An ar inhibitor and its use in medicine

Abstract

The present application relates to a kind of AR inhibitor and its medical use, specifically related to a kind of compound described in general formula (I) or its racemate, stereoisomer, pharmaceutically acceptable salt, and intermediate and preparation method, and in the preparation for the disease related with androgen receptor cut mutant drug application. (I).

Description

Technical Field

[0001] This invention relates to a compound of general formula (I) or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt, intermediates and preparation methods thereof, and its use in the preparation of medicaments for treating diseases such as cancer associated with androgen receptor splicing mutants. Background Technology

[0002] The androgen receptor (AR) is a nuclear hormone receptor structurally divided into an N-terminal activating domain (NTD), a DNA-binding domain (DBD), and a ligand-binding domain (LTD). It regulates gene expression that induces prostate cancer; therefore, inhibiting the androgen receptor is an effective treatment for prostate cancer. Currently marketed androgen receptor inhibitors, such as enzalutamide and bicalutamide, primarily exert their inhibitory effects by interacting with the ligand-binding domain (LTD) of the androgen receptor. However, some patients develop resistance during treatment due to androgen receptor splice variants (AR-Vs) that lack the LTD fragment. Preclinical studies have shown that androgen receptor splice variants can accelerate the progression of enzalutamide-resistant prostate cancer, making the resolution of this resistance a focus of clinical medicine.

[0003] Therefore, it is necessary to develop novel inhibitors of androgen receptor splice variants (AR-Vs, especially AR-V7 mutants) for the treatment of oncological diseases associated with androgen receptor splice variants. Summary of the Invention

[0004] The purpose of this invention is to provide a novel compound with good efficacy, high bioavailability, and greater safety that can inhibit AR and / or AR-Vs (especially AR-V7) for the treatment of diseases related to AR and / or AR-Vs, such as prostate cancer.

[0005] This invention provides a compound of general formula (I) or a racemic, stereoisomer, tautomer, pharmaceutically acceptable salt or eutectic thereof.

[0006] (I)

[0007] In some embodiments, general formula (I) is selected from compounds represented by general formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), and (Ig).

[0008] (Ia) (Ib)

[0009] (Ic) (Id) (Ie) (If)

[0010] (Ig)

[0011] In some implementation schemes, e is selected from 0, 1, 2, or 3;

[0012] In some implementations, ring A is selected from 5-6 membered heteroaryl groups, C 6-14 Carbocyclic group, 7-12 membered heterocyclic group, or ring A is absent;

[0013] In some embodiments, ring A is selected from 5-6-membered heteroaryl, benzo4-6-membered heterocyclic, benzo4-6-membered carbocyclic, 5-6-membered heteroaryl-4-6-membered heterocyclic, and 5-6-membered heteroaryl-4-6-membered carbocyclic.

[0014] In some embodiments, ring A is selected from pyrimidinyl, pyrazinyl, pyrazinyl, pyridinyl, thiazolyl, pyrroleyl, thiopheneyl, furanyl, pyrazolyl, triazolyl, pyridoyl 4- to 6-membered heterocyclic group, and pyridoyl 4- to 6-membered carbocyclic group;

[0015] In some embodiments, ring A is selected from pyrimidinyl, pyridazinyl, pyrazinyl, pyridinyl, thiazolyl, pyridinium imidazolyl, pyridocyclopentyl, and pyridocyclohexyl.

[0016] In some embodiments, ring A is selected from pyrimidinyl, pyridazinyl, pyrazinyl, pyridinyl, thiazolyl, and others. , ;

[0017] In some embodiments, ring A is selected from pyrimidinyl, pyridazinyl, pyrazinyl, pyridinyl, thiazolyl, and others. , ;

[0018] In some implementations, B is selected from rings B and C. 2-6 alkynyl group, C 2-6 alkenyl group, wherein the alkenyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0019] In some implementations, B is selected from rings B and C. 2-4 alkynyl group;

[0020] In some implementation schemes, B is selected from cyclic B and ethynyl group;

[0021] In some embodiments, ring B is selected from 6-14 aryl, 5-12 heteroaryl, benzo4-6 heterocyclic, benzo4-6 carbocyclic, C 4-12 Cycloalkyl or 4- to 12-membered heterocycloalkyl, wherein the ring B is optionally surrounded by 1 to 6 R... b replace;

[0022] In some embodiments, ring B is selected from phenyl, 5-6-membered heteroaryl, benzo4-6-membered heterocyclic, benzo4-6-membered carbocyclic, C 4-8 Cycloalkyl or 4- to 8-membered heterocycloalkyl, wherein the ring B is optionally surrounded by 1 to 4 R... b replace;

[0023] In some embodiments, ring B is selected from pyrazinyl, pyridazinyl, pyridyl, phenyl, pyrimidinyl, and piperidinyl, and ring B is optionally surrounded by 1 to 4 R groups. b replace;

[0024] In some implementations, Z is selected from phenyl, 6-membered heteroaryl, C 2-6 Alkyne group, wherein the heteroaryl group or phenyl group is optionally surrounded by 1 to 6 R groups. z replace;

[0025] In some implementations, Z is selected from phenyl, 6-membered heteroaryl, C 2-4 Alkyne group, wherein the heteroaryl group or phenyl group is optionally surrounded by 1 to 4 R groups. z replace;

[0026] In some embodiments, Z is selected from phenyl, pyrazinyl, pyridinyl, pyridyl, pyrimidinyl, and ethynyl, wherein the pyrazinyl, pyridinyl, pyrimidinyl, and phenyl groups are optionally surrounded by 1 to 4 R groups. z replace;

[0027] In some implementation schemes, Z is selected from phenyl, , , , acetylene group , ;

[0028] In some implementation schemes, Z is selected from Z. A Z A Selected from , acetylene group , ;

[0029] In some implementations, -BZ- is selected from , Its right end is connected to L2;

[0030] In some implementations, ring D is selected from 6-14 aryl or 5-12 heteroaryl;

[0031] In some implementation schemes, ring D is selected from 6-10 aryl and 5-10 heteroaryl groups;

[0032] In some implementation schemes, ring D is selected from 6-membered aryl and 5-6-membered heteroaryl;

[0033] In some implementations, ring D is selected from phenyl, ;

[0034] In some implementation schemes, Selected from , , , ;

[0035] In some implementations, L 1 Selected from -O-, -C 1-4 alkylene-, -C 1-4 Alkylene-O- -O-4 to 8-membered heterocyclic groups -O-C 1-4 alkylene-4 to 8-membered heterocyclic groups -, -C 1-4 Alkylene-NR L0 -、-OC 1-4 Alkylene-, -OC 1-4 Alkylene-O-, C 2-6 alkenyl, -C 3-12 Carbocyclic -C 1-4 Alkylene -O-, -C 3-12 Carbocyclic groups -O-, -4 to 12-membered heterocyclic groups -C 1-4 Alkylene-O-, -4 to 12-membered heterocyclic-O-, -OC 3-8 Carbocyclic group-, , Its right end is connected to B, and the alkylene, alkenyl, carbocyclic, or heterocyclic groups are optionally surrounded by 1 to 4 R groups. k replace;

[0036] In some implementations, L 1 Selected from -O-, -C 1-2 alkylene-, -C 1-2 Alkylene-O- -O-4 to 8-membered heterocyclic groups -O-C 1-2 alkylene-4 to 8-membered heterocyclic groups -, -C 1-2 Alkylene-NR L0 -、-OC 1-2 Alkylene-, -OC 1-2 Alkylene-O-, C2-4 alkenyl, -C 3-8 Carbocyclic -C 1-2 Alkylene -O-, -C 3-8 Carbocyclic -O-, -4 to 8-membered heterocyclic -C 1-2 Alkylene-O-, -4 to 8-membered heterocyclic-O-, -OC 3-8 Carbocyclic group-, , Its right end is connected to B, and the alkylene, alkenyl, carbocyclic, or heterocyclic groups are optionally surrounded by 1 to 4 R groups. k replace;

[0037] In some implementations, L 1 Selected from -O-, -CH2-, -CH2-O-, -O-4 to 8-membered heterocyclic groups-, -O-CH2-4 to 8-membered heterocyclic groups-, -CH2-NR L0 -, -O-CH2-, -O-CH2-CH2-O-, C 2-4 alkenyl, -C 3-8 Carbocyclic groups -CH2--O-, -C 3-8 Carbocyclic group -O-, -4 to 8-membered heterocyclic group -CH2-O-, -4 to 8-membered heterocyclic group -O-, -OC 3-8 Carbocyclic group-, , Its right end is connected to B, and the alkylene, alkenyl, carbocyclic, or heterocyclic groups are optionally surrounded by 1 to 4 R groups. k replace;

[0038] In some implementations, L 1 Selected from -O-, -CH2-, -CH2-O-, -O-oxetanebutyl, -O-oxetanepentyl, -O-oxetanehexyl, -O-azacyclobutyl, -O-azacyclopentyl, -O-azacyclohexyl, -O-CH2-oxetanebutyl, -O-CH2-oxetanepentyl, -O-CH2-oxetanehexyl, -O-CH2-azacyclobutyl, -O-CH2-azacyclopentyl, -O-CH2-azacyclohexyl, -CH2-NR L0 -、-O-CH2-、-O-CH2-CH2-O-、vinyl、-cyclopropyl-CH2-O-、-cyclobutyl-CH2-O-、-cyclopentyl-CH2-O-、-cyclohexyl-CH2-O-、 -Cyclopropyl-O-, -Cyclobutyl-O-, -Cyclopentyl-O-, -Cyclohexyl-O-, -azacyclobutyl-CH2-O-, -azacyclopentyl-CH2-O-, -piperidinyl-CH2-O-, -azacyclobutyl-O-, -azacyclopentyl-O-, -piperidinyl-O-, -phenyl-O-, -phenyl-CH2-O-, -pyridine-CH2-O-, -oxacyclobutyl-CH2-O-, -oxacyclopentyl-CH2-O-, -oxacyclohexyl-CH2-O-, -oxacyclobutyl-O-, -oxacyclopentyl-O-, -oxacyclohexyl-O-, -O-cyclopropyl-, -O-cyclobutyl-, -O-cyclopentyl-, -O-cyclohexyl-, , Its right end is connected to B, and the vinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, aziridine, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, piperidinyl, phenyl, pyridine, Choose from 1 to 4 Rs k replace;

[0039] In some implementations, L 1 Selected from -O-, -CH2-, -CH2-O-, -O-CH2-, -O-CH2-CH2-O-, vinyl, , , , , , , , -O-cyclopropyl-, -O-cyclobutyl-, , Its right end is connected to B;

[0040] In some implementation schemes, Selected from , , ,That Terminal B is connected;

[0041] In some implementation schemes, R L0 R b Together with the atoms attached to it, they form a 4-8 membered heterocyclic group, wherein the heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace;

[0042] In some implementation schemes, R L0 R bTogether with the atoms attached to it, they form azircyclic butyl, azircyclic pentyl, azircyclic hexyl, azircyclic heptyl, azircyclic butylenyl, azircyclic pentenyl, azircyclic hexenyl, azircyclic heptenyl, furanyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, 1,4-dioxanecyclol, 1,4-dioxanecycloalkenyl. , The aziridine, aziridine pentyl, aziridine hexyl, aziridine heptyl, aziridine butenyl, aziridine pentenyl, aziridine heptenyl, furanyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, 1,4-dioxanecycloyl, 1,4-dioxanecycloylene are optionally surrounded by 1 to 4 R groups. k replace;

[0043] In some implementations, -L 1 -B- Selected from 1 to 4 R's. k The following groups are substituted: , , , , , , , , , Its right end is connected to Z;

[0044] In some implementation schemes, R L1 R b Together with the atoms attached to it, they form a 4-8 membered heterocyclic group, wherein the heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace;

[0045] In some implementations, L 2 Selected from -CR 1 R 2 -、-NR L2 -、 C 3-8 A carbocyclic group or a 4-8 membered heterocyclic alkyl group, wherein the right end is connected to a ring D, and the carbocyclic group or heterocyclic alkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0046] In some implementations, L 2 Selected from L 2A ;

[0047] In some implementations, L 2A Selected from -NR L2 -、 C 3-8 A carbocyclic group or a 4-8 membered heterocyclic alkyl group, wherein the right end is connected to a ring D, and the carbocyclic group or heterocyclic alkyl group is optionally surrounded by 1 to 4 R groups. kreplace;

[0048] In some implementations, L 2 Selected from -CR 1 R 2 -、-NR L2 -、 , Cyclopropyl, cyclobutyl, oxacyclobutyl, and aziridine, with their right ends connected to ring D, wherein the cyclopropyl, cyclobutyl, oxacyclobutyl, and aziridine are optionally surrounded by 1 to 4 R groups. k replace;

[0049] In some implementations, L 2A Selected from -NR L2 -、 , Cyclopropyl, cyclobutyl, oxacyclobutyl, aziridine, cyclopentyl, and oxacyclopentyl, with their right ends connected to ring D, wherein the cyclopropyl, cyclobutyl, oxacyclobutyl, aziridine, cyclopentyl, and oxacyclopentyl groups are optionally bounded by 1 to 4 R groups. k replace;

[0050] In some implementations, L 2 Selected from , , , , , , , , , , , , , , , , Its right end is connected to ring D;

[0051] In some implementations, L 2A Selected from , , , , , , , , , , , Its right end is connected to ring D;

[0052] In some implementation schemes, Selected from , ;

[0053] In some implementation schemes, R L2 R z Together with the atoms attached to it, they form a 4-8 membered heterocyclic group, wherein the heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace;

[0054] In some implementation schemes, R L2 R z Together with the atoms attached thereto, they form a pyrrole group, an imidazolyl group, and an imidazolide group, wherein the pyrrole group, imidazolyl group, and imidazolide group are optionally surrounded by 1 to 4 R atoms. k replace;

[0055] In some implementations, -ZL 2 -Selected from , , , Its * end is connected to B;

[0056] In some implementation schemes, R 1 R 2 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, wherein the alkyl, alkenyl, or ynyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0057] In some implementation schemes, R 1 R 2 Together with the atoms bonded to it, they form C 3-8 Carbocyclic groups, 4-8 membered heterocyclic groups, wherein the C 3-8 The carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0058] In some implementation schemes, R 1 R 2 Together with the atoms bonded to it, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, azircyclobutyl, azircyclopentyl, azircyclohexyl, and so on. , The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, azircyclobutyl, azircyclopentyl, azircyclohexyl , Choose from 1 to 4 Rs k replace;

[0059] In some implementation schemes, R 1 R 2 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, wherein the alkyl, alkenyl, or ynyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0060] In some implementation schemes, R 1 R 2 Each of the following is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NH2, -NHCH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, and ethoxy, wherein the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, and ethoxy groups are optionally prefixed with 1 to 4 R groups. k replace;

[0061] In some implementation schemes, R l1 R l2 Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0062] In some implementation schemes, R l1 R l2 The atoms bonded to it together form cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups, wherein the cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups are optionally bounded by 1 to 4 R groups. k replace;

[0063] In some implementation schemes, R 1 R d Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0064] In some implementation schemes, R 1 R d The atoms bonded to it together form cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl groups, wherein the cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl groups are optionally separated by 1 to 4 R groups. k replace;

[0065] In some implementation schemes, R 1 R z Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0066] In some implementation schemes, R 1 R z The atoms bonded to it together form cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl groups, wherein the cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl groups are optionally separated by 1 to 4 R groups. k Replace; in some implementations, R b R z Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0067] In some implementations, two adjacent R z Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0068] In some implementations, two adjacent R z The atoms bonded to it together form cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups, wherein the cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups are optionally bounded by 1 to 4 R groups. k replace;

[0069] In some implementation schemes, R L0 R a Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0070] In some implementation schemes, R L0 R a The atoms bonded to it together form imidazolium, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl groups, wherein the imidazolium, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl groups are optionally surrounded by 1 to 4 R groups. k replace;

[0071] In some implementation schemes, R ASelected from 4- to 12-membered heterocyclic alkyl groups, -4- to 12-membered heterocyclic alkyl groups -S(=O)2R A1 -4 to 12-membered heterocyclic alkyl-S(=O)R A1 -4 to 12-membered heterocyclic alkyl-S(=O)2NR A1 R A2 -4 to 12-membered heterocyclic alkyl-S(=O) (=NR) A1 )R A2 -4 to 12-membered heterocyclic alkyl-C 1-4 Alkylene-S(=O)2R A1 -4 to 12-membered heterocyclic alkyl-C 1-4 Alkylene-S(=O)R A1 -4 to 12-membered heterocyclic alkyl-C 1-4 Alkylene-S(=O)2NR A1 R A2 -4 to 12-membered heterocyclic alkyl-C 1-4 Alkylene-NR A1 -S(=O)2R A2 -4 to 12-membered heterocyclic alkyl-C 1-4 Alkylene-N=S(=O)R A1 R A2 -4 to 12-membered heterocyclic alkyl-C 1-4 Alkylene-S(=O) (=NR) A1 )R A2 -4 to 12-membered heterocyclic alkyl-C 1-4 Alkylene-NR A1 -S(=O)R A1 -P(=O)R A1 R A2 -4 to 12-membered heterocyclic alkyl-P(=O)R A1 R A2 -4 to 12-membered heterocyclic alkyl-C 1-4 Alkylene-P(=O)R A1 R A2 -N=S(=O)R A1 R A2 -4 to 12-membered heterocyclic alkyl groups -N=S(=O)R A1 R A2 , , , , , , , , , , , , , , , , The alkylene, heterocyclic alkyl, , , , , , , , , , , , , , , Choose from 1 to 6 Rs k replace;

[0072] In some implementation schemes, R A Selected from R Aa In some implementation schemes, R Aa Selected from -4 to 12-membered heterocyclic alkyl groups -S(=O)2NHC 1-6 Alkyl group, -S (=O) (=NR) A1 )R A2 -4 to 12-membered heterocyclic alkyl-S(=O) (=NR) A1 -C 1-4 Alkylene-C 3-8 Carbocyclic, -4 to 12-membered heterocyclic alkyl -S(=O)2NR A1 -C 3-8 carbon cyclo group, , , , , , , , The R Aa Choose from 1 to 6 Rs k replace;

[0073] In some implementation schemes, R A Selected from 4- to 10-membered heterocyclic alkyl groups, -4- to 10-membered heterocyclic alkyl groups -S(=O)2R A1 -4 to 10-membered heterocyclic alkyl-S(=O)R A1 -4 to 10-membered heterocyclic alkyl-S(=O)2NR A1 R A2 -4 to 10-membered heterocyclic alkyl-NR A1 -S(=O)2R A2 -4 to 10-membered heterocyclic alkyl groups -N=S(=O)R A1 RA2 -4 to 10-membered heterocyclic alkyl-S(=O) (=NR) A1 )R A2 -4 to 10-membered heterocyclic alkyl-C 1-2 Alkylene-S(=O)2R A1 -4 to 10-membered heterocyclic alkyl-C 1-2 Alkylene-S(=O)R A1 -4 to 10-membered heterocyclic alkyl-C 1-2 Alkylene-S(=O)2NR A1 R A2 -4 to 10-membered heterocyclic alkyl-C 1-2 Alkylene-NR A1 -S(=O)2R A2 -4 to 10-membered heterocyclic alkyl-C 1-2 Alkylene-N=S(=O)R A1 R A2 -4 to 10-membered heterocyclic alkyl-C 1-2 Alkylene-S(=O) (=NR) A1 )R A2 -P(=O)R A1 R A2 -4 to 10-membered heterocyclic alkyl-P(=O)R A1 R A2 -4 to 10-membered heterocyclic alkyl-C 1-2 Alkylene-P(=O)R A1 R A2 -N=S(=O)R A1 R A2 , , , , , , , , , , , , , , , , The alkylene, heterocyclic alkyl, , , , , , , , , , , , , , , Choose from 1 to 4 Rs k replace;

[0074] In some implementation schemes, R Aa Selected from -4 to 10-membered heterocyclic alkyl groups -S(=O)2NHC 1-4 Alkyl group, -S (=O) (=NR) A1 )R A2 -4 to 10-membered heterocyclic alkyl-S(=O) (=NR) A1 -C 1-2 Alkylene-C 3-6 Carbocyclic, -4 to 10-membered heterocyclic alkyl group -S(=O)2NR A1 -C 3-6 carbon cyclo group, , , , , , , , The R Aa Choose from 1 to 4 Rs k replace;

[0075] In some implementation schemes, R A Selected from 4- to 10-membered heterocyclic alkyl groups, -4- to 10-membered heterocyclic alkyl groups -S(=O)2R A1 -4 to 10-membered heterocyclic alkyl-S(=O)R A1 -4 to 10-membered heterocyclic alkyl-S(=O)2NR A1 R A2 -4 to 10-membered heterocyclic alkyl-NR A1 -S(=O)2R A2 -4 to 10-membered heterocyclic alkyl groups -N=S(=O)R A1 R A2 -4 to 10-membered heterocyclic alkyl-S(=O) (=NR) A1 )R A2 -4 to 10-membered heterocyclic alkyl group -CH2-S(=O)2R A1 -4 to 10-membered heterocyclic alkyl group -CH2-S(=O)R A1 -4 to 10-membered heterocyclic alkyl group -CH2-S(=O)2NR A1 R A2 -4 to 10-membered heterocyclic alkyl-CH2-NR A1 -S(=O)2R A2 -4 to 10-membered heterocyclic alkyl groups -CH2-N=S(=O)RA1 R A2 -4 to 10-membered heterocyclic alkyl groups -CH2-S(=O) (=NR) A1 )R A2 -P(=O)R A1 R A2 -4 to 10-membered heterocyclic alkyl-P(=O)R A1 R A2 -4 to 10-membered heterocyclic alkyl groups -CH2-P(=O)R A1 R A2 -N=S(=O)R A1 R A2 , , , , , , , , , , , , , , , , The -CH2-, heterocyclic alkyl, , , , , , , , , , , , , , , Choose from 1 to 4 Rs k replace;

[0076] In some implementation schemes, R Aa Selected from -4 to 10-membered heterocyclic alkyl groups -S(=O)2NHC 1-4 Alkyl group, -S (=O) (=NR) A1 )R A2 -4 to 10-membered heterocyclic alkyl-S(=O) (=NR) A1 ) - CH2-C 3-6 Carbocyclic, -4 to 10-membered heterocyclic alkyl group -S(=O)2NR A1 -C 3-6 carbon cyclo group, , , , , , , , The R Aa Choose from 1 to 4 Rs k replace;

[0077] In some implementation schemes, R A Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , The R A Choose from 1 to 4 Rs k replace;

[0078] In some implementation schemes, R A Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

[0079] In some implementation schemes, R Aa Selected from , , , , , , , , , , , , , , , ;

[0080] In some implementations, p1 is independently selected from 0, 1, 2, 3 or 4;

[0081] In some implementation schemes, R A1 R A2 Together with the atoms attached to it, they form a 4-8 membered heterocyclic group, wherein the heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace;

[0082] In some implementation schemes, R D Selected from C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2, -SC 1-6 Alkyl, -S(=O)-C 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl, C 3-8 Carbocyclic groups, 4- to 8-membered heterocyclic groups, -OC 3-6 Carbocyclic group, -NH-C 3-6 Carbocyclic groups, -NH-4 to 8-membered heterocyclic groups, -SC 3-6 Carbocyclic groups, -S-4 to 8-membered heterocyclic groups, -NH-C 2-6 alkenyl, -NH-C 2-6 alkynyl group, -SC 2-6 alkenyl, -SC 2-6 alkynyl group, -C 1-4 Alkylene-C 3-6 Carbocyclic group, -C 1-4 Alkylene-4 to 8-membered heterocyclic groups, -OC 1-4 Alkylene-C 3-6 carbonyl group, -OC 1-4 Alkyl-4 to 8-membered heterocyclic groups, -NH-C 1-4 Alkylene-C 3-6 Carbocyclic group, -NH-C 1-4 Alkyl-4 to 8-membered heterocyclic groups, -SC 1-4 Alkylene-C 3-6 carbonyl group, -SC 1-4 Alkylene-4 to 8-membered heterocyclic group, wherein the alkylene, alkenyl, alkynyl, alkyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0083] In some implementation schemes, R D Selected from R D1 ;

[0084] In some implementation schemes, R D1 Selected from C 2-6 alkynyl group, -S(=O)-C 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl, -OC 2-6 Alkyne, methoxy, propoxy, wherein the alkynyl, alkyl, methoxy, or propoxy group is optionally surrounded by 1 to 4 R groups. k replace;

[0085] In some implementation schemes, R D1 Selected from -OC 1-4 Alkylene-C 3-6 carbonyl group, -OC1-4 Alkylene-4 to 8-membered heterocycles, wherein the carbocyclic or heterocyclic group is surrounded by 1 to 4 R groups. k The alkylene group is optionally replaced by 1 to 4 R groups. k replace;

[0086] In some implementation schemes, R D Selected from C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -NHC 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -SC 1-4 Alkyl, -S(=O)-C 1-4 Alkyl group, -S(=O)2-C 1-4 Alkyl, C 3-6 Carbocyclic groups, 4- to 8-membered heterocyclic groups, -OC 3-6 Carbocyclic group, -NH-C 3-6 Carbocyclic groups, -NH-4 to 8-membered heterocyclic groups, -SC 3-6 Carbocyclic groups, -S-4 to 8-membered heterocyclic groups, -NH-C 2-6 alkenyl, -NH-C 2-4 alkynyl group, -SC 2-4 alkenyl, -SC 2-4 alkynyl group, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C 1-2 Alkylene-4 to 8-membered heterocyclic groups, -OC 1-2 Alkylene-C 3-6 carbonyl group, -OC 1-2 Alkyl-4 to 8-membered heterocyclic groups, -NH-C 1-2 Alkylene-C 3-6 Carbocyclic group, -NH-C 1-2 Alkyl-4 to 8-membered heterocyclic groups, -SC 1-2 Alkylene-C 3-6 carbonyl group, -SC 1-2 Alkylene-4 to 8-membered heterocyclic group, wherein the alkylene, alkenyl, alkynyl, alkyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0087] In some implementation schemes, R D1 Selected from C 2-4 alkynyl group, -S(=O)-C 1-4 Alkyl group, -S(=O)2-C 1-4 Alkyl, -OC 2-4 Alkyne, methoxy, propoxy, wherein the alkynyl, alkyl, methoxy, or propoxy group is optionally surrounded by 1 to 4 R groups.k replace;

[0088] In some implementation schemes, R D1 Selected from -OC 1-2 Alkylene-C 3-6 carbonyl group, -OC 1-2 Alkylene-4 to 7-membered heterocyclic groups, wherein the carbocyclic or heterocyclic group is surrounded by 1 to 4 R groups. k The alkylene group is optionally replaced by 1 to 4 R... k replace;

[0089] In some implementation schemes, R D1 Selected from -OC 1-2 Alkylene-cyclopropyl-CH2Cl,-OC 1-2 Alkylene-cyclobutyl-CH2Cl,-OC 1-2 alkylene-cyclopentyl-CH2Cl,-OC 1-2 alkylene-oxehericyclobutyl-CH2Cl, The alkylene group is optionally surrounded by 1 to 4 R groups. k The cyclopropyl, cyclobutyl, cyclopentyl, and oxacyclobutyl groups are optionally replaced by 1 to 3 R groups. k replace;

[0090] In some implementation schemes, R D Selected from C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -NHC 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -SC 1-4 Alkyl, -S(=O)-C 1-4 Alkyl group, -S(=O)2-C 1-4 Alkyl, C 3-6 Carbocyclic groups, 4- to 8-membered heterocyclic groups, -OC 3-6 Carbocyclic group, -NH-C 3-6 Carbocyclic groups, -NH-4 to 8-membered heterocyclic groups, -SC 3-6 Carbocyclic groups, -S-4 to 8-membered heterocyclic groups, -NH-C 2-6 alkenyl, -NH-C 2-4 alkynyl group, -SC 2-4 alkenyl, -SC 2-4 alkynyl group, -CH2-C 3-6 Carbocyclic groups, -CH2-4 to 8-membered heterocyclic groups, -O-CH2-C 3-6 Carbocyclic groups, -O-CH2-4 to 8-membered heterocyclic groups, -NH-CH2-C 3-6Carbocyclic groups, -NH-CH2-4 to 8-membered heterocyclic groups, -S-CH2-C 3-6 Carbocyclic, -S-CH2- 4 to 8-membered heterocyclic groups, wherein the -CH2-, alkenyl, alkynyl, alkyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0091] In some implementation schemes, R D Selected from methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -NHCH3, -N(CH3)2, -SCH3, -SCH2CH3, -SCH2CH2CH3, -S-isopropyl, -S(=O)CH3, -S(=O)CH2CH3, -S(=O)CH2CH2CH3, -S(=O)-isopropyl, -S(=O)2CH3, -S(=O)2CH2CH3, -S(= O)2CH2CH2CH3, -S(=O)2-isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, aziridine, aziridinepentyl, aziridinehexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, -NH-oxacyclobutyl, -NH-oxacyclopentyl, -NH-oxacyclohexyl, -NH-aziridine, - NH-azacyclopentyl, -NH-azacyclohexyl, -NH-vinyl, -NH-ethynyl, -S-vinyl, -S-ethynyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-oxacyclobutyl, -CH2-oxacyclopentyl, -CH2-oxacyclohexyl, -CH2-azacyclobutyl, -CH2-azacyclopentyl, -CH2-azacyclohexyl, -O-CH2-cyclopropyl, -O-CH2-cyclobutyl, -O-CH 2-Cyclopentyl, -O-CH2-cyclohexyl, -O-CH2-oxacyclobutyl, -O-CH2-oxacyclopentyl, -O-CH2-oxacyclohexyl, -O-CH2-azacyclobutyl, -O-CH2-azacyclopentyl, -O-CH2-azacyclohexyl, wherein the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, azacyclobutyl, azacyclopentyl, azacyclohexyl, optionally with 1 to 4 R k replace;

[0092] In some implementation schemes, R D Selected from , , , , , , , , , , methoxy, ethoxy , , , , , , , , , , ;

[0093] In some implementation schemes, R D1 Selected from , , , , , , , , , , , , , , , , , ;

[0094] In some implementation schemes, R a R b R d R z Each element is independently selected from H, deuterium, =O, =S, halogens, CN, OH, NH2, CO2H, CONH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -SCN, -NHC 1-6 Alkyl, -OC 3-6 Carbocyclic groups, -O-4 to 8-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-4 to 8-membered heterocyclic groups, -C 1-4 Alkylene-C 3-6 Carbocyclic group, -C 1-4 alkylene-4 to 8-membered heterocyclic groups, C 3-6Carbocyclic, 4- to 8-membered heterocyclic, wherein the alkylene, alkyl, alkenyl, ynyl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0095] In some implementation schemes, R d Each independently selected from R d1 ;

[0096] In some implementation schemes, R d1 Selected from 6-14 aryl, 5-12 heteroaryl, and -SCN;

[0097] In some implementation schemes, R a R b R d R z Each element is independently selected from H, deuterium, =O, =S, halogens, CN, OH, NH2, CO2H, CONH2, and NHC. 1-4 Alkyl, N(C) 1-6 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -SCN, -NHC 1-4 Alkyl, -OC 3-6 Carbocyclic groups, -O-4 to 8-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-4 to 8-membered heterocyclic groups, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C 1-2 alkylene-4 to 8-membered heterocyclic groups, C 3-6 Carbocyclic, 4- to 8-membered heterocyclic, wherein the alkylene, alkyl, alkenyl, ynyl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0098] R d1 Selected from 6-membered aryl, 5-6-membered heteroaryl, and -SCN;

[0099] In some implementation schemes, R a R b R d R z Each element is independently selected from H, deuterium, =O, =S, halogens, CN, OH, NH2, CO2H, CONH2, and NHC. 1-4 Alkyl, N(C) 1-6 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4Alkyl, -SC 1-4 Alkyl, -SCN, -NHC 1-4 Alkyl, -OC 3-6 Carbocyclic groups, -O-4 to 8-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-4 to 8-membered heterocyclic groups, -CH2-C 3-6 Carbocyclic groups, -CH2-4 to 8-membered heterocyclic groups, C 3-6 Carbocyclic, 4- to 8-membered heterocyclic, wherein the -CH2-, alkyl, alkenyl, ynyl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0100] In some implementation schemes, R d1 Selected from 5-6 quinone heteroaryl groups, -SCN;

[0101] In some implementation schemes, R a R b R d R z Each of the following is independently selected from H, deuterium, =O, =S, F, Cl, Br, I, CN, OH, NH2, CO2H, CONH2, -NHCH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, -O-methyl, -O-ethyl, methylthio, -SCN, -O-cyclopropyl, -O-oxetyl, -O-azacyclobutyl, -CH2-cyclopropyl, -CH2-oxetyl, -CH2-azacyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl Cyclohexyl, oxacyclobutyl, aziridine, pyrimidinyl, pyrazinyl, pyrazinyl, pyridinyl, thiazolyl, pyrroleyl, thiopheneyl, furanyl, pyrazolyl, triazolyl, oxazolyl, oxadiazolyl, wherein the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, pyrimidinyl, pyrazinyl, pyridinyl, thiazolyl, pyrroleyl, thiopheneyl, furanyl, pyrazolyl, triazolyl, oxazolyl, oxadiazolyl are optionally surrounded by 1 to 4 R k replace;

[0102] In some implementations, R d1 The group is selected from pyrimidinyl, pyrazinyl, pyrazinyl, pyridinyl, thiazolyl, pyrroleyl, thiopheneyl, furanyl, pyrazolyl, triazolyl, oxazolyl, oxadiazolyl, -SCN, thiazolyl, thiadiazolyl, isoxazolyl, and isoxadiazolyl, wherein the pyrimidinyl, pyrazinyl, pyridinyl, thiazolyl, pyrroleyl, thiopheneyl, furanyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiadiazolyl, isoxazolyl, isoxadiazolyl, and oxadiazolyl groups are optionally surrounded by 1 to 4 R groups. k replace;

[0103] In some implementation schemes, R A1 R A2 R L1 R l1 R l2 Each element is independently selected from H, deuterium, =O, halogens, CN, OH, NH2, CO2H, CONH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbocyclic groups, 4- to 8-membered heterocyclic groups, -C 1-4 Alkylene-C 3-6 Carbocyclic group, -NH-C 3-6 carbonyl group, -OC 3-6 The carbocyclic group, wherein the alkylene group, alkyl group, alkenyl group, alkynyl group, carbocyclic group, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0104] In some implementation schemes, R A1 R A2 R L1 R l1 R l2 Each element is independently selected from H, deuterium, =O, halogens, CN, OH, NH2, CO2H, CONH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Carbocyclic groups, 4- to 8-membered heterocyclic groups, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -NH-C 3-6 carbonyl group, -OC 3-6 The carbocyclic group, wherein the alkylene group, alkyl group, alkenyl group, alkynyl group, carbocyclic group, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0105] In some implementation schemes, R A1 R A2 R L1 R l1 R l2Each of the following is independently selected from H, deuterium, =O, F, Cl, Br, I, CN, OH, NH2, CO2H, CONH2, -NHCH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, aziridine, aziridinepentyl, aziridinehexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2 -cyclopentyl, -CH2-cyclohexyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, wherein the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, aziridine, aziridine, aziridine, aziridine, aziridine are optionally surrounded by 1 to 4 R k replace;

[0106] In some implementation schemes, R k Each is independently selected from deuterium, =O, =S, =NH, halogens, CN, OH, COOH, CONH2, NH2, SF5, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-C 3-6 carbonyl group, -OC 3-6 Carbocyclic groups, -O-4 to 8-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-4 to 8-membered heterocyclic groups, -C 1-4 alkylene-4 to 8-membered heterocyclic groups, C 3-6 Carbocyclic groups, 4- to 8-membered heterocyclic groups, The alkyl, alkylene, alkenyl, alkynyl, carbocyclic, or heterocyclic groups are optionally selected from 1 to 4 deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups;

[0107] In some implementation schemes, R k Each is independently selected from deuterium, =O, =S, =NH, halogens, CN, OH, COOH, CONH2, NH2, SF5, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, -C(=O)-C 3-6 carbonyl group, -OC 3-6 Carbocyclic groups, -O-4 to 8-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-4 to 8-membered heterocyclic groups, -C 1-2 alkylene-4 to 8-membered heterocyclic groups, C 3-6 Carbocyclic groups, 4- to 8-membered heterocyclic groups, The alkyl, alkylene, alkenyl, alkynyl, carbocyclic, or heterocyclic groups are optionally selected from 1 to 4 deuterium, halogen, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0108] In some implementation schemes, R k Each is independently selected from deuterium, =O, =S, =NH, F, Cl, Br, I, CN, OH, COOH, CONH2, NH2, SF5, -NHCH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, -O-methyl, -O-ethyl, methylthio, -C(=O)-CH3, -C(=O)CH2CH3, -C(=O)-cyclopropyl, -O-cyclopropyl -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, -O-oxacyclobutyl, -O-oxacyclopentyl, -O-oxacyclohexyl, -O-azacyclobutyl, -O-azacyclopentyl, -O-azacyclohexyl, -NH-cyclopropyl, -NH-oxacyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, azacyclobutyl, azacyclopentyl, azacyclohexyl , , , The methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxecyclobutyl, oxecyclopentyl, oxecyclohexyl, aziroxybutyl, aziroxypentyl, and aziroxyhexyl groups are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2, methyl, ethyl, propyl, isopropyl, methoxy, and ethoxy groups;

[0109] In some implementations, a and d are each independently selected from 0, 1, 2, 3, or 4;

[0110] The condition is that one of the following is met:

[0111] 1) no , , ;

[0112] 2) no , , , , , ;

[0113] 3) When ring A does not exist, L 1 It is selected from -CH2-O-, and ring D is selected from 6-14 aryl groups, preferably, ring D is selected from phenyl groups;

[0114] 4) When Selected from L 1 When selected from -CH2-, ring B is not ;

[0115] 5) The compound is not .

[0116] As a first embodiment of the present invention, the compound represented by the above general formula (I) or its racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof

[0117] Ring A is selected from 5-6 member heteroaryl groups, C 6-14 Carbocyclic group, 7-12 membered heterocyclic group, or ring A is absent;

[0118] B is selected from rings B and C. 2-6 alkynyl group, C 2-6 alkenyl group, wherein the alkenyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0119] Ring B is selected from 6-14 aryl, 5-12 heteroaryl, benzo4-6 heterocyclic, benzo4-6 carbocyclic, and C. 4-12 Cycloalkyl or 4- to 12-membered heterocycloalkyl, wherein the ring B is optionally surrounded by 1 to 6 R... b replace;

[0120] Z is selected from phenyl, 6-membered heteroaryl, C 2-6Alkyne group, wherein the heteroaryl group or phenyl group is optionally surrounded by 1 to 6 R groups. z replace;

[0121] Ring D is selected from 6-14 aryl and 5-12 heteroaryl groups;

[0122] L 1 Selected from -O-, -C 1-4 alkylene-, -C 1-4 Alkylene-O- -O-4 to 8-membered heterocyclic groups -OC 1-4 alkylene-4 to 8-membered heterocyclic groups -, -C 1-4 Alkylene-NR L0 -、-OC 1-4 Alkylene-, -OC 1-4 Alkylene-O-, C 2-6 alkenyl, -C 3-12 Carbocyclic -C 1-4 Alkylene -O-, -C 3-12 Carbocyclic groups -O-, -4 to 12-membered heterocyclic groups -C 1-4 Alkylene-O-, -4 to 12-membered heterocyclic-O-, -OC 3-8 Carbocyclic group-, , Its right end is connected to B, and the alkylene, alkenyl, carbocyclic, or heterocyclic groups are optionally surrounded by 1 to 4 R groups. k replace;

[0123] R L0 R b Together with the atoms attached to it, they form a 4-8 membered heterocyclic group, wherein the heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace;

[0124] As an option, R L1 R b Together with the atoms attached to it, they form a 4-8 membered heterocyclic group, wherein the heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace;

[0125] L 2 Selected from -CR 1 R 2 -、-NR L2 , C 3-8 A carbocyclic group or a 4-8 membered heterocyclic alkyl group, wherein the right end is connected to a ring D, and the carbocyclic group or heterocyclic alkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0126] Or L 2 Selected from L 2A ;

[0127] L2A Selected from -NR L2 -、 C 3-8 A carbocyclic group or a 4-8 membered heterocyclic alkyl group, wherein the right end is connected to a ring D, and the carbocyclic group or heterocyclic alkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0128] R L2 R z Together with the atoms attached to it, they form a 4-8 membered heterocyclic group, wherein the heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace;

[0129] R 1 R 2 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, wherein the alkyl, alkenyl, or ynyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0130] As an option, R 1 R 2 Together with the atoms bonded to it, they form C 3-8 Carbocyclic groups, 4-8 membered heterocyclic groups, wherein the C 3-8 The carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0131] As an option, R l1 R l2 Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0132] As an option, R 1 R d Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0133] As an option, R 1 R z Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0134] As an option, R b R z Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0135] As an option, two adjacent R z Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0136] As an option, R L0 R a Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0137] R A Selected from 4- to 12-membered heterocyclic alkyl groups, -4- to 12-membered heterocyclic alkyl groups -S(=O)2R A1 -4 to 12-membered heterocyclic alkyl-S(=O)R A1 -4 to 12-membered heterocyclic alkyl-S(=O)2NR A1 R A2 -4 to 12-membered heterocyclic alkyl groups -N=S(=O)R A1 R A2 -4 to 12-membered heterocyclic alkyl-S(=O) (=NR) A1 )R A2 -4 to 12-membered heterocyclic alkyl-C 1-4 Alkylene-S(=O)2R A1 -4 to 12-membered heterocyclic alkyl-C 1-4 Alkylene-S(=O)R A1 -4 to 12-membered heterocyclic alkyl-C 1-4 Alkylene-S(=O)2NR A1 R A2 -4 to 12-membered heterocyclic alkyl-C 1-4 Alkylene-NR A1 -S(=O)2R A2 -4 to 12-membered heterocyclic alkyl-C 1-4 Alkylene-N=S(=O)R A1 R A2 -4 to 12-membered heterocyclic alkyl-C 1-4 Alkylene-S(=O) (=NR) A1 )R A2 -4 to 12-membered heterocyclic alkyl-C 1-4Alkylene-NR A1 -S(=O)R A1 -P(=O)R A1 R A2 -4 to 12-membered heterocyclic alkyl-P(=O)R A1 R A2 -4 to 12-membered heterocyclic alkyl-C 1-4 Alkylene-P(=O)R A1 R A2 -N=S(=O)R A1 R A2 , , , , , , , , , , , , , , , , The alkylene, heterocyclic alkyl, , , , , , , , , , , , , , , Choose from 1 to 6 Rs k replace;

[0138] Or R A Selected from R Aa ;

[0139] R Aa Selected from -4 to 12-membered heterocyclic alkyl groups -S(=O)2NHC 1-6 Alkyl group, -S (=O) (=NR) A1 )R A2 -4 to 12-membered heterocyclic alkyl-S(=O) (=NR) A1 -C 1-4 Alkylene-C 3-8 Carbocyclic, -4 to 12-membered heterocyclic alkyl -S(=O)2NR A1 -C 3-8 carbon cyclo group, , , , , , , , The R Aa Choose from 1 to 6 Rs k replace;

[0140] p1 is independently selected from 0, 1, 2, 3 or 4;

[0141] As an option, R A1 R A2 The atoms bonded to it together form a 4-8 membered heterocyclic group, wherein the heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace;

[0142] R D Selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2, -SC 1-6 Alkyl, -S(=O)-C 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl, C 3-8 Carbocyclic groups, 4- to 8-membered heterocyclic groups, -OC 3-6 Carbocyclic group, -NH-C 3-6 Carbocyclic groups, -NH-4 to 8-membered heterocyclic groups, -SC 3-6 Carbocyclic groups, -S-4 to 8-membered heterocyclic groups, -NH-C 2-6 alkenyl, -NH-C 2-6 alkynyl group, -SC 2-6 alkenyl, -SC 2-6 alkynyl group, -C 1-4 Alkylene-C 3-6 Carbocyclic group, -C 1-4 Alkylene-4 to 8-membered heterocyclic groups, -OC 1-4 Alkylene-C 3-6 carbonyl group, -OC 1-4 Alkyl-4 to 8-membered heterocyclic groups, -NH-C 1-4 Alkylene-C 3-6 Carbocyclic group, -NH-C 1-4 Alkyl-4 to 8-membered heterocyclic groups, -SC 1-4 Alkylene-C 3-6 carbonyl group, -SC 1-4Alkylene-4 to 8-membered heterocyclic group, wherein the alkylene, alkenyl, alkynyl, alkyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0143] Or R D Selected from R D1 ;

[0144] R D1 Selected from C 2-6 alkynyl group, -S(=O)-C 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl, -OC 2-6 Alkyne, ethoxy, propoxy, wherein the alkynyl, alkyl, ethoxy, or propoxy group is optionally surrounded by 1 to 4 R groups. k replace;

[0145] Or R D1 Selected from -OC 1-4 Alkylene-C 3-6 carbonyl group, -OC 1-4 Alkylene-4 to 8-membered heterocycles, wherein the carbocyclic or heterocyclic group is surrounded by 1 to 4 R groups. k The alkylene group is optionally replaced by 1 to 4 R... k replace;

[0146] R a R b R d R z Each element is independently selected from H, deuterium, =O, =S, halogens, CN, OH, NH2, CO2H, CONH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -SCN, -NHC 1-6 Alkyl, -OC 3-6 Carbocyclic groups, -O-4 to 8-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-4 to 8-membered heterocyclic groups, -C 1-4 Alkylene-C 3-6 Carbocyclic group, -C 1-4 alkylene-4 to 8-membered heterocyclic groups, C 3-6 Carbocyclic, 4- to 8-membered heterocyclic, wherein the alkylene, alkyl, alkenyl, ynyl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0147] Or R d Each independently selected from Rd1 ;

[0148] R d1 Selected from 6-14 aryl, 5-12 heteroaryl, and -SCN;

[0149] R A1 R A2 R L1 R l1 R l2 Each element is independently selected from H, deuterium, =O, halogens, CN, OH, NH2, CO2H, CONH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbocyclic groups, 4- to 8-membered heterocyclic groups, -C 1-4 Alkylene-C 3-6 Carbocyclic group, -NH-C 3-6 carbonyl group, -OC 3-6 The carbocyclic group, wherein the alkylene group, alkyl group, alkenyl group, alkynyl group, carbocyclic group, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0150] R k Each is independently selected from deuterium, =O, =S, =NH, halogens, CN, OH, COOH, CONH2, NH2, SF5, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-C 3-6 carbonyl group, -OC 3-6 Carbocyclic groups, -O-4 to 8-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-4 to 8-membered heterocyclic groups, -C 1-4 alkylene-4 to 8-membered heterocyclic groups, C 3-6 Carbocyclic groups, 4- to 8-membered heterocyclic groups, The alkyl, alkylene, alkenyl, alkynyl, carbocyclic, or heterocyclic groups are optionally selected from 1 to 4 deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups;

[0151] a and d are each independently selected from 0, 1, 2, 3 or 4;

[0152] The condition is that one of the following is met:

[0153] 1) no , , ;

[0154] 2) no , , , , , ;

[0155] 3) When ring A does not exist, L 1 It is selected from -CH2-O-, and ring D is selected from 6-14 aryl groups, preferably, ring D is selected from phenyl groups;

[0156] 4) When Selected from L 1 When selected from -CH2-, ring B is not ;

[0157] 5) The compound is not .

[0158] As a second embodiment of the present invention, the compounds shown in the above general formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and (Ig), or their racemic mixtures, stereoisomers, tautomers, or pharmaceutically acceptable salts,

[0159] (Ia) (Ib)

[0160] (Ic) (Id) (Ie) (If)

[0161] (Ig)

[0162] e is selected from 0, 1, 2, 3;

[0163] The definitions of the remaining functional groups are the same as those in the first embodiment of the present invention.

[0164] As a third embodiment of the present invention, the compounds shown in the above general formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and (Ig), or their racemic mixtures, stereoisomers, tautomers, or pharmaceutically acceptable salts,

[0165] Ring A is selected from 5-6-membered heteroaryl, benzo4-6-membered heterocyclic, benzo4-6-membered carbocyclic, 5-6-membered heteroaryl-4-6-membered heterocyclic, and 5-6-membered heteroaryl-4-6-membered carbocyclic. Preferably, ring A is selected from pyrimidinyl, pyridazinyl, pyrazinyl, pyridinyl, thiazolyl, pyrroleyl, thiopheneyl, furanyl, pyrazolyl, triazolyl, pyridino-4-6-membered heterocyclic, and pyridino-4-6-membered carbocyclic.

[0166] B is selected from rings B and C. 2-4 alkynyl group;

[0167] Ring B is selected from phenyl, 5-6-membered heteroaryl, benzo4-6-membered heterocyclic group, benzo4-6-membered carbocyclic group, C 4-8 Cycloalkyl or 4- to 8-membered heterocycloalkyl, wherein the ring B is optionally surrounded by 1 to 4 R... b replace;

[0168] Z is selected from phenyl, 6-membered heteroaryl, C 2-4 Alkyne group, wherein the heteroaryl group or phenyl group is optionally surrounded by 1 to 4 R groups. z replace;

[0169] L 1 Selected from -O-, -C 1-2 alkylene-, -C 1-2 Alkylene-O- -O-4 to 8-membered heterocyclic groups -OC 1-2 alkylene-4 to 8-membered heterocyclic groups -, -C 1-2 Alkylene-NR L0 -、-OC 1-2 Alkylene-, -OC 1-2 Alkylene-O-, C 2-4 alkenyl, -C 3-8 Carbocyclic -C 1-2 Alkylene -O-, -C 3-8 Carbocyclic -O-, -4 to 8-membered heterocyclic -C 1-2 Alkylene-O-, -4 to 8-membered heterocyclic-O-, -OC 3-8Carbocyclic group-, , Its right end is connected to B, and the alkylene, alkenyl, carbocyclic, or heterocyclic groups are optionally surrounded by 1 to 4 R groups. k replace;

[0170] R L0 R b Together with the atoms attached to it, they form a 4-8 membered heterocyclic group, wherein the heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace;

[0171] As an option, R L1 R b Together with the atoms attached to it, they form a 4-8 membered heterocyclic group, wherein the heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace;

[0172] L 2 Selected from -CR 1 R 2 -、-NR L2 -、 C 3-8 A carbocyclic group or a 4-8 membered heterocyclic alkyl group, wherein the right end is connected to a ring D, and the carbocyclic group or heterocyclic alkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0173] R L2 R z Together with the atoms attached to it, they form a 4-8 membered heterocyclic group, wherein the heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace;

[0174] R 1 R 2 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, wherein the alkyl, alkenyl, or ynyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0175] As an option, R 1 R 2 Together with the atoms bonded to it, they form C 3-8 Carbocyclic groups, 4-8 membered heterocyclic groups, wherein the C 3-8 The carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0176] As an option, R l1 R l2Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0177] As an option, R 1 R d Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0178] As an option, R 1 R z Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0179] As an option, R b R z Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0180] As an option, two adjacent R z Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0181] As an option, R L0 R a Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0182] R A Selected from 4- to 10-membered heterocyclic alkyl groups, -4- to 10-membered heterocyclic alkyl groups -S(=O)2R A1 -4 to 10-membered heterocyclic alkyl-S(=O)R A1 -4 to 10-membered heterocyclic alkyl-S(=O)2NR A1 R A2 -4 to 10-membered heterocyclic alkyl-NR A1 -S(=O)2R A2 -4 to 10-membered heterocyclic alkyl groups -N=S(=O)R A1 R A2 -4 to 10-membered heterocyclic alkyl-S(=O) (=NR) A1)R A2 -4 to 10-membered heterocyclic alkyl-C 1-2 Alkylene-S(=O)2R A1 -4 to 10-membered heterocyclic alkyl-C 1-2 Alkylene-S(=O)R A1 -4 to 10-membered heterocyclic alkyl-C 1-2 Alkylene-S(=O)2NR A1 R A2 -4 to 10-membered heterocyclic alkyl-C 1-2 Alkylene-NR A1 -S(=O)2R A2 -4 to 10-membered heterocyclic alkyl-C 1-2 Alkylene-N=S(=O)R A1 R A2 -4 to 10-membered heterocyclic alkyl-C 1-2 Alkylene-S(=O) (=NR) A1 )R A2 -P(=O)R A1 R A2 -4 to 10-membered heterocyclic alkyl-P(=O)R A1 R A2 -4 to 10-membered heterocyclic alkyl-C 1-2 Alkylene-P(=O)R A1 R A2 -N=S(=O)R A1 R A2 , , , , , , , , , , , , , , , , The alkylene, heterocyclic alkyl, , , , , , , , , , , , , , , Choose from 1 to 4 Rs k replace;

[0183] R Aa Selected from -4 to 10-membered heterocyclic alkyl groups -S(=O)2NHC 1-4 Alkyl group, -S (=O) (=NR) A1 )R A2 -4 to 10-membered heterocyclic alkyl-S(=O) (=NR) A1 -C 1-2 Alkylene-C 3-6 Carbocyclic, -4 to 10-membered heterocyclic alkyl group -S(=O)2NR A1 -C 3-6 carbon cyclo group, , , , , , , , The R Aa Choose from 1 to 4 Rs k replace;

[0184] As an option, R A1 R A2 Together with the atoms attached to it, they form a 4-8 membered heterocyclic group, wherein the heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace;

[0185] R D Selected from C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -NHC 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -SC 1-4 Alkyl, -S(=O)-C 1-4 Alkyl group, -S(=O)2-C 1-4 Alkyl, C 3-6 Carbocyclic groups, 4- to 8-membered heterocyclic groups, -OC 3-6 Carbocyclic group, -NH-C 3-6 Carbocyclic groups, -NH-4 to 8-membered heterocyclic groups, -SC 3-6 Carbocyclic groups, -S-4 to 8-membered heterocyclic groups, -NH-C 2-6 alkenyl, -NH-C 2-4 alkynyl group, -SC 2-4 alkenyl, -SC 2-4 alkynyl group, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C 1-2Alkylene-4 to 8-membered heterocyclic groups, -OC 1-2 Alkylene-C 3-6 carbonyl group, -OC 1-2 Alkyl-4 to 8-membered heterocyclic groups, -NH-C 1-2 Alkylene-C 3-6 Carbocyclic group, -NH-C 1-2 Alkyl-4 to 8-membered heterocyclic groups, -SC 1-2 Alkylene-C 3-6 carbonyl group, -SC 1-2 Alkylene-4 to 8-membered heterocyclic group, wherein the alkylene, alkenyl, alkynyl, alkyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0186] R D1 Selected from C 2-4 alkynyl group, -S(=O)-C 1-4 Alkyl group, -S(=O)2-C 1-4 Alkyl, -OC 2-4 Alkyne, ethoxy, propoxy, wherein the alkynyl, alkyl, ethoxy, or propoxy group is optionally surrounded by 1 to 4 R groups. k replace;

[0187] Or R D1 Selected from -OC 1-2 Alkylene-C 3-6 carbonyl group, -OC 1-2 Alkylene-4 to 7-membered heterocyclic groups, wherein the carbocyclic or heterocyclic group is surrounded by 1 to 4 R groups. k The alkylene group is optionally replaced by 1 to 4 R groups. k replace;

[0188] R a R b R d R z Each element is independently selected from H, deuterium, =O, =S, halogens, CN, OH, NH2, CO2H, CONH2, and NHC. 1-4 Alkyl, N(C) 1-6 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -SCN, -NHC 1-4 Alkyl, -OC 3-6 Carbocyclic groups, -O-4 to 8-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-4 to 8-membered heterocyclic groups, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C1-2 alkylene-4 to 8-membered heterocyclic groups, C 3-6 Carbocyclic, 4- to 8-membered heterocyclic, wherein the alkylene, alkyl, alkenyl, ynyl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0189] R d1 Selected from 6-membered aryl, 5-6-membered heteroaryl, and -SCN;

[0190] R A1 R A2 R L1 R l1 R l2 Each element is independently selected from H, deuterium, =O, halogens, CN, OH, NH2, CO2H, CONH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Carbocyclic groups, 4- to 8-membered heterocyclic groups, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -NH-C 3-6 carbonyl group, -OC 3-6 The carbocyclic group, wherein the alkylene group, alkyl group, alkenyl group, alkynyl group, carbocyclic group, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0191] R k Each is independently selected from deuterium, =O, =S, =NH, halogens, CN, OH, COOH, CONH2, NH2, SF5, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, -C(=O)-C 3-6 carbonyl group, -OC 3-6 Carbocyclic groups, -O-4 to 8-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-4 to 8-membered heterocyclic groups, -C 1-2 alkylene-4 to 8-membered heterocyclic groups, C 3-6 Carbocyclic groups, 4- to 8-membered heterocyclic groups, The alkyl, alkylene, alkenyl, alkynyl, carbocyclic, or heterocyclic groups are optionally selected from 1 to 4 deuterium, halogen, =O, CN, OH, NH2, C 1-4Alkyl, C 1-4 Substituents of alkoxy groups;

[0192] The definitions of the remaining functional groups are the same as those in the first or second embodiment of the present invention.

[0193] As a fourth embodiment of the present invention, the compounds shown in the above general formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and (Ig), or their racemic mixtures, stereoisomers, tautomers, or pharmaceutically acceptable salts,

[0194] Ring A is selected from pyrimidinyl, pyridazinyl, pyrazinyl, pyridinyl, thiazolyl, pyridinium imidazolyl, pyridocyclopentyl, and pyridocyclohexyl.

[0195] Ring B is selected from pyrazinyl, pyridinyl, pyridyl, phenyl, alkynyl, pyrimidinyl, and piperidinyl, wherein ring B is optionally surrounded by 1 to 4 R groups. b replace;

[0196] Z is selected from phenyl, C 2-4 Alkyne group, wherein the phenyl group is optionally surrounded by 1 to 4 R groups. z replace;

[0197] L 1 Selected from -O-, -CH2-, -CH2-O-, -O-4 to 8-membered heterocyclic groups-, -O-CH2-4 to 8-membered heterocyclic groups-, -CH2-NR L0 -, -O-CH2-, -O-CH2-CH2-O-, C 2-4 alkenyl, -C 3-8 Carbocyclic groups -CH2--O-, -C 3-8 Carbocyclic group -O-, -4 to 8-membered heterocyclic group -CH2-O-, -4 to 8-membered heterocyclic group -O-, -OC 3-8 Carbocyclic group-, , Its right end is connected to B, and the alkylene, alkenyl, carbocyclic, or heterocyclic groups are optionally surrounded by 1 to 4 R groups. k replace;

[0198] R A Selected from 4- to 10-membered heterocyclic alkyl groups, -4- to 10-membered heterocyclic alkyl groups -S(=O)2R A1 -4 to 10-membered heterocyclic alkyl-S(=O)R A1 -4 to 10-membered heterocyclic alkyl-S(=O)2NR A1 R A2 -4 to 10-membered heterocyclic alkyl-NR A1 -S(=O)2R A2 -4 to 10-membered heterocyclic alkyl groups -N=S(=O)RA1 R A2 -4 to 10-membered heterocyclic alkyl-S(=O) (=NR) A1 )R A2 -4 to 10-membered heterocyclic alkyl group -CH2-S(=O)2R A1 -4 to 10-membered heterocyclic alkyl group -CH2-S(=O)R A1 -4 to 10-membered heterocyclic alkyl group -CH2-S(=O)2NR A1 R A2 -4 to 10-membered heterocyclic alkyl-CH2-NR A1 -S(=O)2R A2 -4 to 10-membered heterocyclic alkyl groups -CH2-N=S(=O)R A1 R A2 -4 to 10-membered heterocyclic alkyl groups -CH2-S(=O) (=NR) A1 )R A2 -P(=O)R A1 R A2 -4 to 10-membered heterocyclic alkyl-P(=O)R A1 R A2 -4 to 10-membered heterocyclic alkyl groups -CH2-P(=O)R A1 R A2 -N=S(=O)R A1 R A2 , , , , , , , , , , , , , , , , The -CH2-, heterocyclic alkyl, , , , , , , , , , , , , , , Choose from 1 to 4 Rs k replace;

[0199] R Aa Selected from -4 to 10-membered heterocyclic alkyl groups -S(=O)2NHC 1-4 Alkyl group, -S (=O) (=NR) A1 )R A2 -4 to 10-membered heterocyclic alkyl-S(=O) (=NR) A1 ) - CH2-C 3-6 Carbocyclic, -4 to 10-membered heterocyclic alkyl group -S(=O)2NR A1 -C 3-6 carbon cyclo group, , , , , , , , The R Aa Choose from 1 to 4 Rs k replace;

[0200] R D Selected from C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -NHC 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -SC 1-4 Alkyl, -S(=O)-C 1-4 Alkyl group, -S(=O)2-C 1-4 Alkyl, C 3-6 Carbocyclic groups, 4- to 8-membered heterocyclic groups, -OC 3-6 Carbocyclic group, -NH-C 3-6 Carbocyclic groups, -NH-4 to 8-membered heterocyclic groups, -SC 3-6 Carbocyclic groups, -S-4 to 8-membered heterocyclic groups, -NH-C 2-6 alkenyl, -NH-C 2-4 alkynyl group, -SC 2-4 alkenyl, -SC 2-4 alkynyl group, -CH2-C 3-6 Carbocyclic groups, -CH2-4 to 8-membered heterocyclic groups, -O-CH2-C 3-6 Carbocyclic groups, -O-CH2-4 to 8-membered heterocyclic groups, -NH-CH2-C 3-6 Carbocyclic groups, -NH-CH2-4 to 8-membered heterocyclic groups, -S-CH2-C 3-6 Carbocyclic, -S-CH2- 4 to 8-membered heterocyclic groups, wherein the -CH2-, alkenyl, alkynyl, alkyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. kreplace;

[0201] R D1 Selected from C 2-4 alkynyl group, -S(=O)-C 1-4 Alkyl group, -S(=O)2-C 1-4 Alkyl, -OC 2-4 Alkyne, ethoxy, propoxy, wherein the alkynyl, alkyl, ethoxy, or propoxy group is optionally surrounded by 1 to 4 R groups. k replace;

[0202] Or R D1 Selected from -OC 1-2 Alkylene-C 3-6 carbonyl group, -OC 1-2 Alkylene-4 to 7-membered heterocyclic groups, wherein the carbocyclic or heterocyclic group is surrounded by 1 to 4 R groups. k The alkylene group is optionally replaced by 1 to 4 R... k replace;

[0203] R a R b R d R z Each element is independently selected from H, deuterium, =O, =S, halogens, CN, OH, NH2, CO2H, CONH2, and NHC. 1-4 Alkyl, N(C) 1-6 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -SCN, -NHC 1-4 Alkyl, -OC 3-6 Carbocyclic groups, -O-4 to 8-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-4 to 8-membered heterocyclic groups, -CH2-C 3-6 Carbocyclic groups, -CH2-4 to 8-membered heterocyclic groups, C 3-6 Carbocyclic, 4- to 8-membered heterocyclic, wherein the -CH2-, alkyl, alkenyl, ynyl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0204] R d1 Selected from 5-6 quinone heteroaryl groups, -SCN;

[0205] The definitions of the remaining functional groups are the same as those in the first, second, or third embodiments of the present invention.

[0206] As a fifth embodiment of the present invention, the compounds shown in the above general formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and (Ig), or their racemic mixtures, stereoisomers, tautomers, or pharmaceutically acceptable salts,

[0207] Ring A is selected from pyrimidinyl, pyridazinyl, pyrazinyl, pyridinyl, thiazolyl, , ;

[0208] Z is selected from phenyl, pyrazinyl, pyridinyl, pyridinyl, pyrimidinyl, and ethynyl, wherein the pyrazinyl, pyridinyl, pyrimidinyl, or phenyl group is optionally surrounded by 1 to 4 R groups. z replace;

[0209] Or -BZ- selected from , ;

[0210] L 1 Selected from -O-, -CH2-, -CH2-O-, -O-oxetanebutyl, -O-oxetanepentyl, -O-oxetanehexyl, -O-azacyclobutyl, -O-azacyclopentyl, -O-azacyclohexyl, -O-CH2-oxetanebutyl, -O-CH2-oxetanepentyl, -O-CH2-oxetanehexyl, -O-CH2-azacyclobutyl, -O-CH2-azacyclopentyl, -O-CH2-azacyclohexyl, -CH2-NR L0 -、-O-CH2-、-O-CH2-CH2-O-、vinyl、-cyclopropyl-CH2-O-、-cyclobutyl-CH2-O-、-cyclopentyl-CH2-O-、-cyclohexyl-CH2-O-、 -Cyclopropyl-O-, -Cyclobutyl-O-, -Cyclopentyl-O-, -Cyclohexyl-O-, -azacyclobutyl-CH2-O-, -azacyclopentyl-CH2-O-, -piperidinyl-CH2-O-, -azacyclobutyl-O-, -azacyclopentyl-O-, -piperidinyl-O-, -phenyl-O-, -phenyl-CH2-O-, -pyridine-CH2-O-, -oxacyclobutyl-CH2-O-, -oxacyclopentyl-CH2-O-, -oxacyclohexyl-CH2-O-, -oxacyclobutyl-O-, -oxacyclopentyl-O-, -oxacyclohexyl-O-, -O-cyclopropyl-, -O-cyclobutyl-, -O-cyclopentyl-, -O-cyclohexyl-, , Its right end is connected to B, and the vinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine-, aziridine-, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, piperidinyl, phenyl, pyridine, Choose from 1 to 4 Rsk replace;

[0211] R L0 R b Together with the atoms attached to it, they form azircyclic butyl, azircyclic pentyl, azircyclic hexyl, azircyclic heptyl, azircyclic butylenyl, azircyclic pentenyl, azircyclic hexenyl, azircyclic heptenyl, furanyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, 1,4-dioxanecyclol, 1,4-dioxanecycloalkenyl. , The aziridine, aziridine pentyl, aziridine hexyl, aziridine heptyl, aziridine butenyl, aziridine pentenyl, aziridine heptenyl, furanyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, 1,4-dioxanecycloyl, 1,4-dioxanecycloylene are optionally surrounded by 1 to 4 R groups. k replace;

[0212] As an option, R L1 R b Together with the atoms attached to it, they form a 4-8 membered heterocyclic group, wherein the heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace;

[0213] R L2 R z Together with the atoms attached thereto, they form a pyrrole group, an imidazolyl group, and an imidazolide group, wherein the pyrrole group, imidazolyl group, and imidazolide group are optionally surrounded by 1 to 4 R atoms. k replace;

[0214] As an option, R 1 R 2 Together with the atoms bonded to it, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, azircyclobutyl, azircyclopentyl, azircyclohexyl, and so on. , The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, azircyclobutyl, azircyclopentyl, azircyclohexyl , Choose from 1 to 4 Rs k replace;

[0215] As an option, R l1 R l2 The atoms bonded to it together form cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups, wherein the cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups are optionally bounded by 1 to 4 R groups. k replace;

[0216] As an option, R 1 R dThe atoms bonded to it together form cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl groups, wherein the cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl groups are optionally separated by 1 to 4 R groups. k replace;

[0217] As an option, R 1 R z The atoms bonded to it together form cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl groups, wherein the cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl groups are optionally separated by 1 to 4 R groups. k replace;

[0218] As an option, two adjacent R z The atoms bonded to it together form cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups, wherein the cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups are optionally bounded by 1 to 4 R groups. k replace;

[0219] As an option, R L0 R a The atoms bonded to it together form imidazolium, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl groups, wherein the imidazolium, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl groups are optionally surrounded by 1 to 4 R groups. k replace;

[0220] R A Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , The R A Choose from 1 to 4 Rs k replace;

[0221] R D Selected from methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -NHCH3, -N(CH3)2, -SCH3, -SCH2CH3, -SCH2CH2CH3, -S-isopropyl, -S(=O)CH3, -S(=O)CH2CH3, -S(=O)CH2CH2CH3, -S(=O)-isopropyl, -S(=O)2CH3, -S(=O)2CH2CH3, -S(= O)2CH2CH2CH3, -S(=O)2-isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, aziridine, aziridinepentyl, aziridinehexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, -NH-oxacyclobutyl, -NH-oxacyclopentyl, -NH-oxacyclohexyl, -NH-aziridine, - NH-azacyclopentyl, -NH-azacyclohexyl, -NH-vinyl, -NH-ethynyl, -S-vinyl, -S-ethynyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-oxacyclobutyl, -CH2-oxacyclopentyl, -CH2-oxacyclohexyl, -CH2-azacyclobutyl, -CH2-azacyclopentyl, -CH2-azacyclohexyl, -O-CH2-cyclopropyl, -O-CH2-cyclobutyl, -O-C H2-cyclopentyl, -O-CH2-cyclohexyl, -O-CH2-oxacyclobutyl, -O-CH2-oxacyclopentyl, -O-CH2-oxacyclohexyl, -O-CH2-azacyclobutyl, -O-CH2-azacyclopentyl, -O-CH2-azacyclohexyl, wherein the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, azacyclobutyl, azacyclopentyl, azacyclohexyl are optionally surrounded by 1 to 4 R k replace;

[0222] R a R b R dR z Each of the following is independently selected from H, deuterium, =O, =S, F, Cl, Br, I, CN, OH, NH2, CO2H, CONH2, -NHCH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, -O-methyl, -O-ethyl, methylthio, -SCN, -O-cyclopropyl, -O-oxetyl, -O-azacyclobutyl, -CH2-cyclopropyl, -CH2-oxetyl, -CH2-azacyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl Cyclohexyl, oxacyclobutyl, aziridine, pyrimidinyl, pyrazinyl, pyrazinyl, pyridinyl, thiazolyl, pyrroleyl, thiopheneyl, furanyl, pyrazolyl, triazolyl, oxazolyl, oxadiazolyl, wherein the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, pyrimidinyl, pyrazinyl, pyridinyl, thiazolyl, pyrroleyl, thiopheneyl, furanyl, pyrazolyl, triazolyl, oxazolyl, oxadiazolyl are optionally surrounded by 1 to 4 R k replace

[0223] R d1 The group is selected from pyrimidinyl, pyrazinyl, pyrazinyl, pyridinyl, thiazolyl, pyrroleyl, thiopheneyl, furanyl, pyrazolyl, triazolyl, oxazolyl, oxadiazolyl, -SCN, thiazolyl, thiadiazolyl, isoxazolyl, and isoxadiazolyl, wherein the pyrimidinyl, pyrazinyl, pyridinyl, thiazolyl, pyrroleyl, thiopheneyl, furanyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiadiazolyl, isoxazolyl, isoxadiazolyl, and oxadiazolyl groups are optionally surrounded by 1 to 4 R groups. k replace;

[0224] L 2 Selected from -CR 1 R 2 -、-NR L2 -、 , Cyclopropyl, cyclobutyl, oxacyclobutyl, and aziridine, with their right ends connected to ring D, wherein the cyclopropyl, cyclobutyl, oxacyclobutyl, and aziridine are optionally surrounded by 1 to 4 R groups. k replace;

[0225] L 2A Selected from -NR L2 -、 , Cyclopropyl, cyclobutyl, oxacyclobutyl, aziridine, cyclopentyl, and oxacyclopentyl, with their right ends connected to ring D, wherein the cyclopropyl, cyclobutyl, oxacyclobutyl, aziridine, cyclopentyl, and oxacyclopentyl groups are optionally bounded by 1 to 4 R groups. k replace;

[0226] R1 R 2 Each of the following is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NH2, -NHCH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, and ethoxy, wherein the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, and ethoxy groups are optionally prefixed with 1 to 4 R groups. k replace;

[0227] R A1 R A2 R L1 R l1 R l2 Each of the following is independently selected from H, deuterium, =O, F, Cl, Br, I, CN, OH, NH2, CO2H, CONH2, -NHCH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, aziridine, aziridinepentyl, aziridinehexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2 -cyclopentyl, -CH2-cyclohexyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, wherein the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, aziridine, aziridine, aziridine, aziridine, aziridine are optionally surrounded by 1 to 4 R k replace;

[0228] R k Each is independently selected from deuterium, =O, =S, =NH, F, Cl, Br, I, CN, OH, COOH, CONH2, NH2, SF5, -NHCH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, -O-methyl, -O-ethyl, methylthio, -C(=O)-CH3, -C(=O)CH2CH3, -C(=O)-cyclopropyl, -O-cyclopropyl -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, -O-oxacyclobutyl, -O-oxacyclopentyl, -O-oxacyclohexyl, -O-azacyclobutyl, -O-azacyclopentyl, -O-azacyclohexyl, -NH-cyclopropyl, -NH-oxacyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, azacyclobutyl, azacyclopentyl, azacyclohexyl , , , The methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxecyclobutyl, oxecyclopentyl, oxecyclohexyl, aziroxybutyl, aziroxypentyl, and aziroxyhexyl groups are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2, methyl, ethyl, propyl, isopropyl, methoxy, and ethoxy groups;

[0229] The definitions of the remaining functional groups are the same as those in the first, second, third, or fourth embodiments of the present invention.

[0230] As a sixth embodiment of the present invention, the compounds shown in the above general formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and (Ig), or their racemic mixtures, stereoisomers, tautomers, or pharmaceutically acceptable salts,

[0231] Ring A is selected from pyrimidinyl, pyridazinyl, pyrazinyl, pyridinyl, thiazolyl, , ;

[0232]

[0233] Z is selected from phenyl, ethynyl, ... , , , , , ;

[0234] R A Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

[0235] R Aa Selected from , , , , , , , , , , , , , , , ;

[0236] L 1 Selected from -O-, -CH2-, -CH2-O-, -O-CH2-, -O-CH2-CH2-O-, vinyl, , , , , , , , -O-cyclopropyl-, -O-cyclobutyl-, , Its right end is connected to B;

[0237] L 2 Selected from , , , , , , , , , , , , , , , , Its right end is connected to ring D;

[0238] L 2A Selected from , , , , , , , , , , , Its right end is connected to ring D;

[0239] R D Selected from , , , , , , , , , , methoxy, ethoxy , , , , , , , , , , ;

[0240] R D1 Selected from , , , , , , , , , , , , , , , , ;

[0241] The definitions of the remaining functional groups are the same as those in the first, second, third, fourth, or fifth embodiments of the present invention.

[0242] This invention relates to compounds shown below, or their racemates, stereoisomers, tautomers, or pharmaceutically acceptable salts, wherein the compounds are selected from the structures shown in Table E.

[0243] This invention relates to a pharmaceutical composition comprising any of the above-described compounds, their racemic, stereoisomer, tautomer, pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

[0244] This invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the racemic, stereoisomer, tautomer, pharmaceutically acceptable salt of the above-described compound of this invention, and a pharmaceutically acceptable carrier.

[0245] In some embodiments, the pharmaceutical composition of the present invention may be in unit dosage form (the amount of the active pharmaceutical ingredient in a unit dosage form is also referred to as a "dosage strength").

[0246] The term "effective amount" or "therapeutic effective amount" as used in this application means that administering a sufficient amount of the compound disclosed in this application will alleviate, to some extent, one or more symptoms of the disease or condition being treated (e.g., tumor or cancer (preferably prostate cancer)). In some embodiments, the result is a reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of the compound disclosed in this application required to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective doses 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, and 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.

[0247] 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 mg, etc. The compounds of the present invention, or their stereoisomers, pharmaceutically acceptable salts, or eutectics, in mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, and 840 mg.

[0248] A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound of the present invention or its stereoisomers, pharmaceutically acceptable salts or eutectics, preferably 1-1500 mg, wherein the disease is selected from tumors or cancers (preferably prostate cancer).

[0249] A method for treating or alleviating a disease in a mammal. The method comprises administering a medicament, a compound of the present invention or its stereoisomers, pharmaceutically acceptable salts, or cocrystals, to a subject at a daily dose of 1-1000 mg / day. The daily dose may be a single dose or multiple 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, and 25-400 mg / day. The daily dose may be 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, or 1000 mg / day.

[0250] This invention relates to a kit that may include a single-dose or multi-dose composition comprising the compound of the present invention or its stereoisomers, pharmaceutically acceptable salts thereof, wherein the amount of the compound of the present invention or its racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt is the same as that in the above-described pharmaceutical composition.

[0251] This invention relates to the use of any of the above-described compounds, or their racemates, stereoisomers, tautomers, or pharmaceutically acceptable salts, in the preparation of medicaments for diseases associated with androgen receptor splicing mutants.

[0252] This invention relates to the use of any of the above-described pharmaceutical compositions in the preparation of medicaments for diseases associated with androgen receptor splicing mutants.

[0253] The amounts of racemic, stereoisomer, tautomer, and pharmaceutically acceptable salts of the compounds of this invention are converted in each case as free bases.

[0254] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0255] The compounds of this invention include their racemic, stereoisomer, tautomer, isotopic compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals.

[0256] The carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I, etc. involved in the groups and compounds described in this invention include their isotopic forms. That is, the carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I, etc. involved in the groups and compounds described in this invention may be optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 11 C 12 C 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include 15 O、 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S, 35 S and 36 S, nitrogen isotopes include 13 N、 14 N and 15 N, isotopes of fluorine include 17 F, 18 F and 19 F, isotopes of chlorine include35 Cl、 36 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br, an isotope of iodine, includes 123 I, 125 I, phosphorus isotopes include 31 P, 32 P.

[0257] “CN” refers to cyano.

[0258] "Halogen" refers to F, Cl, Br or I.

[0259] "Halogen-substituted" refers to substitution with F, Cl, Br, or I, including but not limited to 1 to 10 substituents selected from F, Cl, Br, or I, 1 to 6 substituents selected from F, Cl, Br, or I, and 1 to 4 substituents selected from F, Cl, Br, or I. "Halogen-substituted" is abbreviated as "halogenated".

[0260] "alkyl" refers to a substituted or unsubstituted straight-chain or branched saturated aliphatic hydrocarbon group, including but not limited to alkyl groups with 1 to 20 carbon atoms, alkyl groups with 1 to 8 carbon atoms, alkyl groups with 1 to 6 carbon atoms, and alkyl groups with 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 their various branched isomers; the alkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0261] "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), alkylene examples include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0262] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, 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-spirobutyl, adamantane, etc. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0263] "Heterocyclic alkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 12 atoms or 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O, S, or Se. The C, N, and S atoms on the ring of the heterocyclic alkyl group can be oxidized to various oxidation states. Heterocyclic alkyl groups can be monocyclic, fused, bridged, or spirocyclic. Heterocyclic alkyl groups can be attached to heteroatoms or carbon atoms. Non-limiting examples include epoxyethyl, aziridinepropyl, oxacyclobutyl, aziridinebutyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxopentyl, dioxohexyl, pyrrolylalkyl, piperidinyl, imidazoalkyl, oxazolidinyl, oxazinylalkyl, morpholinyl, hexahydropyrimidinyl, piperazineyl, etc. , , , , , , , Heterocyclic alkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0264] "Alkenyl" refers to a substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon group having at least one, typically one, two, or three, carbon-carbon double bonds. The main chain has, but is not limited to, 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-... The alkenyl group can be monovalent, divalent, trivalent, or tetravalent, including methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene.

[0265] "Alynyl" refers to a substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon group having at least one, typically one, two, or three, carbon-carbon triple bonds. The main chain comprises 2 to 10 carbon atoms, including but not limited to having 2 to 6 carbon atoms on the main chain, or 2 to 4 carbon atoms on the main chain. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, and 4-pentynyl. The alkynyl group can be monovalent, divalent, trivalent, or tetravalent. Examples of alkynyl groups include: 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-hepynyl, 2-hepynyl, 3-hepynyl, 4-hepynyl, 1-octyynyl, 3-octyynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, etc.

[0266] "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, cyclopropoxy, and cyclobutoxy.

[0267] "Carbocyclic group" or "carbocyclic ring" refers to a substituted or unsubstituted aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, a 10- to 15-membered tricyclic ring, or a 12- to 18-membered quaternary system. The carbocyclic group can be attached to an aromatic or non-aromatic ring, and the ring can be optionally a monocyclic, fused, bridged, or spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, etc. , , or "Carbocyclic group" or "carbon ring" can be monovalent, divalent, trivalent or tetravalent.

[0268] "Heterocyclic group" or "heterocyclic" refers to a substituted or unsubstituted aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, a 10- to 15-membered tricyclic ring, or a 12- to 18-membered quaternary system, 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 selectively substituted in the ring of the heterocyclic group 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 epoxyethyl, azirropropyl, oxacyclobutyl, azirrobutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxahexacycloyl, azirroheptyl, pyridinyl, furanyl, thiophene, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithioyl, dihydrofuranyl, dihydropyranyl, dithiapentylcycloyl. Tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophene, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzooxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptyl, , , , , , , , , , , , , , , , , , , , , , "Heterocyclic group" or "heterocyclic ring" can be monovalent, divalent, trivalent or tetravalent.

[0269] "Spirocyclic" or "spirocyclic group" refers to a polycyclic group in which substituted or unsubstituted rings share a single atom (called a spiro atom). The number of ring atoms in a spirocyclic system includes, but is not limited to, 5 to 20, 6 to 14, 6 to 12, or 6 to 10. 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 double bonds selected from N, O, or S (=O). n Heteroatoms (n is 0, 1, or 2). Non-limiting embodiments include:

[0270] "Spirocyclic" or "spirocyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0271] "Burying" or "burying group" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with the other rings in the system. One or more rings may contain zero or more (including but not limited to 1, 2, 3 or 4) double bonds and may be substituted or unsubstituted. Each ring in the burying system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to those selected from N, S (=O)). n Or O, where n is 0, 1, or 2). The number of ring atoms in a 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:

[0272] "Cyclone" or "cyclone base" can be monovalent, divalent, trivalent, or tetravalent.

[0273] A “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 a bridged ring system may contain 0 to 5 groups selected from heteroatoms or 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: Cubicane, adamantane. "Bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent, or tetravalent.

[0274] "Carbon spirocyclic", "spirocyclic carbon cyclic", "spirocarbon cyclic", or "carbon spirocyclic" refers to a spirocyclic system composed only of carbon atoms.

[0275] "Carbon fused ring", "fused cyclic carbon cyclic group", "fused carbon cyclic group" or "carbon fused cyclic group" refers to a ring system composed only of carbon atoms.

[0276] "Carbon bridged ring", "bridged ring carbon cyclo group", "bridged carbon cyclo group" or "carbon bridged ring group" refers to a ring system composed only of carbon atoms.

[0277] "Hybrid monocyclic", "monocyclic heterocyclic group" or "hybrid monocyclic group" refers to the "heterocyclic group" or "heterocyclic" in a monocyclic system.

[0278] "Hydrocyclic ring", "hydrocyclic cyclic group", "fused cyclic heterocyclic group" or "fused heterocyclic group" refers to a "fused ring" containing heteroatoms.

[0279] "Heterospirocyclic", "heterospirocyclic group", "spirocyclic heterocyclic group" or "spiroheterocyclic group" refers to a "spirocycle" containing heteroatoms.

[0280] "Hybrid-bridged ring", "hybrid-bridged ring group", "bridged ring heterocyclic group" or "bridged heterocyclic group" refers to a "bridged ring" containing heteroatoms.

[0281] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a monocyclic or 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 can be fused to a saturated or unsaturated carbon ring, wherein the ring connected to the parent structure is the aryl ring. Non-limiting embodiments include benzene rings, naphthalene rings, etc. The "aryl" or "aryl ring" can be monovalent, divalent, trivalent, or tetravalent. When it is divalent, trivalent, or tetravalent, the linker site is located on the aryl ring.

[0282] "Heteroaryl" or "heteroary ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or a group 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 heteroaryl ring includes, but is not limited to, 5 to 15, 5 to 10, or 5 to 6. The atoms C, N, and S on the ring may be optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, where n is 1 or 2). Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furanyl, thiophenyl, selenyl, pyridyl, pyranyl, N-alkylpyrrolithyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazoleyl, benzopyrazolyl, benzimidazoleyl, benzopyridyl, pyrrolopyridyl, pyridinoneyl, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbon ring or heterocycle, wherein the ring connected to the parent structure is an aryl ring. Non-limiting embodiments include: , , The definition of heteroaryl groups used in this paper is consistent with that in this paper. Heteroaryl groups can be monovalent, divalent, trivalent, or tetravalent. When they are divalent, trivalent, or tetravalent, the linking site is located on an aromatic ring.

[0283] "Substituted" or "substituted" means substituted 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 cyclic, spirocyclic, fused cyclic, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, and ‒(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 ‒Alkyne‒R a (where m and n are 0, 1, or 2), arylthio, thiocarbonyl, silyl, or ‒NR b R c Groups, wherein R b With R c Independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, R b With R c It can form five- or six-membered cycloalkyl or heterocyclic groups, R a With R d Each group is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic, carbonyl, ester, bridged cyclic, spirocyclic, or fused cyclic groups.

[0284] "1 to X substituents selected from..." means substituted by 1, 2, 3...X substituents selected from..., where X is any integer between 1 and 10. For example, "1 to 4 R..." k "Replace" refers to being replaced by 1, 2, 3, or 4 Rs. k Substitution. For example, "1 to 5 substituents selected from ..." means that the ring is substituted by 1, 2, 3, 4 or 5 substituents selected from ... . For example, "the 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.

[0285] X-Y member rings (where X and Y are integers, and 3 ≤ X < Y, X < Y ≤ 20, selected from any integer between 4 and 20) include rings of the X, X+1, X+2, X+3, X+4…Y member categories. These rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterofused rings, heterospirocyclic rings, or heterobridged rings. For example, “4-7 member heteromonocyclic rings” refers to heteromonocyclic rings of 4, 5, 6, or 7 members, and “5-10 member heterofused rings” refers to heterofused rings of 5, 6, 7, 8, 9, or 10 members.

[0286] C x-y Carbocyclic rings (including aryl, cycloalkyl, monocyclic, spirocyclic, fused, or bridged carbocyclic rings) include C x C x+1 C x+2 C x+3 C x+4 …. C y A ring of elements (x is an integer, and 3 ≤ x < y, where y is any integer between 4 and 20), for example, C. 3‒6 "Cycloalkyl" refers to C3, C4, C5, or C6 cycloalkyl groups.

[0287] When a functional group has one or more connectable sites, any one or more of these sites can be linked to other functional groups via chemical bonds. When the chemical bond connection is non-directional and a hydrogen atom is present at the connectable site, the number of hydrogen atoms at that site decreases accordingly with the number of bonds being formed, resulting in a functional group with a corresponding valence. For example... This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... These four connection methods, even if an H atom is drawn on -N-, This also includes .For example This indicates that the R group on the piperidinyl group can be located on C or N, and at least includes [missing information]. For example, the general formula fragment is: When X is selected from CH2 or NH, it means that the R group on the general formula fragment can be located on C or X. When X is selected from CH2, the general formula fragment can be... , When X is selected from NH, the general formula fragment can be... .

[0288] When the listed linking groups do not specify their linking direction, the linking direction includes the direction of the reading order from left to right and from right to left. For example, when ALB is selected from -MW-, it includes AMWB and AWMB.

[0289] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or possibility that the event or environment may or may not occur. For example, "optionally substituted F alkyl" means that the alkyl group may but does not have to be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.

[0290] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" means that the compound of the present invention retains the bioavailability and properties of a free acid or a free base, and that the free acid is obtained by reacting with a non-toxic inorganic or organic base, and the free base is obtained by reacting with a non-toxic inorganic or organic acid.

[0291] "Pharmaceutical composition" refers to a mixture of one or more compounds described in this invention, or their stereoisomers, tautomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents.

[0292] "Product specification" refers to the weight of the active pharmaceutical ingredient contained in each vial, tablet, or other unit of preparation.

[0293] "Carrier" refers to a material that does not cause significant stimulation to an organism and does not eliminate the biological activity and properties of the compound given.

[0294] "Prodrug" refers to a compound of the present invention that can be metabolized in vivo and converted into a biologically active compound. The prodrug of the present invention is prepared by modifying the amino or carboxyl groups in the compound of the present invention. This modification can be performed through conventional procedures or removed in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian individual, the prodrug is cleaved to form free amino or carboxyl groups.

[0295] "Co-crystal" refers to a crystal formed by the bonding of an active pharmaceutical ingredient (API) and a co-crystal form (CCF) through hydrogen bonds or other non-covalent bonds. Both API and CCF are solids at room temperature in their pure states, and a fixed stoichiometric ratio exists between the components. Co-crystal is a multi-component crystal, encompassing both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.

[0296] "Animals" refers to mammals, such as humans, companion animals, zoo animals, and livestock, with humans, horses, or dogs being preferred.

[0297] "Stereoisomers" refer to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0298] "Tautomers" refer to functional group isomers that are produced by the rapid movement of an atom in two positions within a molecule, such as keto-enol isomers and amide-imine alcohol isomers.

[0299] Synthesis Scheme 1:

[0300]

[0301] Compound (Z-1) and compound (Z-2) of general formula were reacted via a nucleophilic substitution reaction to give compound (Z-3) of general formula.

[0302] The general formula compound (Z-3) reacts with a methyl Grignard reagent via a Grignard reaction to yield the general formula compound (Z-4);

[0303] Compound of general formula (Z-4) and compound of general formula (Z-5) are reacted via an FC reaction to yield compound of general formula (Z-6);

[0304] The general formula compound (Z-6) is given by the general formula compound (Z-7) via a nucleophilic substitution reaction;

[0305] The general formula compound (Z-7) is coupled to give the general formula compound (Z-8);

[0306] The compound of general formula (Z-8) and the compound of general formula (Z-9) are coupled together to give the compound of general formula (Z-10);

[0307] Compounds of general formula (Z-10) and (Z-11) are reacted via a nucleophilic substitution reaction to yield compound of general formula (Ia);

[0308] R m1 Each is independently selected from structures such as Me, Et, and Bn;

[0309] R m2 Each is independently selected from structures such as Br, I, OMs, OTf, and OTs;

[0310] R m3 Each is independently selected from structures such as boric acid and boron ester;

[0311] R m4 Each is independently selected from structures such as F and Cl;

[0312] R m5 Each is independently selected from structures such as Br, I, and OTf;

[0313] The definitions of the remaining groups are the same as those of compounds of general formula (I).

[0314] Synthesis Scheme 2:

[0315]

[0316] Compounds of general formula (Z-12) and (Z-13) are reacted via an FC reaction to yield compound of general formula (Z-14);

[0317] The general formula compound (Z-14) was reacted with methylphosphine ylide via a Wittig reaction to give the general formula compound (Z-15);

[0318] Compound of general formula (Z-15) and compound of general formula (Z-16) undergo a cycloaddition reaction to give compound of general formula (Z-17);

[0319] The general formula compound (Z-17) was deprotected to give the general formula compound (Z-18);

[0320] The general formula compound (Z-18) was given by a nucleophilic substitution reaction to the general formula compound (Z-19);

[0321] The general formula compound (Z-19) is coupled to give the general formula compound (Z-20);

[0322] The compound of general formula (Z-20) and the compound of general formula (Z-21) are coupled together to give the compound of general formula (Z-22);

[0323] Compounds of general formula (Z-22) and (Z-23) are reacted via a nucleophilic substitution reaction to yield compound of general formula (Ia);

[0324] R m6 Each is independently selected from structures such as TES and TBS;

[0325] R m7 Each is independently selected from structures such as Br and I;

[0326] R m8 Each is independently selected from structures such as boric acid and boron ester;

[0327] R m10 Each is independently selected from structures such as F and Cl;

[0328] R m9 Each is independently selected from structures such as Br, I, and OTf;

[0329] The definitions of the remaining groups are the same as those of compounds of general formula (I). Detailed Implementation

[0330] The following embodiments illustrate the technical solution of the present invention in detail, but the scope of protection of the present invention includes, but is not limited to, these embodiments.

[0331] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ increments. 6 The unit (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0332] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0333] HPLC determinations were performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM).

[0334] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The silica gel plates used for TLC have a diameter of 0.15 mm to 0.20 mm, and the diameter of the plates used for TLC separation and purification is 0.4 mm to 0.5 mm.

[0335] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0336] To accomplish the objectives of this invention, compounds used in the reactions described herein are prepared from commercially available chemicals and / or compounds described in chemical literature, according to organic synthesis techniques known to those skilled in the art. "Commercially available chemicals" are obtained from standard commercial sources, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai Maclean Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Esa (China) Chemical Co., Ltd., THIAI (Shanghai) Chemical Industry Development Co., Ltd., Energie Chemicals, Shanghai Titan Technology Co., Ltd., Kelon Chemical, Bailingwei Technology Co., Ltd., etc.

[0337] TCFH: Tetramethylchlorourea hexafluorophosphate; THF: Tetrahydrofuran; DMF: N,N-Dimethylformamide; DIPEA: N,N-Diisopropylethylamine; HATU: CAS 148893-10-1

[0338] Retention time: Unless otherwise specified in the embodiments, this represents the retention time corresponding to the analysis method.

[0339] Synthesis of intermediate A

[0340]

[0341] Step 1: Synthesis of intermediate A2

[0342] Substrate A1 (7.8 g, 50 mmol) and 2-bromo-5-fluoropyrazine (9.7 g, 55 mmol) were dissolved in 100 mL of tetrahydrofuran. Potassium tert-butoxide (7.3 g, 65 mmol) was added under ice-water bath conditions, and the mixture was reacted overnight at room temperature. A suitable amount of water was added, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, dried, concentrated, and the residue was purified by silica gel column chromatography to give intermediate A2 (5.3 g, 34%).

[0343] LCMS m / z = 312.9 315.0 [M+H] +

[0344] Step 2: Synthesis of intermediate A3

[0345] Intermediate A2 (5.3 g, 17 mmol) was dissolved in 50 mL of dichloromethane. Under ice-water bath conditions, m-chloroperoxybenzoic acid (7.3 g, 42.3 mmol) was added, and the reaction was carried out at room temperature for 2 hours. The reaction solution was diluted with dichloromethane, washed with saturated sodium thiosulfate and sodium bicarbonate solutions, and the organic layer was dried and concentrated. The residue was purified by silica gel column chromatography to obtain intermediate A3 (3.2 g, 55%).

[0346] LCMS m / z = 344.9 346.9 [M+H] +

[0347] Step 3: Synthesis of intermediate A

[0348] A3 (2.5 g, 7.25 mmol), A4 (1.1 g, 7.25 mmol), cesium carbonate (7.07 g, 21.7 mmol), and 20 mL of acetonitrile were added sequentially to the reaction flask, and the mixture was reacted overnight at room temperature. A suitable amount of water was added, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, dried, concentrated, and the residue was purified by silica gel column chromatography to obtain intermediate A (1.4 g, 51%).

[0349] LCMS m / z = 380.0 382.0 [M+H] +

[0350] Example 1-1: Preparation of Compound 1 (Method 1)

[0351]

[0352] Characterization of chiral isomer 1 of compound 1:

[0353] LCMS m / z = 704.2 [M+1] +

[0354] Characterization of chiral isomer 2 of compound 1:

[0355] LCMS m / z = 704.2 [M+1] +

[0356] Chiral isomer 1 and chiral isomer 2 of compound 1 are either isomers of compound 1-A or compound 1-B. That is, when chiral isomer 1 of compound 1 is compound 1-A, chiral isomer 2 of compound 1 is compound 1-B; when chiral isomer 1 of compound 1 is compound 1-B, chiral isomer 2 of compound 1 is compound 1-A.

[0357] Examples 1-2:

[0358] Synthesis of Compound 1 (Method 2)

[0359]

[0360] Step 1: Synthesis of compound 1b

[0361] The starting material 1a (10 g, 32 mmol) was dissolved in 100 mL of toluene, and 1,1-cyclopropanediethanol (4.9 g, 48 mmol) and cyanomethylenetri-n-butylphosphine (15.45 g, 64 mmol) were added. After nitrogen purging, the mixture was heated to 100 °C and reacted for 16 h. The mixture was then concentrated under reduced pressure and purified by column chromatography to obtain compound 1b (7.1 g, yield: 56%).

[0362] 1 H NMR (400 MHz, CD3OD) δ 8.32 – 8.25 (m, 1H), 8.00 – 7.94 (m, 1H), 3.99 (s, 2H), 3.90 (s, 3H), 3.74 (s, 2H), 0.78 – 0.71 (m, 2H), 0.70 – 0.63(m, 2H).

[0363] Step 2: Synthesis of compound 1c

[0364] Raw material 1b (7 g, 17.65 mmol) was dissolved in 70 mL of toluene, thionyl chloride (4.2 g, 35.3 mmol) was added and nitrogen was added to purge the mixture. The mixture was then heated to 100 °C and reacted for 4 h. The mixture was concentrated under reduced pressure, and the residue was dissolved in 100 mL of dichloromethane. The pH was adjusted to approximately 8 by adding saturated sodium bicarbonate aqueous solution. The organic phase was separated, concentrated under reduced pressure, and purified by column chromatography to obtain compound 1c (3.2 g, yield: 43%).

[0365] 1 H NMR (400 MHz, CD3OD) δ 8.33 (d, 1H), 8.01 (d, 1H), 4.02 (s, 2H), 3.90 (s, 3H), 3.85 (s, 2H), 0.98 – 0.91 (m, 2H), 0.85 – 0.77 (m, 2H).

[0366] Step 3: Synthesis of compound 1d

[0367] The starting material 1c (3 g, 7.23 mmol) was dissolved in 10 mL of dioxane, and zinc cyanide (1 g, 8.68 mmol) and tetra(triphenylphosphine)palladium (0.84 g, 0.72 mmol) were added. Under nitrogen protection, the mixture was reacted in a microwave at 120 °C for 1 h, concentrated under reduced pressure, and purified by column chromatography to obtain compound 1d (1.8 g, yield: 79%).

[0368] 1 H NMR (400 MHz, CD3OD) δ 8.29 (d, 1H), 8.23 ​​(d, 1H), 4.29 (s, 2H), 3.93 (s, 3H), 3.83 (s, 2H), 0.91 – 0.85 (m, 2H), 0.85 – 0.79 (m, 2H).

[0369] Step 4: Synthesis of compound 1e

[0370] The starting material 1d (1.8 g, 5.73 mmol) was dissolved in 40 mL of tetrahydrofuran under nitrogen protection. Methyl magnesium bromide (5.7 mL, 17.2 mmol) was added dropwise at 0 °C. After the addition was complete, the reaction was continued for 2 h. The reaction was quenched by adding saturated ammonium chloride aqueous solution. The mixture was extracted with 50 mL of ethyl acetate, the organic phase was separated, concentrated under reduced pressure, and purified by column chromatography to obtain compound 1e (1.6 g, yield: 88%).

[0371] 1H NMR (400 MHz, CDCl3) δ 7.74 (d, 1H), 7.60 (d, 1H), 4.14 (s, 2H), 3.81 (s, 2H), 1.57 (s, 6H), 0.92 – 0.85 (m, 2H), 0.83 – 0.77 (m, 2H).

[0372] Step 5: Synthesis of compound 1f

[0373] The starting material 1e (1.6 g, 5.1 mmol) was dissolved in 20 mL of carbon tetrachloride, and phenol (0.57 g, 6.11 mmol) was added. Under nitrogen protection, boron trifluoride diethyl ether (1.44 g, 10.2 mmol) was added dropwise at 0 °C. After the addition was complete, the reaction was continued for 4 h. The reaction was quenched with water, and 50 mL of dichloromethane was added for extraction. The organic phase was separated, concentrated under reduced pressure, and purified by column chromatography to obtain compound 1f (1.7 g, yield: 85%).

[0374] 1 H NMR (400 MHz, CDCl3) δ 7.43 (d, 1H), 7.31 (d, 1H), 7.04 (d, 2H), 6.78 (d, 2H), 5.11 (s, 1H), 4.12 (s, 2H), 3.79 (s, 2H), 1.62 (s, 6H), 0.90 –0.83 (m, 2H), 0.82 – 0.75 (m, 2H).

[0375] Step 6: Synthesis of 1g of compound

[0376] The starting material 1f (1.7 g, 4.36 mmol) was dissolved in 30 mL of dichloromethane, and pyridine (1.7 g, 21.8 mmol) was added. Under nitrogen protection, trifluoromethanesulfonic anhydride (1.85 g, 6.54 mmol) was added dropwise at 0 °C. After the addition was complete, the reaction was carried out at room temperature for 2 h. The mixture was then concentrated under reduced pressure and purified by column chromatography to give compound 1 g (1.8 g, yield: 79%).

[0377] 1 H NMR (400 MHz, CDCl3) δ 7.40 (d, 1H), 7.32 (d, 1H), 7.28 – 7.18 (m,6H), 4.14 (s, 2H), 3.80 (s, 2H), 1.67 (s, 6H), 0.92 – 0.77 (m, 4H).

[0378] Step 7: Synthesis of compound 1h

[0379] 1 g (0.5 g, 0.96 mmol) of the starting material was dissolved in 10 mL of dioxane, and pinacol diboronic acid ester (0.37 g, 1.44 mmol), potassium acetate (0.28 g, 2.88 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.078 g, 0.096 mmol) were added. Under nitrogen protection, the mixture was heated to 90 °C for 6 h, concentrated under reduced pressure, and purified by column chromatography to obtain compound 1 h (0.4 g, yield: 83%).

[0380] 1 H NMR (400 MHz, CDCl3) δ 7.76 (d, 2H), 7.40 (d, 1H), 7.30 (d, 1H), 7.18 (d, 2H), 4.12 (s, 2H), 3.79 (s, 2H), 1.66 (s, 6H), 1.34 (s, 12H), 1.29 –1.24 (m, 3H), 0.91 – 0.83 (m, 2H), 0.82 – 0.75 (m, 1H).

[0381] Step 8: Synthesis of Compound 1i

[0382] The starting material 1h (50 mg, 0.1 mmol) was dissolved in 2 mL of dioxane and 0.2 mL of water. Intermediate A (46 mg, 0.12 mmol), potassium carbonate (41 mg, 0.3 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (8 mg, 0.01 mmol) were added. Under nitrogen protection, the mixture was heated to 100 °C for 6 h. The mixture was then concentrated under reduced pressure and purified by column chromatography to obtain compound 1i (55 mg, yield: 82%).

[0383] LCMS m / z = 673.3 [M+H] + ;

[0384] 1H NMR (400 MHz, CDCl3) δ 8.47 (d, 1H), 8.41 (d, 1H), 8.30 (d, 1H), 7.86 (d, 2H), 7.44 (d, 1H), 7.35 (d, 1H), 7.29 (d, 2H), 6.71 (d, 0.90 – 0.76 (m, 4H).

[0385] Step 9: Synthesis of Compound 1

[0386] The starting material 1 (55 mg, 0.082 mmol) was dissolved in 10 mL of methanol. Ammonium carbamate (64 mg, 0.82 mmol) and diethyl iodophenyl ester (130 mg, 0.41 mmol) were added at 0 °C. After the addition was complete, the mixture was stirred overnight at room temperature. The mixture was then concentrated under reduced pressure. The residue was subjected to preparative HPLC (instrument: CAS-05-Prep-HPLC-O; preparative column: C18 column; mobile phase: A was 10 mmol / L NH4HCO3 aqueous solution; B was acetonitrile; elution conditions: 55% to 75% B in A solution, gradient elution for 10 min; flow rate: 75 mL / min; column temperature: room temperature; detection wavelength: 220 nm) to obtain compound 1 28 mg. Compound 1 was prepared by chiral HPLC to obtain compounds 1-1 (6 mg, retention time: 3.119 min) and 1-2 (5 mg, retention time: 5.156 min). Chiral HPLC preparation method (min): Instrument: CAS-05-Prep-HPLC-D; Preparative column: IA column; Mobile phase: A is n-hexane; B is 0.1% NH3•H2O to ammonia water to ethanol / acetonitrile mixed solvent; Elution conditions: 10% to 35% B in A solution, gradient elution for 10 min; Flow rate: 50 mL / min; Column temperature: room temperature; Detection wavelength: 220 nm;

[0387] Of compounds 1-1 and 1-2, one has the structure of compound 1-A and the other has the structure of compound 1-B. That is, when compound 1-1 is compound 1-A, compound 1-2 is compound 1-B; when compound 1-1 is compound 1-B, compound 1-2 is compound 1-A.

[0388] Compound 1-1: LCMS m / z = 704.2 [M+H] + ;

[0389] 1 H NMR (400 MHz, CD3OD) δ 8.58 (d, 1H), 8.41 (d, 1H), 8.32 (d, 1H), 7.92 (d, 2H), 7.55 (d, 1H), 7.52 (d, J 1H), 7.36 (d, 2H), 6.84 (d, 1H), 5.40(s, 2H), 4.66 – 4.60 (m, 2H), 4.30 – 4.21 (m, 2H), 4.13 (s, 2H), 4.04 – 3.89(m, 2H), 3.82 (s, 2H), 2.56 – 2.40 (m, 2H), 1.72 (s, 6H), 0.87 – 0.83 (m,2H), 0.82 – 0.76 (m,2H).

[0390] Compounds 1-2: LCMS m / z = 704.1 [M+H] + ;

[0391] 1 H NMR (400 MHz, CD3OD) δ 8.58 (d, 1H), 8.41 (d, 1H), 8.32 (d, 1H), 7.92 (d, 2H), 7.55 (d, 1H), 7.52 (d, J 1H), 7.36 (d, 2H), 6.84 (d, 1H), 5.40(s, 2H), 4.66 – 4.59 (m, 2H), 4.31 – 4.19 (m, 2H), 4.13 (s, 2H), 4.05 – 3.89(m, 2H), 3.81 (s, 2H), 2.57 – 2.40 (m, 2H), 1.72 (s, 6H), 0.87 – 0.82 (m,2H), 0.82 – 0.76 (m,2H).

[0392] Example 2: Synthesis of Compound 2

[0393]

[0394] Step 1: Synthesis of compound 2b

[0395] Under nitrogen protection, at 0°C, n-butyllithium (6.0 mL, 15.0 mmol) was dissolved in 40 mL of tetrahydrofuran, and isopropyl magnesium chloride (7.5 mL, 7.5 mmol) was added dropwise. After the addition was complete, the reaction was continued for 0.5 h. The temperature was lowered to -78°C, and 2a (2.93 g, 10.0 mmol) was dissolved in tetrahydrofuran and added dropwise to the reaction solution. After the addition was complete, the mixture was stirred for 1 h. Then, cyclobutanone (1.05 g, 15.0 mmol) was added dropwise and the mixture was stirred for 2 h. The reaction was quenched by adding saturated ammonium chloride aqueous solution. The mixture was extracted with 50 mL of ethyl acetate, the organic phase was separated, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound 2b (0.57 g, yield: 20.0%).

[0396] 1 H NMR (400 MHz, CDCl3) δ 7.77 (d, 1H), 7.64 (d, 1H), 4.45 (t, 2H), 3.89 (t, 2H), 2.56 – 2.45 (m, 2H), 2.44 – 2.33 (m, 2H), 1.84 – 1.69 (m, 2H).

[0397] Step 2: Synthesis of compound 2c

[0398] The starting material 2b (0.57 g, 2.0 mmol) was dissolved in 20 mL of dichloromethane, and phenol (0.56 g, 6.0 mmol) was added. Under nitrogen protection, aluminum trichloride (0.91 g, 6.0 mmol) was added at 0 °C, and the mixture was heated to room temperature and the reaction continued for 2 h. The reaction was quenched with water, and the mixture was extracted with 50 mL of dichloromethane. The organic phase was separated, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound 2c (0.54 g, yield: 75.01%).

[0399] 1 H NMR (400 MHz, CD3OD) δ 7.59 (d, 1H), 7.55 (d, 1H), 7.14 (d, 2H), 6.73 (d, 2H), 4.38 (t, 2H), 3.87 (t, 2H), 2.78 – 2.57 (m, 4H), 1.99 – 1.87(m, 2H).

[0400] Step 3: Synthesis of compound 2d

[0401] The starting material 2c (0.54 g, 1.50 mmol) was dissolved in 30 mL of dichloromethane, and pyridine (0.35 g, 4.50 mmol) was added. Under nitrogen protection, trifluoromethanesulfonic anhydride (0.85 g, 3.0 mmol) was added dropwise at 0 °C. After the addition was complete, the reaction was carried out at room temperature for 2 h. The mixture was then concentrated under reduced pressure and purified by column chromatography to obtain the target compound 2d (0.51 g, yield: 68.96%).

[0402] 1 H NMR (400 MHz, CD3OD) δ 7.69 (d, 1H), 7.65 (d, 1H), 7.52 (d, 2H), 7.30 (d, 2H), 4.40 (t, 2H), 3.88 (t, 2H), 2.84 – 2.73 (m, 4H), 2.03 – 1.92(m, 2H).

[0403] Step 4: Synthesis of compound 2e

[0404] The starting material 2d (0.47 g, 0.96 mmol) was dissolved in 10 mL of dioxane, and pinacol diboronic acid ester (0.37 g, 1.44 mmol), potassium acetate (0.28 g, 2.88 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.078 g, 0.096 mmol) were added. Under nitrogen protection, the mixture was heated to 90 °C for 6 h, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound 2e (0.4 g, yield: 88.46%).

[0405] 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, 2H), 7.50 (d, 1H), 7.40 (d, 1H), 7.26 (d, 2H), 4.37 (t, 2H), 3.84 (t, 2H), 2.83 – 2.73 (m, 2H), 2.70 – 2.60 (m, 2H), 2.06 – 1.92 (m, 2H), 1.33 (s, 12H).

[0406] Step 5: Synthesis of compound 2f

[0407] The starting material 2e (49 mg, 0.1 mmol) was dissolved in 2 mL of dioxane and 0.2 mL of water. Intermediate A (46 mg, 0.12 mmol), potassium carbonate (41 mg, 0.3 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (8 mg, 0.01 mmol) were added. Under nitrogen protection, the mixture was heated to 100 °C for 6 h. The mixture was then concentrated under reduced pressure and purified by column chromatography to obtain the target compound 2f (53 mg, yield: 82.42%).

[0408] 1 H NMR (400 MHz, CDCl3) δ 8.46 (d, 1H), 8.40 (d, 1H), 8.29 (d, 1H), 7.88 (d, 2H), 7.52 (d, 1H), 7.44 (d, 1H), 7.36 (d, 2H), 6.68 (d, 1H), 5.34(s, 2H), 4.39 (t, 2H), 4.37 – 4.32 (m, 4H), 3.85 (t, 2H), 3.25 – 3.18 (m,2H), 3.17 – 3.10 (m, 2H), 2.86 – 2.76 (m, 2H), 2.73 – 2.64 (m, 2H), 2.09 –1.97 (m, 2H).

[0409] Step 6: Synthesis of Compound 2

[0410] The starting material 2f (53 mg, 0.082 mmol) was dissolved in 10 mL of methanol, and ammonium carbamate (64 mg, 0.82 mmol) and diethyl iodophenyl ester (130 mg, 0.41 mmol) were added at 0 °C. After the addition was complete, the mixture was stirred overnight at room temperature. The mixture was then concentrated under reduced pressure, and the residue was subjected to preparative HPLC (instrument: CAS-05-PREP-HPLC K, preparative column: C18 column, mobile phase: A was 10 mmol / L NH4HCO3 aqueous solution; B was acetonitrile; elution conditions: gradient elution of B in A solution from 55% to 75% for 10 min; flow rate: 25 mL / min; column temperature: room temperature; detection wavelength: 220 nm) to obtain compound 2 (8 mg, 14%).

[0411] Compound 2: LCMS m / z = 676.3 [M+H] + ;

[0412] 1H NMR (400 MHz, CD3OD) δ 8.56 (d, 1H), 8.40 (d, 1H), 8.32 (d, 1H), 7.92 (d, 2H), 7.69 (d, 1H), 7.65 (d, 1H), 7.47 (d, 2H), 6.84 (d, 1H), 5.39(s, 2H), 4.66 – 4.60 (m, 2H), 4.39 (t, 2H), 4.30 – 4.20 (m, 2H), 4.04 – 3.90(m, 2H), 3.87 (t, 2H), 2.87 – 2.71 (m, 4H), 2.56 – 2.39 (m, 2H), 2.04 – 1.94 (m, 2H).

[0413] Compound 2 (43 mg) was prepared by chiral HPLC to give compounds 2-1 (17 mg, retention time: 3.753 min) and 2-2 (10 mg, retention time: 6.255 min). Chiral HPLC preparation method: Instrument: CAS-05-Prep-HPLC-X; Preparative column: IA column; Mobile phase: A was n-hexane; B was 0.1% NH3•H2O to ammonia water to ethanol / acetonitrile mixed solvent; Elution conditions: 10% to 35% B in A solution, gradient elution for 10 min; Flow rate: 50 mL / min; Column temperature: room temperature; Detection wavelength: 220 nm.

[0414] Of compounds 2-1 and 2-2, one has the structure of compound 2-A and the other has the structure of compound 2-B. That is, when compound 2-1 is compound 2-A, compound 2-2 is compound 2-B; and when compound 2-1 is compound 2-B, compound 2-2 is compound 2-A.

[0415] Compound 2-1:

[0416] 1H NMR (400 MHz, CD3OD) δ 8.56 (d, 1H), 8.40 (d, 1H), 8.32 (d, 1H), 7.92 (d, 2H), 7.67 (dd, 2H), 7.47 (d, 2H), 6.84 (d, 1H), 5.40 (s, 2H), 4.67 –4.60 (m, 2H), 4.40 (t, 2H), 4.30 – 4.20 (m, 2H), 4.02 – 3.91 (m, 2H), 3.88(t, 2H), 2.88 – 2.73 (m, 4H), 2.55 – 2.42 (m, 2H), 2.05 – 1.95 (m, 2H).

[0417] Compound 2-2:

[0418] 1 H NMR (400 MHz, CD3OD) δ 8.56 (d, 1H), 8.40 (d, 1H), 8.32 (d, 1H), 7.92 (d, 2H), 7.67 (dd, 2H), 7.47 (d, 2H), 6.84 (d, 1H), 5.40 (s, 2H), 4.66 –4.60 (m, 2H), 4.40 (t, 2H), 4.30 – 4.20 (m, 2H), 4.02 – 3.92 (m, 2H), 3.88(t, 2H), 2.88 – 2.72 (m, 4H), 2.55 – 2.41 (m, 2H), 2.05 – 1.95 (m, 2H).

[0419] Example 3: Synthesis of Compound 3

[0420]

[0421] Step 1: Synthesis of 3b

[0422] The starting material N-BOC-azacyclobutane-3-sulfonyl chloride (3a) (0.5 g, 1.96 mmol) was dissolved in 10 mL of dichloromethane, and triethylamine (0.59 g, 5.88 mmol) was added. Under nitrogen protection, the mixture was cooled to 0 °C and cyclopropylamine (0.17 g, 2.94 mmol) was added. The reaction was continued for 2 h, and the product was concentrated under reduced pressure and purified by column chromatography to obtain the target product 3b (0.5 g, yield: 92.5%).

[0423] Step 2: Synthesis of 3C

[0424] Starting material 3b (0.1 g, 0.36 mmol) was dissolved in 5 mL of dichloromethane, and 0.2 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 2 h, concentrated under reduced pressure, and used directly in the next reaction without purification.

[0425] LCMS m / z = 177.1 [M+H] + ;

[0426] Step 3: 3D compositing

[0427] Intermediate A3 (0.1 g, 0.29 mmol) was dissolved in 5 mL of acetonitrile, crude product 3c and cesium carbonate (0.28 g, 0.87 mmol) were added, and the mixture was reacted at room temperature for 16 h. The mixture was concentrated under reduced pressure and purified by column chromatography to obtain the target product 3d (0.1 g, yield: 72.2%).

[0428] LCMS m / z = 440.9 [M+H] + ;

[0429] Step 4: Synthesis of Compound 3

[0430] The starting material 3d (100 mg, 0.23 mmol) was dissolved in 2 mL of dioxane and 0.2 mL of water. Intermediate C (110 mg, 0.23 mmol), potassium carbonate (95 mg, 0.69 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (19 mg, 0.01 mmol) were added. Under nitrogen protection, the mixture was heated to 100 °C and reacted for 16 h. The mixture was then concentrated under reduced pressure and purified by column chromatography to obtain the target product 3 (17 mg, yield: 10.8%).

[0431] LCMS m / z = 693.9 [M+H] + ;

[0432] 1 HNMR: 1 H NMR (400 MHz, CD3OD) δ 8.58 (d, 1H), 8.42 (d, 1H), 8.32 (d,1H), 7.91 (d, 2H), 7.54 (dd, 2H), 7.36 (d, 2H), 6.87 (d, 1H), 5.44 (s, 2H), 4.48 – 4.33 (m, 7H), 3.90 (t, 2H), 2.58 – 2.49 (m, 1H), 1.72 (s, 6H), 0.71 –0.56 (m, 4H).

[0433] Example 4: Preparation of Compound 4

[0434]

[0435] Step 1: Synthesis of compound 4b

[0436] Substrate 4a (2.4 g, 5 mmol), trimethylsilylacetylene (3.5 mL, 25 mmol), bis(triphenylphosphine)palladium dichloride (351 mg, 0.5 mmol), cuprous iodide (96 mg, 0.5 mmol), triethylamine (3.4 mL, 25 mmol), and 10 mL of DMF were added to a reaction flask. After purging with nitrogen three times, the reaction mixture was reacted overnight at 80 °C. The reaction solution was diluted with an appropriate amount of ethyl acetate, washed three times with water, and the resulting organic phase was concentrated and subjected to silica gel column chromatography to obtain product 4b (1.6 g, 74%).

[0437] Step 2: Synthesis of compound 4c

[0438] Substrate 4b (1.6 g, 3.7 mmol) was dissolved in 12 mL of methanol, and potassium fluoride (1.51 g, 26 mmol) was added. The mixture was reacted at room temperature for one hour. The reaction solution was directly concentrated and subjected to silica gel column chromatography to obtain product 4c (1.2 g, 91%).

[0439] Step 3: Synthesis of compound 4e

[0440] Substrate 4c (108 mg, 0.3 mmol), 4d (76 mg, 0.2 mmol), palladium dichloride bis(triphenylphosphine) (14 mg, 0.02 mmol), cuprous iodide (4 mg, 0.02 mmol), triethylamine (101 mL, 1 mmol), and 3 mL of DMF were added to a reaction flask. After purging with nitrogen three times, the reaction mixture was reacted overnight at 80 °C. The reaction solution was diluted with an appropriate amount of ethyl acetate, washed three times with water, and the resulting organic phase was concentrated and subjected to silica gel column chromatography to obtain product 4e (105 mg, 80%).

[0441] Step 4: Synthesis of Compound 4

[0442] Substrate 4e (110 mg, 0.17 mmol) was dissolved in 1 mL of dichloromethane and 3 mL of methanol. Ammonium carbamate (28 mg, 0.34 mmol) and iodophenylacetic acid (136 mg, 0.42 mmol) were added, and the mixture was reacted overnight at room temperature. The reaction solution was directly concentrated and subjected to silica gel column chromatography to give product 4 (80 mg, 70%). Product 4 was prepared by chiral HPLC to give compounds 4-1 (9.9 mg, retention time: 3.630 min) and 4-2 (10.3 mg, retention time: 6.546 min). Chiral HPLC preparation method: Instrument: CAS-05-Prep-HPLC-X; Preparative column: IA column; Mobile phase: A was n-hexane; B was 0.1% NH3•H2O to ammonia water to ethanol / acetonitrile mixed solvent; Elution conditions: 10% to 35% B in A solution, gradient elution for 10 min; Flow rate: 50 mL / min; Column temperature: room temperature; Detection wavelength: 220 nm.

[0443] Of compounds 4-1 and 4-2, one has the structure of compound 4-A and the other has the structure of compound 4-B. That is, when compound 4-1 is compound 4-A, compound 4-2 is compound 4-B; when compound 4-1 is compound 4-B, compound 4-2 is compound 4-A.

[0444] 4-1:

[0445] LCMS m / z = 688.3 [M+H] +

[0446] 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (d, 1H), 8.43 (d, 1H), 8.37 (d, 1H), 7.68 (d, 1H), 7.62 (d, 1H), 7.54 (d, 2H), 7.33 (d, 2H), 6.77 (d, 1H), 5.37(s, 2H), 4.76 (s, 1H), 4.48 (d, 1H), 4.45 – 4.40 (m, 2H), 4.37 (d, 1H), 4.22(d, 1H), 4.15 (d, 1H), 3.98 – 3.93 (m, 2H), 3.91 – 3.79 (m, 2H), 2.45 – 2.30 (m, 2H), 1.67 (s, 6H).

[0447] 4-2:

[0448] LCMS m / z = 688.3 [M+H]+

[0449] 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (d, 1H), 8.43 (d, 1H), 8.37 (d, 1H), 7.68 (d, 1H), 7.62 (d, 1H), 7.54 (d, 2H), 7.33 (d, 2H), 6.77 (d, 1H), 5.37(s, 2H), 4.76 (s, 1H), 4.48 (d, 1H), 4.45 – 4.41 (m, 2H), 4.37 (d, 1H), 4.22(d, 1H), 4.15 (d, 1H), 3.98 – 3.94 (m, 2H), 3.90 – 3.79 (m, 2H), 2.46 – 2.30 (m, 2H), 1.67 (s, 6H).

[0450] Example 5: Preparation of Compound 5

[0451]

[0452] Step 1: Synthesis of 5B

[0453] Compound 5A (583 mg, 1.62 mmol), DCM (6 mL), and pyridine (0.26 mL, 3.24 mmol) were added sequentially to a 50 mL single-necked flask, stirred to dissolve, and cooled to 0°C. Tf₂O (0.41 mL, 2.43 mmol) was added dropwise, and the mixture was kept at this temperature with stirring for hours. The reaction mixture was poured into a saturated sodium bicarbonate solution (20 mL), and extracted twice with DCM (20 mL). The organic phases were combined, washed with saturated brine (50 mL), concentrated under reduced pressure, and rapidly purified by silica gel column chromatography to give compound 5B (673 mg, yield: 83.95%).

[0454] LC-Ms m / z (ESI): 494.0 [M+H] +

[0455] Step 2: Synthesis of 5C

[0456] Under nitrogen protection, 5B (673 mg, 1.36 mmol) was dissolved in 1,4-dioxane (15 mL), followed by the sequential addition of pinacol diboronate (691 mg, 2.72 mmol), Pd(dppf)Cl2 (111 mg, 0.14 mmol), and potassium acetate (400 mg, 4.08 mmol). The reaction was carried out at 100°C for 12 h. Extraction was performed with ethyl acetate (80 mL), followed by washing with water (50 mL × 2) and saturated brine (50 mL × 1). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then subjected to silica gel column chromatography to obtain 5C (656 mg, yield: 100%).

[0457] LC-Ms m / z (ESI): 472.1 [M+H]+

[0458] Step 3: 5D Synthesis

[0459] Under nitrogen protection, intermediate A (621 mg, 1.63 mmol) was dissolved in 1,4-dioxane (15 mL) and water (1 mL), followed by the addition of 5C (656 mg, 1.39 mmol), Pd(dppf)Cl2 (155 mg, 0.19 mmol), and potassium carbonate (525 mg, 3.8 mmol). The reaction was carried out at 100°C for 12 h. Extraction was performed with ethyl acetate (80 mL), followed by washing with water (50 mL × 2) and saturated brine (50 mL × 1), drying over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure. The filtrate was then subjected to silica gel column chromatography to obtain 5D (682 mg, yield: 76%). Intermediate 5D was resolved by chiral SFC (SFC chiral preparation method: instrument: CAS-05-Prep-SFC-E; preparative column type: AD column; mobile phase: A is CO2; B is a mixed solvent of 0.1% NH3•H2O ethanol acetonitrile; elution conditions: 35% B isocratic elution; flow rate: 105 mL / min; column pressure: 100 bar; column temperature: 25 ℃; detection wavelength: 220 nm) to obtain compounds 5D-1 (226 mg, retention time: 1.975 min) and 5D-2 (208 mg, retention time: 2.793 min).

[0460] Of compounds 5D-1 and 5D-2, one has a structure designated as compound 5D-A, and the other as compound 5D-B. That is, when compound 5D-1 is compound 5D-A, compound 5D-2 is compound 5D-B; and when compound 5D-1 is compound 5D-B, compound 5D-2 is compound 5D-A.

[0461] Compound 5D: LC-Ms m / z (ESI): 645.1 [M+H] +

[0462] Step 4: Synthesis of compounds 5-1-1 and 5-1-2

[0463] Under nitrogen protection, intermediate 5D-1 (226 mg, 0.35 mmol) was dissolved in ultradry DCM (3.5 mL) and methanol (7 mL) solution, and ammonium carbamate (273 mg, 3.5 mmol) was added. Then, diethyl iodophenyl ester (564 mg, 1.75 mmol) was added under ice bath conditions. The system was heated to room temperature and reacted overnight, concentrated under reduced pressure, and rapidly purified by silica gel column chromatography to obtain 5-1 (256 mg). 5-1 was resolved by chiral SFC (SFC chiral preparation method: instrument: CAS-05-Prep-SFC-F; preparative column model: ADcolumn; mobile phase: A is CO2; B is a mixed solvent of 0.1% NH3•H2O ethanol acetonitrile; elution conditions: 35% B isocratic elution; flow rate: 110 mL / min; column pressure: 100 bar; column temperature: 25 ℃; detection wavelength: 220 nm) to obtain compounds 5-1-1 (28.4 mg, retention time: 1.024 min) and 5-1-2 (22.8 mg, retention time: 1.287 min).

[0464] Of compounds 5-1-1 and 5-1-2, one has the structure 5-1-A and the other has the structure 5-1-B. That is, when compound 5-1-1 is compound 5-1-A, compound 5-1-2 is compound 5-1-B; when compound 5-1-1 is compound 5-1-B, compound 5-1-2 is compound 5-1-A.

[0465] Compound 5-1-1: LC-Ms m / z (ESI): 675.2 [M+H] +

[0466] 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, 1H), 8.53 (d, 1H), 8.37 (d, 1H), 7.97 (d, 2H), 7.24 – 7.16 (m, 3H), 6.79 (d, 1H), 5.37 (s, 2H), 4.76 (s, 1H),4.49 (d, 1H), 4.43 – 4.36 (m, 3H), 4.29 – 4.14 (m, 3H), 3.97 (t, 2H), 3.93 –3.78 (m, 2H), 2.93 – 2.85 (m, 2H), 2.45 – 2.31 (m, 2H), 2.11 – 2.00 (m, 1H), 1.92 – 1.69 (m, 3H).

[0467] Compound 5-1-2: LC-Ms m / z (ESI): 675.2 [M+H] +

[0468] 1 H NMR (400 MHz, DMSO-d6) δ 8.74 (d, 1H), 8.53 (d, 1H), 8.37 (d, 1H), 7.97 (d, 2H), 7.23 – 7.15 (m, 3H), 6.79 (d, 1H), 5.37 (s, 2H), 4.76 (s, 1H),4.49 (d, 1H), 4.44 – 4.35 (m, 3H), 4.29 – 4.13 (m, 3H), 3.97 (t, 2H), 3.92 –3.78 (m, 2H), 2.94 – 2.84 (m, 2H), 2.44 – 2.30 (m, 2H), 2.11 – 2.00 (m, 1H), 1.92 – 1.70 (m, 3H).

[0469] Step 5: Synthesis of compounds 5-2-1 and 5-2-2

[0470] Under nitrogen protection, intermediate 5D-2 (208 mg, 0.32 mmol) was dissolved in ultradry DCM (3.5 mL) and methanol (7 mL) solution, and ammonium carbamate (252 mg, 3.5 mmol) was added. Then, diethyl iodophenyl ester (519 mg, 1.62 mmol) was added under ice bath conditions. The system was heated to room temperature and reacted overnight. The mixture was concentrated under reduced pressure and rapidly purified by silica gel column chromatography to obtain crude 5-2. 5-2 was resolved by chiral SFC to give compounds 5-2-1 and 5-2-2.

[0471] Of compounds 5-2-1 and 5-2-2, one has the structure 5-2-A and the other has the structure 5-2-B. That is, when compound 5-2-1 is compound 5-2-A, compound 5-2-2 is compound 5-2-B; and when compound 5-2-1 is compound 5-2-B, compound 5-2-2 is compound 5-2-A.

[0472] Compound 5-2-1: LC-Ms m / z (ESI): 675.2 [M+H] +

[0473] 1 H NMR (400 MHz, DMSO-d6) δ 8.74 (d, 1H), 8.53 (d, 1H), 8.37 (d, 1H), 7.97 (d, 2H), 7.24 – 7.16 (m, 3H), 6.78 (d, 1H), 5.37 (s, 2H), 4.76 (s, 1H), 4.53 – 4.46 (m, 1H), 4.44 – 4.36 (m, 3H), 4.30 – 4.13 (m, 3H), 4.01 – 3.95 (m, 2H), 3.94 – 3.78 (m, 2H), 2.98 – 2.81 (m, 2H), 2.46 – 2.29 (m, 2H), 2.11– 2.00 (m, 1H), 1.94 – 1.70 (m, 3H).

[0474] Compound 5-2-2: LC-Ms m / z (ESI): 675.2 [M+H] +

[0475] 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, 1H), 8.53 (d, 1H), 8.37 (d, 1H), 7.97 (d, 2H), 7.23 – 7.14 (m, 3H), 6.78 (d, 1H), 5.37 (s, 2H), 4.76 (s, 1H), 4.52 – 4.46 (m, 1H), 4.44 – 4.35 (m, 3H), 4.30 – 4.13 (m, 3H), 4.00 – 3.94 (m, 2H), 3.94 – 3.78 (m, 2H), 2.98 – 2.81 (m, 2H), 2.46 – 2.30 (m, 2H), 2.11– 1.99 (m, 1H), 1.93 – 1.70 (m, 3H).

[0476] Example 6: Synthesis of Compound 6

[0477]

[0478] Step 1: Synthesis of compound 6a

[0479] 2a (2.92 g, 10.0 mmol) was dissolved in 30 mL of 1,4-dioxane, and 5-methoxyindole (1.47 g, 10.0 mmol), cesium carbonate (6.51 g, 20.0 mmol), tris(dibenzylindeneacetone)dipalladium (0.92 g, 1.0 mmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (1.16 g, 2.0 mmol) were added sequentially. After the addition was complete, nitrogen was used for protection, and the mixture was heated to 100 °C and stirred for 16 h. The mixture was cooled to room temperature, and the reaction was quenched with 30 mL of water. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to give 6a as a colorless oil (2.4 g, yield: 66.44%).

[0480] LCMS m / z = 361.0 [M+H] +

[0481] Step 2: Synthesis of compound 6b

[0482] 6a (2.4 g, 6.64 mmol) was dissolved in 30 mL of dichloromethane, cooled to 0 °C, and boron tribromide (19.92 mL, 19.92 mmol) was added dropwise, and the reaction was continued for 2 h. The reaction was quenched with water, extracted with 50 mL of dichloromethane, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to give 6b as a colorless oil (1.0 g, yield: 43.22%).

[0483] 1 H NMR (400 MHz, CD3OD) δ 7.91 (d, 1H), 7.80 (d, 1H), 7.40 – 7.34 (m,2H), 6.99 (d, 1H), 6.78 (dd, 1H), 6.54 (d, 1H), 4.51 (t, 2H), 3.95 (t, 2H).

[0484] Step 3: Synthesis of compound 6c

[0485] 6b (0.52 g, 1.50 mmol) was dissolved in 15 mL of dichloromethane, and pyridine (0.35 g, 4.50 mmol) was added. Under nitrogen protection, trifluoromethanesulfonic anhydride (0.85 g, 3.0 mmol) was added dropwise at 0 °C. After the addition was complete, the reaction was carried out at room temperature for 2 h. The mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography to give 6c as a colorless oil (0.52 g, yield: 72.59%).

[0486] 1 H NMR (400 MHz, CD3OD) δ 8.01 (d, 1H), 7.91 (d, 1H), 7.66 – 7.59 (m,3H), 7.22 (dd, 1H), 6.82 (d, 1H), 4.56 (t, 2H), 3.97 (t, 2H).

[0487] Step 4: Synthesis of compound 6d

[0488] 6c (0.46 g, 0.96 mmol) was dissolved in 10 mL of dioxane, and pinacol diboronate (0.37 g, 1.44 mmol), potassium acetate (0.28 g, 2.88 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.078 g, 0.096 mmol) were added. Under nitrogen protection, the mixture was heated to 90 °C for 6 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography to give 6d as a white solid (0.20 g, yield: 45.67%).

[0489] 1 H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.79 (d, 1H), 7.72 (d, 1H), 7.65 (d, 1H), 7.45 (d, 1H), 7.23 (d, 1H), 6.74 (d, 1H), 4.53 (t, 2H), 3.94(t, 2H), 1.38 (s, 12H).

[0490] Step 5: Synthesis of compound 6e

[0491] 6d (46 mg, 0.1 mmol) was dissolved in 2 mL of dioxane and 0.2 mL of water. Intermediate 1 (46 mg, 0.12 mmol), potassium carbonate (41 mg, 0.3 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (8 mg, 0.01 mmol) were added. The mixture was heated to 100 °C for 6 h under nitrogen protection. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography to give 6e as a white solid (51.5 mg, yield: 82.42%).

[0492] 1 H NMR (400 MHz, CDCl3) δ 8.54 (d, 1H), 8.44 (d, 1H), 8.29 (d, 1H), 8.24 (d, 1H), 7.86 (dd, 1H), 7.82 (d, 1H), 7.68 (d, 1H), 7.56 (d, 1H), 7.29(d, 1H), 6.81 (d, 1H), 6.75 (d, 1H), 5.38 (s, 2H), 4.55 (t, 2H), 4.49 – 4.37(m, 4H), 3.95 (t, 2H), 3.26 – 3.20 (m, 2H), 3.16 – 3.10 (m, 2H).

[0493] Step 6: Synthesis of Compound 6

[0494] 6e (51 mg, 0.081 mmol) was dissolved in 10 mL of methanol, and ammonium carbamate (64 mg, 0.82 mmol) and diethyl iodophenyl ester (130 mg, 0.41 mmol) were added at 0 °C. The mixture was stirred overnight at room temperature. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 6 (27 mg, yield: 50%).

[0495] LCMS m / z = 661.1 [M+H] +

[0496] Example 7: Synthesis of Compound 7

[0497]

[0498] Step 1: Synthesis of compound 7b

[0499] Starting material 7a (15 g, 80.39 mmol) was dissolved in 150 mL of acetonitrile, and N-bromosuccinimide (17.17 g, 96.47 mmol) was added in portions. The reaction was carried out at room temperature for 16 h. The reaction solution was slowly poured into ice water, and a large amount of white solid precipitated. After filtration, the solid was concentrated under reduced pressure to obtain compound 7b (20.3 g, 95%).

[0500] 1 H NMR (400 MHz, CDCl3) δ 11.28 (s, 1H), 7.93 – 7.87 (m, 1H), 7.68 (d,1H), 3.98 (s, 3H).

[0501] Step 2: Synthesis of compound 7c

[0502] Starting material 7b (20.3 g, 76.46 mmol) was dissolved in a mixed solvent of 100 mL N,N-dimethylformamide and 15 mL water. 1-Bromo-2-chloroethane (21.93 g, 152.92 mmol) and cesium carbonate (49.82 g, 152.92 mmol) were added, and the reaction was carried out at 65 °C for 16 h. After cooling to room temperature, water (100 mL) was added, and the mixture was extracted twice with ethyl acetate (150 mL × 2). The organic phases were combined and washed twice with water (150 mL × 2) and once with a saturated NaCl aqueous solution (150 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the residue was purified by column chromatography to obtain compound 7c (21 g, 84%).

[0503] 1 H NMR (400 MHz, CDCl3) δ 7.83 (d, 1H), 7.68 (d, 1H), 4.28 (t, 2H), 3.91 (s, 3H), 3.86 (t, 2H).

[0504] Step 3: Synthesis of compound 7d

[0505] The starting material 7c (12 g, 36.59 mmol) was dissolved in a mixed solvent of 80 mL methanol and 15 mL water, and lithium hydroxide (8.76 g, 365.9 mmol) was added. The reaction was carried out at room temperature for 3 h. The solvent was removed by concentration under reduced pressure. The residue was adjusted to pH 2 with 2 N dilute hydrochloric acid and extracted twice with dichloromethane (150 mL × 2). The organic phases were combined and washed once with a saturated aqueous solution of NaCl (150 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound 7d (11.4 g, 99%).

[0506] Step 4: Synthesis of compound 7e

[0507] The starting material 7d (11.4 g, 36.31 mmol) was dissolved in 50 mL of N,N-dimethylformamide, followed by the addition of formyl hydrazine (4.03 g, 54.47 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (20.38 g, 72.62 mmol), and N-methylimidazole (8.94 g, 108.93 mmol). The reaction was carried out at room temperature for 16 h. The mixture was then extracted twice with water (80 mL) and ethyl acetate (100 mL × 2). The organic phases were combined and washed twice with water (100 mL × 2) and once with saturated NaCl aqueous solution (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the residue was purified by column chromatography to give compound 7e (6.4 g, 48%).

[0508] Step 5: Synthesis of compound 7f

[0509] The starting material 7e (6.4 g, 17.30 mmol) was dissolved in 40 mL of dry tetrahydrofuran solution, and Burgess reagent (8.25 g, 34.6 mmol) was added. The reaction was carried out at 80 °C for 16 h. After cooling to room temperature, the residue was concentrated under reduced pressure and purified by column chromatography to give compound 7f (4.8 g, 79%).

[0510] Step 6: Synthesis of 7g of compound

[0511] The starting material 7f (4.8 g, 13.64 mmol) was dissolved in a mixed solvent of 30 mL toluene and 30 mL anhydrous methanol. Triethylamine (1.38 g, 13.64 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (2.23 g, 2.73 mmol) were added sequentially. After three CO substitutions, the reaction was carried out at 75 °C for 16 h. After cooling to room temperature, the solvent was removed by concentration under reduced pressure. The residue was purified by column chromatography to give compound 7 g (2.8 g, 48%).

[0512] Steps 7 to 12: Synthesis of Compound 7

[0513] The synthesis of compound 7g to compound 7 followed the synthetic route of compound 1 (Method 2). The final product 7 was purified by preparative HPLC to obtain a white solid (14 mg). The preparation conditions were as follows: Instrument: CAS-05-PREP-HPLC K; Column: C18; Mobile phase: A was 10 mmol / L NH4HCO3 aqueous solution; B was acetonitrile; Flow rate: 25 mL / min; Column temperature: room temperature; Detection wavelength: 210 & 254 nm;

[0514] LCMS m / z = 721.3 [M+H] +

[0515] 1 H NMR (400 MHz, CD3OD) δ 8.57 (d, 1H), 8.41 (d, 1H), 8.32 (d, 1H), 7.91 (d, 2H), 7.75 (d, 1H), 7.53 (d, 1H), 7.39 (d, 2H), 6.84 (d, 1H), 5.40(s, 2H), 4.67 – 4.60 (m, 2H), 4.31 (t, 2H), 4.29 – 4.20 (m, 2H) 4.02 – 3.91 (m,2H), 3.89 (t, 2H), 2.60 (s, 3H), 2.57 – 2.41 (m, 2H), 1.76 (s, 6H).

[0516] Example 8: Synthesis of Compound 8

[0517]

[0518] Step 1: Synthesis of 8b

[0519] Intermediate A3 (0.2 g, 0.58 mmol) was dissolved in 10 mL of acetonitrile, and 8a (0.12 g, 0.87 mmol) and cesium carbonate (0.57 g, 1.74 mmol) were added. The reaction mixture was reacted at room temperature for 16 h. The reaction solution was directly concentrated under reduced pressure and subjected to silica gel column chromatography to obtain a white solid 8b (0.16 g, 68%).

[0520] LCMS m / z = 408.1 [M+H] +

[0521] Step 2: 8c synthesis

[0522] Starting material 8b (160 mg, 0.39 mmol) was dissolved in 5 mL of dioxane and 1 mL of water. Intermediate C (200 mg, 0.43 mmol), potassium carbonate (160 mg, 1.17 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (32 mg, 0.039 mmol) were added. After three nitrogen purgings, the mixture was reacted at 100 °C for 16 h. The reaction solution was directly concentrated under reduced pressure and subjected to silica gel column chromatography to obtain a white solid 8c (180 mg, 69%).

[0523] LCMS m / z = 661.2 [M+H] +

[0524] Step 3: Synthesis of Compound 8

[0525] The starting material 8c (180 mg, 0.27 mmol) was dissolved in a mixed solvent of 10 mL methanol and 2 mL dichloromethane. Ammonium carbamate (210 mg, 2.7 mmol) and diethyl iodophenyl ester (430 mg, 1.35 mmol) were added at 0 °C, and the reaction was carried out overnight at room temperature. The reaction solution was concentrated under reduced pressure and resolved by chiral HPLC to obtain compounds 8-1 (69.4 mg, 37%, retention time: 1.277 min) and 8-2 (63.9 mg, 37%, retention time: 1.416 min). The resolution conditions were as follows: Instrument: CAS-05-Prep-SFC-F; Column: IK column; Mobile phase: A was CO2; B was 0.1% NH3•H2O methanol / acetonitrile solution; Flow rate: 110 mL / min; Column temperature: room temperature; Detection wavelength: 220 nm.

[0526] Of compounds 8-1 and 8-2, one has the structure of compound 8-A and the other has the structure of compound 8-B.

[0527] Compound 8-1:

[0528] 1H NMR (400 MHz, CDCl3) δ 8.45 (dd, 2H), 8.32 (d, 1H), 7.86 (d, 2H), 7.46 (d, 1H), 7.37 (d, 1H), 7.29 (d, 2H), 6.82 (d, 1H), 5.39 (s, 2H), 4.69 –4.50 (m, 4H), 4.49 – 4.39 (m, 3H), 3.87 (t, 2H), 3.25 – 3.10 (m, 2H), 1.70(s, 6H), 1.28 – 1.16 (m, 1H), 0.86 – 0.75 (m, 2H), 0.50 – 0.38 (m, 2H).

[0529] Compound 8-2:

[0530] 1 H NMR (400 MHz, CDCl3) δ 8.45 (dd, 2H), 8.33 (d, 1H), 7.86 (d, 2H), 7.46 (d, 1H), 7.37 (d, 1H), 7.29 (d, 2H), 6.80 (d, 1H), 5.38 (s, 2H), 4.63 –4.46 (m, 4H), 4.45 – 4.35 (m, 3H), 3.16 – 3.04 (m, 2H), 3.25 – 3.10 (m, 2H), 1.70 (s, 6H), 1.25 – 1.15 (m, 1H), 0.82 – 0.75 (m, 2H), 0.47 – 0.36 (m, 2H).

[0531] LCMS m / z = 692.2 [M+H] +

[0532] Example 9: Synthesis of Compound 9

[0533]

[0534] Step 1: Synthesis of compound 9b

[0535] Starting material 9a (3 g, 8 mmol) was dissolved in 20 mL of DMF, and cuprous iodide (0.3 g, 1.6 mmol), triethylamine (1.62 g, 16 mmol), and palladium dichloride bis(triphenylphosphine) (0.56 g, 0.8 mmol) were added. After purging with nitrogen three times, the reaction was carried out at 80 °C for 2 hours. The reaction solution was directly concentrated under reduced pressure and subjected to silica gel column chromatography to obtain a colorless oily substance 9b (3 g, 87%).

[0536] 1 H NMR (400 MHz, CD3OD) δ 8.00 (d, 1H), 7.94 (d, 1H), 4.50 (t, 2H), 3.90 (s, 3H), 3.86 (t, 2H), 1.21 – 1.12 (m, 21H).

[0537] Step 2: Synthesis of 9c

[0538] The starting material 9b (3 g, 7 mmol) was dissolved in 40 mL of tetrahydrofuran, and methyl magnesium bromide (7 mL, 21 mmol) was added dropwise under ice-water bath conditions. The reaction was continued for 2 hours. The reaction was quenched by adding an appropriate amount of saturated ammonium chloride aqueous solution, and the product was extracted twice with ethyl acetate. The organic phase was concentrated under reduced pressure and subjected to silica gel column chromatography to obtain a colorless oily substance 9c (2.3 g, 77%).

[0539] 1 H NMR (400 MHz, CD3OD) δ 7.53 (d, 1H), 7.49 (d, 1H), 4.36 (t, 2H), 3.84 (t, 2H), 1.49 (s, 6H), 1.21 – 1.14 (m, 21H).

[0540] Step 3: Synthesis of 9D

[0541] The starting material 9c (2.3 g, 5.36 mmol) was dissolved in 40 mL of dichloromethane, and phenol (1.0 g, 10.72 mmol) was added. Boron trifluoride diethyl ether (0.76 g, 5.36 mmol) was added dropwise under ice-water bath conditions, and the reaction was continued for 2 hours. The reaction was quenched with an appropriate amount of saturated sodium bicarbonate aqueous solution. The mixture was extracted twice with dichloromethane, and the organic phase was concentrated under reduced pressure and subjected to silica gel column chromatography to obtain a colorless oily substance 9d (2.2 g, 81%).

[0542] Step 4: Synthesis of 9e

[0543] Starting material 9d (2.2 g, 4.35 mmol) and pyridine (1.72 g, 21.8 mmol) were dissolved in 30 mL of dichloromethane. Trifluoromethanesulfonic anhydride (2.45 g, 8.7 mmol) was added dropwise under ice-water bath conditions, and the reaction was continued at room temperature for 2 hours. The reaction solution was directly concentrated under reduced pressure and subjected to silica gel column chromatography to obtain a colorless oil 9e (2.3 g, 82%).

[0544] 1 H NMR (400 MHz, CD3OD) δ 7.44 – 7.37 (m, 2H), 7.31 – 7.25 (m, 3H), 7.15 (d, 1H), 4.35 (t, 2H), 3.83 (t, 2H), 1.68 (s, 6H), 1.17 – 1.08 (m, 21H).

[0545] Step 5: Synthesis of 9f

[0546] The starting material 9e (2 g, 3.14 mmol) was dissolved in 20 mL of dioxane, and pinacol diboronate (1.2 g, 4.71 mmol), potassium acetate (0.92 g, 9.42 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.26 g, 0.31 mmol) were added. After purging with nitrogen three times, the reaction was carried out at 90 °C for 16 hours. The reaction solution was directly concentrated under reduced pressure and subjected to silica gel column chromatography to obtain a white solid 9f (1.3 g, 67%).

[0547] Step 6: Synthesis of 9g

[0548] The starting material 9f (300 mg, 0.49 mmol) was dissolved in 10 mL of dioxane and 1 mL of water. Intermediate A (170 mg, 0.44 mmol), potassium carbonate (200 mg, 1.47 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (40 mg, 0.05 mmol) were added. After purging with nitrogen three times, the reaction was carried out at 100 °C for 16 hours. The reaction solution was directly concentrated under reduced pressure and subjected to silica gel column chromatography to obtain 9 g (170 mg, 44%) of white solid.

[0549] 1H NMR (400 MHz, CDCl3) δ 8.47 (d, 1H), 8.40 (d, 1H), 8.29 (d, 1H), 7.83 (d, 2H), 7.31 (d, 2H), 7.28 – 7.25 (m, 1H), 7.14 (d, 1H), 6.69 (d, 1H), 5.34 (s, 2H), 4.42 – 4.31 (m, 6H), 3.85 – 3.77 (m, 2H), 3.25 – 3.09 (m, 4H), 1.68 (s, 6H), 1.17 – 1.09 (m, 21H).

[0550] Step 7: Synthesis over 9 hours

[0551] 9 g (170 mg, 0.22 mmol) of the starting material was dissolved in a mixed solvent of 10 mL methanol and 2 mL dichloromethane. Ammonium carbamate (170 mg, 2.2 mmol) and diethyl iodophenyl ester (350 mg, 1.1 mmol) were added at 0 °C, and the mixture was stirred overnight at room temperature. The reaction solution was directly concentrated under reduced pressure and subjected to silica gel column chromatography to give a white solid 9f (120 mg, 68%).

[0552] Step 8: Synthesis of Compound 9

[0553] The starting material (120 mg, 0.15 mmol) was dissolved in 3 mL of DMF, and cesium fluoride (110 mg, 0.75 mmol) was added. The reaction was carried out at room temperature for 2 h. Ethyl acetate was added, and the mixture was washed three times with water. The organic phase was concentrated under reduced pressure and separated by chiral HPLC to obtain compound 9-1 (16.4 mg, 16%, retention time: 1.107 min) and compound 9-2 (18.6 mg, 17%, retention time: 1.786 min). The separation conditions were as follows: Instrument: CAS-05-Prep-SFC-F; Column: AD column; Mobile phase: A was CO2; B was 0.1% NH3•H2O ethanol / acetonitrile solution; Flow rate: 107 mL / min; Column temperature: room temperature; Detection wavelength: 220 nm.

[0554] Of compounds 9-1 and 9-2, one has the structure of compound 9-A and the other has the structure of compound 9-B.

[0555] 9-1: 1H NMR (400 MHz, CDCl3) δ 8.47 (d, 1H), 8.42 (d, 1H), 8.32 (d,1H), 7.84 (d, 2H), 7.31 (d, 2H), 7.26 – 7.20 (m, 2H), 6.81 (d, 1H), 5.39 (s,2H), 4.86 – 4.76 (m, 2H), 4.39 – 4.29 (m, 4H), 4.06 – 3.95 (m, 2H), 3.84 (t,2H), 3.29 (s, 1H), 2.50 (t, 2H), 1.68 (s, 6H).

[0556] 9-2: 1 H NMR (400 MHz, CDCl3) δ 8.50 – 8.28 (m, 3H), 7.84 (d, 2H), 7.35 – 7.28 (m, 2H), 7.26 – 7.22 (m, 2H), 6.78 (d, 1H), 5.37 (s, 2H), 4.83 – 4.71(m, 2H), 4.35 (t, 2H), 4.28 (t, 2H), 4.01 (t, 2H), 3.84 (t, 2H), 3.29 (s,1H), 2.49 (t, 2H), 1.68 (s, 6H).

[0557] LCMS m / z = 663.1 [M+H] + ;

[0558] Example 10: Synthesis of Compound 10

[0559]

[0560] Starting with 10a, product 10 was obtained by following the synthesis method in Example 8. Further purification by preparative HPLC yielded a white solid (24 mg). The HPLC preparation conditions were as follows: Instrument: CAS-05-Semi-prep K; Column: C18 column; Mobile phase: A was 10 mmol / L NH4HCO3 aqueous solution; B was acetonitrile; Flow rate: 25 mL / min; Column temperature: room temperature; Detection wavelength: 210 & 254 nm.

[0561] Example 11: Synthesis of Compound 11

[0562]

[0563] Following the synthesis method of Example 8, product 11 was obtained from 10b as the starting material. Further purification by preparative HPLC yielded a white solid (31 mg). The HPLC preparation conditions were as follows: Instrument: CAS-05-Semi-prep K; Column: C18 column; Mobile phase: A was 10 mmol / L NH4HCO3 aqueous solution; B was acetonitrile; Flow rate: 25 mL / min; Column temperature: room temperature; Detection wavelength: 210 & 254 nm.

[0564] 1 H NMR (400 MHz, CDCl3) δ 8.48 (d, 1H), 8.42 (d, 1H), 8.33 (d, 1H), 7.86 (d, 2H), 7.45 (d, 1H), 7.35 (d, 1H), 7.33 – 7.27 (m, 2H), 6.78 (d, 1H), 5.38 (s, 2H), 4.59 – 4.41 (m, 4H), 4.34 – 4.15 (m, 1H), 4.13 (s, 2H), 3.80 (s, 2H), 2.50 – 2.41 (m, 1H), 1.70 (s, 6H), 1.29 – 1.16 (m, 2H), 1.08 – 0.97(m, 2H), 0.91 – 0.82 (m, 2H), 0.83 – 0.74 (m, 2H).

[0565] LCMS m / z = 718.3 [M+H] +

[0566] Example 12: Synthesis of Compound 12

[0567]

[0568] Step 1: Synthesis of compound 12a

[0569] 2a (2.92 g, 10.0 mmol) was dissolved in 30 mL of 1,4-dioxane and 6 mL of water. 1-Cyclopentenyl borate pinacol ester (2.91 g, 15.0 mmol), potassium carbonate (2.76 g, 20.0 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (0.73 g, 1.0 mmol) were added. After three nitrogen purgings, the mixture was reacted at 100 °C for 16 h. The mixture was extracted twice with 30 mL of ethyl acetate. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography to obtain a colorless oil, 12a (2.0 g, 71%).

[0570] Step 2: Synthesis of compound 12b

[0571] Starting material 12a (0.56 g, 2.0 mmol) and phenol (0.56 g, 6.0 mmol) were dissolved in 20 mL of dichloromethane. Aluminum trichloride (0.91 g, 6.0 mmol) was added at 0 °C, and the reaction was continued at room temperature for 2 h. The reaction was quenched with water, and the product was extracted twice with dichloromethane. The organic phase was concentrated under reduced pressure and subjected to silica gel column chromatography to obtain a colorless oily substance 12b (0.54 g, 72%).

[0572] Step 3: Synthesis of compound 12c

[0573] Starting material 12b (0.52 g, 1.38 mmol) and pyridine (0.35 g, 4.50 mmol) were dissolved in 15 mL of dichloromethane. Trifluoromethanesulfonic anhydride (0.85 g, 3.0 mmol) was added dropwise at 0 °C, and the reaction was continued at room temperature for 2 hours. The reaction solution was directly concentrated under reduced pressure and subjected to silica gel column chromatography to obtain a colorless oil 12c (0.52 g, 74%).

[0574] Step 4: Synthesis of compound 12d

[0575] The starting material 12c (0.46 g, 0.91 mmol) was dissolved in 10 mL of dioxane, and pinacol diboronate (0.37 g, 1.44 mmol), potassium acetate (0.28 g, 2.88 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.078 g, 0.096 mmol) were added. After three nitrogen purgings, the mixture was reacted at 90 °C for 6 h. The reaction solution was directly concentrated under reduced pressure and subjected to silica gel column chromatography to obtain a white solid 12d (0.25 g, 57%).

[0576] Step 5: Synthesis of compound 12e

[0577] Starting material 12d (49 mg, 0.1 mmol) was dissolved in 2 mL of dioxane and 0.2 mL of water. Intermediate A (46 mg, 0.12 mmol), potassium carbonate (41 mg, 0.3 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (8 mg, 0.01 mmol) were added. After three nitrogen purgings, the mixture was reacted at 100 °C for 6 h. The reaction solution was directly concentrated under reduced pressure and subjected to silica gel column chromatography to obtain a white solid 12e (51 mg, 74%).

[0578] Step 6: Synthesis of Compound 12

[0579] The starting material 12e (51 mg, 0.077 mmol) was dissolved in 10 mL of methanol, and ammonium carbamate (64 mg, 0.82 mmol) and diethyl iodophenyl ester (130 mg, 0.41 mmol) were added at 0 °C. The mixture was stirred overnight at room temperature. The reaction solution was directly concentrated under reduced pressure and subjected to silica gel column chromatography to give a white solid 12 (10 mg, 18%).

[0580] LCMS m / z = 690.2 [M+H] +

[0581] 1 H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.52 (s, 1H), 8.37 (d, 1H), 7.93 (d, 2H), 7.83 (d, 1H), 7.79 (d, 1H), 7.51 (d, 2H), 6.78 (d, 1H), 5.36(s, 2H), 4.76 (s, 1H), 4.49 (d, 1H), 4.42 – 4.34 (m, 3H), 4.22 (d, 1H), 4.16(d, 1H), 3.93 (t, 2H), 3.90 – 3.78 (m, 2H), 2.44 – 2.29 (m, 6H), 1.66 – 1.58 (m, 4H).

[0582] Example 13: Synthesis of Compound 13

[0583]

[0584] Step 1: Synthesis of compound 13b

[0585] 13a (1.73 g, 10.0 mmol) was dissolved in 30 mL of toluene, and (2-(methimazole)pyrimidin-4-yl)methanol (1.56 g, 10.0 mmol) and cyanomethylenetri-n-butylphosphine (7.23 g, 30.0 mmol) were added successively. The mixture was purged with nitrogen three times, heated to 100 °C, and stirred for 16 h. The reaction was quenched with 30 mL of water, and the mixture was extracted three times with ethyl acetate. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography to obtain a colorless oily substance 13b (1.5 g, 44%).

[0586] LCMS m / z = 312.0 [M+H] +

[0587] Step 2: Synthesis of compound 13c

[0588] Starting material 13b (1.50 g, 4.80 mmol) was dissolved in 20 mL of tetrahydrofuran and 5 mL of water, and potassium peroxide monosulfonate (6.64 g, 19.2 mmol) was added. The reaction was carried out at room temperature for 6 h. After the reaction was monitored by TLC, the reaction was quenched with water, and the product was extracted twice with ethyl acetate. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography to obtain a colorless oil 13c (1.2 g, 73%).

[0589] LCMS m / z = 344.0 [M+H] +

[0590] Step 3: Synthesis of compound 13d

[0591] The starting material 13c (1.2 g, 3.51 mmol) was dissolved in 25 mL of acetonitrile, and cesium carbonate (2.28 g, 7.02 mmol) and 3-methylthio-azabutane hydrochloride (0.44 g, 3.51 mmol) were added. The reaction mixture was reacted at 80 °C for 12 h. The reaction solution was directly concentrated under reduced pressure and subjected to silica gel column chromatography to obtain a colorless oily substance 13d (1.0 g, 78%).

[0592] LCMS m / z = 367.0 [M+H] +

[0593] Step 4: Synthesis of compound 13e

[0594] The starting material 2e (47 mg, 0.1 mmol) was dissolved in 2 mL of dioxane and 0.2 mL of water. Intermediate 13d (37 mg, 0.10 mmol), potassium carbonate (41 mg, 0.3 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (8 mg, 0.01 mmol) were added. The mixture was purged with nitrogen three times and reacted at 100 °C for 6 h. The reaction solution was directly concentrated under reduced pressure and subjected to silica gel column chromatography to obtain a white solid 13e (45 mg, 71%).

[0595] Step 5: Synthesis of Compound 13

[0596] Starting material 12e (45 mg, 0.071 mmol) was dissolved in 10 mL of methanol, and ammonium carbamate (64 mg, 0.82 mmol) and diethyl iodophenyl ester (130 mg, 0.41 mmol) were added at 0 °C. The mixture was stirred overnight at room temperature. The reaction was directly concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 13. Chiral SFC separation yielded products 13-1 (5 mg, 11%, retention time: 1.032 min) and 13-2 (5 mg, 11%, retention time: 1.602 min), respectively. The SFC preparation conditions were as follows: Instrument: CAS-05-Prep-SFC-F; Column: AD column; Mobile phase: A was CO2; B was a mixed solvent of isopropanol / acetonitrile containing 0.1% NH3H2O; Flow rate: 25 mL / min; Column temperature: room temperature; Detection wavelength: 210 & 254 nm.

[0597] Of compounds 13-1 and 13-2, one has the structure of compound 13-A and the other has the structure of compound 13-B.

[0598] 13-1: LCMS m / z = 663.2 [M+H] +

[0599] 1 H NMR (400 MHz, CD3OD) δ 8.38 – 8.34 (m, 2H), 7.84 (d, 2H), 7.76 (d,1H), 7.68 (d, 1H), 7.64 (d, 1H), 7.50 (dd, 1H), 7.44 (d, 2H), 6.92 (d, 1H),5.15 (s, 2H), 4.47 – 4.34 (m, 7H), 3.87 (t, 2H), 3.02 (s, 3H), 2.86 – 2.70(m, 4H), 2.05 – 1.96 (m, 2H)..

[0600] 13-2: LCMS m / z = 663.2 [M+H] +

[0601] 1H NMR (400 MHz, CD3OD) δ 8.38 – 8.34 (m, 2H), 7.84 (d, 2H), 7.76 (d,1H), 7.68 (d, 1H), 7.64 (d, 1H), 7.50 (dd, 1H), 7.44 (d, 2H), 6.92 (d, 1H), 5.15 (s, 2H), 4.47 – 4.34 (m, 7H), 3.87 (t, 2H), 3.02 (s, 3H), 2.86 – 2.70 (m, 4H), 2.05 – 1.96 (m, 2H).

[0602] Example 14: Synthesis of Compound 14

[0603]

[0604] Compound 14 (13 mg) was prepared using the same method as compound 13. The HPLC preparation conditions were as follows: Instrument: CAS-05-Semi-prep K; Column: C18 column; Mobile phase: A was 10 mmol / L NH4HCO3 aqueous solution; B was acetonitrile; Flow rate: 25 mL / min; Column temperature: room temperature; Detection wavelength: 210 & 254 nm.

[0605] LCMS m / z = 690.8 [M+H] +

[0606] 1 H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.38 (d, 1H), 7.93 (d, 2H), 7.74 (d, 1H), 7.48 (d, 1H), 7.44 (d, 1H), 7.34 (d, 1H), 7.31 (d, 2H), 6.85(d, 1H), 5.11 (s, 2H), 4.54 – 4.44 (m, 4H), 4.24 – 4.15 (m, 1H), 4.13 (s, 2H), 3.80 (s, 2H), 3.03 (s, 3H), 1.69 (s, 6H), 0.89 – 0.76 (m, 4H).

[0607] Example 15: Preparation of Compound 15

[0608]

[0609] Following the synthetic route of compound 1, compound 15f (617 mg) was obtained. Chiral HPLC resolution yielded compounds 15f-1 (212.4 mg, retention time: 2.029 min) and 15f-2 (178 mg, retention time: 2.283 min). Resolution conditions were as follows: Instrument: Waters 150 SFC; Preparative column: Chiral Column (250×30 mm, ID 30 mm, 10 μm particle size); Mobile phase: A was CO2; B was isopropanol and acetonitrile solution containing 0.1% ammonia; Elution conditions: 35% isocratic elution with B; Flow rate: 200 mL / min; Column pressure: 100 bar; Column temperature: 25 ℃; Detection wavelength: 220 nm.

[0610] Of compounds 15f-1 and 15f-2, one has the structure of compound 15f-A and the other has the structure of compound 15f-B.

[0611] LC-Ms m / z (ESI): 715.2 [M+H] +

[0612] Synthesis of compound 15A:

[0613]

[0614] Under nitrogen protection, intermediate 15f-1 (224 mg, 0.31 mmol) was dissolved in ultradry DCM (3.5 mL) and methanol (7 mL) solution, and ammonium carbamate (244 mg, 3.1 mmol) was added. Diethyl iodophenyl ester (503 mg, 1.56 mmol) was added under ice bath conditions, and the mixture was allowed to react overnight at room temperature. The solution was concentrated under reduced pressure and rapidly purified by silica gel column chromatography to obtain 15g-A (208 mg, 90%).

[0615] Under nitrogen protection, intermediate 15g-A (208 mg, 0.29 mmol) was dissolved in THF (2 mL), and a tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 6 mL, 6 mmol) was added in an ice bath. The system was then heated to room temperature and reacted overnight. The reaction solution was concentrated under reduced pressure, and rapid silica gel column chromatography was used to obtain crude 15A. Chiral HPLC resolution yielded compounds 15A-1 (9.2 mg, retention time: 1.684 min) and 15A-2 (9.8 mg, retention time: 2.004 min). The separation conditions were as follows: Instrument: Waters 150 SFC; Preparative column: Chiral Column (250×30mm, ID 30mm, 10µm particle size); Mobile phase: A was CO2; B was isopropanol and acetonitrile solution containing 0.1% ammonia; Elution conditions: 35% B isocratic elution; Flow rate: 200 mL / min; Column pressure: 100 bar; Column temperature: 25 ℃; Detection wavelength: 220 nm.

[0616] Of compounds 15A-1 and 15A-2, one has the structure of compound 15A-A and the other has the structure of compound 15A-B.

[0617] 15A-1: LC-Ms m / z (ESI): 674.1 [M+H] +

[0618] 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (d, 1H), 8.50 (d, 1H), 8.36 (d, 1H), 8.03 (d, 1H), 7.96 (dd, 1H), 7.77 (d, 1H), 7.62 (d, 1H), 7.51 (d, 1H), 6.96(d, 1H), 6.76 (t, 2H), 5.36 (s, 2H), 4.75 (s, 1H), 4.49 (d, 1H), 4.43 – 4.35(m, 3H), 4.22 (d, 1H), 4.16 (d, 1H), 3.97 – 3.78 (m, 4H), 2.46 – 2.30 (m, 3H), 1.73 (s, 3H).

[0619] 15A-2: LC-Ms m / z (ESI): 674.1 [M+H] +

[0620] 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, 1H), 8.50 (d, 1H), 8.36 (d, 1H), 8.03 (d, 1H), 7.96 (dd, 1H), 7.77 (d, 1H), 7.62 (d, 1H), 7.51 (d, 1H), 6.96(d, 1H), 6.76 (t, 2H), 5.36 (s, 2H), 4.75 (s, 1H), 4.49 (d, 1H), 4.43 – 4.35(m, 3H), 4.22 (d, 1H), 4.16 (d, 1H), 3.97 – 3.78 (m, 4H), 2.46 – 2.30 (m, 3H), 1.73 (s, 3H).

[0621] Synthesis of compound 15B:

[0622]

[0623] 15B was synthesized using the same method as 15A, and further purified by HPLC to obtain a white solid (12 mg). The HPLC preparation conditions were as follows: Instrument: CAS-05-Semi-prep K; Column: C18 column; Mobile phase: A was 10 mmol / L NH4HCO3 aqueous solution; B was acetonitrile; Flow rate: 25 mL / min; Column temperature: room temperature; Detection wavelength: 210 & 254 nm.

[0624] 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (d, 1H), 8.50 (d, 1H), 8.36 (d, 1H), 8.06 – 8.01 (m, 1H), 7.98 – 7.93 (m, 1H), 7.86 – 7.77 (m, 1H), 7.70 – 7.60(m, 1H), 7.53 – 7.48 (m, 1H), 6.99 – 6.93 (m, 1H), 6.79 – 6.74 (m, 2H), 5.36(s, 2H), 4.75 (s, 1H), 4.51 – 4.46 (d, 1H), 4.43 – 4.35 (m, 3H), 4.22 (d,1H), 4.16 (d, 1H), 3.97 – 3.78 (m, 4H), 2.46 – 2.30 (m, 3H), 1.76 – 1.70 (m,3H).

[0625] LC-Ms m / z (ESI): 674.2 [M+H] +

[0626] Example 16: Preparation of Compound 16

[0627]

[0628] Steps 1 to 4: Synthesis of compound 16e

[0629] Substrate 16d (5.8 g, 48.6 mmol, synthesis of 16d reference WO2020227549) and intermediate C (7 g, 24.3 mmol) were dissolved in 100 mL of dichloromethane. BF3·Et2O (1.72 g, 12.2 mmol) was added dropwise to the solution under ice-water bath conditions, and the reaction was continued overnight at room temperature. The reaction was quenched by adding an appropriate amount of saturated sodium bicarbonate solution. The mixture was extracted twice with dichloromethane, and the resulting organic phase was concentrated and purified by silica gel column chromatography to give product 16e (2.0 g, 22%).

[0630] 1 H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 7.61 (d, 1H), 7.57 (d, 1H), 6.81 (d, 1H), 6.51 (d, 1H), 4.50 – 4.39 (m, 2H), 3.99 – 3.91 (m, 2H), 2.96 –2.86 (m, 2H), 2.85 – 2.74 (m, 2H), 1.58 (s, 6H).

[0631] Step 5: Synthesis of compound 16f

[0632] Substrate 16e (2.0 g, 5.3 mmol) and pyridine (838 mg, 10.6 mmol) were dissolved in 30 mL of dichloromethane. Trifluoromethanesulfonic anhydride (2.24 g, 8 mmol) was added dropwise under ice-water bath conditions, and the reaction was continued at room temperature for 2 hours. The reaction was quenched with an appropriate amount of water. The reaction mixture was diluted with dichloromethane and washed three times with dilute hydrochloric acid. The resulting organic phase was then concentrated and subjected to silica gel column chromatography to obtain product 16f (2.2 g, 82%).

[0633] Step 6: Synthesis of 16g ​​of compound

[0634] Substrate 16f (1.8 g, 3.54 mmol), pinacol diboronate (1.08 g, 4.25 mmol), Pd(dppf)Cl2 (264 mg, 0.36 mmol), potassium acetate (694 mg, 7.1 mmol), and 20 mL of 1,4-dioxane were added to a reaction flask. After purging with nitrogen three times, the reaction mixture was reacted overnight at 100 °C. The reaction solution was directly concentrated and subjected to silica gel column chromatography to obtain 16 g (1.05 g, 62%) of product.

[0635] Step 7: Synthesis of Compound 16h

[0636] 16 g (243 mg, 0.5 mmol) of substrate, intermediate A (214 mg, 0.5 mmol), Pd(dppf)Cl2 (37 mg, 0.05 mmol), potassium carbonate (138 mg, 1 mmol), 5 mL of 1,4-dioxane, and 1 mL of water were added to a reaction flask. After purging with nitrogen three times, the reaction mixture was reacted overnight at 100 °C. The reaction solution was directly concentrated and subjected to silica gel column chromatography to obtain product 16 h (150 mg, 46%).

[0637] LCMS m / z = 659.3 [M+H] +

[0638] Step 8: Synthesis of Compound 16

[0639] Substrate 16h (130 mg, 0.2 mmol), ammonium carbamate (31 mg, 0.4 mmol), 3 mL methanol, and 1 mL dichloromethane were added to a reaction flask. Iodophenylacetic acid (258 mg, 0.8 mmol) was added under ice-water bath, and the reaction was carried out overnight at room temperature. The reaction solution was directly concentrated and purified by silica gel column chromatography to obtain product 16 (112 mg, 81%). Product 16 was resolved by chiral SFC to obtain products 16-1 (19.9 mg, 15%, retention time: 1.294 min) and 16-2 (20.8 mg, 15%, retention time: 1.985 min). The separation conditions were as follows: Instrument: CAS-05-Prep-SFC-F; Column: AD column; Mobile phase: A is CO2; B is an ethanol solution containing 0.1% NH3•H2O; Flow rate: 110 mL / min; Column temperature: room temperature; Detection wavelength: 220 nm.

[0640] Of compounds 16-1 and 16-2, one has the structure of compound 16-A and the other has the structure of compound 16-B.

[0641] 16-1: LCMS m / z = 690.3 [M+H]+

[0642] 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (d, 1H), 8.49 (d, 1H), 8.37 (d, 1H), 7.83 (d, 1H), 7.69 (d, 1H), 7.66 (d, 1H), 7.14 (d, 1H), 6.78 (d, 1H), 5.36(s, 2H), 4.76 (s, 1H), 4.49 (d, 1H), 4.46 – 4.41 (m, 2H), 4.38 (d, 1H), 4.22(d, 1H), 4.16 (d, 1H), 4.00 – 3.94 (m, 2H), 3.92 – 3.79 (m, 2H), 3.35 – 3.32(m, 2H), 3.02 – 2.97 (m, 2H), 2.45 – 2.31 (m, 2H), 1.67 (s, 6H).

[0643] 16-2: LCMS m / z = 690.3 [M+H] +

[0644] 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (d, 1H), 8.49 (d, 1H), 8.37 (d, 1H), 7.83 (d, 1H), 7.69 (d, 1H), 7.66 (d, 1H), 7.14 (d, 1H), 6.78 (d, 1H), 5.36(s, 2H), 4.76 (s, 1H), 4.49 (d, 1H), 4.46 – 4.41 (m, 2H), 4.38 (d, 1H), 4.22(d, 1H), 4.16 (d, 1H), 4.00 – 3.94 (m, 2H), 3.93 – 3.79 (m, 2H), 3.35 – 3.32(m, 2H), 3.02 – 2.97 (m, 2H), 2.45 – 2.31 (m, 2H), 1.67 (s, 6H).

[0645] Example 17: Preparation of Compound 17

[0646]

[0647] Step 1: Synthesis of compound 17c

[0648] Substrate 17a (1.64 g, 11 mmol), 17b (1.73 g, 10 mmol), cesium carbonate (6.52 g, 20 mmol), and 20 mL of DMF were added sequentially to a reaction flask, and the reaction was carried out overnight at 80 °C. Ethyl acetate was added to the reaction mixture, and the mixture was washed three times with water. The resulting organic phase was concentrated and subjected to silica gel column chromatography to obtain product 17c (2.4 g, 84%).

[0649] Step 2: Synthesis of compound 17e

[0650] Substrate 17c (858 mg, 3 mmol), 17d (456 mg, 3 mmol), potassium carbonate (828 mg, 6 mmol), and 10 mL of acetonitrile were added sequentially to the reaction flask, and the reaction was carried out overnight at 80 °C. An appropriate amount of ethyl acetate was added to the reaction solution, and the mixture was washed three times with water. The resulting organic phase was concentrated and subjected to silica gel column chromatography to obtain product 17e (620 mg, 57%).

[0651] Step 3: Synthesis of compound 17f

[0652] Substrate 17e (390 mg, 1.07 mmol) was dissolved in 2 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 2 h, and the crude product 17f was obtained by direct concentration.

[0653] Step 4: Synthesis of 17g of compound

[0654] The crude product 17f obtained in the previous step, 2,5-dibromopyrazine (238 mg, 1.1 mmol), Pd2(dba)3 (23 mg, 0.025 mmol), XPhos (48 mg, 0.1 mmol), potassium carbonate (414 mg, 3 mmol), and 5 mL of DMF were added to a reaction flask. After purging with nitrogen three times, the reaction was carried out overnight at 70 °C. The reaction solution was diluted with ethyl acetate and filtered. The filtrate was washed three times with water, and the organic phase was concentrated and subjected to silica gel column chromatography to obtain 17 g of product (320 mg, two-step yield 71%).

[0655] Step 5: Synthesis of compound 17h

[0656] 17 g (129 mg, 0.3 mmol) of substrate, intermediate B (138 mg, 0.3 mmol), Pd(dppf)Cl2 (22 mg, 0.03 mmol), potassium carbonate (84 mg, 0.6 mmol), 5 mL of 1,4-dioxane, and 1 mL of water were added to a reaction flask. After purging with nitrogen three times, the reaction mixture was reacted overnight at 100 °C. The reaction solution was directly concentrated and subjected to silica gel column chromatography to obtain product 17 h (142 mg, 70%).

[0657] Step 6: Synthesis of Compound 17

[0658] Substrate 17h (140 mg, 0.2 mmol), ammonium carbamate (31 mg, 0.4 mmol), 3 mL methanol, and 1 mL dichloromethane were added to a reaction flask. Iodophenyl diacetic acid (258 mg, 0.8 mmol) was added under ice-water bath conditions, and the reaction was carried out overnight at room temperature. The reaction solution was directly concentrated and purified by silica gel column chromatography to obtain product 16 (125 mg, 88%). Product 17 was separated by chiral HPLC to obtain products 17-1 (26 mg, retention time: 1.324 min) and 17-2 (30 mg, retention time: 1.677 min). The separation conditions were as follows: Instrument: CAS-05-Prep-SFC-A; Column: AS column; Mobile phase: A was CO2; B was isopropanol / acetonitrile solution containing 0.1% NH3H2O; Flow rate: 130 mL / min; Column temperature: room temperature; Detection wavelength: 220 nm.

[0659] Of compounds 17-1 and 17-2, one has the structure of compound 17-A and the other has the structure of compound 17-B.

[0660] 17-1: LCMS m / z = 705.4 [M+H] +

[0661] 1H NMR (400 MHz, DMSO-d6) δ 8.65 (d, 1H), 8.18 (d, 1H), 8.02 (d, 1H), 7.89 (d, 2H), 7.69 (d, 1H), 7.62 (d, 1H), 7.33 (d, 2H), 6.27 (d, 1H), 5.53 –5.46 (m, 1H), 4.79 (s, 1H), 4.56 – 4.47 (m, 3H), 4.45 – 4.37 (m, 3H), 4.24(d, 1H), 4.18 (d, 1H), 4.10 (dd, 2H), 3.97 – 3.94 (m, 2H), 3.93 – 3.80 (m,2H), 2.46 – 2.31 (m, 2H), 1.69 (s, 6H).

[0662] 17-2: LCMS m / z = 705.4 [M+H] +

[0663] 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (d, 1H), 8.18 (d, 1H), 8.02 (d, 1H), 7.89 (d, 2H), 7.69 (d, 1H), 7.62 (d, 1H), 7.33 (d, 2H), 6.27 (d, 1H), 5.54 –5.46 (m, 1H), 4.79 (s, 1H), 4.56 – 4.47 (m, 3H), 4.45 – 4.37 (m, 3H), 4.24(d, 1H), 4.18 (d, , 1H), 4.10 (dd, 2H), 3.98 – 3.94 (m, 2H), 3.92 – 3.80 (m,2H), 2.46 – 2.31 (m, 2H), 1.69 (s, 6H).

[0664] Example 18: Preparation of Compound 18

[0665]

[0666]

[0667] Step 1: Synthesis of compound 18b

[0668] Substrate 18a (14.8 g, 100 mmol), DIPEA (38.7 g, 300 mmol), and 200 mL of dichloromethane were added to a reaction flask. Bromomethyl ether (25 g, 200 mmol) was then added dropwise under ice-water bath conditions, and the reaction was carried out at room temperature for 2 h. The reaction solution was directly concentrated and subjected to silica gel column chromatography to give product 18b (18.5 g, 96%).

[0669] Step 2: Synthesis of compound 18c

[0670] Substrate 18b (18 g, 93.8 mmol) and 2,6-di-tert-butyl-4-methylpyridine (38.5 g, 187.6 mmol) were dissolved in 500 mL of dichloromethane. Trifluoromethanesulfonic anhydride (29.1 g, 103.2 mmol) was added dropwise under ice-water bath conditions, and the reaction was carried out at room temperature for 4 hours. The reaction solution was directly concentrated and subjected to silica gel column chromatography to give product 18c (6.5 g, 22%).

[0671] Step 3: Synthesis of compound 18e

[0672] Substrate 18c (2.59 g, 8 mmol), 18d (2.7 g, 8 mmol), Pd(dppf)Cl2 (586 mg, 0.8 mmol), potassium carbonate (2.2 g, 16 mmol), 20 mL of 1,4-dioxane, and 2 mL of water were added to a reaction flask. After purging with nitrogen three times, the reaction mixture was reacted overnight at 100 °C. The reaction solution was directly concentrated and subjected to silica gel column chromatography to obtain product 18e (1.5 g, 48%).

[0673] Step 4: Synthesis of compound 18f

[0674] Substrate 18e (1.5 g, 3.85 mmol) was dissolved in 20 mL of trifluoroacetic acid, and triethylsilane (893 mg, 7.7 mmol) was added. The mixture was reacted at room temperature for 2 hours. The reaction solution was directly concentrated and subjected to silica gel column chromatography to obtain product 18f (805 mg, 60%).

[0675] Step 5: Synthesis of 18g of compound

[0676] Substrate 18e (805 mg, 2.31 mmol) and pyridine (360 mg, 4.62 mmol) were dissolved in 12 mL of dichloromethane. Trifluoromethanesulfonic anhydride (977 mg, 3.47 mmol) was added dropwise under ice-water bath conditions, and the reaction was carried out at room temperature for 1 hour. The reaction solution was washed three times with dilute hydrochloric acid, and the organic phase was directly concentrated and subjected to silica gel column chromatography to give 18 g (1.05 g, 95%) of product.

[0677] Steps 6 and 7: Synthesis of compound 18i

[0678] 18 g (1.05 g, 2.19 mmol) of substrate, pinacol diboronate (611 mg, 2.4 mmol), Pd(dppf)Cl2 (161 mg, 0.22 mmol), potassium acetate (429 mg, 4.38 mmol), and 10 mL of dioxane were added to a reaction flask. After purging with nitrogen three times, the mixture was reacted overnight at 100 °C. Intermediate A (832 mg, 2.19 mmol), Pd(dppf)Cl2 (161 mg, 0.22 mmol), potassium carbonate (604 mg, 4.38 mmol), and 2 mL of water were added to the reaction solution. After purging with nitrogen three times, the mixture was reacted overnight at 100 °C. The reaction solution was directly concentrated and subjected to silica gel column chromatography to obtain product 18i (620 mg, 45%). Product 18i was resolved by chiral HPLC to yield compounds 18i-A (165.4 mg, retention time: 0.883 min) and 18i-B (137.1 mg, retention time: 1.090 min). The resolution conditions were as follows: Instrument: CAS-05-Prep-SFC-E; Column: OXcolumn; Mobile phase: A was CO2; B was an ethanol / acetonitrile solution containing 0.1% NH3H2O; Flow rate: 110 mL / min; Column temperature: room temperature; Detection wavelength: 220 nm.

[0679] Of compounds 18i-1 and 18i-2, one has the structure of compound 18i-A and the other has the structure of compound 18i-B.

[0680] Step 8: Synthesis of Compound 18A

[0681] Substrate 18i-1 (126 mg, 0.2 mmol), ammonium carbamate (32 mg, 0.4 mmol), 3 mL methanol, and 1 mL dichloromethane were added to a reaction flask. Iodophenyl diacetic acid (258 mg, 0.8 mmol) was added under ice-water bath conditions, and the reaction was carried out overnight at room temperature. The reaction solution was directly concentrated and purified by silica gel column chromatography to obtain product 18A (125 mg, 88%). Product 18A was resolved by chiral HPLC to obtain products 18A-1 (38.2 mg, retention time: 2.285 min) and 18A-2 (36.2 mg, retention time: 3.203 min). The separation conditions were as follows: Instrument: CAS-05-Prep-SFC-G; Column: IG column; Mobile phase: A is CO2; B is isopropanol / acetonitrile solution containing 0.1% NH3H2O; Flow rate: 105 mL / min; Column temperature: room temperature; Detection wavelength: 220 nm.

[0682] Of compounds 18A-1 and 18A-2, one has the structure of compound 18A-A and the other has the structure of compound 18A-B.

[0683] 18A-1: LCMS m / z = 662.3 [M+H] +

[0684] 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (d, 1H), 8.52 (d, 1H), 8.38 (d, 1H), 7.97 (s, 1H), 7.82 (d, 1H), 7.69 (d, 1H), 7.66 (d, 1H), 7.02 (d, 1H), 6.79(d, 1H), 5.37 (s, 2H), 4.76 (s, 1H), 4.52 – 4.42 (m, 4H), 4.38 (d, 1H), 4.23(d, 1H), 4.17 (d, 1H), 3.99 – 3.94 (m, 2H), 3.93 – 3.78 (m, 2H), 3.16 – 3.07(m, 1H), 3.03 – 2.93 (m, 1H), 2.62 – 2.54 (m, 1H), 2.46 – 2.31 (m, 2H), 2.15– 2.06 (m, 1H).

[0685] 18A-2: LCMS m / z = 662.3 [M+H] +

[0686] 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (d, 1H), 8.52 (d, 1H), 8.38 (d, 1H), 7.97 (s, 1H), 7.82 (d, 1H), 7.69 (d, 1H), 7.66 (d, 1H), 7.02 (d, 1H), 6.79(d, 1H), 5.37 (s, 2H), 4.76 (s, 1H), 4.53 – 4.41 (m, 4H), 4.38 (d, 1H), 4.23(d, 1H), 4.17 (d, 1H), 3.99 – 3.94 (m, 2H), 3.93 – 3.80 (m, 2H), 3.17 – 3.07(m, 1H), 3.03 – 2.93 (m, 1H), 2.61 – 2.53 (m, 1H), 2.44 – 2.31 (m, 2H), 2.15– 2.05 (m, 1H).

[0687] Step 9: Synthesis of Compound 18B

[0688] Substrate 18i-2 (126 mg, 0.2 mmol), ammonium carbamate (32 mg, 0.4 mmol), 3 mL methanol, and 1 mL dichloromethane were added to a reaction flask. Iodophenyl diacetic acid (258 mg, 0.8 mmol) was added under ice-water bath conditions, and the reaction was carried out overnight at room temperature. The reaction solution was directly concentrated and purified by silica gel column chromatography to obtain product 18B (125 mg, 88%). Product 18B was resolved by chiral HPLC to obtain products 18B-1 (23.8 mg, retention time: 1.611 min) and 18B-2 (30.1 mg, retention time: 2.099 min). The separation conditions were as follows: Instrument: CAS-05-Prep-SFC-A; Column: Cellulose-2 column; Mobile phase: A was CO2; B was an ethanol / acetonitrile solution containing 0.1% NH3H2O; Flow rate: 100 mL / min; Column temperature: room temperature; Detection wavelength: 220 nm.

[0689] Of compounds 18B-1 and 18B-2, one has the structure of compound 18B-A and the other has the structure of compound 18B-B.

[0690] 18B-1: LCMS m / z = 662.3 [M+H] +

[0691] 1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, 1H), 8.52 (d, 1H), 8.38 (d, 1H), 7.97 (s, 1H), 7.82 (d, 1H), 7.69 (d, 1H), 7.66 (d, 1H), 7.02 (d, 1H), 6.79(d, 1H), 5.37 (s, 2H), 4.76 (s, 1H), 4.52 – 4.41 (m, 4H), 4.38 (d, 1H), 4.23(d, 1H), 4.17 (d, 1H), 3.98 – 3.95 (m, 2H), 3.93 – 3.79 (m, 2H), 3.18 – 3.13(m, 1H), 3.03 – 2.92 (m, 1H), 2.62 – 2.54 (m, 1H), 2.46 – 2.31 (m, 2H), 2.14– 2.06 (m, 1H).

[0692] 18B-2: LCMS m / z = 662.3 [M+H] +

[0693] 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (d, 1H), 8.52 (d, 1H), 8.38 (d, 1H), 7.97 (s, 1H), 7.82 (d, 1H), 7.69 (d, 1H), 7.66 (d, 1H), 7.02 (d, 1H), 6.79(d, 1H), 5.37 (s, 2H), 4.76 (s, 1H), 4.52 – 4.42 (m, 4H), 4.38 (d, 1H), 4.23(d, 1H), 4.17 (d, 1H), 3.99 – 3.94 (m, 2H), 3.93 – 3.79 (m, 2H), 3.16 – 3.07(m, 1H), 3.03 – 3.01 (m, 1H), 2.61 – 2.54 (m, 1H), 2.45 – 2.31 (m, 2H), 2.15– 2.06 (m, 1H).

[0694] Example 19: Preparation of Compound 19

[0695]

[0696] Step 1: Synthesis of compound 19c

[0697] Substrate 19a (1.18 g, 3 mmol, refer to the synthesis of intermediate A3 9), 19b (530 mg, 3 mmol), cesium carbonate (2.9 g, 9 mmol), and 20 mL of acetonitrile were added to a reaction flask and reacted overnight at room temperature. The reaction solution was directly concentrated and subjected to silica gel column chromatography to give product 19c (900 mg, 67%).

[0698] Step 2: Synthesis of Compound 19

[0699] Substrate 19c (129 mg, 0.3 mmol), 2e (144 mg, 0.3 mmol), Pd(dppf)Cl2 (22 mg, 0.03 mmol), potassium carbonate (84 mg, 0.6 mmol), 5 mL of 1,4-dioxane, and 1 mL of water were added to a reaction flask. After purging with nitrogen three times, the reaction was carried out overnight at 100 °C. The reaction solution was directly concentrated and subjected to silica gel column chromatography to obtain product 19 (120 mg, 60%), which was further purified by preparative HPLC to obtain a white solid (53 mg). The preparation conditions were as follows: Instrument: CAS-05-Semi-prepK; Column: C18; Mobile phase: A was 10 mmol / L NH4HCO3 aqueous solution; B was acetonitrile; Flow rate: 25 mL / min; Column temperature: room temperature; Detection wavelength: 210 & 254 nm;

[0700] LCMS m / z = 666.3 [M+H] +

[0701] 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (d, 1H), 8.52 (d, 1H), 8.36 (d, 1H), 7.95 (d, 2H), 7.88 (d, 1H), 7.84 (d, 1H), 7.54 (d, 2H), 7.16 (s, 2H), 6.76(d, 1H), 5.35 (s, 2H), 4.43 – 4.35 (m, 2H), 4.32 – 4.23 (m, 2H), 4.21 – 4.13(m, 3H), 3.98 – 3.89 (m, 2H), 2.75 (t, 4H), 1.91 – 1.80 (m, 2H).

[0702] Example 20: Preparation of Compound 20

[0703]

[0704] Substrate 19c (129 mg, 0.3 mmol), 1h (150 mg, 0.3 mmol), Pd(dppf)Cl2 (22 mg, 0.03 mmol), potassium carbonate (84 mg, 0.6 mmol), 5 mL of 1,4-dioxane, and 1 mL of water were added to the reaction flask. After purging with nitrogen three times, the reaction was carried out overnight at 100 °C. The reaction solution was directly concentrated and subjected to silica gel column chromatography to obtain product 20 (108 mg, 52%). Further purification by preparative HPLC yielded a white solid (64 mg). The preparation conditions were as follows: Instrument: CAS-05-Semi-prepK; Column: C18; Mobile phase: A was 10 mmol / L NH4HCO3 aqueous solution; B was acetonitrile; Flow rate: 25 mL / min; Column temperature: room temperature; Detection wavelength: 210 & 254 nm;

[0705] LCMS m / z = 694.3 [M+H] +

[0706] 1 H NMR (400 MHz, DMSO-d6) δ 8.75 (d, 1H), 8.53 (d, 1H), 8.36 (d, 1H), 7.96 (d, 2H), 7.69 (d, 1H), 7.62 (d, 1H), 7.37 (d, 2H), 7.16 (s, 2H), 6.76(d, 1H), 5.36 (s, 2H), 4.34 – 4.24 (m, 2H), 4.22 – 4.12 (m, 3H), 4.08 (s,2H), 3.85 (s, 2H), 1.69 (s, 6H), 0.85 – 0.80 (m, 2H), 0.80 – 0.75 (m, 2H).

[0707] Biological Test Example 1

[0708] 1. Inhibition of 22RV1 cell proliferation experiment

[0709] Prostate cancer cells 22RV1 were purchased from ATCC and cultured in RPMI 1640 + 10% FBS at 37°C in a 5% CO2 incubator. On the first day, cells in the exponential growth phase were collected and plated with 1% CSS-FBS phenol red-free medium at a concentration of 2000 cells / well, and incubated overnight. On the second day, different concentrations of the compound were added and incubated for another 7 days. After the culture was completed, 50 µL of pre-melted and equilibrated CellTiter-Glo reagent was added to each well according to the CellTiter-Glo kit (Promega, G7573) instructions. The wells were mixed with a microplate shaker for 2 minutes and then incubated at room temperature for 10 minutes before the fluorescence signal was measured using a microplate reader (PHERAstar FSX). The results were processed according to formula (1), and the inhibition rate of each compound concentration was calculated. The IC50 of a 50% inhibition rate was calculated using the DoseResp function in Origin 9.2 software. 50 Value. Where RLU compound For the drug treatment group, RLU readings control This represents the average value of the DMSO solvent control group.

[0710] Inhibition % = [1-RLU compound / RLU control ]×100% Equation (1)

[0711] The test results are shown in Table 1.

[0712] compound <![CDATA[IC 50 ]]> Compound 1-1 <1μM Compounds 1-2 <1μM Compound 2 <1μM Compound 5-1-1 <1μM Compound 5-1-2 <1μM Compound 12 <1μM Compound 13-1 <1μM Compound 13-2 <1μM

[0713] Conclusion: The compounds of the present invention, such as the compounds in the examples, have an inhibitory effect on prostate cancer cells 22RV1.

Claims

1. A compound or its racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is selected from compounds represented by general formula (I). (I) Ring A is selected from 5-6 member heteroaryl groups, C 6-14 Carbocyclic group, 7-12 membered heterocyclic group, or ring A is absent; B is selected from rings B and C. 2-6 alkynyl group, C 2-6 alkenyl group, wherein the alkenyl group is optionally surrounded by 1 to 4 R groups. k replace; Ring B is selected from 6-14 aryl, 5-12 heteroaryl, benzo4-6 heterocyclic, benzo4-6 carbocyclic, and C. 4-12 Cycloalkyl or 4- to 12-membered heterocycloalkyl, wherein the ring B is optionally surrounded by 1 to 6 R... b replace; Z is selected from phenyl, 6-membered heteroaryl, C 2-6 Alkyne group, wherein the heteroaryl group or phenyl group is optionally surrounded by 1 to 6 R groups. z replace; Ring D is selected from 6-14 aryl and 5-12 heteroaryl groups; L 1 Selected from -O-, -C 1-4 alkylene-, -C 1-4 Alkylene-O- -O-4 to 8-membered heterocyclic groups -OC 1-4 alkylene-4 to 8-membered heterocyclic groups -, -C 1-4 Alkylene-NR L0 -、-OC 1-4 Alkylene-, -OC 1-4 Alkylene-O-, C 2-6 alkenyl, -C 3-12 Carbocyclic -C 1-4 Alkylene -O-, -C 3-12 Carbocyclic groups -O-, -4 to 12-membered heterocyclic groups -C 1-4 Alkylene-O-, -4 to 12-membered heterocyclic-O-, -OC 3-8 Carbocyclic group-, , Its right end is connected to B, and the alkylene, alkenyl, carbocyclic, or heterocyclic groups are optionally surrounded by 1 to 4 R groups. k replace; R L0 R b Together with the atoms attached to it, they form a 4-8 membered heterocyclic group, wherein the heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace; As an option, R L1 R b Together with the atoms attached to it, they form a 4-8 membered heterocyclic group, wherein the heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace; L 2 Selected from -CR 1 R 2 -、-NR L2 -、 C 3-8 Carbocyclic group, 4-8 membered heterocyclic alkyl group, wherein the carbocyclic group or heterocyclic alkyl group is optionally surrounded by 1 to 4 R groups. k Replace it, with its right end connected to ring D; Or L 2 Selected from L 2A ; L 2A Selected from -NR L2 -、 C 3-8 A carbocyclic group or a 4-8 membered heterocyclic alkyl group, wherein the right end is connected to a ring D, and the carbocyclic group or heterocyclic alkyl group is optionally surrounded by 1 to 4 R groups. k replace; R L2 R z Together with the atoms attached to it, they form a 4-8 membered heterocyclic group, wherein the heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace; R 1 R 2 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, wherein the alkyl, alkenyl, or ynyl group is optionally surrounded by 1 to 4 R groups. k replace; As an option, R 1 R 2 Together with the atoms bonded to it, they form C 3-8 Carbocyclic groups, 4-8 membered heterocyclic groups, wherein the C 3-8 The carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; As an option, R l1 R l2 Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; As an option, R 1 R d Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; As an option, R 1 R z Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; As an option, R b R z Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; As an option, two adjacent R z Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; As an option, R L0 R a Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R A Selected from 4- to 12-membered heterocyclic alkyl groups, -4- to 12-membered heterocyclic alkyl groups -S(=O)2R A1 -4 to 12-membered heterocyclic alkyl-S(=O)R A1 -4 to 12-membered heterocyclic alkyl-S(=O)2NR A1 R A2 -4 to 12-membered heterocyclic alkyl groups -N=S(=O)R A1 R A2 -4 to 12-membered heterocyclic alkyl-S(=O) (=NR) A1 )R A2 -4 to 12-membered heterocyclic alkyl-C 1-4 Alkylene-S(=O)2R A1 -4 to 12-membered heterocyclic alkyl-C 1-4 Alkylene-S(=O)R A1 -4 to 12-membered heterocyclic alkyl-C 1-4 Alkylene-S(=O)2NR A1 R A2 -4 to 12-membered heterocyclic alkyl-C 1-4 Alkylene-NR A1 -S(=O)2R A2 -4 to 12-membered heterocyclic alkyl-C 1-4 Alkylene-S(=O) (=NR) A1 )R A2 -4 to 12-membered heterocyclic alkyl-C 1-4 Alkylene-NR A1 -S(=O)R A1 -P(=O)R A1 R A2 -4 to 12-membered heterocyclic alkyl-P(=O)R A1 R A2 -4 to 12-membered heterocyclic alkyl-C 1-4 Alkylene-P(=O)R A1 R A2 -N=S(=O)R A1 R A2 -4 to 12-membered heterocyclic alkyl-C 1-4 Alkylene-N=S(=O)R A1 R A2 , , , , , , , , , , , , , , , , The alkylene, heterocyclic alkyl, , , , , , , , , , , , , , , , Choose from 1 to 6 Rs k replace; Or R A Selected from R Aa ; R Aa Selected from -4 to 12-membered heterocyclic alkyl groups -S(=O)2NHC 1-6 Alkyl group, -S (=O) (=NR) A1 )R A2 -4 to 12-membered heterocyclic alkyl-S(=O) (=NR) A1 -C 1-4 Alkylene-C 3-8 Carbocyclic, -4 to 12-membered heterocyclic alkyl -S(=O)2NR A1 -C 3-8 carbon cyclo group, , , , , , , , The R Aa Choose from 1 to 6 Rs k replace; p1 is independently selected from 0, 1, 2, 3 or 4; As an option, R A1 R A2 Together with the atoms attached to it, they form a 4-8 membered heterocyclic group, wherein the heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace; R D Selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2, -SC 1-6 Alkyl, -S(=O)-C 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl, C 3-8 Carbocyclic groups, 4- to 8-membered heterocyclic groups, -OC 3-6 Carbocyclic group, -NH-C 3-6 Carbocyclic groups, -NH-4 to 8-membered heterocyclic groups, -SC 3-6 Carbocyclic groups, -S-4 to 8-membered heterocyclic groups, -NH-C 2-6 alkenyl, -NH-C 2-6 alkynyl group, -SC 2-6 alkenyl, -SC 2-6 alkynyl group, -C 1-4 Alkylene-C 3-6 Carbocyclic group, -C 1-4 Alkylene-4 to 8-membered heterocyclic groups, -OC 1-4 Alkylene-C 3-6 carbonyl group, -OC 1-4 Alkyl-4 to 8-membered heterocyclic groups, -NH-C 1-4 Alkylene-C 3-6 Carbocyclic group, -NH-C 1-4 Alkyl-4 to 8-membered heterocyclic groups, -SC 1-4 Alkylene-C 3-6 carbonyl group, -SC 1-4 Alkylene-4 to 8-membered heterocyclic group, wherein the alkylene, alkenyl, alkynyl, alkyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; Or R D Selected from R D1 ; R D1 Selected from C 2-6 alkynyl group, -S(=O)-C 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl, -OC 2-6 Alkyne, methoxy, propoxy, wherein the alkynyl, alkyl, methoxy, or propoxy group is optionally surrounded by 1 to 4 R groups. k Replace; or R D1 Selected from -OC 1-4 Alkylene-C 3-6 carbonyl group, -OC 1-4 alkylene-4 to 8-membered heterocyclic groups, wherein the carbocyclic or heterocyclic group is surrounded by 1 to 4 R groups. k The alkylene group is optionally replaced by 1 to 4 R... k replace; R a R b R d R z Each element is independently selected from H, deuterium, =O, =S, halogens, CN, OH, NH2, CO2H, CONH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -SCN, -NHC 1-6 Alkyl, -OC 3-6 Carbocyclic groups, -O-4 to 8-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-4 to 8-membered heterocyclic groups, -C 1-4 Alkylene-C 3-6 Carbocyclic group, -C 1-4 alkylene-4 to 8-membered heterocyclic groups, C 3-6 Carbocyclic, 4- to 8-membered heterocyclic, wherein the alkylene, alkyl, alkenyl, ynyl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; Or R d Each independently selected from R d1 ; R d1 Selected from -SCN, 6-14 aryl, and 5-12 heteroaryl groups; R A1 R A2 R L1 R l1 R l2 Each element is independently selected from H, deuterium, =O, halogens, CN, OH, NH2, CO2H, CONH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbocyclic groups, 4- to 8-membered heterocyclic groups, -C 1-4 Alkylene-C 3-6 Carbocyclic group, -NH-C 3-6 carbonyl group, -OC 3-6 The carbocyclic group, wherein the alkylene group, alkyl group, alkenyl group, alkynyl group, carbocyclic group, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R k Each is independently selected from deuterium, =O, =S, =NH, halogens, CN, OH, COOH, CONH2, NH2, SF5, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-C 3-6 carbonyl group, -OC 3-6 Carbocyclic groups, -O-4 to 8-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-4 to 8-membered heterocyclic groups, -C 1-4 alkylene-4 to 8-membered heterocyclic groups, C 3-6 Carbocyclic groups, 4- to 8-membered heterocyclic groups, The alkyl, alkylene, alkenyl, alkynyl, carbocyclic, or heterocyclic groups are optionally selected from 1 to 4 deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups; a and d are each independently selected from 0, 1, 2, 3 or 4; The condition is that one of the following is met: 1) no , , ; 2) no , , , , , , ; 3) When ring A does not exist, L 1 It is selected from -CH2-O-, and ring D is selected from 6-14 aryl groups, preferably, ring D is selected from phenyl groups; 4) When Selected from L 1 When selected from -CH2-, ring B is not ; 5) The compound is not .

2. The compound according to claim 1, or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein, General formula (I) is selected from compounds represented by general formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), and (Ig), wherein... (It) (Ib) (Ic) (Id) (Ie) (If) (Ig) e is selected from 0, 1, 2, 3.

3. The compound according to claim 1 or 2, or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt, wherein, Ring A is selected from 5-6-membered heteroaryl, benzo4-6-membered heterocyclic, benzo4-6-membered carbocyclic, 5-6-membered heteroaryl-4-6-membered heterocyclic, and 5-6-membered heteroaryl-4-6-membered carbocyclic. Preferably, ring A is selected from pyrimidinyl, pyridazinyl, pyrazinyl, pyridinyl, thiazolyl, pyrroleyl, thiopheneyl, furanyl, pyrazolyl, triazolyl, pyridino-4-6-membered heterocyclic, and pyridino-4-6-membered carbocyclic. B is selected from rings B and C. 2-4 alkynyl group; Ring B is selected from phenyl, 5-6-membered heteroaryl, benzo4-6-membered heterocyclic group, benzo4-6-membered carbocyclic group, C 4-8 Cycloalkyl or 4- to 8-membered heterocycloalkyl, wherein the ring B is optionally surrounded by 1 to 4 R... b replace; Z is selected from phenyl, 6-membered heteroaryl, C 2-4 Alkyne group, wherein the heteroaryl group or phenyl group is optionally surrounded by 1 to 4 R groups. z replace; L 1 Selected from -O-, -C 1-2 alkylene-, -C 1-2 Alkylene-O- -O-4 to 8-membered heterocyclic groups -OC 1-2 alkylene-4 to 8-membered heterocyclic groups -, -C 1-2 Alkylene-NR L0 -、-OC 1-2 Alkylene-, -OC 1-2 Alkylene-O-, C 2-4 alkenyl, -C 3-8 Carbocyclic -C 1-2 Alkylene -O-, -C 3-8 Carbocyclic -O-, -4 to 8-membered heterocyclic -C 1-2 Alkylene-O-, -4 to 8-membered heterocyclic-O-, -OC 3-8 Carbocyclic group-, , Its right end is connected to B, and the alkylene, alkenyl, carbocyclic, or heterocyclic groups are optionally surrounded by 1 to 4 R groups. k replace; R L0 R b Together with the atoms attached to it, they form a 4-8 membered heterocyclic group, wherein the heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace; As an option, R L1 R b Together with the atoms attached to it, they form a 4-8 membered heterocyclic group, wherein the heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace; L 2 Selected from -CR 1 R 2 -、-NR L2 -、 C 3-8 A carbocyclic group or a 4-8 membered heterocyclic alkyl group, wherein the right end is connected to a ring D, and the carbocyclic group or heterocyclic alkyl group is optionally surrounded by 1 to 4 R groups. k replace; R L2 R z Together with the atoms attached to it, they form a 4-8 membered heterocyclic group, wherein the heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace; R 1 R 2 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, wherein the alkyl, alkenyl, or ynyl group is optionally surrounded by 1 to 4 R groups. k replace; As an option, R 1 R 2 Together with the atoms bonded to it, they form C 3-8 Carbocyclic groups, 4-8 membered heterocyclic groups, wherein the C 3-8 The carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; As an option, R l1 R l2 Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; As an option, R 1 R d Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; As an option, R 1 R z Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; As an option, R b R z Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; As an option, two adjacent R z Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; As an option, R L0 R a Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R A Selected from 4- to 10-membered heterocyclic alkyl groups, -4- to 10-membered heterocyclic alkyl groups -S(=O)2R A1 -4 to 10-membered heterocyclic alkyl-S(=O)R A1 -4 to 10-membered heterocyclic alkyl-S(=O)2NR A1 R A2 -4 to 10-membered heterocyclic alkyl groups -N=S(=O)R A1 R A2 -4 to 10-membered heterocyclic alkyl-S(=O) (=NR) A1 )R A2 -4 to 10-membered heterocyclic alkyl-C 1-2 Alkylene-S(=O)2R A1 -4 to 10-membered heterocyclic alkyl-C 1-2 Alkylene-S(=O)R A1 -4 to 10-membered heterocyclic alkyl-C 1-2 Alkylene-S(=O)2NR A1 R A2 -4 to 10-membered heterocyclic alkyl-C 1-2 Alkylene-NR A1 -S(=O)2R A2 -4 to 10-membered heterocyclic alkyl-C 1-2 Alkylene-N=S(=O)R A1 R A2 -4 to 10-membered heterocyclic alkyl-C 1-2 Alkylene-S(=O) (=NR) A1 )R A2 -P(=O)R A1 R A2 -4 to 10-membered heterocyclic alkyl-P(=O)R A1 R A2 -4 to 10-membered heterocyclic alkyl-C 1-2 Alkylene-P(=O)R A1 R A2 -N=S(=O)R A1 R A2 , , , , , , , , , , , , , , , , The alkylene, heterocyclic alkyl, , , , , , , , , , , , , , , , Choose from 1 to 4 Rs k replace; R Aa Selected from -4 to 10-membered heterocyclic alkyl groups -S(=O)2NHC 1-4 Alkyl group, -S (=O) (=NR) A1 )R A2 -4 to 10-membered heterocyclic alkyl-S(=O) (=NR) A1 -C 1-2 Alkylene-C 3-6 Carbocyclic, -4 to 10-membered heterocyclic alkyl group -S(=O)2NR A1 -C 3-6 carbon cyclo group, , , , , , , , The R Aa Choose from 1 to 4 Rs k replace; As an option, R A1 R A2 Together with the atoms attached to it, they form a 4-8 membered heterocyclic group, wherein the heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace; R D Selected from C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -NHC 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -SC 1-4 Alkyl, -S(=O)-C 1-4 Alkyl group, -S(=O)2-C 1-4 Alkyl, C 3-6 Carbocyclic groups, 4- to 8-membered heterocyclic groups, -OC 3-6 Carbocyclic group, -NH-C 3-6 Carbocyclic groups, -NH-4 to 8-membered heterocyclic groups, -SC 3-6 Carbocyclic groups, -S-4 to 8-membered heterocyclic groups, -NH-C 2-6 alkenyl, -NH-C 2-4 alkynyl group, -SC 2-4 alkenyl, -SC 2-4 alkynyl group, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C 1-2 Alkylene-4 to 8-membered heterocyclic groups, -OC 1-2 Alkylene-C 3-6 carbonyl group, -OC 1-2 Alkyl-4 to 8-membered heterocyclic groups, -NH-C 1-2 Alkylene-C 3-6 Carbocyclic group, -NH-C 1-2 Alkyl-4 to 8-membered heterocyclic groups, -SC 1-2 Alkylene-C 3-6 carbonyl group, -SC 1-2 Alkylene-4 to 8-membered heterocyclic group, wherein the alkylene, alkenyl, alkynyl, alkyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R D1 Selected from C 2-4 alkynyl group, -S(=O)-C 1-4 Alkyl group, -S(=O)2-C 1-4 Alkyl, -OC 2-4 Alkyne, methoxy, propoxy, wherein the alkynyl, alkyl, methoxy, or propoxy group is optionally surrounded by 1 to 4 R groups. k replace; Or R D1 Selected from -OC 1-2 Alkylene-C 3-6 carbonyl group, -OC 1-2 Alkylene-4 to 7-membered heterocyclic groups, wherein the carbocyclic or heterocyclic group is surrounded by 1 to 4 R groups. k The alkylene group is optionally replaced by 1 to 4 R... k replace; R a R b R d R z Each element is independently selected from H, deuterium, =O, =S, halogens, CN, OH, NH2, CO2H, CONH2, and NHC. 1-4 Alkyl, N(C) 1-6 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -SCN, -NHC 1-4 Alkyl, -OC 3-6 Carbocyclic groups, -O-4 to 8-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-4 to 8-membered heterocyclic groups, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C 1-2 alkylene-4 to 8-membered heterocyclic groups, C 3-6 Carbocyclic, 4- to 8-membered heterocyclic, wherein the alkylene, alkyl, alkenyl, ynyl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R d1 Selected from 6-membered aryl, 5-6-membered heteroaryl, and -SCN; R A1 R A2 R L1 R l1 R l2 Each element is independently selected from H, deuterium, =O, halogens, CN, OH, NH2, CO2H, CONH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Carbocyclic groups, 4- to 8-membered heterocyclic groups, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -NH-C 3-6 carbonyl group, -OC 3-6 The carbocyclic group, wherein the alkylene group, alkyl group, alkenyl group, alkynyl group, carbocyclic group, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R k Each is independently selected from deuterium, =O, =S, =NH, halogens, CN, OH, COOH, CONH2, NH2, SF5, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, -C(=O)-C 3-6 carbonyl group, -OC 3-6 Carbocyclic groups, -O-4 to 8-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-4 to 8-membered heterocyclic groups, -C 1-2 alkylene-4 to 8-membered heterocyclic groups, C 3-6 Carbocyclic groups, 4- to 8-membered heterocyclic groups, The alkyl, alkylene, alkenyl, alkynyl, carbocyclic, or heterocyclic groups are optionally selected from 1 to 4 deuterium, halogen, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 The alkoxy group is replaced by a substituent.

4. The compound according to claim 3, or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein, Ring A is selected from pyrimidinyl, pyridazinyl, pyrazinyl, pyridinyl, thiazolyl, pyridinium imidazolyl, pyridocyclopentyl, and pyridocyclohexyl. Ring B is selected from pyrazinyl, pyridazinyl, pyridyl, phenyl, pyrimidinyl, and piperidinyl, and ring B is optionally surrounded by 1 to 4 R groups. b replace; Z is selected from pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, phenyl, C 2-4 The pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, or phenyl group is optionally surrounded by 1 to 4 R groups. z replace; L 1 Selected from -O-, -CH2-, -CH2-O-, -O-4 to 8-membered heterocyclic groups-, -O-CH2-4 to 8-membered heterocyclic groups-, -CH2-NR L0 -, -O-CH2-, -O-CH2-CH2-O-, C 2-4 alkenyl, -C 3-8 Carbocyclic groups -CH2-O-, -C 3-8 Carbocyclic group -O-, -4 to 8-membered heterocyclic group -CH2-O-, -4 to 8-membered heterocyclic group -O-, -OC 3-8 Carbocyclic group-, , Its right end is connected to B, and the -CH2-, alkenyl, carbocyclic, or heterocyclic groups are optionally replaced by 1 to 4 R groups. k replace; R A Selected from 4- to 10-membered heterocyclic alkyl groups, -4- to 10-membered heterocyclic alkyl groups -S(=O)2R A1 -4 to 10-membered heterocyclic alkyl-S(=O)R A1 -4 to 10-membered heterocyclic alkyl-S(=O)2NR A1 R A2 -4 to 10-membered heterocyclic alkyl-NR A1 -S(=O)2R A2 -4 to 10-membered heterocyclic alkyl groups -N=S(=O)R A1 R A2 -4 to 10-membered heterocyclic alkyl-S(=O) (=NR) A1 )R A2 -4 to 10-membered heterocyclic alkyl group -CH2-S(=O)2R A1 -4 to 10-membered heterocyclic alkyl group -CH2-S(=O)R A1 -4 to 10-membered heterocyclic alkyl group -CH2-S(=O)2NR A1 R A2 -4 to 10-membered heterocyclic alkyl-CH2-NR A1 -S(=O)2R A2 -4 to 10-membered heterocyclic alkyl groups -CH2-N=S(=O)R A1 R A2 -4 to 10-membered heterocyclic alkyl groups -CH2-S(=O) (=NR) A1 )R A2 -P(=O)R A1 R A2 -4 to 10-membered heterocyclic alkyl-P(=O)R A1 R A2 -4 to 10-membered heterocyclic alkyl groups -CH2-P(=O)R A1 R A2 -N=S(=O)R A1 R A2 , , , , , , , , , , , , , , , , The -CH2-, heterocyclic alkyl, , , , , , , , , , , , , , , , Choose from 1 to 4 Rs k replace; R Aa Selected from -4 to 10-membered heterocyclic alkyl groups -S(=O)2NHC 1-4 Alkyl group, -S (=O) (=NR) A1 )R A2 -4 to 10-membered heterocyclic alkyl-S(=O) (=NR) A1 ) - CH2-C 3-6 Carbocyclic, -4 to 10-membered heterocyclic alkyl group -S(=O)2NR A1 -C 3-6 carbon cyclo group, , , , , , , , The R Aa Choose from 1 to 4 Rs k replace; R D Selected from C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -NHC 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -SC 1-4 Alkyl, -S(=O)-C 1-4 Alkyl group, -S(=O)2-C 1-4 Alkyl, C 3-6 Carbocyclic groups, 4- to 8-membered heterocyclic groups, -OC 3-6 Carbocyclic group, -NH-C 3-6 Carbocyclic groups, -NH-4 to 8-membered heterocyclic groups, -SC 3-6 Carbocyclic groups, -S-4 to 8-membered heterocyclic groups, -NH-C 2-6 alkenyl, -NH-C 2-4 alkynyl group, -SC 2-4 alkenyl, -SC 2-4 alkynyl group, -CH2-C 3-6 Carbocyclic groups, -CH2-4 to 8-membered heterocyclic groups, -O-CH2-C 3-6 Carbocyclic groups, -O-CH2-4 to 8-membered heterocyclic groups, -NH-CH2-C 3-6 Carbocyclic groups, -NH-CH2-4 to 8-membered heterocyclic groups, -S-CH2-C 3-6 Carbocyclic, -S-CH2- 4 to 8-membered heterocyclic groups, wherein the -CH2-, alkenyl, alkynyl, alkyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R D1 Selected from C 2-4 alkynyl group, -S(=O)-C 1-4 Alkyl group, -S(=O)2-C 1-4 Alkyl, -OC 2-4 Alkyne, methoxy, propoxy, wherein the alkynyl, alkyl, methoxy, or propoxy group is optionally surrounded by 1 to 4 R groups. k replace; Or R D1 Selected from -OC 1-2 Alkylene-C 3-6 carbonyl group, -OC 1-2 Alkylene-4 to 7-membered heterocyclic groups, wherein the carbocyclic or heterocyclic group is surrounded by 1 to 4 R groups. k The alkylene group is optionally replaced by 1 to 4 R... k replace; R a R b R d R z Each element is independently selected from H, deuterium, =O, =S, halogens, CN, OH, NH2, CO2H, CONH2, and NHC. 1-4 Alkyl, N(C) 1-6 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -SCN, -NHC 1-4 Alkyl, -OC 3-6 Carbocyclic groups, -O-4 to 8-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-4 to 8-membered heterocyclic groups, -CH2-C 3-6 Carbocyclic groups, -CH2-4 to 8-membered heterocyclic groups, C 3-6 Carbocyclic, 4- to 8-membered heterocyclic, wherein the -CH2-, alkyl, alkenyl, ynyl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R d1 Selected from 5-6 aryl heteroaryl groups and -SCN.

5. The compound according to claim 4, or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein, Ring A is selected from pyrimidinyl, pyridazinyl, pyrazinyl, pyridinyl, thiazolyl, , ; Z is selected from phenyl, pyrazinyl, pyridinyl, pyridinyl, pyrimidinyl, and ethynyl, wherein the pyrazinyl, pyridinyl, pyrimidinyl, or phenyl group is optionally surrounded by 1 to 4 R groups. z replace; Or -BZ- selected from , ; L 1 Selected from -O-, -CH2-, -CH2-O-, -O-oxetanebutyl, -O-oxetanepentyl, -O-oxetanehexyl, -O-azacyclobutyl, -O-azacyclopentyl, -O-azacyclohexyl, -O-CH2-oxetanebutyl, -O-CH2-oxetanepentyl, -O-CH2-oxetanehexyl, -O-CH2-azacyclobutyl, -O-CH2-azacyclopentyl, -O-CH2-azacyclohexyl, -CH2-NR L0 -、-O-CH2-、-O-CH2-CH2-O-、vinyl、-cyclopropyl-CH2-O-、-cyclobutyl-CH2-O-、-cyclopentyl-CH2-O-、-cyclohexyl-CH2-O-、 -Cyclopropyl-O-, -Cyclobutyl-O-, -Cyclopentyl-O-, -Cyclohexyl-O-, -azacyclobutyl-CH2-O-, -azacyclopentyl-CH2-O-, -piperidinyl-CH2-O-, -azacyclobutyl-O-, -azacyclopentyl-O-, -piperidinyl-O-, -phenyl-O-, -phenyl-CH2-O-, -pyridine-CH2-O-, -oxacyclobutyl-CH2-O-, -oxacyclopentyl-CH2-O-, -oxacyclohexyl-CH2-O-, -oxacyclobutyl-O-, -oxacyclopentyl-O-, -oxacyclohexyl-O-, -O-cyclopropyl-, -O-cyclobutyl-, -O-cyclopentyl-, -O-cyclohexyl-, , Its right end is connected to B, and the -CH2-, vinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, aziridine, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, piperidinyl, phenyl, pyridine, Choose from 1 to 4 Rs k replace; R L0 R b Together with the atoms attached to it, they form azircyclic butyl, azircyclic pentyl, azircyclic hexyl, azircyclic heptyl, azircyclic butylenyl, azircyclic pentenyl, azircyclic hexenyl, azircyclic heptenyl, furanyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, 1,4-dioxanecyclol, 1,4-dioxanecycloalkenyl. , The aziridine, aziridine pentyl, aziridine hexyl, aziridine heptyl, aziridine butenyl, aziridine pentenyl, aziridine heptenyl, furanyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, 1,4-dioxanecycloyl, 1,4-dioxanecycloylene are optionally surrounded by 1 to 4 R groups. k replace; As an option, R L1 R b Together with the atoms attached to it, they form a 4-8 membered heterocyclic group, wherein the heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace; R L2 R z Together with the atoms attached thereto, they form a pyrrole group, an imidazolyl group, and an imidazolide group, wherein the pyrrole group, imidazolyl group, and imidazolide group are optionally surrounded by 1 to 4 R atoms. k replace; As an option, R 1 R 2 Together with the atoms bonded to it, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, azircyclobutyl, azircyclopentyl, azircyclohexyl, and so on. , The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, azircyclobutyl, azircyclopentyl, azircyclohexyl , Choose from 1 to 4 Rs k replace; As an option, R l1 R l2 The atoms bonded to it together form cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups, wherein the cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups are optionally bounded by 1 to 4 R groups. k replace; As an option, R 1 R d The atoms bonded to it together form cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl groups, wherein the cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl groups are optionally separated by 1 to 4 R groups. k replace; As an option, R 1 R z The atoms bonded to it together form cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl groups, wherein the cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl groups are optionally separated by 1 to 4 R groups. k Replace; as an alternative, two adjacent R z The atoms bonded to it together form cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups, wherein the cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups are optionally bounded by 1 to 4 R groups. k replace; As an option, R L0 R a The atoms bonded to it together form imidazolium, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl groups, wherein the imidazolium, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl groups are optionally surrounded by 1 to 4 R groups. k replace; R A Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , The R A Choose from 1 to 4 Rs k replace; R D Selected from methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -NHCH3, -N(CH3)2, -SCH3, -SCH2CH3, -SCH2CH2CH3, -S-isopropyl, -S(=O)CH3, -S(=O)CH2CH3, -S(=O)CH2CH2CH3, -S(=O)-isopropyl, -S(=O)2CH3, -S(=O)2CH2CH3, -S(= O)2CH2CH2CH3, -S(=O)2-isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, aziridine, aziridinepentyl, aziridinehexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, -NH-oxacyclobutyl, -NH-oxacyclopentyl, -NH-oxacyclohexyl, -NH-aziridine, - NH-azacyclopentyl, -NH-azacyclohexyl, -NH-vinyl, -NH-ethynyl, -S-vinyl, -S-ethynyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-oxacyclobutyl, -CH2-oxacyclopentyl, -CH2-oxacyclohexyl, -CH2-azacyclobutyl, -CH2-azacyclopentyl, -CH2-azacyclohexyl, -O-CH2-cyclopropyl, -O-CH2-cyclobutyl, -O-C H2-cyclopentyl, -O-CH2-cyclohexyl, -O-CH2-oxacyclobutyl, -O-CH2-oxacyclopentyl, -O-CH2-oxacyclohexyl, -O-CH2-azacyclobutyl, -O-CH2-azacyclopentyl, -O-CH2-azacyclohexyl, wherein the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, azacyclobutyl, azacyclopentyl, azacyclohexyl are optionally surrounded by 1 to 4 R k replace; R a R b R d R z Each of the following is independently selected from H, deuterium, =O, =S, F, Cl, Br, I, CN, OH, NH2, CO2H, CONH2, -NHCH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, -O-methyl, -O-ethyl, methylthio, -SCN, -O-cyclopropyl, -O-oxetyl, -O-azacyclobutyl, -CH2-cyclopropyl, -CH2-oxetyl, -CH2-azacyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl Cyclohexyl, oxacyclobutyl, aziridine, pyrimidinyl, pyrazinyl, pyrazinyl, pyridinyl, thiazolyl, pyrroleyl, thiopheneyl, furanyl, pyrazolyl, triazolyl, oxazolyl, oxadiazolyl, wherein the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, pyrimidinyl, pyrazinyl, pyridinyl, thiazolyl, pyrroleyl, thiopheneyl, furanyl, pyrazolyl, triazolyl, oxazolyl, oxadiazolyl are optionally surrounded by 1 to 4 R k replace; R d1 The group is selected from pyrimidinyl, pyrazinyl, pyrazinyl, pyridinyl, thiazolyl, pyrroleyl, thiopheneyl, furanyl, pyrazolyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiazolyl, isoxazolyl, isoxadiazolyl, -SCN, wherein the pyrimidinyl, pyrazinyl, pyridinyl, thiazolyl, pyrroleyl, thiopheneyl, furanyl, pyrazolyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiazolyl, isoxazolyl, isoxadiazolyl, isoxadiazolyl, isooxazolyl, isoxadiazolyl is optionally surrounded by 1 to 4 R groups. k replace; L 2 Selected from -CR 1 R 2 -、-NR L2 -、 , Cyclopropyl, cyclobutyl, oxacyclobutyl, and aziridine, with their right ends connected to ring D, wherein the cyclopropyl, cyclobutyl, oxacyclobutyl, and aziridine are optionally surrounded by 1 to 4 R groups. k replace; L 2A Selected from -NR L2 -、 , Cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, aziridine, and oxacyclopentyl, with their right ends connected to ring D, wherein the cyclopropyl, cyclobutyl, oxacyclobutyl, aziridine, cyclopentyl, and oxacyclopentyl groups are optionally bounded by 1 to 4 R groups. k replace; R 1 R 2 Each of the following is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NH2, -NHCH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, and ethoxy, wherein the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, and ethoxy groups are optionally prefixed with 1 to 4 R groups. k replace; R A1 R A2 R L1 R l1 R l2 Each of the following is independently selected from H, deuterium, =O, F, Cl, Br, I, CN, OH, NH2, CO2H, CONH2, -NHCH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, aziridine, aziridinepentyl, aziridinehexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2 -cyclopentyl, -CH2-cyclohexyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, wherein the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, aziridine, aziridine, aziridine, aziridine, aziridine are optionally surrounded by 1 to 4 R k replace; R k Each is independently selected from deuterium, =O, =S, =NH, F, Cl, Br, I, CN, OH, COOH, CONH2, NH2, SF5, -NHCH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, -O-methyl, -O-ethyl, methylthio, -C(=O)-CH3, -C(=O)CH2CH3, -C(=O)-cyclopropyl, -O-cyclopropyl -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, -O-oxacyclobutyl, -O-oxacyclopentyl, -O-oxacyclohexyl, -O-azacyclobutyl, -O-azacyclopentyl, -O-azacyclohexyl, -NH-cyclopropyl, -NH-oxacyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, azacyclobutyl, azacyclopentyl, azacyclohexyl , , , The methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxecyclobutyl, oxecyclopentyl, oxecyclohexyl, azircyclobutyl, azircyclopentyl, and azircyclohexyl groups are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2, methyl, ethyl, propyl, isopropyl, methoxy, and ethoxy groups.

6. The compound according to claim 5, or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein, Ring A is selected from pyrimidinyl, pyridazinyl, pyrazinyl, pyridinyl, thiazolyl, , ; Z is selected from phenyl, ethynyl, ... , , , , , ; R A Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ; R Aa Selected from , , , , , , , , , , , , , , , ; L 1 Selected from -O-, -CH2-, -CH2-O-, -O-CH2-, -O-CH2-CH2-O-, vinyl, , , , , , , , -O-cyclopropyl-, -O-cyclobutyl-, , Its right end is connected to B; L 2 Selected from , , , , , , , , , , , , , , , , Its right end is connected to ring D; L 2A Selected from , , , , , , , , , , , , , , Its right end is connected to ring D; R D Selected from , , , , , , , , , , methoxy, ethoxy , , , , , , , , , , ; R D1 Selected from , , , , , , , , , , , , , , , , , .

7. The compound according to claim 6, or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein, The compounds are selected from the structures shown in Table E. Table E 8. A pharmaceutical composition comprising the compound of any one of claims 1-7 or a racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, preferably comprising 1-1500 mg of the compound of any one of claims 1-7 or a racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

9. The use of the compound according to any one of claims 1-7, or a racemic, stereoisomer, tautomer, pharmaceutically acceptable salt thereof, or the composition according to claim 8, in the preparation of a medicament for diseases associated with androgen receptor splicing mutants.

10. The application according to claim 9, wherein the disease associated with the androgen receptor splicing mutant is selected from tumors or cancers (e.g., prostate cancer).

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