Step 2: 4-(4-(((3-(dibenzylamino)oxetan-3-yl)methyl)amino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Synthesis of -1,1-dioxide

[0721] In a 25 mL reaction bottle, 2-chloro-N-((3-(dibenzylamino)oxetane-3-yl)methyl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (100 mg, 0.22 mmol), 2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -1,1-dioxide (47 mg, 0.24 mmol), p-toluenesulfonic acid monohydrate (8.4 mg, 0.044 mmol), n-butanol (2 mL), the reaction solution was reacted at 120 ° C for 4 hours. LCMS showed that the reaction was complete. After treatment, ethyl acetate was added to dilute, and the obtained organic phase was washed with saturated sodium bicarbonate aqueous solution and water respectively. The organic phase was concentrated to dryness under reduced pressure, and the concentrate was prepared by TLC (DCM: MeOH = 10: 1) to obtain 4-(4-(((3-(dibenzylamino)oxetane-3-yl)methyl)amino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -1,1-dioxide (60 mg). ESI-MS (m / z): 625.29 [M+H] + .

[0722] Step 3: 4-(4-(((3-aminooxetan-3-yl)methyl)amino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Synthesis of -1,1-dioxide

[0723] In a 25 mL reaction bottle, 4-(4-(((3-(dibenzylamino)oxetane-3-yl)methyl)amino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -1,1-dioxide (60 mg, 0.096 mmol) was dissolved in methanol (5 ml) and 20% carbon-supported Pd(OH) 2(40 mg), reacted at room temperature overnight under hydrogen atmosphere. LCMS showed that the reaction was complete, filtered, the filtrate was collected, concentrated under reduced pressure, and then prepared by TLC (DCM: MeOH = 10: 1) to obtain 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -1,1-dioxide (20 mg). ESI-MS (m / z): 445.19 [M+H] + ; 1 H NMR (600 MHz, CDCl 3 )δ8.05(d,J=7.7Hz,1H),7.72(d,J=7.4Hz,1H),7.52(t,J=7.3Hz,1H),7.40(t,J=7.6Hz,1H),5.12(s,2H),4.80(s,1H),4.51(dd,J=2 6.3, 6.0Hz, 4H), 3.88 (s, 2H), 3.43 (s, 2H), 3.23 (s, 2H), 3.12 (q, J = 7.3Hz, 2H), 2.81–2.61 (m, 4H), 2.51 (s, 3H), 1.43 (t, J = 7.3Hz, 2H).

[0724] Example 1-2: 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Synthesis of -1,1-dioxide

[0725]

[0726] The synthesis method is the same as that of Example 1-1, except that 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine is used as the starting material instead of 2,4-dichloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine to obtain 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -1,1-dioxide (3 mg). ESI-MS (m / z): 417.16 [M+H] + .

[0727] Example 1-3: 4-(6-(((3-aminooxetane-3-yl)methyl)amino)-9-methyl-8,9-dihydro-7H-purin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Synthesis of -1,1-dioxide

[0728]

[0729] The synthesis method is the same as that of Example 1-1, except that 2,4-dichloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine is replaced by 2,6-dichloro-9-methyl-9H-purine as the starting material to obtain 4-(6-(((3-aminooxetane-3-yl)methyl)amino)-9-methyl-8,9-dihydro-7H-purin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -1,1-dioxide (25 mg). ESI-MS (m / z): 432.17 [M+H] + ; 1 H NMR (600 MHz, DMSO-d 6 )δ7.91(d,J=7.7Hz,1H),7.65(s,1H),7.60(t,J=7.4Hz,1H),7.44(dd,J=11.5,7.7Hz,2H),3.68(d, J=3.9Hz,2H),3.58(t,J=6.7Hz,2H),3.47(m,4H),3.25(m,4H),3.05(d,J=14.0Hz,2H),2.63(s,3H).

[0730] Example 1-4: 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Synthesis of -1,1-dioxide

[0731]

[0732] The synthesis method is the same as that of Example 1-1, except that 2,4-dichloro-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine is used as the starting material instead of 2,4-dichloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine to obtain 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -1,1-dioxide (3 mg). ESI-MS (m / z): 445.19 [M+H] + .

[0733] Example 1-5: 4-(((3-aminooxetane-3-yl)methyl)amino)-2-(1,1-dioxido-2,3-dihydrobenzo[f][1,4]thiazepine Synthesis of methyl 4-(5H)-pyrimidine-5-carboxylate

[0734]

[0735] Step 1: Synthesis of methyl 2-chloro-4-(((3-(dibenzylamino)oxetan-3-yl)methyl)amino)pyrimidine-5-carboxylate

[0736] 2,4-Dichloropyrimidine-5-carboxylic acid (500 mg, 2.59 mmol), DMF (10 mL), potassium carbonate (715 mg, 5.18 mmol), and MeI (404 mg, 2.85 mmol) were added to a 50 mL reaction bottle in sequence, and the mixture was reacted at room temperature for 2 h. Et 3 N (503 mg, 5.18 mmol) and 3-(aminomethyl)-N,N-dibenzyloxetane-3-amine (500 mg, 1.77 mmol) were reacted at room temperature for 2 h. LCMS showed that the reaction was complete. EA was diluted, washed with water, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then medium pressure preparation (PE: EA = 3: 1) was performed to obtain 2-chloro-4-(((3-(dibenzylamino)oxetane-3-yl)methyl)amino)pyrimidine-5-carboxylic acid methyl ester (270 mg, 0.6 mmol). ESI-MS (m / z): 453.16 [M+H] + .

[0737] Step 2: 4-(((3-(Dibenzylamino)oxetan-3-yl)methyl)amino)-2-(1,1-dioxido-2,3-dihydrobenzo[f][1,4]thiazepine Synthesis of methyl 4-(5H)-pyrimidine-5-carboxylate

[0738] In a 50 mL reaction bottle, methyl 2-chloro-4-(((3-(dibenzylamino)oxetane-3-yl)methyl)amino)pyrimidine-5-carboxylate (270 mg, 0.6 mmol), DMF (4 mL), Et 3 N (121 mg, 1.2 mmol) and 2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -1,1-dioxide (129 mg, 0.66 mmol), react at 80 °C for 2 h, LCMS showed the reaction was complete. EA was diluted, washed with water, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, and medium pressure preparation (PE: EA = 2: 1) gave 4-(((3-(dibenzylamino)oxetane-3-yl)methyl)amino)-2-(1,1-dioxido-2,3-dihydrobenzo[f][1,4]thiazepine -4(5H)-yl)pyrimidine-5-carboxylic acid methyl ester (170 mg, 0.28 mmol). ESI-MS (m / z): 614.24 [M+H] + .

[0739] Step 3: 4-(((3-aminooxetan-3-yl)methyl)amino)-2-(1,1-dioxido-2,3-dihydrobenzo[f][1,4]thiazepine Synthesis of methyl 4-(5H)-pyrimidine-5-carboxylate

[0740] In a 25 mL reaction bottle, 4-(((3-(dibenzylamino)oxetane-3-yl)methyl)amino)-2-(1,1-dioxido-2,3-dihydrobenzo[f][1,4]thiazepine -4(5H)-yl)pyrimidine-5-carboxylic acid methyl ester (150 mg, 0.24 mmol) was dissolved in methanol (5 ml) and Pd(OH) 2 / C (150 mg) was reacted at room temperature under hydrogen atmosphere overnight. After the reaction was completed, the filtrate was collected by filtration, dried by rotation, and prepared by TLC (DCM: MeOH = 20: 1) to obtain 4-(((3-aminooxetane-3-yl)methyl)amino)-2-(1,1-dioxido-2,3-dihydrobenzo[f][1,4]thiazepine -4(5H)-yl)pyrimidine-5-carboxylic acid methyl ester (17.67 mg). ESI-MS (m / z): 434.14 [M+H] + ; 1 H NMR (600 MHz, CDCl 3 )δ8.58(d,J=37.5Hz,2H),8.07(dd,J=32.6,7.5Hz,1H),7.73(dd,J=41.0,7.2Hz,1H),7.62–7.54(m,1H),7. 49–7.39(m,1H),5.20(s,2H),4.68–4.49(m,6H),4.05(s,1H),3.86(s,1H),3.81(s,3H),3.50–3.32(m,2H).

[0741] Example 1-6: 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-5-(hydroxymethyl)pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Synthesis of -1,1-dioxide

[0742]

[0743] Step 1: 4-(4-(((3-(dibenzylamino)oxetan-3-yl)methyl)amino)-5-(hydroxymethyl)pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Synthesis of -1,1-dioxide

[0744] In a 25 mL reaction bottle, 4-(((3-(dibenzylamino)oxetane-3-yl)methyl)amino)-2-(1,1-dioxido-2,3-dihydrobenzo[f][1,4]thiazepine -4-(5H)-yl)pyrimidine-5-carboxylic acid methyl ester (60 mg, 0.1 mmol) was dissolved in tetrahydrofuran (5 ml), and DIBAL-H (0.3 mL, 0.3 mmol) was added and reacted at room temperature for three hours. After the reaction was completed by LCMS, the reaction solution was quenched with methanol, dried by spin drying, and then prepared by TLC (DCM: MeOH = 20: 1) to obtain 4-(4-(((3-(dibenzylamino)oxetane-3-yl)methyl)amino)-5-(hydroxymethyl)pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -1,1-dioxide (26 mg). ESI-MS (m / z): 586.24 [M+H] + .

[0745] Step 2: 4-(4-(((3-aminooxetan-3-yl)methyl)amino)-5-(hydroxymethyl)pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Synthesis of -1,1-dioxide

[0746] In a 25 mL reaction bottle, 4-(4-(((3-(dibenzylamino)oxetane-3-yl)methyl)amino)-5-(hydroxymethyl)pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -1,1-dioxide (26 mg, 0.04 mmol) was dissolved in methanol (5 ml) and Pd(OH) 2 / C (30 mg), reacted at room temperature under hydrogen atmosphere overnight. After the reaction was completed by LCMS, the filtrate was collected by filtration, and then TLC was prepared (DCM: MeOH = 10: 1) to obtain 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-5-(hydroxymethyl)pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -1,1-dioxide (10 mg). ESI-MS (m / z): 406.15 [M+H] + ; 1H NMR (600MHz, DMSO-d 6 )δ7.88(t,J=18.1Hz,2H),7.66–7.59(m,2H),7.50(t,J=7.7Hz,1H),6.51(s,1H),5.00(s,2H),4.4 6–4.31(m,6H),4.22(d,J=4.7Hz,2H),3.78(d,J=22.7Hz,2H),3.52(s,2H),3.18(d,J=5.1Hz,1H).

[0747] Example 1-7: 4-(6-(((3-aminooxetane-3-yl)methyl)amino)-9-methyl-9H-purin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Synthesis of -1,1-dioxide

[0748]

[0749] Step 1: Synthesis of 4-methoxybenzyl (3-(((2-chloro-9-methyl-9H-purin-6-yl)amino)methyl)oxetan-3-yl)carbamate

[0750] 4-methoxybenzyl (3-(aminomethyl) oxetane-3-yl) carbamate (260 mg, 0.98 mmol) and methanol (10 mL) were added to a 100 mL reaction bottle, followed by 2,6-dichloro-9-methyl-9H-purine (200 mg, 0.98 mmol) and triethylamine (200 mg, 1.98 mmol). The reaction solution was reacted at room temperature for 4 hours. LCMS showed that the reaction was complete, and after post-treatment, the reaction solution was directly concentrated to dryness under reduced pressure. The concentrate was purified by silica gel column (DCM: MeOH = 30: 1) to obtain 4-methoxybenzyl (3-(((2-chloro-9-methyl-9H-purin-6-yl) amino) methyl) oxetane-3-yl) carbamate (280 mg), ESI-MS (m / z): 433.13 [M+H] + .

[0751] Step 2: 4-methoxybenzyl(3-(((2-(1,1-dioxido-2,3-dihydrobenzo[f][1,4]thiazepine Synthesis of 4-(5H)-yl)-9-methyl-9H-purin-6-yl)amino)methyl)oxetane-3-yl)carbamate

[0752] In a 25 mL reaction bottle, 4-methoxybenzyl (3-(((2-chloro-9-methyl-9H-purin-6-yl)amino)methyl)oxetane-3-yl)carbamate (260 mg, 0.60 mmol), 2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -1,1-dioxide (120 mg, 0.61 mmol), p-toluenesulfonic acid monohydrate (115 mg, 0.60 mmol), n-butanol (3 mL), the reaction solution was reacted at 120 ° C for 6 hours. LCMS showed that the reaction was complete. Dilute with ethyl acetate, wash the obtained organic phase with saturated sodium bicarbonate aqueous solution and water, respectively, and concentrate to dryness under reduced pressure. The concentrate was prepared by TLC (DCM: MeOH = 10: 1) to obtain 4-methoxybenzyl (3-(((2-(1,1-dioxido-2,3-dihydrobenzo[f][1,4]thiazepine -4(5H)-yl)-9-methyl-9H-purin-6-yl)amino)methyl)oxetan-3-yl)carbamate (200 mg). ESI-MS (m / z): 594.21 [M+H] + .

[0753] Step 3: 4-(6-(((3-aminooxetan-3-yl)methyl)amino)-9-methyl-9H-purin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Synthesis of -1,1-dioxide

[0754] In a 100 mL reaction flask, add 4-methoxybenzyl (3-(((2-(1,1-dioxido-2,3-dihydrobenzo[f][1,4]thiazepine) -4(5H)-yl)-9-methyl-9H-purin-6-yl)amino)methyl)oxetane-3-yl)carbamate (100 mg, 0.17 mmol), DCM (4 mL), trifluoroacetic acid (1 mL), the reaction solution was stirred at room temperature for 1 h. LCMS showed that the reaction was complete, and the concentrate was concentrated to dryness under reduced pressure. Methanol was added to dissolve the concentrate, and ammonia methanol was added to adjust the pH of the solution to 10. The obtained solution was concentrated to dryness under reduced pressure and then prepared by liquid phase preparation to obtain 4-(6-(((3-aminooxetane-3-yl)methyl)amino)-9-methyl-9H-purin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -1,1-dioxide (40 mg). ESI-MS (m / z): 430.16 [M+H] + ; 1 H NMR (600 MHz, CDCl 3 )δ8.09(d,J=7.4Hz,1H),7.53–7.44(m,2H),7.40(d,J=7.3Hz,1H),7.38–7.31(m,1H),4.83(s,2H),3. 96(d,J=18.2Hz,3H),3.89–3.74(m,2H),3.57(d,J=14.7Hz,4H),3.48(s,3H),3.40(d,J=15.6Hz,1H).

[0755] Example 1-8: 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Synthesis of -1,1-dioxide

[0756]

[0757] The synthesis method is the same as that of Example 1-7, except that 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine is used as the starting material instead of 2,6-dichloro-9-methyl-9H-purine to obtain 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -1,1-dioxide (30 mg). ESI-MS (m / z): 415.15 [M+H] + .

[0758] Example 1-9: 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Synthesis of -1,1-dioxide

[0759]

[0760] The synthesis method is the same as that of Example 1-7, except that 2,6-dichloro-9-methyl-9H-purine is replaced by tert-butyl 2,4-dichloro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate as the starting material to obtain 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -1,1-dioxide (18 mg). ESI-MS (m / z): 431.53 [M+H] + ; 1 H NMR (600 MHz, CDCl 3 )δ8.06(d,J=7.6Hz,1H),7.72(d,J=7.3Hz,1H),7.52(t,J=7.2Hz,1H),7.40(t,J=7.5Hz,1H),5.13(s,2H),4.73( s,2H),4.50(dd,J=35.1,6.1Hz,4H),3.87(s,2H),3.58(s,2H),3.43(s,2H),3.08(t,J=5.7Hz,2H),2.56(s,2H).

[0761] Example 1-10: 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-5-methoxypyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Synthesis of 1,1-dioxide

[0762]

[0763] Step 1: Synthesis of 2-chloro-N-((3-(dibenzylamino)oxetan-3-yl)methyl)-5-methoxypyrimidin-4-amine

[0764] 3-(Aminomethyl)-N, N-dibenzyloxetane-3-amine (347 mg, 1.23 mmol) and methanol (10 mL) were added to a 100 mL reaction bottle, followed by 2,4-dichloro-5-methoxypyrimidine (200 mg, 1.12 mmol) and triethylamine (170 mg, 1.68 mmol). The reaction solution was heated to 50 °C for 3 hours. LCMS showed that the reaction was complete, and the reaction solution was concentrated to dryness under reduced pressure. The concentrate was purified by column chromatography (DCM: MeOH = 30: 1) to give 2-chloro-N-((3-(dibenzylamino)oxetane-3-yl)methyl)-5-methoxypyrimidine-4-amine (440 mg). ESI-MS (m / z): 425.17 [M+H] + .

[0765] Step 2: 4-(4-(((3-(dibenzylamino)oxetan-3-yl)methyl)amino)-5-methoxypyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Synthesis of -1,1-dioxide

[0766] 2-Chloro-N-((3-(dibenzylamino)oxetane-3-yl)methyl)-5-methoxypyrimidin-4-amine (160 mg, 0.36 mmol), 2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine were added sequentially into a microwave tube. -1,1-dioxide (70 mg, 0.36 mmol), p-toluenesulfonic acid monohydrate (13.6 mg, 0.07 mmol), n-butanol (3 mL), the reaction solution was reacted at 145 ° C in a microwave for 2 hours. LCMS showed that the reaction was complete. Ethyl acetate was added for dilution, and the obtained organic phase was washed with saturated sodium bicarbonate aqueous solution and water respectively. The organic phase was concentrated to dryness under reduced pressure, and the concentrate was prepared by TLC (DCM: MeOH = 15: 1) to obtain 4-(4-(((3-(dibenzylamino)oxetane-3-yl)methyl)amino)-5-methoxypyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -1,1-dioxide (15 mg). ESI-MS (m / z): 586.24 [M+H] + .

[0767] Step 3: 4-(4-(((3-aminooxetan-3-yl)methyl)amino)-5-methoxypyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Synthesis of -1,1-dioxide

[0768] In a 25 mL reaction flask, 4-(4-(((3-(dibenzylamino)oxetane-3-yl)methyl)amino)-5-methoxypyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -1,1-dioxide (15 mg, 0.026 mmol) was dissolved in methanol (5 ml) and 20% loaded Pd(OH) 2 Carbon (20 mg), reacted at room temperature overnight in a hydrogen atmosphere. LCMS showed that the reaction was complete, post-processed, filtered and collected the filtrate, the filtrate was concentrated under reduced pressure and then prepared by Prep-HPLC to obtain 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-5-methoxypyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -1,1-dioxide (2.7 mg). ESI-MS (m / z): 406.15 [M+H] + .

[0769] Example 1-11: 4-((3-aminooxetane-3-yl)methyl)amino)-2-(1,1-dioxido-2,3-dihydrobenzo[f][1,4]thiazepine Synthesis of ethyl 4(5H)-pyrimidine-5-carboxylate

[0770]

[0771] Step 1: Synthesis of ethyl 2-chloro-4-(((3-(dibenzylamino)oxetan-3-yl)methyl)amino)pyrimidine-5-carboxylate

[0772] 3-(Aminomethyl)-N,N-dibenzyloxetane-3-amine (670 mg, 2.37 mmol) and DCM (10 mL) were added to a 100 mL reaction bottle, followed by ethyl 2,4-dichloropyrimidine-5-carboxylate (500 mg, 2.26 mmol) and triethylamine (343 mg, 3.39 mmol). The reaction solution was heated to 40 °C for 3 hours. LCMS showed that the reaction was complete, and after post-treatment, the reaction solution was concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (EA: PE = 1: 1) to give ethyl 2-chloro-4-(((3-(dibenzylamino)oxetane-3-yl)methyl)amino)pyrimidine-5-carboxylate (710 mg). ESI-MS (m / z): 467.18 [M+H] + .

[0773] Step 2: 4-((3-(dibenzylamino)oxetane-3-yl)methyl)amino)-2-(1,1-dioxido-2,3-dihydrobenzo[f][1,4]thiazepine Synthesis of ethyl 4(5H)pyrimidine-5-carboxylate

[0774] In a microwave tube, ethyl 2-chloro-4-(((3-(dibenzylamino)oxetane-3-yl)methyl)amino)pyrimidine-5-carboxylate (660 mg, 1.42 mmol), 2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -1,1-dioxide (279 mg, 1.42 mmol), p-toluenesulfonic acid monohydrate (135 mg, 0.71 mmol), n-butanol (10 mL), the reaction solution was reacted at 145 ° C in a microwave for 2 hours. LCMS showed that the reaction was complete. After post-treatment, ethyl acetate was added to dilute, and the obtained organic phase was washed with saturated sodium bicarbonate aqueous solution and water respectively. The organic phase was concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM: MeOH = 20: 1) to obtain 4-((3-(dibenzylamino)oxetane-3-yl)methyl)amino)-2-(1,1-dioxido-2,3-dihydrobenzo[f][1,4]thiazepine -4(5H)-1-pyrimidine-5-carboxylic acid ethyl ester (340 mg). ESI-MS (m / z): 628.3 [M+H] + .

[0775] Step 3: 4-(4-(((3-aminooxetan-3-yl)methyl)amino)-5-methoxypyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Synthesis of -1,1-dioxide

[0776] In a 25 mL reaction flask, 4-((3-(dibenzylamino)oxetane-3-yl)methyl)amino)-2-(1,1-dioxido-2,3-dihydrobenzo[f][1,4]thiazepine -4(5H)-1-pyrimidine-5-carboxylic acid ethyl ester (190 mg, 0.3 mmol) was dissolved in trifluoroethanol (8 ml) and 10% loaded Pd(OH) 2 Carbon (100 mg), replaced with hydrogen balloon three times, and reacted at room temperature overnight. LCMS showed that the reaction was complete, and the filtrate was collected by filtration. The filtrate was concentrated under reduced pressure and then prepared by Prep-HPLC to obtain 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-5-methoxypyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -1,1-dioxide (30 mg). ESI-MS (m / z): 448.16 [M+H] + . 1 H NMR (600 MHz, CDCl 3)δ8.55(dd,J=40.1,19.9Hz,2H),8.06(d,J=12.5Hz,1H),7.71(d,J=27.8Hz,1H),7.56(s,1H),7.43(s,1H),5.17(s,2 H), 4.52 (s, 3H), 4.45 (s, 1H), 4.25 (d, J = 6.6Hz, 2H), 4.02 (s, 1H), 3.80 (s, 1H), 3.40 (s, 2H), 1.77 (s, 2H), 1.31 (s, 3H).

[0777] Example 1-12: 4-((3-aminooxetane-3-yl)methyl)amino)-2-(1,1-dioxido-2,3-dihydrobenzo[f][1,4]thiazepine Synthesis of 4-(5H)-yl)-N-methylpyrimidine-5-carboxamide

[0778]

[0779] Step 1: Synthesis of 2-chloro-4-(((3-(dibenzylamino)oxetan-3-yl)methyl)amino)pyrimidine-5-carboxylic acid

[0780] Add 2,4-dichloropyrimidine-5-carboxylic acid (250 mg, 1.29 mmol) and DCM (10 mL) to a 100 mL reaction bottle, then add 3-(aminomethyl)-N,N-dibenzyloxetane-3-amine (402 mg, 1.29 mmol) and triethylamine (261 mg, 2.58 mmol). The reaction solution was reacted at room temperature overnight. LCMS showed that the reaction was completed and used directly in the next step without treatment. ESI-MS (m / z): 439.15 [M+H] + .

[0781] Step 2: Synthesis of 2-chloro-4-(((3-(dibenzylamino)oxetan-3-yl)methyl)amino)-N-methylpyrimidine-5-carboxamide

[0782] Methylamine hydrochloride (99.2 mg, 1.42 mmol) was added to the reaction solution of the previous step, and then N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate (640 mg, 1.68 mmol) and N,N-diisopropylethylamine (409 mg, 3.23 mmol) were added. The reaction solution was reacted overnight at room temperature. After treatment, the reaction solution was concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM: MeOH = 20: 1) to obtain 2-chloro-4-(((3-(dibenzylamino)oxetane-3-yl)methyl)amino)-N-methylpyrimidine-5-carboxamide (350 mg). ESI-MS (m / z): 452.18 [M+H] + .

[0783] Step 3: 4-(((3-(Dibenzylamino)oxetan-3-yl)methyl)amino)-2-(1,1-dioxido-2,3-dihydrobenzo[f][1,4]thiazepine Synthesis of 4-(5H)-yl)-N-methylpyrimidine-5-carboxamide

[0784] 2-Chloro-4-(((3-(dibenzylamino)oxetane-3-yl)methyl)amino)-N-methylpyrimidine-5-carboxamide (300 mg, 0.66 mmol), 2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine were added in sequence into a microwave tube. -1,1-dioxide (131 mg, 0.66 mmol), triethylamine (135 mg, 1.32 mmol), DMF (10 mL), the reaction solution was reacted at 120 ° C in a microwave for 1 hour. Water was added to the reaction solution, extracted with ethyl acetate, and the obtained organic phase was washed with water and saturated sodium chloride, respectively, and the organic phase was concentrated to dryness under reduced pressure. The concentrate was purified by column chromatography (DCM: MeOH = 30: 1) to obtain 4-(((3-(dibenzylamino)oxetane-3-yl)methyl)amino)-2-(1,1-dioxido-2,3-dihydrobenzo[f][1,4]thiazepine -4(5H)-yl)-N-methylpyrimidine-5-carboxamide (160 mg). ESI-MS (m / z): 613.25 [M+H] + .

[0785] Step 4: 4-((3-aminooxetane-3-yl)methyl)amino)-2-(1,1-dioxido-2,3-dihydrobenzo[f][1,4]thiazepine Synthesis of 4-(5H)-yl)-N-methylpyrimidine-5-carboxamide

[0786] In a 25 mL reaction flask, 4-(((3-(dibenzylamino)oxetane-3-yl)methyl)amino)-2-(1,1-dioxido-2,3-dihydrobenzo[f][1,4]thiazepine -4(5H)-yl)-N-methylpyrimidine-5-carboxamide (160 mg, 0.26 mmol) was dissolved in trifluoroethanol (10 ml) and 20% loaded Pd(OH) 2 Carbon (80 mg), replaced with hydrogen balloon three times, reacted at room temperature overnight. LCMS showed that the reaction was complete, post-processed, filtered and collected the filtrate, the filtrate was concentrated under reduced pressure and then Prep-TLC was used to prepare 4-((3-aminooxetane-3-yl)methyl)amino)-2-(1,1-dioxido-2,3-dihydrobenzo[f][1,4]thiazepine -4(5H)-yl)-N-methylpyrimidine-5-carboxamide (20 mg). ESI-MS (m / z): 433.16 [M+H]+. 1 HNMR (600MHz, CDCl 3 )δ9.09(d,J=43.1Hz,1H),8.04(d,J=28.3Hz,2H),7.69(d,J=52.2Hz,1H),7.53(s,1H),7.38(d,J=35.8Hz,2H),5.87(s,1H),5. 14(s,2H),4.51(s,3H),4.00(s,1H),3.79(s,1H),3.36(d,J=47.2Hz,2H),3.19(s,1H),2.90(s,2H),2.70(s,1H),1.88(s,3H).

[0787] Example 1-13: 4-(4-(((3-aminooxetane-3-yl)methyl)amino)thieno[2,3-d]pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Synthesis of -1,1-dioxide

[0788]

[0789] Step 1: Synthesis of 4-methoxybenzyl(3-((2-chlorothieno[2,3-d]pyrimidin-4-yl)amino)methyl)oxetan-3-yl)carbamate

[0790] 2,4-Dichlorothieno[2,3-d]pyrimidine (130 mg, 0.63 mmol) and MeOH (5 mL) were added to a 25 mL reaction bottle, followed by 4-methoxybenzyl(3-(aminomethyl)oxetane-3-yl)carbamate (170 mg, 0.63 mmol) and triethylamine (129 mg, 1.26 mmol). The reaction solution was reacted at room temperature for 3 h. After LCMS showed that the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (EA:PE=1:1) to obtain 4-methoxybenzyl(3-((2-chlorothieno[2,3-d]pyrimidin-4-yl)amino)methyl)oxetane-3-yl)carbamate (210 mg). ESI-MS (m / z): 435.08 [M+H] + .

[0791] Step 2: 4-(4-(((3-aminooxetan-3-yl)methyl)amino)thieno[2,3-d]pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Synthesis of -1,1-dioxide

[0792] 4-Methoxybenzyl (3-((2-chlorothieno[2,3-d]pyrimidin-4-yl)amino)methyl)oxetane-3-yl)carbamate (210 mg, 0.47 mmol), 2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -1,1-dioxide (92 mg, 0.47 mmol), p-toluenesulfonic acid monohydrate (89 mg, 0.47 mmol), n-butanol (3 mL), the reaction solution was reacted at 140 ° C for 2 hours in a microwave. LCMS showed that the reaction was complete. The pH was adjusted to 8-9, and the concentrate was concentrated to dryness under reduced pressure. The concentrate was purified by Prep-HPLC to obtain 4-(4-(((3-aminooxetane-3-yl)methyl)amino)thieno[2,3-d]pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -1,1-dioxide (8 mg). ESI-MS (m / z): 432.1 [M+H] + . 1 H NMR (600 MHz, CDCl 3)δ8.09(d,J=6.5Hz,1H),7.46(dd,J=11.6,6.1Hz,2H),7.35–7.24(m,3H),6.95(d,J=5.6Hz,1H),4.82(s,2H),3.99–3. 85(m,4H),3.78(d,J=12.2Hz,1H),3.54(d,J=15.7Hz,3H),3.48(s,1H),3.38(d,J=15.6Hz,1H),2.05(d,J=38.7Hz,2H).

[0793] Example 1-14: 4-(7-(((3-aminooxetane-3-yl)methyl)amino)thiazolo[5,4-d]pyrimidin-5-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Synthesis of -1,1-dioxide

[0794]

[0795] The synthesis method is the same as that of Example 1-13, except that 5,7-dichlorothiazolo[5,4-d]pyrimidine is used as the starting material instead of 2,4-dichlorothieno[2,3-d]pyrimidine to obtain 4-(7-(((3-aminooxetane-3-yl)methyl)amino)thiazolo[5,4-d]pyrimidin-5-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -1,1-dioxide (10 mg). ESI-MS (m / z): 433.1 [M+H] + . 1 H NMR (600 MHz, CDCl 3 )δ8.33(s,1H),8.09(d,J=7.5Hz,1H),7.55–7.44(m,3H),5.06(s,2H),4.25(s,2H),4.10(s,2H),3.83( d, J=11.3Hz, 1H), 3.60 (d, J=11.2Hz, 1H), 3.09 (d, J=12.2Hz, 1H), 2.73 (d, J=12.2Hz, 1H), 2.41 (s, 4H).

[0796] Example 1-15: 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Synthesis of -1,1-dioxide

[0797]

[0798] The synthesis method is the same as that of Example 1-13, except that 2,4-dichloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine is used as the starting material instead of 2,4-dichlorothieno[2,3-d]pyrimidine to obtain 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -1,1-dioxide (25 mg). ESI-MS (m / z): 429.2 [M+H] + . 1 H NMR (600MHz, CD 3 OD)δ8.03(d,J=7.6Hz,1H),7.53(dt,J=27.7,7.3Hz,2H),7.45(d,J=7.2Hz,1H),6.78(d,J=3.1Hz,1H),6.47(d,J=3.2Hz,1H),4.81(s ,2H),4.12(d,J=12.5Hz,1H),3.98–3.91(m,3H),3.53–3.43(m,6H),3.30(dd,J=4.2,2.8Hz,1H),3.27(s,1H),2.61(q,J=7.2Hz,1H).

[0799] Example 1-16: 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylpyrido[2,3-d]pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Synthesis of -1,1-dioxide

[0800]

[0801] The synthesis method is the same as that of Example 2-5, except that 2,4-dichloro-6-methylpyrido[2,3-d]pyrimidine is used as the starting material instead of 2,4-dichloro-6-methylquinazoline, and 2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine is used in step 2. -1,1-dioxide substituted 2,3,4,5-tetrahydropyrido[3,4-f][1,4]thiazepine 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylpyrido[2,3-d]pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -1,1-dioxide (30 mg). ESI-MS (m / z): 441.16 [M+H] + . 1H NMR (600MHz, CD 3 OD)δ8.52(s,1H),8.19(s,1H),8.01(d,J=52.4Hz,2H),7.60(s,1H),7.44(s,1H),5.2 3(s,2H),4.59(d,J=35.0Hz,5H),4.06(d,J=117.7Hz,3H),3.53(s,2H),2.38(s,3H).

[0802] Example 1-17: 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylpyrido[3,4-d]pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Synthesis of -1,1-dioxide

[0803]

[0804] The synthesis of the compound was the same as in Example 2-5, except that 2,4-dichloro-6-methylpyridone[3,4-d]pyrimidine was used in the first step to replace 2,4-dichloro-6-methylquinazoline, and 2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine was used in step 2. -1,1-dioxide substituted 2,3,4,5-tetrahydropyrido[3,4-f][1,4]thiazepine 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylpyrido[3,4-d]pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -1,1-dioxide (90 mg). ESI-MS (m / z): 441.16 [M+H] + , 1 H NMR (600 MHz, CDCl 3 )δ8.80(s,1H),8.04(d,J=7.6Hz,1H),7.78(s,1H),7.53(td,J=7.5,1.1Hz,1H),7.38(t,J=7.4Hz,1H), 7.07(d,J=12.4Hz,1H),6.16(s,1H),5.24(s,2H),4.54(s,5H),4.02(s,2H),3.48(s,2H),1.60(s,6H).

[0805] Example 1-18: 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methyl-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Synthesis of -1,1-dioxide

[0806]

[0807] The synthesis method of the compound is the same as that of Example 1-1, except that 2,4-dichloro-6-methylpyridone[3,4-d]pyrimidine is used in the first step instead of 2,4-dichloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine to obtain 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -1,1-dioxide (23 mg). ESI-MS (m / z): 445.19 [M+H] + , 1 HNMR (600MHz, CDCl 3 )δ8.02(d,J=7.7Hz,1H),7.68(d,J=7.4Hz,1H),7.49(t,J=7.4Hz,1H),7.36 (t,J=7.6Hz,1H),5.09(s,2H),4.89(s,1H),4.59–4.42(m,5H),3.85(d,J=24 .7Hz,2H),3.73(q,J=17.1Hz,2H),3.39(s,2H),2.97(dt,J=10.1,5.1Hz,1H) ,2.20(dd,J=14.8,3.3Hz,1H),2.04(d,J=8.1Hz,5H),1.24(d,J=6.3Hz,3H).

[0808] Example 1-22: 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-cyclopropyl-5,6,7,8-tetrahydropyridin[4,3-d]pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine Synthesis of -1,1-dioxide

[0809]

[0810] The synthesis method of the compound is the same as that of Example 1-1, except that 2,4-dichloro-6-cyclopropyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine is used in the first step to replace 2,4-dichloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine to obtain 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-cyclopropyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine -1,1-dioxide (23 mg). ESI-MS (m / z): 471.21 [M+H] + . 1 H NMR (600MHz, CD 3 OD)δ7.97(d,J=7.4Hz,1H),7.79(d,J=6.9Hz,1H),7.59(t,J=7.1Hz,1H),7.45(t,J=7.3Hz,1H),5.51(s,2H),5.10(s,2H),4.5 8(d,J=5.7Hz,2H),4.49(d,J=5.5Hz,2H),3.90(s,2H),3.44(s,4H),2.91(s,2H),2.63(s,2H),1.91(s,1H),0.74-0.33(m,4H).

[0811] The preparation methods of the target compounds of Examples 1-19 to 1-21, 1-23 to 1-26 are shown in the following table:

[0812]

[0813] Example 1-27: 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-(difluoromethyl)quinazolin-2-yl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]thiazepine Synthesis of -1,1-dioxide

[0814]

[0815] Step 1: Synthesis of 6-bromo-2-chloro-N-((3-(dibenzylamino)oxetan-3-yl)methyl)quinazolin-4-amine

[0816] 3-(Aminomethyl)-N,N-dibenzyloxetane-3-amine (3g, 10.6mmol) and methanol (50mL) were added to a 100mL reaction bottle, followed by 6-bromo-2,4-dichloroquinazoline (2.6g, 9.4mmol) and triethylamine (0.2g, 1.88mmol). The reaction solution was reacted at room temperature for 3 hours. LCMS showed that the reaction was complete, and the reaction solution was directly concentrated under reduced pressure, and then medium pressure was used to prepare 6-bromo-2-chloro-N-((3-(dibenzylamino)oxetane-3-yl)methyl)quinazoline-4-amine (2.7g). ESI-MS (m / z): 523.08 [M+H] + .

[0817] Step 2: Synthesis of 2-chloro-N-((3-(dibenzylamino)oxetan-3-yl)methyl)-6-(difluoromethyl)quinazolin-4-amine

[0818] In a 100 mL reaction bottle, add 6-bromo-2-chloro-N-((3-(dibenzylamino)oxetane-3-yl)methyl)quinazolin-4-amine (2.7 g, 5 mmol), Pd(dba) 2 (137.3 mg, 0.15 mmol), BrettPhos (80.5 mg, 0.15 mmol), CsF (1.5 g, 10 mmol), dioxane (15 mL, 0.33 M) and TMSCF 2 H (1.24 g, 10 mmol), argon replacement 3 times. The reaction solution was reacted at 100 ° C for 16 hours. LCMS showed that the reaction was complete, and the reaction solution was directly concentrated under reduced pressure, and then medium pressure was used to prepare 2-chloro-N-((3-(dibenzylamino)oxetane-3-yl)methyl)-6-(difluoromethyl)quinazolin-4-amine (0.5 g). ESI-MS (m / z): 495.17 [M+H] + .

[0819] Step 3: 2-(Dibenzo[b,f][1,4]azaoxe Synthesis of N-((3-(dibenzylamino)oxetane-3-yl)methyl)-6-(difluoromethyl)quinazolin-4-amine

[0820] In a 100 mL reaction bottle, 2-chloro-N-((3-(dibenzylamino)oxetane-3-yl)methyl)-6-(difluoromethyl)quinazolin-4-amine (217 mg, 0.44 mmol), 10,11-dihydrodibenzo[b,f][1,4]azepine (86 mg, 0.44 mmol), tridibenzylideneacetone dipalladium (160 mg, 0.17 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (100 mg, 0.17 mmol), sodium tert-butoxide (126 mg, 1.31 mmol), DMF (10 mL), the reaction system was stirred at N 2 The reaction was carried out at 100°C for 2 hours under protection. LCMS showed that the reaction was complete. After treatment, the reaction solution was filtered through diatomaceous earth and the filter cake was washed with ethyl acetate. The filtrate was collected and the solvent was concentrated to dryness under reduced pressure. The concentrate was purified by silica gel column (DCM: MeOH = 50:1) to obtain 2-(dibenzo[b,f][1,4]oxazine -10(11H)-yl)-N-((3-(dibenzylamino)oxetane-3-yl)methyl)-6-(difluoromethyl)quinazolin-4-amine (250 mg). ESI-MS (m / z): 656.24 [M+H] + .

[0821] Step 4: 4-(4-(((3-aminooxetan-3-yl)methyl)amino)-6-(difluoromethyl)quinazolin-2-yl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]thiazepine Synthesis of -1,1-dioxide

[0822] In a 25 mL reaction bottle, 2-(dibenzo[b,f][1,4]azepine -10(11H)-yl)-N-((3-(dibenzylamino)oxetane-3-yl)methyl)-6-(difluoromethyl)quinazolin-4-amine (64 mg, 0.097 mmol) was dissolved in methanol (5 ml) and 20% carbon-supported Pd(OH) was added 2 (40 mg), the reaction was allowed to react overnight at room temperature under a hydrogen atmosphere. LCMS showed that the reaction was complete, and after post-treatment, the reaction solution was filtered and the filtrate was collected. The filtrate was concentrated under reduced pressure and prepared by TLC (DCM: MeOH = 10: 1) to obtain 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-(difluoromethyl)quinazolin-2-yl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]thiazepine -1,1-dioxide (20 mg). ESI-MS (m / z): 489.18 [M+H] + .

[0823] Example 1-32: 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-(trifluoromethyl)quinazolin-2-yl)-1-((methyl-D3)imino)-2,3,4,5-tetrahydro-1H-1λ4 -Benzo[f][1,4]thiazepine -1-Oxide Synthesis

[0824]

[0825] The synthesis method is the same as that of Example 2-5, except that 2,4-dichloro-6-trifluoromethylquinazoline is used instead of 2,4-dichloro-6-methylquinazoline in step 1, and 1-((methyl-D3)imino)-2,3,4,5-tetrahydro-1H-1λ is used in step 2. 4 -Benzo[f][1,4]thiazepine -1-oxide substituted for 2,3,4,5-tetrahydropyrido[3,4-f][1,4]thiazepine -1,1-dioxide to obtain the target compound (19 mg). ESI-MS (m / z): 510.57 [M+H] + ; 1 H NMR (600MHz, CD 3 OD)δ8.32(s,1H),7.95(s,1H),7.88(d,J=5.9Hz,1H),7.67(d,J=8.0Hz,1H),7.58(s,1H),7.42(s,2H),5.51–5.39(m,1H),4.76(d,J=14. 5Hz,1H),4.63(d,J=5.9Hz,2H),4.55(s,1H),3.94(s,1H),3.62(d,J=14.1Hz,1H),3.49(s,1H),1.32–1.23(m,3H),0.89(t,J=6.6Hz,2H).

[0826] The preparation methods of the target compounds of Examples 1-28 to 1-31 and 1-33 are as follows:

[0827]

[0828]

[0829] Example 2-1: N-((3-aminooxetane-3-yl)methyl)-2-(dibenzo[b,f][1,4]azepine Synthesis of 1-(10(11H)-yl)-6-methylquinazolin-4-amine

[0830]

[0831] Step 1: Synthesis of 2-chloro-N-((3-(dibenzylamino)oxetane-3-yl)methyl)-6-methylquinazolin-4-amine

[0832] 3-(Aminomethyl)-N,N-dibenzyloxetane-3-amine (3g, 10.6mmol) and methanol (50mL) were added to a 100mL reaction bottle, followed by 2,4-dichloro-6-methylquinazoline (2g, 9.4mmol) and triethylamine (0.2g, 1.88mmol). The reaction solution was reacted at room temperature for 3 hours. LCMS showed that the reaction was complete, and the reaction solution was concentrated under reduced pressure, and then medium pressure preparation (PE:EA=3:1) was performed to obtain 2-chloro-N-((3-(dibenzylamino)oxetane-3-yl)methyl)-6-methylquinazoline-4-amine (2.4g, 5.2mmol). ESI-MS (m / z): 459.19 [M+H] + .

[0833] Step 2: 2-(Dibenzo[b,f][1,4]azaoxe Synthesis of N-((3-(dibenzylamino)oxetane-3-yl)methyl)-6-methylquinazolin-4-amine

[0834] In a 100 mL reaction bottle, 2-chloro-N-((3-(dibenzylamino)oxetane-3-yl)methyl)-6-methylquinazolin-4-amine (200 mg, 0.44 mmol), 10,11-dihydrodibenzo[b,f][1,4]azepine (86 mg, 0.44 mmol), tridibenzylideneacetone dipalladium (160 mg, 0.17 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (100 mg, 0.17 mmol), sodium tert-butoxide (126 mg, 1.31 mmol), DMF (10 mL), the reaction system was stirred at N 2 The reaction was carried out at 100°C for 2 hours under protection. LCMS showed that the reaction was complete. After treatment, the reaction solution was filtered through diatomaceous earth and the filter cake was washed with ethyl acetate. The filtrate was collected and the solvent was concentrated to dryness under reduced pressure. The concentrate was purified by silica gel column (DCM: MeOH = 50:1) to obtain 2-(dibenzo[b,f][1,4]oxazine -10(11H)-yl)-N-((3-(dibenzylamino)oxetane-3-yl)methyl)-6-methylquinazolin-4-amine (250 mg). ESI-MS (m / z): 620.29 [M+H] + .

[0835] Step 3: N-((3-aminooxetane-3-yl)methyl)-2-(dibenzo[b,f][1,4]azepine Synthesis of 1-(10(11H)-yl)-6-methylquinazolin-4-amine

[0836] In a 25 mL reaction bottle, 2-(dibenzo[b,f][1,4]azepine -10(11H)-yl)-N-((3-(dibenzylamino)oxetane-3-yl)methyl)-6-methylquinazolin-4-amine (60 mg, 0.097 mmol) was dissolved in methanol (5 ml) and 20% carbon-supported Pd(OH) was added 2 (40 mg), the reaction was allowed to react overnight at room temperature under a hydrogen atmosphere. LCMS showed that the reaction was complete, and after post-treatment, the reaction solution was filtered and the filtrate was collected. The filtrate was concentrated under reduced pressure and prepared by TLC (DCM: MeOH = 10: 1) to obtain N-((3-aminooxetane-3-yl)methyl)-2-(dibenzo[b, f][1,4]azepine -10(11H)-yl)-6-methylquinazolin-4-amine (20 mg). ESI-MS (m / z): 440.20 [M+H] + ; 1 H NMR (600 MHz, DMSO-d 6 )δ7.96(t,J=5.8Hz,1H),7.87(s,1H),7.48(d,J=7.7Hz,1H),7.37(t,J=9.2Hz,2H),7.26(d,J=4.2Hz,2H),7.23–7.13(m,3H),7.09(d ,J=8.1Hz,1H),7.02(t,J=7.4Hz,1H),5.24(s,2H),4.38(d,J=5.9Hz,2H),4.22(d,J=5.9Hz,2H),3.67(d,J=5.7Hz,2H),2.37(s,3H).

[0837] Example 2-2: 10-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-10,11-dihydrodibenzo[b,f][1,4]thiazepine Synthesis of -5,5-dioxide

[0838]

[0839] The synthesis method is the same as that of Example 2-1, except that 10,11-dihydrodibenzo[b,f][1,4]thiazepine is used in step 2 -5,5-dioxide substituted for 10,11-dihydrodibenzo[b,f][1,4]nitrazole , to obtain 10-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-10,11-dihydrodibenzo[b,f][1,4]thiazepine -5,5-dioxide (0.03 g, 0.1 mmol). ESI-MS (m / z): 488.34 [M+H] + ; 1 H NMR (600 MHz, DMSO-d 6 )δ2.37(s,3H),3.50(d,J=5.80Hz,2H),4.11(d,J=6.0Hz,2H),4.29(d,J=6.0H z,2H),5.60(s,2H),7.25(d,J=8.5Hz,1H),7.40(dd,J=8.5Hz,J=1.9Hz,1H),7 .52-7.55(m,1H),7.60(t,J=7.1Hz,1H),7.64(d,J=7.8Hz,1H),7.68-7.71(m, 2H),7.82-7.85(m,1H),7.88(s,1H),8.01-8.03(m,2H),8.09(d,J=9.3Hz,1H).

[0840] Example 2-3: 5-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine Synthesis of -1,1-dioxide.

[0841]

[0842] The synthesis method is the same as that of Example 2-1, except that 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine is used in step 2 -1,1-dioxide substituted for 10,11-dihydrodibenzo[b,f][1,4]nitrazole , to obtain 5-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine -1,1-dioxide (46 mg). ESI-MS (m / z): 440.37 [M+H] + ; 1 H NMR (600 MHz, MeOH-d 4)δ:2.44(s,3H),3.21(q,J=7.3Hz,2H),3.31-3.34(m,2H),3.37-3.44(m,2H),3.63-3.90(m,2H),4.37(s,2 H), 4.46 (s, 2H), 7.40-7.46 (m, 1H), 7.46-7.50 (m, 1H), 7.55-7.63 (m, 2H), 8.10 (dd, J = 7.8Hz, J = 1.6Hz, 1H).

[0843] Example 2-4: 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]thiazepine Synthesis of -1,1-dioxide

[0844]

[0845] Step 1: Synthesis of 2-chloro-N-((3-(dibenzylamino)oxetane-3-yl)methyl)-6-methylquinazolin-4-amine

[0846] 3-(Aminomethyl)-N, N-dibenzyloxetane-3-amine (517 mg, 1.83 mmol) and methanol (10 mL) were added to a 100 mL reaction bottle, followed by 2,4-dichloro-6-methylquinazoline (400 mg, 1.83 mmol) and triethylamine (270 mg, 2.67 mmol). The reaction solution was reacted at room temperature for 3 hours. LCMS showed that the reaction was complete, and after post-treatment, the reaction solution was concentrated to dryness under reduced pressure, and the concentrate was purified by silica gel column chromatography (DCM: MeOH = 30: 1) to give 2-chloro-N-((3-(dibenzylamino)oxetane-3-yl)methyl)-6-methylquinazoline-4-amine (110 mg). ESI-MS (m / z): 460.18 [M+H] + .

[0847] Step 2: 4-(4-(((3-(dibenzylamino)oxetan-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]thiazepine Synthesis of -1,1-dioxide

[0848] In a 25 mL reaction bottle, 2-chloro-N-((3-(dibenzylamino)oxetane-3-yl)methyl)-6-methylquinazolin-4-amine (110 mg, 0.24 mmol), 2,3,4,5-tetrahydropyrido[2,3-f][1,4]thiazepine were added in sequence. -1,1-dioxide (60 mg, 0.30 mmol), NH 4 Cl (3 mg, 0.06 mmol), ethanol (10 mL), the reaction solution was heated to 78 ° C for 30 hours. LCMS showed that the reaction was complete. After treatment, the reaction solution was concentrated to dryness under reduced pressure, and the concentrate was purified by column silica gel chromatography (DCM: MeOH = 30: 1 ~ 20: 1) to obtain 4-(4-(((3-(dibenzylamino)oxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]thiazepine -1,1-dioxide (60 mg). ESI-MS (m / z): 621.77 [M+H] + .

[0849] Step 3: 4-(4-(((3-aminooxetan-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]thiazepine Synthesis of -1,1-dioxide

[0850] In a 25 mL reaction bottle, 4-(4-(((3-(dibenzylamino)oxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]thiazepine -1,1-dioxide (60 mg, 0.096 mmol) was dissolved in methanol (5 ml) and 20% carbon-supported Pd(OH) 2 (40 mg), the reaction was allowed to react overnight at room temperature under a hydrogen atmosphere. LCMS showed that the reaction was complete, the filtrate was collected by filtration, concentrated under reduced pressure, and then prepared by TLC (DCM: MeOH = 10: 1) to obtain 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]thiazepine -1,1-dioxide (10 mg). ESI-MS (m / z): 441.52 [M+H] + ; 1 HNMR (600MHz, CD 3OD)δ8.76(d,J=4.9Hz,1H),8.36(d,J=7.8Hz,1H),7.74(dd,J=5.7,3.4Hz,1H),7.64(d,J=3.3Hz,1H),7.49(ddd,J=31.0,15.7, 11.4Hz, 3H), 5.38 (d, J = 19.5Hz, 2H), 4.76–4.49 (m, 6H), 4.22 (s, 2H), 4.13 (d, J = 3.2Hz, 2H), 3.07 (d, J = 7.3Hz, 2H), 2.42 (s, 3H).

[0851] Example 2-5: 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydropyrido[3,4-f][1,4]thiazepine Synthesis of -1,1-dioxide

[0852]

[0853] Step 1: Synthesis of 4-methoxybenzyl (3-(((2-chloro-6-methylquinazolin-4-yl)amino)methyl)oxetan-3-yl)carbamate

[0854] 4-methoxybenzyl (3-(aminomethyl) oxetane-3-yl) carbamate (260 mg, 0.98 mmol) and methanol (10 mL) were added to a 100 mL reaction bottle, followed by 2,4-dichloro-6-methylquinazoline (210 mg, 0.98 mmol) and triethylamine (200 mg, 1.98 mmol). The reaction solution was reacted at room temperature for 4 hours. LCMS showed that the reaction was complete, and after post-treatment, the reaction solution was directly concentrated to dryness under reduced pressure. The concentrate was purified by silica gel column (DCM: MeOH = 30: 1) to obtain 4-methoxybenzyl (3-(((2-chloro-6-methylquinazoline-4-yl) amino) methyl) oxetane-3-yl) carbamate (260 mg). ESI-MS (m / z): 443.90 [M+H] + .

[0855] Step 2: 4-methoxybenzyl (3-((2-(1,1-dioxo-2,3-dihydropyrido[3,4-f][1,4]thiazepine Synthesis of 4-(5H)-6-methylquinazolin-4-yl)amino)methyl)oxetane-3-yl)carbamate

[0856] In a 25 mL reaction bottle, 4-methoxybenzyl (3-(((2-chloro-6-methylquinazolin-4-yl)amino)methyl)oxetane-3-yl)carbamate (260 mg, 0.60 mmol), 2,3,4,5-tetrahydropyrido [3,4-f][1,4]thiazepine were added in sequence. -1,1-dioxide (120 mg, 0.60 mmol), NH 4 Cl (8 mg, 0.15 mmol), ethanol (10 mL), the reaction solution was heated to 78 ° C for 30 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (DCM: MeOH = 30: 1 ~ 20: 1) to obtain 4-methoxybenzyl (3-((2-(1,1-dioxo-2,3-dihydropyrido [3,4-f][1,4] thiazepine -4(5H)-yl)-6-methylquinazolin-4-yl)amino)methyl)oxetan-3-yl)carbamate (100 mg). ESI-MS (m / z): 605.68 [M+H] + .

[0857] Step 3: 4-(4-(((3-aminooxetan-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydropyrido[3,4-f][1,4]thiazepine Synthesis of -1,1-dioxide

[0858] In a 100 mL reaction flask, add 4-methoxybenzyl (3-((2-(1,1-dioxo-2,3-dihydropyrido [3,4-f][1,4]thiazepine -4(5H)-yl)-6-methylquinazolin-4-yl)amino)methyl)oxetane-3-yl)carbamate (100 mg, 0.16 mmol), DCM (4 mL), trifluoroacetic acid (1 mL), the reaction solution was stirred at room temperature for 1 h. LCMS showed that the reaction was complete, post-treatment, and concentrated to dryness under reduced pressure. The concentrate was dissolved in methanol, and ammonia methanol was added to adjust the pH of the solution to 10. The obtained solution was concentrated to dryness under reduced pressure and then prepared by liquid phase preparation to obtain 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydropyrido[3,4-f][1,4]thiazepine -1,1-dioxide (15 mg). ESI-MS (m / z): 441.52 [M+H] + ; 1 H NMR (600MHz, CD 3OD)δ9.01(s,1H),8.76(s,1H),7.96(d,J=4.8Hz,1H),7.73(s,1H),7.44(d,J=7.8Hz,1H),7.38(d,J=8.5Hz,1H),5.52(s,1H),5. 21(d,J=19.4Hz,2H),4.74–4.63(m,3H),4.59(d,J=6.8Hz,3H),4.12(s,2H),3.70–3.65(m,2H),3.09–3.05(m,2H),2.42(s,3H).

[0859] Example 2-6: 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydropyrido[4,3-f][1,4]thiazepine Synthesis of -1,1-dioxide

[0860]

[0861] The synthesis method is the same as that of Example 2-5, except that 2,3,4,5-tetrahydropyrido[4,3-f][1,4]thiazepine is used in step 2 1,1-Dioxide substituted 2,3,4,5-tetrahydropyrido[3,4-f][1,4]thiazepine -1,1-dioxide to give 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydropyrido[4,3-f][1,4]thiazepine 1,1-dioxide (20 mg). ESI-MS (m / z): 441.52 [M+H] + ; 1 H NMR (600MHz, CD 3 OD)δ8.98(s,1H),8.73(s,1H),7.93(d,J=4.8Hz,1H),7.70(s,1H),7.40(d,J=8.4Hz,1H),7.33(dd,J=9.8,6 .8Hz,1H),6.85–6.78(m,1H),5.19(s,2H),4.69–4.44(m,6H),4.06(s,2H),3.60–3.57(m,2H),2.39(s,5H).

[0862] Example 2-7: 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]thiazepine -1,1-dioxide

[0863]

[0864] The synthesis method is the same as that of Example 2-5, except that 2,3,4,5-tetrahydropyrido[3,2-f][1,4]thiazepine is used in step 2 -1,1-dioxide substituted 2,3,4,5-tetrahydropyrido[3,4-f][1,4]thiazepine -1,1-dioxide to give 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]thiazepine -1,1-dioxide (13 mg). ESI-MS (m / z): 441.52 [M+H] + ; 1 H NMR (600MHz, CD 3 OD)δ8.53(d,J=3.9Hz,1H),8.41(d,J=6.8Hz,1H),7.72(s,1H),7.65(dd,J=7.6,4.7Hz,1H),7.41(d,J=1.1Hz,1H),7.36(d,J=8.5Hz ,1H),5.51(s,1H),5.22(s,2H),4.71–4.52(m,6H),4.07(s,2H),3.65–3.57(m,2H),3.37(s,1H),3.07(q,J=7.3Hz,1H),2.41(s,3H).

[0865] Example 2-8: 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-4,5-dihydro-3H-spiro[benzo[f][1,4]thiazepine -2,1'-cyclopropane] 1,1-dioxide.

[0866]

[0867] The synthesis method is the same as that of Example 2-5, except that the raw material in the second step is 4,5-dihydro-3H-spiro[benzo[f][1,4]thiazepine -2,1'-cyclopropane]-1,1-dioxide instead of 2,3,4,5-tetrahydropyrido[3,4-f][1,4]thiazepine -1,1-dioxide to give 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-4,5-dihydro-3H-spiro[benzo[f][1,4]thiazepine -2,1'-cyclopropane]-1,1-dioxide (52 mg). ESI-MS (m / z): 466.35 [M+H] + ; 1 H NMR (600 MHz, MeOH-d 4 )δ:0.90(t,J=6.9Hz,2H),1.21-1.41(m,6H),2.38(s,3H),3.99-4.12(m,2H),4.55(d,J=6.3Hz,2H),4.63(d,J=6.2Hz,2H),7.26-7.30 (m,1H),7.38(d,J=8.5Hz,1H),7.42(t,J=7.6Hz,1H),7.61(t,J=7.5Hz,1H),7.68(s,1H),7.87(d,J=7.8Hz,1H),7.94(d,J=7.5Hz,1H).

[0868] Example 2-9: N-((3-aminooxetane-3-yl)methyl)-6-methyl-2-(1,3,4,6-tetrahydro-2H-azepine Synthesis of [5,4,3-cd]indol-2-yl)quinazolin-4-amine

[0869]

[0870] The synthesis method is the same as that of Example 2-5, except that 2,3,4,6-tetrahydro-1H-aza- [5,4,3-cd]indole substituted 2,3,4,5-tetrahydropyrido[3,4-f][1,4]thiazepine -1,1-dioxide to obtain N-((3-aminooxetane-3-yl)methyl)-6-methyl-2-(1,3,4,6-tetrahydro-2H-azepine [5,4,3-cd]indol-2-yl)quinazolin-4-amine (12 mg). ESI-MS (m / z): 415.51 [M+H] + ; 1 H NMR (600MHz, CD 3 OD)δ7.66(s,1H),7.37(s,2H),7.22(d,J=8.0Hz,1H),7.06(t,J=7.6Hz,1H),7.01(d,J=6.1Hz,2H),5.26(s ,2H),4.61(d,J=5.8Hz,2H),4.40(s,2H),4.27–4.15(m,2H),4.00(s,2H),3.31–3.27(m,2H),2.38(s,3H).

[0871] Example 2-10: N-((3-aminooxetane-3-yl)methyl)-2-(8-fluoro-1,3,4,6-tetrahydro-2H-azepine Synthesis of [5,4,3-cd]indol-2-yl)-6-methylquinazolin-4-amine

[0872]

[0873] The synthesis method is the same as that of Example 2-5, except that 8-fluoro-2,3,4,6-tetrahydro-1H-aza- [5,4,3-cd]indole substituted 2,3,4,5-tetrahydropyrido[3,4-f][1,4]thiazepine -1,1-dioxide to obtain N-((3-aminooxetane-3-yl)methyl)-2-(8-fluoro-1,3,4,6-tetrahydro-2H-azepine [5,4,3-cd]indol-2-yl)-6-methylquinazolin-4-amine (18 mg). ESI-MS (m / z): 433.50 [M+H] + ; 1 H NMR (600 MHz, CDCl 3 )δ8.03(s,1H),7.41(d,J=8.2Hz,1H),7.35(d,J=8.4Hz,1H),7.23(s,1H),6.96(s,1H),6.90(t,J=8.2Hz,2H),5.90(s,1 H), 5.34 (d, J = 8.3Hz, 4H), 4.63 (d, J = 6.3Hz, 2H), 4.50 (s, 2H), 4.35–4.18 (m, 2H), 3.99 (s, 2H), 3.35 (s, 2H), 2.39 (s, 3H).

[0874] Example 2-11: N-((3-aminooxetane-3-yl)methyl)-2-(4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -5(6H)-yl)-6-methylquinazolin-4-amine

[0875]

[0876] The synthesis method is the same as that of Example 2-5, except that 5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine is used in step 2. Substitute for 2,3,4,5-tetrahydropyrido[3,4-f][1,4]thiazepine 1,1-dioxide to obtain N-((3-aminooxetane-3-yl)methyl)-2-(4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -5(6H)-yl)-6-methylquinazolin-4-amine (48 mg). ESI-MS (m / z): 429.50 [M+H] + ; 1 H NMR (600MHz, CD 3 OD)δ9.01(s,1H),7.78(s,1H),7.72–7.70(m,2H),7.57(t,J=7.7Hz,2H),7.50–7.44(m,3H),7.42(s,1H),5. 49(s,1H),5.12(s,2H),4.96(s,2H),4.71(d,J=6.5Hz,2H),4.56(d,J=6.5Hz,2H),4.14(s,2H),2.43(s,3H).

[0877] Example 2-12: Synthesis of 1'-((4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)methyl]-6'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one

[0878]

[0879] Step 1: Synthesis of 6'-fluoro-1'-((6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0880] 6'-Fluorospiro[cyclopropane-1,3'-indolin]-2'-one (110 mg, 0.62 mmol) and anhydrous DMF (20 mL) were added to a 100 mL reaction bottle, followed by 60% NaH (88 mg, 2.2 mmol), stirred at room temperature for 0.5 h, and 2-(bromomethyl)-6-methylquinazolin-4(3H)-one (140 mg, 0.55 mmol) was added, and the reaction was continued at room temperature for 1 h. LCMS showed that the reaction was complete, and aqueous ammonium chloride was added and filtered to obtain 6'-fluoro-1'-((6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)spiro[cyclopropane-1,3'-indolin]-2'-one (160 mg). ESI-MS (m / z): 350.12 [M+H] + .

[0881] Step 2: Synthesis of 4-methoxybenzyl(3-((2-((6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)-6-methylquinazolin-4-yl)amino)methyl)oxetan-3-yl)carbamate

[0882] In a 100 mL reaction bottle, 6'-fluoro-1'-((6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)spiro[cyclopropane-1,3'-indolin]-2'-one (140 mg, 0.40 mmol), 4-methoxybenzyl(3-(aminomethyl)oxetane-3-yl)carbamate (130 mg, 0.49 mmol), BOP (230 mg, 0.52 mmol), DMF (5 mL), and triethylamine (130 mg, 1.28 mmol) were added in sequence, and the reaction solution was reacted at room temperature for 8 hours. LCMS showed that the reaction was complete, and ethyl acetate was added to dilute. The obtained organic phase was washed with water, and the organic phase was concentrated to dryness under reduced pressure. The concentrate was prepared by TLC (DCM: MeOH = 10: 1) to give 4-methoxybenzyl (3-((2-((6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)-6-methylquinazolin-4-yl)amino)methyl)oxetane-3-yl)carbamate (114 mg). ESI-MS (m / z): 598.65 [M+H] + .

[0883] Step 3: Synthesis of 1'-((4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)methyl]-6'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one

[0884] In a 100 mL reaction bottle, 4-methoxybenzyl (3-((2-((6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)-6-methylquinazolin-4-yl)amino)methyl)oxetan-3-yl)carbamate (110 mg, 0.16 mmol), DCM (4 mL), and trifluoroacetic acid (1 mL) were added in sequence, and the reaction solution was stirred at room temperature for 1 h. LCMS showed that the reaction was complete, and the mixture was concentrated to dryness under reduced pressure. The concentrate was dissolved in DCM and washed with saturated sodium bicarbonate. The organic phase was concentrated to dryness under reduced pressure. The concentrate was prepared by TLC (DCM: MeOH = 10: 1) to give 1'-((4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)methyl]-6'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one (74 mg). ESI-MS (m / z): 434.19 [M+H] + ; 1H NMR (600 MHz, CDCl 3 )δ7.72(d,J=8.5Hz,1H),7.57(dd,J=8.5,1.5Hz,1H),7.44(s,1H),6.78(dd,J=8.1,5.2Hz,1H),6.75–6.64(m,2H),6.19(t,J=5.1Hz,1H),5.2 1–5.02(m,2H),4.41(d,J=6.7Hz,2H),4.35(d,J=6.6Hz,2H),3.78(t,J=7.5Hz,2H),2.50(s,3H),1.83(q,J=4.0Hz,2H),1.57(q,J=4.0Hz,2H).

[0885] Example 2-13: Synthesis of 3-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)methyl-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one

[0886]

[0887] The synthesis method is the same as that of Example 2-12, except that 1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one is used as the starting material instead of 6'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one to obtain 3-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)methyl-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (10 mg). ESI-MS (m / z): 474.18 [M+H] + ; 1 H NMR (600 MHz, CDCl 3 )δ8.36(d,J=5.1Hz,1H),8.31(s,1H),7.70(d,J=8.5Hz,1H),7.57(d,J=8.5Hz,1H),7.43(s,1H),7.07(d,J=5.1Hz,1H ), 6.20 (s, 1H), 5.28 (s, 2H), 4.58 (d, J = 8.6Hz, 2H), 4.32 (dd, J = 14.6, 6.4Hz, 4H), 3.68 (d, J = 4.9Hz, 2H), 2.50 (s, 3H).

[0888] Example 2-14: 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-1-(methylimino)-2,3,4,5-tetrahydro-1H-1λ 4 -Benzo[f][1,4]thiazepine Synthesis of 1-oxide

[0889]

[0890] The synthesis method is the same as that of Example 2-5, except that 1-(methylimino)-2,3,4,5-tetrahydro-1H-1λ is used in step 2 4 -Benzo[f][1,4]thiazepine -1-oxide substituted for 2,3,4,5-tetrahydropyrido[3,4-f][1,4]thiazepine 1,1-dioxide to obtain 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-1-(methylimino)-2,3,4,5-tetrahydro-1H-1λ 4 -Benzo[f][1,4]thiazepine -1-oxide (52 mg). ESI-MS (m / z): 453.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.85(dd,J=20.1,7.2Hz,4H),7.56(t,J=7.1Hz,1H),7.46(s,1H),7.36(d,J=8.2Hz,1H),7.22(s,1H),5.31(s,1H),4.97(s,1H),4.6 9(d,J=13.7Hz,1H),4.50(s,2H),4.37(s,2H),3.91(d,J=42.8Hz,3H),3.68(d,J=58.2Hz,2H),2.92(s,2H),2.44(s,3H),2.34(s,3H).

[0891] Example 2-15: N-((3-aminooxetane-3-yl)methyl)-2-(4H-benzo[f]imidazo[1,2-a][1,4]diazepine -5(6H)-yl)-6-methylquinazolin-4-amine

[0892]

[0893] The synthesis method is the same as that of Example 2-5, except that 5,6-dihydro-4H-benzo[f]imidazole[1,2-a][1,4]diazepine is used in step 2. Substitute for 2,3,4,5-tetrahydropyrido[3,4-f][1,4]thiazepine -1,1-dioxide to obtain N-((3-aminooxetane-3-yl)methyl)-2-(4H-benzo[f]imidazo[1,2-a][1,4]diazepine -5(6H)-yl)-6-methylquinazolin-4-amine (22 mg). ESI-MS (m / z): 428.21 [M+H] + .

[0894] Example 2-16: 1-(4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-1-oxido-2,3,4,5-tetrahydro-1λ 4 -Benzo[f][1,4]thiazepine Synthesis of urea

[0895]

[0896] The synthesis method is the same as that of Example 2-5, except that in step 2, N-(1-oxy-2,3,4,5-tetrahydro-1λ 4 -Benzo[f][1,4]thiazepine -1-ylidene) cyanamide instead of 2,3,4,5-tetrahydropyrido[3,4-f][1,4]thiazepine -1,1-dioxide to obtain 1-(4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-1-oxido-2,3,4,5-tetrahydro-1λ 4 -Benzo[f][1,4]thiazepine -1-ylidene) urea (43 mg). ESI-MS (m / z): 482.18 [M+H] + . 1 HNMR (600 MHz, DMSO-d 6 )δ8.07(s,1H),7.93(s,1H),7.89–7.80(m,2H),7.60(t,J=7.2Hz,1H), 7.49(s,1H),7.39(s,1H),7.31(s,1H),6.60(s,1H),6.14(s,1H),5.34( s,1H),5.08(s,1H),4.87(s,1H),4.57(d,J=5.9Hz,2H),4.44(s,2H),4. 07(d,J=39.7Hz,3H),3.84(s,1H),3.52(s,1H),2.38(d,J=24.8Hz,3H).

[0897] Example 2-17: 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-4,5-dihydro-2H-spiro[benzo[f][1,4]thiazepine Synthesis of 3,1'-cyclopropane]-1-oxide

[0898]

[0899] Step 1: 4-methoxybenzyl (3-(((6-methyl-2-(2H-spiro[benzo[f][1,4]thiazepine) Synthesis of [3,1'-cyclopropane]-4(5H)-yl)quinazolin-4-yl)amino)methyl)oxetane-3-yl)carbamate

[0900] 4-Methoxybenzyl (3-((2-chloro-6-methylquinazolin-4-yl)amino)methyl)oxetane-3-yl)carbamate (400 mg, 0.90 mmol) and EtOH (8 mL) were added to a 20 mL sealed tube, and then 4,5-dihydro-2H-spiro[benzo[f][1,4]thiazepine -3,1'-cyclopropane] (173 mg, 0.90 mmol) and ammonium chloride (477 mg, 9 mmol). The reaction solution was reacted at 120 ° C overnight. The reaction solution was concentrated to dryness under reduced pressure, and the concentrate was extracted with ethyl acetate and sodium bicarbonate aqueous solution. The organic phase was collected and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by column chromatography (DCM: MeOH = 30: 1) to obtain 4-methoxybenzyl (3-(((6-methyl-2-(2H-spiro[benzo[f][1,4]thiazepine) -3,1'-cyclopropane]-4(5H)-yl)quinazolin-4-yl)amino)methyl)oxetane-3-yl)carbamate (60 mg). ESI-MS (m / z): 598.24 [M+H] + .

[0901] Step 2: 4-methoxybenzyl (3-(((6-methyl-2-(1-oxido-2H-spiro[benzo[f][1,4]thiazepine) Synthesis of [3,1'-cyclopropane]-4(5H)-yl)quinazolin-4-yl)amino)methyl)oxetane-3-yl)carbamate

[0902] In a 25 mL reaction flask, add 4-methoxybenzyl (3-(((6-methyl-2-(2H-spiro[benzo[f][1,4]thiazepine) -3,1'-cyclopropane]-4(5H)-yl)quinazolin-4-yl)amino)methyl)oxetane-3-yl)carbamate (30 mg, 0.05 mmol) and dichloromethane (10 mL), slowly add m-CPBA (5.2 mg, 0.03 mmol) at 0°C, and react at room temperature for 1 h. LCMS detected that the raw material remained, and then m-CPBA (5.2 mg, 0.03 mmol) was added, and the reaction continued at room temperature for 1 h. LCMS detected that the reaction was complete, and the mixture was washed with a saturated aqueous sodium bicarbonate solution, washed with sodium thiosulfate, and then washed with an aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product of 4-methoxybenzyl (3-(((6-methyl-2-(1-oxidized-2H-spiro[benzo[f][1,4]thiazepine -3,1'-cyclopropane]-4(5H)-yl)quinazolin-4-yl)amino)methyl)oxetane-3-yl)carbamate (30 mg). ESI-MS (m / z): 614.24 [M+H] + .

[0903] Step 3: 4-(4-(((3-aminooxetan-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-4,5-dihydro-2H-spiro[benzo[f][1,4]thiazepine Synthesis of 3,1'-cyclopropane]-1-oxide

[0904] In a 100 mL reaction bottle, add 4-methoxybenzyl (3-(((6-methyl-2-(1-oxido-2H-spiro[benzo[f][1,4]thiazepine) -3,1'-cyclopropane]-4(5H)-yl)quinazolin-4-yl)amino)methyl)oxetane-3-yl)carbamate (30 mg, 0.049 mmol), DCM (4 mL), trifluoroacetic acid (1 mL), the reaction solution was stirred at room temperature for 1 h. LCMS showed that the reaction was complete, post-treatment, concentrated to dryness under reduced pressure, the concentrate was dissolved in DCM, washed with saturated sodium bicarbonate, the organic phase was concentrated to dryness under reduced pressure, and the concentrate was prepared by TLC (DCM: MeOH = 10: 1) to give 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-4,5-dihydro-2H-spiro[benzo[f][1,4]thiazepine -3,1'-cyclopropane]-1-oxide (8 mg). ESI-MS (m / z): 450.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6)δ7.84–7.77(m,2H),7.64(s,2H),7.43(t,J=7.4Hz,1H),7.38(d,J=8.6Hz, 1H),7.34(s,1H),7.29(d,J=8.3Hz,1H),5.24(s,1H),4.48(s,2H),4.31(d, J=27.6Hz,3H),4.09(d,J=5.2Hz,1H),3.90(s,2H),3.62(s,1H),3.17(d,J= 5.1Hz, 1H), 3.03 (s, 1H), 2.35 (s, 3H), 1.33 (d, J = 42.3Hz, 2H), 1.13 (s, 2H).

[0905] Example 2-18: 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-4,5-dihydro-2H-spiro[benzo[f][1,4]thiazepine Synthesis of 3,1'-cyclopropane-1,1-dioxide

[0906]

[0907] Step 1: 4-methoxybenzyl (3-(((6-methyl-2-(2H-spiro[benzo[f][1,4]thiazepine) Synthesis of [3,1'-cyclopropane]-4(5H)-yl)quinazolin-4-yl)amino)methyl)oxetane-3-yl)carbamate

[0908] 4-Methoxybenzyl (3-((2-chloro-6-methylquinazolin-4-yl)amino)methyl)oxetane-3-yl)carbamate (400 mg, 0.90 mmol) and EtOH (8 mL) were added to a 20 mL sealed tube, followed by the addition of 4,5-dihydro-2H-spiro[benzo[f][1,4]thiazepine -3,1'-cyclopropane] (173 mg, 0.90 mmol) and ammonium chloride (477 mg, 9 mmol). The reaction solution was reacted at 120 ° C overnight. The reaction solution was concentrated to dryness under reduced pressure, and the concentrate was extracted with ethyl acetate and sodium bicarbonate aqueous solution. The organic phase was collected and washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by column chromatography (DCM: MeOH = 30: 1) to obtain 4-methoxybenzyl (3-(((6-methyl-2-(2H-spiro[benzo[f][1,4]thiazepine) -3,1'-cyclopropane]-4(5H)-yl)quinazolin-4-yl)amino)methyl)oxetane-3-yl)carbamate (60 mg). ESI-MS (m / z): 598.24 [M+H]+ .

[0909] Step 2: 4-methoxybenzyl (3-(((2-(1,1-dioxido-2H-spiro[benzo[f][1,4]thiazepine Synthesis of [3,1'-cyclopropane]-4(5H)-yl)-6-methylquinazolin-4-yl)amino)methyl)oxetane-3-yl)carbamate

[0910] In a 25 mL reaction flask, add 4-methoxybenzyl (3-(((6-methyl-2-(2H-spiro[benzo[f][1,4]thiazepine) -3,1'-cyclopropane]-4(5H)-yl)quinazolin-4-yl)amino)methyl)oxetane-3-yl)carbamate (30 mg, 0.05 mmol) and dichloromethane (10 mL), slowly add m-CPBA (5.2 mg, 0.03 mmol) at 0°C, and react at room temperature for 1 h. LCMS detected that the raw material was remaining, and then m-CPBA (5.2 mg, 0.03 mmol) was added, and the reaction continued at room temperature for 1 h. Subsequently, m-CPBA (20.4 mg, 0.12 mmol) was added. LCMS detected that the reaction was complete, and the mixture was washed with a saturated aqueous sodium bicarbonate solution, washed with sodium thiosulfate, and then washed with an aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product of 4-methoxybenzyl (3-(((2-(1,1-dioxido-2H-spiro[benzo[f][1,4]thiazepine -3,1'-cyclopropane]-4(5H)-yl)-6-methylquinazolin-4-yl)amino)methyl)oxetane-3-yl)carbamate (30 mg). ESI-MS (m / z): 630.23 [M+H] + .

[0911] Step 3: 4-(4-(((3-aminooxetan-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-4,5-dihydro-2H-spiro[benzo[f][1,4]thiazepine Synthesis of 3,1'-cyclopropane-1,1-dioxide

[0912] In a 100 mL reaction flask, 4-methoxybenzyl (3-(((2-(1,1-dioxido-2H-spiro[benzo[f][1,4]thiazepine) -3,1'-cyclopropane]-4(5H)-yl)-6-methylquinazolin-4-yl)amino)methyl)oxetane-3-yl)carbamate (30 mg, 0.048 mmol), DCM (4 mL), trifluoroacetic acid (1 mL), the reaction solution was stirred at room temperature for 1 h. LCMS showed that the reaction was complete, post-treatment, concentrated to dryness under reduced pressure, the concentrate was dissolved in DCM, washed with saturated sodium bicarbonate, the organic phase was concentrated to dryness under reduced pressure, and the concentrate was prepared by TLC (DCM: MeOH = 10: 1) to give 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-4,5-dihydro-2H-spiro[benzo[f][1,4]thiazepine -3,1'-cyclopropane]-1,1-dioxide (7 mg). ESI-MS (m / z): 466.18 [M+H] + .

[0913] Example 2-19: N-((3-aminooxetane-3-yl)methyl)-6-methyl-2-(1-(methylsulfonyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine Synthesis of quinazoline-4-yl)

[0914]

[0915] The synthesis method is the same as that of Example 2-5, except that the raw material in step 2 is 1-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine Substitute for 2,3,4,5-tetrahydropyrido[3,4-f][1,4]thiazepine -1,1-dioxide to obtain N-((3-aminooxetane-3-yl)methyl)-6-methyl-2-(1-(methylsulfonyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine -4-yl)quinazolin-4-amine (10 mg). ESI-MS (m / z): 469.58 [M+H] + .

[0916] Example 2-20: N-((3-aminooxetane-3-yl)methyl)-2-(8-chloro-5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepine Synthesis of 6-methylquinazolin-4-amine

[0917]

[0918] Step 1: 8-Chloro-5-methyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine Synthesis of -1-ketone

[0919] Add 8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine to a 50 mL reaction flask. -1-ketone (500 mg, 2.04 mmol) and DMF (10 mL), Cs 2 CO 3 (700 mg, 2.15 mmol) and MeI (305 mg, 2.15 mmol), and then reacted at room temperature for 3 hours. LCMS detection showed that the reaction was complete, diluted with water, and extracted with ethyl acetate (30 mL×3), and the concentrate was purified by column chromatography (DCM:MeOH=50:1) to obtain 8-chloro-5-methyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine -1-ketone (528 mg). ESI-MS (m / z): 258.06 / 260.06 [M+H] + .

[0920] Step 2: 8-Chloro-5-methyl-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine Synthesis

[0921] Add 8-chloro-5-methyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine to a 50 mL reaction bottle. -1-ketone (528 mg, 2.04 mmol) and THF (20 mL), lithium aluminum hydride (260 mg, 6.85 mmol) was added under stirring at 0°C, and then reacted at room temperature for 5 hours. LCMS detection showed that the reaction was complete, and water (0.26 mL), 15% NaOH (0.26 mL), and water (0.78 mL) were slowly added, and then anhydrous sodium sulfate was added for drying, filtration, and concentration under reduced pressure to obtain 8-chloro-5-methyl-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine (280mg). ESI-MS(m / z):245.08 / 247.08[M+H] + .

[0922] Step 3: 2-(8-chloro-5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepine Synthesis of N-((3-(dibenzylamino)oxetane-3-yl)methyl)-6-methylquinazolin-4-amine

[0923] In a 25 mL reaction bottle, 2-chloro-N-((3-(dibenzylamino)oxetane-3-yl)methyl)-6-methylquinazolin-4-amine (179 mg, 0.39 mmol), 8-chloro-5-methyl-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine were added in sequence. (80 mg, 0.33 mmol), tridibenzylideneacetone dipalladium (121 mg, 0.13 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (76 mg, 0.13 mmol), sodium tert-butoxide (95 mg, 0.99 mmol), DMF (10 mL), the reaction system was reacted at 100 ° C for 2 hours in a nitrogen atmosphere. LCMS showed that the reaction was complete. After treatment, the reaction solution was filtered through diatomaceous earth and the filter cake was washed with ethyl acetate. The filtrate was collected and the solvent was concentrated to dryness under reduced pressure. The concentrate was purified by silica gel column (DCM: MeOH = 50: 1) to obtain 2-(8-chloro-5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepine -10-yl)-N-((3-(dibenzylamino)oxetane-3-yl)methyl)-6-methylquinazolin-4-amine (85 mg). ESI-MS (m / z): 667.29 / 668.29

[0924] [M+H] + .

[0925] Step 4: N-((3-aminooxetane-3-yl)methyl)-2-(8-chloro-5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepine Synthesis of 6-methylquinazolin-4-amine

[0926] Add 2-(8-chloro-5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepine) into a 25 mL reaction bottle. -10-yl)-N-((3-(dibenzylamino)oxetane-3-yl)methyl)-6-methylquinazolin-4-amine (20 g, 0.03 mmol) was dissolved in methanol (5 ml) and 20% carbon-supported Pd(OH) 2 (10 mg), the reaction was allowed to react overnight at room temperature under a hydrogen atmosphere. LCMS showed that the reaction was complete, the reaction solution was filtered, the filtrate was collected, the filtrate was concentrated under reduced pressure and purified by thin layer chromatography (DCM: MeOH = 10: 1) to obtain N-((3-aminooxetane-3-yl)methyl)-2-(8-chloro-5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepine -10-yl)-6-methylquinazolin-4-amine (3 mg), ESI-MS (m / z): 487.19 / 489.19 [M+H] + .

[0927] Example 2-21: N-((3-aminooxetane-3-yl)methyl)-6-methyl-2-(5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepine Synthesis of quinazoline-4-amine

[0928]

[0929] Add 2-(8-chloro-5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepine) into a 25 mL reaction bottle. -10-yl)-N-((3-(dibenzylamino)oxetane-3-yl)methyl)-6-methylquinazolin-4-amine (60 mg, 0.09 mmol) was dissolved in trifluoroethanol (5 ml) and 20% carbon-supported Pd(OH) 2 (30 mg), the reaction was allowed to react overnight at room temperature under a hydrogen atmosphere. LCMS showed that the reaction was complete, and after post-treatment, the reaction solution was filtered and the filtrate was collected. The filtrate was concentrated under reduced pressure and purified by thin layer chromatography (DCM: MeOH = 10: 1) to obtain N-((3-aminooxetane-3-yl)methyl)-6-methyl-2-(5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepine -10-yl)quinazolin-4-amine (13 mg). ESI-MS (m / z): 453.23 [M+H] + , 1 H NMR (600 MHz, CDCl 3 )δ7.55(d,J=7.7Hz,1H),7.44(dd,J=7.8,1.4Hz,

[0930] 1H),7.41–7.35(m,3H),7.32(dd,J=12.9,7.8Hz,3H),7.18–7.13(m,1H),6.87–6.79(m,2H),5.98(s,1H),4.43(d ,J=6.5Hz,2H),4.30(t,J=7.6Hz,2H),3.62(d,J=5.1Hz,2H),3.04(s,2H),2.45–2.39(m,3H),1.36–1.22(m,5H).

[0931] Example 2-22: N-((3-aminooxetane-3-yl)methyl)-2-(3,4-dihydronaphtho[1,8-cd]azepine Synthesis of 2-(1H)-yl)-6-methylquinazolin-4-amine

[0932]

[0933] The synthesis method of the compound is the same as that of Example 2-5, except that 1,2,3,4-tetrahydronaphtho[1,8-cd]azepine is used in the second step. Substitute for 2,3,4,5-tetrahydropyrido[3,4-f][1,4]thiazepine -1,1-dioxide to obtain N-((3-aminooxetane-3-yl)methyl)-2-(3,4-dihydronaphtho[1,8-cd]azepine -2(1H)-yl)-6-methylquinazolin-4-amine (35 mg). ESI-MS (m / z): 426.22 [M+H] + , 1 H NMR (600MHz, CD 3 OD)δ7.58(t,J=6.6Hz,1H),7.57–7.53(m,2H),7.52(d,J=6.9Hz,1H),7.2 8(dd,J=14.7,7.3Hz,1H),7.25(s,1H),7.22(d,J=8.7Hz,1H),7.21–7.18 (m,2H),5.33(s,2H),4.87(s,4H),4.64(d,J=6.2Hz,2H),4.50(d,J=6.2H z, 2H), 4.06–4.00 (m, 4H), 3.48 (t, J = 6.1Hz, 2H), 2.26 (d, J = 13.1Hz, 3H).

[0934] Example 2-23: 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-1-imino-2,3,4,5-tetrahydro-1H-1λ 4 -Benzo[f][1,4]thiazepine Synthesis of -1-oxide

[0935]

[0936] The synthesis method is the same as that of Example 2-5, except that 1-imino-2,3,4,5-tetrahydro-1H-1λ is used in step 2 4 -Benzo[f][1,4]thiazepine -1-oxide substituted for 2,3,4,5-tetrahydropyrido[3,4-f][1,4]thiazepine -1,1-dioxide to give 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-1-imino-2,3,4,5-tetrahydro-1H-1λ 4 -Benzo[f][1,4]thiazepine -1-oxide (32 mg). ESI-MS (m / z): 439.18 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.94(d,J=12.9Hz,1H),7.86–7.76(m,3H),7.52(t,J=6.9Hz,1H),7.42(s,1H),7.36(d,J=7.9Hz,1H),7.23(s,1H),5.08( s,2H),4.62(s,1H),4.49(s,2H),4.36(s,3H),3.89(d,J=95.3Hz,3H),3.38(s,1H),2.89(s,1H),2.73(s,1H),2.34(s,3H).

[0937] Example 2-24: 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-1-((deuterated methyl)imino)-2,3,4,5-tetrahydro-1H-1λ 4 -Benzo[f][1,4]thiazepine Synthesis of -1-oxide

[0938]

[0939] The synthesis method is the same as that of Example 2-5, except that 1-((deuterated methyl)imino)-2,3,4,5-tetrahydro-1H-1λ is used in step 2. 4 -Benzo[f][1,4]thiazepine -1-oxide substituted for 2,3,4,5-tetrahydropyrido[3,4-f][1,4]thiazepine -1,1-dioxide to give 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-1-((deuterated methyl)imino)-2,3,4,5-tetrahydro-1H-1λ 4 -Benzo[f][1,4]thiazepine -1-oxide (32 mg). ESI-MS (m / z): 456.22 [M+H] + . 1 H NMR (600MHz, CD 3OD)δ7.97(d,J=7.7Hz,1H),7.89(d,J=7.4Hz,1H),7.69(s,1H),7.58(t,J=7.3Hz,1H),7.44(t ,J=7.6Hz,1H),7.38(d,J=8.5Hz,1H),7.32(d,J=8.5Hz,1H),5.53–5.39(m,1H),4.78(d,J=14 .9Hz,1H),4.67(d,J=5.7Hz,1H),4.64(d,J=6.2Hz,1H),4.55(s,2H),4.12(d,J=12.0Hz,1H), 4.06–3.93(m,2H),3.62(d,J=14.7Hz,1H),3.52(t,J=12.5Hz,1H),3.33(s,2H),2.38(s,3H).

[0940] Example 2-25: 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-1-(oxetane-3-ylimino)-2,3,4,5-tetrahydro-1H-1λ 4 -Benzo[f][1,4]thiazepine Synthesis of -1-oxide

[0941]

[0942] The synthesis method is the same as that of Example 2-5, except that 1-(oxacyclobutylimino)-2,3,4,5-tetrahydro-1H-1λ is used in step 2. 4 -Benzo[f][1,4]thiazepine -1-oxide substituted 2,3,4,5-tetrahydropyrido[3,4-f][1,4]thiazepine -1,1-dioxide to give 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-1-(oxetane-3-ylimino)-2,3,4,5-tetrahydro-1H-1λ 4 -Benzo[f][1,4]thiazepine -1-oxide (32 mg). ESI-MS (m / z): 495.21 [M+H] + . 1 H NMR (600 MHz, Methanol-d 4)δ7.99(dd,J=7.9,1.3Hz,1H),7.92–7.88(m,1H),7.71–7.68(m,1H),7.64–7.58(m,1H),7.48(td,J= 7.7,1.3Hz,1H),7.38(dd,J=8.6,1.9Hz,1H),7.32(d,J=8.6Hz,1H),5.45(d,J=15.2Hz,1H),5.08(s,1 H),4.98–4.84(m,2H),4.83–4.73(m,2H),4.64(dd,J=20.2,6.3Hz,2H),4.53(dd,J=6.3,3.5Hz,2H), 4.05(dd,J=63.1,12.8Hz,2H),3.68–3.48(m,2H),3.24–2.86(m,2H),2.73–2.60(m,1H),2.37(s,3H).

[0943] Example 2-26: 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-1-(cyclopropylimino)-2,3,4,5-tetrahydro-1H-1λ 4 -Benzo[f][1,4]thiazepine Synthesis of -1-oxide

[0944]

[0945] The synthesis method is the same as that of Example 2-5, except that 1-(cyclopropylimino)-2,3,4,5-tetrahydro-1H-1λ is used in step 2. 4 -Benzo[f][1,4]thiazepine -1-oxide substituted 2,3,4,5-tetrahydropyrido[3,4-f][1,4]thiazepine -1,1-dioxide to give 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-1-(cyclopropylimino)-2,3,4,5-tetrahydro-1H-1λ 4 -Benzo[f][1,4]thiazepine -1-oxide (80 mg). ESI-MS (m / z): 479.45 [M+H] + ; 1 H NMR (600 MHz, Methanol-d 4)δ8.03(d,J=7.9Hz,1H),7.87(d,J=7.9Hz,1H),7.70(s,1H),7.59(t,J=7.5Hz,1H),7 .45(t,J=7.1Hz,1H),7.39(dd,J=8.6,1.9Hz,1H),7.33(d,J=8.5Hz,1H),4.82(d,J=1 5.1Hz,2H),4.66(dd,J=20.6,6.4Hz,2H),4.57–4.53(m,2H),4.19–3.92(m,4H),3.63 –3.43(m,2H),2.38(s,3H),2.38–2.32(m,1H),0.55–0.39(m,2H),0.29–0.18(m,2H).

[0946] Example 2-29: 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-1-((trifluoromethyl)imino)-2,3,4,5-tetrahydro-1H-1λ 4 -Benzo[f][1,4]thiazepine Synthesis of -1-oxide

[0947]

[0948] Step 1: 3-(((6-methyl-2-(1-oxido-1-((trifluoromethyl)imine)-1,2,3,5-tetrahydro-4H-1λ 4 -Benzo[f][1,4]thiazepine Synthesis of (4-methoxy)benzyl (4-methoxy)quinazoline-4-yl)amino)methyl)oxetane-3-ylcarbamate

[0949] In a 25 mL flask, add 3-(((2-(1-imine-1-oxido)-1,2,3,5-tetrahydro-4H-1λ 4 -Benzo[f][1,4]thiazepine (4-methoxy)benzyl (6-methylquinazoline-4-yl)amino)methyl)oxetan-3-ylcarbamate (120 mg, 0.2 mmol), TMSCF 3 (142 mg, 1.0 mmol), Ag 2 CO 3(11 mg, 0.04 mmol), 1,10-phenanthroline (14 mg, 0.08 mmol) and 1,4-dioxane (4.0 mL), oxygen was replaced 3 times, and stirred at 60 ° C for 12 h. LCMS detection showed that the reaction was complete, the solvent was removed, and thin layer chromatography (DCM: MeOH = 10: 1) was used for purification to obtain 3-(((6-methyl-2-(1-oxido-1-((trifluoromethyl)imine)-1,2,3,5-tetrahydro-4H-1λ 4 -Benzo[f][1,4]thiazepine (4-methoxy)benzyl (4-yl)quinazolin-4-yl)amino)methyl)oxetan-3-ylcarbamate (28 mg).

[0950] Step 2: 4-(4-(((3-aminooxetan-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-1-((trifluoromethyl)imino)-2,3,4,5-tetrahydro-1H-1λ 4 -Benzo[f][1,4]thiazepine Synthesis of -1-oxide

[0951] In a 25 mL flask, add 3-(((6-methyl-2-(1-oxido-1-((trifluoromethyl)imine)-1,2,3,5-tetrahydro-4H-1λ 4 -Benzo[f][1,4]thiazepine To the mixture of (4-methoxy)benzyl)quinazolin-4-yl)amino)methyl)oxetane-3-ylcarbamate (134 mg, 0.2 mmol) and DCM (8 mL) was stirred and TFA (1 mL) was added, and the mixture was stirred at room temperature for 2 h. LCMS detection showed that the reaction was complete, and the solvent was removed by rotary evaporation. TLC chromatography (DCM: MeOH = 10:1) was used for purification to obtain 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-1-((trifluoromethyl)imino)-2,3,4,5-tetrahydro-1H-1λ 4 -Benzo[f][1,4]thiazepine -1-oxide (20 mg). ESI-MS (m / z): 507.17 [M+H] + .

[0952] Example 2-30: 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-1-((trifluoromethylthio)imin...

Claims

1. A compound as represented by formula (I) or its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt, which has the following structure: in, Cy1 is independently selected from the group consisting of absence, C 4-12 Carbocyclic group, 4-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl; when Cy1 is absent, R 1 Connected to the heteroaromatic ring, R 1 are independently selected from: hydrogen, deuterium, halogen, oxo, hydroxy, amino, nitro, cyano, -R a1 、-OR a1 、-SR a1 、-N(R a1 )2, -S(O)2R a1 、-S(O)2N(R a1 )2. -S(O)R a1 、-S(O)(NR a1 )R a1 、-S(O)N(R a1 )2、-P(O)(OR a1 )2、-P(O)(N(R a1 )2)2、-SC(R a1 )3. -C(R a1 )2OR a1 ,-C(R a1 )2N(R a1 )2. -C(O)R a1 、-C(O)OR a1 、-C(O)N(R a1 )2. -C(O)OR a1 -OC(O)R a1 、-C(O)N(R a1 )OR a1 、-OC(O)R a1 、-OC(O)N(R a1 )2、-N(R a1 )C(O)OR a1 、-N(R a1 )C(O)R a1 、-N(R a1 )C(O)N(R a1 )2、-N(R a1 )S(O)2R a1 、-C(S)R a1 、-C(S)OR a1 、-C(S)N(R a1 )2. -C(S)N(R a1 )OR a1 、-OC(S)R a1 、-OC(S)N(R a1 )2; R a1 Independently selected from: hydrogen, deuterium, C 1-6 Alkyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, optionally substituted with one or more R a2 replace; or two R attached to the same atom a1 Together with the atoms to which they are attached, they form deuterated, halogen, oxo, hydroxyl, amino, nitro, cyano, thiol, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl, one or more arbitrarily substituted C 3-12 Carbocyclyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl; R a2 are independently selected from: deuterium, halogen, oxo, hydroxyl, amino, nitro, cyano, thiol, C 1-6 Alkyl, C 1-6 Alkoxy; X 1 Independently selected from CR 2 or N; X is independently selected from CR 2 or N; R 2 are independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano, -OR b1 、-SR b1 、-N(R b1 )2, -S(O)2R b1 、-S(O)2N(R b1 )2. -S(O)R b1 、-S(O)(NR b1 )R b1 、-S(O)N(R b1 )2、-P(O)(OR b1 )2、-P(O)(N(R b1 )2)2、-C(R b1 )2(OR b1 )、-C(R b1 )2N(R b1 )2. -C(O)R b1 、-C(O)OR b1 、-C(O)N(R b1 )2、-C(O)N(R b1 )OR b1 、-OC(O)R b1 、-OC(O)N(R b1 )2、-N(R b1 )C(O)OR b1 、-N(R b1 )C(O)R b1 、-N(R b1 )C(O)N(R b1 )2、-N(R b1 )S(O)2R b1 , C 1-6 Alkyl, C 3-7 Carbocyclic group, 3-7 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl is optionally substituted with one or more R b2 replace; R b1 Independently selected from: hydrogen, deuterium, C 1-6 Alkyl, C 3-7 carbocyclic group, 4-7 membered heterocyclic group, phenyl group, 5-6 membered heteroaryl group; the C 1-6 Alkyl, C 3-7 The carbocyclic group, 4-7 membered heterocyclic group, phenyl group or 5-6 membered heteroaryl group are optionally substituted with one or more selected from deuterium, halogen, oxo, hydroxyl, amino, nitro, cyano, mercapto, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 substituted by a substituent of an aryl group or a 5-12-membered heteroaryl group; or two R attached to the same atom b1 Together with the atoms to which they are attached, they form deuterated, halogen, oxo, hydroxyl, amino, nitro, cyano, thiol, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl, 5-12 membered heteroaryl, one or more arbitrarily substituted C 3-12 Carbocyclyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl; R b2 are independently selected from: deuterium, halogen, oxo, hydroxyl, amino, nitro, cyano, thiol, C 1-6 Alkyl, C 1-6 Alkoxy; m is independently selected from: 0, 1, 2, 3, 4; Q is independently selected from: deuterium, halogen, -R 3 、-OR 3 、-SR 3 、-N(R 3 )-C 0-6 Alkylene-R 3 、-N(R 3 )-C 0-6 Alkylene-N(R 3 )2, -S(O)2R 3 、-S(O)2N(R 3 )2. -S(O)R 3 、-S(O)(NR 3 )R 3 、-S(O)N(R 3 )2、-P(O)(OR 3 )2、-P(O)(N(R 3 )2)2、-C(R 3 )2(OR 3 )、-C(R 3 )2N(R 3 )2. -C(O)R 3 、-C(O)OR 3 、-C(O)N(R 3 )2、-C(O)N(R 3 )OR 3 、-OC(O)R 3 、-OC(O)N(R 3 )2、-N(R 3 )C(O)OR 3 、-N(R 3 )C(O)R 3 、-N(R 3 )C(O)N(R 3 )2、-N(R 3 )S(O)2R 3 The alkylene group is optionally replaced by one or more R c1 replace; R 3 Each independently selected from: hydrogen, deuterium, C 1-6 Alkyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, optionally substituted with one or more R c2 replace; or two R attached to the same nitrogen atom 3 Together with the nitrogen atom to which they are attached, they form halogen, hydroxyl, amino, -C(O)NH2, -(CH2) 1-6 NH2, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, oxetanylamino, C 1-6 One or more arbitrarily substituted 3-12 membered heterocyclic groups or 5-12 membered heteroaryl groups in the alkylpiperazinyl group; R c1 are independently selected from: deuterium, halogen, hydroxyl, amino, nitro, cyano, thiol, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; R c2 Independently selected from: deuterium, oxo, halogen, hydroxyl, amino, cyano, -OR c3 、-SR c3 、-N(R c3 )2, -S(O)2R c3 、-S(O)2N(R c3 )2. -S(O)R c3 、-S(O)(NR c3 )R c3 、-P(O)(OR c3 )2、-P(O)(N(R c3 )2)2、-C(R c3 )2(OR c3 )、-C(R c3 )2N(R c3 )2. -C(O)R c3 、-C(O)OR c3 、-C(O)N(R c3 )2、-C(O)N(R c3 )OR c3 、-OC(O)R c3 、-OC(O)N(R c3 )2、-N(R c3 )C(O)OR c3 、-N(R c3 )C(O)R c3 、-N(R c3 )C(O)N(R c3 )2、-N(R c3 )C(O)R c3 N(R c3 )OC(O)R c3 、-N(R c3 )S(O)2R c3 , C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl; said C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl or 5-8 membered heteroaryl is optionally substituted with one or more R c4 replace; R c3 , R c4 are independently selected from: hydrogen, deuterium, oxo, halogen, hydroxyl, amino, C 1-18 Alkyl, C 1-6 Alkoxy, C 1-6 haloalkyl, optionally substituted with one or more hydroxyl groups 1-6 alkyl, optionally substituted by one or more amino groups 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-6 membered heteroaryl; Het has the following structure: in, When A or B and When connected, A and B are independently selected from -C(R d1 )-、-N-、 The "#" is a connection one end of When A or B does not When connected, A and B are independently selected from a bond, -C(R d1 )2-、-NR d1 -、-C(R d1 )2N(R d1 )-、-NR d1 C(R d1 )2-; R d1 are independently selected from: absence, bond, hydrogen, deuterium, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl; or two R attached to the same carbon atom d1 Together they form an oxo group; When R d1 When it does not exist, That is Y is independently selected from -O-, -N(R d2 )-、-C(R d2 )2-, -S-, -C(O)-, -C(=N-OC 0-6 alkyl)-, -S(O)-, -S(O)2-, -S(O)(=NR d2 )-; R d2 Independently selected from: hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano, -OR d3 、-SR d3 、-N(R d3 )2. -C(O)R d3 、-(C 1-6 Alkylene)-C(O)R d3 、-(C 1-6 Alkylene)-S(O)2R d3 、-C(O)OR d3 、-(C 1-6 Alkylene)-C(O)OR d3 、-C(O)N(R d3 )2、-(C 1-6 Alkylene)-C(O)N(R d3 )2. -C(O)-(C 1-6 Alkylene)-N(R d3 )2, -S(O)2R d3 、-S(O)2N(R d3 )2. -S(O)R d3 、-C(O)N(R d3 )OR d3 、-OC(O)R d3 、-OC(O)N(R d3 )2、-N(R d3 )C(O)OR d3 、-N(R d3 )C(O)R d3 、-N(R d3 )C(O)N(R d3 )2、-N(R d3 )S(O)2R d3 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 1-6 Alkylene, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, optionally substituted with one or more selected from deuterium, halogen, oxo, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by a substituent of an aryl group or a 5-12-membered heteroaryl group; R d3 are independently selected from: hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, optionally substituted with one or more selected from deuterium, halogen, oxo, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent; R 13 , R 14 , R 15 , R 16 are independently selected from: hydrogen, deuterium, oxo, halogen, hydroxyl, amino, imino, sulfinamide, nitro, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, optionally substituted with one or more R d4 Replace; when R 13 , R 14 When one of them is selected from oxo and imino, the other is absent; when R 15 , R 16 When one of them is selected from an oxo group and an imino group, the other one does not exist; or R 13 and R 14 Together with the carbon atoms to which they are attached, they form groups that are substituted by halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 One or more arbitrarily substituted C 3-12 Carbocyclic group or 3-12 membered heterocyclic group; or R 15 and R 16 Together with the carbon atoms to which they are attached, they form groups that are substituted by halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 One or more arbitrarily substituted C 3-12 Carbocyclic group or 3-12 membered heterocyclic group; R d4 are independently selected from: deuterium, halogen, oxo, hydroxy, amino, cyano, sulfonyl, urea, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl; said C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl is optionally substituted with one or more halogens; Cy2 is independently selected from: phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl; Cy3 is independently selected from: phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl; R 17 and R 18 are independently selected from: deuterium, halogen, hydroxyl, amino, cyano, nitro, carboxyl, oxo, -OR d5 、-SR d5 、-N(R d5 )2, -S(O)2R d5 、-S(O)2N(R d5 )2. -S(O)R d5 、-S(O)(NR d5 )R d5 、-S(O)N(R d5 )2、-P(O)(OR d5 )2、-P(O)(N(R d5 )2)2、-C(R d5 )2(OR d5 )、-C(R d5 )2N(R d5 )2. -C(O)R d5 、-C(O)OR d5 、-C(O)N(R d5 )2、-C(O)N(R d5 )OR d5 、-OC(O)R d5 、-OC(O)N(R d5 )2、-N(R d5 )C(O)OR d5 、-N(R d5 )C(O)R d5 、-N(R d5 )C(O)N(R d5 )2、-N(R d5 )S(O)2R d5 、-N(R d5 )S(O)2N(R d5 )2、-N(R d5 )S(O)2O(R d5 ), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, optionally substituted with one or more selected from deuterium, halogen, oxo, hydroxyl, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Substituted by a cycloalkyl substituent; R d5 Independently selected from: hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are optionally substituted by one or more substituents selected from deuterium, halogen, hydroxyl, amino, cyano and carboxyl; Z is independently selected from C, N; E is independently selected from: -C(R d6 )2-、-N(R d6 )-; R d6 are independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, amino, cyano, nitro, sulfenamide, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl may be optionally substituted by one or more substituents selected from deuterium, halogen, oxo, hydroxyl, amino, carboxyl, cyano; or two R groups attached to the same carbon atom may be substituted by one or more substituents selected from deuterium, halogen, oxo, hydroxyl, amino, carboxyl, cyano. d6 Together they form an oxo group, a thio group, or an imino group; or two R groups connected to the same carbon atom d6 Together with the carbon atoms to which they are attached, they form a C 3-15 Carbocyclic group, 3-15 membered heterocyclic group; n and q are independently selected from 0, 1, 2, 3, and 4; When multiple R a1 , R a2 , R b1 , R b2 , R c1 , R c2 , R c3 , R c4 , R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R 1 , R 3 , R 17 , R 18 When they appear simultaneously, each R a1 , each R a2 , each R b1 , each R b2 , each R c1 , each R c2 , each R c3 , each R d1 , each R d2 , each R d3 , each R d4 , each R d5 , each R d6 , each R 1 , each R 3 , each R 17 , each R 18 Can be the same or different.

2. The compound according to claim 1 or its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt thereof, characterized in that: Cy1 is independently selected from 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; Preferably, Cy1 is independently selected from C 4-6 Carbocyclyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; Preferably, Cy1 is independently selected from a 5-6 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group; the heteroatom in the heterocyclic group or heteroaryl group is selected from N or S, and the number of heteroatoms is 1, 2 or 3; Preferably, Cy1 is independently selected from 4-12 membered heterocyclic groups, C 5-12 Aryl; Preferably, Cy1 is independently selected from 5-6 membered heterocyclic group, phenyl; Preferably, Cy1 is independently selected from phenyl; Preferably, Cy1 is independently selected from a 5-6 membered heterocyclic group; the heteroatom in the heterocyclic group is selected from N or S; Preferably, Cy1 is independently selected from the following groups: Preferably, Cy1 is independently selected from the following groups: Preferably, Independently selected from the following groups: Preferably, Selected from the following groups: Preferably, Selected from the following groups: Preferably, Independently selected from the following groups: Preferably, Cy1 is absent; R 1 Independently selected from: -C(O)C 1-4 Alkyl, -C 1-4 Alkyl-OH, C 1-4 Alkoxy, -C(O)OC 1-4 Alkyl, -C(O)NHC 1-4 Alkyl, C 1-4 alkyl; Preferably, Cy1 is absent; R 1 Independently selected from: -C(O)OCH3, -CH2OH, -OCH3, -C(O)OCH2CH3, -C(O)NHCH3; Preferably, R 1 are independently selected from: hydrogen, halogen, oxo, hydroxy, amino, nitro, cyano, -R a1 、-OR a1 、-SR a1 、-N(R a1 )2, -S(O)2R a1 、-S(O)2N(R a1 )2. -C(O)R a1 、-C(O)OR a1 、-C(O)N(R a1 )2. -C(O)OR a1 -OC(O)R a1 、-N(R a1 )C(O)R a1 ; Preferably, R 1 are independently selected from: hydrogen, halogen, oxo, hydroxy, amino, cyano, -R a1 、-S(O)2R a1 、-C(O)R a1 、-C(O)OR a1 、-C(O)N(R a1 )2. -C(O)OR a1 -OC(O)R a1 ; Preferably, R a1 Independently selected from: hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group optionally with one or more R a2 replace; or two R attached to the same atom a1 Together with the atoms to which they are attached, they form groups that are halogen, oxo, hydroxy, amino, nitro, cyano, mercapto, C 1-6 Alkyl, C 1-6 One or more arbitrarily substituted C 3-6 Carbocyclyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl; Preferably, R a1 Independently selected from: hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; said C 1-6 Alkyl, C 3-6 The cycloalkyl group is optionally substituted with one or more R a2 replace; Preferably, wherein R a2 are independently selected from: deuterium, halogen, oxo, hydroxyl, amino, nitro, cyano, thiol, C 1-4 Alkyl, C 1-4 Alkoxy; Preferably, R a2 independently selected from halogen (e.g. fluorine, chlorine, bromine), hydroxyl; Preferably, R a2 Independently selected from fluorine, hydroxyl; Preferably, R a2 independently selected from fluorine; Preferably, wherein R 1 are independently selected from: hydrogen, fluorine, chlorine, bromine, oxo, hydroxyl, amino, -R a1 、-OR a1 、-S(O)2R a1 、-C(O)R a1 、-C(O)OR a1 、-C(O)N(R a1 )2. -C(O)OR a1 -OC(O)R a1 ; R a1 Independently selected from: hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; said C 1-6 Alkyl, C 3-6 The cycloalkyl group is optionally substituted with one or more R a2 Replacement; R a2 Independently selected from: fluorine, chlorine, bromine, oxo, hydroxyl, amino; Preferably, R 1 are independently selected from: hydrogen, halogen, oxo, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, -C(O)OC 1-6 Alkyl, -C(O)NHC 1-6 Alkyl, -C(O)O-(C 1-6 Alkyl)-OC(O)C 1-6 alkyl; Preferably, R 1 Independently selected from: hydrogen, halogen, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkyl, -S(O)2C 1-4 Alkyl, -C(O)C 1-4 Alkyl, -C(O)C 1-4 Haloalkyl, -C(O)OC 1-4 Alkyl, -C(O)NHC 1-4 Alkyl, -C(O)O-(C 1-4 Alkyl)-OC(O)C 1-4 alkyl; Preferably, R 1 Independently selected from: hydrogen, C 1-2 Alkyl, C 1-2 Haloalkyl, -C(O)C 1-2 Haloalkyl; Preferably, R 1 Independently selected from: hydrogen, C 1-2 Alkyl, C 1-2 Haloalkyl; Preferably, R 1 independently selected from: hydrogen, fluorine, chlorine, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2F, -CF2H, -CF3, -C(O)CH3, -C(O)CH2CH3, -S(O)2CH3, -CH2OH, -C(O)CF3, -C(O)CF2H, -C(O)OCH3, -C(O)OCH2CH3, -C(O)NHCH3, -C(O)O-CH(CH3)-OC(O)CH(CH3)2; Preferably, R 1 Independently selected from: hydrogen, methyl, -CF2H, -C(O)CF3; Preferably, R 1 Independently selected from: methyl, -CF2H; Preferably, R 1 Independently selected from C 1-4 alkyl; Preferably, R 1 independently selected from methyl; Preferably, m is independently selected from: 0, 1, 2, 3; Preferably, m is independently selected from: 0, 1, 2; Preferably, m is independently selected from 1; Preferably, X 1 is selected from N, and X is selected from N; Preferably, X 1 Selected from N; Preferably, X 1 Selected from CR 2 ; Preferably, X is selected from N; Preferably, X is selected from CR 2 ; Preferably, R 2 are independently selected from halogen (e.g. fluorine, chlorine, bromine, preferably fluorine), cyano, C 1-4 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl); 1-4 The alkyl group is optionally substituted with one or more R b2 replace; Preferably, R 2 independently selected from halogen (e.g. fluorine, chlorine, bromine, preferably fluorine), cyano; Preferably, X is selected from CR 2 or N; R 2 independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, cyano, C 1-4 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl); Preferably, X is selected from CR 2 ; R 2 Independently selected from fluoro, cyano, methyl.

3. The compound according to any one of claims 1 to 2, or its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt thereof, characterized in that: Q is independently selected from: halogen, -R 3 、-OR 3 、-N(R 3 )-C 0-6 Alkylene-R 3 、-N(R 3 )-C 0-6 Alkylene-N(R 3 )2、-C(R 3 )2(OR 3 )、-C(R 3 )2N(R 3 )2. -C(O)R 3 、-C(O)OR 3 、-C(O)N(R 3 )2、-C(O)N(R 3 )OR 3 、-OC(O)R 3 、-OC(O)N(R 3 )2、-N(R 3 )C(O)OR 3 、-N(R 3 )C(O)R 3 、-N(R 3 )C(O)N(R 3 )2、-N(R 3 )S(O)2R 3 The alkylene group is optionally replaced by one or more R c1 replace; Preferably, Q is independently selected from: -R 3 、-N(R 3 )-C 0-6 Alkylene-R 3 、-N(R 3 )-C 0-6 Alkylene-N(R 3 )2、-N(R 3 )C(O)OR 3 、-N(R 3 )C(O)R 3 、-N(R 3 )C(O)N(R 3 )2、-N(R 3 )S(O)2R 3 The alkylene group is optionally replaced by one or more R c1 replace; Preferably, Q is independently selected from: -R 3 、-N(R 3 )-C 0-6 Alkylene-R 3 、-N(R 3 )-C 0-6 Alkylene-N(R 3 )2; the alkylene group is optionally replaced by one or more R c1 replace; Preferably, Q is independently selected from: -R 3 、-NH-C 0-4 Alkylene-R 3 、-NH-C 0-4 Alkylene-NHR 3 The alkylene group is optionally replaced by one or more R c1 replace; Preferably, R 3 Independently selected from: hydrogen, C 1-6 Alkyl, C 3-7 carbocyclic group, 3-7 membered heterocyclic group, phenyl group, 5-6 membered heteroaryl group; the C 1-6 Alkyl, C 3-7 Carbocyclic group, 3-7 membered heterocyclic group, phenyl group, 5-6 membered heteroaryl group are optionally substituted with one or more R c2 replace; or two R attached to the same nitrogen atom 3 Together with the nitrogen atom to which they are attached, they form halogen, hydroxyl, amino, -C(O)NH2, -(CH2) 1-4 NH2, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, oxetanylamino, C 1-4 One or more optionally substituted 3-7 membered heterocyclic groups or 5-6 membered heteroaryl groups in the alkylpiperazinyl group; Preferably, R 3 Independently selected from: hydrogen, C 1-6 Alkyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group; 1-6 Alkyl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group is replaced by one or more R c2 replace; Preferably, R 3 Independently selected from: hydrogen, C 1-6 Alkyl, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group; said C 1-6 Alkyl, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group is replaced by one or more R c2 replace; Preferably, R 3 Independently selected from: hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 6-9 membered heterospirocyclic group; the C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 6-9 membered heterospirocyclic group are optionally substituted with one or more R c2 replace; Preferably, R 3 Independently selected from: hydrogen, C 1-4 Alkyl, C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 7 membered heterospirocyclic group; the heteroatom in the 4-6 membered heterocycloalkyl, 7 membered heterospirocyclic group is selected from N or O, and the number of heteroatoms is 1 or 2; the C 1-4 Alkyl, C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 7 membered heterospirocycloalkyl are optionally substituted with one or more R c2 replace; Preferably, R 3 Independently selected from: hydrogen, C 1-4 alkyl, 4-6 membered heterocycloalkyl, 7 membered heterospirocycloalkyl; the heteroatom in the 4-6 membered heterocycloalkyl and 7 membered heterospirocycloalkyl is selected from N or O, and the number of heteroatoms is 1; the C 1-4 Alkyl, 4-6 membered heterocycloalkyl, 7 membered heterospirocyclic group are optionally substituted with one or more R c2 replace; Preferably, R 3 are independently selected from: hydrogen, methyl, ethyl, n-propyl, isopropyl, The above groups are optionally replaced by one or more R c2 replace; Preferably, R c1 are independently selected from: deuterium, halogen, hydroxyl, amino, nitro, cyano, thiol, C 1-4 Alkyl, C 1-4 Alkoxy; Preferably, R c1 Independently selected from: fluorine, chlorine, bromine, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl; Preferably, R c1 independently selected from: fluorine; Preferably, R c2 Independently selected from: deuterium, oxo, halogen, hydroxyl, amino, -OR c3 、-N(R c3 )2、-C(R c3 )2(OR c3 )、-C(R c3 )2N(R c3 )2. -C(O)R c3 、-C(O)OR c3 、-C(O)N(R c3 )2、-C(O)N(R c3 )OR c3 、-OC(O)R c3 、-OC(O)N(R c3 )2、-N(R c3 )C(O)OR c3 、-N(R c3 )C(O)R c3 、-N(R c3 )C(O)N(R c3 )2、-N(R c3 )S(O)2R c3 , C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, optionally substituted with one or more R c4 replace; Preferably, R c2 Independently selected from: halogen, hydroxy, amino, C 1-4 Alkyl; the C 1-4 The alkyl group is optionally substituted with one or more R c4 replace; Preferably, R c2 Independently selected from: halogen (e.g., fluorine, chlorine, bromine), hydroxyl, amino, methyl, ethyl, n-propyl, isopropyl; the above groups are optionally substituted by one or more substituents selected from halogen (e.g., fluorine, chlorine, bromine), hydroxyl, amino; Preferably, R c3 , R c4 are independently selected from: hydrogen, halogen, hydroxyl, amino, C 1-6 Alkyl, C 1-6 haloalkyl, optionally substituted with one or more hydroxyl groups 1-6 alkyl; Preferably, R c3 Independently selected from: hydrogen, methyl, ethyl, n-propyl, isopropyl; Preferably, R c4 Independently selected from: halogen, hydroxyl, amino; Preferably, R c4 Independently selected from: hydroxyl, amino; Preferably, Q is independently selected from: -R 3 、-N(R 3 )-C 0-6 Alkylene-R 3 、-N(R 3 )-C 0-6 Alkylene-N(R 3 )2; the alkylene group is optionally substituted by one or more selected from halogen, hydroxyl, amino, C 1-6 substituted by an alkyl substituent; R 3 Each independently selected from: hydrogen, C 1-6 Alkyl, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group; said C 1-6 Alkyl, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group optionally with one or more R c2 replace; R c2 Independently selected from: halogen, hydroxy, amino, C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from halogen, hydroxyl, and amino; Preferably, Q is independently selected from: C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -NH-C 0-6 Alkylene-R 3 、-NH-C 0-6 Alkylene-N(R 3 )2; the alkylene group is optionally substituted by one or more substituents selected from halogen, hydroxy, amino, methyl, and ethyl; R 3 Each independently selected from: hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, 6-9 membered heterospirocyclic group; the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, 6-9 membered heterospirocyclic group are optionally substituted with one or more R c2 replace; R c2 Independently selected from: halogen, hydroxy, amino, C 1-6 Alkyl, amino substituted C 1-6 Alkyl, hydroxy substituted C 1-6 alkyl; Preferably, Q is independently selected from: C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -NH-C 0-4 Alkylene-C 3-6 Cycloalkyl, -NH-C 0-4 Alkylene-3-6 membered heterocyclic group, -NH-C 0-4 Alkylene-7-membered heterospirocyclic group, -NH-C 0-4 Alkylene -NH2, -NH-C 0-4 Alkylene-NH(C 1-4 Alkyl), -NH-C 0-4 Alkylene-N(C 1-4 alkyl)2; the alkylene group is optionally substituted by one or more substituents selected from halogen (eg, fluorine, chlorine, bromine); the C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, 7 membered heterospirocyclic group are optionally substituted by one or more selected from halogen (e.g., fluorine, chlorine, bromine), hydroxyl, amino, C 1-4 Alkyl, amino substituted C 1-4 Alkyl, hydroxy substituted C 1-4 substituted by an alkyl substituent; Preferably, Q is independently selected from: 3-10 membered nitrogen-containing heterocyclic group (preferably 3-8 membered nitrogen-containing heterocyclic group), -NH-C 0-2 Alkylene-C 3-6 Cycloalkyl-NH2, -NH-C 0-2 Alkylene-3-6 membered heterocyclic group; Connected to the nitrogen atom in a 3-10-membered nitrogen-containing heterocyclic group, is a connection site; the heteroatom in the 3-6 membered heterocyclic group is selected from N or O, and the number of heteroatoms is 1 or 2; the 3-10 membered nitrogen-containing heterocyclic group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, optionally substituted by one or more selected from halogen (e.g., fluorine, chlorine, bromine), hydroxyl, amino, -C 1-2 Alkyl-NH2, -C 1-2 Alkyl-OH, -C(O)OC 1-2 substituted by an alkyl substituent; Preferably, Q is independently selected from: 3-7 membered nitrogen-containing heterocyclic group, -NH-C 0-2 Alkylene-C 3-6 Cycloalkyl-NH2, -NH-C 0-2 Alkylene-3-6 membered heterocyclic group; Connected to the nitrogen atom in the 3-7 membered nitrogen-containing heterocyclic group, is a connection site; the heteroatom in the 3-6 membered heterocyclic group is selected from N or O, and the number of heteroatoms is 1 or 2; the 3-7 membered nitrogen-containing heterocyclic group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, optionally substituted by one or more selected from halogen (e.g., fluorine, chlorine, bromine), hydroxyl, amino, -C 1-2 Alkyl-NH2, -C 1-2 Alkyl-OH, -C(O)OC 1-2 substituted by an alkyl substituent; Preferably, Q is independently selected from: 4-6 membered nitrogen-containing heterocyclic group, -NH-C 4-5 Cycloalkyl-NH2, -NH-C 0-2 Alkylene-4-6 membered heterocyclic group; Connected to the nitrogen atom in a 4-6-membered nitrogen-containing heterocyclic group, is a connection site; the heteroatom in the 4-6 membered heterocyclic group is selected from N or O, and the number of heteroatoms is 1 or 2; the 4-6 membered nitrogen-containing heterocyclic group and the 4-6 membered heterocyclic group are optionally substituted by one or more selected from halogen (e.g., fluorine, chlorine, bromine), hydroxyl, amino, -C 1-2 Alkyl-NH2, -C 1-2 Alkyl-OH, -C(O)OC 1-2 substituted by an alkyl substituent; Preferably, Q is independently selected from: 4-6 membered nitrogen-containing heterocyclic group, -NH-C 4-5 Cycloalkyl-NH2, -NH-C 0-2 Alkylene-4-6 membered heterocyclic group; Connected to the nitrogen atom in a 4-6-membered nitrogen-containing heterocyclic group, is a connection site; the heteroatom in the 4-6 membered heterocyclic group is selected from N or O, and the number of heteroatoms is 1; the 4-6 membered nitrogen-containing heterocyclic group and the 4-6 membered heterocyclic group are optionally substituted by one or more substituents selected from fluorine, chlorine, hydroxyl, amino, -CH2NH2, -CH2OH, -C(O)OCH3; Preferably, Q is independently selected from: Preferably, Q is selected from: Preferably, Het is selected from B is -N-; A is -CH2-; Preferably, Het is selected from the following structures: Cy2 is selected from phenyl or pyridyl; Preferably, Y is independently selected from -O-, -N(R d2 )-, -S(O)-, -S(O)2-, -S(O)(=NR d2 )-; Preferably, Y is independently selected from -S(O)-, -S(O)2-, -S(O)(=NR d2 )-; Preferably, Y is independently selected from -S(O)2-, -S(O)(=NR d2 )-; Preferably, Y is independently selected from -S(O)2-; Preferably, R d2 Independently selected from: hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano, -SR d3 、-N(R d3 )2. -C(O)R d3 、-(C 1-6 Alkylene)-C(O)R d3 、-C(O)OR d3 、-(C 1-6 Alkylene)-C(O)OR d3 、-C(O)N(R d3 )2、-(C 1-6 Alkylene)-C(O)N(R d3 )2. -C(O)-(C 1-6 Alkylene)-N(R d3 )2, -S(O)2R d3 、-C(O)N(R d3 )OR d3 、-OC(O)R d3 、-OC(O)N(R d3 2. C 1-6 Alkyl, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-8 Aryl, 5-10 membered heteroaryl; said C 1-6 Alkyl, C 1-6 Alkylene, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-8 Aryl, 5-10 membered heteroaryl, optionally substituted with one or more selected from deuterium, halogen, oxo, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent; Preferably, R d2 Independently selected from: hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano, -SR d3 、-N(R d3 )2. -C(O)R d3 、-(C 1-4 Alkylene)-C(O)R d3 、-C(O)OR d3 、-(C 1-4 Alkylene)-C(O)OR d3 、-C(O)N(R d3 )2、-(C 1-4 Alkylene)-C(O)N(R d3 )2. -C(O)-(C 1-4 Alkylene)-N(R d3 )2, -S(O)2R d3 , C 1-4 Alkyl, C 3-6 carbocyclic group, 3-6 membered heterocyclic group, phenyl group, 5-6 membered heteroaryl group; the C 1-4 Alkyl, C 1-4 Alkylene, C 3-6 Carbocyclic group, 3-6 membered heterocyclic group, phenyl group, 5-6 membered heteroaryl group are optionally substituted with one or more selected from deuterium, halogen, oxo group, hydroxyl, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; Preferably, R d2 Independently selected from: hydrogen, -SR d3 、-C(O)R d3 、-(C 1-4 Alkylene)-C(O)R d3 、-(C 1-4 Alkylene)-C(O)OR d3 、-C(O)N(R d3 )2、-(C 1-4 Alkylene)-C(O)N(R d3 )2. -C(O)-(C 1-4 Alkylene)-N(R d3 )2, -S(O)2R d3 , C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl; the heteroatom in the 3-6 membered heterocyclic group and 5-6 membered heteroaryl is selected from N or O, and the number of heteroatoms is 1 or 2; the C 1-4 Alkyl, C 1-4 Alkylene, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl are optionally substituted by one or more substituents selected from deuterium, halogen (e.g. fluorine, chlorine, bromine, preferably fluorine), oxo, hydroxy, amino, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, n-propoxy, isopropoxy; Preferably, R d3 are independently selected from: hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, optionally substituted with one or more selected from deuterium, halogen, oxo, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent; Preferably, R d3 are independently selected from: hydrogen, halogen, hydroxy, amino, nitro, cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; the C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, optionally substituted by one or more selected from halogen, oxo, hydroxyl, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; Preferably, R d3 Independently selected from: hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl; the above groups are optionally substituted by one or more substituents selected from fluorine, chlorine, bromine, hydroxyl, amino; Preferably, R d2 Independently selected from: hydrogen, -SR d3 、-C(O)R d3 、-(C 1-6 Alkylene)-C(O)R d3 、-C(O)OR d3 、-(C 1-6 Alkylene)-C(O)OR d3 、-C(O)N(R d3 )2、-(C 1-6 Alkylene)-C(O)N(R d3 )2. -C(O)-(C 1-6 Alkylene)-N(R d3 )2, -S(O)2R d3 , C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; the C 1-6 Alkyl, C 1-6 Alkylene, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, optionally substituted with one or more selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent; R d3 are independently selected from: hydrogen, halogen, hydroxy, amino, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, optionally substituted with one or more selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent; Preferably, R d2 Independently selected from: hydrogen, -SC 1-4 Alkyl, -C(O)NH2, -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 Alkyl)2, -C(O)C 1-4 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)3-6 membered heterocyclic group, -C(O)-(C 1-4 Alkylene)-NH(C 1-4 alkyl), -C(O)-(C 1-4 Alkylene)-N(C 1-4 Alkyl)2, -(C 1-4 Alkylene)-C(O)OC 1-4 Alkyl, -(C 1-4 Alkylene)-C(O)C 1-4 Alkyl, -(C 1-4 Alkylene)-C(O)NH2, -(C 1-4 Alkylene)-C(O)NH(C 1-4 Alkyl), -(C 1-4 Alkylene)-C(O)N(C 1-4 Alkyl)2, -S(O)2C 1-4 Alkyl, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; the C 1-4 Alkyl, C 1-4 Alkylene, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl are optionally substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl; Preferably, R d2 are independently selected from: hydrogen, -C(O)NH2, -C(O)NH(C 1-3 Alkyl), -C(O)C 1-3 Alkyl, -C(O)C 3-6 Cycloalkyl, -(C 1-3 Alkylene)-S(O)2(C 1-3 Alkyl), C 1-6 Alkyl (more preferably C 1-5 Alkyl, more preferably C 1-3 Alkyl), C 3-6 Cycloalkyl (more preferably C 3-4 cycloalkyl), 3-7 membered heterocyclyl (more preferably 4-5 membered heterocyclyl), 5-6 membered heteroaryl (more preferably 5 membered heteroaryl containing 2 nitrogen atoms); the alkyl, cycloalkyl, heterocyclyl, heteroaryl are optionally substituted with one or more selected from deuterium, halogen (more preferably fluorine, chlorine, bromine, more preferably fluorine), hydroxyl, amino, cyano, C 1-3 Alkyl (more preferably methyl), C 1-3 The substituent is substituted by an alkoxy group (more preferably a methoxy group) or a 3-6-membered heterocyclic group (more preferably a 4-5-membered oxygen-containing heterocyclic group); the heteroatoms in the heterocyclic group or heteroaryl group are independently selected from O or N, and the number of heteroatoms is 1 or 2; Preferably, R d2 are independently selected from: hydrogen, -C(O)NH2, -C(O)NH(C 1-2 Alkyl), -C(O)C 1-2 Alkyl, -C(O)C 3-4 Cycloalkyl, -(C 1-2 Alkylene)-S(O)2(C 1-2 Alkyl), C 1-6 Alkyl (more preferably C 1-5 Alkyl, more preferably C 1-3 Alkyl), -C 1-3 Alkylene-C 1-2 Alkoxy, -C 1-2 Alkylene-(3-6 membered heterocyclic group) (more preferably -C 1-2 Alkylene-(4-5 membered heterocyclic group)), C 3-6 Cycloalkyl (more preferably C 3-4 The alkyl group is optionally substituted with one or more substituents selected from deuterium, halogen (more preferably fluorine, chlorine, bromine, more preferably fluorine), hydroxyl, and cyano; the cycloalkyl group is optionally substituted with one or more substituents selected from halogen (more preferably fluorine, chlorine, bromine, more preferably fluorine); the heteroaryl group is optionally substituted with one or more substituents selected from C 1-2 The heterocyclic group and the heteroaryl group are substituted by a substituent of an alkyl group (preferably a methyl group); the heteroatoms in the heterocyclic group and the heteroaryl group are independently selected from O or N, and the number of heteroatoms is 1 or 2; Preferably, R d2 Independently selected from: -(C 1-3 Alkylene)-S(O)2(C 1-3 Alkyl), C 1-6 Alkyl (more preferably C 1-5 Alkyl, more preferably C 1-3 Alkyl), C 3-6 Cycloalkyl (more preferably C 3-4 cycloalkyl), 3-6 membered heterocyclic group (more preferably 4-5 membered heterocyclic group); the alkyl, cycloalkyl, heterocyclic group are optionally substituted by one or more selected from deuterium, halogen (more preferably fluorine, chlorine, bromine, more preferably fluorine), hydroxyl, cyano, C 1-3 Alkyl (more preferably methyl), C 1-3 The substituent is substituted by an alkoxy group (more preferably a methoxy group) or a 3-6-membered heterocyclic group (more preferably a 4-5-membered heterocyclic group); the heteroatom in the heterocyclic group is O, and the number of heteroatoms is 1; Preferably, R d2 Independently selected from: -(C 1-2 Alkylene)-S(O)2(C 1-2 Alkyl), C 1-6 Alkyl (more preferably C 1-5 Alkyl, more preferably C 1-3 Alkyl), -C 1-3 Alkylene-C 1-2 Alkoxy, -C 1-2 Alkylene-(3-6 membered heterocyclic group) (more preferably -C 1-2 Alkylene-(4-5 membered heterocyclic group)), C 3-6 Cycloalkyl (more preferably C 3-4 cycloalkyl), 4-6 membered heterocyclic group (more preferably 4-5 membered heterocyclic group); the alkyl group is optionally substituted by one or more substituents selected from deuterium, halogen (more preferably fluorine, chlorine, bromine, more preferably fluorine), hydroxyl, cyano; the heteroatom in the heterocyclic group is O, and the number of heteroatoms is 1; Preferably, R d2 Independently selected from: -C 1-2 Alkylene-(3-6 membered heterocyclic group) (more preferably -C 1-2 Alkylene-(4-5 membered heterocyclic group)), C 3-6 Cycloalkyl (more preferably C 3-4 cycloalkyl), 3-6 membered heterocyclic group (more preferably 4-5 membered heterocyclic group); the heteroatom in the heterocyclic group is O, and the number of heteroatoms is 1; Preferably, R d2 independently selected from: hydrogen, -C(O)NH2, -CD3, -CF3, -SCF3, -C(O)CH3, -C(O)CH2OH, -C(O)CH2N(CH3)2, -CH2CN, -CH2CH2CH2CN, -CH2CH2C(CH3)2OH, -CH2CH2CH2OH, -CH(CH3)CH2OCH3, -CH2CH2CH2OCH3, -CH2-C(O)OCH3, -C(O)NHCH3, -CH2-C(O)NH2, -S(O)2CH3, -C(O)N(CH3)2, -CH2CF3, -CH2CH2F, -CH2CHF2, -CH2CH2SO2CH3, methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, Preferably, R 13 , R 14 , R 15 , R 16 are independently selected from: hydrogen, deuterium, oxo, fluorine, chlorine, bromine, methyl; when R 13 , R 14 When one of them is selected from oxo, the other is absent; when R 15 , R 16 When one of them is selected from oxo, the other is absent; or R 13 and R 14 Together with the carbon atoms to which they are attached, they form cyclopropane, cyclobutane, cyclopentane, cyclohexane; or R 15 and R 16 Together with the carbon atoms to which they are attached, they form cyclopropane, cyclobutane, cyclopentane, cyclohexane; Preferably, R 13 , R 14 , R 15 , R 16 are independently selected from: hydrogen, oxo, methyl; when R 13 , R 14 When one of them is selected from oxo, the other is absent; when R 15 , R 16 When one of them is selected from oxo, the other is absent; or R 13 and R 14 Together with the carbon atom to which they are attached they form a cyclopropane group; or R 15 and R 16 Together with the carbon atom to which they are attached they form a cyclopropane group; Preferably, R 13 , R 14 , R 15 , R 16 are independently selected from: hydrogen; Preferably, R d4 Independently selected from: deuterium, fluorine, chlorine, bromine, oxo, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, isopropyl; the methyl, ethyl, n-propyl, isopropyl is optionally substituted by one or more substituents selected from fluorine, chlorine, and bromine; preferably, Cy2 is independently selected from: phenyl, 5-6 membered heterocyclic group, 5-6 membered heteroaryl, the heteroatom in the 5-6 membered heterocyclic group, 5-6 membered heteroaryl is selected from N, and the number of heteroatoms is 1, 2 or 3; Preferably, Cy2 is independently selected from: phenyl, 5-membered heteroaryl, 6-membered heteroaryl; Preferably, Cy2 is independently selected from: phenyl, pyridyl, pyrazolyl, imidazolyl, pyrrole, triazole; Preferably, Cy2 is independently selected from: phenyl, 6-membered heteroaryl; Preferably, Cy2 is independently selected from: phenyl, pyridyl; Preferably, Cy2 is independently selected from: phenyl, Preferably, Cy2 is independently selected from phenyl; preferably, Cy3 is independently selected from: phenyl, 5-6 membered heterocyclic group, 5-6 membered heteroaryl group, the heteroatom in the 5-6 membered heterocyclic group, 5-6 membered heteroaryl group is selected from N, and the number of heteroatoms is 1, 2 or 3; Preferably, Cy3 is independently selected from: phenyl, 5-membered heteroaryl, 6-membered heteroaryl; Preferably, Cy3 is independently selected from: phenyl, pyridyl, pyrazolyl, imidazolyl, pyrrole, triazole; Preferably, Cy3 is independently selected from: phenyl, Preferably, R 17 and R 18 are independently selected from: deuterium, halogen; Preferably, R 17 and R 18 are independently selected from: fluorine, chlorine; Preferably, R d5 Independently selected from: hydrogen, C 1-6 alkyl; Preferably, R d5 is hydrogen; Preferably, n and q are independently selected from 0, 1, and 2; Preferably, n and q are independently selected from 0 and 1; Preferably, n and q are each independently selected from 0.

4. The compound according to any one of claims 1 to 3, or its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt thereof, characterized in that: The compound has the structure shown in formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (IV), formula (IV-a), formula (IV-1), formula (IV-2), formula (IV-3), formula (IV-4), formula (IV-5), formula (IV-6), and formula (IV-7): Among them, Cy1, Cy2, R 1 ,Q,X,X 1 , m, n, R d2 , R 13 , R 14 , R 15 , R 16 , R 17 As defined in any one of claims 1 to 3.

5. The compound according to claim 1 or its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from:

6. An intermediate for preparing a compound according to any one of claims 1 to 5, having a structure as shown in formula (Ra), formula (R-a5) or (R-a6): in, R e is selected from protecting groups, hydrogen; R d2 As defined in any one of claims 1 to 5; provided that R e and R d2 Not at the same time as hydrogen.

7. The following intermediate for preparing the compound according to any one of claims 1 to 6:

8. A pharmaceutical composition, characterized in that: The invention comprises the compound according to any one of claims 1 to 7 or its tautomer, stereoisomer, isotopic derivative or pharmaceutically acceptable salt thereof.

9. Use of the compound according to any one of claims 1 to 7 or its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt or the pharmaceutical composition according to claim 8 in the preparation of a medicament for preventing and / or treating diseases caused by RSV virus infection.

10. A pharmaceutical composition, characterized in that: A compound according to any one of claims 1 to 7 or its tautomer, stereoisomer, isotope derivative or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8, and other compounds.

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