Heterocyclic derivatives and use thereof in medicine

Abstract

The present invention relates to heterocyclic derivatives and the use thereof in medicine, in particular to compounds represented by general formula (I) or stereoisomers, pharmaceutically acceptable salts or cocrystals and intermediates thereof, a preparation method therefor, and the use thereof in the preparation of drugs for treating autoimmune diseases or inflammatory diseases.

Description

A heterocyclic derivative and its application in medicine Technical Field

[0001] The present invention relates to a compound of general formula (I) or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt, and intermediates and preparation methods, as well as use of the compound in preparing drugs for treating autoimmune diseases or inflammatory diseases. Background Art

[0002] Tumor necrosis factor (TNFα), a member of the tumor necrosis factor superfamily, is a cytokine involved in systemic inflammation. It plays a crucial role in immune responses by regulating multiple signaling pathways, including direct inflammatory responses in immune cells and subsequent proliferation and programmed cell necrosis or apoptosis. It is a type II transmembrane protein. Its precursor consists of 233 amino acids, including a 76-amino acid signal peptide, and is bound to the cell membrane as a trimer (tmTNFα). Under the action of TNFα-converting enzyme (TACE), the signal peptide of membrane-bound TNFα is cleaved, forming a soluble mature TNFα (sTNFα) consisting of 157 amino acid residues. This sTNFα is secreted into the cell and exerts its biological effects by binding to the tumor necrosis factor receptor (TNFR). TNFα is primarily produced by activated monocytes and macrophages, but is also produced by other immune cells such as T cells, B cells, NK cells, and neutrophils. Its biological functions are diverse. In general, TNF-α interacts with transmembrane TNFRs to control cell survival or induce apoptosis through unique and complex signaling pathways, thereby conferring resistance to certain types of infections. Summary of the Invention

[0003] The purpose of the present invention is to provide a class of compounds with inhibitory activity against TNFα. This class of compounds has good inhibitory activity against TNF-α / TNFR1 binding and good oral bioavailability. It has weak inhibitory effects on various CYP enzyme subtypes CYP1A2, CYP2C9, CYP2D6, CYP2C19, and CYP3A4-M, especially on CYP1A2. It has better human liver microsome stability, lower clearance rate and longer half-life.

[0004] The present invention provides a compound represented by general formula (IA) or a stereoisomer, a pharmaceutically acceptable salt or a cocrystal thereof.

[0005] In some embodiments, the compound represented by general formula (IA) is selected from the group consisting of general formula (I)

[0006] Represents the presence or absence of a chemical bond;

[0007] In some embodiments, Selected from

[0008] In some embodiments, ring M is selected from 5-membered heteroaryl or 5-membered unsaturated heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted by 1 to 4 R m replace;

[0009] In some embodiments, the compound represented by general formula (I) is selected from the compounds represented by general formula (Ia) and (Ib). In some embodiments, the compound represented by general formula (IA) is selected from the compounds represented by (Ic), (Id), and (Ie).

[0010] In some embodiments, R m Each independently selected from deuterium, halogen, CN, =O, =S, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4 to 7 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R k replace;

[0011] In some embodiments, R m Each independently selected from deuterium, halogen, CN, =O, =S, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4 to 7 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R k replace;

[0012] In some embodiments, R m Each independently selected from deuterium, F, Cl, Br, CN, OH, methyl, ethyl, methoxy, ethoxy, cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, cyclopropyl is optionally substituted by 1 to 4 selected from deuterium, halogen, CF3, CHF2, CH2F, CD3, CHD2, CH2D, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0013] In some embodiments, R mEach independently selected from deuterium, F, Cl, Br, CN, methyl, ethyl, cyclopropyl, CF3, CHF2, CH2F, CD3, CHD2, CH2D, CH2CD3, CH2CF3;

[0014] In some embodiments, X is selected from N, O, S, C(R x )、C(R x )2 or N(R x );

[0015] In some embodiments, R x Each independently selected from H, -C(=O)-C 1-6 Alkyl, -C(=O)-C 3-6 Cycloalkyl, C 1-6 Alkyl, -C 0-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene or cycloalkyl group is optionally substituted by 1 to 4 R k replace;

[0016] In some embodiments, R x Selected from H, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH(CH3)2, -C(=O)-cyclopropyl, methyl, ethyl, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, cyclopropyl, cyclobutyl is optionally substituted by 1 to 4 R k replace;

[0017] In some embodiments, R x Each independently selected from H, -C(=O)-C 1-4 Alkyl, -C(=O)-C 3-6 Cycloalkyl, C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 1-2 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene or cycloalkyl group is optionally substituted by 1 to 4 R k replace;

[0018] In some embodiments, R x is selected from H, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH(CH3)2, -C(=O)-cyclopropyl, methyl, ethyl, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, cyclopropyl, cyclobutyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl or ethyl;

[0019] In some embodiments, Q is selected from C, C(R q1)、C(R q1 )2. C(=O), C(=S), C=N(R q2 ), C=C(R q3 )2, S(=O), S(=O)(=NH), S(=O)2;

[0020] In some embodiments, R q1 Selected from H, deuterium, C 1-6 Alkyl, said alkyl being optionally substituted by 1 to 4 R k replace;

[0021] In some embodiments, R q1 Selected from H, deuterium, C 1-4 Alkyl, said alkyl being optionally substituted by 1 to 4 R k replace;

[0022] In some embodiments, R q2 、R q3 Each independently selected from H, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, said alkyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0023] In some embodiments, R q2 、R q3 Each independently selected from H, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, said alkyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0024] In some embodiments, R q1 is selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl or cyclopropyl, wherein the methyl, ethyl and cyclopropyl groups are optionally substituted by 1 to 4 groups selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0025] In some embodiments, R q2is selected from H, OH, CN, NH2, methyl, ethyl, methoxy, ethoxy, wherein the methyl, ethyl, methoxy, ethoxy is optionally substituted by 1 to 4 deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0026] In some embodiments, R q1 is selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl or cyclopropyl, wherein the methyl, ethyl or cyclopropyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl or ethyl;

[0027] In some embodiments, R q2 is selected from H, OH, CN, NH2, methyl, ethyl, methoxy, ethoxy, wherein the methyl, ethyl, methoxy, ethoxy is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl or ethyl;

[0028] In some embodiments, W is selected from -CR w1 R w2 -、-(CR w1 R w2 )2-;

[0029] In some embodiments, R w1 、R w2 Each independently selected from H, deuterium, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, said alkyl or cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0030] Alternatively, R w1 、R w2 Direct connection to form C 3-6 Cycloalkyl, the cycloalkyl group is optionally substituted by 1 to 4 R k replace;

[0031] In some embodiments, R w1 、R w2 Each independently selected from H, deuterium, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, said alkyl or cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0032] In some embodiments, alternatively, R w1 、R w2 Direct connection to form C 3-6 Cycloalkyl, the cycloalkyl group is optionally substituted by 1 to 4 R k replace;

[0033] In some embodiments, W is selected from -CH2-, -CH(CH3)-, -CH(CF3)-, -CH(CD3)-, -CFH-, -CF2-, -CH2CH2-, or

[0034] In some embodiments, Ring A is selected from 5-membered heteroaryl, In some embodiments, Ring A is selected from thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, In some embodiments, Z1 is selected from N or C(R z1 );

[0035] In some embodiments, Z2 is selected from N or C(R z2 );

[0036] In some embodiments, Z3 is selected from N or C(R z3 );

[0037] In some embodiments, Z4 is selected from N or C;

[0038] In some embodiments, Z5 is selected from N or C;

[0039] In some embodiments, Z6 is selected from N or C;

[0040] In some embodiments, Z3 is selected from N;

[0041] In some embodiments, R 1 Selected from C 5-10 Bicyclic cycloalkyl, C 7-12 tricyclic cycloalkyl, -6 to 12 membered bicyclic heterocycloalkyl-R 1b , the R 1 Optional 1 to 4 R 1a replace;

[0042] In some embodiments, R 1 Selected from C 5-10 Bridged cycloalkyl, C 6-10 Cycloalkyl, C 5-10 Spirocycloalkyl, -6 to 10 membered bridged heterocycloalkyl-R 1b 、-6 to 12 membered heterocyclic alkyl-R 1b 、-6 to 12-membered spirocyclic heterocycloalkyl-R1b , the R 1 Optional 1 to 4 R 1a replace;

[0043] In some embodiments, R 1 Selected from The R 1 Optional 1 to 4 R 1a Substitution, s1, s3, s5 are each independently selected from 0, 1 or 2, s2, s4 are each independently selected from 0 or 1; in some embodiments, s3 and s4 are not 0 at the same time, s1 and s2 are not 0 at the same time;

[0044] In some embodiments, R 1 Selected from The R 1 Optional 1 to 4 R 1a replace;

[0045] In some embodiments, R 1 is selected from one of the following groups wherein the ring is optionally substituted: When substituted, it is optionally substituted with 1 to 3 substituents selected from deuterium, F, Cl, Br, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, -CH2OH, methyl, ethyl, methoxy, ethoxy;

[0046] In some embodiments, R 1a Each independently selected from deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -C 0-4 Alkylene-C 3-6 Cycloalkyl, -C 0-4 alkylene-4 to 7 membered heterocycloalkyl, -C(=O)C 1-6 Alkyl, -C(=O)C 3-7 carbocyclyl, -C(=O)-4 to 7 membered heterocyclyl, -NHC(=O)C 1-6 Alkyl, -NHC(=O)C 3-6 Cycloalkyl, -S(=O)C 1-6Alkyl, -S(=O)C 3-7 Carbocyclyl, -NHS(=O)C 1-6 Alkyl, -S(=O)2C 1-6 Alkyl, -S(=O)2C 3-7 Carbocyclic group, -NHS(=O)2C 1-6 Alkyl, -S(=O)2NHC 1-6 Alkyl, -P(=O)(C 1-6 alkyl) 2, wherein the alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R k replace;

[0047] In some embodiments, R 1a Each independently selected from deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-6 Cycloalkyl, C 1-2 alkylene-4 to 7 membered heterocycloalkyl, -C(=O)C 1-4 Alkyl, -C(=O)C 3-6 Cycloalkyl, -C(=O)-4 to 7 membered heterocycloalkyl, -NHC(=O)C 1-4 Alkyl, -NHC(=O)C 3-6 Cycloalkyl, -S(=O)C 1-4 Alkyl, -S(=O)C 3-6 Cycloalkyl, -NHS(=O)C 1-4 Alkyl, -S(=O)2C 1-4 Alkyl, -S(=O)2C 3-6 Cycloalkyl, -NHS(=O)2C 1-4 Alkyl, -S(=O)2NHC 1-4 Alkyl, -P(=O)(C 1-4 alkyl) 2, wherein the alkylene, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R k replace;

[0048] In some embodiments, R 1aEach independently selected from deuterium, F, Cl, Br, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, methoxy, ethoxy, cyclopropyl, -CH2-cyclopropyl, -S(=O)CH3, -S(=O)cyclopropyl, -NHS(=O)-CH3, -S(=O)2-CH3, -S(=O)2cyclopropyl, -NHS(=O)2CH3, -S(=O)2NHCH3, -P(=O)(CH3)2, wherein the CH2, methyl, ethyl, methoxy, ethoxy, cyclopropyl are optionally substituted by 1 to 4 R k replace;

[0049] In some embodiments, R 1a Each independently selected from OH, NH2, CN, -NHS(=O)-CH3, -NHS(=O)2-CH3, -S(=O)-CH3, -S(=O)2-CH3;

[0050] In some embodiments, R 1b Selected from H, C 1-6 Alkyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, 4 to 7 membered heterocyclic group, -C 1-2 Alkylene-C 3-7 Carbocyclic group, -C 1-2 Alkylene-4 to 7 membered heterocyclic group, -C(=O)C 1-2 Alkylene-C 3-7 Carbocyclic group, -C(=O)C 1-6 Alkyl, -C(=O)C 3-7 Carbocyclic group, -C(=O)C 1-2 Alkylene-4 to 7 membered heterocyclic group, -C(=O)-4 to 7 membered heterocyclic group, wherein the alkylene, alkyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0051] In some embodiments, R 1b Selected from H, C 1-4 Alkyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-6 Cycloalkyl, -C 1-2 alkylene-4 to 7 membered heterocycloalkyl, -C(=O)C 1-2 Alkylene-C 3-6 Cycloalkyl, -C(=O)C 1-4 Alkyl, -C(=O)C 3-6 Cycloalkyl, -C(=O)-C 1-2Alkylene-4 to 7 membered heterocycloalkyl, -C(=O)-4 to 7 membered heterocycloalkyl, wherein the alkylene, alkyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R k replace;

[0052] In some embodiments, R 1b Selected from H or optionally 1 to 4 R k substituted with one of the following groups: methyl, ethynyl, -CH2-ethynyl, propynyl, butynyl, butyn-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-oxetanyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl , -C(=O)-CH2-cyclopropyl, -C(=O)-CH2-cyclobutyl, -C(=O)-CH2-cyclopentyl, -C(=O)-CH2-cyclohexyl, -C(=O)-methyl, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl, -C(=O)-cyclohexyl, -C(=O)-oxetanyl, -C(=O)-tetrahydrofuranyl, -C(=O)-oxetanyl, -C(=O)-azetidinyl, -C(=O)-pyrrolidinyl, -C(=O)-piperidinyl, -C(=O)-piperazinyl;

[0053] In some embodiments, R 1b is selected from H, methyl, ethynyl, -CH2-ethynyl, propynyl, butynyl, butyn-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -C(=O)-CH2-cyclopropyl, -C(=O)-CH2-cyclobutyl, -C(=O)-CH2-cyclopentyl, -C(=O)-CH2-cyclohexyl, -C(=O)-methyl wherein the methyl, ethynyl, propynyl, butynyl, butyn-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl or ethyl;

[0054] In some embodiments, R 3 Selected from H, deuterium, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, the alkyl, alkenyl, alkynyl, cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0055] In some embodiments, R 3 Selected from H, deuterium, halogen, CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, the alkyl, alkenyl, alkynyl, cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0056] In some embodiments, R 3 is selected from H, deuterium, F, Cl, methyl, deuterated methyl or fluoromethyl;

[0057] In some embodiments, ring S is selected from C 6-10 aryl or 5- to 10-membered heteroaryl;

[0058] In some embodiments, ring S is selected from phenyl, benzo 4-6 Carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, or 8- to 10-membered heteroaryl;

[0059] In some embodiments, ring S is selected from phenyl or 5- to 6-membered heteroaryl;

[0060] In some embodiments, ring S is selected from phenyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl;

[0061] In some embodiments, ring S is selected from Left side and R 1 Direct connection;

[0062] In some embodiments, Selected from Left side and R 1 Direct connection;

[0063] In some embodiments, ring T is selected from phenyl, 5- to 6-membered heteroaryl, benzo 4-6 Carbocyclyl, benzo 4- to 6-membered heterocyclyl or 8- to 10-membered heteroaryl;

[0064] In some embodiments, ring T is selected from phenyl, thienyl, furanyl, pyridinyl, pyrimidinyl, pyridonyl, benzocyclopentyl, imidazopyridinyl, pyrazolopyridinyl, pyrrolopyridinyl;

[0065] In some embodiments, ring T is selected from phenyl, thienyl, or pyridinyl;

[0066] In some embodiments, Selected from In some embodiments, Selected from

[0067] In some embodiments, Selected from

[0068] In some embodiments, R t2 is selected from methyl and ethyl, wherein the methyl and ethyl groups are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl or ethyl;

[0069] In some embodiments, R 2 、R z1 、R z2 、R z3 Each independently selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-7 Carbocyclic group, -C 0-4 Alkylene-C 3-7 Carbocyclic group, -C 0-4 Alkylene-4 to 7 membered heterocyclic group, -S(=O)C 1-6 Alkyl, -S(=O)C 3-7 Carbocyclyl, -NHS(=O)C 1-6 Alkyl, -S(=O)2C 1-6 Alkyl, -S(=O)2C 3-7 Carbocyclic group, -NHS(=O)2C 1-6 Alkyl, -S(=O)2NHC 1-6 Alkyl, -P(=O)(C 1-6alkyl) 2, wherein the alkylene, alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0070] In some embodiments, alternatively, R 2 、R z3 Direct connection to form C 4-6 Carbocyclic group or 4 to 6 membered heterocyclic group, said carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0071] In some embodiments, alternatively, R 2 、R z1 Direct connection to form C 4-6 Carbocyclic group or 4 to 6 membered heterocyclic group, said carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0072] In some embodiments, R 2 、R z1 、R z2 、R z3 Each independently selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-7 Carbocyclic group, -C 1-2 Alkylene-4 to 7 membered heterocyclic group, -S(=O)C 1-4 Alkyl, -S(=O)C 3-6 Cycloalkyl, -NHS(=O)C 1-4 Alkyl, -S(=O)2C 1-4 Alkyl, -S(=O)2C 3-6 Cycloalkyl, -NHS(=O)2C 1-4 Alkyl, -S(=O)2NHC 1-4 Alkyl, -P(=O)(C 1-4 alkyl) 2, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0073] In some embodiments, alternatively, R 2 、Rz3 Direct connection to form C 4-6 Carbocyclic group or 4 to 6 membered heterocyclic group, said carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0074] In some embodiments, alternatively, R 2 、R z1 Direct connection to form C 4-6 Carbocyclic group or 4 to 6 membered heterocyclic group, said carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0075] In some embodiments, R 2 、R z1 、R z2 、R z3 Each independently selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-7 Carbocyclic group, -C 1-2 Alkylene-4 to 7 membered heterocyclic group, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0076] In some embodiments, R s 、R t Each independently selected from deuterium, halogen, CN, OH, NH2, SF5, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-7 Carbocyclic group, -OC 1-4 Alkylene-C 3-7 Carbocyclic group, -SC 3-7 Carbocyclic group, -SC 1-4 Alkylene-C 3-7 Carbocyclic group, -C 0-4 Alkylene-C 3-7Carbocyclic group, -C 0-4 Alkylene-4 to 7 membered heterocyclic group, -S(=O)C 1-6 Alkyl, -S(=O)C 3-7 Carbocyclyl, -NHS(=O)C 1-6 Alkyl, -S(=O)2C 1-6 Alkyl, -S(=O)2C 3-7 Carbocyclic group, -NHS(=O)2C 1-6 Alkyl, -S(=O)2NHC 1-6 Alkyl, -P(=O)(C 1-6 alkyl) 2, wherein the alkylene, alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0077] In some embodiments, R s 、R t Each independently selected from deuterium, halogen, CN, OH, NH2, SF5, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, -OC 1-2 Alkylene-C 3-6 Cycloalkyl, -SC 3-6 Cycloalkyl, -SC 1-2 Alkylene-C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-7 Carbocyclic group, -C 1-2 Alkylene-4 to 7 membered heterocyclic group, -S(=O)C 1-4 Alkyl, -S(=O)C 3-6 Cycloalkyl, -NHS(=O)C 1-4 Alkyl, -S(=O)2C 1-4 Alkyl, -S(=O)2C 3-6 Cycloalkyl, -NHS(=O)2C 1-4 Alkyl, -S(=O)2NHC 1-4 Alkyl, -P(=O)(C 1-4 alkyl) 2, phenyl or or 5 to 6 membered heteroaryl, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, carbocyclyl, heterocyclyl, phenyl or heteroaryl is optionally substituted by 1 to 4 R k replace;

[0078] In some embodiments, R s 、R t Each independently selected from deuterium, F, Cl, Br, CN, OH, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, -O-CH2-cyclopropyl, -O-CH2-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -S-CH 2-cyclopropyl, -S-CH2-cyclobutyl, -P(=O)(CH3)2, phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl, triazolyl, said CH2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl, triazolyl optionally substituted by 1 to 4 R k replace;

[0079] In some embodiments, R s each independently selected from deuterium, F, Cl, Br, CN, OH, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, -P(=O)(CH3)2, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, thiadiazole wherein CH2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl, triazolyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy or ethoxy;

[0080] In some embodiments, R 2 、R z1 、R z2 Each independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy, cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, cyclopropyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, C 1-4 Alkyl, C1-4 substituted by an alkoxy substituent;

[0081] In some embodiments, R 2 、R z1 、R z2 Each is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy, and cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, and cyclopropyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, or ethyl;

[0082] In some embodiments, R 2 、R z1 、R z2 Each is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy, and cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, and cyclopropyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy, or ethoxy;

[0083] In some embodiments, R 2 Selected from H, R z1 Selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, CF3, CHF2, CH2F, CD3, CHD2, CH2D, cyclopropyl;

[0084] In some embodiments, R t1 Selected from H, deuterium, halogen, CN, OH, NH2, SF5, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, -OC 1-2 Alkylene-C 3-6 Cycloalkyl, -SC 3-6 Cycloalkyl, -SC 1-2 Alkylene-C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-7 Carbocyclic group, -C 1-2Alkylene-4 to 7 membered heterocyclic group, -S(=O)C 1-4 Alkyl, -S(=O)C 3-6 Cycloalkyl, -NHS(=O)C 1-4 Alkyl, -S(=O)2C 1-4 Alkyl, -S(=O)2C 3-6 Cycloalkyl, -NHS(=O)2C 1-4 Alkyl, -S(=O)2NHC 1-4 Alkyl, -P(=O)(C 1-4 alkyl) 2, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0085] In some embodiments, R t1 is selected from H, deuterium, F, Cl, Br, CN, OH, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, -O-CH2-cyclopropyl, -O-CH2-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -S-C H2-cyclopropyl, -S-CH2-cyclobutyl, oxetanyl, tetrahydrofuranyl, -S(=O)CH3, -S(=O)cyclopropyl, -NHS(=O)-CH3, -S(=O)2-CH3, -S(=O)2cyclopropyl, -NHS(=O)2CH3, -S(=O)2NHCH3, -P(=O)(CH3)2, the CH2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl are optionally substituted by 1 to 4 R k replace;

[0086] In some embodiments, R t1 Selected from SF5, methyl, ethyl, methoxy, ethoxy, -S-methyl, -S-ethyl, -O-cyclopropyl, -O-cyclobutyl, -OCH2-cyclopropyl, -OCH2-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -SCH2-cyclopropyl, -SCH2-cyclobutyl, wherein the methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl or ethyl;

[0087] In some embodiments, R kEach independently selected from deuterium, =O, halogen, CN, OH, COOH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclyl, -O-4 to 7 membered heterocyclyl, -NH-C 3-6 Carbocyclic group, -NH-4 to 7 membered heterocyclic group, -C 1-4 Alkylene-C 3-6 Carbocyclic group, -C 1-4 Alkylene-4 to 7 membered heterocyclic group, C 3-6 Carbocyclic group, 4 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0088] In some embodiments, R k Each independently selected from deuterium, =O, F, Cl, Br, I, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally substituted by 1 to 4 selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0089] In some embodiments, R k Each independently selected from deuterium, =O, halogen, CN, OH, COOH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Carbocyclyl, -O-4 to 7 membered heterocyclyl, -NH-C 3-6Carbocyclic group, -NH-4 to 7 membered heterocyclic group, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C 1-2 Alkylene-4 to 7 membered heterocyclic group, C 3-6 Carbocyclic group, 4 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0090] In some embodiments, R k Each independently selected from deuterium, F, Cl, Br, I, CN, OH, -CH2OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0091] In some embodiments, n1 and n2 are each independently selected from 0, 1, 2, 3 or 4;

[0092] In some embodiments, Selected from 1 to 3 R m One of the following groups substituted:

[0093] In some embodiments, Selected from

[0094] In some embodiments, ring S is selected from phenyl or 5- to 6-membered heteroaryl;

[0095] In some embodiments, ring S is selected from Left side and R 1 Direct connection;

[0096] In some embodiments, Y is selected from N or CH;

[0097] In some embodiments, n3 is selected from 0, 1, 2 or 3.

[0098] As a first embodiment of the present invention, the compound represented by the above general formula (IA) or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt,

[0099] Selected from

[0100] Ring M is selected from 5-membered heteroaryl or 5-membered unsaturated heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted by 1 to 4 R m replace;

[0101] R m Each independently selected from deuterium, halogen, CN, =O, =S, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4 to 7 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R k replace;

[0102] X is selected from N, O, S, C(R x )、C(R x )2 or N(R x );

[0103] R x Each independently selected from H, -C(=O)-C 1-6 Alkyl, -C(=O)-C 3-6 Cycloalkyl, C 1-6 Alkyl, -C 0-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene or cycloalkyl group is optionally substituted by 1 to 4 R k replace;

[0104] Q is selected from C, C(R q1 )、C(R q1 )2. C(=O), C(=S), C=N(R q2 ), C=C(R q3 )2, S(=O), S(=O)(=NH), S(=O)2; R q1 Selected from H, deuterium, C 1-6 Alkyl, said alkyl being optionally substituted by 1 to 4 R k replace;

[0105] R q2 、R q3 Each independently selected from H, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, said alkyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0106] W is selected from -CRw1 R w2 -、-(CR w1 R w2 )2-;

[0107] R w1 、R w2 Each independently selected from H, deuterium, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, said alkyl or cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0108] Alternatively, R w1 、R w2 Direct connection to form C 3-6 Cycloalkyl, the cycloalkyl group is optionally substituted by 1 to 4 R k replace;

[0109] Ring A is selected from 5-membered heteroaryl,

[0110] Z1 is selected from N or C(R z1 );

[0111] Z2 is selected from N or C(R z2 );

[0112] Z3 is selected from N or C(R z3 );

[0113] Z4 is selected from N or C;

[0114] Z5 is selected from N or C; Z6 is selected from N or C;

[0115] R 1 Selected from C 5-10 Bicyclic cycloalkyl, C 7-12 tricyclic cycloalkyl, -6 to 12 membered bicyclic heterocycloalkyl-R 1b , the R 1 Optional 1 to 4 R 1a replace;

[0116] R 1a Each independently selected from deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -C 0-4 Alkylene-C 3-6 Cycloalkyl, -C 0-4 alkylene-4 to 7 membered heterocycloalkyl, -C(=O)C 1-6Alkyl, -C(=O)C 3-7 carbocyclyl, -C(=O)-4 to 7 membered heterocyclyl, -NHC(=O)C 1-6 Alkyl, -NHC(=O)C 3-6 Cycloalkyl, -S(=O)C 1-6 Alkyl, -S(=O)C 3-7 Carbocyclyl, -NHS(=O)C 1-6 Alkyl, -S(=O)2C 1-6 Alkyl, -S(=O)2C 3-7 Carbocyclic group, -NHS(=O)2C 1-6 Alkyl, -S(=O)2NHC 1-6 Alkyl, -P(=O)(C 1-6 alkyl) 2, wherein the alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R k replace;

[0117] R 1b Selected from H, C 1-6 Alkyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, 4 to 7 membered heterocyclic group, -C 1-2 Alkylene-C 3-7 Carbocyclic group, -C 1-2 Alkylene-4 to 7 membered heterocyclic group, -C(=O)C 1-2 Alkylene-C 3-7 Carbocyclic group, -C(=O)C 1-6 Alkyl, -C(=O)C 3-7 Carbocyclic group, -C(=O)C 1-2 Alkylene-4 to 7 membered heterocyclic group, -C(=O)-4 to 7 membered heterocyclic group, wherein the alkylene, alkyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0118] R 3 Selected from H, deuterium, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, the alkyl, alkenyl, alkynyl, cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0119] Ring S is selected from C 6-10 aryl or 5- to 10-membered heteroaryl;

[0120] Ring T is selected from phenyl, 5 to 6 membered heteroaryl, benzo 4-6 Carbocyclyl, benzo 4- to 6-membered heterocyclyl or 8- to 10-membered heteroaryl;

[0121] R 2 、R z1 、R z2 、R z3 Each independently selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-7 Carbocyclic group, -C 0-4 Alkylene-C 3-7 Carbocyclic group, -C 0-4 Alkylene-4 to 7 membered heterocyclic group, -S(=O)C 1-6 Alkyl, -S(=O)C 3-7 Carbocyclyl, -NHS(=O)C 1-6 Alkyl, -S(=O)2C 1-6 Alkyl, -S(=O)2C 3-7 Carbocyclic group, -NHS(=O)2C 1-6 Alkyl, -S(=O)2NHC 1-6 Alkyl, -P(=O)(C 1-6 alkyl) 2, wherein the alkylene, alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0122] Alternatively, R 2 、R z3 Direct connection to form C 4-6 Carbocyclic group or 4 to 6 membered heterocyclic group, said carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0123] Alternatively, R 2 、R z1 Direct connection to form C 4-6 Carbocyclic group or 4 to 6 membered heterocyclic group, said carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0124] R s 、R t Each independently selected from deuterium, halogen, CN, OH, NH2, SF5, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-7 Carbocyclic group, -OC 1-4 Alkylene-C 3-7 Carbocyclic group, -SC 3-7 Carbocyclic group, -SC 1-4 Alkylene-C 3-7 Carbocyclic group, -C 0-4 Alkylene-C 3-7 Carbocyclic group, -C 0-4 Alkylene-4 to 7 membered heterocyclic group, -S(=O)C 1-6 Alkyl, -S(=O)C 3-7 Carbocyclyl, -NHS(=O)C 1-6 Alkyl, -S(=O)2C 1-6 Alkyl, -S(=O)2C 3-7 Carbocyclic group, -NHS(=O)2C 1-6 Alkyl, -S(=O)2NHC 1-6 Alkyl, -P(=O)(C 1-6 alkyl) 2, wherein the alkylene, alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0125] R k Each independently selected from deuterium, =O, halogen, CN, OH, COOH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclyl, -O-4 to 7 membered heterocyclyl, -NH-C 3-6 Carbocyclic group, -NH-4 to 7 membered heterocyclic group, -C 1-4 Alkylene-C 3-6 Carbocyclic group, -C 1-4 Alkylene-4 to 7 membered heterocyclic group, C 3-6 Carbocyclic group, 4 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0126] n1 and n2 are each independently selected from 0, 1, 2, 3 or 4.

[0127] As a second embodiment of the present invention, the compounds represented by the above-mentioned general formula (IA), (I), (Ia), (Ib), (Ic), (Id), (Ie) or their racemates, stereoisomers, tautomers, and pharmaceutically acceptable salts,

[0128] R m Each independently selected from deuterium, halogen, CN, =O, =S, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4 to 7 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R k replace;

[0129] R x Each independently selected from H, -C(=O)-C 1-4 Alkyl, -C(=O)-C 3-6 Cycloalkyl, C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 1-2 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene or cycloalkyl group is optionally substituted by 1 to 4 R k replace;

[0130] R q1 Selected from H, deuterium, C 1-4 Alkyl, said alkyl being optionally substituted by 1 to 4 R k replace;

[0131] R q2 、R q3 Each independently selected from H, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, said alkyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0132] R 1 Selected from C 5-10 Bridged cycloalkyl, C 6-10 Cycloalkyl, C 5-10 Spirocycloalkyl, -6 to 10 membered bridged heterocycloalkyl-R 1b 、-6 to 12 membered heterocyclic alkyl-R 1b 、-6 to 12-membered spirocyclic heterocycloalkyl-R 1b , the R 1Optional 1 to 4 R 1a replace;

[0133] R 1a Each independently selected from deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-6 Cycloalkyl, C 1-2 alkylene-4 to 7 membered heterocycloalkyl, -C(=O)C 1-4 Alkyl, -C(=O)C 3-6 Cycloalkyl, -C(=O)-4 to 7 membered heterocycloalkyl, -NHC(=O)C 1-4 Alkyl, -NHC(=O)C 3-6 Cycloalkyl, -S(=O)C 1-4 Alkyl, -S(=O)C 3-6 Cycloalkyl, -NHS(=O)C 1-4 Alkyl, -S(=O)2C 1-4 Alkyl, -S(=O)2C 3-6 Cycloalkyl, -NHS(=O)2C 1-4 Alkyl, -S(=O)2NHC 1-4 Alkyl, -P(=O)(C 1-4 alkyl) 2, wherein the alkylene, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R k replace;

[0134] R 1b Selected from H, C 1-4 Alkyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-6 Cycloalkyl, -C 1-2 alkylene-4 to 7 membered heterocycloalkyl, -C(=O)C 1-2 Alkylene-C 3-6 Cycloalkyl, -C(=O)C 1-4 Alkyl, -C(=O)C 3-6 Cycloalkyl, -C(=O)-C 1-2 Alkylene-4 to 7 membered heterocycloalkyl, -C(=O)-4 to 7 membered heterocycloalkyl, wherein the alkylene, alkyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R kreplace;

[0135] R w1 、R w2 Each independently selected from H, deuterium, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, said alkyl or cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0136] Alternatively, R w1 、R w2 Direct connection to form C 3-6 Cycloalkyl, the cycloalkyl group is optionally substituted by 1 to 4 R k replace;

[0137] R 3 Selected from H, deuterium, halogen, CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, the alkyl, alkenyl, alkynyl, cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0138] Ring S is selected from phenyl, benzo 4-6 Carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, or 8- to 10-membered heteroaryl;

[0139] R 2 、R z1 、R z2 、R z3 Each independently selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-7 Carbocyclic group, -C 1-2 Alkylene-4 to 7 membered heterocyclic group, -S(=O)C 1-4 Alkyl, -S(=O)C 3-6 Cycloalkyl, -NHS(=O)C 1-4 Alkyl, -S(=O)2C 1-4 Alkyl, -S(=O)2C 3-6 Cycloalkyl, -NHS(=O)2C 1-4 Alkyl, -S(=O)2NHC1-4 Alkyl, -P(=O)(C 1-4 alkyl) 2, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0140] Alternatively, R 2 、R z3 Direct connection to form C 4-6 Carbocyclic group or 4 to 6 membered heterocyclic group, said carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0141] Alternatively, R 2 、R z1 Direct connection to form C 4-6 Carbocyclic group or 4 to 6 membered heterocyclic group, said carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0142] R s 、R t Each independently selected from deuterium, halogen, CN, OH, NH2, SF5, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, -OC 1-2 Alkylene-C 3-6 Cycloalkyl, -SC 3-6 Cycloalkyl, -SC 1-2 Alkylene-C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-7 Carbocyclic group, -C 1-2 Alkylene-4 to 7 membered heterocyclic group, -S(=O)C 1-4 Alkyl, -S(=O)C 3-6 Cycloalkyl, -NHS(=O)C 1-4 Alkyl, -S(=O)2C 1-4 Alkyl, -S(=O)2C 3-6 Cycloalkyl, -NHS(=O)2C 1-4 Alkyl, -S(=O)2NHC 1-4 Alkyl, -P(=O)(C 1-4alkyl) 2, phenyl or 5 to 6 membered heteroaryl, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, carbocyclyl, heterocyclyl, phenyl or heteroaryl is optionally substituted by 1 to 4 R k replace;

[0143] R k Each independently selected from deuterium, =O, halogen, CN, OH, COOH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Carbocyclyl, -O-4 to 7 membered heterocyclyl, -NH-C 3-6 Carbocyclic group, -NH-4 to 7 membered heterocyclic group, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C 1-2 Alkylene-4 to 7 membered heterocyclic group, C 3-6 Carbocyclic group, 4 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0144] The remaining groups are defined the same as in the first embodiment of the present invention.

[0145] As a third embodiment of the present invention, the compounds represented by the above-mentioned general formula (IA), (I), (Ia), (Ib), (Ic), (Id), (Ie) or their racemates, stereoisomers, tautomers, and pharmaceutically acceptable salts,

[0146] Selected from

[0147] Selected from 1 to 3 R m One of the following groups substituted:

[0148] Selected from

[0149] R w1 、R w2Each independently selected from H, deuterium, F, Cl, Br, methyl, ethyl, cyclopropyl, wherein the methyl, ethyl, cyclopropyl is optionally substituted by 1 to 4 R k replace;

[0150] Alternatively, R w1 、R w2 Direct connection forms cyclopropyl, cyclobutyl, and the cyclopropyl, cyclobutyl are optionally substituted by 1 to 4 R k replace;

[0151] Ring S is selected from phenyl or 5- to 6-membered heteroaryl;

[0152] Selected from

[0153] Y is selected from N or CH;

[0154] R 1 Selected from The R 1 Optional 1 to 4 R 1a replace;

[0155] s1, s3, and s5 are each independently selected from 0, 1, or 2;

[0156] s2 and s4 are each independently selected from 0 or 1;

[0157] R t1 Selected from H, deuterium, halogen, CN, OH, NH2, SF5, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, -OC 1-2 Alkylene-C 3-6 Cycloalkyl, -SC 3-6 Cycloalkyl, -SC 1-2 Alkylene-C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-7 Carbocyclic group, -C 1-2 Alkylene-4 to 7 membered heterocyclic group, -S(=O)C 1-4 Alkyl, -S(=O)C 3-6 Cycloalkyl, -NHS(=O)C 1-4 Alkyl, -S(=O)2C1-4 Alkyl, -S(=O)2C 3-6 Cycloalkyl, -NHS(=O)2C 1-4 Alkyl, -S(=O)2NHC 1-4 Alkyl, -P(=O)(C 1-4 alkyl) 2, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0158] n3 is selected from 0, 1, 2 or 3;

[0159] The remaining groups are defined the same as in the first or second embodiment of the present invention.

[0160] As a fourth embodiment of the present invention, the compounds represented by the above-mentioned general formulas (IA), (I), (Ia), (Ib), (Ic), (Id), (Ie) or their racemates, stereoisomers, tautomers, and pharmaceutically acceptable salts,

[0161] R m Each independently selected from deuterium, F, Cl, Br, CN, OH, methyl, ethyl, methoxy, ethoxy, cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, cyclopropyl is optionally substituted by 1 to 4 selected from deuterium, halogen, CF3, CHF2, CH2F, CD3, CHD2, CH2D, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0162] W is selected from -CH2-, -CH(CH3)-, -CH(CF3)-, -CH(CD3)-, -CFH-, -CF2-, -CH2CH2- or

[0163] R 2 、R z1 、R z2 Each independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy, cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, cyclopropyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0164] R xSelected from H, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH(CH3)2, -C(=O)-cyclopropyl, methyl, ethyl, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, cyclopropyl, cyclobutyl is optionally substituted by 1 to 4 R k replace;

[0165] R q1 is selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl or cyclopropyl, wherein the methyl, ethyl and cyclopropyl groups are optionally substituted by 1 to 4 groups selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0166] R q2 is selected from H, OH, CN, NH2, methyl, ethyl, methoxy, ethoxy, wherein the methyl, ethyl, methoxy, ethoxy is optionally substituted by 1 to 4 deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0167] Ring S is selected from phenyl, thienyl, thiazolyl, furyl, oxazolyl, pyrazolyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl;

[0168] R 1 Selected from The R 1 Optional 1 to 4 R 1a replace;

[0169] R 1a Each independently selected from deuterium, F, Cl, Br, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, methoxy, ethoxy, cyclopropyl, -CH2-cyclopropyl, -S(=O)CH3, -S(=O)cyclopropyl, -NHS(=O)-CH3, -S(=O)2-CH3, -S(=O)2cyclopropyl, -NHS(=O)2CH3, -S(=O)2NHCH3, -P(=O)(CH3)2, wherein the CH2, methyl, ethyl, methoxy, ethoxy, cyclopropyl are optionally substituted by 1 to 4 R k replace;

[0170] R 1bSelected from H or optionally 1 to 4 R k substituted with one of the following groups: methyl, ethynyl, -CH2-ethynyl, propynyl, butynyl, butyn-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-oxetanyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl , -C(=O)-CH2-cyclopropyl, -C(=O)-CH2-cyclobutyl, -C(=O)-CH2-cyclopentyl, -C(=O)-CH2-cyclohexyl, -C(=O)-methyl, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl, -C(=O)-cyclohexyl, -C(=O)-oxetanyl, -C(=O)-tetrahydrofuranyl, -C(=O)-oxetanyl, -C(=O)-azetidinyl, -C(=O)-pyrrolidinyl, -C(=O)-piperidinyl, -C(=O)-piperazinyl;

[0171] R s 、R t Each independently selected from deuterium, F, Cl, Br, CN, OH, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, -O-CH2-cyclopropyl, -O-CH2-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -S-CH 2-cyclopropyl, -S-CH2-cyclobutyl, -P(=O)(CH3)2, phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl, triazolyl, said CH2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl, triazolyl optionally substituted by 1 to 4 R k replace;

[0172] R t1is selected from H, deuterium, F, Cl, Br, CN, OH, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, -O-CH2-cyclopropyl, -O-CH2-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -S-C H2-cyclopropyl, -S-CH2-cyclobutyl, oxetanyl, tetrahydrofuranyl, -S(=O)CH3, -S(=O)cyclopropyl, -NHS(=O)-CH3, -S(=O)2-CH3, -S(=O)2cyclopropyl, -NHS(=O)2CH3, -S(=O)2NHCH3, -P(=O)(CH3)2, the CH2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl are optionally substituted by 1 to 4 R k replace;

[0173] R k Each independently selected from deuterium, =O, F, Cl, Br, I, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally substituted by 1 to 4 selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0174] Preferably, R k Each independently selected from deuterium, F, Cl, Br, I, CN, OH, -CH2OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0175] The remaining groups are defined the same as in the first, second or third embodiment of the present invention.

[0176] As a fifth embodiment of the present invention, the compounds represented by the above-mentioned general formulas (IA), (I), (Ia), (Ib), (Ic), (Id), (Ie) or their racemates, stereoisomers, tautomers, and pharmaceutically acceptable salts,

[0177] R m Each independently selected from deuterium, F, Cl, Br, CN, methyl, ethyl, cyclopropyl, CF3, CHF2, CH2F, CD3, CHD2, CH2D, CH2CD3, CH2CF3;

[0178] R 1 is selected from one of the following groups wherein the ring is optionally substituted: When substituted, it is optionally substituted with 1 to 3 substituents selected from deuterium, F, Cl, Br, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, -CH2OH, methyl, ethyl, methoxy, ethoxy;

[0179] R 1a Each independently selected from OH, NH2, CN, -NHS(=O)-CH3, -NHS(=O)2-CH3, -S(=O)-CH3, -S(=O)2-CH3;

[0180] R 1b is selected from H, methyl, ethynyl, -CH2-ethynyl, propynyl, butynyl, butyn-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -C(=O)-CH2-cyclopropyl, -C(=O)-CH2-cyclobutyl, -C(=O)-CH2-cyclopentyl, -C(=O)-CH2-cyclohexyl, -C(=O)-methyl wherein the methyl, ethynyl, propynyl, butynyl, butyn-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl or ethyl;

[0181] Ring S is selected from Left side and R 1 Direct connection;

[0182] R t1 Selected from SF5, methyl, ethyl, methoxy, ethoxy, -S-methyl, -S-ethyl, -O-cyclopropyl, -O-cyclobutyl, -OCH2-cyclopropyl, -OCH2-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -SCH2-cyclopropyl, -SCH2-cyclobutyl, wherein the methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl or ethyl;

[0183] R x is selected from H, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH(CH3)2, -C(=O)-cyclopropyl, methyl, ethyl, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, cyclopropyl, cyclobutyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl or ethyl;

[0184] R q1 is selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl or cyclopropyl, wherein the methyl, ethyl or cyclopropyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl or ethyl;

[0185] R q2 is selected from H, OH, CN, NH2, methyl, ethyl, methoxy, ethoxy, wherein the methyl, ethyl, methoxy, ethoxy is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl or ethyl;

[0186] R 2 、R z1 、R z2 Each is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy, and cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, and cyclopropyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy, or ethoxy;

[0187] Preferably, R s each independently selected from deuterium, F, Cl, Br, CN, OH, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, -P(=O)(CH3)2, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, thiadiazole wherein CH2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl, triazolyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy or ethoxy;

[0188] The remaining groups are defined the same as in the first, second, third or fourth embodiment of the present invention.

[0189] The present invention relates to the compound shown below or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt, wherein the compound is selected from one of the structures shown below in Table E.

[0190] Table E

[0191] The present invention relates to a pharmaceutical composition comprising any of the above compounds, their racemates, stereoisomers, tautomers, pharmaceutically acceptable salts, and pharmaceutically acceptable carriers.

[0192] The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention, its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

[0193] In some embodiments, the pharmaceutical composition of the present invention may be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as the "preparation strength").

[0194] As used herein, an "effective amount" or "therapeutically effective amount" refers to administering a sufficient amount of a compound disclosed herein to alleviate, to some extent, one or more symptoms of the disease or condition being treated (e.g., an autoimmune disease or inflammatory disease (preferably psoriasis or rheumatoid arthritis)). In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg , 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-40 0mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250- 400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg , 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1000mg, 80-800mg.

[0195] In some embodiments, the pharmaceutical composition includes but is not limited to 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 The invention can be administered in an amount of 1 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 640 mg or 840 mg of a compound of the present invention or a stereoisomer, a pharmaceutically acceptable salt or a cocrystal thereof.

[0196] A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, a pharmaceutically acceptable salt or a cocrystal thereof, preferably 1-1500 mg, wherein the disease is preferably an autoimmune disease or an inflammatory disease (preferably psoriasis or rheumatoid arthritis).

[0197] A method for treating or alleviating a disease in a mammal, comprising administering a compound of the present invention or a stereoisomer, a pharmaceutically acceptable salt or a cocrystal thereof to a subject at a daily dose of 1-1000 mg / day, wherein the daily dose may be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 25-400 In some embodiments, the daily dose includes but is not limited to 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 80 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 160 mg / day, 200 mg / day, 300 mg / day, 320 mg / day, 400 mg / day, 480 mg / day, 600 mg / day, 640 mg / day, 800 mg / day, 1000 mg / day.

[0198] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form, wherein the kit contains a compound of the present invention or a stereoisomer, a pharmaceutically acceptable salt or a cocrystal thereof, and the amount of the compound of the present invention or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt is the same as that in the above-mentioned pharmaceutical composition.

[0199] The present invention relates to the use of any of the above compounds or their racemates, stereoisomers, tautomers, and pharmaceutically acceptable salts in the preparation of drugs for treating autoimmune diseases or inflammatory diseases (preferably psoriasis or rheumatoid arthritis).

[0200] The present invention relates to the use of the above-mentioned pharmaceutical composition in preparing medicines for treating autoimmune diseases or inflammatory diseases (preferably psoriasis or rheumatoid arthritis).

[0201] The amount of the compound of the present invention, its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt is in each case calculated based on the free base form.

[0202] Synthesis method 1:

[0203] The general formula (Z1) reacts with diphenylphosphoryl azide under alkaline conditions and is then reduced with triphenylphosphine to obtain the corresponding general formula (Z2). The general formula (Z2) reacts with carbon monoxide under palladium catalysis to obtain the corresponding general formula (Z3). The general formula (Z3) reacts with iodomethane under alkaline conditions to obtain the corresponding general formula (Z4). The general formula (Z4) reacts with pinacol diboron under a palladium catalyst to obtain the corresponding general formula (Z5). The general formula (Z5) and the general formula (Z6) are coupled under a palladium catalyst to obtain the corresponding general formula (Ia').

[0204] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0205] The compounds of the present invention include racemates, stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof.

[0206] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0207] "CN" refers to cyano.

[0208] "Halogen" refers to F, Cl, Br or I.

[0209] "Halogen-substituted" refers to substitution with F, Cl, Br or I, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br or I, substitution with 1 to 6 substituents selected from F, Cl, Br or I, and substitution with 1 to 4 substituents selected from F, Cl, Br or I. "Halogen-substituted" is abbreviated as "halo".

[0210] "Alkyl" refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof; alkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0211] "Alkylene" refers to substituted or unsubstituted straight-chain and branched divalent saturated hydrocarbon groups, including -(CH2) v -(v is an integer from 1 to 10), examples of alkylene include but are not limited to methylene, ethylene, propylene and butylene.

[0212] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 12 carbon atoms. Cycloalkyl groups can be monocyclic, fused, bridged, or spirocyclic. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirocyclobutyl, and adamantane. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0213] " Heterocycloalkyl " refers to a saturated cyclic hydrocarbon radical containing heteroatoms that is substituted or unsubstituted, including but not limited to 3 to 12 atoms, 3 to 8 atoms, comprising 1 to 3 heteroatoms selected from N, O, S or Se, and the C, N, S on the ring of heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl can be a monocycle, a ring, a bridged ring and a spirocycle. Heterocycloalkyl can be connected to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazolidinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl, The heterocycloalkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0214] "Alkenyl" refers to a substituted or unsubstituted straight-chain or branched unsaturated hydrocarbon group having at least one, typically one, two or three, carbon-carbon double bonds, with a backbone of 2 to 10, 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, and the like; an alkenyl group can be monovalent, divalent, trivalent or tetravalent.

[0215] "Alkynyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three, carbon-carbon triple bonds, with a backbone comprising 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the backbone and 2 to 4 carbon atoms in the backbone. Examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, and the like; alkynyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0216] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.

[0217] "Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocycle, a 4-12 membered bicycle, a 10-15 membered tricycle, or a 12-18 membered quaternary system. The carbocyclyl can be attached to the aromatic or non-aromatic ring, and the ring can be optionally a monocycle, a cyclic ring, a bridged ring, or a spirocycle. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, a benzene ring, a naphthalene ring, "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0218] "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring, a 10-15 membered tricyclic ring, or a 12-18 membered quaternary ring, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O, S or Se. The C, N, S or Se optionally substituted in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, and can be attached to an aromatic ring or a non-aromatic ring. The heterocyclic group is optionally a monocyclic, bridged, fused or spirocyclic ring. Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolane, 1,4-dioxolane, 1,3-dioxane, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiazyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophenyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl, "Heterocyclyl" or "heterocycle" can be monovalent, divalent, trivalent or tetravalent.

[0219] "Spirocycle" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom), and the number of ring atoms in the spirocycle system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and optionally may contain 0 to 5 atoms selected from N, O or S (=O) n (n is 0, 1 or 2).

[0220] "Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

[0221] "Parallel ring" or "parallel ring group" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds and may be substituted or unsubstituted, and each ring in the parallel ring system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O) n or O, n is 0, 1 or 2). The number of ring atoms in the cyclic system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include: "Bicyclic" or "bicyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0222] "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, and may contain zero or more double bonds. Any ring in the bridged ring system may contain zero to five atoms selected from heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O)n or O, where n is 0, 1, or 2). The number of ring atoms includes but is not limited to 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include "Bridged ring" or "bridged ring group" may be monovalent, divalent, trivalent or tetravalent.

[0223] "Carbospirocycle," "spirocarbocyclyl," "spirocarbocyclyl," or "carbospirocyclyl" refers to a "spirocycle" wherein the ring system consists of only carbon atoms.

[0224] "Carbocyclyl," "carbocyclyl," "carbocyclyl," or "carbocyclyl" refers to a "carbocyclyl" ring system consisting of only carbon atoms.

[0225] "Carbobridged ring," "bridged carbocyclic group," "bridged carbocyclic group," or "carbon-bridged cyclic group" refers to a "bridged ring" wherein the ring system consists of only carbon atoms.

[0226] "Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a monocyclic ring system of "heterocyclyl" or "heterocycle",

[0227] "Heterocyclo", "heterocycloalkyl", "cycloheterocyclyl" or "cycloheterocyclyl" refers to a "cyclo" containing a heteroatom.

[0228] "Heterospirocycle," "heterospirocyclyl," "spiroheterocyclyl," or "spiroheterocyclyl" refers to a "spirocycle" containing a heteroatom.

[0229] "Heterobridged ring", "heterobridged cyclic group", "bridged ring heterocyclic group" or "bridged heterocyclic group" refers to a "bridged ring" containing a heteroatom.

[0230] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbon ring, wherein the ring connected to the parent structure is the aryl ring, non-limiting examples of which include benzene ring, naphthalene ring, "Aryl" or "aromatic ring" can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.

[0231] "Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, O, S(=O)n or Se(=O)n, where n is 0, 1 or 2). The number of ring atoms in the heteroaromatic ring is, but not limited to, 5 to 15, 5 to 10 or 5 to 6. The ring atoms C, N, and S are optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, where n is 1 or 2). Non-limiting examples of heteroaryl include but are not limited to pyridyl, furyl, thienyl, selenophenyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, pyridonyl and the like. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include When heteroaryl appears in this document, its definition is consistent with this definition. Heteroaryl can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the attachment point is located on the ring with aromaticity.

[0232] "Substituted" or "substituted" refers to substitution by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cycloalkyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH2), m -C(=O)-R a 、-O-(CH2) m -C(=O)-R a 、-(CH2) m -C(=O)-NR b R c 、-(CH2) m S(=O) n R a 、-(CH2) m -alkenyl-R a , OR d or -(CH2) m -alkynyl-R a (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c etc., where R b With R c R is independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, b With R c Can form five or six-membered cycloalkyl or heterocyclic group, R a With R d Each is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring or paracyclic group.

[0233] "1 to X substituents selected from..." means substituted by 1, 2, 3, ..., X substituents selected from ..., where X is any integer from 1 to 10. For example, "1 to 4 R k "Substituted" means replaced by 1, 2, 3 or 4 R k Substitution. For example, "substituted by 1 to 5 substituents selected from..." means substituted by 1, 2, 3, 4, or 5 substituents selected from..." For example, "a heterobridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 1, 2, 3, or 4 substituents selected from H or F.

[0234] An XY-membered ring (X and Y are integers, and 3≤X<Y, X<Y≤20 is selected from any integer between 4 and 20) includes rings with X, X+1, X+2, X+3, X+4, ..., Y members. Rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterocyclic rings, heterospirocyclic rings, or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" refers to a 4-, 5-, 6-, or 7-membered heteromonocyclic ring, and "5-10 membered heterocyclic ring" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic ring.

[0235] C x-y Carbocycles (including aryl, cycloalkyl, monocyclic carbocycle, spirocyclic carbocycle, fused carbocycle or bridged carbocycle) include C x 、C x+1 、C x+2 、C x+3 、C x+4 ….C y A ring of 1-membered ring (x is an integer, and 3≤x<y, y is selected from any integer between 4 and 20), for example. 3-6 "Cycloalkyl" refers to C3, C4, C5 or C6 cycloalkyl;

[0236] When a group has one or more bondable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are hydrogen atoms at the bondable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of chemical bonds connected, and the group will become a group with the corresponding valence. For example Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Also included For example Indicates that the R group on the piperidinyl group can be located on C, can be located on N, and at least includes

[0237] When the listed linking groups do not specify their connection direction, their connection directions include connection from left to right and from right to left in the reading order, for example, when ALB, L is selected from -MW-, it includes AMWB and AWMB.

[0238] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0239] "Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0240] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, optical isomers, enantiomers, diastereomers and conformational isomers.

[0241] "Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomers and amide-imino alcohol isomers. DETAILED DESCRIPTION

[0242] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0243] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Vance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and tetramethylsilane (TMS) as the internal standard.

[0244] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0245] HPLC determination was performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

[0246] Thin layer chromatography silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used for thin layer chromatography (TLC) were 0.15 mm to 0.20 mm, and the specifications used for thin layer chromatography separation and purification products were 0.4 mm to 0.5 mm.

[0247] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0248] In order to accomplish the purpose of the present invention, the compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., TCI (Shanghai) Chemical Industry Development Co., Ltd., Anage Chemical, Shanghai Titan Technology Co., Ltd., Kelon Chemical, Bailingwei Technology Co., Ltd., etc.

[0249] Retention time: Unless otherwise specified in the examples, it represents the retention time corresponding to the analytical method.

[0250] Example 1: Preparation of Compound 1

[0251] Step 1: Preparation of 1c

[0252] 1a (300 mg, 3.12 mmol) was dissolved in tetrahydrofuran (5 mL), and 1b (378 mg, 3.12 mmol) and tetraisopropyl titanate (1.8 g, 6.24 mmol) were added. The mixture was stirred at 60°C for 12 hours. Water (10 mL) was added, the mixture was filtered, and the filter cake was washed with ethyl acetate. The organic layer was washed with water (15 mL) and saturated brine (15 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated on a silica gel column to afford 1c (440 mg, 70.7% yield).

[0253] Step 2: Preparation of 1e

[0254] 1d (881 mg, 3.09 mmol) was dissolved in dichloromethane (15 mL), cooled to -78°C, and n-butyllithium (2.5 M in hexane, 1.2 mL) was added dropwise. The mixture was stirred at -78°C for 2 hours. A solution of 1c (440 mg, 2.21 mmol) in dichloromethane (5 mL) was added, and the mixture was stirred at -78°C for 2 hours. The mixture was then allowed to warm to room temperature and the reaction continued for 12 hours. The reaction solution was quenched by adding saturated ammonium chloride solution (20 mL) dropwise and extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography to afford 1e (230 mg, 29.1% yield).

[0255] Step 3: Preparation of 1f

[0256] Dissolve 1e (230 mg, 0.64 mmol) in methanol (2 mL), add hydrochloric acid (4 M in MeOH, 2 mL), and stir at room temperature for 2 hours. Concentrate the mixture, add ether:methanol (10:1, 2 mL), stir, and filter. Wash the filter cake with ether. Dry the filter cake to obtain 1f (230 mg, crude product).

[0257] Step 4: Preparation of 1g

[0258] Dissolve 1f (230 mg, crude product) in tetrahydrofuran (3 mL) and add di-tert-butyl dicarbonate (199 mg, 0.91 mmol) and triethylamine (0.38 mL, 2.73 mmol) at 0°C. Stir at 0°C for 30 minutes and then at room temperature for 1 hour. Dilute with water and extract with ethyl acetate (10 mL x 3). The combined organic phases are washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated and separated on a silica gel column to obtain 1g (175 mg, 54.6% yield).

[0259] Step 5: Preparation of 1i

[0260] 1g (35mg, 0.1mmol) and 1h (50mg, 0.1mmol) were added to 1,4-dioxane and water (5:1, 1.8mL), and PdCl2(dppf) was added. . DCM (CAS: 95464-05-4) (4 mg, 0.005 mmol) and potassium carbonate (35 mg, 0.25 mmol) were stirred at 90°C under nitrogen for 12 hours. The reaction solution was diluted with water and extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated brine (10 mL). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated on a silica gel column to obtain 1i (30 mg, 45.9% yield).

[0261] LCMS m / z=629.4[M+H] + ;

[0262] Step 6: Preparation of compound 1

[0263] 1i (30 mg, 0.048 mmol) was dissolved in 1,4-dioxane (0.5 mL) and hydrochloric acid (4 M in 1,4-dioxane, 1 mL) was added. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated and diluted with water. The aqueous phase was washed with ethyl acetate. The combined aqueous phases were adjusted to pH 9 with 1N sodium hydroxide solution. The precipitated solid was extracted with ethyl acetate (5 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and analyzed by pre-HPLC to obtain compound 1 (5 mg, 20.2% yield).

[0264] 1H NMR (400MHz, CD3OD) δ9.08(s,2H),8.36(dd,1H),7.87(d,1H),7.78(d,1H),7.60(dd,1H),7.51-7.41(m,2H),7.31(t,1H),7.13(s,1H),6.45( d,1H),5.22(d,1H),3.64-3.53(m,1H),3.48(s,3H),3.06-2.97(m,2H) ,2.91(d,1H),2.55-2.47(m,2H),0.71-0.63(m,2H),0.62-0.55(m,2H).

[0265] LCMS m / z=529.3[M+H] + ;

[0266] Pre-HPLC conditions: Instrument: Waters 2767 Preparative HPLC; Column: XSelect CSH C18 (19 mm × 250 mm). Samples were dissolved in DMF and filtered through a 0.45 μM filter to prepare the sample solution. Preparative chromatography conditions: a. Mobile phase A: acetonitrile; b. Water (50 mM ammonium bicarbonate); Gradient elution from 15% to 60% mobile phase A; c. Flow rate: 12 mL / min; d. Elution time: 15 minutes.

[0267] Example 2: Preparation of Compound 2

[0268] Referring to the synthetic method of compound 1, compound 2 (2.5 mg) was prepared.

[0269] 1 H NMR(400MHz,CD3OD)δ9.02(s,2H),8.38(dd,1H),7.87-7.84(m,1H),7.78(d,1H),7.60(dd,1H),7.51-7.45(m,2H),7.31(t,1H),6.46(d,1H), 5.23(d,1H),3.64-3.55(m,1H),3.49(s,3H),2.96-2.89(m,3H),2.36- 2.29(m,2H),2.22-2.15(m,2H),2.09-2.02(m,2H),1.91-1.80(m,2H).

[0270] LCMS m / z=543.2[M+H] +

[0271] Example 3: Preparation of Compound 3

[0272] Step 1: Preparation of 3B

[0273] 3A (0.135 g, 0.36 mmol) was dissolved in 4.5 mL of toluene, and cyclopropylboronic acid (0.062 g, 0.72 mmol), cuprous acetate (0.066 g, 0.54 mmol), and sodium carbonate (0.057 g, 0.54 mmol) were added sequentially. The mixture was reacted at 80°C under an oxygen atmosphere for 2 days. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 3B (82 mg, 54.89% yield).

[0274] LCMS m / z=416.1[M+H] +

[0275] Step 2: Preparation of 3C

[0276] Under nitrogen atmosphere, 3B (40 mg, 0.096 mmol) was dissolved in 1 mL of 1,4-dioxane, and diboronic acid pinacol ester (37 mg, 0.15 mmol), potassium acetate (29 mg, 0.30 mmol), tricyclohexylphosphine tetrafluoroborate (CAS No.: 58656-04-5) (1 mg, 0.0027 mmol), and Pd2(dba)3 (4.8 mg, 0.05 mmol) were added in sequence. The reaction was microwaved at 140°C for 3 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 3C (42 mg, 86.06% yield).

[0277] LCMS m / z=508.2[M+H] +

[0278] Step 3: 3D preparation

[0279] 3C (40 mg, 0.079 mmol) was dissolved in 4 mL of 1,4-dioxane and 0.4 mL of water, and 1 g (42 mg, 0.12 mmol), potassium carbonate (33 mg, 0.24 mmol), PdCl2(dppf) were added. . DCM (13 mg, 0.016 mmol) was reacted at 100°C under nitrogen atmosphere for 16 h. The reaction mixture was cooled to room temperature, diluted with 10 mL of ethyl acetate, and washed once with 10 mL of water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to afford 3D (30 mg, yield: 60.06%).

[0280] LCMS m / z=655.3[M+H] +

[0281] Step 4: Preparation of compound 3

[0282] 3D (30 mg, 0.046 mmol) was dissolved in 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 3 h. The reaction solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 3 (11 mg, yield: 43.29%).

[0283] 1 H NMR(400MHz,CD3OD)δ9.08(s,2H),8.23(dd,1H),7.89(d,1H),7.79(d,1H),7.61( dd,1H),7.49-7.43(m,2H),7.42-7.09(m,1H),6.44(d,1H),5.39(d,1H),3.65-3.5 3(m,1H),3.25-3.16(m,1H),3.00(d,2H),2.89(d,1H),2.48(d,2H),1.41-1.27(m ,1H),1.15-1.02(m,2H),0.79-0.70(m,1H),0.70-0.63(m,2H),0.62-0.54(m,2H).

[0284] LCMS m / z=555.3[M+H] +

[0285] Example 4: Synthesis of Compound 4

[0286] Compound 4f was prepared by referring to the synthetic route of WO2018206820.

[0287] 4f (16 mg, 0.042 mmol), 1h (20 mg, 0.042 mmol), Pd(dppf)Cl2 (3 mg, 0.0042 mmol), potassium carbonate (13 mg, 0.082 mmol), 2 mL of dioxane, and 0.4 mL of water were added to a reaction flask and reacted at 100°C overnight under nitrogen. The reaction solution was concentrated and purified by silica gel column chromatography to yield 4 g (16 mg, 60%).

[0288] LCMS m / z=645.3[M+H] +

[0289] To 4 g (16 mg, 0.025 mmol) were added 2 mL of dichloromethane and 2 mL of trifluoroacetic acid, and the mixture was stirred at room temperature for 3 hours. After concentration, the mixture was redissolved in 10 mL of dichloromethane, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product of compound 4, which was purified by preparative TLC to obtain compound 4 (10 mg, 74%).

[0290] 1H NMR (400MHz, CD3OD) δ8.41-8.34(m,1H),7.78(s,1H),7.69(d,1H),7.52-7.35(m,6H),7.20(t,1H),6.41(d,1H),5.21(d,1H) ),3.62-3.52(m,1H),3.48(s,3H),2.90(d,1H),2.69-2.61(m,2H),2.52-2.44(m,2H),0.66-0.57(m,2H),0.56-0.47(m,2H).

[0291] LCMS m / z=545.3[M+H] +

[0292] Example 5: Synthesis of Compound 5

[0293] Step 1: Synthesis of 5b

[0294] 4f (23 mg, 0.06 mmol), 3C (20 mg, 0.04 mmol), Pd2dba3 (2 mg, 0.002 mmol), PCy3 . HBF4 (2 mg, 0.004 mmol), potassium phosphate (22 mg, 0.1 mmol), 2 mL of dioxane, and 0.1 mL of water were added to the reaction flask. After nitrogen displacement, the reaction was allowed to proceed at 100°C overnight. The reaction solution was concentrated and purified by silica gel column chromatography to obtain 5b (22 mg, 55%).

[0295] LCMS m / z=671.2[M+H] +

[0296] Step 2: Synthesis of compound 5

[0297] To 5b (22 mg, 0.033 mmol) were added 2 mL of dichloromethane and 2 mL of trifluoroacetic acid, and the mixture was stirred at room temperature for 3 hours. After concentration, the mixture was redissolved in 10 mL of dichloromethane, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product of compound 5, which was purified by preparative TLC to give compound 5 (11 mg, 59%).

[0298] 1H NMR(400MHz,CD3OD)δ8.26-8.20(m,1H),7.78(s,1H),7.69(d,1H),7.52(t,1H), 7.47-7.35(m,5H),7.17(t,1H),6.38(d,1H),5.36(d,1H),3.62-3.52(m,1H),3.2 5-3.17(m,1H),2.86(d,1H),2.74-2.67(m,2H),2.59-2.51(m,2H),1.12-1.04(m, 2H),0.94-0.86(m,1H),0.77-0.70(m,1H),0.67-0.60(m,2H),0.57-0.50(m,2H).

[0299] LCMS m / z=571.3[M+H] +

[0300] Example 6: Preparation of Compound 6

[0301] Step 1: Preparation of 6b

[0302] 6a (150 mg, 0.27 mmol) was dissolved in 2 mL of 1,4-dioxane and 0.2 mL of water, and 1 g (160 mg, 0.46 mmol), potassium carbonate (86 mg, 0.62 mmol), PdCl2(dppf) . DCM (5.1 mg, 0.062 mmol) was reacted at 100°C under nitrogen atmosphere for 16 h. The reaction mixture was cooled to room temperature, diluted with 10 mL of ethyl acetate, and washed once with 10 mL of water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to afford 6b (0.12 g, yield: 61.34%).

[0303] LCMS m / z=632.6[M+H] +

[0304] Step 2: Preparation of compound 6

[0305] 6b (60 mg, 0.095 mmol) was dissolved in 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The reaction was allowed to react at room temperature for 3 h. The reaction solvent was removed by concentration under reduced pressure, and the residue was purified by preparative HPLC (Preparation conditions: 1. Instrument: Waters Automated Purification System; Column: SunFire (19 mm × 250 mm); 2. The sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. Mobile phase A and B composition: Mobile phase A: acetonitrile, mobile phase B: water (5 mM ammonium acetate); b. Gradient elution; c. Flow rate: 15 ml / min) to obtain compound 6 (12 mg, yield: 23.76%).

[0306] 1 H NMR (400MHz, CD3OD) δ9.04(s,2H),8.37(dd,1H),7.87(d,1H),7.78(d,1H),7.61(dd,1H),7.51-7.43(m,2H),7.31(t,J=72.9Hz ,1H),6.46(d,1H),5.22(d,1H),3.63-3.54(m,1H),3.01-2.87(m,3H),2.41-2.31(m,2H),0.67-0.56(m,2H),0.54-0.45(m,2H).

[0307] LCMS m / z=532.5[M+H] + .

[0308] Example 7: Preparation of Compound 7

[0309] Step 1: Preparation of 7B

[0310] 7A (50 g, 196.51 mmol) was dissolved in 450 mL of toluene and 150 mL of water. Potassium cyclopropyltrifluoroborate (34.90 g, 235.81 mmol), tricyclohexylphosphine (16.53 g, 58.95 mmol), cesium carbonate (384.16 g, 1179.06 mmol), and palladium acetate (8.82 g, 39.30 mmol) were added and reacted at 120°C for 16 hours. The mixture was cooled to room temperature and diluted with ethyl acetate (300 mL). The organic phase was washed once with water (400 mL) and then with a saturated aqueous solution of NaCl (250 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated on a silica gel column to obtain 7B (28 g, 66.09% yield).

[0311] 1H NMR (400MHz, CDCl3) δ7.68(d,1H),7.32(d,1H),2.18-2.10(m,1H),1.14-1.08(m,2H),0.77-0.71(m,2H).

[0312] Step 2: Preparation of 7C

[0313] Dissolve 7B (25 g, 115.95 mmol) in 250 mL of acetonitrile, add 7B-1 (39.21 g, 115.95 mmol) and potassium carbonate (48.08 g, 347.85 mmol). React at 80°C for 16 hours. Cool to room temperature, dilute with ethyl acetate (250 mL), and wash the organic phase with water (300 mL) and then with a saturated aqueous solution of NaCl (250 mL). Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Separate the resulting mixture on a silica gel column to obtain 7C (22 g, 35.55% yield).

[0314] 1 H NMR(400MHz, CDCl3)δ8.74(d,1H),7.79(s,1H),7.45(dd,1H),7.19-7.10(m,3H),6.83-6.43(t,1H),5.85-5.77(m,1H) ,4.14(q,2H),3.27-3.15(m,1H),2.91(dd,1H),1.98-1.90(m,1H),1.22(t,3H),0.98-0.85(m,2H),0.65-0.55(m,2H).

[0315] Step 3: Preparation of 7D

[0316] Under a nitrogen atmosphere, 7C (22 g, 41.22 mmol) was dissolved in 300 mL of dichloromethane. Diisobutylaluminum hydride (55 mL, 1.5 mol / L in toluene, 82.70 mmol) was slowly added dropwise at -78°C. The reaction was maintained at -78°C for 2 hours. Slowly add 200 mL of a saturated aqueous solution of NH4Cl at -78°C, slowly return the mixture to room temperature, stir for 20 minutes, and filter. The filter cake was washed twice with dichloromethane (150 mL x 2) and the filtrate was washed once with a saturated aqueous solution of NaCl (250 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield 19.5 g of crude 7D.

[0317] Step 4: Preparation of 7E

[0318] 7D (19.5 g, 41.22 mmol) was dissolved in 150 mL of dichloromethane, and R-tert-butylsulfenamide (5.79 g, 47.78 mmol) and cesium carbonate (6.49 g, 19.91 mmol) were added in sequence. The mixture was allowed to react at room temperature for 16 hours. 150 mL of water was added, and the aqueous phase was extracted with (150 mL x 2) dichloromethane. The organic phases were combined and washed once with a saturated aqueous solution of NaCl (250 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated on a silica gel column to obtain 7E (14.5 g, 61.42% yield).

[0319] LCMS m / z=592.1[M+H] +

[0320] Step 5: Preparation of 7F

[0321] 7E (14.5 g, 24.46 mmol) was dissolved in 100 mL of tetrahydrofuran, and cesium fluoride (7.43 g, 48.92 mmol) and trimethylsilyl cyanide (4.85 g, 48.92 mmol) were added sequentially. The mixture was allowed to react at room temperature for 30 minutes. 150 mL of saturated aqueous NaHCO₃ was added, and the mixture was extracted twice with ethyl acetate (200 mL x 2). The ethyl acetate layers were combined, washed once with saturated aqueous NaCl (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 15 g of crude 7F.

[0322] LCMS m / z=619.1[M+H] +

[0323] Step 6: Preparation of 7G

[0324] 7F (15 g, 24.20 mmol) was dissolved in 100 mL of anhydrous ethanol, and 60 mL of titanium trichloride solution was slowly added. The reaction was carried out at 80°C for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to remove the reaction solvent. The residue was adjusted to pH 8 with 300 mL of saturated aqueous NaHCO₃ solution, diluted with 300 mL of ethyl acetate, and filtered. The filter cake was washed twice with ethyl acetate (150 mL x 2). The organic phases were combined and washed once with saturated aqueous NaCl solution (250 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and separated on a silica gel column to obtain 7G (4.6 g, 45.72% yield).

[0325] LCMS m / z=468.1[M+H]+

[0326] Step 7: Preparation of 7H

[0327] 7G (4.6 g, 9.81 mmol) was dissolved in 40 mL of 1,4-dioxane, and Xant-PHOS (0.28 g, 0.49 mmol), potassium carbonate (6.78 g, 49.05 mmol), and palladium acetate (0.44 g, 1.96 mmol) were added sequentially. The mixture was reacted at 100°C under a carbon monoxide atmosphere for 16 hours. The mixture was cooled to room temperature and diluted with 30 mL of ethyl acetate. The organic phase was washed once with water (30 mL) and once with a saturated aqueous solution of NaCl (25 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified on a silica gel column to obtain 7H (0.88 g, 21.56% yield).

[0328] LCMS m / z=416.1[M+H] +

[0329] Step 8: Preparation of 7I

[0330] 7H (0.4 g, 0.96 mmol) was dissolved in 15 mL of tetrahydrofuran. KHMDS (1.92 mL, 1.0 mol / L in THF, 1.92 mmol) was slowly added dropwise at -78°C under a nitrogen atmosphere. The reaction was incubated at -78°C for 30 min. Iodomethane (0.2 g, 1.44 mmol) was slowly added dropwise while maintaining -78°C. The temperature was slowly returned to room temperature and the reaction was continued for 2 hours. 25 mL of saturated aqueous NH4Cl was added, and the mixture was extracted twice with ethyl acetate (25 mL x 2). The organic phases were combined, washed once with saturated aqueous NaCl (25 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified on a silica gel column to yield 7I (0.25 g, 60.46% yield).

[0331] LCMS m / z=430.1[M+H] +

[0332] Step 9: Preparation of 7J

[0333] Under nitrogen, 7I (0.15 g, 0.35 mmol) was dissolved in 2 mL of 1,4-dioxane. Bis(pyraclostrobin) (0.13 g, 0.52 mmol), potassium acetate (0.10 g, 1.05 mmol), tricyclohexylphosphine fluoroborate (4 mg, 0.01 mmol), and Pd2(dba)3 (32 mg, 0.035 mmol) were added sequentially. The reaction was microwaved at 140°C for 3.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The residue was then separated on a silica gel column to afford 7J (0.12 g, 65.96% yield).

[0334] LCMS m / z=522.2.[M+H] +

[0335] Step 10: Preparation of 7K

[0336] 7J (20 mg, 0.038 mmol) was dissolved in 2 mL of 1,4-dioxane and 0.2 mL of water, and 1 g (20 mg, 0.057 mmol), potassium carbonate (11 mg, 0.076 mmol), PdCl2(dppf) . DCM (6 mg, 0.0076 mmol) was reacted at 100°C under nitrogen atmosphere for 16 hours. The reaction was cooled to room temperature, diluted with 10 mL of ethyl acetate, and washed once with 10 mL of water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 7K (11 mg, yield: 42.88%).

[0337] LCMS m / z=669.3.[M+H] +

[0338] Step 11: Preparation of compound 7

[0339] 7K (11 mg, 0.020 mmol) was dissolved in 4 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The reaction was allowed to react at room temperature for 2 hours. The reaction solvent was removed by concentration under reduced pressure, and the residue was purified by preparative HPLC (1. Apparatus: Waters 2767 Preparative HPLC; Column: SUNFIRE@Prep C18 (19 mm × 250 mm); 2. The sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution; 3. Preparative chromatography conditions: a. Mobile phase A and B composition: Mobile phase A: acetonitrile, Mobile phase B: Water (containing 50 mM ammonium bicarbonate); b. Gradient elution, mobile phase A content ranging from 25% to 70%; c. Flow rate: 12 mL / min; d. Elution time: 15 min) to obtain compound 7 (4.3 mg, yield: 45.97%).

[0340] LCMS m / z=569.4[M+H] +

[0341] 1 H NMR(400MHz,CD3OD)δ8.88(s,2H),8.41-8.30(m,1H),7.51-7.41(m,4H),7.19(t,1H),6.38(d,1H),5.20(d,1H),3.61-3.51(m,1H),3.47 (s,3H),3.06-2.94(m,2H),2.88(d,1H),2.42-2.33(m,2H),1.91-1.86(m,1H),0.93-0.78(m,2H),0.71-0.57(m,4H),0.56-0.47(m,2H).

[0342] Example 8: Synthesis of Compound 8

[0343] Step 1: Synthesis of 8b

[0344] 8a (0.5 g, 1.28 mmol) was dissolved in 10 mL of tetrahydrofuran, and KHMDS (6.4 mL, 6.4 mmol) was added dropwise at 0°C. The mixture was reacted at room temperature for 2 h, and then quenched by adding aqueous ammonium chloride. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 8b (0.35 g, 80% yield) was obtained by column chromatography.

[0345] LCMS m / z=340.1[M+H] +

[0346] Step 2: Synthesis of 8c

[0347] 8b (0.35 g, 1.03 mmol) was dissolved in 10 mL of DMF, and 1,1-difluoro-2-iodoethane (0.3 g, 1.54 mmol) and cesium carbonate (0.67 g, 2.06 mmol) were added. The reaction was carried out at 80°C for 2 h, and 30 mL of water was added to quench the reaction. The reaction was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 8c (0.35 g, yield 84%) was obtained by column chromatography.

[0348] LCMS m / z=404.1[M+H] +

[0349] Step 3: 8d combination

[0350] 8c (0.35 g, 0.87 mmol) was dissolved in 1 mL of 1,4-dioxane, and diboronic acid pinacol ester (0.44 g, 1.74 mmol), potassium acetate (0.26 g, 2.61 mmol), tricyclohexylphosphine tetrafluoroborate (32 mg, 0.087 mmol), and Pd2(dba)3 (80 mg, 0.087 mmol) were added in sequence. The reaction was carried out in a microwave oven at 140°C for 3 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 8d (0.32 g, 74% yield).

[0351] LCMS m / z=496.2[M+H] +

[0352] Step 4: Synthesis of 8f

[0353] 8d (80 mg, 0.16 mmol) was dissolved in 4 mL of 1,4-dioxane and 0.4 mL of water, and 1 g (63 mg, 0.18 mmol), potassium carbonate (44 mg, 0.32 mmol), PdCl2(dppf) .DCM (13 mg, 0.016 mmol) was reacted at 100°C under nitrogen atmosphere for 16 h. The reaction mixture was cooled to room temperature, diluted with 10 mL of ethyl acetate, and washed once with 10 mL of water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to afford 8f (70 mg, 70% yield).

[0354] LCMS m / z=643.2[M+H] +

[0355] Step 5: Preparation of compound 8

[0356] 8f (70 mg, 0.11 mmol) was dissolved in 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 3 h. The reaction solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 8 (35 mg, yield: 60%).

[0357] 1 H NMR(400MHz,CD3OD)δ9.09-8.94(m,2H),8.16(d,1H),7.98-7.86(m,1H),7. 80-7.71(m,1H),7.61-7.51(m,1H),7.45-7.28(m,2H),6.68-6.35(m,2H),5. 19(d,1H),4.72-4.59(m,1H),4.56-4.42(m,1H),3.60-3.51(m,1H),3.48(s ,3H),3.00-2.90(m,2H),2.86(d,1H),2.41-2.30(m,2H),0.65-0.44(m,4H).

[0358] LCMS m / z=543.2[M+H] +

[0359] Example 9: Preparation of Compound 9

[0360] Step 1: Synthesis of 9b

[0361] 9a (60 g, 151.9 mmol) was dissolved in 300 mL of dichloromethane. A 20% aqueous solution of potassium hydroxide (255.2 g, 911.4 mmol) was added dropwise on an ice bath. A 200 mL solution of TMSCF2Br (61.6 g, 303.8 mmol) in dichloromethane was then added dropwise. The reaction was continued for 0.5 hour. The reaction solution was concentrated, and ethyl acetate and water were added. The resulting organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to afford 9b (28.5 g, 42%).

[0362] LCMS m / z=446.1[M+H] +

[0363] Step 4: Synthesis of 9c

[0364] 9b (25 g, 56.2 mmol) was dissolved in 112 mL of dichloromethane. 25 mL of a dichloromethane solution of DBU (25.6 g, 168.6 mmol) was added dropwise under ice-bath conditions. The mixture was reacted in an ice-bath for 0.5 h. The reaction solution was concentrated and purified by silica gel column chromatography to obtain 9c (6.1 g, 49%).

[0365] LCMS m / z=224.0[M+H] +

[0366] Step 5: 9d synthesis

[0367] 9c (10.5 g, 47.1 mmol) and cuprous bromide (10.2 g, 70.7 mmol) were added to 95 mL of acetonitrile. A solution of tert-butyl nitrite (5.82 g, 56.5 mmol) in acetonitrile (20 mL) was added dropwise in an ice bath. The reaction was allowed to react overnight at room temperature. The reaction solution was concentrated and purified by silica gel column chromatography to afford 9d (3.7 g, 27%).

[0368] Step 6: Synthesis of 9e

[0369] 9d (3.7 g, 12.9 mmol) was dissolved in 40 mL of dichloromethane, and a toluene solution of DIBAL-H (1.5 M, 17.2 mL, 25.8 mmol) was added dropwise at -78°C. The reaction was allowed to proceed for 1 hour. Saturated ammonium chloride solution was slowly added to quench the reaction. The reaction solution was filtered, and the filter cake was washed with dichloromethane to obtain an organic phase which was then dried, concentrated, and purified by silica gel column chromatography to afford 9e (3.1 g, 93%).

[0370] Step 7: Synthesis of 9f

[0371] 9e (3.1 g, 12.0 mmol) was dissolved in 36 mL of dichloromethane, and Dess-Martin periodinane (10.18 g, 24.0 mmol) was added in an ice bath. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was filtered, washed, concentrated, and purified by silica gel column chromatography to afford 9f (2.7 g, 86%).

[0372] Step 8: Synthesis of 9g

[0373] 9f (2.7 g, 10.5 mmol), (S)-tert-butylsulfenamide (1.4 g, 11.6 mmol), and cesium carbonate (3.4 g, 10.5 mmol) were added to 30 mL of dichloromethane and reacted at room temperature for 4 hours. Appropriate amounts of water and dichloromethane were added, and the obtained organic phase was dried, concentrated, and purified by silica gel column chromatography to obtain 9g (3.6 g, 95%).

[0374] Step 9: 9h synthesis

[0375] Zinc powder (13 g, 200 mmol) and cuprous chloride (2.97 g, 30 mmol) were added to 40 mL of tetrahydrofuran and reacted at 70°C for 2 hours. Ethyl bromoacetate (15.0 g, 90 mmol) was slowly added at room temperature and reacted at 50°C for 1 hour. The filtrate obtained by filtering the reaction solution at room temperature was slowly added to 20 mL of a tetrahydrofuran solution of 9 g (3.6 g, 10 mmol). After reacting at room temperature for 1 hour, saturated ammonium chloride solution was added to quench the reaction. An appropriate amount of ethyl acetate was added to the mixture. The mixture was filtered and washed to obtain an organic phase which was dried, concentrated, and purified by silica gel column chromatography to yield 9h (3.7 g, 83%).

[0376] Step 10: Synthesis of 9i

[0377] Dissolve 9i (3.7 g, 8.3 mmol) in 30 mL of dichloromethane, add 4 M HCl in dioxane (30 mL, 120 mmol), and react at room temperature for 4 hours. The reaction solution is directly concentrated to obtain the crude product of 9i.

[0378] LCMS m / z=343.9,346.0[M+H] +

[0379] Step 11: Synthesis of 9j

[0380] To the compound 9i from the previous step, 4-chloro-2-fluoronitrobenzene (2.9 g, 16.6 mmol), potassium carbonate (3.4 g, 24.9 mmol), and 30 mL of acetonitrile were added and reacted at 80°C overnight. The reaction mixture was directly concentrated and purified by silica gel column chromatography to afford 9j (3.2 g, 78% yield over two steps).

[0381] LCMS m / z=500.8[M+H] +

[0382] Step 12: 9k synthesis

[0383] 9j (3.2 g, 6.4 mmol) was dissolved in 25 mL of dichloromethane, and a toluene solution of DIBAL-H (1.5 M, 4.3 mL, 6.4 mmol) was added at -78°C. The reaction was allowed to react for 40 min at -78°C. The reaction was quenched by adding a saturated ammonium chloride solution, and an appropriate amount of dichloromethane was added. The reaction solution was filtered and washed, and the obtained organic phase was dried and concentrated to obtain the crude product of 9k.

[0384] Step 13: Synthesis of 9l

[0385] To 9k in the previous step, (R)-tert-butylsulfenamide (847 mg, 7.0 mmol), cesium carbonate (2.1 g, 6.4 mmol) and 20 mL of dichloromethane were added and reacted at room temperature for 4 h. The reaction solution was directly concentrated and purified by silica gel column chromatography to obtain 9l (2.5 g, two-step yield 70%).

[0386] Step 14: Synthesis of 9m

[0387] 9l (2.5 g, 4.5 mmol) and cesium fluoride (1.4 g, 9.0 mmol) were added to 20 mL of tetrahydrofuran, followed by the addition of TMSCN (891 mg, 9.0 mmol). The mixture was allowed to react at room temperature for 1 hour. The reaction solution was directly concentrated and purified by silica gel column chromatography to afford 9m (2.5 g, 94% overall yield).

[0388] LCMS m / z=587.0[M+H] +

[0389] Step 15: Synthesis of 9n

[0390] 9m, 25mL of ethanol, and a hydrochloric acid solution of titanium trichloride (15%, 28.6g, 36mmol) were added to a reaction flask and reacted at 80°C for 5 hours. The reaction solution was concentrated, and appropriate amounts of saturated sodium bicarbonate solution and ethyl acetate were added. The organic phase obtained after filtration and washing was dried, concentrated, and purified by silica gel column chromatography to obtain 9n (950mg, two-step yield 49%).

[0391] LCMS m / z=436.0[M+H] +

[0392] Step 16: Synthesis of 9o

[0393] 9n (950 mg, 2.2 mmol), palladium acetate (49 mg, 0.22 mmol), XantPhos (127 mg, 0.22 mmol), and potassium carbonate (1.5 g, 11.0 mmol) were added to 10 mL of dioxane and reacted at 100°C overnight under a carbon monoxide atmosphere. The reaction solution was directly concentrated and purified by silica gel column chromatography to afford 9o (220 mg, 27%).

[0394] LCMS m / z=382.0[M+H] +

[0395] Step 17: Synthesis of 9p

[0396] 9o (220 mg, 0.58 mmol) was dissolved in 10 mL of tetrahydrofuran and a 1.0 M solution of KHMDS in tetrahydrofuran (1.16 mL, 1.16 mmol) was added dropwise at -78°C. The mixture was allowed to react for 0.5 hours at -78°C. Methyl iodide (165 mg, 1.16 mmol) was then added and the reaction was allowed to proceed overnight at room temperature. The reaction was quenched by the addition of an appropriate amount of saturated ammonium chloride solution and extracted twice with ethyl acetate. The resulting organic phase was dried, concentrated, and purified by silica gel column chromatography to afford 9p (210 mg, 92%).

[0397] Step 18: Synthesis of 9q

[0398] 9p (210 mg, 0.53 mmol), pinacol diboronate (202 mg, 0.80 mmol), Pd2dba3 (25 mg, 0.027 mmol), PCy3.HBF4 (20 mg, 0.054 mmol), potassium acetate (156 mg, 1.59 mmol), and 5 mL of dioxane were added to a 30 mL microwave tube and reacted at 140°C under a nitrogen atmosphere for 4 hours. The reaction solution was directly concentrated and purified by silica gel column chromatography to afford 9q (220 mg, 86%).

[0399] LCMS m / z=488.1[M+H] +

[0400] Step 19: Synthesis of 9s

[0401] 9q (20 mg, 0.04 mmol), 1g (22 mg, 0.06 mmol), Pd(dppf)Cl2 (5 mg, 0.006 mmol), and potassium carbonate (11 mg, 0.08 mmol) were added to 1 mL of dioxane and 0.2 mL of water and reacted at 100°C overnight under a nitrogen atmosphere. The reaction solution was directly concentrated and purified by silica gel column chromatography to obtain crude product 9s.

[0402] LCMS m / z=635.2[M+H] +

[0403] Step 20: Synthesis of compound 9

[0404] The crude product 9s from the previous step was dissolved in 2 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The reaction mixture was allowed to react at room temperature for 1 hour. After concentration, an appropriate amount of ethyl acetate and saturated sodium bicarbonate solution were added and stirred for 2 minutes. The organic phase was concentrated to obtain a crude product that was purified by preparative HPLC (Preparative conditions: Instrument: Waters Automated Purification System; Column: SunFire (19 mm × 250 mm); 2. The sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution; 3. Preparative chromatography conditions: a. Mobile phase A and B composition: Mobile phase A: acetonitrile, mobile phase B: water (0.1% trifluoroacetic acid); b. Gradient elution; c. Flow rate: 15 mL / min.) to obtain the trifluoroacetic acid salt of compound 9 (4 mg, two-step yield: 18%).

[0405] LCMS m / z=535.2[M+H] +

[0406] 1 H NMR(400MHz,CD3OD)δ9.17(s,2H),7.86(d,1H),7.82(d,1H),7.65(dd,1H),7.34-6.94(m,2H),5.95(d,1H),5.33(d ,1H),3.63-3.53(m,1H),3.48(s,3H),3.11-3.04(m,2H),3.01-2.95(m,1H),2.71-2.63(m,2H),0.77-0.65(m,4H).

[0407] Example 10: Preparation of Compound 10

[0408] Step 1: Synthesis of 10c

[0409] 10a (420 mg, 2 mmol) was dissolved in 6 mL of tetrahydrofuran. A 2.5 M solution of n-butyllithium in n-hexane (0.9 mL, 2.2 mmol) was added dropwise at -78°C. The mixture was allowed to react for 0.5 h at -78°C. 10b (440 mg, 2.2 mmol) in tetrahydrofuran (4 mL) was then added and allowed to react at room temperature for 2 h. The mixture was quenched with an appropriate amount of saturated ammonium chloride solution and extracted twice with ethyl acetate. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to afford 10c (390 mg, 59%).

[0410] LCMS m / z=331.0[M+H] +

[0411] Step 2: Synthesis of 10d

[0412] Dissolve 10c (390 mg, 1.18 mmol) in 3 mL of methanol, add 3 mL of a 4 M solution of hydrogen chloride in dioxane (12 mmol), and react at room temperature for two hours. The reaction solution is then concentrated to obtain the crude product 10d.

[0413] Step 3: Synthesis of 10e

[0414] To the crude product from the previous step, DIPEA (774 mg, 6 mmol), di-tert-butyl dicarbonate (646 mg, 3 mmol), and 6 mL of tetrahydrofuran were added and allowed to react at room temperature for 3 h. The reaction solution was directly concentrated and purified by silica gel column chromatography to afford 10e (330 mg, 86% yield over two steps).

[0415] Step 4: Synthesis of 10g

[0416] 10e (65 mg, 0.2 mmol), 10f (96 mg, 0.2 mmol), Pd2dba3 (9.2 mg, 0.01 mmol), PCy3.HBF4 (7.4 mg, 0.024 mmol), and potassium phosphate (106 mg, 0.5 mmol) were added to 2 mL of dioxane and 0.2 mL of water and reacted at 100°C overnight under a nitrogen atmosphere. The reaction solution was directly concentrated and purified by silica gel column chromatography to yield 10 g (96 mg, 74%).

[0417] LCMS m / z=646.2[M+H] +

[0418] Step 5: Synthesis of compound 10

[0419] Dissolve 10 g (96 mg, 0.15 mmol) of the compound in 2 mL of dichloromethane, add 2 mL of trifluoroacetic acid, and allow to react at room temperature for 1 hour. After concentration, the reaction mixture was added with appropriate amounts of ethyl acetate and saturated sodium bicarbonate solution and stirred for 2 minutes. The organic phase was concentrated and purified by silica gel column chromatography to yield compound 10 (71 mg, 86%).

[0420] 1 H NMR (400MHz, CD3OD) δ8.64-8.59(m,1H),8.37(dd,1H),7.85(d,1H),7.81(dd,1H),7.74(d,1H),7.58(dd,1H),7.51-7.43(m,2H),7.31(t,1H),6. 45(d,1H),5.21(d,1H),3.63-3.53(m,1H),3.48(s,3H),3.04-2.96(m,2H ),2.91(d,1H),2.40-2.33(m,2H),0.66-0.57(m,2H),0.46-0.38(m,2H).

[0421] LCMS m / z=546.3[M+H] +

[0422] Example 11: Preparation of Compound 11

[0423] Using compound 11a as the starting material and referring to the synthetic route of compound 10, the target compound 11 (29 mg) was prepared.

[0424] 1 H NMR(400MHz,CD3OD)δ8.57(s,1H),8.42-8.35(m,1H),7.76(d,1H),7.62- 7.57(m,1H),7.50-7.44(m,2H),7.30(dd,1H),7.19(t,1H),6.42(d,1H),5 .23(d,1H),3.63-3.53(m,1H),3.49(s,3H),3.00-2.94(m,2H),2.91(d,1 H),2.50(s,3H),2.40-2.32(m,2H),0.66-0.57(m,2H),0.55-0.46(m,2H).

[0425] LCMS m / z=543.3[M+H] +

[0426] Example 12: Preparation of Compound 12

[0427] Step 1: Preparation of 12b

[0428] Sodium hydride (60%, 88 mg, 2.2 mmol) and 2 mL of DMA were added to a reaction flask. A 2 mL solution of 12a (198 mg, 1 mmol) and 1,1-bis-bromomethylcyclopropane (251 mg, 1.1 mmol) in DMA was added dropwise at 0°C. The mixture was allowed to react for 1 h at room temperature. The reaction was quenched by the addition of an appropriate amount of saturated ammonium chloride solution and extracted twice with ethyl acetate. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to afford 12b (45 mg, 17%).

[0429] LCMS m / z=264.0 266.0[M+H] +

[0430] Step 2: Preparation of compound 12

[0431] 12a (17 mg, 0.062 mmol), 10f (30 mg, 0.084 mmol), Pd2dba3 (2.8 mg, 0.003 mmol), PCy3.HBF4 (2.3 mg, 0.007 mmol), potassium phosphate (33 mg, 0.155 mmol), 2 mL of dioxane, and 0.2 mL of water were added to a reaction flask. After nitrogen purge, the reaction was allowed to proceed at 100°C overnight. The reaction solution was directly concentrated and purified by silica gel column chromatography to afford compound 12 (3 mg, 7%).

[0432] LCMS m / z=539.2[M+H] +

[0433] Example 13: Preparation of Compound 13

[0434] Step 1: Preparation of 13B

[0435] Dissolve 13A (0.10 g, 0.25 mmol) in 2 mL of 1,4-dioxane, and add pinacol diboron (0.13 g, 0.50 mmol), potassium acetate (0.074 g, 0.75 mmol), tricyclohexylphosphine fluoroborate (4.6 mg, 0.01 mmol), and Pd2(dba)3 (23 mg, 0.025 mmol) in sequence. Microwave under nitrogen atmosphere at 140°C for 3 hours. Cool to room temperature and filter to obtain the filtrate containing 13B.

[0436] LCMS m / z=500.2.[M+H] +

[0437] Step 2: Preparation of 13C

[0438] The filtrate containing 13B in the previous step was added with 0.2 mL of water, 1 g (70 mg, 0.2 mmol), potassium carbonate (55 mg, 0.4 mmol), PdCl2 (dppf) . DCM (16 mg, 0.02 mmol) was reacted at 100°C under nitrogen atmosphere for 16 hours. The reaction was cooled to room temperature, diluted with 10 mL of ethyl acetate, and washed once with 10 mL of water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 13C (46 mg, two-step yield: 35.5%).

[0439] LCMS m / z=647.2.[M+H] +

[0440] Step 3: Preparation of compound 13

[0441] 13C (46 mg, 0.071 mmol) was dissolved in 4 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The mixture was allowed to react at room temperature for 2 hours. The reaction solvent was removed by concentration under reduced pressure, and 20 mL of dichloromethane and 5 mL of saturated sodium bicarbonate solution were added, followed by stirring for 2 minutes. The organic phase was concentrated to obtain a crude product, which was then separated on a silica gel column to afford compound 13 (22 mg, 56% yield).

[0442] LCMS m / z=547.3[M+H] +

[0443] 1 H NMR(400MHz,CD3OD)δ8.96(d,2H),8.41-8.35(m,1H),7.70(d,1H),7.53(d,1H),7.50-7.44(m,2H),7.27(t,1H),6.44(d,1H ),5.23(d,1H),3.63-3.54(m,1H),3.48(s,3H),3.30-2.87(m,3H),2.41-2.34(m,2H),0.65-0.58(m,2H),0.55-0.47(m,2H).

[0444] Example 14: Preparation of Compound 14

[0445] Compound 14 (5 mg) was prepared using 13B and 11d as starting materials and referring to the synthesis of compound 13.

[0446] LCMS m / z=561.3[M+H] +

[0447] 1 H NMR(400MHz,CD3OD)δ8.56(s,1H),8.39(dd,1H),7.55-7.44(m,4H),7.18(t,1H),6.40(d,1H),5.23(d,1H),3.63-3 .54(m,1H),3.48(s,3H),3.01-2.95(m,2H),2.91(d,1H),2.43-2.34(m,5H),0.64-0.58(m,2H),0.55-0.48(m,2H).

[0448] Example 15: Preparation of Compound 15

[0449] Compound 15 (26 mg) was prepared using 13B and 10e as starting materials and referring to the synthesis of compound 13.

[0450] LCMS m / z=564.1[M+H] +

[0451] 1 H NMR (400MHz, CD3OD) δ8.54-8.49(m,1H),8.41-8.34(m,1H),7.80-7.74(m,1H),7.69(d,1H),7.53-7.46(m,3H),7.26(t,1H),6.43(d,1H) ,5.22(d,1H),3.63-3.53(m,1H),3.48(s,3H),3.05-2.97(m,2H),2.91(d,1H),2.41-2.34(m,2H),0.66-0.58(m,2H),0.47-0.38(m,2H).

[0452] Example 16: Preparation of Compound 16

[0453] To the filtrate of 13B (0.03 g, 0.06 mmol) was added 0.2 mL of water, 12b (15 mg, 0.06 mmol), potassium carbonate (17 mg, 0.12 mmol), PdCl2(dppf) . DCM (5 mg, 0.006 mmol) was added and reacted at 100°C under nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature and concentrated. The crude product was purified by column chromatography to obtain compound 16 (3 mg, 9%).

[0454] LCMS m / z=547.3[M+H] +

[0455] Example 17: Synthesis of Compound 17

[0456] Step 1: Synthesis of 17b

[0457] 17a (7 g, 31.96 mmol) was dissolved in 70 mL of acetonitrile. Aqueous potassium hydroxide (8.97 g, 159.8 mmol) was added dropwise at -20°C, followed by the addition of TMSCF2Br (12.9 g, 63.92 mmol). The reaction was continued for 0.5 hour after the addition was complete. Ethyl acetate and water were added, and the resulting organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to afford 17b (28.5 g, 42%).

[0458] LCMS m / z=250.9[M+H] +

[0459] Step 2: Synthesis of 17c

[0460] 17b (6.3 g, 25.1 mmol), (S)-tert-butylsulfenamide (3.35 g, 27.61 mmol), and cesium carbonate (12.27 g, 37.65 mmol) were added to 100 mL of dichloromethane and reacted at room temperature for 4 hours. Appropriate amounts of water and dichloromethane were added, and the obtained organic phase was dried, concentrated, and purified by silica gel column chromatography to obtain 17c (7.3 g, 78%).

[0461] Step 3: Synthesis of 17d

[0462] Zinc powder (12.89 g, 197.1 mmol) and cuprous chloride (5.85 g, 59.13 mmol) were added to 150 mL of tetrahydrofuran and reacted at 70°C for 2 hours. Ethyl bromoacetate (9.87 g, 59.13 mmol) was slowly added at room temperature and reacted at 50°C for 1 hour. The reaction solution was cooled to room temperature and a solution of 17c (7.3 g, 19.71 mmol) in tetrahydrofuran (30 mL) was added dropwise. After reacting at room temperature for 1 hour, saturated ammonium chloride solution was added to quench the reaction. An appropriate amount of ethyl acetate was added to the mixture. The mixture was filtered and washed to obtain an organic phase which was dried, concentrated, and purified by silica gel column chromatography to afford 17d (7.3 g, 80%).

[0463] Step 4: Synthesis of 17e

[0464] Dissolve 17d (7.3 g, 15.86 mmol) in 30 mL of dichloromethane, add 4 M HCl in dioxane (30 mL, 120 mmol), and react at room temperature for 4 hours. The reaction solution is directly concentrated to obtain the crude hydrochloride of 17e.

[0465] LCMS m / z=356[M+H] +

[0466] Step 5: Synthesis of 17f

[0467] To the crude hydrochloride of 17e (5.6 g, 15.81 mmol) from the previous step, 4-chloro-2-fluoronitrobenzene (3.33 g, 18.97 mmol), potassium carbonate (10.93 g, 79.05 mmol), and 80 mL of acetonitrile were added and reacted at 80°C overnight. The reaction mixture was directly concentrated and purified by silica gel column chromatography to afford 17f (3.5 g, 43.4% yield over two steps).

[0468] LCMS m / z=510.8[M+H] +

[0469] Step 6: Synthesis of 17g

[0470] 17f (3.5 g, 6.84 mmol) was dissolved in 25 mL of dichloromethane. A toluene solution of DIBAL-H (1.5 M, 9.1 mL, 13.68 mmol) was added at -78°C and reacted for 40 min. The reaction was quenched by adding saturated ammonium chloride solution and an appropriate amount of dichloromethane was added. The reaction solution was filtered and washed, and the obtained organic phase was dried and concentrated to give 17 g of the crude product.

[0471] Steps 7 to 14: Synthesis of compound 17:

[0472] The synthesis was carried out from Step 13 to Step 20 of Example 9 to obtain trifluoroacetic acid salt of Compound 17 (21 mg).

[0473] (Preparative conditions: Instrument: Waters Automated Purification System; Chromatographic column: SunFire (19 mm × 250 mm); 2. Dissolve the sample in DMF and filter through a 0.45 μm filter to prepare a sample solution; 3. Preparative chromatography conditions: a. Mobile phase A and B composition: Mobile phase A: acetonitrile, Mobile phase B: Water (0.1% trifluoroacetic acid); b. Gradient elution; c. Flow rate: 15 mL / min.)

[0474] LCMS m / z=547.2[M+H] +

[0475] 1 H NMR(400MHz,CD3OD)δ9.16(s,2H),8.12(dd,1H),7.91-7.87(m,1H),7.82(d,1H),7.65(dd,1H),7.56-7.15(m,2H),6.41(d ,1H),5.25(d,1H),3.64-3.55(m,1H),3.49(s,3H),3.11-3.03(m,2H),2.93(d,1H),2.71-2.63(m,2H),0.78-0.64(m,4H).

[0476] Example 18: Synthesis of Compound 18

[0477] Compound 18 (36 mg) was obtained by referring to the synthetic route of compound 13

[0478] LCMS m / z=550.2[M+H] +

[0479] 1H NMR (400MHz, CD3OD) δ8.99-8.93(m,2H),8.41-8.34(m,1H),7.70(d,1H),7.53(d,1H),7.50-7.07(m,3H),6.44(d, 1H),5.22(d,1H),3.64-3.53(m,1H),3.00-2.87(m,3H),2.40-2.32(m,2H),0.65-0.56(m,2H),0.54-0.44(m,2H).

[0480] Example 19: Synthesis of Compound 19

[0481] Compound 19 (30 mg) was obtained by referring to the synthetic route of compound 15

[0482] LCMS m / z=567.3[M+H] +

[0483] 1 H NMR (400MHz, CD3OD) δ8.54-8.49(m,1H),8.42-8.34(m,1H),7.80-7.73(m,1H),7.69(d,1H),7.54-7.46(m,3H),7.26(t,1H),6.43 (d,1H),5.22(d,1H),3.64-3.53(m,1H),3.05-2.97(m,2H),2.91(d,1H),2.41-2.33(m,2H),0.66-0.58(m,2H),0.47-0.38(m,2H).

[0484] Example 20: Preparation of Compound 20

[0485] Step 1: Synthesis of compound 20c

[0486] Under nitrogen, substrate 20a (33 mg, 0.1 mmol), 6a (49 mg, 0.1 mmol), Pd2dba3 (4.6 mg, 0.005 mmol), PCy3.HBF4 (3.7 mg, 0.012 mmol), potassium phosphate (54 mg, 0.25 mmol), 2 mL of dioxane, and 0.2 mL of water were added to a reaction flask and reacted at 100°C overnight. The reaction solution was directly concentrated and purified by silica gel column chromatography to afford compound 20c (50 mg, 77%).

[0487] LCMS m / z=649.2[M+H] +

[0488] Step 2: Synthesis of compound 20

[0489] Substrate 20c (50 mg, 0.077 mmol) was dissolved in 2 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated, and appropriate amounts of ethyl acetate and saturated sodium bicarbonate solution were added, followed by stirring for 2 minutes. The organic phase was concentrated and purified by silica gel column chromatography to yield compound 20 (26 mg, 62%).

[0490] 1 H NMR(400MHz,CD3OD)δ8.62(s,1H),8.37(dd,1H),7.85(d,1H),7.81(dd,1H),7.75(d,1H),7.58(dd,1H),7.50-7.45(m,2H),7.31(t,1H) ,6.45(d,1H),5.21(d,1H),3.63-3.53(m,1H),3.04-2.96(m,2H),2.91(d,1H),2.40-2.33(m,2H),0.66-0.58(m,2H),0.45-0.37(m,2H).

[0491] LCMS m / z=549.3[M+H] +

[0492] Example 21: Preparation of Compound 21

[0493] Step 1: Synthesis of compound 21b

[0494] 21a (4.2 g, 17.3 mmol) and diiodomethane (26.8 g, 86.5 mmol) were dissolved in 80 mL of acetonitrile. t-Butyl nitrite (3.56 g, 34.6 mmol) was slowly added and the mixture was reacted at 70°C for 2 hours. The reaction solution was directly concentrated and purified by silica gel column chromatography to obtain product 21b (4.7 g, 77%).

[0495] Step 2: Synthesis of compound 21d

[0496] Compound 21b (4.7 g, 13.3 mmol) was dissolved in 50 mL of dichloromethane and cooled to -78°C. A solution of n-butyllithium (2.5 M, 5.32 mL, 13.3 mmol) in n-hexane was added dropwise. The mixture was allowed to react for half an hour. A solution of compound 21c (2.65 g, 13.3 mmol) in dichloromethane was then added. The mixture was slowly warmed to room temperature and the reaction was continued for two hours. An appropriate amount of saturated ammonium chloride solution was then added to quench the reaction. The mixture was extracted twice with ethyl acetate. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to afford compound 21d (720 mg, 13%).

[0497] LCMS m / z=426.1 428.1[M+H] +

[0498] Step 3: Synthesis of compound 21e

[0499] 21d (720 mg, 1.69 mmol) was dissolved in 3 mL of dichloromethane, and 3 mL of a 4 M solution of hydrogen chloride in dioxane (12 mmol) was added. The mixture was reacted at room temperature for two hours. The reaction solution was directly concentrated to obtain a crude product of compound 21e.

[0500] LCMS m / z=322.0 324.0[M+H] +

[0501] Step 4: Synthesis of compound 21f

[0502] To the crude product of 21e from the previous step, DIPEA (968 mg, 7.5 mmol), di-tert-butyl dicarbonate (1.09 mg, 5 mmol), and 6 mL of tetrahydrofuran were added and allowed to react at room temperature for three hours. The reaction mixture was directly concentrated and purified by silica gel column chromatography to afford compound 21f (420 mg, 59% yield over two steps).

[0503] Step 5: Synthesis of compound 21g

[0504] Substrate 21f (42 mg, 0.1 mmol), 6a (49 mg, 0.1 mmol), Pd(dppf)Cl2 (7.4 mg, 0.01 mmol), potassium carbonate (27 mg, 0.2 mmol), 2 mL of dioxane, and 0.2 mL of water were added to a reaction flask. The atmosphere was purged with nitrogen three times and then reacted at 100°C overnight. The reaction solution was directly concentrated and purified by silica gel column chromatography to yield compound 21g (42 mg, 63%).

[0505] LCMS m / z=700.2[M+H] +

[0506] Step 6: Synthesis of compound 21

[0507] Substrate 21f (42 mg, 0.06 mmol) was dissolved in 2 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated, and appropriate amounts of ethyl acetate and saturated sodium bicarbonate solution were added, followed by stirring for 2 minutes. The organic phase was concentrated and purified by silica gel column chromatography to yield compound 21 (20 mg, 56%).

[0508] 1H NMR(400MHz,CD3OD)δ8.95(s,1H),8.41-8.35(m,1H),7.76(d,1H),7.62(s,1H),7.50-7.43(m,2H),7.29(dd,1H),7.14(t,1H ),6.41(d,1H),5.23(d,1H),3.64-3.54(m,1H),2.97-2.87(m,3H),2.48-2.39(m,2H),0.64-0.57(m,2H),0.55-0.49(m,2H).

[0509] LCMS m / z=600.3[M+H] +

[0510] Example 22: Synthesis of Compound 22

[0511] Step 1: Preparation of 22b

[0512] 22a (3 g, 10.98 mmol) and tert-butylsulfenamide (1.33 g, 10.98 mmol) were dissolved in 50 mL of tetrahydrofuran. Tetraisopropyl titanate (6.25 g, 21.96 mmol) was slowly added dropwise at 0°C. The reaction was allowed to proceed at 60°C for 16 h. The reaction mixture was cooled to room temperature, and 100 mL of water and 100 mL of ethyl acetate were added. The mixture was filtered, and the filter cake was washed twice with ethyl acetate (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column to obtain the target compound 22b (2.60 g, 62.92% yield).

[0513] LCMS m / z=377.1[M+H] +

[0514] Step 2: Preparation of 22c

[0515] 5-Bromo-2-iodopyrimidine (2.29 g, 7.60 mmol) was dissolved in 100 mL of dichloromethane. Under a nitrogen atmosphere, n-butyllithium (3.0 mL, 2.5 M n-hexane solution) was slowly added dropwise at -78°C. The mixture was allowed to react at -78°C for 2 h. A 30 mL dichloromethane solution of 14b (2.6 g, 6.91 mmol) was slowly added dropwise. The mixture was allowed to return to room temperature and react for 16 h. 100 mL of saturated aqueous NH4Cl was added to the reaction mixture, and the layers were separated. The aqueous phase was extracted with 100 mL of dichloromethane. The organic phases were combined, washed once with 100 mL of saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was then chromatographed on a silica gel column to obtain the target compound 22c (1.50 g, 40.62% yield).

[0516] LCMS m / z=535.1[M+H] +

[0517] Step 3: Preparation of 22d

[0518] Compound 22c (1.5 g, 2.81 mmol) was dissolved in 10 mL of dichloromethane, and HCl (10 mL, 4 mol / L in 1,4-dioxane) was added. The mixture was reacted at room temperature for 2 h and concentrated to afford crude compound 22d (1.2 g).

[0519] LCMS m / z=431.1[M+H] +

[0520] Step 4: Preparation of 22e

[0521] Dissolve 22d (1.2 g, 2.79 mmol) in 30 mL of tetrahydrofuran, add triethylamine (0.56 g, 5.58 mmol) and di-tert-butyl dicarbonate (0.61 g, 2.79 mmol), and react at room temperature for 16 h. After concentration under reduced pressure, the residue was purified by silica gel chromatography to obtain the target compound 22e (0.9 g, 60.84% ​​yield).

[0522] LCMS m / z=531.1[M+H] +

[0523] Step 5: Preparation of 22f

[0524] 22e (33 mg, 0.063 mmol) and 4g (20 mg, 0.042 mmol) were added to a mixed solution of 1,4-dioxane and water (5:1, 1.8 mL), followed by the addition of Pd(dppf)Cl2 dichloromethane complex (3.4 mg, 0.0042 mmol) and potassium carbonate (17 mg, 0.13 mmol). The reaction system was purged with nitrogen three times. The mixture was stirred at 90°C for 12 hours. The reaction solution was diluted with water and extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated brine (10 mL). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated on a silica gel column to give 22f (15 mg, 44.36%).

[0525] LCMS m / z=806.3[M+H] +

[0526] Step 6: Preparation of 22g

[0527] 22f (30 mg, 0.04 mmol) was dissolved in methanol, 10 mg of Pd / C (10%) was added, and hydrogen was replaced for protection. The reaction was carried out at room temperature for 16 h, filtered, and the filtrate was concentrated under reduced pressure to obtain 22g (12 mg) and 22h (17 mg), which were directly used in the next step.

[0528] LCMS m / z=672.3[M+H] +

[0529] Step 7: Preparation of compound 22

[0530] Dissolve 22 g (12 mg, 0.017 mmol) of the compound 22 in 3 mL of dichloromethane, then add 0.5 mL of trifluoroacetic acid. Stir at room temperature for 1 hour. The mixture was concentrated, and pre-HPLC was performed to yield the trifluoroacetic acid salt of compound 22 (2.6 mg, 20.7%). HPLC conditions: Instrument: Waters 2767 Preparative HPLC; Column: XSelect CSH C18 (19 mm × 250 mm). The sample was dissolved in DMF and filtered through a 0.45 μM filter to prepare the sample solution. Preparative chromatography conditions: a. Mobile phase A: acetonitrile; b. Water (50 mM trifluoroacetic acid); Gradient elution from 15% to 60% mobile phase A; c. Flow rate: 12 mL / min; d. Elution time: 15 minutes.

[0531] 1 H NMR(400MHz,CD3OD)δ9.15(s,2H),8.42-8.34(m,1H),7.89(d,1H),7.81(d,1H),7.63(dd,1H),7.51-7.10(m,3H),6.45(d,1H),5.24(d ,1H),3.64-3.55(m,1H),3.49(s,3H),3.25-3.16(m,4H),2.97-2.88(m,3H),2.59-2.50(m,2H),2.35-2.26(m,2H),2.16-2.08(m,2H).

[0532] LCMS m / z=571.2[M+H] + .

[0533] Example 23: Synthesis of Compound 23

[0534] Step 1: Preparation of 15a

[0535] 22f (15 mg, 0.019) was dissolved in ethyl acetate, and 5 mg of Pd / C (10%) was added. The mixture was replaced with hydrogen and reacted at room temperature for 16 h. After the reaction was completed, the filtrate was filtered and concentrated under reduced pressure to obtain 23a (12 mg), which was used directly in the next step.

[0536] LCMS m / z=714.3[M+H] +

[0537] Step 2: Preparation of compound 23

[0538] 23a (12 mg, 0.017 mmol) was dissolved in 3 mL of dichloromethane, followed by the addition of 0.5 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 1 hour. The system was concentrated, and the trifluoroacetic acid salt of compound 23 (2.6 mg, 20.7%) was obtained by pre-HPLC. HPLC conditions: Instrument: Waters 2767 Preparative HPLC; Column: XSelect CSH C18 (19 mm × 250 mm). The sample was dissolved in DMF and filtered through a 0.45 μM filter to prepare the sample solution. Preparative chromatography conditions: a. Mobile phase A: acetonitrile; b. Water (50 mM trifluoroacetic acid); Gradient elution from 15% to 60% mobile phase A; c. Flow rate: 12 mL / min; d. Elution time: 15 minutes.

[0539] 1 H NMR(400MHz,CD3OD)δ9.14(s,2H),8.41-8.34(m,1H),7.92-7.87(m,1H),7.81(d,1H),7.63(dd,1H),7.50-7.10(m,3H),6.46(d ,1H),5.24(d,1H),3.63-3.46(m,8H),2.96-2.85(m,3H),2.50-2.41(m,2H),2.11(s,3H),2.09-1.96(m,2H),1.94-1.88(m,2H).

[0540] LCMS m / z=614.3.2[M+H] + .

[0541] Example 24: Synthesis of Compound 24:

[0542] 22h (17 mg, 0.025 mmol) was dissolved in 3 mL of dichloromethane, followed by the addition of 0.5 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 1 hour. The system was concentrated, and the trifluoroacetic acid salt of compound 22 (1.4 mg, 9.6%) was obtained by pre-HPLC. HPLC conditions: Instrument: Waters 2767 Preparative HPLC; Column: XSelect CSH C18 (19 mm × 250 mm). The sample was dissolved in DMF and filtered through a 0.45 μM filter to prepare the sample solution. Preparative chromatography conditions: a. Mobile phase A: acetonitrile; b. Water (50 mM trifluoroacetic acid); Gradient elution from 15% to 60% mobile phase A; c. Flow rate: 12 mL / min; d. Elution time: 15 minutes.

[0543] 1 H NMR(400MHz,CD3OD)δ9.15(s,2H),8.42-8.34(m,1H),7.91-7.86(m,1H),7.81(d,1H),7.63(dd,1H),7.50-7.08(m,3H),6 .45(d,1H),5.24(d,1H),3.63-3.54(m,1H),3.52-3.44(m,5H),3.11-2.80(m,10H),2.59-2.49(m,2H),2.05-1.81(m,2H).

[0544] LCMS m / z=585.3[M+H] + .

[0545] Example 25: Synthesis of Compound 25

[0546] Compound 25 (30 mg) was obtained by referring to the synthetic route of compound 18.

[0547] 1 H NMR(400MHz,CD3OD)δ9.12(s,1H),8.39(dd,1H),7.60-7.52(m,2H),7.52-7.39(m,2H),7.12(t,1H),6.40(d ,1H),5.24(d,1H),3.64-3.54(m,1H),3.08-3.00(m,2H),2.91(d,1H),2.81-2.73(m,2H),0.80-0.67(m,4H).

[0548] LCMS m / z=618.2[M+H] + .

[0549] Example 26: Preparation of Compound 26

[0550] Step 1: Synthesis of compound 26b

[0551] 26a (19.4 g, 100 mmol) was dissolved in 200 mL of acetonitrile, and NBS (17.8 g, 100 mmol) was added portionwise in an ice bath. The reaction was continued for one hour, concentrated, and an appropriate amount of ethyl acetate was added. After washing twice with water, the organic phase was concentrated and purified by silica gel column chromatography to obtain the target compound 26b (26.8 g, 98.3%).

[0552] Step 2: Synthesis of compound 26c

[0553] Substrate 26b (5.45 g, 20 mmol) and hydrochloric acid (6N, 16.7 mL, 100 mmol) were added to a reaction flask. 10 mL of sodium nitrite (2.76 g, 40 mmol) was added dropwise in an ice-salt bath. The reaction was continued for one hour. Hypophosphorous acid (50 wt.%, 5.12 g, 40 mmol) was then added dropwise and the reaction continued for another two hours. The reaction mixture was extracted twice with ethyl acetate. The resulting organic phase was dried, concentrated, and purified by silica gel column chromatography to yield compound 26c (3.45 g, 67%).

[0554] Step 3: Synthesis of compound 26d

[0555] Substrate 26c (3.45 g, 13.4 mmol) was dissolved in 40 mL of tetrahydrofuran. LDA (2 M, 7.4 mL, 14.7 mmol) was added dropwise in a dry ice-ethanol bath and the reaction was continued for 2 hours. An appropriate amount of dry ice thoroughly rinsed with tetrahydrofuran was added to the reaction solution. After the reaction was continued for 2 hours, the reaction solution was concentrated and dilute hydrochloric acid was slowly added to adjust the pH to about 3. The reaction solution was extracted twice with ethyl acetate to obtain an organic phase, which was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product of the target compound 26d.

[0556] Step 4: Synthesis of compound 26e

[0557] The crude product of compound 26d was dissolved in 30 mL of tetrahydrofuran, and a borane dimethyl sulfide solution (10.0 M, 2.7 mL, 26.8 mmol) was slowly added dropwise in an ice bath. After the addition was complete, the reaction was allowed to react at 50°C overnight. An appropriate amount of methanol was added in an ice bath to quench the reaction. The reaction solution was concentrated, and an appropriate amount of water was added. The organic phase was extracted twice with ethyl acetate, concentrated, and purified by silica gel column chromatography to obtain the target product 26e (3.0 g, two-step yield 78%).

[0558] 1H NMR (400MHz, CDCl3) δ7.56(dd,1H),7.33-7.28(m,1H),7.24(t,1H),4.87(s,2H).

[0559] Steps 5 to 18: Synthesis of compound 26

[0560] Referring to the synthetic route of steps 5 to 18 in Example 9, the target compound 26 (12 mg) was obtained using 26e as a substrate. LCMS m / z = 564.2 [M+H] +

[0561] 1 H NMR(400MHz,CD3OD)δ9.03(s,2H),8.51(d,1H),7.83-7.72(m,2H),7.67(d,1H),7.61(dd,1H),7.53(t,1H),6.38(d,1H ),5.25(d,1H),3.69-3.57(m,1H),3.49(s,3H),3.02-2.91(m,3H),2.37(d,2H),0.66-0.56(m,2H),0.54-0.45(m,2H).

[0562] Example 27: Preparation of Compound 27

[0563] Referring to the synthetic route from steps 15 to 18 in Example 9, the target compound 27 (8 mg) was obtained using 26o as a substrate. LCMS m / z = 567.2 [M+H] + .

[0564] 1 H NMR(400MHz,CD3OD)δ9.13(s,2H),8.52(d,1H),7.82(d,1H),7.80-7.76(m,1H),7.69-7.61(m,2H),7.54(t, 1H),6.38(d,1H),5.27(d,1H),3.72-3.58(m,1H),3.07(d,2H),2.98(d,1H),2.67(d,2H),0.78-0.64(m,4H).

[0565] Biological Test Example 1

[0566] 1.TNF-α / TNFR1 binding assay

[0567] The compounds were tested for their inhibition of TNF-α / TNFR1 binding using the TR-FRET method. Protein TNF-α (ACRO, Cat#TNA-H82E3) and TNFR1 (ACRO, Cat#TN1-H5251) solutions were prepared in reaction buffer PPI (Revvity, Cat#61DB10RDF). The final concentration of TNF-α / TNFR1 in the reaction mixture was 0.15 nM. The starting concentration of the test compound was 1 μM, diluted 3 times, and 10 doses. 0.1 μL of the diluted test compound in the reaction buffer was transferred to a 384-well plate (Grenier, Cat#784075) using acoustic liquid delivery technology (Echo655) and centrifuged at 1000 rpm for 1 minute; 2.5 μL of TNF-α solution was transferred to the 384 reaction plate and centrifuged at 1000 rpm for 1 minute, incubated at 25°C for 15 minutes; 2.5 μL of TNFR1 solution was transferred to the 384 reaction plate and centrifuged at 1000 rpm for 1 minute; 5 μL of Streptavidin-Tb was transferred to the 384 reaction plate and centrifuged at 1000 rpm for 1 minute. The cryptate and PAb Anti Human IgG-XL665 detection mixture was added to a 384 reaction plate and centrifuged at 1000 rpm for 1 minute. The mixture was incubated at 25°C for 60 minutes. The HTRF signal (Ratio 665 / 620 nm) was read using a BMG high-throughput drug screening multifunctional microplate reader. IC values ​​were obtained using GraphPad Prism software. 50 Values ​​and nonlinear regression curve fitting.

[0568] The experimental results are shown in Table 1 below:

[0569] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good inhibitory activity against TNF-α / TNFR1 binding.

[0570] 2. Membrane TNFα and H_TNFR1 / H_TNFR2 reporter cell detection experiment:

[0571] Cell line GM-C33297:Membrane Bound H_TNFα (cleavage-resistant) CHO-K1 Cell Line;

[0572] GM-C27615:H_TNFR2 Null Reporter Cell Line

[0573] GM-C25776: H_TNFR2 Reporter V2 Cell Line

[0574] Experimental methods:

[0575] 16-24 hours before the experiment, collect the Membrane Bound H_TNFα CHO-K1 Cell Line cell pellet by digestion and centrifugation. Resuspend the cells in complete medium, calculate the cell density and viability, and adjust the cell density to the appropriate level by adding complete medium. Add 100 μL of cells / well to the center well using a pipette, and add 100 μL of PBS to the surrounding wells. Cover the plate and incubate overnight in an incubator. 1-2 hours before the experiment, collect the effector cells (H_TNFR1 / H_TNFR2 reporter cell line) by centrifugation and resuspend them in Assay Buffer. Calculate the cell density and viability, and adjust the cell density to the appropriate level by adding Assay Buffer. In a sterile 96-well V-bottom plate, serially dilute the anti-TNFα drug in Assay Buffer. Remove the overnight Membrane Bound H_TNFα CHO-K1 Cell Line plate, discard the supernatant, and add the serially diluted drug at 50 μL / well, incubating for 1 hour. After 1 hour, add effector cells (H_TNFR1 / H_TNFR2 reporter cell line) at 50 μL / well, cover the plate, and continue incubation for 6 hours. Collect samples for luciferase detection.

[0576] The experimental results are shown in Table 2 below:

[0577] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good inhibitory activity on mTNFα / TNFR1 binding. Specifically, the inhibitory activity of compound 1 on mTNFα / TNFR1 binding is 6.81 nM.

[0578] 3. HT-29 cell apoptosis assay

[0579] HT-29 (ATCC) cells were seeded at 12,000 cells / 100 μL / well in a 96-well plate (corning, 3599) and allowed to adhere overnight. TNF-α (R&D, 210-TA-020) was diluted in culture medium to a final concentration of 20 pg / mL. Compounds were added at varying concentrations (starting at 10 μM, with 3-fold serial dilutions across nine concentration points) and pre-incubated at 37°C for 1 hour. Transfer 100 μL of the pre-incubated mixture of TNF-α and the compound to 100 μL of cells, add Z-VAD (MCE, HY-16658B) and 25 μM AT406 (MCE, HY-15454) at a final concentration of 20 μM, and incubate at 37°C, 5% CO2 for 24 hours. Add CellCounting-Lite (vazyme, DD1102), shake in the dark for 2 minutes, incubate in the dark at room temperature for 30 minutes, and read the luminescence signal value using a microplate reader.

[0580] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good inhibitory activity against HT-29 cells.

[0581] 4. Pharmacokinetic Testing in Mice

[0582] Experimental animals: Male C57 mice, 20-25 g, 6 mice per compound, purchased from Beijing Huafukang Biotechnology Co., Ltd.

[0583] Experimental Design: On the day of the experiment, six C57 mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0584] Dosing Information Note: Intravenous administration solvent: 10% DMA + 10% Solutol + 80% Saline; Oral administration solvent: 0.5% MC

[0585] DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; 0.5% MC: 0.5% methylcellulose aqueous solution

[0586] Before and after drug administration, 0.06 mL of blood was collected via the orbital cavity under isoflurane anesthesia. The blood was placed in an EDTAK2 centrifuge tube and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected from both the intravenous and oral gavage groups at 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0587] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic properties.

[0588] 5. Pharmacokinetic Test in Rat

[0589] 1.1 Experimental Animals: Male SD rats, approximately 220 g, 6 to 8 weeks old, 6 rats per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0590] 1.2 Experimental Design: On the day of the experiment, SD rats (6 per compound) were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0591] Dosing Information Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC.

[0592] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; 0.5% MC: 0.5% aqueous solution of methylcellulose)

[0593] Before and after drug administration, 0.15 ml of blood was collected intraorbitally under isoflurane anesthesia. The blood was placed in an EDTAK2 centrifuge tube and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected from both the intravenous and oral gavage groups at 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0594] The test results are shown in Table 3 below:

[0595] Table 3

[0596] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption effect in rats.

[0597] 6. Pharmacokinetic Testing in Beagle Dogs

[0598] Experimental animals: Male beagle dogs, weighing approximately 8-11 kg, 3 per compound, purchased from Beijing Masi Biotechnology Co., Ltd.

[0599] Test method: On the day of the test, beagle dogs (3 per compound) were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0600] Dosing Information Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC.

[0601] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; 0.5% MC: 0.5% aqueous solution of methylcellulose)

[0602] Before and after dosing, 1 ml of blood was collected from the jugular vein or limb vein into an EDTAK2 centrifuge tube. The samples were centrifuged at 5000 rpm at 4°C for 10 minutes, and plasma was collected. For both the intravenous and oral administration groups, blood was collected at the following time points: 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0603] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption effects in beagle dogs.

[0604] 7. Monkey Pharmacokinetic Test

[0605] Experimental animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 6 per compound, purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0606] Test method: On the day of the test, monkeys (6 per compound) were randomly divided into groups according to body weight. They were fasted but not watered for 14-18 hours before administration and fed 4 hours after administration.

[0607] Dosing Information Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC.

[0608] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; 0.5% MC: 0.5% aqueous solution of methylcellulose) *Dosage is based on free base.

[0609] Before and after dosing, 1.0 mL of blood was collected from a limb vein and placed in an EDTAK2 centrifuge tube. The samples were centrifuged at 5000 rpm at 4°C for 10 minutes, and plasma was collected. Blood was collected from both the intravenous and oral administration groups at the following time points: 0, 5 minutes, 15 minutes, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, and 24 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0610] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption effect in monkeys.

[0611] 8.CYP450 enzyme inhibition test

[0612] The purpose of this study was to evaluate the effects of test substances on the activities of five isoenzymes of cytochrome P450 (CYP) in human liver microsomes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4-M). Specific probe substrates for the CYP450 isoenzymes were incubated with human liver microsomes and various concentrations of the test substances. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction, the samples were processed and the metabolites produced by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). Changes in CYP enzyme activity were measured, and the IC values ​​were calculated. 50 The inhibitory potential of the test substance on each CYP enzyme subtype CYP1A2, CYP2C9, CYP2D6, CYP2C19, and CYP3A4-M (with midazolam as substrate) was evaluated.

[0613] The test results are shown in Table 4 below:

[0614] Table 4

[0615] Conclusion: The compounds of the present invention have no significant inhibitory effect on any subtype of CYP enzymes. For example, the inhibitory activity IC values ​​of the example compounds on CYP1A2, CYP2C9, CYP2D6, CYP2C19, and CYP3A4-M are 50 The inhibitory effects of compounds 1, 6, 11, 13, 15 and 20 on CYP1A2 were significantly weaker than those of the control compound A.

[0616] 9. hERG potassium channel effect test

[0617] Experimental platform: electrophysiology manual patch clamp system

[0618] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel

[0619] Experimental Methods: hERG potassium channel currents were recorded using the whole-cell patch-clamp technique at room temperature in CHO (Chinese Hamster Ovary) cells stably expressing the hERG potassium channel. Glass microelectrodes were pulled from glass electrode blanks (BF150-86-10, Sutter) using a puller. After perfusion with electrode solution, the tip resistance was approximately 2-5 MΩ. The microelectrodes were connected to the patch-clamp amplifier by inserting them into the amplifier headstage. Clamping voltage and data recording were controlled and recorded by a computer using pClamp 10 software with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After whole-cell recordings were obtained, cells were clamped at -80 mV. To elicit hERG potassium currents (I hERG ), a 2-second depolarization step from -80 mV to +20 mV was applied, followed by repolarization to -50 mV, which was maintained for 1 second before returning to -80 mV. This voltage stimulus was applied every 10 seconds, and drug administration was initiated after confirming the stability of the hERG potassium current (at least 1 minute). Compounds were administered for at least 1 minute at each tested concentration, and at least two cells were tested at each concentration (n≥2).

[0620] Data processing: Data analysis was performed using pClamp 10, GraphPad Prism 5, and Excel. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) by different compound concentrations was calculated using the following formula: Inhibition% = [1-(I / Io)] × 100%

[0621] Wherein, Inhibition% represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitudes of hERG potassium current before and after drug addition, respectively.

[0622] The IC50 of the compound was calculated using GraphPad Prism 5 software by fitting the following equation: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)×HillSlope))

[0623] Where X is the Log value of the test sample concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0624] Conclusion: The compounds of the present invention, such as the compounds in the examples, have no significant hERG inhibitory activity.

[0625] 10. Human microsome stability test

[0626] At 37°C, 1 μM of the test compound was incubated with human liver microsomes (0.5 mg / mL) supplemented with NADPH regeneration system for 5, 10, 20, 30, and 60 minutes. The concentration of the test compound in the resulting samples was determined by LC-MS / MS. The half-life (T) of the compound in the human liver microsome solution was obtained by calculating the remaining percentage of the compound at each time point. 1 / 2 ), intrinsic clearance (CL int(mic) ) and the percentage of compound remaining after 60 minutes.

[0627] The test results are shown in Table 5 below:

[0628] Table 5

[0629] Conclusion: Compared with the control compound A, the compounds of the present invention, such as compounds 1 and 6, have lower clearance rates and longer half-lives, and have better stability in human liver microsomes.

[0630] 11. Detection of CD11b expression on granulocytes activated by zymosan in human whole blood:

[0631] 1. Human Whole Blood (HWB) Preparation: Draw venous blood directly from the donor into a tube containing EDTA anticoagulant. Place the blood in a 4°C refrigerator, monitoring the temperature with a thermometer throughout the process. Transport the blood from the hospital to Pharmaron via a dedicated vehicle. Upon receipt, store it at 4°C.

[0632] 2. Compound Preparation: Add 8 μL of DMSO to columns 2 through 8 of a new 384-LDV plate. Transfer 12 μL of the 10 mM stock solution to column 1 of the 384-LDV plate. Perform three-fold dilutions within the 384-LDV plate to create a gradient of eight compound stock concentrations. Briefly centrifuge the LDV source plate. Use an Echo655 to transfer the compound from the source plate to a 96-well cell culture plate (Corning, 3799). Use DMSO as a positive control, and DMSO without stimulant as a negative control.

[0633] 3. Human Whole Blood Addition: Gently invert the tube 7-8 times to mix the fresh whole blood. Then, add 90 μL of fresh whole blood to a 96-well plate, mix gently, and incubate at 37°C, 5% CO2 for 1 hour. Add 10 μL of 10 μg / mL Zymosan to each well (final concentration 1 μg / mL), mix gently, and incubate at 37°C, 5% CO2 for 3 hours. The final concentration of the compound will be diluted 1000-fold. Add 10 μL of antibody to each well and incubate the stained whole blood at 4°C for 30 minutes. Dilute BD Phosflow™ Lysis / Fixation Buffer (5×) 1:5 with distilled water (perform at room temperature) and prewarm the solution to 37°C. Prepare the working solution fresh for each experiment. Using a 1200 μL pipette, add 1 mL of 1× BD Phosflow™ Lysis / Fixation Buffer to each well of a deep-well plate. Transfer the blood to the prewarmed solution, mix thoroughly, and incubate in a 37°C water bath for 15 minutes. Centrifuge at 1200 g / min for 5 minutes and discard the supernatant. Add 1 mL of PBS to each well and centrifuge at 1200 g / min for 5 minutes. Discard the supernatant. Resuspend the cells in 100 μL of cell staining buffer and store the plate at 4°C overnight. Data were acquired on a CytoFLEX S flow cytometer.

[0634] 4. Data processing and analysis: Data were analyzed by FlowJo to obtain the MFI (mean fluorescence intensity) of each sample: Noise removal: Use forward scatter (FSC) and side scatter (SSC) to create an initial gate that includes the main granulocyte population and excludes debris and noise. Adjust the gate to include most of the cell population while excluding small particles and debris. Remove adherent cells: Use FSC-A (area) and FSC-H (height) to distinguish single cells from doublets and cell clusters. Draw a gate around the single cell population to exclude doublets and cell clusters. Gating: In the single cell population, sort CD45+CD11b+ cells (APC+PE+) by fluorescence intensity and detect the MFI of CD11b activated (FITC) in CD45+CD11b+ cells.

[0635] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good inhibitory activity on the expression of CD11b on granulocytes activated by zymosan in human whole blood.

[0636] 12.Caco2 permeability test

[0637] The experiment used Caco-2 cell monolayers in 96-well Transwell plates, incubated in triplicate. Transport buffer (HBSS, 10 mM HEPES, pH 7.4 ± 0.05) containing the compound of the invention (2 μM) or the control compounds digoxin (10 μM), nadolol (2 μM), and metoprolol (2 μM) was added to the apical or basolateral wells of the cell monolayer. Transport buffer containing DMSO was added to the corresponding receiving wells. After incubation at 37 ± 1°C for 2 hours, the cell plate was removed and appropriate samples were taken from the apical and basolateral wells to a new 96-well plate. Proteins were then precipitated by adding acetonitrile containing an internal standard. Samples were analyzed using LC-MS / MS to determine the concentrations of the compound of the invention and the control compound. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical to basolateral side of the cell monolayer and from the basolateral to apical side, thereby calculating the efflux rate. The integrity of the cell monolayer after 2 hours of incubation was assessed by leakage of Lucifer Yellow.

[0638] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good permeability.

Claims

1. A compound or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt, wherein the compound is selected from the compounds represented by general formula (IA), Selected from Ring M is selected from 5-membered heteroaryl or 5-membered unsaturated heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally substituted by 1 to 4 R m replace; R m Each independently selected from deuterium, halogen, CN, =O, =S, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4 to 7 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R k replace; X is selected from N, O, S, C(R x )、C(R x )2 or N(R x ); R x Each independently selected from H, -C(=O)-C 1-6 Alkyl, -C(=O)-C 3-6 Cycloalkyl, C 1-6 Alkyl, -C 0-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene or cycloalkyl group is optionally substituted by 1 to 4 R k replace; Q is selected from C, C(R q1 )、C(R q1 )2. C(=O), C(=S), C=N(R q2 ), C=C(R q3 )2, S(=O), S(=O)(=NH), S(=O)2; R q1 Selected from H, deuterium, C 1-6 Alkyl, said alkyl being optionally substituted by 1 to 4 R k replace; R q2 、R q3 Each independently selected from H, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, said alkyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 R k replace; W is selected from -CR w1 R w2 -、-(CR w1 R w2 )2-; R w1 、R w2 Each independently selected from H, deuterium, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, said alkyl or cycloalkyl is optionally substituted by 1 to 4 R k replace; Alternatively, R w1 、R w2 Direct connection to form C 3-6 Cycloalkyl, the cycloalkyl group is optionally substituted by 1 to 4 R k replace; Ring A is selected from 5-membered heteroaryl, Z1 is selected from N or C(R z1 ); Z2 is selected from N or C(R z2 ); Z3 is selected from N or C(R z3 ); Z4 is selected from N or C; Z5 is selected from N or C; Z6 is selected from N or C; R 1 Selected from C 5-10 Bicyclic cycloalkyl, C 7-12 tricyclic cycloalkyl, -6 to 12 membered bicyclic heterocycloalkyl-R 1b , the R 1 Optional 1 to 4 R 1a replace; R 1a Each independently selected from deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -C 0-4 Alkylene-C 3-6 Cycloalkyl, -C 0-4 alkylene-4 to 7 membered heterocycloalkyl, -C(=O)C 1-6 Alkyl, -C(=O)C 3-7 carbocyclyl, -C(=O)-4 to 7 membered heterocyclyl, -NHC(=O)C 1-6 Alkyl, -NHC(=O)C 3-6 Cycloalkyl, -S(=O)C 1-6 Alkyl, -S(=O)C 3-7 Carbocyclyl, -NHS(=O)C 1-6 Alkyl, -S(=O)2C 1-6 Alkyl, -S(=O)2C 3-7 Carbocyclic group, -NHS(=O)2C 1-6 Alkyl, -S(=O)2NHC 1-6 Alkyl, -P(=O)(C 1-6 alkyl) 2, wherein the alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R k replace; R 1b Selected from H, C 1-6 Alkyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, 4 to 7 membered heterocyclic group, -C 1-2 Alkylene-C 3-7 Carbocyclic group, -C 1-2 Alkylene-4 to 7 membered heterocyclic group, -C(=O)C 1-2 Alkylene-C 3-7 Carbocyclic group, -C(=O)C 1-6 Alkyl, -C(=O)C 3-7 Carbocyclic group, -C(=O)C 1-2 Alkylene-4 to 7 membered heterocyclic group, -C(=O)-4 to 7 membered heterocyclic group, wherein the alkylene, alkyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace; R 3 Selected from H, deuterium, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, the alkyl, alkenyl, alkynyl, cycloalkyl is optionally substituted by 1 to 4 R k replace; Ring S is selected from C 6-10 aryl or 5- to 10-membered heteroaryl; Ring T is selected from phenyl, 5 to 6 membered heteroaryl, benzo 4-6 Carbocyclyl, benzo 4- to 6-membered heterocyclyl or 8- to 10-membered heteroaryl; R 2 、R z1 、R z2 、R z3 Each independently selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-7 Carbocyclic group, -C 0-4 Alkylene-C 3-7 Carbocyclic group, -C 0-4 Alkylene-4 to 7 membered heterocyclic group, -S(=O)C 1-6 Alkyl, -S(=O)C 3-7 Carbocyclyl, -NHS(=O)C 1-6 Alkyl, -S(=O)2C 1-6 Alkyl, -S(=O)2C 3-7 Carbocyclic group, -NHS(=O)2C 1-6 Alkyl, -S(=O)2NHC 1-6 Alkyl, -P(=O)(C 1-6 alkyl) 2, wherein the alkylene, alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 R k replace; Alternatively, R 2 、R z3 Direct connection to form C 4-6 Carbocyclic group or 4 to 6 membered heterocyclic group, said carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace; Alternatively, R 2 、R z1 Direct connection to form C 4-6 Carbocyclic group or 4 to 6 membered heterocyclic group, said carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace; R s 、R t Each independently selected from deuterium, halogen, CN, OH, NH2, SF5, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-7 Carbocyclic group, -OC 1-4 Alkylene-C 3-7 Carbocyclic group, -SC 3-7 Carbocyclic group, -SC 1-4 Alkylene-C 3-7 Carbocyclic group, -C 0-4 Alkylene-C 3-7 Carbocyclic group, -C 0-4 Alkylene-4 to 7 membered heterocyclic group, -S(=O)C 1-6 Alkyl, -S(=O)C 3-7 Carbocyclyl, -NHS(=O)C 1-6 Alkyl, -S(=O)2C 1-6 Alkyl, -S(=O)2C 3-7 Carbocyclic group, -NHS(=O)2C 1-6 Alkyl, -S(=O)2NHC 1-6 Alkyl, -P(=O)(C 1-6 alkyl) 2, wherein the alkylene, alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 R k replace; R k Each independently selected from deuterium, =O, halogen, CN, OH, COOH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclyl, -O-4 to 7 membered heterocyclyl, -NH-C 3-6 Carbocyclic group, -NH-4 to 7 membered heterocyclic group, -C 1-4 Alkylene-C 3-6 Carbocyclic group, -C 1-4 Alkylene-4 to 7 membered heterocyclic group, C 3-6 Carbocyclic group, 4 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent; n1 and n2 are each independently selected from 0, 1, 2, 3 or 4.

2. The compound according to claim 1 or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt, R m Each independently selected from deuterium, halogen, CN, =O, =S, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4 to 7 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R k replace; R x Each independently selected from H, -C(=O)-C 1-4 Alkyl, -C(=O)-C 3-6 Cycloalkyl, C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 1-2 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene or cycloalkyl group is optionally substituted by 1 to 4 R k replace; R q1 Selected from H, deuterium, C 1-4 Alkyl, said alkyl being optionally substituted by 1 to 4 R k replace; R q2 、R q3 Each independently selected from H, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, said alkyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 R k replace; R 1 Selected from C 5-10 Bridged cycloalkyl, C 6-10 Cycloalkyl, C 5-10 Spirocycloalkyl, -6 to 10 membered bridged heterocycloalkyl-R 1b 、-6 to 12 membered heterocyclic alkyl-R 1b 、-6 to 12-membered spirocyclic heterocycloalkyl-R 1b , the R 1 Optional 1 to 4 R 1a replace; R 1a Each independently selected from deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-6 Cycloalkyl, C 1-2 alkylene-4 to 7 membered heterocycloalkyl, -C(=O)C 1-4 Alkyl, -C(=O)C 3-6 Cycloalkyl, -C(=O)-4 to 7 membered heterocycloalkyl, -NHC(=O)C 1-4 Alkyl, -NHC(=O)C 3-6 Cycloalkyl, -S(=O)C 1-4 Alkyl, -S(=O)C 3-6 Cycloalkyl, -NHS(=O)C 1-4 Alkyl, -S(=O)2C 1-4 Alkyl, -S(=O)2C 3-6 Cycloalkyl, -NHS(=O)2C 1-4 Alkyl, -S(=O)2NHC 1-4 Alkyl, -P(=O)(C 1-4 alkyl) 2, wherein the alkylene, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R k replace; R 1b Selected from H, C 1-4 Alkyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-6 Cycloalkyl, -C 1-2 alkylene-4 to 7 membered heterocycloalkyl, -C(=O)C 1-2 Alkylene-C 3-6 Cycloalkyl, -C(=O)C 1-4 Alkyl, -C(=O)C 3-6 Cycloalkyl, -C(=O)-C 1-2 Alkylene-4 to 7 membered heterocycloalkyl, -C(=O)-4 to 7 membered heterocycloalkyl, wherein the alkylene, alkyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R k replace; R w1 、R w2 Each independently selected from H, deuterium, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, said alkyl or cycloalkyl is optionally substituted by 1 to 4 R k replace; Alternatively, R w1 、R w2 Direct connection to form C 3-6 Cycloalkyl, the cycloalkyl group is optionally substituted by 1 to 4 R k replace; R 3 Selected from H, deuterium, halogen, CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, the alkyl, alkenyl, alkynyl, cycloalkyl is optionally substituted by 1 to 4 R k replace; Ring S is selected from phenyl, benzo 4-6 Carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, or 8- to 10-membered heteroaryl; R 2 、R z1 、R z2 、R z3 Each independently selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-7 Carbocyclic group, -C 1-2 Alkylene-4 to 7 membered heterocyclic group, -S(=O)C 1-4 Alkyl, -S(=O)C 3-6 Cycloalkyl, -NHS(=O)C 1-4 Alkyl, -S(=O)2C 1-4 Alkyl, -S(=O)2C 3-6 Cycloalkyl, -NHS(=O)2C 1-4 Alkyl, -S(=O)2NHC 1-4 Alkyl, -P(=O)(C 1-4 alkyl) 2, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 R k replace; Alternatively, R 2 、R z3 Direct connection to form C 4-6 Carbocyclic group or 4 to 6 membered heterocyclic group, said carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace; Alternatively, R 2 、R z1 Direct connection to form C 4-6 Carbocyclic group or 4 to 6 membered heterocyclic group, said carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace; R s 、R t Each independently selected from deuterium, halogen, CN, OH, NH2, SF5, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, -OC 1-2 Alkylene-C 3-6 Cycloalkyl, -SC 3-6 Cycloalkyl, -SC 1-2 Alkylene-C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-7 Carbocyclic group, -C 1-2 Alkylene-4 to 7 membered heterocyclic group, -S(=O)C 1-4 Alkyl, -S(=O)C 3-6 Cycloalkyl, -NHS(=O)C 1-4 Alkyl, -S(=O)2C 1-4 Alkyl, -S(=O)2C 3-6 Cycloalkyl, -NHS(=O)2C 1-4 Alkyl, -S(=O)2NHC 1-4 Alkyl, -P(=O)(C 1-4 alkyl) 2, phenyl or 5 to 6 membered heteroaryl, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, carbocyclyl, heterocyclyl, phenyl or heteroaryl is optionally substituted by 1 to 4 R k replace; R k Each independently selected from deuterium, =O, halogen, CN, OH, COOH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Carbocyclyl, -O-4 to 7 membered heterocyclyl, -NH-C 3-6 Carbocyclic group, -NH-4 to 7 membered heterocyclic group, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C 1-2 Alkylene-4 to 7 membered heterocyclic group, C 3-6 Carbocyclic group, 4 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent.

3. The compound according to claim 2 or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt, Selected from Selected from 1 to 3 R m One of the following groups substituted: Selected from R w1 、R w2 Each independently selected from H, deuterium, F, Cl, Br, methyl, ethyl, cyclopropyl, wherein the methyl, ethyl, cyclopropyl is optionally substituted by 1 to 4 R k replace; Alternatively, R w1 、R w2 Direct connection forms cyclopropyl, cyclobutyl, and the cyclopropyl, cyclobutyl are optionally substituted by 1 to 4 R k replace; Ring S is selected from phenyl or 5- to 6-membered heteroaryl; Selected from Y is selected from N or CH; R 1 Selected from The R 1 Optional 1 to 4 R 1a replace; s1, s3, and s5 are each independently selected from 0, 1, or 2; s2 and s4 are each independently selected from 0 or 1; R t1 Selected from H, deuterium, halogen, CN, OH, NH2, SF5, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, -OC 1-2 Alkylene-C 3-6 Cycloalkyl, -SC 3-6 Cycloalkyl, -SC 1-2 Alkylene-C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-7 Carbocyclic group, -C 1-2 Alkylene-4 to 7 membered heterocyclic group, -S(=O)C 1-4 Alkyl, -S(=O)C 3-6 Cycloalkyl, -NHS(=O)C 1-4 Alkyl, -S(=O)2C 1-4 Alkyl, -S(=O)2C 3-6 Cycloalkyl, -NHS(=O)2C 1-4 Alkyl, -S(=O)2NHC 1-4 Alkyl, -P(=O)(C 1-4 alkyl) 2, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 R k replace; n3 is selected from 0, 1, 2 or 3.

4. The compound according to claim 3 or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt, wherein: R m Each independently selected from deuterium, F, Cl, Br, CN, OH, methyl, ethyl, methoxy, ethoxy, cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, cyclopropyl is optionally substituted by 1 to 4 selected from deuterium, halogen, CF3, CHF2, CH2F, CD3, CHD2, CH2D, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; W is selected from -CH2-, -CH(CH3)-, -CH(CF3)-, -CH(CD3)-, -CFH-, -CF2-, -CH2CH2- or R 2 、R z1 、R z2 Each independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy, cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, cyclopropyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; R x Selected from H, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH(CH3)2, -C(=O)-cyclopropyl, methyl, ethyl, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, cyclopropyl, cyclobutyl is optionally substituted by 1 to 4 R k replace; R q1 is selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl or cyclopropyl, wherein the methyl, ethyl and cyclopropyl groups are optionally substituted by 1 to 4 groups selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; R q2 is selected from H, OH, CN, NH2, methyl, ethyl, methoxy, ethoxy, wherein the methyl, ethyl, methoxy, ethoxy is optionally substituted by 1 to 4 deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; Ring S is selected from phenyl, thienyl, thiazolyl, furyl, oxazolyl, pyrazolyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl; R 1 Selected from The R 1 Optional 1 to 4 R 1a replace; R 1a Each independently selected from deuterium, F, Cl, Br, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, methoxy, ethoxy, cyclopropyl, -CH2-cyclopropyl, -S(=O)CH3, -S(=O)cyclopropyl, -NHS(=O)-CH3, -S(=O)2-CH3, -S(=O)2cyclopropyl, -NHS(=O)2CH3, -S(=O)2NHCH3, -P(=O)(CH3)2, wherein the CH2, methyl, ethyl, methoxy, ethoxy, cyclopropyl are optionally substituted by 1 to 4 R k replace; R 1b Selected from H or optionally 1 to 4 R k substituted with one of the following groups: methyl, ethynyl, -CH2-ethynyl, propynyl, butynyl, butyn-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-oxetanyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl , -C(=O)-CH2-cyclopropyl, -C(=O)-CH2-cyclobutyl, -C(=O)-CH2-cyclopentyl, -C(=O)-CH2-cyclohexyl, -C(=O)-methyl, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl, -C(=O)-cyclohexyl, -C(=O)-oxetanyl, -C(=O)-tetrahydrofuranyl, -C(=O)-oxetanyl, -C(=O)-azetidinyl, -C(=O)-pyrrolidinyl, -C(=O)-piperidinyl, -C(=O)-piperazinyl; R s 、R t Each independently selected from deuterium, F, Cl, Br, CN, OH, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, -O-CH2-cyclopropyl, -O-CH2-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -S-CH 2-cyclopropyl, -S-CH2-cyclobutyl, -P(=O)(CH3)2, phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl, triazolyl, said CH2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl, triazolyl optionally substituted by 1 to 4 R k replace; R t1 is selected from H, deuterium, F, Cl, Br, CN, OH, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, -O-CH2-cyclopropyl, -O-CH2-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -S-C H2-cyclopropyl, -S-CH2-cyclobutyl, oxetanyl, tetrahydrofuranyl, -S(=O)CH3, -S(=O)cyclopropyl, -NHS(=O)-CH3, -S(=O)2-CH3, -S(=O)2cyclopropyl, -NHS(=O)2CH3, -S(=O)2NHCH3, -P(=O)(CH3)2, the CH2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl are optionally substituted by 1 to 4 R k replace; R k Each independently selected from deuterium, =O, F, Cl, Br, I, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally substituted by 1 to 4 selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; Preferably, R k Each is independently selected from deuterium, F, Cl, Br, I, CN, OH, -CH2OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

5. The compound according to claim 4 or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt, wherein: R m Each independently selected from deuterium, F, Cl, Br, CN, methyl, ethyl, cyclopropyl, CF3, CHF2, CH2F, CD3, CHD2, CH2D, CH2CD3, CH2CF3; R 1 is selected from one of the following groups wherein the ring is optionally substituted: When substituted, it is optionally substituted with 1 to 3 substituents selected from deuterium, F, Cl, Br, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, -CH2OH, methyl, ethyl, methoxy, ethoxy; R 1a Each independently selected from OH, NH2, CN, -NHS(=O)-CH3, -NHS(=O)2-CH3, -S(=O)-CH3, -S(=O)2-CH3; R 1b is selected from H, methyl, ethynyl, -CH2-ethynyl, propynyl, butynyl, butyn-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -C(=O)-CH2-cyclopropyl, -C(=O)-CH2-cyclobutyl, -C(=O)-CH2-cyclopentyl, -C(=O)-CH2-cyclohexyl, -C(=O)-methyl wherein the methyl, ethynyl, propynyl, butynyl, butyn-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl or ethyl; Ring S is selected from Left side and R 1 Direct connection; R t1 Selected from SF5, methyl, ethyl, methoxy, ethoxy, -S-methyl, -S-ethyl, -O-cyclopropyl, -O-cyclobutyl, -OCH2-cyclopropyl, -OCH2-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -SCH2-cyclopropyl, -SCH2-cyclobutyl, wherein the methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl or ethyl; R x is selected from H, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH(CH3)2, -C(=O)-cyclopropyl, methyl, ethyl, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, cyclopropyl, cyclobutyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl or ethyl; R q1 is selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl or cyclopropyl, wherein the methyl, ethyl or cyclopropyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl or ethyl; R q2 is selected from H, OH, CN, NH2, methyl, ethyl, methoxy, ethoxy, wherein the methyl, ethyl, methoxy, ethoxy is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl or ethyl; R 2 、R z1 、R z2 Each is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy, and cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, and cyclopropyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy, or ethoxy; Preferably, R s each independently selected from deuterium, F, Cl, Br, CN, OH, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, -P(=O)(CH3)2, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, thiadiazole The CH2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl, triazolyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy or ethoxy.

6. The compound according to claim 1 or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt, wherein the compound is selected from one of the structures shown in Table E.

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition comprises 1 to 1500 mg of the compound according to any one of claims 1 to 6 or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt.

8. Use of the compound according to any one of claims 1 to 6 or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt in the preparation of a medicament for treating autoimmune diseases or inflammatory diseases (preferably psoriasis or rheumatoid arthritis).

9. A method for treating or alleviating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 6 or a racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, the therapeutically effective amount preferably being 1 to 1500 mg, wherein the disease is preferably an autoimmune disease or an inflammatory disease (preferably psoriasis or rheumatoid arthritis).

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